This file contains full details on each clinical trial selected for download. Where multi-state trials have been downloaded full information for each of the member states/countries involved in the trial are included separately.

Summary
EudraCT Number: 2022-002568-62
Sponsor's Protocol Code Number: AVB-PGRN-001
National Competent Authority: Spain - AEMPS
Clinical Trial Type: EEA CTA
Trial Status: Ongoing
Date on which this record was first entered in the EudraCT database: 2023-01-16
Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2022-002568-62/ES/

A. Protocol Information
A.1 Member State Concerned: Spain - AEMPS
A.2 EudraCT number: 2022-002568-62
A.3 Full title of the trial: A Phase 1/2 Open-Label, Ascending Dose, Multicenter Study to Evaluate the Safety and Preliminary Efficacy of AVB-101 Administered by Bilateral Intrathalamic Infusion in Subjects With Frontotemporal Dementia With Progranulin Mutations (FTD-GRN)
A.3 Full title of the trial (es): Estudio de fase 1/2, abierto, de dosis ascendentes y multicéntrico para evaluar la seguridad y la eficacia preliminar de AVB-101 administrado mediante infusión intratalámica bilateral en sujetos con demencia frontotemporal con mutaciones en el gen de la progranulina (DFT-GRN).
A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: A study to test whether AVB-101 is both safe and efficacious in a sub-population of genetically defined FTD patients that currently have no other treatment options
A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language (es): Un estudio para probar si AVB-101 es seguro y eficaz en una subpoblación de pacientes con DFT genéticamente definidos que actualmente no tienen otras opciones de tratamiento.
A.3.2 Name or abbreviated title of the trial where available: Ph1/2 study of AVB-101 in Subjects with Frontotemporal Dementia with Progranulin Mutations (FTD-GRN)
A.4.1 Sponsor's protocol code number: AVB-PGRN-001
A.7 Trial is part of a Paediatric Investigation Plan: JSON_ERROR_HERE
A.8 EMA Decision number of Paediatric Investigation Plan:

B. Sponsor Information
Sponsor 1
B.1.1 Name of Sponsor: AviadoBio Ltd
B.1.3.4	Country: United Kingdom
B.3.1 and B.3.2	Status of the sponsor: Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1 Name of organisation providing support: AviadoBio Limited
B.4.2 Country: United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1 Name of organisation: Medpace
B.5.2 Functional name of contact point: Clinical Trial Management
B.5.3 Address
B.5.3.1 Street Address: Via Olona 2
B.5.3.2 Town/ city: Milan
B.5.3.3 Post code: 20123
B.5.3.4 Country: Italy
B.5.4 Telephone number: 390283413400
B.5.6 E-mail: S.Zambruno@Medpace.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3 IMP Role: Test
D.2 Status of the IMP to be used in the clinical trial
D.2.1 IMP to be used in the trial has a marketing authorisation: No
D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: Yes
D.2.5.1 Orphan drug designation number: EMA/OD/0000068610
D.3 Description of the IMP
D.3.1 Product name: Recombinant AAV-9 vector expressing the human progranulin protein
D.3.2 Product code: AVB-101
D.3.4 Pharmaceutical form: Solution for injection
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Intracerebral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8 INN - Proposed INN: AVB-101
D.3.9.2 Current sponsor code: AVB-101
D.3.9.4 EV Substance Code: SUB216576
D.3.10 Strength
D.3.10.1 Concentration unit: vector genomes (vg)/mL
D.3.10.2 Concentration type: not less then
D.3.10.3 Concentration number: 800000000000
D.3.11 The IMP contains an
D.3.11.1 Active substance of chemical origin: No
D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No
D.3.11.3 Advanced Therapy IMP (ATIMP): Yes
D.3.11.3.1 Somatic cell therapy medicinal product: No
D.3.11.3.2 Gene therapy medical product: Yes
D.3.11.3.3 Tissue Engineered Product: No
D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No
D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No
D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No
D.3.11.5 Radiopharmaceutical medicinal product: No
D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No
D.3.11.7 Plasma derived medicinal product: No
D.3.11.8 Extractive medicinal product: No
D.3.11.9 Recombinant medicinal product: No
D.3.11.10 Medicinal product containing genetically modified organisms: Yes
D.3.11.11 Herbal medicinal product: No
D.3.11.12 Homeopathic medicinal product: No
D.3.11.13 Another type of medicinal product: No

D.8 Information on Placebo

E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1 Medical condition(s) being investigated: Frontotemporal Dementia With Progranulin Mutations (FTD-GRN)
E.1.1 Medical condition(s) being investigated (es): Demencia Frontotemporal con mutaciones en el gen de la progranulina (DFT-GRN)
E.1.1.1 Medical condition in easily understood language: Dementia
E.1.1.1 Medical condition in easily understood language (es): Demencia
E.1.1.2 Therapeutic area: Diseases [C] - Nervous System Diseases [C10]
MedDRA Classification
E.1.3 Condition being studied is a rare disease: Yes
E.2 Objective of the trial
E.2.1 Main objective of the trial: To evaluate the safety and tolerability of a one-time, bilateral, intrathalamic administration of AVB-101 in subjects with FTD-GRN.
E.2.1 Main objective of the trial (es): Evaluar la seguridad y la tolerabilidad de una administración intratalámica única de AVB-101 en sujetos con DFT-GRN.
E.2.2 Secondary objectives of the trial: To evaluate the preliminary clinical and biomarker measures of efficacy of a one-time, bilateral, intrathalamic administration of AVB-101 in subjects with FTD-GRN.
E.2.2 Secondary objectives of the trial (es): Evaluar las variables clínicas y de biomarcadores preliminares de la eficacia de una administración intratalámica bilateral única de AVB-101 en sujetos con DFT-GRN.
E.2.3 Trial contains a sub-study: No
E.3 Principal inclusion criteria: 1. Male or female, 30 to 75 years of age, inclusive, at Screening;
2. Carriers of a pathogenic granulin (GRN) mutation as confirmed by a sponsor approved genetic test;
3. EITHER symptomatic frontotemporal dementia (FTD) OR pre-symptomatic carrier of a pathogenic GRN mutation at risk of conversion based on plasma neurofilament light chain >20 pg/mL;
4. If symptomatic, presence of 1 or more of the criteria for diagnosis of possible behavioral variant FTD or Primary Progressive Aphasia;
5. Identified, informed study partner able to support the subject for the duration of the study
6. The subject and/or legally authorized representative is able and willing to give written informed consent prior to study participation. If a subject lacks capacity to consent in the investigator’s opinion, the subject’s assent should be obtained, if required in accordance with local laws, regulations and customs, plus the written informed consent of a legal representative should be obtained. In countries where local laws, regulations, and customs do not permit subjects who lack capacity to consent to participate in this study, they will not be enrolled.
E.3 Principal inclusion criteria (es): 1. Ser varón o mujer de entre 30 y 75 años, ambos inclusive, en el momento de selección.
2. Ser portador de una mutación patógena en el gen de la granulina (GRN) confirmada mediante un análisis genético aprobado por el promotor.
3. Tener demencia frontotemporal (DFT) sintomática O ser portador presintomático de una mutación patógena en el gen GRN con riesgo de conversión según una concentración plasmática de cadenas ligeras de los neurofilamentos (NfL) >20 pg/ml.
4. En caso de encontrarse sintomático, presencia de uno o más de los criterios diagnósticos de una posible variante conductual de DFT o de afasia progresiva primaria.
5. Contar con un acompañante para el estudio identificado e informado que pueda ayudar al sujeto durante todo el estudio.
6. Las mujeres en edad fértil deberán tener una prueba de embarazo en suero negativa en la fase de selección, así como una prueba en orina con tira reactiva negativa y no estar amamantando en las dos semanas previas al tratamiento.
7. Los sujetos sexualmente activos deberán comprometerse a utilizar un método anticonceptivo de barrera muy eficaz hasta que se obtengan al menos tres muestras negativas consecutivas de diseminación del vector en sangre (o en semen en los varones, si es posible) con una semana de diferencia como mínimo.
8. Capacidad y disposición para cumplir todos los procedimientos y el calendario de visitas del estudio descritos en el protocolo.
9. El sujeto o su representante legal pueden y están dispuestos a otorgar su consentimiento informado por escrito antes de participar en el estudio. Si, en opinión del investigador, un sujeto no es capaz de otorgar su consentimiento, deberá obtenerse su asentimiento, si así lo exigen las leyes, normativas y costumbres locales, además del consentimiento informado por escrito de un representante legal. En los países en que las leyes, normativas y costumbres locales no permitan la participación de sujetos que carezcan de la capacidad para otorgar su consentimiento para participar en este estudio, no se incluirá a este tipo de sujetos.
E.4 Principal exclusion criteria: 1. Classification of the mutation in the GRN gene as “not pathogenic,” “likely benign variant,” or “benign variant” in the Alzheimer’s Disease and Frontotemporal Dementia Mutation Database;
2. Severe dementia that precludes ability to comply with study procedures and/or poses unacceptable safety risk to the subject (i.e. CDR+ NACC FTLD score of 3.0);
3. Concurrent disease that may cause cognitive impairment unrelated to mutations in the GRN gene, such as other causes of dementia, neurosyphilis,
hydrocephalus, stroke, small vessel ischemic disease, uncontrolled hypothyroidism, or vitamin B12 deficiency;
4. Clinically significant abnormality on magnetic resonance imaging (MRI) at Screening considered to be a contraindication to intrathalamic infusion;
5. Surgically significant pattern of brain atrophy on MRI at Screening that interferes with planned surgical trajectory;
6. Previous treatment with any gene or cell therapy;
7. Previous treatment with any investigational medicinal product within 60 days or 5 half-lives (whichever is longer) prior to study drug dosing;
8. Concomitant disease or treatment which, in the opinion of the Investigator, may pose an unacceptable safety risk to the participant or interfere with study conduct or the subject's ability to comply with study procedures;
9. Contraindications to MRI as per local guidelines;
10. Contraindications to gadolinium-based contrast agents per local guidelines;
11. Contraindications to general anesthesia for a period of up to 10 hours and/or cardiopulmonary disorders that would result in a higher ASA risk classification;
12. Contraindications to lumbar puncture as per local guidelines;
E.4 Principal exclusion criteria (es): 1. Tener una mutación en el gen GRN clasificada como “no patógena”, “variante probablemente benigna” o “variante benigna” en la Alzheimer’s Disease and Frontotemporal Dementia Mutation Database.
2. Presentar demencia grave, definida como una puntuación global de 3,0 en la escala CDR+NACC FTLD (Escala de valoración clínica de la demencia + degeneración del lóbulo frontotemporal del National Alzheimer’s Coordinating Center), que impida el cumplimiento de los procedimientos del estudio o suponga un riesgo inaceptable para la seguridad del sujeto.
3. Presentar cualquier enfermedad concomitante que pueda causar deterioro cognitivo no relacionado con mutaciones en el gen GRN, como otras causas de demencia, neurosífilis, hidrocefalia, ictus, enfermedad isquémica de pequeños vasos, hipotiroidismo no controlado o carencia de vitamina B12.
4. Tener una anomalía clínicamente significativa en la resonancia magnética (RM) de selección que se considere una contraindicación de la infusión intratalámica.
5. Patrón quirúrgicamente significativo de atrofia cerebral en la RM de selección que interfiera en la trayectoria neuroquirúrgica prevista.
6. Tratamiento previo con terapia génica o celular.
7. Tratamiento previo con cualquier medicamento en investigación en los 60 días o el equivalente a 5 semividas (lo que suponga más tiempo) previos al tratamiento con el fármaco del estudio.
8. Haber tenido una enfermedad, cualquier anomalía analítica clínicamente significativa o tratamiento concomitante que, en opinión del investigador, pueda suponer un riesgo inaceptable para la seguridad del sujeto o interferir en la realización del estudio o en su capacidad para cumplir los procedimientos del estudio.
9. Neoplasia maligna en los 5 años previos a la selección, excepto carcinoma basocelular o espinocelular de piel o carcinoma in situ de cuello uterino tratado con éxito.
10. Tener contraindicaciones de la RM según las directrices locales.
11. Tener contraindicaciones del uso de medios de contraste con gadolinio según las directrices locales.
12. Tener contraindicaciones de la anestesia general durante un período de hasta 10 horas o trastornos cardiopulmonares que supondrían un mayor riesgo según la clasificación de la American Society of Anesthesiology.
13.	 ener contraindicaciones de la punción lumbar según las directrices locales.
14. Hospitalización por cualquier procedimiento médico o quirúrgico importante con anestesia general en las 12 semanas previas a la selección o procedimiento previsto durante el estudio.
15. Uso activo de anticoagulantes en la fase de selección o necesidad prevista de los mismos durante el período de tratamiento. Los antiagregantes plaquetarios se consideran medicamentos concomitantes aceptables siempre que puedan suspenderse al menos 48 horas antes del tratamiento.
16. Antecedentes de enfermedad por coronavirus de 2019 (COVID-19) grave o reciente, definida como 1) antecedentes de hospitalización por enfermedad grave en cualquier momento, 2) antecedentes de síntomas respiratorios importantes en cualquier momento o 3) positividad para COVID-19 presintomática o levemente sintomática en las 12 semanas previas al tratamiento previsto.
17. Análisis toxicológico positivo para drogas.
18.	Antecedentes de trastorno por abuso de sustancias.
19. Tener un dispositivo implantado de estimulación cerebral profunda, una derivación ventriculoperitoneal u otra derivación del líquido cefalorraquídeo u otro dispositivo implantado.
20. Tener indicios de riesgo de suicidio, evaluado mediante la Escala de valoración del riesgo de suicidio de Columbia y definido como un intento de suicidio en los 6 meses previos a la selección o tener un riesgo importante de suicidio según el criterio del investigador.
21. Intolerancia o hipersensibilidad conocida o sospechada al fármaco del estudio o a cualquiera de sus componentes indicados.
E.5 End points
E.5.1 Primary end point(s): Over a 26-week initial and 5year total follow up period:
• Number and incidence of AEs, SAEs, and clinically meaningful laboratory test abnormalities;
• Change from baseline in vital signs, ECG parameters, and physical and neurological examinations, and MMSE
• Change from baseline in mini-mental state examination (MMSE);
• Change from baseline in biochemistry and hematology safety laboratory tests;
• Time to achieve clearance of vector genomes in plasma and semen (male only)
• Incidence of treatment emergent suicidal ideation or behavior as measured using the C-SSRS.
• Change from baseline in MRI including oedema, inflammation, pre-symptomatic/symptomatic hemorrhage and other structural changes
E.5.1 Primary end point(s) (es): Durante un período inicial de 26 semanas y un período total de seguimiento de 5 años:
• Número e incidencia de AA, AAG y anomalías analíticas clínicamente significativas.
• Variación de las constantes vitales, los parámetros electrocardiográficos y las exploraciones físicas y neurológicas con respecto al momento basal.
• Variación de la puntuación MEC con respecto al momento basal.
• Variación de los análisis clínicos de bioquímica y hematología con respecto al momento basal.
• Tiempo en lograr la eliminación de los genomas del vector en plasma y semen (únicamente en varones).
• Incidencia de ideas o comportamientos suicidas surgidos durante el tratamiento, según lo determinado mediante la escala C-SSRS.
• Variación de los resultados de la RM, como edema, inflamación, hemorragia presintomática/sintomática y otros cambios estructurales, con respecto al momento basal.
E.5.1.1 Timepoint(s) of evaluation of this end point: 26 weeks and 5 years
E.5.1.1 Timepoint(s) of evaluation of this end point (es): 26 semanas y 5 años
E.5.2 Secondary end point(s): Over a 26-week initial and 5-year total follow up period:
• Change from baseline in PGRN protein levels in CSF and blood;
Over a 52-week initial and 5-year total follow up period:
• Change from baseline in NfL levels in CSF and blood
Over a 5-year follow up period:
• Change from baseline in CDR+NACC FTLD-SB score;
• Change in CGI C, PGI-C, CaGI-C
E.5.2 Secondary end point(s) (es): Durante un período inicial de 26 semanas y un período total de seguimiento de 5 años:
• Variación de la concentración de proteína PGRN en LCR y sangre con respecto al momento basal.
Durante un período inicial de 52 semanas y un período total de seguimiento de 5 años:
• Variación de la concentración de NfL en LCR y sangre con respecto al momento basal.
Durante un período de seguimiento de 5 años:
• Variación de la puntuación CDR+NACC FTLD-SB con respecto al momento basal.
• Variación de las puntuaciones CGI-C, PGI-C y CaGI-C
E.5.2.1 Timepoint(s) of evaluation of this end point: 26 weeks and 5 years
E.5.2.1 Timepoint(s) of evaluation of this end point (es): 26 semanas y 5 años
E.6 and E.7 Scope of the trial
E.6 Scope of the Trial
E.6.1 Diagnosis: Yes
E.6.2 Prophylaxis: No
E.6.3 Therapy: Yes
E.6.4 Safety: Yes
E.6.5 Efficacy: Yes
E.6.6 Pharmacokinetic: No
E.6.7 Pharmacodynamic: No
E.6.8 Bioequivalence: No
E.6.9 Dose response: Yes
E.6.10 Pharmacogenetic: No
E.6.11 Pharmacogenomic: No
E.6.12 Pharmacoeconomic: No
E.6.13 Others: No
E.7 Trial type and phase
E.7.1 Human pharmacology (Phase I): Yes
E.7.1.1 First administration to humans: Yes
E.7.1.2 Bioequivalence study: No
E.7.1.3 Other: No
E.7.1.3.1 Other trial type description:
E.7.2 Therapeutic exploratory (Phase II): Yes
E.7.3 Therapeutic confirmatory (Phase III): No
E.7.4 Therapeutic use (Phase IV): No
E.8 Design of the trial
E.8.1 Controlled: No
E.8.1.1 Randomised: No
E.8.1.2 Open: Yes
E.8.1.3 Single blind: No
E.8.1.4 Double blind: No
E.8.1.5 Parallel group: No
E.8.1.6 Cross over: No
E.8.1.7 Other: Information not present in EudraCT
E.8.2 Comparator of controlled trial
E.8.2.1 Other medicinal product(s): No
E.8.2.2 Placebo: No
E.8.2.3 Other: No
E.8.3 The trial involves single site in the Member State concerned: Yes
E.8.4 The trial involves multiple sites in the Member State concerned: Yes
E.8.4.1 Number of sites anticipated in Member State concerned: 2
E.8.5 The trial involves multiple Member States: Yes
E.8.5.1 Number of sites anticipated in the EEA: 12
E.8.6 Trial involving sites outside the EEA
E.8.6.1 Trial being conducted both within and outside the EEA: Yes
E.8.6.2 Trial being conducted completely outside of the EEA: No
E.8.6.3 If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned:
United States
United Kingdom
E.8.7 Trial has a data monitoring committee: Yes
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: LVLS
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial (es): LPLV
E.8.9 Initial estimate of the duration of the trial
E.8.9.1 In the Member State concerned years: 6
E.8.9.1 In the Member State concerned months: 0
E.8.9.1 In the Member State concerned days: 0
E.8.9.2 In all countries concerned by the trial years: 6
E.8.9.2 In all countries concerned by the trial months: 0
E.8.9.2 In all countries concerned by the trial days: 0

F. Population of Trial Subjects
F.1 Age Range
F.1.1 Trial has subjects under 18: No
F.1.1.1 In Utero: No
F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No
F.1.1.3 Newborns (0-27 days): No
F.1.1.4 Infants and toddlers (28 days-23 months): No
F.1.1.5 Children (2-11years): No
F.1.1.6 Adolescents (12-17 years): No
F.1.2 Adults (18-64 years): Yes
F.1.2.1 Number of subjects for this age range: 8
F.1.3 Elderly (>=65 years): Yes
F.1.3.1 Number of subjects for this age range: 7
F.2 Gender
F.2.1 Female: Yes
F.2.2 Male: Yes
F.3 Group of trial subjects
F.3.1 Healthy volunteers: No
F.3.2 Patients: Yes
F.3.3 Specific vulnerable populations: Yes
F.3.3.1 Women of childbearing potential not using contraception : No
F.3.3.2 Women of child-bearing potential using contraception: Yes
F.3.3.3 Pregnant women: No
F.3.3.4 Nursing women: No
F.3.3.5 Emergency situation: No
F.3.3.6 Subjects incapable of giving consent personally: Yes
F.3.3.6.1 Details of subjects incapable of giving consent: Participants will not be enrolled if they are unable to consent at initial screening/consent, but patients' disease may progress during the 5 year follow up period of the
study, such that they will lack capacity to consent for themselves.
F.3.3.7 Others: No
F.4 Planned number of subjects to be included
F.4.1 In the member state: 5
F.4.2 For a multinational trial
F.4.2.1 In the EEA: 7
F.4.2.2 In the whole clinical trial: 15
F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): Participants will receive their usual standard of care.

G. Investigator Networks to be involved in the Trial


N. Review by the Competent Authority or Ethics Committee in the country concerned
N. Competent Authority Decision: Authorised
N. Date of Competent Authority Decision: 2023-05-18
N. Ethics Committee Opinion of the trial application: Favourable
N. Ethics Committee Opinion: Reason(s) for unfavourable opinion:
N. Date of Ethics Committee Opinion: 2023-02-03

P. End of Trial
P. End of Trial Status: Ongoing

Summary
EudraCT Number: 2022-002568-62
Sponsor's Protocol Code Number: AVB-PGRN-001
National Competent Authority: Sweden - MPA
Clinical Trial Type: EEA CTA
Trial Status: Ongoing
Date on which this record was first entered in the EudraCT database: 2023-01-17
Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2022-002568-62/SE/

A. Protocol Information
A.1 Member State Concerned: Sweden - MPA
A.2 EudraCT number: 2022-002568-62
A.3 Full title of the trial: A Phase 1/2 Open-Label, Ascending Dose, Multicenter Study to Evaluate the Safety and Preliminary Efficacy of AVB-101 Administered by Bilateral Intrathalamic Infusion in Subjects With Frontotemporal Dementia With Progranulin Mutations (FTD-GRN)
A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: A study to test whether AVB-101 is both safe and efficacious in a sub-population of genetically defined FTD patients that currently have no other treatment options
A.3.2 Name or abbreviated title of the trial where available: Ph1/2 study of AVB-101 in Subjects with Frontotemporal Dementia with Progranulin Mutations (FTD-GRN)
A.4.1 Sponsor's protocol code number: AVB-PGRN-001
A.7 Trial is part of a Paediatric Investigation Plan: No
A.8 EMA Decision number of Paediatric Investigation Plan:

B. Sponsor Information
Sponsor 1
B.1.1 Name of Sponsor: AviadoBio Ltd
B.1.3.4	Country: United Kingdom
B.3.1 and B.3.2	Status of the sponsor: Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1 Name of organisation providing support: AviadoBio Limited
B.4.2 Country: United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1 Name of organisation: Medpace
B.5.2 Functional name of contact point: Clinical Trial Management
B.5.3 Address
B.5.3.1 Street Address: Via Olona 2
B.5.3.2 Town/ city: Milan
B.5.3.3 Post code: 20123
B.5.3.4 Country: Italy
B.5.4 Telephone number: 39 0283413400
B.5.6 E-mail: S.Zambruno@Medpace.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3 IMP Role: Test
D.2 Status of the IMP to be used in the clinical trial
D.2.1 IMP to be used in the trial has a marketing authorisation: No
D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: Yes
D.2.5.1 Orphan drug designation number: EMA/OD/0000068610
D.3 Description of the IMP
D.3.1 Product name: Recombinant AAV-9 vector expressing the human progranulin protein
D.3.2 Product code: AVB-101
D.3.4 Pharmaceutical form: Solution for infusion
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Intracerebral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2 Current sponsor code: AVB-101
D.3.9.3 Other descriptive name: AVB-101
D.3.9.4 EV Substance Code: SUB296517
D.3.10 Strength
D.3.10.1 Concentration unit: vector genomes (vg)/mL
D.3.10.2 Concentration type: equal
D.3.10.3 Concentration number: 8X10^11
D.3.11 The IMP contains an
D.3.11.1 Active substance of chemical origin: No
D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No
D.3.11.3 Advanced Therapy IMP (ATIMP): Yes
D.3.11.3.1 Somatic cell therapy medicinal product: No
D.3.11.3.2 Gene therapy medical product: Yes
D.3.11.3.3 Tissue Engineered Product: No
D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No
D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No
D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No
D.3.11.5 Radiopharmaceutical medicinal product: No
D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No
D.3.11.7 Plasma derived medicinal product: No
D.3.11.8 Extractive medicinal product: No
D.3.11.9 Recombinant medicinal product: No
D.3.11.10 Medicinal product containing genetically modified organisms: Yes
D.3.11.11 Herbal medicinal product: No
D.3.11.12 Homeopathic medicinal product: No
D.3.11.13 Another type of medicinal product: No

D.8 Information on Placebo

E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1 Medical condition(s) being investigated: Frontotemporal Dementia With Progranulin Mutations (FTD-GRN)
E.1.1.1 Medical condition in easily understood language: Dementia
E.1.1.2 Therapeutic area: Diseases [C] - Nervous System Diseases [C10]
MedDRA Classification
E.1.3 Condition being studied is a rare disease: Yes
E.2 Objective of the trial
E.2.1 Main objective of the trial: To evaluate the safety and tolerability of a one-time, bilateral, intrathalamic administration of AVB-101 in subjects with FTD-GRN.
E.2.2 Secondary objectives of the trial: To evaluate the preliminary clinical and biomarker measures of efficacy of a one-time, bilateral, intrathalamic administration of AVB-101 in subjects with FTD-GRN.
E.2.3 Trial contains a sub-study: No
E.3 Principal inclusion criteria: 1. Male or female, 30 to 75 years of age, inclusive, at Screening;
2. Carriers of a pathogenic granulin (GRN) mutation as confirmed by a sponsor approved genetic test;
3. EITHER symptomatic frontotemporal dementia (FTD) OR pre-symptomatic carrier of a pathogenic GRN mutation at risk of conversion based on plasma
neurofilament light chain 20 pg/mL;
4. If symptomatic, presence of 1 or more of the criteria for diagnosis of possible behavioral variant FTD or Primary Progressive Aphasia;
5. Identified, informed study partner able to support the subject for the duration of the study and who sees the subject at least once per week;
6. The subject and/or legally authorized representative is able and willing to give written informed consent prior to study participation. If a subject lacks capacity to
consent in the investigator’s opinion, the subject’s assent should be obtained, if required in accordance with local laws, regulations and customs, plus the written
informed consent of a legal representative should be obtained. In countries where local laws, regulations, and customs do not permit subjects who lack capacity to
consent to participate in this study, they will not be enrolled.
E.4 Principal exclusion criteria: 1. Classification of the mutation in the GRN gene as “not pathogenic,” “likely benign variant,” or “benign variant” in the Alzheimer’s Disease and Frontotemporal
Dementia Mutation Database;
2. Severe dementia that precludes ability to comply with study procedures and/or poses unacceptable safety risk to the subject (i.e. CDR+ NACC FTLD score of 3.0);
3. Concurrent disease that may cause cognitive impairment unrelated to mutations in the GRN gene, such as other causes of dementia, neurosyphilis,
hydrocephalus, stroke, small vessel ischemic disease, uncontrolled hypothyroidism, or vitamin B12 deficiency;
4. Clinically significant abnormality on magnetic resonance imaging (MRI) at Screening considered to be a contraindication to intrathalamic infusion;
5. Surgically significant pattern of brain atrophy on MRI at Screening that interferes with planned surgical trajectory;
6. Previous treatment with any gene or cell therapy;
7. Previous treatment with any investigational medicinal product within 60 days or 5 half-lives (whichever is longer) prior to study drug dosing;
8. Concomitant disease or treatment which, in the opinion of the Investigator, may pose an unacceptable safety risk to the participant or interfere with study conduct
or the subject's ability to comply with study procedures;
9. Contraindications to MRI as per local guidelines;
10. Contraindications to gadolinium-based contrast agents per local guidelines;
11. Contraindications to general anesthesia for a period of up to 10 hours and/or cardiopulmonary disorders that would result in a higher ASA risk classification;
12. Contraindications to lumbar puncture as per local guidelines;
E.5 End points
E.5.1 Primary end point(s): Over a 26-week initial and 5year total follow up period:
• Number and incidence of AEs, SAEs, and clinically meaningful laboratory test abnormalities;
• Change from baseline in vital signs, ECG parameters, and physical and neurological examinations, and MMSEChange from baseline in mini-mental state
examination (MMSE);;
• Change from baseline in clinical chemistry and hematology safety laboratory tests;
• Time to achieve clearance of vector genomes in plasma and semen (male only)
• Incidence of treatment emergent suicidal ideation or behavior as measured using the C-SSRS.
• Change from baseline in MRI including oedema, inflammation, asymptomatic/symptomatic hemorrhage and other structural changes
E.5.1.1 Timepoint(s) of evaluation of this end point: 26 weeks and 5 years
E.5.2 Secondary end point(s): Over a 26-week initial and 5-year total follow up period:
• Change from baseline in PGRN protein levels in CSF and blood;
Over a 52-week initial and 5-year total follow up period:
• Change from baseline in NfL levels in CSF and blood
Over a 5-year follow up period:
• Change from baseline in CDR+NACC FTLD-SB score;
• Change in CGI C, PGI-C, CaGI-C
E.5.2.1 Timepoint(s) of evaluation of this end point: 26 weeks and 5 years
E.6 and E.7 Scope of the trial
E.6 Scope of the Trial
E.6.1 Diagnosis: Yes
E.6.2 Prophylaxis: No
E.6.3 Therapy: Yes
E.6.4 Safety: Yes
E.6.5 Efficacy: Yes
E.6.6 Pharmacokinetic: No
E.6.7 Pharmacodynamic: No
E.6.8 Bioequivalence: No
E.6.9 Dose response: Yes
E.6.10 Pharmacogenetic: No
E.6.11 Pharmacogenomic: No
E.6.12 Pharmacoeconomic: No
E.6.13 Others: No
E.7 Trial type and phase
E.7.1 Human pharmacology (Phase I): Yes
E.7.1.1 First administration to humans: Yes
E.7.1.2 Bioequivalence study: No
E.7.1.3 Other: No
E.7.1.3.1 Other trial type description:
E.7.2 Therapeutic exploratory (Phase II): Yes
E.7.3 Therapeutic confirmatory (Phase III): No
E.7.4 Therapeutic use (Phase IV): No
E.8 Design of the trial
E.8.1 Controlled: No
E.8.1.1 Randomised: No
E.8.1.2 Open: Yes
E.8.1.3 Single blind: No
E.8.1.4 Double blind: No
E.8.1.5 Parallel group: No
E.8.1.6 Cross over: No
E.8.1.7 Other: Information not present in EudraCT
E.8.2 Comparator of controlled trial
E.8.2.1 Other medicinal product(s): No
E.8.2.2 Placebo: No
E.8.2.3 Other: No
E.8.3 The trial involves single site in the Member State concerned: Yes
E.8.4 The trial involves multiple sites in the Member State concerned: No
E.8.5 The trial involves multiple Member States: Yes
E.8.5.1 Number of sites anticipated in the EEA: 12
E.8.6 Trial involving sites outside the EEA
E.8.6.1 Trial being conducted both within and outside the EEA: Yes
E.8.6.2 Trial being conducted completely outside of the EEA: No
E.8.6.3 If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned:
United States
Belgium
France
Italy
Netherlands
Poland
Spain
United Kingdom
E.8.7 Trial has a data monitoring committee: Yes
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: LVLS
E.8.9 Initial estimate of the duration of the trial
E.8.9.1 In the Member State concerned years: 6
E.8.9.1 In the Member State concerned months: 0
E.8.9.1 In the Member State concerned days: 0
E.8.9.2 In all countries concerned by the trial years: 6
E.8.9.2 In all countries concerned by the trial months: 0
E.8.9.2 In all countries concerned by the trial days: 0

F. Population of Trial Subjects
F.1 Age Range
F.1.1 Trial has subjects under 18: No
F.1.1.1 In Utero: No
F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No
F.1.1.3 Newborns (0-27 days): No
F.1.1.4 Infants and toddlers (28 days-23 months): No
F.1.1.5 Children (2-11years): No
F.1.1.6 Adolescents (12-17 years): No
F.1.2 Adults (18-64 years): Yes
F.1.2.1 Number of subjects for this age range: 8
F.1.3 Elderly (>=65 years): Yes
F.1.3.1 Number of subjects for this age range: 7
F.2 Gender
F.2.1 Female: Yes
F.2.2 Male: Yes
F.3 Group of trial subjects
F.3.1 Healthy volunteers: No
F.3.2 Patients: Yes
F.3.3 Specific vulnerable populations: Yes
F.3.3.1 Women of childbearing potential not using contraception : No
F.3.3.2 Women of child-bearing potential using contraception: Yes
F.3.3.3 Pregnant women: No
F.3.3.4 Nursing women: No
F.3.3.5 Emergency situation: No
F.3.3.6 Subjects incapable of giving consent personally: Yes
F.3.3.6.1 Details of subjects incapable of giving consent: Participants will not be enrolled if they are unable to consent at initial screening/consent, but patients' disease may progress during the 5 year follow up period of the
study, such that they will lack capacity to consent for themselves.
F.3.3.7 Others: No
F.4 Planned number of subjects to be included
F.4.1 In the member state: 2
F.4.2 For a multinational trial
F.4.2.1 In the EEA: 7
F.4.2.2 In the whole clinical trial: 15
F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): Participants will receive their usual standard of care.

G. Investigator Networks to be involved in the Trial


N. Review by the Competent Authority or Ethics Committee in the country concerned
N. Competent Authority Decision: Authorised
N. Date of Competent Authority Decision: 2023-04-13
N. Ethics Committee Opinion of the trial application: Favourable
N. Ethics Committee Opinion: Reason(s) for unfavourable opinion:
N. Date of Ethics Committee Opinion: 2023-06-16

P. End of Trial
P. End of Trial Status: Ongoing

Summary
EudraCT Number: 2022-002568-62
Sponsor's Protocol Code Number: AVB-PGRN-001
National Competent Authority: Sweden - MPA
Clinical Trial Type: EEA CTA
Trial Status: Ongoing
Date on which this record was first entered in the EudraCT database: 2023-01-17
Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2022-002568-62/SE/

A. Protocol Information
A.1 Member State Concerned: Sweden - MPA
A.2 EudraCT number: 2022-002568-62
A.3 Full title of the trial: A Phase 1/2 Open-Label, Ascending Dose, Multicenter Study to Evaluate the Safety and Preliminary Efficacy of AVB-101 Administered by Bilateral Intrathalamic Infusion in Subjects With Frontotemporal Dementia With Progranulin Mutations (FTD-GRN)
A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: A study to test whether AVB-101 is both safe and efficacious in a sub-population of genetically defined FTD patients that currently have no other treatment options
A.3.2 Name or abbreviated title of the trial where available: Ph1/2 study of AVB-101 in Subjects with Frontotemporal Dementia with Progranulin Mutations (FTD-GRN)
A.4.1 Sponsor's protocol code number: AVB-PGRN-001
A.7 Trial is part of a Paediatric Investigation Plan: No
A.8 EMA Decision number of Paediatric Investigation Plan:

B. Sponsor Information
Sponsor 1
B.1.1 Name of Sponsor: AviadoBio Ltd
B.1.3.4	Country: United Kingdom
B.3.1 and B.3.2	Status of the sponsor: Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1 Name of organisation providing support: AviadoBio Limited
B.4.2 Country: United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1 Name of organisation: Medpace
B.5.2 Functional name of contact point: Clinical Trial Management
B.5.3 Address
B.5.3.1 Street Address: Via Olona 2
B.5.3.2 Town/ city: Milan
B.5.3.3 Post code: 20123
B.5.3.4 Country: Italy
B.5.4 Telephone number: 39 0283413400
B.5.6 E-mail: S.Zambruno@Medpace.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3 IMP Role: Test
D.2 Status of the IMP to be used in the clinical trial
D.2.1 IMP to be used in the trial has a marketing authorisation: No
D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: Yes
D.2.5.1 Orphan drug designation number: EMA/OD/0000068610
D.3 Description of the IMP
D.3.1 Product name: Recombinant AAV-9 vector expressing the human progranulin protein
D.3.2 Product code: AVB-101
D.3.4 Pharmaceutical form: Solution for infusion
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Intracerebral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2 Current sponsor code: AVB-101
D.3.9.3 Other descriptive name: AVB-101
D.3.9.4 EV Substance Code: SUB296517
D.3.10 Strength
D.3.10.1 Concentration unit: vector genomes (vg)/mL
D.3.10.2 Concentration type: equal
D.3.10.3 Concentration number: 1.0E13
D.3.11 The IMP contains an
D.3.11.1 Active substance of chemical origin: No
D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No
D.3.11.3 Advanced Therapy IMP (ATIMP): Yes
D.3.11.3.1 Somatic cell therapy medicinal product: No
D.3.11.3.2 Gene therapy medical product: Yes
D.3.11.3.3 Tissue Engineered Product: No
D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No
D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No
D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No
D.3.11.5 Radiopharmaceutical medicinal product: No
D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No
D.3.11.7 Plasma derived medicinal product: No
D.3.11.8 Extractive medicinal product: No
D.3.11.9 Recombinant medicinal product: No
D.3.11.10 Medicinal product containing genetically modified organisms: Yes
D.3.11.11 Herbal medicinal product: No
D.3.11.12 Homeopathic medicinal product: No
D.3.11.13 Another type of medicinal product: No

D.8 Information on Placebo

E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1 Medical condition(s) being investigated: Frontotemporal Dementia With Progranulin Mutations (FTD-GRN)
E.1.1.1 Medical condition in easily understood language: Dementia
E.1.1.2 Therapeutic area: Diseases [C] - Nervous System Diseases [C10]
MedDRA Classification
E.1.3 Condition being studied is a rare disease: Yes
E.2 Objective of the trial
E.2.1 Main objective of the trial: To evaluate the safety and tolerability of a one-time, bilateral, intrathalamic administration of AVB-101 in subjects with FTD-GRN.
E.2.2 Secondary objectives of the trial: To evaluate the preliminary clinical and biomarker measures of efficacy of a one-time, bilateral, intrathalamic administration of AVB-101 in subjects with FTD-GRN.
E.2.3 Trial contains a sub-study: No
E.3 Principal inclusion criteria: Subjects will be eligible to be included in the study if all of the following criteria apply:
1.	Are male or female, 30 to 75 years of age, inclusive, at Screening;
2.	Are carriers of a pathogenic granulin (GRN) mutation as confirmed by a Sponsor approved genetic test;
3.	Have frontotemporal dementia (FTD) as evidenced by Clinical Dementia Rating (CDR) + National Alzheimer’s Coordinating Center (NACC) frontotemporal lobar degeneration (FTLD) global score of 0.5, 1.0, or 2.0;
4.	Have presence of 1 or more of the criteria for diagnosis of possible behavioral variant FTD or primary progressive aphasia;
5.	Have a thalamic volume of 5.0 cm3 on each side on Screening magnetic resonance imaging (MRI);
6.	For women of childbearing potential, must have a negative serum pregnancy test at Screening, a negative urine dipstick, and not be breastfeeding within 2 weeks prior to treatment;
7.	Are willing to practice a highly effective birth control method as outlined in the Protocol if the subject or partner is of childbearing potential;
8.	Able and willing to comply with all procedures and the study visit schedule as outlined in the Protocol;
9.	Able and willing to give written informed consent prior to study participation, and agree to designate a legal representative to act on their wishes to continue participation should they lose capacity to consent at some point during the study; and
10.	Have an identified, informed study partner who is able and willing to support the subject’s participation in the study and to provide assessments of the subject during the study (separate, written informed consent to be obtained from the study partner for their participation, where required to do so by the relevant country’s competent authorities).


E.4 Principal exclusion criteria: Subjects will be excluded from the study if any of the following criteria apply:
1.	Have a classification of the mutation in the GRN gene as “not pathogenic,” “likely benign variant,” or “benign variant”;
2.	Have severe dementia, defined as CDR + NACC FTLD global score of 3.0, or other symptoms that preclude the ability to comply with study procedures and/or pose unacceptable safety risk to the subject;
3.	Have any concurrent disease that may cause cognitive impairment unrelated to mutations in the GRN gene, such as other causes of dementia, neurosyphilis, hydrocephalus, stroke, small vessel ischemic disease, uncontrolled hypothyroidism, or vitamin B12 deficiency;
4.	Have a clinically significant abnormality on MRI at Screening considered to be a contraindication to intrathalamic infusion;
5.	Have a surgically significant pattern of brain atrophy on MRI at Screening that in the determination of the neurosurgeon interferes with planned neurosurgical trajectory;
6.	Have had previous treatment with any gene or cell therapy;
7.	Have had previous treatment with any investigational medicinal product within 60 days or 5 half-lives (whichever is longer) prior to study drug treatment;
8.	Have had a concomitant disease, any clinically significant laboratory abnormality, or treatment which, in the opinion of the Investigator, may pose an unacceptable safety risk to the subject or interfere with study conduct or the subject's ability to comply with study procedures;
9.	Have a malignancy within 5 years of Screening, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated;
10.	Have any contraindications to MRI as per local guidelines;
11.	Have any contraindications to gadolinium-based contrast agents per local guidelines;
12.	Have any contraindications to general anesthesia for a period of up to 10 hours and/or cardiopulmonary disorders that would result in higher American Society of Anesthesiology risk classification;
13.	Have any contraindications to lumbar puncture as per local guidelines;
14.	Have been hospitalized for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned procedure during the study;
15.	Are using anticoagulants at Screening, or will have an anticipated need during the period of treatment. Antiplatelet therapies are acceptable concomitant medications if they can be stopped at least 48 hours prior to treatment;
16.	Have a history of previous serious or recent Coronavirus Disease 2019 (COVID-19) as defined by (1) any history of hospitalization for severe illness at any time, (2) any history of significant respiratory symptoms at any time, or (3) any pre-symptomatic or mildly symptomatic COVID 19 positivity within 12 weeks prior to planned treatment;
17.	Have a positive drug screen for drugs of abuse;
18.	Have a history of substance abuse disorder;
19.	Have the presence of an implanted deep brain stimulation device, ventriculoperitoneal or other cerebrospinal fluid shunt, or other implanted device;
20.	Have evidence of suicide risk, as assessed by the Columbia-Suicide Severity Rating Scale, defined as either a suicide attempt within 6 months prior to Screening or have a significant risk of suicide as judged by the Investigator; or
21.	Have a known or suspected intolerance or hypersensitivity to the study drug or any of the stated ingredients.

E.5 End points
E.5.1 Primary end point(s): Over a 26-week initial and 5year total follow up period:
• Number and incidence of AEs, SAEs, and clinically meaningful laboratory test abnormalities;
• Change from baseline in vital signs, ECG parameters, and physical and neurological examinations, and MMSEChange from baseline in mini-mental state
examination (MMSE);;
• Change from baseline in clinical chemistry and hematology safety laboratory tests;
• Time to achieve clearance of vector genomes in plasma and semen (male only)
• Incidence of treatment emergent suicidal ideation or behavior as measured using the C-SSRS.
• Change from baseline in MRI including oedema, inflammation, asymptomatic/symptomatic hemorrhage and other structural changes
E.5.1.1 Timepoint(s) of evaluation of this end point: 26 weeks and 5 years
E.5.2 Secondary end point(s): Over a 26-week initial and 5-year total follow up period:
• Change from baseline in PGRN protein levels in CSF and blood;
Over a 26-week initial and 5-year total follow up period:
• Change from baseline in NfL levels in CSF and blood
Over a 5-year follow up period:
• Change from baseline in CDR+NACC FTLD-SB score;
• Change in CGI C, PGI-C, CaGI-C
E.5.2.1 Timepoint(s) of evaluation of this end point: 26 weeks and 5 years
E.6 and E.7 Scope of the trial
E.6 Scope of the Trial
E.6.1 Diagnosis: Yes
E.6.2 Prophylaxis: No
E.6.3 Therapy: Yes
E.6.4 Safety: Yes
E.6.5 Efficacy: Yes
E.6.6 Pharmacokinetic: No
E.6.7 Pharmacodynamic: No
E.6.8 Bioequivalence: No
E.6.9 Dose response: Yes
E.6.10 Pharmacogenetic: No
E.6.11 Pharmacogenomic: No
E.6.12 Pharmacoeconomic: No
E.6.13 Others: No
E.7 Trial type and phase
E.7.1 Human pharmacology (Phase I): Yes
E.7.1.1 First administration to humans: Yes
E.7.1.2 Bioequivalence study: No
E.7.1.3 Other: No
E.7.1.3.1 Other trial type description:
E.7.2 Therapeutic exploratory (Phase II): Yes
E.7.3 Therapeutic confirmatory (Phase III): No
E.7.4 Therapeutic use (Phase IV): No
E.8 Design of the trial
E.8.1 Controlled: No
E.8.1.1 Randomised: No
E.8.1.2 Open: Yes
E.8.1.3 Single blind: No
E.8.1.4 Double blind: No
E.8.1.5 Parallel group: No
E.8.1.6 Cross over: No
E.8.1.7 Other: Information not present in EudraCT
E.8.2 Comparator of controlled trial
E.8.2.1 Other medicinal product(s): No
E.8.2.2 Placebo: No
E.8.2.3 Other: No
E.8.3 The trial involves single site in the Member State concerned: Yes
E.8.4 The trial involves multiple sites in the Member State concerned: No
E.8.5 The trial involves multiple Member States: Yes
E.8.5.1 Number of sites anticipated in the EEA: 12
E.8.6 Trial involving sites outside the EEA
E.8.6.1 Trial being conducted both within and outside the EEA: Yes
E.8.6.2 Trial being conducted completely outside of the EEA: No
E.8.6.3 If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned:
Belgium
France
Italy
Netherlands
Poland
Spain
Sweden
United Kingdom
United States
E.8.7 Trial has a data monitoring committee: Yes
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: LVLS
E.8.9 Initial estimate of the duration of the trial
E.8.9.1 In the Member State concerned years: 6
E.8.9.1 In the Member State concerned months: 0
E.8.9.1 In the Member State concerned days: 0
E.8.9.2 In all countries concerned by the trial years: 6
E.8.9.2 In all countries concerned by the trial months: 0
E.8.9.2 In all countries concerned by the trial days: 0

F. Population of Trial Subjects
F.1 Age Range
F.1.1 Trial has subjects under 18: No
F.1.1.1 In Utero: No
F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No
F.1.1.3 Newborns (0-27 days): No
F.1.1.4 Infants and toddlers (28 days-23 months): No
F.1.1.5 Children (2-11years): No
F.1.1.6 Adolescents (12-17 years): No
F.1.2 Adults (18-64 years): Yes
F.1.2.1 Number of subjects for this age range: 5
F.1.3 Elderly (>=65 years): Yes
F.1.3.1 Number of subjects for this age range: 4
F.2 Gender
F.2.1 Female: Yes
F.2.2 Male: Yes
F.3 Group of trial subjects
F.3.1 Healthy volunteers: No
F.3.2 Patients: Yes
F.3.3 Specific vulnerable populations: Yes
F.3.3.1 Women of childbearing potential not using contraception : No
F.3.3.2 Women of child-bearing potential using contraception: Yes
F.3.3.3 Pregnant women: No
F.3.3.4 Nursing women: No
F.3.3.5 Emergency situation: No
F.3.3.6 Subjects incapable of giving consent personally: Yes
F.3.3.6.1 Details of subjects incapable of giving consent: Participants will not be enrolled if they are unable to consent at initial screening/consent, but patients' disease may progress during the 5 year follow up period of the
study, such that they will lack capacity to consent for themselves.
F.3.3.7 Others: No
F.4 Planned number of subjects to be included
F.4.1 In the member state: 2
F.4.2 For a multinational trial
F.4.2.1 In the EEA: 6
F.4.2.2 In the whole clinical trial: 9
F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): Participants will receive their usual standard of care.

G. Investigator Networks to be involved in the Trial


N. Review by the Competent Authority or Ethics Committee in the country concerned
N. Competent Authority Decision: Authorised
N. Date of Competent Authority Decision: 2023-04-13
N. Ethics Committee Opinion of the trial application: Favourable
N. Ethics Committee Opinion: Reason(s) for unfavourable opinion:
N. Date of Ethics Committee Opinion: 2023-06-16

P. End of Trial
P. End of Trial Status: Ongoing

Summary
EudraCT Number: 2021-002179-21
Sponsor's Protocol Code Number: AB21004
National Competent Authority: France - ANSM
Clinical Trial Type: EEA CTA
Trial Status: Ongoing
Date on which this record was first entered in the EudraCT database: 2022-03-10
Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-002179-21/FR/

A. Protocol Information
A.1 Member State Concerned: France - ANSM
A.2 EudraCT number: 2021-002179-21
A.3 Full title of the trial: A multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 study to evaluate the safety and efficacy of masitinib as add-on therapy in patients with mild to moderate Alzheimer's disease, treated with standard of care : cholinesterase inhibitors, memantine
A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: A phase 3 study to evaluate the safety and efficacy of masitinib as add-on therapy in patients with mild to moderate Alzheimer's disease treated with standard of care: cholinesterase inhibitors, memantine
A.4.1 Sponsor's protocol code number: AB21004
A.7 Trial is part of a Paediatric Investigation Plan: No
A.8 EMA Decision number of Paediatric Investigation Plan: JSON_ERROR_HERE

B. Sponsor Information
Sponsor 1
B.1.1 Name of Sponsor: AB Science
B.1.3.4	Country: France
B.3.1 and B.3.2	Status of the sponsor: Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1 Name of organisation providing support: AB Science
B.4.2 Country: France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1 Name of organisation: AB Science
B.5.2 Functional name of contact point: Alain Moussy
B.5.3 Address
B.5.3.1 Street Address: 3 avenue George V
B.5.3.2 Town/ city: Paris
B.5.3.3 Post code: 75008
B.5.3.4 Country: France
B.5.4 Telephone number: 0033147202311
B.5.5 Fax number: 0033147202411
B.5.6 E-mail: regulatoryaffairs@ab-science.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3 IMP Role: Test
D.2 Status of the IMP to be used in the clinical trial
D.2.1 IMP to be used in the trial has a marketing authorisation: No
D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No
D.2.5.1 Orphan drug designation number:
D.3 Description of the IMP
D.3.1 Product name: Masitinib
D.3.2 Product code: AB1010
D.3.4 Pharmaceutical form: Film-coated tablet
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8 INN - Proposed INN: Masitinib mesilate
D.3.9.1 CAS number: 790299-79-5
D.3.9.2 Current sponsor code: AB1010
D.3.9.4 EV Substance Code: SUB32266
D.3.10 Strength
D.3.10.1 Concentration unit: mg milligram(s)
D.3.10.2 Concentration type: equal
D.3.10.3 Concentration number: 100
D.3.11 The IMP contains an
D.3.11.1 Active substance of chemical origin: Yes
D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No
D.3.11.3 Advanced Therapy IMP (ATIMP): No
D.3.11.3.1 Somatic cell therapy medicinal product: No
D.3.11.3.2 Gene therapy medical product: No
D.3.11.3.3 Tissue Engineered Product: No
D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No
D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No
D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No
D.3.11.5 Radiopharmaceutical medicinal product: No
D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No
D.3.11.7 Plasma derived medicinal product: No
D.3.11.8 Extractive medicinal product: No
D.3.11.9 Recombinant medicinal product: No
D.3.11.10 Medicinal product containing genetically modified organisms: No
D.3.11.11 Herbal medicinal product: No
D.3.11.12 Homeopathic medicinal product: No
D.3.11.13 Another type of medicinal product: No
D.IMP: 2
D.1.2 and D.1.3 IMP Role: Test
D.2 Status of the IMP to be used in the clinical trial
D.2.1 IMP to be used in the trial has a marketing authorisation: No
D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No
D.2.5.1 Orphan drug designation number:
D.3 Description of the IMP
D.3.1 Product name: Masitinib
D.3.2 Product code: AB1010
D.3.4 Pharmaceutical form: Film-coated tablet
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8 INN - Proposed INN: Masitinib mesilate
D.3.9.1 CAS number: 790299-79-5
D.3.9.4 EV Substance Code: SUB32266
D.3.10 Strength
D.3.10.1 Concentration unit: mg milligram(s)
D.3.10.2 Concentration type: equal
D.3.10.3 Concentration number: 200
D.3.11 The IMP contains an
D.3.11.1 Active substance of chemical origin: Yes
D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No
D.3.11.3 Advanced Therapy IMP (ATIMP): No
D.3.11.3.1 Somatic cell therapy medicinal product: No
D.3.11.3.2 Gene therapy medical product: No
D.3.11.3.3 Tissue Engineered Product: No
D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No
D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No
D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No
D.3.11.5 Radiopharmaceutical medicinal product: No
D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No
D.3.11.7 Plasma derived medicinal product: No
D.3.11.8 Extractive medicinal product: No
D.3.11.9 Recombinant medicinal product: No
D.3.11.10 Medicinal product containing genetically modified organisms: No
D.3.11.11 Herbal medicinal product: No
D.3.11.12 Homeopathic medicinal product: No
D.3.11.13 Another type of medicinal product: No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1 Is a Placebo used in this Trial? Yes
D.8.3 Pharmaceutical form of the placebo: Film-coated tablet
D.8.4 Route of administration of the placebo: Oral use
D.8 Placebo: 2
D.8.1 Is a Placebo used in this Trial? Yes
D.8.3 Pharmaceutical form of the placebo: Film-coated tablet
D.8.4 Route of administration of the placebo: Oral use

E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1 Medical condition(s) being investigated:
E.1.1.1 Medical condition in easily understood language: Alzheimer's disease
E.1.1.2 Therapeutic area: Diseases [C] - Nervous System Diseases [C10]
MedDRA Classification
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 20.0
E.1.2 Level: HLT
E.1.2 Classification code: 10001897
E.1.2 Term: Alzheimer's disease (incl subtypes)
E.1.2 System Organ Class: 100000004852
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 20.0
E.1.2 Level: LLT
E.1.2 Classification code: 10001896
E.1.2 Term: Alzheimer's disease
E.1.2 System Organ Class: 100000004852
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 24.1
E.1.2 Level: LLT
E.1.2 Classification code: 10086384
E.1.2 Term: Early onset Alzheimer's disease
E.1.2 System Organ Class: 100000004852
E.1.3 Condition being studied is a rare disease: No
E.2 Objective of the trial
E.2.1 Main objective of the trial: The primary objective of the study is to evaluate whether masitinib treatment will show a significant improvement ADCS-ADL and ADAS-Cog versus placebo in the study patients.
E.2.2 Secondary objectives of the trial: The secondary objectives of the study are to evaluate the efficacy of masitinib compared with placebo on a range of clinical parameters of Alzheimer's disease.  The secondary objectives also include the assessment of safety and tolerability of masitinib as compared to placebo in terms of adverse events, vital signs, physical examination, ECG, and clinical laboratory tests.
E.2.3 Trial contains a sub-study: No
E.3 Principal inclusion criteria: 1.	Patient with clinical diagnosis of Alzheimer's disease based on the International Working Group criteria according to the European Guideline on the clinical investigation of medicines for the treatment of Alzheimer’s disease (CPMP/EWP/553/95 Rev.2 – 2018) at screening visit;

2.	Patient with ADCS-ADL score at screening visit and baseline visit <73;

3.	Patient with MMSE ≥ 14 and ≤ 25 at screening visit and baseline visit;

4. Patient with Alzheimer’s Disease biomarker profile at screening visit:
- A positive amyloid PET scan
- Alternatively, a-beta 1-42 <1000pg/ml AND p-tau >19pg/ml OR a p-tau/a-beta ratio > 0.024, as measured by a central laboratory according to the Elecsys assay for Cerebrospinal fluid (CSF) biomarkers;

5.	Patients treated for a minimum of 6 months with a stable dose of cholinesterase inhibitors (donepezil, rivastigmine or galantamine) at baseline visit, and/or a stable dose of memantine for a minimum of 6 months at baseline visit, with no changes foreseen in therapy throughout the study;

6.	If receiving a supplement for cognition (eg, gingko biloba, omega-3 polyunsaturated fatty acid, vitamin E, curcumin, souvenaid) must be taking a stable dose for at least 4 months prior to screening visit;

7.	Patients with a caregiver who, at screening visit and baseline visit:
-	Agrees to accompany the participant to all study visits and able to supervise the participant's compliance with the study procedures and provide detailed information about the participant.
-	Either lives with the participant or sees the participant on average for ≥1 hours/day ≥3 days/week, or in the Investigator's opinion, the extent of contact is sufficient to provide meaningful assessment of changes in participant behaviour and function over time and provide information on safety and tolerability.
-	Is able to read, understand, and speak the designated language at the study centre.
-	Caregiver must be cognitively able to fulfil the requirements of the study.

Other inclusion criteria
8.	Male or non-pregnant female adult ≥50 years of age at time of enrolment at screening visit;

9.	Patients with bodyweight >45 kg and BMI between 18 and 35 kg/m2 at screening visit or baseline visit

10.	Contraception, at screening and baseline visit:
Female patients of childbearing potential (entering the study after a menstrual period and who has a negative pregnancy test), who agree to use a highly effective method of contraception and an effective method of contraception by their male partner during the study and for 3 months and a half after the last treatment intake
Male patients with a female partner of childbearing potential who agree to use a highly effective method of contraception and an effective method of contraception by their female partner during the study and for 3 months and a half after the last treatment intake OR who agree to use an effective method of contraception and a highly effective method of contraception by their female partner during the study and for 3 months and a half after the last treatment intake.

Highly effective and effective methods of contraception are detailed in the Appendix 1.1 of the protocol.

11.	Subjects must be able and willing to comply, both at screening visit and at baseline visit, with study visits and procedures;

12.	Subjects able to understand, sign, and date the written informed consent form at screening visit prior to any protocol-specific procedures;

13.	Subjects able to understand, and willing to follow the safety procedures mentioned on the patient card in case of signs or symptoms of severe neutropenia or severe cutaneous toxicity, at screening and baseline visit. Patient card will be provided at baseline visit.

E.4 Principal exclusion criteria: 1. Patients with any other cause of dementia shown by MRI findings and neurological examination in the last 12 months prior to screening visit;
2. Systemic conditions known to cause dementia, e.g., hypothyroidism, untreated vitamin B12 or folic acid deficiency, niacin deficiency, neurosyphilis, HIV infection at screening visit;
3. Patients with substance-induced dementia at screening visit;
4. Patients with Alzheimer’s disease with delirium at screening visit;
5. Patients with severe forms of delusions (e.g, NPI-12 delusion score of 4 or more) at screening visit;
6. Patients with evidence of psychosis and/or use of antipsychotic drugs at screening, or history of significant psychiatric disorder at screening visit;
7. Patients with hypersensitivity to masitinib or its excipients at screening;
8. Patients with history (or family history) of drug-induced severe skin toxicities or reactions at screening or patients taking concomitant treatment or therapies associated with severe drug-induced skin toxicity;
9. Patients with history of severe bone marrow disorders such as agranulocytosis or aplasia, or with abnormal laboratory results from local laboratory assessments at screening and baseline defined as:
- Neutropenia with ANC <1.5 × 109/L
- Anemia with Hgb <LLN or Red blood cell count < LLN
- Thrombocytopenia with platelet counts <150 × 109/L
- Lymphocytes <1.0 × 109/L;
10. Patients with history of severe hepatic disorders, such as viral hepatitis or steatohepatitis, and alcoholic steatosis, or with abnormal laboratory results defined as:
- Hepatic transaminase levels >2 ULN at baseline, or
- Total bilirubin level >1.5 ULN at baseline, or
- Both hepatic transaminase levels and total bilirubin level outside of the normal ranges at screening and baseline, or
- Albuminemia <1 × LLN at screening and baseline, or
- Patients with concomitant medication known to be associated with severe hepatotoxicity;
11. Patients with pre-existing severe renal impairment, or with abnormal laboratory results at screening:
- Creatinine clearance <60 mL/min (Cockcroft and Gault formula) or
- Proteinuria >30 mg/dL (1+) on dipstick; in case of the proteinuria ≥1+ on the dipstick, 24 hours proteinuria must be >1.5 g/24 hours;
12. Patients with current or history of severe cardiovascular disease, assessed at screening:
- Myocardial infarction
- Unstable angina pectoris
- Coronary revascularization procedure
- Congestive heart failure of NYHA Class III or IV
- Stroke, including a transient ischemic attack
- Second degree or third-degree atrioventricular block not successfully treated with a pacemaker
- Bi-fascicular block
- QTc Fridericia interval > 450 milliseconds for males and > 470 milliseconds for females
- Drug induced heart failure or ischemic heart disease
- Radiotherapy induced cardiomyopathy
- Family history of unexpected death of cardiovascular origin
- Edema of cardiac origin and left ventricular ejaculation fraction ≤50%;
13. Patients, with two or more of the risk factors listed below assessed by a cardiologist at screening as Very High Risk (calculated SCORE* ≥10%.) according to the Systematic Coronary Risk Estimation (SCORE*):
- Hypertension (uncontrolled)
- Diabetes
- Kidney disease
- Current smoking (≥ 10 Pack-year: equivalent to 1 pack of 20 cigarettes for 10 years with the formula N (number of packs of 20 cigarettes smoked daily) × T (number years smoking)) Patients who stopped smoking 6 months prior to the evaluation, are not concerned.
- Hypercholesterolemia,
- COPD;
14. Patients with active severe infection identified by tests for tuberculosis (Interferon gamma release assay), viral hepatitis B (serology for anti-HBs) and C (serological screening), HIV 1/2 (serological screening), syphilis (VDRL assay) and COVID-19 (confirmed by positive RT-PCR and/or other applicable methods) at screening or at baseline;
 15. Patient treated concomitantly with known substrates of Permeability-GlycoProtein (P-gp) and/or Breast Cancer Resistance Protein (BCRP) with narrow therapeutic index;
16. Any medical condition at screening and baseline that, in the opinion of the Investigator, might interfere with the patients’ participation in the trial, poses any added risk for the patients, or confounds the assessment of the patients;
17. Patients under psychiatric care, patients protected by law under guardianship or curatorship, patients in emergency situations, prisoners and patients without national health insurance at screening and baseline;
18. Patients who had major surgery within 2 weeks prior to screening visit;
19. Pregnant, or nursing female patients at screening or baseline;
20. Patients with a diagnosis of cancer or evidence of continued disease within five years before screening
21. Previous participation in an earlier study with masitinib, assessed at screening

E.5 End points
E.5.1 Primary end point(s): The study has two following primary endpoints:
•	Absolute change from baseline in ADCS-ADL score at week 24
and
•	Absolute change from baseline in ADAS-Cog score at week 24
E.5.1.1 Timepoint(s) of evaluation of this end point: week 24
E.5.2 Secondary end point(s): The key secondary endpoint consists of:
•	Time to severe dementia (MMSE<10)
The secondary endpoints of the study are:
•	Absolute change from baseline in ADAS-Cog score at week 48
•	Absolute change from baseline in ADCS-ADL score at week 48
•	Clinical Responder rate at Week 24.
•	Clinician’s Interview Based Impression of Change-plus (CIBIC-plus) at Week 24
•	Mini-Mental State Examination (MMSE) at Week 24
•	Clinical Dementia Rating (CDR) at Week 24
•	Neuropsychiatric Inventory (NPI) at Week 24

E.5.2.1 Timepoint(s) of evaluation of this end point: week 24, week 48
E.6 and E.7 Scope of the trial
E.6 Scope of the Trial
E.6.1 Diagnosis: No
E.6.2 Prophylaxis: No
E.6.3 Therapy: Yes
E.6.4 Safety: Yes
E.6.5 Efficacy: Yes
E.6.6 Pharmacokinetic: No
E.6.7 Pharmacodynamic: No
E.6.8 Bioequivalence: No
E.6.9 Dose response: No
E.6.10 Pharmacogenetic: No
E.6.11 Pharmacogenomic: No
E.6.12 Pharmacoeconomic: No
E.6.13 Others: No
E.7 Trial type and phase
E.7.1 Human pharmacology (Phase I): No
E.7.1.1 First administration to humans: No
E.7.1.2 Bioequivalence study: No
E.7.1.3 Other: No
E.7.1.3.1 Other trial type description:
E.7.2 Therapeutic exploratory (Phase II): No
E.7.3 Therapeutic confirmatory (Phase III): Yes
E.7.4 Therapeutic use (Phase IV): No
E.8 Design of the trial
E.8.1 Controlled: Yes
E.8.1.1 Randomised: Yes
E.8.1.2 Open: No
E.8.1.3 Single blind: No
E.8.1.4 Double blind: Yes
E.8.1.5 Parallel group: Yes
E.8.1.6 Cross over: No
E.8.1.7 Other: No
E.8.2 Comparator of controlled trial
E.8.2.1 Other medicinal product(s): Yes
E.8.2.2 Placebo: Yes
E.8.2.3 Other: Yes
E.8.2.3.1 Comparator description: cholinesterase inhibitors (donepezil, rivastigmine, or galantamine), memantine
E.8.2.4 Number of treatment arms in the trial: 2
E.8.3 The trial involves single site in the Member State concerned: Yes
E.8.4 The trial involves multiple sites in the Member State concerned: Yes
E.8.4.1 Number of sites anticipated in Member State concerned: 5
E.8.5 The trial involves multiple Member States: Yes
E.8.5.1 Number of sites anticipated in the EEA: 155
E.8.6 Trial involving sites outside the EEA
E.8.6.1 Trial being conducted both within and outside the EEA: Yes
E.8.6.2 Trial being conducted completely outside of the EEA: No
E.8.6.3 If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned:
Argentina
Canada
Colombia
Israel
Peru
South Africa
United States
Finland
France
Poland
Sweden
Bulgaria
Netherlands
Romania
Spain
Switzerland
Czechia
Germany
Greece
Italy
Belgium
Denmark
Ireland
Norway
Portugal
Russian Federation
Serbia
Slovakia
Slovenia
Ukraine
United Kingdom
E.8.7 Trial has a data monitoring committee: Yes
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: Last Visit Last Subject
E.8.9 Initial estimate of the duration of the trial
E.8.9.1 In the Member State concerned years: 2
E.8.9.1 In the Member State concerned months:
E.8.9.1 In the Member State concerned days:
E.8.9.2 In all countries concerned by the trial years: 2

F. Population of Trial Subjects
F.1 Age Range
F.1.1 Trial has subjects under 18: No
F.1.1.1 In Utero: No
F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No
F.1.1.3 Newborns (0-27 days): No
F.1.1.4 Infants and toddlers (28 days-23 months): No
F.1.1.5 Children (2-11years): No
F.1.1.6 Adolescents (12-17 years): No
F.1.2 Adults (18-64 years): Yes
F.1.2.1 Number of subjects for this age range: 24
F.1.3 Elderly (>=65 years): Yes
F.1.3.1 Number of subjects for this age range: 576
F.2 Gender
F.2.1 Female: Yes
F.2.2 Male: Yes
F.3 Group of trial subjects
F.3.1 Healthy volunteers: No
F.3.2 Patients: Yes
F.3.3 Specific vulnerable populations: Yes
F.3.3.1 Women of childbearing potential not using contraception : No
F.3.3.2 Women of child-bearing potential using contraception: Yes
F.3.3.3 Pregnant women: No
F.3.3.4 Nursing women: No
F.3.3.5 Emergency situation: No
F.3.3.6 Subjects incapable of giving consent personally: No
F.3.3.7 Others: No
F.4 Planned number of subjects to be included
F.4.1 In the member state: 30
F.4.2 For a multinational trial
F.4.2.1 In the EEA: 480
F.4.2.2 In the whole clinical trial: 600
F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): None

G. Investigator Networks to be involved in the Trial


N. Review by the Competent Authority or Ethics Committee in the country concerned
N. Competent Authority Decision: Authorised
N. Date of Competent Authority Decision: 2022-10-07
N. Ethics Committee Opinion of the trial application: Favourable
N. Ethics Committee Opinion: Reason(s) for unfavourable opinion:
N. Date of Ethics Committee Opinion: 2022-06-07

P. End of Trial
P. End of Trial Status: Ongoing

Summary
EudraCT Number: 2021-002179-21
Sponsor's Protocol Code Number: AB21004
National Competent Authority: Spain - AEMPS
Clinical Trial Type: EEA CTA
Trial Status: Ongoing
Date on which this record was first entered in the EudraCT database: 2022-05-18
Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-002179-21/ES/

A. Protocol Information
A.1 Member State Concerned: Spain - AEMPS
A.2 EudraCT number: 2021-002179-21
A.3 Full title of the trial: A multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 study to evaluate the safety and efficacy of masitinib as add-on therapy in patients with mild to moderate Alzheimer's disease, treated with standard of care : cholinesterase inhibitors, memantine
A.3 Full title of the trial (es): Estudio de fase 3, multicéntrico, randomizado, doble ciego, controlado con placebo, para evaluar la seguridad y eficacia de masitinib como tratamiento complementario en pacientes con enfermedad de Alzheimer de leve a moderada, tratados con el estándar de cuidado: inhibidores de la colinesterasa, memantina
A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: A phase 3 study to evaluate the safety and efficacy of masitinib as add-on therapy in patients with mild to moderate Alzheimer's disease treated with standard of care: cholinesterase inhibitors, memantine
A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language (es): Un estudio de fase 3 para evaluar la seguridad y la eficacia de masitinib como terapia complementaria en pacientes con enfermedad de Alzheimer de leve a moderada tratados con el tratamiento estándar: inhibidores de la colinesterasa, memantina
A.3.2 Name or abbreviated title of the trial where available: Alzheimer
A.3.2 Name or abbreviated title of the trial where available (es): Alzheimer
A.4.1 Sponsor's protocol code number: AB21004
A.7 Trial is part of a Paediatric Investigation Plan: No
A.8 EMA Decision number of Paediatric Investigation Plan:

B. Sponsor Information
Sponsor 1
B.1.1 Name of Sponsor: ABScience
B.1.3.4	Country: France
B.3.1 and B.3.2	Status of the sponsor: Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1 Name of organisation providing support: ABScience
B.4.2 Country: France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1 Name of organisation: ABScience
B.5.2 Functional name of contact point: Alain Moussy
B.5.3 Address
B.5.3.1 Street Address: 3 avenue George V
B.5.3.2 Town/ city: Paris
B.5.3.3 Post code: 75008
B.5.3.4 Country: France
B.5.4 Telephone number: 0033147202311
B.5.5 Fax number: 0033147202411
B.5.6 E-mail: regulatoryaffairs@ab-science.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3 IMP Role: Test
D.2 Status of the IMP to be used in the clinical trial
D.2.1 IMP to be used in the trial has a marketing authorisation: No
D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No
D.2.5.1 Orphan drug designation number:
D.3 Description of the IMP
D.3.1 Product name: Masitinib
D.3.2 Product code: AB1010
D.3.4 Pharmaceutical form: Film-coated tablet
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8 INN - Proposed INN: Masitinib mesilate
D.3.9.1 CAS number: 790299-79-5
D.3.9.2 Current sponsor code: AB1010
D.3.9.4 EV Substance Code: SUB32266
D.3.10 Strength
D.3.10.1 Concentration unit: mg milligram(s)
D.3.10.2 Concentration type: equal
D.3.10.3 Concentration number: 100
D.3.11 The IMP contains an
D.3.11.1 Active substance of chemical origin: Yes
D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No
D.3.11.3 Advanced Therapy IMP (ATIMP): No
D.3.11.3.1 Somatic cell therapy medicinal product: No
D.3.11.3.2 Gene therapy medical product: No
D.3.11.3.3 Tissue Engineered Product: No
D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No
D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No
D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No
D.3.11.5 Radiopharmaceutical medicinal product: No
D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No
D.3.11.7 Plasma derived medicinal product: No
D.3.11.8 Extractive medicinal product: No
D.3.11.9 Recombinant medicinal product: No
D.3.11.10 Medicinal product containing genetically modified organisms: No
D.3.11.11 Herbal medicinal product: No
D.3.11.12 Homeopathic medicinal product: No
D.3.11.13 Another type of medicinal product: No
D.IMP: 2
D.1.2 and D.1.3 IMP Role: Test
D.2 Status of the IMP to be used in the clinical trial
D.2.1 IMP to be used in the trial has a marketing authorisation: No
D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No
D.2.5.1 Orphan drug designation number:
D.3 Description of the IMP
D.3.1 Product name: Masitinib
D.3.2 Product code: AB1010
D.3.4 Pharmaceutical form: Film-coated tablet
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8 INN - Proposed INN: Masitinib mesilate
D.3.9.1 CAS number: 790299-79-5
D.3.9.4 EV Substance Code: SUB32266
D.3.10 Strength
D.3.10.1 Concentration unit: mg milligram(s)
D.3.10.2 Concentration type: equal
D.3.10.3 Concentration number: 200
D.3.11 The IMP contains an
D.3.11.1 Active substance of chemical origin: Yes
D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No
D.3.11.3 Advanced Therapy IMP (ATIMP): No
D.3.11.3.1 Somatic cell therapy medicinal product: No
D.3.11.3.2 Gene therapy medical product: No
D.3.11.3.3 Tissue Engineered Product: No
D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No
D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No
D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No
D.3.11.5 Radiopharmaceutical medicinal product: No
D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No
D.3.11.7 Plasma derived medicinal product: No
D.3.11.8 Extractive medicinal product: No
D.3.11.9 Recombinant medicinal product: No
D.3.11.10 Medicinal product containing genetically modified organisms: No
D.3.11.11 Herbal medicinal product: No
D.3.11.12 Homeopathic medicinal product: No
D.3.11.13 Another type of medicinal product: No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1 Is a Placebo used in this Trial? Yes
D.8.3 Pharmaceutical form of the placebo: Film-coated tablet
D.8.4 Route of administration of the placebo: Oral use
D.8 Placebo: 2
D.8.1 Is a Placebo used in this Trial? Yes
D.8.3 Pharmaceutical form of the placebo: Film-coated tablet
D.8.4 Route of administration of the placebo: Oral use

E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1 Medical condition(s) being investigated: Alzheimer's disease
E.1.1 Medical condition(s) being investigated (es): Alzheimer
E.1.1.1 Medical condition in easily understood language: Alzheimer's disease
E.1.1.1 Medical condition in easily understood language (es): Alzheimer
E.1.1.2 Therapeutic area: Diseases [C] - Nervous System Diseases [C10]
MedDRA Classification
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 20.0
E.1.2 Level: HLT
E.1.2 Classification code: 10001897
E.1.2 Term: Alzheimer's disease (incl subtypes)
E.1.2 System Organ Class: 100000004852
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 20.0
E.1.2 Level: LLT
E.1.2 Classification code: 10001896
E.1.2 Term: Alzheimer's disease
E.1.2 System Organ Class: 100000004852
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 24.1
E.1.2 Level: LLT
E.1.2 Classification code: 10086384
E.1.2 Term: Early onset Alzheimer's disease
E.1.2 System Organ Class: 100000004852
E.1.3 Condition being studied is a rare disease: No
E.2 Objective of the trial
E.2.1 Main objective of the trial: The primary objective of the study is to evaluate whether masitinib treatment will show a significant improvement ADCS-ADL and ADAS-Cog versus placebo in the study patients.
E.2.1 Main objective of the trial (es): El objetivo principal del estudio es evaluar si el tratamiento con masitinib mostrará una mejora significativa de ADCS-ADL y ADAS-Cog frente a placebo en los pacientes del estudio.
E.2.2 Secondary objectives of the trial: The secondary objectives of the study are to evaluate the efficacy of masitinib compared with placebo on a range of clinical parameters of Alzheimer's disease.  The secondary objectives also include the assessment of safety and tolerability of masitinib as compared to placebo in terms of adverse events, vital signs, physical examination, ECG, and clinical laboratory tests.
E.2.2 Secondary objectives of the trial (es): Los objetivos secundarios del estudio son evaluar la eficacia de masitinib en comparación con un placebo en una variedad de parámetros clínicos de la enfermedad de Alzheimer. Los objetivos secundarios también incluyen la evaluación de la seguridad y tolerabilidad de masitinib en comparación con el placebo en términos de eventos adversos, signos vitales, examen físico, ECG y pruebas de laboratorio clínico.
E.2.3 Trial contains a sub-study: No
E.3 Principal inclusion criteria: 1.	Patient with clinical diagnosis of Alzheimer's disease based on cognitive impairment and daily functional dependency at screening visit
2.	Patient with ADCS-ADL score at screening visit and baseline visit <73
3.	Patient with MMSE ≥ 14 and ≤ 25 at screening visit and baseline visit
4.	Patient with Alzheimer’s Disease biomarker profile at screening visit:
- A positive amyloid PET scan
- Alternatively, a-beta 1-42 <1000pg/ml AND p-tau >19pg/ml OR a p-tau/a-beta ratio > 0.024, as measured by a central laboratory according to the Elecsys assay for CSF biomarkers
5.	Patients treated for a minimum of 6 months with a stable dose of cholinesterase inhibitors (donepezil, rivastigmine or galantamine) at baseline visit, and/or a stable dose of memantine for a minimum of 6 months at baseline visit, with no changes foreseen in therapy throughout the study
6.	If receiving a supplement for cognition (eg, gingko biloba, omega-3 polyunsaturated fatty acid, vitamin E, curcumin, souvenaid) must be taking a stable dose for at least 4 months prior to screening visit
7.	Patients with a caregiver who, at screening visit and baseline visit:
-	Agrees to accompany the participant to all study visits and able to supervise the participant's compliance with the study procedures and provide detailed information about the participant.
-	Either lives with the participant or sees the participant on average for ≥1 hours/day ≥3 days/week, or in the Investigator's opinion, the extent of contact is sufficient to provide meaningful assessment of changes in participant behaviour and function over time and provide information on safety and tolerability.
-	Is able to read, understand, and speak the designated language at the study centre.
-	Caregiver must be cognitively able to fulfil the requirements of the study.

Other inclusion criteria
8.	Male or non-pregnant female adult ≥50 years of age at time of enrolment at screening visit
9.	Patients with bodyweight >45 kg and BMI between 18 and 35 kg/m2 at screening visit or baseline visit
10.	Contraception, at screening and baseline visit:
Female patients of childbearing potential (entering the study after a menstrual period and who has a negative pregnancy test), who agree to use a highly effective method of contraception and an effective method of contraception by their male partner during the study and for 3 months and a half after the last treatment intake
Male patients with a female partner of childbearing potential who agree to use a highly effective method of contraception and an effective method of contraception by their female partner during the study and for 3 months and a half after the last treatment intake OR who agree to use an effective method of contraception and a highly effective method of contraception by their female partner during the study and for 3 months and a half after the last treatment intake.

Highly effective and effective methods of contraception are detailed in the Appendix 14.1 of the protocol.
11.	Subjects must be able and willing to comply, both at screening visit and at baseline visit, with study visits and procedures
12.	Subjects able to understand, sign, and date the written informed consent form at screening visit prior to any protocol-specific procedures
13.	Subjects able to understand, and willing to follow the safety procedures mentioned on the patient card in case of signs or symptoms of severe neutropenia or severe cutaneous toxicity, at screening and baseline visit. Patient card will be provided at baseline visit
E.3 Principal inclusion criteria (es): Relacionados con la enfermedad:
1.	Paciente con diagnóstico clínico de enfermedad de Alzheimer basado en el deterioro cognitivo y la dependencia funcional diaria en la visita de selección.
2.	Paciente con puntuación ADCS-ADL en la visita de selección y en la visita inicial < 73.
3.	Paciente con puntuación MMSE ≥ 14 y ≤ 25 en la visita de selección y en la visita inicial.
4.	Pacientes con presencia de biomarcadores para la enfermedad de Alzheimer en la visita de selección:
- Scaner PET amiloide positivo.
- Alternativamente, valores de a-beta 1-42 <1000 pg/ml Y p-tau >19 pg/ml o una relación p-tau/a-beta > 0,024, medida por un laboratorio central según el ensayo Elecsys para biomarcadores de LCR.

5.	Pacientes tratados, durante un mínimo de 6 meses, con una dosis estable de inhibidores de la colinesterasa (donepezilo, rivastigmina o galantamina), en la visita inicial, y/o una dosis estable de memantina, durante un mínimo de 6 meses, en la visita inicial, sin cambios previstos en la terapia a lo largo del estudio.

6.	Si reciben un suplemento para mejorar la cognición (p. ej.: gingko biloba, ácido graso poliinsaturado omega-3, vitamina E, curcumina, souvenaid (Nutricia)), deben tomar una dosis estable, durante al menos 4 meses antes de la visita de selección.

7.	Pacientes con un cuidador que, en la visita de selección y en la visita inicial:
o	 Acepta acompañar al participante a todas las visitas del estudio y ser capaz de supervisar el cumplimiento de los procedimientos del estudio, por parte del participante y proporcionar información detallada sobre el mismo.
o	 Vive con el participante o lo ve una media de ≥1 hora/día ≥3 días/semana, o en opinión del investigador, el grado de contacto es suficiente para proporcionar una evaluación, de los cambios significativos en el comportamiento y la función del participante a lo largo del tiempo y proporcionar información sobre la seguridad y la tolerabilidad.
o	 Es capaz de leer, comprender y hablar el idioma designado en el centro del estudio.
o	 El cuidador debe ser cognitivamente capaz de cumplir los requisitos del estudio.

Otros criterios de inclusión
8.	Hombre o mujer adulta no embarazada ≥ 50 años de edad, en el momento de la inscripción en la visita de selección
9.	Pacientes con peso corporal > 45 kg, e IMC entre 18 y 35 kg/m2, en la visita de selección o en la visita inicial.
10.	Anticoncepción en la visita de selección y en la visita inicial:
Pacientes mujeres en edad fértil (inscritas en el estudio después de un periodo menstrual con una prueba de embarazo negativa), que se comprometen a usar un método anticonceptivo altamente efectivo y un método anticonceptivo aceptable para su pareja masculina, durante el estudio y 3 meses después de la última toma de tratamiento.
Pacientes varones con una pareja femenina en edad fértil que se comprometen a usar un método anticonceptivo, altamente efectivo, y un método anticonceptivo, aceptable, para su pareja femenina, durante el estudio y 3 meses después de la última administración del tratamiento.
Los métodos anticonceptivos efectivos y altamente efectivos se detallan en el anexo 14.1 del protocolo.
11.	Los sujetos deben ser capaces y estar dispuestos a cumplir, tanto en la visita de selección como en la visita inicial, con las visitas y procedimientos del estudio.
12.	Los sujetos son capaces de comprender, firmar y fechar el formulario de consentimiento informado por escrito en la visita de selección antes de iniciar los procedimientos específicos del protocolo.
13.	Los sujetos deben de ser capaces de entender y estar dispuestos a seguir los procedimientos de seguridad mencionados en la tarjeta del paciente, en caso de signos o síntomas de neutropenia grave o toxicidad cutánea grave, en la visita de selección y en la visita inicial. La tarjeta del paciente se entregará en la visita inicial.
E.4 Principal exclusion criteria: 1.	Patients with any other cause of dementia shown by MRI findings and neurological examination in the last 12 months prior to screening visit
2.	Systemic conditions known to cause dementia, e.g., hypothyroidism, untreated vitamin B12 or folic acid deficiency, niacin deficiency, neurosyphilis, HIV infection at screening visit
3.	Patients with substance-induced dementia at screening visit
4.	Patients with Alzheimer’s disease with delirium at screening visit
5.	Patients with severe forms of delusions (e.g, NPI delusion score of 4 or more) at screening visit
6.	Patients with evidence of psychosis and/or use of antipsychotic drugs at screening, or history of significant psychiatric disorder at screening visit
7.	Patients with hypersensitivity to masitinib or its excipients at screening
8.	Patients with history (or family history) of drug-induced severe skin toxicities or reactions at screening or patients taking concomitant treatment or therapies associated with severe drug-induced skin toxicity

9.	Patients with history of severe bone marrow disorders such as agranulocytosis or aplasia, or with abnormal laboratory results from local laboratory assessments at screening and baseline defined as:
-	Neutropenia with ANC <1.5 × 109/L
-	Anemia with Hgb <10 g/dl
-	Thrombocytopenia with platelet counts <75 × 109/L

10.	Patients with history of severe hepatic disorders, such as viral hepatitis or steatohepatitis, and alcoholic steatosis, or with abnormal laboratory results defined as:
-	Hepatic transaminase levels >2 ULN at baseline, or
-	Total bilirubin level >1.5 ULN at baseline, or
-	Both hepatic transaminase levels and total bilirubin level outside of the normal ranges at screening and baseline, or
-	Albuminemia <1 × LLN at screening and baseline, or
-	Patients with concomitant medication known to be associated with severe hepatotoxicity

11.	Patients with pre-existing severe renal impairment, or with abnormal laboratory results at screening:
-	Creatinine clearance <60 mL/min (Cockcroft and Gault formula) or
-	Proteinuria >30 mg/dL (1+) on dipstick; in case of the proteinuria ≥1+ on the dipstick, 24 hours proteinuria must be >1.5 g/24 hours

12.	Patients with current or history of severe cardiovascular disease, assessed at screening:
-	Myocardial infarction
-	Unstable angina pectoris
-	Coronary revascularization procedure
-	Congestive heart failure of NYHA Class III or IV
-	Stroke, including a transient ischemic attack
-	Second degree or third-degree atrioventricular block not successfully treated with a pacemaker
-	Bi-fascicular block
-	QTc Fridericia interval > 450 milliseconds for males and > 470 milliseconds for females
-	Drug induced heart failure or ischemic heart disease
-	Radiotherapy induced cardiomyopathy
-	Family history of unexpected death of cardiovascular origin
-	Edema of cardiac origin and left ventricular ejaculation fraction ≤50%

13.	Patients, with two or more of the risk factors listed below assessed by a cardiologist at screening as Very High Risk (calculated SCORE* ≥10%.) according to the Systematic Coronary Risk Estimation (SCORE*):
-	Hypertension (uncontrolled)
-	Diabetes
-	Kidney disease
-	Current smoking (≥ 10 Pack-year: equivalent to 1 pack of 20 cigarettes for 10 years with the formula N (number of packs of 20 cigarettes smoked daily) × T (number years smoking)) Patients who stopped smoking 6 months prior to the evaluation, are not concerned.
-	Hypercholesterolemia,
-	COPD
* This assessment is done according to the Systematic Coronary Risk Estimation (SCORE) using the country specific free full version of HeartScore®, the interactive tool for predicting and managing the risk of heart attack and stroke in Europe, available at https://www.heartscore.org/en_GB/access
If the country specific version is not available, EU one should be used.


19.	Pregnant, or nursing female patients at screening or baseline

20.	Patients with a diagnosis of cancer or evidence of continued disease within five years before screening
22.	Patient who has been exposed to an investigational treatment within 3 months (9 months for immunotherapies) or five half-lives of an investigational product, whichever is longer, before the screening visit
23.	Subjects who have received a live vaccine within 30 days prior to first IMP administration
E.4 Principal exclusion criteria (es): Relacionados con la enfermedad
1.	Pacientes con cualquier otra causa de demencia, demostrada por los hallazgos de la resonancia magnética y el examen neurológico, en los últimos 12 meses anteriores a la visita de selección.
2.	Afecciones sistémicas que se sabe que causan demencia, por ejemplo, hipotiroidismo, deficiencia de vitamina B12 o de ácido fólico sin tratar; deficiencia de niacina, neurosífilis o infección por VIH, en la visita de selección.
3.	Pacientes demencia inducida por sustanciasen la visita de selección.
4.	Pacientes con enfermedad de Alzheimer con delirio, en la visita de selección.
5.	Pacientes con formas graves de delirio (por ejemplo, puntuación de delirio NPI de 4 o más) en la visita de selección.
6.	Pacientes con evidencia de psicosis y/o uso de fármacos antipsicóticos, en el momento de la selección, o antecedentes de trastornos psiquiátricos significativos, en la visita de selección.
Otros criterios de exclusión
7.	Pacientes con hipersensibilidad a masitinib o a sus excipientes en el momento de la selección.
8.	Pacientes con antecedentes (o antecedentes familiares) de toxicidades o reacciones cutáneas graves, inducidas por fármacos en el momento de la selección.  O pacientes que estén tomando tratamientos o terapias concomitantes asociados a toxicidad cutánea grave inducida por fármacos.
9.	Pacientes con antecedentes de trastornos graves de la médula ósea, como agranulocitosis o aplasia, o con resultados anormales en las evaluaciones de laboratorio locales en la visita de selección y en la visita inicial definidos como:
o	Neutropenia con RAN <1,5 × 109/l.
o	Anemia con Hgb <10 g/dl.
o	Trombocitopenia con recuento plaquetario <75 × 109/l.

10.	Pacientes con antecedentes de trastornos hepáticos graves, como hepatitis viral o esteatohepatitis, y esteatosis alcohólica, o con resultados de laboratorio anormales definidos como:
o	Niveles de transaminasas hepáticas > 2 ULN al inicio del estudio.
o	Nivel total de bilirrubina > 1,5 ULN al inicio del estudio.
o	Ambos, los niveles de transaminasas hepáticas y el nivel de bilirrubina total, fuera de los rangos normales en la selección y desde el inicio.
o	Albuminemia <1× LLN en la selección y desde el inicio.
o	Pacientes con medicación concomitante que se sabe asociada a una hepatotoxicidad grave.
11.	Pacientes con insuficiencia renal grave preexistente o con resultados de laboratorio anormales en el momento de la selección:
o	Aclaramiento de creatina < 60 mL/min (fórmula de Cockcroft y Gault).
o	Proteinuria >30 mg/dL (1+) en la tira reactiva; en caso de proteinuria ≥1+ en la tira reactiva, la proteinuria de 24 horas debe ser >1,5 g/24 horas.
12.	Pacientes con enfermedades cardiovasculares graves actuales o con antecedentes de estas, evaluadas en el momento de la selección:
o	Infarto de miocardio.
o	Angina de pecho inestable.
o	Revascularización coronaria.
o	Insuficiencia cardíaca congestiva de clase III o IV según la NYHA.
o	Accidente cerebrovascular, incluido un ataque isquémico transitorio.
o	Bloqueo auriculoventricular de segundo o tercer grado no tratado con éxito con un marcapasos.
o	Bloqueo bifascicular.
o	Intervalo QTc Fridericia > 450 milisegundos para los hombres y > 470 milisegundos para las mujeres.
o	Insuficiencia cardíaca inducida por fármacos o cardiopatía isquémica.
o	Miocardiopatía inducida por radioterapia.
o	Antecedentes familiares de muerte inesperada de origen cardiovascular.
o	Insuficiencia cardíaca con fracción de eyección del ventrículo izquierdo ≤ 50 %.
13.	Pacientes, con dos o más de los factores de riesgo enumerados a continuación,  evaluados por un cardiólogo en el momento de la selección como de muy alto riesgo (SCORE* ≥ 10 %):
o	Hipertensión (no controlada).
o	Diabetes.
o	Insuficiencia renal.
o	Tabaquismo (≥ 10 paquetes-año: equivalente a 1 paquete de 20 cigarrillos durante 10 años con la fórmula N (número de paquetes de 20 cigarrillos fumados diariamente) × T (número de años fumando)).Esto no aplica a los pacientes que dejaron de fumar en los 6 meses previos a la evaluación.
o	Hipercolesterolemia.
o	EPOC.
* Esta evaluación se realiza según la evaluación sistemática del riesgo coronario (SCORE), utilizando la versión completa gratuita específica para cada país de HeartScore®, la herramienta interactiva para predecir y gestionar el riesgo de infarto e ictus en Europa, disponible en https://www.heartscore.org/en_GB/access.
Si la versión específica del país no está disponible, debe utilizarse la de la UE.
14.	Pacientes con infección grave activa, como tuberculosis, hepatitis viral, infección por el virus de la inmunodeficiencia humana, sífilis o COVID-19 (confirmada por RT-PCR positiva y/u otros métodos aplicables), a partir de los expedientes médicos evaluados en el momento de la selección y al inicio del estudio.
15. .........
E.5 End points
E.5.1 Primary end point(s): The study has two following primary endpoints:
•	Absolute change from baseline in ADCS-ADL score at week 24
and
•	Absolute change from baseline in ADAS-Cog score at week 24
E.5.1 Primary end point(s) (es): Criterios de valoración primarios:
•	Cambio absoluto en la puntuación de ADCS-ADL, entre el inicio del estudio y la semana 24.
•	Cambio absoluto en la puntuación de ADAS- Cog, entre el inicio del estudio y la semana 24.
E.5.1.1 Timepoint(s) of evaluation of this end point: week 24
E.5.1.1 Timepoint(s) of evaluation of this end point (es): Semana 24
E.5.2 Secondary end point(s): The key secondary endpoint consists of:
 Time to severe dementia (MMSE<10)
The secondary endpoints of the study are:
 Absolute change from baseline in ADAS-Cog score at week 48
 Absolute change from baseline in ADCS-ADL score at week 48
 Clinical Responder rate at Week 24.
 Clinician’s Interview Based Impression of Change-plus (CIBIC-plus) at Week 24
 Absolute change from baseline in Mini-Mental State Examination (MMSE) at Week 24
 Absolute change from baseline in Clinical Dementia Rating (CDR) at Week 24
 Absolute change from baseline in Neuropsychiatric Inventory (NPI) at Week 24
E.5.2 Secondary end point(s) (es): Criterios de valoración secundarios:
•	Tiempo hasta la demencia grave (MMSE<10).
•	Cambio absoluto en la puntuación de ADAS- Cog, entre el inicio del estudio y la semana 48.
•	Cambio absoluto en la puntuación de ADCS-ADL, entre el inicio del estudio y la semana 48.
•	Tasa de respuesta clínica en la semana 24.
•	Criterio del médico basado en la impresión de cambio (CIBIC-plus), en la semana 24.
•	Cambio absoluto del estudio en MMSE desde el inicio y la semana 24.
•	Cambio absoluto del estudio en CDR desde el inicio y la semana 24.
•	Cambio absoluto del estudio en NPI desde el inicio y la semana 24.
E.5.2.1 Timepoint(s) of evaluation of this end point: week 24, week 48
E.5.2.1 Timepoint(s) of evaluation of this end point (es): Semana 24, semana 48
E.6 and E.7 Scope of the trial
E.6 Scope of the Trial
E.6.1 Diagnosis: No
E.6.2 Prophylaxis: No
E.6.3 Therapy: Yes
E.6.4 Safety: Yes
E.6.5 Efficacy: Yes
E.6.6 Pharmacokinetic: No
E.6.7 Pharmacodynamic: No
E.6.8 Bioequivalence: No
E.6.9 Dose response: No
E.6.10 Pharmacogenetic: No
E.6.11 Pharmacogenomic: No
E.6.12 Pharmacoeconomic: No
E.6.13 Others: No
E.7 Trial type and phase
E.7.1 Human pharmacology (Phase I): No
E.7.1.1 First administration to humans: No
E.7.1.2 Bioequivalence study: No
E.7.1.3 Other: No
E.7.1.3.1 Other trial type description:
E.7.2 Therapeutic exploratory (Phase II): No
E.7.3 Therapeutic confirmatory (Phase III): Yes
E.7.4 Therapeutic use (Phase IV): No
E.8 Design of the trial
E.8.1 Controlled: Yes
E.8.1.1 Randomised: Yes
E.8.1.2 Open: No
E.8.1.3 Single blind: No
E.8.1.4 Double blind: Yes
E.8.1.5 Parallel group: Yes
E.8.1.6 Cross over: No
E.8.1.7 Other: No
E.8.2 Comparator of controlled trial
E.8.2.1 Other medicinal product(s): Yes
E.8.2.2 Placebo: Yes
E.8.2.3 Other: Yes
E.8.2.3.1 Comparator description: cholinesterase inhibitors (donepezil, rivastigmine, or galantamine), and/or memantine
E.8.2.3.1 Comparator description (es): inhibidores de la colinesterasa (donepezilo, rivastigmina o galantamina), y/o memantina
E.8.2.4 Number of treatment arms in the trial: 2
E.8.3 The trial involves single site in the Member State concerned: Yes
E.8.4 The trial involves multiple sites in the Member State concerned: Yes
E.8.4.1 Number of sites anticipated in Member State concerned: 1
E.8.5 The trial involves multiple Member States: Yes
E.8.5.1 Number of sites anticipated in the EEA: 155
E.8.6 Trial involving sites outside the EEA
E.8.6.1 Trial being conducted both within and outside the EEA: Yes
E.8.6.2 Trial being conducted completely outside of the EEA: No
E.8.6.3 If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned:
Argentina
Canada
Colombia
Israel
Peru
South Africa
United States
Finland
France
Poland
Sweden
Bulgaria
Netherlands
Romania
Spain
Switzerland
Czechia
Germany
Greece
Italy
Belgium
Denmark
Ireland
Norway
Portugal
Russian Federation
Serbia
Slovakia
Slovenia
Ukraine
United Kingdom
E.8.7 Trial has a data monitoring committee: Yes
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: Last Visit Last Subject
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial (es): Última visita del último paciente
E.8.9 Initial estimate of the duration of the trial
E.8.9.1 In the Member State concerned years: 2
E.8.9.1 In the Member State concerned months:
E.8.9.1 In the Member State concerned days:
E.8.9.2 In all countries concerned by the trial years: 2

F. Population of Trial Subjects
F.1 Age Range
F.1.1 Trial has subjects under 18: No
F.1.1.1 In Utero: No
F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No
F.1.1.3 Newborns (0-27 days): No
F.1.1.4 Infants and toddlers (28 days-23 months): No
F.1.1.5 Children (2-11years): No
F.1.1.6 Adolescents (12-17 years): No
F.1.2 Adults (18-64 years): Yes
F.1.2.1 Number of subjects for this age range: 24
F.1.3 Elderly (>=65 years): Yes
F.1.3.1 Number of subjects for this age range: 576
F.2 Gender
F.2.1 Female: Yes
F.2.2 Male: Yes
F.3 Group of trial subjects
F.3.1 Healthy volunteers: No
F.3.2 Patients: Yes
F.3.3 Specific vulnerable populations: Yes
F.3.3.1 Women of childbearing potential not using contraception : No
F.3.3.2 Women of child-bearing potential using contraception: Yes
F.3.3.3 Pregnant women: No
F.3.3.4 Nursing women: No
F.3.3.5 Emergency situation: No
F.3.3.6 Subjects incapable of giving consent personally: No
F.3.3.7 Others: No
F.4 Planned number of subjects to be included
F.4.1 In the member state: 50
F.4.2 For a multinational trial
F.4.2.1 In the EEA: 550
F.4.2.2 In the whole clinical trial: 600
F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): None
F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition) (es): Ninguno

G. Investigator Networks to be involved in the Trial


N. Review by the Competent Authority or Ethics Committee in the country concerned
N. Competent Authority Decision: Authorised
N. Date of Competent Authority Decision: 2022-09-29
N. Ethics Committee Opinion of the trial application: Favourable
N. Ethics Committee Opinion: Reason(s) for unfavourable opinion:
N. Date of Ethics Committee Opinion: 2022-06-07

P. End of Trial
P. End of Trial Status: Ongoing

Summary
EudraCT Number: 2021-002179-21
Sponsor's Protocol Code Number: AB21004
National Competent Authority: Greece - EOF
Clinical Trial Type: EEA CTA
Trial Status: Ongoing
Date on which this record was first entered in the EudraCT database: 2022-06-01
Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-002179-21/GR/

A. Protocol Information
A.1 Member State Concerned: Greece - EOF
A.2 EudraCT number: 2021-002179-21
A.3 Full title of the trial: A multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 study to evaluate the safety and efficacy of masitinib as add-on therapy in patients with mild to moderate Alzheimer's disease, treated with standard of care : cholinesterase inhibitors, memantine
A.3 Full title of the trial (el): Μια πολυκεντρική, τυχαιοποιημένη, διπλά-τυφλή, ελεγχόμενη με εικονικό φάρμακο, σε δύο ομάδες μελέτη φάσης ΙΙΙ για την αξιολόγηση της ασφάλειας και της αποτελεσματικότητας της μασιτινίμπης σε ασθενείς με ήπια έως μέτρια νόσο Alzheimer, που σε θεραπεία με καθιερωμένη φροντίδα: αναστολείς χολινεστεράσης, μεμαντίνη
A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: A phase 3 study to evaluate the safety and efficacy of masitinib as add-on therapy in patients with mild to moderate Alzheimer's disease treated with standard of care: cholinesterase inhibitors, memantine
A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language (el): Μια μελέτη φάσης 3 για την αξιολόγηση της ασφάλειας και της αποτελεσματικότητας της μασιτινίμπης ως συμπληρωματικής θεραπείας σε ασθενείς με ήπια έως μέτρια νόσο του Αλτσχάιμερ που έλαβαν θεραπεία με τυπική φροντίδα: αναστολείς χολινεστεράσης, μεμαντίνη
A.3.2 Name or abbreviated title of the trial where available: Alzheimer's disease
A.3.2 Name or abbreviated title of the trial where available (el): Νόσος Αλτσχάιμερ
A.4.1 Sponsor's protocol code number: AB21004
A.7 Trial is part of a Paediatric Investigation Plan: No
A.8 EMA Decision number of Paediatric Investigation Plan:

B. Sponsor Information
Sponsor 1
B.1.1 Name of Sponsor: AB Science
B.1.3.4	Country: France
B.3.1 and B.3.2	Status of the sponsor: Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1 Name of organisation providing support: AB Science
B.4.2 Country: France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1 Name of organisation: AB Science
B.5.2 Functional name of contact point: Alain Moussy
B.5.3 Address
B.5.3.1 Street Address: 3 avenue George V
B.5.3.2 Town/ city: Paris
B.5.3.3 Post code: 75008
B.5.3.4 Country: France
B.5.4 Telephone number: 0033147202311
B.5.5 Fax number: 0033147202411
B.5.6 E-mail: regulatoryaffairs@ab-science.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3 IMP Role: Test
D.2 Status of the IMP to be used in the clinical trial
D.2.1 IMP to be used in the trial has a marketing authorisation: No
D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No
D.2.5.1 Orphan drug designation number:
D.3 Description of the IMP
D.3.1 Product name: Masitinib
D.3.2 Product code: AB1010
D.3.4 Pharmaceutical form: Film-coated tablet
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8 INN - Proposed INN: Masitinib mesilate
D.3.9.1 CAS number: 790299-79-5
D.3.9.2 Current sponsor code: AB1010
D.3.9.4 EV Substance Code: SUB32266
D.3.10 Strength
D.3.10.1 Concentration unit: mg milligram(s)
D.3.10.2 Concentration type: equal
D.3.10.3 Concentration number: 100
D.3.11 The IMP contains an
D.3.11.1 Active substance of chemical origin: Yes
D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No
D.3.11.3 Advanced Therapy IMP (ATIMP): No
D.3.11.3.1 Somatic cell therapy medicinal product: No
D.3.11.3.2 Gene therapy medical product: No
D.3.11.3.3 Tissue Engineered Product: No
D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No
D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No
D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No
D.3.11.5 Radiopharmaceutical medicinal product: No
D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No
D.3.11.7 Plasma derived medicinal product: No
D.3.11.8 Extractive medicinal product: No
D.3.11.9 Recombinant medicinal product: No
D.3.11.10 Medicinal product containing genetically modified organisms: No
D.3.11.11 Herbal medicinal product: No
D.3.11.12 Homeopathic medicinal product: No
D.3.11.13 Another type of medicinal product: No
D.IMP: 2
D.1.2 and D.1.3 IMP Role: Test
D.2 Status of the IMP to be used in the clinical trial
D.2.1 IMP to be used in the trial has a marketing authorisation: No
D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No
D.2.5.1 Orphan drug designation number:
D.3 Description of the IMP
D.3.1 Product name: Masitinib
D.3.2 Product code: AB1010
D.3.4 Pharmaceutical form: Film-coated tablet
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8 INN - Proposed INN: Masitinib mesilate
D.3.9.1 CAS number: 790299-79-5
D.3.9.4 EV Substance Code: SUB32266
D.3.10 Strength
D.3.10.1 Concentration unit: mg milligram(s)
D.3.10.2 Concentration type: equal
D.3.10.3 Concentration number: 200
D.3.11 The IMP contains an
D.3.11.1 Active substance of chemical origin: Yes
D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No
D.3.11.3 Advanced Therapy IMP (ATIMP): No
D.3.11.3.1 Somatic cell therapy medicinal product: No
D.3.11.3.2 Gene therapy medical product: No
D.3.11.3.3 Tissue Engineered Product: No
D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No
D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No
D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No
D.3.11.5 Radiopharmaceutical medicinal product: No
D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No
D.3.11.7 Plasma derived medicinal product: No
D.3.11.8 Extractive medicinal product: No
D.3.11.9 Recombinant medicinal product: No
D.3.11.10 Medicinal product containing genetically modified organisms: No
D.3.11.11 Herbal medicinal product: No
D.3.11.12 Homeopathic medicinal product: No
D.3.11.13 Another type of medicinal product: No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1 Is a Placebo used in this Trial? Yes
D.8.3 Pharmaceutical form of the placebo: Film-coated tablet
D.8.4 Route of administration of the placebo: Oral use
D.8 Placebo: 2
D.8.1 Is a Placebo used in this Trial? Yes
D.8.3 Pharmaceutical form of the placebo: Film-coated tablet
D.8.4 Route of administration of the placebo: Oral use

E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1 Medical condition(s) being investigated: Patients with mild-to-moderate Alzheimer’s disease
E.1.1 Medical condition(s) being investigated (el): Ασθενείς με ήπια έως μέτρια νόσο του Αλτσχάιμερ
E.1.1.1 Medical condition in easily understood language: Alzheimer's disease
E.1.1.1 Medical condition in easily understood language (el): νόσος Aλτσχάιμερ
E.1.1.2 Therapeutic area: Diseases [C] - Nervous System Diseases [C10]
MedDRA Classification
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 20.0
E.1.2 Level: HLT
E.1.2 Classification code: 10001897
E.1.2 Term: Alzheimer's disease (incl subtypes)
E.1.2 System Organ Class: 100000004852
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 20.0
E.1.2 Level: LLT
E.1.2 Classification code: 10001896
E.1.2 Term: Alzheimer's disease
E.1.2 System Organ Class: 100000004852
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 24.1
E.1.2 Level: LLT
E.1.2 Classification code: 10086384
E.1.2 Term: Early onset Alzheimer's disease
E.1.2 System Organ Class: 100000004852
E.1.3 Condition being studied is a rare disease: No
E.2 Objective of the trial
E.2.1 Main objective of the trial: The primary objective of the study is to evaluate whether masitinib treatment will show a significant improvement ADCS-ADL and ADAS-Cog versus placebo in the study patients.
E.2.1 Main objective of the trial (el): Ο κύριος στόχος της μελέτης είναι να αξιολογηθεί εάν η θεραπεία με μασιτινίμπη θα παρουσιάσει σημαντική βελτίωση στις βαθμολογίες ADCS-ADL και ADAS-Cog έναντι του εικονικού φαρμάκου στους ασθενείς της μελέτης.
E.2.2 Secondary objectives of the trial: The secondary objectives of the study are to evaluate the efficacy of masitinib compared with placebo on a range of clinical parameters of Alzheimer's disease.  The secondary objectives also include the assessment of safety and tolerability of masitinib as compared to placebo in terms of adverse events, vital signs, physical examination, ECG, and clinical laboratory tests.
E.2.2 Secondary objectives of the trial (el): Οι δευτερεύοντες στόχοι της μελέτης είναι η αξιολόγηση της αποτελεσματικότητας της μασιτινίμπης σε σύγκριση με το εικονικό φάρμακο σε μια σειρά κλινικών παραμέτρων της νόσου του Αλτσχάιμερ.  Οι δευτερεύοντες στόχοι περιλαμβάνουν επίσης την αξιολόγηση της ασφάλειας και της ανεκτικότητας της μασιτινίμπης σε σύγκριση με το εικονικό φάρμακο όσον αφορά τις ανεπιθύμητες ενέργειες, τα ζωτικά σημεία, τη φυσική εξέταση, το ΗΚΓ και τις κλινικές εργαστηριακές εξετάσεις.
E.2.3 Trial contains a sub-study: No
E.3 Principal inclusion criteria: 1.	Patients with clinical diagnosis of Alzheimer's disease based on cognitive impairment and daily functional dependency at screening visit
2.	Patients with ADCS-ADL score at screening visit and baseline visit <73
3.	Patients with MMSE ≥ 14 and ≤ 25 at screening visit and baseline visit
4.	Patients with Alzheimer’s Disease biomarker profile at screening visit:
- A positive amyloid PET scan
- Alternatively, a-beta 1-42 <1000pg/ml AND p-tau >19pg/ml OR a p-tau/a-beta ratio > 0.024, as measured by a central laboratory according to the Elecsys assay for CSF biomarkers
5.	Patients treated for a minimum of 6 months with a stable dose of cholinesterase inhibitors (donepezil, rivastigmine or galantamine) at baseline visit, and/or a stable dose of memantine for a minimum of 6 months at baseline visit, with no changes foreseen in therapy throughout the study
6.	If receiving a supplement for cognition (eg, gingko biloba, omega-3 polyunsaturated fatty acid, vitamin E, curcumin, souvenaid) must be taking a stable dose for at least 4 months prior to screening visit
7.	Patients with a caregiver who, at screening visit and baseline visit:
-	Agrees to accompany the participant to all study visits and able to supervise the participant's compliance with the study procedures and provide detailed information about the participant.
-	Either lives with the participant or sees the participant on average for ≥1 hours/day ≥3 days/week, or in the Investigator's opinion, the extent of contact is sufficient to provide meaningful assessment of changes in participant behaviour and function over time and provide information on safety and tolerability.
-	Is able to read, understand, and speak the designated language at the study centre.
-	Caregiver must be cognitively able to fulfil the requirements of the study.

Other inclusion criteria
8.	Male or non-pregnant female adult ≥50 years of age at time of enrolment at screening visit
9.	Patients with bodyweight >45 kg and BMI between 18 and 35 kg/m2 at screening visit or baseline visit
10.	Contraception, at screening and baseline visit:
Female patients of childbearing potential (entering the study after a menstrual period and who has a negative pregnancy test), who agree to use a highly effective method of contraception and an effective method of contraception by their male partner during the study and for 3 months and a half after the last treatment intake
Male patients with a female partner of childbearing potential who agree to use a highly effective method of contraception and an effective method of contraception by their female partner during the study and for 3 months and a half after the last treatment intake OR who agree to use an effective method of contraception and a highly effective method of contraception by their female partner during the study and for 3 months and a half after the last treatment intake.

Highly effective and effective methods of contraception are detailed in the Appendix 14.1 of the protocol.

11.	Subjects must be able and willing to comply, both at screening visit and at baseline visit, with study visits and procedures

12.	Subjects able to understand, sign, and date the written informed consent form at screening visit prior to any protocol-specific procedures

13.	Subjects able to understand, and willing to follow the safety procedures mentioned on the patient card in case of signs or symptoms of severe neutropenia or severe cutaneous toxicity, at screening and baseline visit. Patient card will be provided at baseline visit
E.3 Principal inclusion criteria (el): 1.Ασθενείς με κλινική διάγνωση της νόσου του Αλτσχάιμερ βάσει γνωστικής διαταραχής και καθημερινής λειτουργικής εξάρτησης κατά την επίσκεψη εξέτασης
2.Ασθενείς με βαθμολογία ADCS-ADL κατά την επίσκεψη εξέτασης και την αρχική επίσκεψη < 73
3.Ασθενείς με MMSE ≥ 14 και ≤ 25 κατά την επίσκεψη εξέτασης και την αρχική επίσκεψη
4.Ασθενείς με προφίλ βιοδεικτών της νόσου του Αλτσχάιμερ κατά την επίσκεψη εξέτασης:
- Θετική σε αμυλοειδές τομογραφία εκπομπής ποζιτρονίων (PET)
- Εναλλακτικά, a-beta 1-42 <1000pg/ml ΚΑΙ p-tau >19pg/ml Ή αναλογία p-tau/a-beta > 0,024, όπως μετράται από κεντρικό εργαστήριο σύμφωνα με τη δοκιμασία Elecsys για βιοδείκτες εγκεφαλονωτιαίου υγρού (ΕΝΥ)
5.Ασθενείς που έχουν υποβληθεί σε θεραπεία για τουλάχιστον 6 μήνες με σταθερή δόση αναστολέων χολινεστεράσης (δονεπεζίλη, ριβαστιγμίνη ή γαλανταμίνη) κατά την αρχική επίσκεψη ή/και σταθερή δόση μεμαντίνης για τουλάχιστον 6 μήνες κατά την αρχική επίσκεψη, χωρίς να προβλέπονται αλλαγές στη θεραπεία καθ’ όλη τη διάρκεια της μελέτης
6.Σε περίπτωση λήψης συμπληρώματος για την υποστήριξη των γνωστικών λειτουργιών (π.χ. gingko biloba, ωμέγα-3 πολυακόρεστα λιπαρά οξέα, βιταμίνη Ε, κουρκουμίνη, souvenaid), θα πρέπει να λαμβάνεται σταθερή δόση για τουλάχιστον 4 μήνες πριν την επίσκεψη εξέτασης
7.Ασθενείς με φροντιστή που, κατά την επίσκεψη εξέτασης και την αρχική επίσκεψη:
- Συμφωνεί να συνοδεύει τον ασθενή σε όλες επισκέψεις της μελέτης και είναι ικανός να επιβλέπει τη συμμόρφωση του συμμετέχοντος με τις διαδικασίες της μελέτης και να παρέχει λεπτομερείς πληροφορίες σχετικά με τον συμμετέχοντα.
- Είτε ζει με τον συμμετέχοντα είτε βλέπει τον συμμετέχοντα κατά μέσο όρο για ≥1 ώρα/ημέρα ≥3 ημέρες/εβδομάδα ή, κατά τη γνώμη του Ερευνητή, ο βαθμός επαφής είναι αρκετός για την παροχή ουσιαστικής αξιολόγησης των αλλαγών στη συμπεριφορά και τη λειτουργία του συμμετέχοντος με την πάροδο του χρόνου και για την παροχή πληροφοριών ασφάλειας και ανεκτικότητας.
- Είναι σε θέση να διαβάσει, κατανοήσει και μιλήσει τη γλώσσα που έχει καθοριστεί στο κέντρο διεξαγωγής της μελέτης.
- Ο φροντιστής πρέπει να είναι σε θέση βάσει γνωστικών ικανοτήτων να ανταποκρίνεται στις απαιτήσεις της μελέτης.

Άλλα κριτήρια ένταξης
8. Ενήλικος άρρεν ή ενήλικη μη εγκυμονούσα ≥50 ετών κατά τον χρόνο εγγραφής κατά την επίσκεψη εξέτασης
9. Ασθενείς με σωματικό βάρος >45 kg και ΔΜΣ μεταξύ 18 και 35 kg/m2 κατά την επίσκεψη εξέτασης ή την αρχική επίσκεψη
10. Αντισύλληψη κατά την επίσκεψη εξέτασης και την αρχική επίσκεψη:
Γυναίκες σε αναπαραγωγική ηλικία (που εισέρχονται στη μελέτη μετά από έμμηνο ρύση και έχουν αρνητικό τεστ εγκυμοσύνης), οι οποίες συμφωνούν να χρησιμοποιήσουν εξαιρετικά αποτελεσματική μέθοδο αντισύλληψης και αποτελεσματική μέθοδο αντισύλληψης από την πλευρά του συντρόφου τους κατά τη διάρκεια της μελέτης και για 3μιση μήνες από την τελευταία λήψη θεραπείας
Άρρενες ασθενείς με γυναίκα σύντροφο σε αναπαραγωγική ηλικία που συμφωνούν να χρησιμοποιήσουν μια εξαιρετικά αποτελεσματική μέθοδο αντισύλληψης και μια αποτελεσματική μέθοδο αντισύλληψης από την πλευρά της γυναίκας συντρόφου κατά τη διάρκεια της μελέτης και για 3μιση μήνες από την τελευταία λήψη θεραπείας Ή που συμφωνούν να χρησιμοποιήσουν αποτελεσματική μέθοδο αντισύλληψης και μια εξαιρετικά αποτελεσματική μέθοδο αντισύλληψης από την πλευρά της γυναίκας συντρόφου κατά τη διάρκεια της μελέτης και για 3μιση μήνες από την τελευταία λήψη θεραπείας.

Οι εξαιρετικά αποτελεσματικές και αποτελεσματικές μέθοδοι αντισύλληψης περιγράφονται λεπτομερώς στο Παράρτημα 1.1 του πρωτοκόλλου.

11.Τα υποκείμενα πρέπει να είναι σε θέση και πρόθυμα να συμμορφωθούν με τις επισκέψεις και τις διαδικασίες της μελέτης τόσο κατά την επίσκεψη εξέτασης όσο και κατά την αρχική επίσκεψη

12.Υποκείμενα που μπορούν να κατανοήσουν, να υπογράψουν και να αναγράψουν την ημερομηνία υπογραφής στο έντυπο συναίνεσης κατά την επίσκεψη εξέτασης πριν από οποιεσδήποτε διαδικασίες που αφορούν το πρωτόκολλο

13.Υποκείμενα που μπορούν να κατανοήσουν και είναι πρόθυμα να ακολουθήσουν τις διαδικασίες ασφαλείας που αναφέρονται στην κάρτα ασθενούς σε περίπτωση σημείων ή συμπτωμάτων σοβαρής ουδετεροπενίας ή σοβαρής δερματικής τοξικότητας κατά την επίσκεψη εξέτασης και την αρχική επίσκεψη. Η κάρτα ασθενούς θα παρέχεται κατά την αρχική επίσκεψη
E.4 Principal exclusion criteria: 1.	Patients with any other cause of dementia shown by MRI findings and neurological examination in the last 12 months prior to screening visit
2.	Systemic conditions known to cause dementia, e.g., hypothyroidism, untreated vitamin B12 or folic acid deficiency, niacin deficiency, neurosyphilis, HIV infection at screening visit
3.	Patients with substance-induced dementia at screening visit
4.	Patients with Alzheimer’s disease with delirium at screening visit
5.	Patients with severe forms of delusions (e.g, NPI delusion score of 4 or more) at screening visit
6.	Patients with evidence of psychosis and/or use of antipsychotic drugs at screening, or history of significant psychiatric disorder at screening visit

Other exclusion criteria
7.	Patients with hypersensitivity to masitinib or its excipients at screening
8.	Patients with history (or family history) of drug-induced severe skin toxicities or reactions at screening or patients taking concomitant treatment or therapies associated with severe drug-induced skin toxicity

9.	Patients with history of severe bone marrow disorders such as agranulocytosis or aplasia, or with abnormal laboratory results from local laboratory assessments at screening and baseline defined as:
-	Neutropenia with ANC <1.5 × 109/L
-	Anemia with Hgb <10 g/dl
-	Thrombocytopenia with platelet counts <75 × 109/L

10.	Patients with history of severe hepatic disorders, such as viral hepatitis or steatohepatitis, and alcoholic steatosis, or with abnormal laboratory results defined as:
-	Hepatic transaminase levels >2 ULN at baseline, or
-	Total bilirubin level >1.5 ULN at baseline, or
-	Both hepatic transaminase levels and total bilirubin level outside of the normal ranges at screening and baseline, or
-	Albuminemia <1 × LLN at screening and baseline, or
-	Patients with concomitant medication known to be associated with severe hepatotoxicity

11.	Patients with pre-existing severe renal impairment, or with abnormal laboratory results at screening:
-	Creatinine clearance <60 mL/min (Cockcroft and Gault formula) or
-	Proteinuria >30 mg/dL (1+) on dipstick; in case of the proteinuria ≥1+ on the dipstick, 24 hours proteinuria must be >1.5 g/24 hours

12.	Patients with current or history of severe cardiovascular disease, assessed at screening:
-	Myocardial infarction
-	Unstable angina pectoris
-	Coronary revascularization procedure
-	Congestive heart failure of NYHA Class III or IV
-	Stroke, including a transient ischemic attack
-	Second degree or third-degree atrioventricular block not successfully treated with a pacemaker
-	Bi-fascicular block
-	QTc Fridericia interval > 450 milliseconds for males and > 470 milliseconds for females
-	Drug induced heart failure or ischemic heart disease
-	Radiotherapy induced cardiomyopathy
-	Family history of unexpected death of cardiovascular origin
-	Edema of cardiac origin and left ventricular ejaculation fraction ≤50%

13.	Patients, with two or more of the risk factors listed below assessed by a cardiologist at screening as Very High Risk (calculated SCORE* ≥10%.) according to the Systematic Coronary Risk Estimation (SCORE*):
-	Hypertension (uncontrolled)
-	Diabetes
-	Kidney disease
-	Current smoking (≥ 10 Pack-year: equivalent to 1 pack of 20 cigarettes for 10 years with the formula N (number of packs of 20 cigarettes smoked daily) × T (number years smoking)) Patients who stopped smoking 6 months prior to the evaluation, are not concerned.
-	Hypercholesterolemia,
-	COPD
* This assessment is done according to the Systematic Coronary Risk Estimation (SCORE) using the country specific free full version of HeartScore®, the interactive tool for predicting and managing the risk of heart attack and stroke in Europe, available at https://www.heartscore.org/en_GB/access
If the country specific version is not available, EU one should be used.

19.	Pregnant, or nursing female patients at screening or baseline

20.	Patients with a diagnosis of cancer or evidence of continued disease within five years before screening
22.	Patient who has been exposed to an investigational treatment within 3 months (9 months for immunotherapies) or five half-lives of an investigational product, whichever is longer, before the screening visit
23.	Subjects who have received a live vaccine within 30 days prior to first IMP administration
E.4 Principal exclusion criteria (el): 1.Ασθενείς με οποιαδήποτε άλλη αιτία άνοιας που αποδεικνύεται από ευρήματα μαγνητικής τομογραφίας&νευρολογικής εξέτασης τους τελευταίους 12 μήνες προ επίσκεψης εξέτασης
2.Συστημικές παθήσεις που είναι γνωστό ότι προκαλούν άνοια,π.χ. υποθυρεοειδισμός,ανεπάρκεια βιταμίνης Β12 ή φυλλικού οξέος που δεν έχει αντιμετωπιστεί,ανεπάρκεια νιασίνης,νευρική σύφιλη,λοίμωξη HIV κατά την επίσκεψη εξέτασης
3. Ασθενείς με άνοια που προκαλείται από ουσίες κατά την επίσκεψη εξέτασης
4.Ασθενείς με νόσο του Αλτσχάιμερ με παραλήρημα κατά την επίσκεψη εξέτασης
5.Ασθενείς με σοβαρές μορφές παραληρητικών ιδεών(π.χ.βαθμολογία παραληρητικών ιδεώνNPI4 ή >)κατά την επίσκεψη εξέτασης
6.Ασθενείς με τεκμηρίωση ψύχωσης ή/και χρήση αντιψυχωσικών φαρμάκων κατά την εξέταση ή ιστορικό σημαντικής ψυχιατρικής διαταραχής κατά την επίσκεψη εξέτασης

Άλλα κριτήρια αποκλεισμού
7.Ασθενείς με υπερευαισθησία στη μασιτινίμπη ή στα έκδοχά κατά την εξέταση
8.Ασθενείς με ιστορικό(ή οικογενειακό ιστορικό)σοβαρών τοξικοτήτων ή αντιδράσεων στο δέρμα που προκαλούνται από φάρμακα κατά την εξέταση ή ασθενείς που λαμβάνουν συνοδό αγωγή ή θεραπείες που σχετίζονται με σοβαρή τοξικότητα στο δέρμα που προκαλείται από φάρμακα
9.Ασθενείς με ιστορικό σοβαρών διαταραχών του μυελού των οστών, όπως ακοκκιοκυττάρωση ή απλασία,ή με μη φυσιολογικά εργαστηριακά αποτελέσματα από τοπικές εργαστηριακές αξιολογήσεις κατά τον προσυμπτωματικό έλεγχο και την αρχική επίσκεψη που ορίζονται ως εξής:
-Ουδετεροπενία με απόλυτο αριθμό ουδετεροφίλων<1,5 ×109/L
- Αναιμία με Hgb<10g/dl
-Θρομβοπενία με αριθμό αιμοπεταλίων<75×109/L
10.Ασθενείς με ιστορικό σοβαρών ηπατικών διαταραχών,όπως ιογενής ηπατίτιδα ή στεατοηπατίτιδα και αλκοολική στεάτωση,ή με μη φυσιολογικά εργαστηριακά αποτελέσματα που ορίζονται ως: - Επίπεδα ηπατικών τρανσαμινασών > 2 ULN κατά την αρχική επίσκεψη ή
- Ολικό επίπεδο χολερυθρίνης > 1,5 ULN κατά την αρχική επίσκεψη ή
- Τόσο τα επίπεδα ηπατικών τρανσαμινασών όσο και το ολικό επίπεδο χολερυθρίνης εκτός των φυσιολογικών ορίων κατά την εξέταση και την αρχική επίσκεψη ή
-Αλβουμιναιμία<1×LLN κατά την εξέταση και την αρχική επίσκεψη ή
-Ασθενείς με συνοδό αγωγή που είναι γνωστό ότι σχετίζεται με σοβαρή ηπατοτοξικότητα
11.Ασθενείς με προϋπάρχουσα σοβαρή νεφρική δυσλειτουργία ή με μη φυσιολογικά εργαστηριακά αποτελέσματα κατά την εξέταση:
- Κάθαρση κρεατινίνης <60 mL/min (τύπος Cockcroft and Gault) ή
-Πρωτεϊνουρία>30mg/dL (1+)σε δείκτη στάθμης. IΣε περίπτωση πρωτεϊνουρίας ≥1+ στον δείκτη στάθμης, η 24ωρη πρωτεϊνουρία πρέπει να είναι>1,5g/24h
12.Ασθενείς με τρέχουσα ή ιστορικό σοβαρής καρδιαγγειακής νόσου, αξιολόγηση κατά την εξέταση: - Έμφραγμα μυοκαρδίου
- Ασταθής στηθάγχη
- Διαδικασία επαναγγείωσης του στεφανιαίου
- Συμφορητική καρδιακή ανεπάρκεια της κατηγορίας III ή IV τηςNYHA
-Εγκεφαλικό επεισόδιο, συμπεριλαμβανομένου παροδικού ισχαιμικού επεισοδίου
-Κολποκοιλιακός αποκλεισμός δευτέρου ή τρίτου βαθμού που δεν αντιμετωπίζεται επιτυχώς με βηματοδότη
- Διδεσμιδικός αποκλεισμός
- Διάστημα QTc Fridericia > 450 χιλιοστά του δευτερολέπτου για τους άνδρες και > 470 χιλιοστά του δευτερολέπτου για τις γυναίκες
- Καρδιακή ανεπάρκεια ή ισχαιμική καρδιακή πάθηση που προκαλείται από φάρμακα - Καρδιομυοπάθεια που προκαλείται από ακτινοθεραπεία
- Οικογενειακό ιστορικό απροσδόκητου θανάτου καρδιαγγειακής προέλευσης
- Οίδημα καρδιακής προέλευσης και κλάσμα εξώθησης αριστερής κοιλίας ≤50%
13.Ασθενείς με δύο ή περισσότερους από τους παράγοντες κινδύνου που αναφέρονται παρακάτω, που αξιολογούνται από καρδιολόγο κατά την εξέταση ως Πολύ Υψηλού Κινδύνου(υπολογιζόμενη συστηματική εκτίμηση του στεφανιαίου κινδύνου* ≥10%.)σύμφωνα με τη Συστηματική εκτίμηση του στεφανιαίου κινδύνου (SCORE):
- Υπέρταση(μη ελεγχόμενη)
- Διαβήτης
- Νεφρική νόσος
- Τρέχον κάπνισμα(≥10 Πακέτα-έτος: ισοδύναμο με1πακέτο20τσιγάρων για10 χρόνια με τον τύποΝ (αριθμός πακέτων20τσιγάρων που καπνίζονται καθημερινά)×Τ(αριθμός ετών καπνίσματος)).Δεν αφορά ασθενείς που σταμάτησαν το κάπνισμα 6 μήνες πριν από την αξιολόγηση.
- Υπερχοληστερολαιμία
- ΧΑΠ
*Αυτή η αξιολόγηση πραγματοποιείται σύμφωνα με τη Συστηματική εκτίμηση του στεφανιαίου κινδύνου (SCORE) χρησιμοποιώντας τη δωρεάν,πλήρη έκδοση του HeartScore® για τη συγκεκριμένη χώρα,το διαδραστικό εργαλείο πρόβλεψης&διαχείρισης του κινδύνου καρδιακής προσβολής&εγκεφαλικού στην Ευρώπη,διαθέσιμο στη διεύθυνση https://www.heartscore.org/en_GB/access
Εάν η έκδοση για τη συγκεκριμένη χώρα δεν είναι διαθέσιμη, θα πρέπει να χρησιμοποιηθεί η έκδοση για την ΕΕ.
19.Έγκυες ή θηλάζουσες γυναίκες ασθενείς κατά την εξέταση ή την αρχική επίσκεψη
20.Ασθενείς με διάγνωση καρκίνου ή ενδείξεις συνέχισης της νόσου εντός πέντε ετών πριν από την εξέταση
22.Ασθενής που έχει εκτεθεί σε ερευνητική θεραπεία εντός3μηνών(9μήνες για ανοσοθεραπείες)ήπέντε χρονικά διαστήματα ημίσειας ζωής ενός ερευνητικού προϊόντος, όποιο είναι μεγαλύτερο, πριν από την επίσκεψη εξέτασης
23. Υποκείμενα που έχουν κάνει ζων εμβόλιο εντός30ημερών πριν την πρώτη χορήγησηΕΦΠ
E.5 End points
E.5.1 Primary end point(s): The study has two following primary endpoints:
•	Absolute change from baseline in ADCS-ADL score at week 24
and
•	Absolute change from baseline in ADAS-Cog score at week 24
E.5.1 Primary end point(s) (el): Η μελέτη έχει τα δύο παρακάτω κύρια καταληκτικά σημεία:
• Απόλυτη αλλαγή από την αρχική επίσκεψη στη βαθμολογία ADCS-ADL κατά την εβδομάδα 24
και
•Απόλυτη αλλαγή από την αρχική επίσκεψη στη βαθμολογία ADAS-Cog κατά την εβδομάδα 24


E.5.1.1 Timepoint(s) of evaluation of this end point: week 24
E.5.1.1 Timepoint(s) of evaluation of this end point (el): εβδομάδα 24
E.5.2 Secondary end point(s): The key secondary endpoint consists of:
•	Time to severe dementia (MMSE<10)

The secondary endpoints of the study are:
•	Absolute change from baseline in ADAS-Cog score at week 48
•	Absolute change from baseline in ADCS-ADL score at week 48
•	Clinical Responder rate at Week 24.
•	Clinician’s Interview Based Impression of Change-plus (CIBIC-plus) at Week 24
•	Mini-Mental State Examination (MMSE) at Week 24
•	Clinical Dementia Rating (CDR) at Week 24
•	Neuropsychiatric Inventory (NPI) at Week 24

E.5.2 Secondary end point(s) (el): Τα βασικά δευτερεύοντα καταληκτικά σημεία αποτελούνται από τα εξής:
• Χρόνος έως τη σοβαρή άνοια (MMSE<10)

Τα δευτερεύοντα καταληκτικά σημεία της μελέτης είναι:
• Απόλυτη αλλαγή από την αρχική επίσκεψη στη βαθμολογία ADAS-Cog κατά την εβδομάδα 48
• Απόλυτη αλλαγή από την αρχική επίσκεψη στη βαθμολογία ADCS-ADL κατά την εβδομάδα 48
• Ρυθμός κλινικού ανταποκριτή κατά την εβδομάδα 24
• Εντύπωση κλινικού ιατρού βασιζόμενη σε συνέντευξη σε σχέση με την αλλαγή-plus (CIBIC-plus) κατά την εβδομάδα 24
• Απόλυτη αλλαγή από την αρχική επίσκεψη σε Εξέταση ελάχιστης νοητικής κατάστασης (MMSE) κατά την εβδομάδα 24
• Απόλυτη αλλαγή από την αρχική επίσκεψη στην Κλινική αξιολόγηση άνοιας (CDR) κατά την εβδομάδα 24
• Απόλυτη αλλαγή από την αρχική επίσκεψη στο Νευροψυχιατρικό Ερωτηματολόγιο (NPI) κατά την εβδομάδα 24
E.5.2.1 Timepoint(s) of evaluation of this end point: week 24, week 48
E.5.2.1 Timepoint(s) of evaluation of this end point (el): εβδομάδα 24, εβδομάδα 48
E.6 and E.7 Scope of the trial
E.6 Scope of the Trial
E.6.1 Diagnosis: No
E.6.2 Prophylaxis: No
E.6.3 Therapy: Yes
E.6.4 Safety: Yes
E.6.5 Efficacy: Yes
E.6.6 Pharmacokinetic: No
E.6.7 Pharmacodynamic: No
E.6.8 Bioequivalence: No
E.6.9 Dose response: No
E.6.10 Pharmacogenetic: No
E.6.11 Pharmacogenomic: No
E.6.12 Pharmacoeconomic: No
E.6.13 Others: No
E.7 Trial type and phase
E.7.1 Human pharmacology (Phase I): No
E.7.1.1 First administration to humans: No
E.7.1.2 Bioequivalence study: No
E.7.1.3 Other: No
E.7.1.3.1 Other trial type description:
E.7.2 Therapeutic exploratory (Phase II): No
E.7.3 Therapeutic confirmatory (Phase III): Yes
E.7.4 Therapeutic use (Phase IV): No
E.8 Design of the trial
E.8.1 Controlled: Yes
E.8.1.1 Randomised: Yes
E.8.1.2 Open: No
E.8.1.3 Single blind: No
E.8.1.4 Double blind: Yes
E.8.1.5 Parallel group: Yes
E.8.1.6 Cross over: No
E.8.1.7 Other: No
E.8.2 Comparator of controlled trial
E.8.2.1 Other medicinal product(s): Yes
E.8.2.2 Placebo: Yes
E.8.2.3 Other: Yes
E.8.2.3.1 Comparator description: cholinesterase inhibitors (donepezil, rivastigmine, or galantamine), memantine
E.8.2.3.1 Comparator description (el): αναστολείς χολινεστεράσης (δονεπεζίλη, ριβαστιγμίνη, ή γαλανταμίνη), μεμαντίνη
E.8.2.4 Number of treatment arms in the trial: 2
E.8.3 The trial involves single site in the Member State concerned: No
E.8.4 The trial involves multiple sites in the Member State concerned: Yes
E.8.4.1 Number of sites anticipated in Member State concerned: 7
E.8.5 The trial involves multiple Member States: Yes
E.8.5.1 Number of sites anticipated in the EEA: 145
E.8.6 Trial involving sites outside the EEA
E.8.6.1 Trial being conducted both within and outside the EEA: Yes
E.8.6.2 Trial being conducted completely outside of the EEA: No
E.8.6.3 If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned:
Argentina
Canada
Colombia
Israel
Peru
South Africa
United States
Finland
France
Poland
Sweden
Bulgaria
Netherlands
Romania
Spain
Switzerland
Czechia
Germany
Greece
Italy
Belgium
Denmark
Ireland
Norway
Portugal
Russian Federation
Slovakia
Slovenia
Ukraine
United Kingdom
Serbia
E.8.7 Trial has a data monitoring committee: Yes
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: Last Visit Last Subject
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial (el): Τελευταία Επίσκεψη Τελευταίος Ασθενής (LVLS)
E.8.9 Initial estimate of the duration of the trial
E.8.9.1 In the Member State concerned years: 3
E.8.9.1 In the Member State concerned months:
E.8.9.1 In the Member State concerned days:
E.8.9.2 In all countries concerned by the trial years: 3

F. Population of Trial Subjects
F.1 Age Range
F.1.1 Trial has subjects under 18: No
F.1.1.1 In Utero: No
F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No
F.1.1.3 Newborns (0-27 days): No
F.1.1.4 Infants and toddlers (28 days-23 months): No
F.1.1.5 Children (2-11years): No
F.1.1.6 Adolescents (12-17 years): No
F.1.2 Adults (18-64 years): Yes
F.1.2.1 Number of subjects for this age range: 24
F.1.3 Elderly (>=65 years): Yes
F.1.3.1 Number of subjects for this age range: 576
F.2 Gender
F.2.1 Female: Yes
F.2.2 Male: Yes
F.3 Group of trial subjects
F.3.1 Healthy volunteers: No
F.3.2 Patients: Yes
F.3.3 Specific vulnerable populations: Yes
F.3.3.1 Women of childbearing potential not using contraception : No
F.3.3.2 Women of child-bearing potential using contraception: Yes
F.3.3.3 Pregnant women: No
F.3.3.4 Nursing women: No
F.3.3.5 Emergency situation: No
F.3.3.6 Subjects incapable of giving consent personally: No
F.3.3.7 Others: No
F.4 Planned number of subjects to be included
F.4.1 In the member state: 50
F.4.2 For a multinational trial
F.4.2.1 In the EEA: 480
F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): None

G. Investigator Networks to be involved in the Trial


N. Review by the Competent Authority or Ethics Committee in the country concerned
N. Competent Authority Decision: Authorised
N. Date of Competent Authority Decision: 2022-09-30
N. Ethics Committee Opinion of the trial application: Favourable
N. Ethics Committee Opinion: Reason(s) for unfavourable opinion:
N. Date of Ethics Committee Opinion: 2022-10-21

P. End of Trial
P. End of Trial Status: Ongoing

Summary
EudraCT Number: 2021-002179-21
Sponsor's Protocol Code Number: AB21004
National Competent Authority: Poland - Office for Medicinal Products
Clinical Trial Type: EEA CTA
Trial Status: Ongoing
Date on which this record was first entered in the EudraCT database: 2022-06-13
Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-002179-21/PL/

A. Protocol Information
A.1 Member State Concerned: Poland - Office for Medicinal Products
A.2 EudraCT number: 2021-002179-21
A.3 Full title of the trial: A multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 study to evaluate the safety and efficacy of masitinib as add-on therapy in patients with mild to moderate Alzheimer's disease, treated with standard of care : cholinesterase inhibitors, memantine
A.3 Full title of the trial (pl): Wieloośrodkowe, randomizowane, prowadzone metodą podwójnie ślepej próby, kontrolowane z użyciem placebo, prowadzone w grupach równoległych badanie fazy III, oceniające bezpieczeństwo i skuteczność masytinibu jako leczenia dodatkowego u pacjentów z chorobą Alzheimera o nasileniu łagodnym do umiarkowanego, leczonych zgodnie ze standardami postępowania: inhibitorami cholinesterazy, memantyną
A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: A multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 study to evaluate the safety and efficacy of masitinib as add-on therapy in patients with mild to moderate Alzheimer's disease, treated with standard of care : cholinesterase inhibitors, memantine
A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language (pl): Wieloośrodkowe, randomizowane, prowadzone metodą podwójnie ślepej próby, kontrolowane z użyciem placebo, prowadzone w grupach równoległych badanie fazy III, oceniające bezpieczeństwo i skuteczność masytinibu jako leczenia dodatkowego u pacjentów z chorobą Alzheimera o nasileniu łagodnym do umiarkowanego, leczonych zgodnie ze standardami postępowania: inhibitorami cholinesterazy, memantyną
A.4.1 Sponsor's protocol code number: AB21004
A.7 Trial is part of a Paediatric Investigation Plan: No
A.8 EMA Decision number of Paediatric Investigation Plan:

B. Sponsor Information
Sponsor 1
B.1.1 Name of Sponsor: AB Science
B.1.3.4	Country: France
B.3.1 and B.3.2	Status of the sponsor: Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1 Name of organisation providing support: AB Science
B.4.2 Country: France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1 Name of organisation: AB Science
B.5.2 Functional name of contact point: Alain Moussy
B.5.3 Address
B.5.3.1 Street Address: 3 avenue George V
B.5.3.2 Town/ city: Paris
B.5.3.3 Post code: 75008
B.5.3.4 Country: France
B.5.4 Telephone number: 0033147202311
B.5.5 Fax number: 0033147202411
B.5.6 E-mail: regulatoryaffairs@ab-science.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3 IMP Role: Test
D.2 Status of the IMP to be used in the clinical trial
D.2.1 IMP to be used in the trial has a marketing authorisation: No
D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No
D.2.5.1 Orphan drug designation number:
D.3 Description of the IMP
D.3.1 Product name: Masitinib
D.3.2 Product code: AB1010
D.3.4 Pharmaceutical form: Film-coated tablet
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8 INN - Proposed INN: Masitinib mesilate
D.3.9.1 CAS number: 790299-79-5
D.3.9.2 Current sponsor code: AB1010
D.3.9.4 EV Substance Code: SUB32266
D.3.10 Strength
D.3.10.1 Concentration unit: mg milligram(s)
D.3.10.2 Concentration type: equal
D.3.10.3 Concentration number: 100
D.3.11 The IMP contains an
D.3.11.1 Active substance of chemical origin: Yes
D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No
D.3.11.3 Advanced Therapy IMP (ATIMP): No
D.3.11.3.1 Somatic cell therapy medicinal product: No
D.3.11.3.2 Gene therapy medical product: No
D.3.11.3.3 Tissue Engineered Product: No
D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No
D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No
D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No
D.3.11.5 Radiopharmaceutical medicinal product: No
D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No
D.3.11.7 Plasma derived medicinal product: No
D.3.11.8 Extractive medicinal product: No
D.3.11.9 Recombinant medicinal product: No
D.3.11.10 Medicinal product containing genetically modified organisms: No
D.3.11.11 Herbal medicinal product: No
D.3.11.12 Homeopathic medicinal product: No
D.3.11.13 Another type of medicinal product: No
D.IMP: 2
D.1.2 and D.1.3 IMP Role: Test
D.2 Status of the IMP to be used in the clinical trial
D.2.1 IMP to be used in the trial has a marketing authorisation: No
D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No
D.2.5.1 Orphan drug designation number:
D.3 Description of the IMP
D.3.1 Product name: Masitinib
D.3.2 Product code: AB1010
D.3.4 Pharmaceutical form: Film-coated tablet
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8 INN - Proposed INN: Masitinib mesilate
D.3.9.1 CAS number: 790299-79-5
D.3.9.4 EV Substance Code: SUB32266
D.3.10 Strength
D.3.10.1 Concentration unit: mg milligram(s)
D.3.10.2 Concentration type: equal
D.3.10.3 Concentration number: 200
D.3.11 The IMP contains an
D.3.11.1 Active substance of chemical origin: Yes
D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No
D.3.11.3 Advanced Therapy IMP (ATIMP): No
D.3.11.3.1 Somatic cell therapy medicinal product: No
D.3.11.3.2 Gene therapy medical product: No
D.3.11.3.3 Tissue Engineered Product: No
D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No
D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No
D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No
D.3.11.5 Radiopharmaceutical medicinal product: No
D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No
D.3.11.7 Plasma derived medicinal product: No
D.3.11.8 Extractive medicinal product: No
D.3.11.9 Recombinant medicinal product: No
D.3.11.10 Medicinal product containing genetically modified organisms: No
D.3.11.11 Herbal medicinal product: No
D.3.11.12 Homeopathic medicinal product: No
D.3.11.13 Another type of medicinal product: No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1 Is a Placebo used in this Trial? Yes
D.8.3 Pharmaceutical form of the placebo: Film-coated tablet
D.8.4 Route of administration of the placebo: Oral use
D.8 Placebo: 2
D.8.1 Is a Placebo used in this Trial? Yes
D.8.3 Pharmaceutical form of the placebo: Film-coated tablet
D.8.4 Route of administration of the placebo: Oral use

E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1 Medical condition(s) being investigated:
E.1.1.1 Medical condition in easily understood language: Alzheimer's disease
E.1.1.2 Therapeutic area: Diseases [C] - Nervous System Diseases [C10]
MedDRA Classification
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 20.0
E.1.2 Level: HLT
E.1.2 Classification code: 10001897
E.1.2 Term: Alzheimer's disease (incl subtypes)
E.1.2 System Organ Class: 100000004852
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 20.0
E.1.2 Level: LLT
E.1.2 Classification code: 10001896
E.1.2 Term: Alzheimer's disease
E.1.2 System Organ Class: 100000004852
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 24.1
E.1.2 Level: LLT
E.1.2 Classification code: 10086384
E.1.2 Term: Early onset Alzheimer's disease
E.1.2 System Organ Class: 100000004852
E.1.3 Condition being studied is a rare disease: No
E.2 Objective of the trial
E.2.1 Main objective of the trial: The primary objective of the study is to evaluate whether masitinib treatment will show a significant improvement ADCS-ADL and ADAS-Cog versus placebo in the study patients.
E.2.2 Secondary objectives of the trial: The secondary objectives of the study are to evaluate the efficacy of masitinib compared with placebo on a range of clinical parameters of Alzheimer's disease.  The secondary objectives also include the assessment of safety and tolerability of masitinib as compared to placebo in terms of adverse events, vital signs, physical examination, ECG, and clinical laboratory tests.
E.2.3 Trial contains a sub-study: No
E.3 Principal inclusion criteria: 1.	Patient with clinical diagnosis of Alzheimer's disease based on cognitive impairment and daily functional dependency at screening visit
2.	Patient with ADCS-ADL score at screening visit and baseline visit <73

3.	Patient with MMSE ≥ 14 and ≤ 25 at screening visit and baseline visit

4.	Patient with Alzheimer’s Disease biomarker profile at screening visit:
- A positive amyloid PET scan
- Alternatively, a-beta 1-42 <1000pg/ml AND p-tau >19pg/ml OR a p-tau/a-beta ratio > 0.024, as measured by a central laboratory according to the Elecsys assay for CSF biomarkers

5.	Patients treated for a minimum of 6 months with a stable dose of cholinesterase inhibitors (donepezil, rivastigmine or galantamine) at baseline visit, and/or a stable dose of memantine for a minimum of 6 months at baseline visit, with no changes foreseen in therapy throughout the study

6.	If receiving a supplement for cognition (eg, gingko biloba, omega-3 polyunsaturated fatty acid, vitamin E, curcumin, souvenaid) must be taking a stable dose for at least 4 months prior to screening visit

7.	Patients with a caregiver who, at screening visit and baseline visit:
-	Agrees to accompany the participant to all study visits and able to supervise the participant's compliance with the study procedures and provide detailed information about the participant.
-	Either lives with the participant or sees the participant on average for ≥1 hours/day ≥3 days/week, or in the Investigator's opinion, the extent of contact is sufficient to provide meaningful assessment of changes in participant behaviour and function over time and provide information on safety and tolerability.
-	Is able to read, understand, and speak the designated language at the study centre.
-	Caregiver must be cognitively able to fulfil the requirements of the study.

Other inclusion criteria
8.	Male or non-pregnant female adult ≥50 years of age at time of enrolment at screening visit

9.	Patients with bodyweight >45 kg and BMI between 18 and 35 kg/m2 at screening visit or baseline visit

10.	Contraception, at screening and baseline visit:
Female patients of childbearing potential (entering the study after a menstrual period and who has a negative pregnancy test), who agree to use a highly effective method of contraception and an effective method of contraception by their male partner during the study and for 3 months and a half after the last treatment intake
Male patients with a female partner of childbearing potential who agree to use a highly effective method of contraception and an effective method of contraception by their female partner during the study and for 3 months and a half after the last treatment intake OR who agree to use an effective method of contraception and a highly effective method of contraception by their female partner during the study and for 3 months and a half after the last treatment intake.

Highly effective and effective methods of contraception are detailed in the Appendix 14.1 of the protocol.

11.	Subjects must be able and willing to comply, both at screening visit and at baseline visit, with study visits and procedures

12.	Subjects able to understand, sign, and date the written informed consent form at screening visit prior to any protocol-specific procedures

13.	Subjects able to understand, and willing to follow the safety procedures mentioned on the patient card in case of signs or symptoms of severe neutropenia or severe cutaneous toxicity, at screening and baseline visit. Patient card will be provided at baseline visit

E.4 Principal exclusion criteria: 1.	Patients with any other cause of dementia shown by MRI findings and neurological examination in the last 12 months prior to screening visit
2.	Systemic conditions known to cause dementia, e.g., hypothyroidism, untreated vitamin B12 or folic acid deficiency, niacin deficiency, neurosyphilis, HIV infection at screening visit
3.	Patients with substance-induced dementia at screening visit
4.	Patients with Alzheimer’s disease with delirium at screening visit
5.	Patients with severe forms of delusions (e.g, NPI delusion score of 4 or more) at screening visit
6.	Patients with evidence of psychosis and/or use of antipsychotic drugs at screening, or history of significant psychiatric disorder at screening visit
7.	Patients with hypersensitivity to masitinib or its excipients at screening
8.	Patients with history (or family history) of drug-induced severe skin toxicities or reactions at screening or patients taking concomitant treatment or therapies associated with severe drug-induced skin toxicity

9.	Patients with history of severe bone marrow disorders such as agranulocytosis or aplasia, or with abnormal laboratory results from local laboratory assessments at screening and baseline defined as:
-	Neutropenia with ANC <1.5 × 109/L
-	Anemia with Hgb <10 g/dl
-	Thrombocytopenia with platelet counts <75 × 109/L

10.	Patients with history of severe hepatic disorders, such as viral hepatitis or steatohepatitis, and alcoholic steatosis, or with abnormal laboratory results defined as:
-	Hepatic transaminase levels >2 ULN at baseline, or
-	Total bilirubin level >1.5 ULN at baseline, or
-	Both hepatic transaminase levels and total bilirubin level outside of the normal ranges at screening and baseline, or
-	Albuminemia <1 × LLN at screening and baseline, or
-	Patients with concomitant medication known to be associated with severe hepatotoxicity

11.	Patients with pre-existing severe renal impairment, or with abnormal laboratory results at screening:
-	Creatinine clearance <60 mL/min (Cockcroft and Gault formula) or
-	Proteinuria >30 mg/dL (1+) on dipstick; in case of the proteinuria ≥1+ on the dipstick, 24 hours proteinuria must be >1.5 g/24 hours

12.	Patients with current or history of severe cardiovascular disease, assessed at screening:
-	Myocardial infarction
-	Unstable angina pectoris
-	Coronary revascularization procedure
-	Congestive heart failure of NYHA Class III or IV
-	Stroke, including a transient ischemic attack
-	Second degree or third-degree atrioventricular block not successfully treated with a pacemaker
-	Bi-fascicular block
-	QTc Fridericia interval > 450 milliseconds for males and > 470 milliseconds for females
-	Drug induced heart failure or ischemic heart disease
-	Radiotherapy induced cardiomyopathy
-	Family history of unexpected death of cardiovascular origin
-	Edema of cardiac origin and left ventricular ejaculation fraction ≤50%

13.	Patients, with two or more of the risk factors listed below assessed by a cardiologist at screening as Very High Risk (calculated SCORE* ≥10%.) according to the Systematic Coronary Risk Estimation (SCORE*):
-	Hypertension (uncontrolled)
-	Diabetes
-	Kidney disease
-	Current smoking (≥ 10 Pack-year: equivalent to 1 pack of 20 cigarettes for 10 years with the formula N (number of packs of 20 cigarettes smoked daily) × T (number years smoking)) Patients who stopped smoking 6 months prior to the evaluation, are not concerned.
-	Hypercholesterolemia,
-	COPD
14. Patients with active severe infection such as tuberculosis, viral hepatitis, human immunodeficiency virus infection, syphilis or COVID-19 (confirmed by positive RT-PCR and/or other applicable methods), from medical files assessed at screening or baseline
15. Patient treated concomitantly with known substrates of Permeability-GlycoProtein (P-gp) and/or Breast Cancer Resistance Protein (BCRP) with narrow therapeutic index
16. Any medical condition at screening and baseline that, in the opinion of the Investigator, might interfere with the patients’ participation in the trial, poses any added risk for the patients, or confounds the assessment of the patients
17. Patients under psychiatric care, patients protected by law under guardianship or curatorship, patients in emergency situations, prisoners and patients without national health insurance at screening and baseline

18. Patients who had major surgery within 2 weeks prior to screening visit
19.	Pregnant, or nursing female patients at screening or baseline

20.	Patients with a diagnosis of cancer or evidence of continued disease within five years before screening
22.	Patient who has been exposed to an investigational treatment within 3 months (9 months for immunotherapies) or five half-lives of an investigational product, whichever is longer, before the screening visit
23.	Subjects who have received a live vaccine within 30 days prior to first IMP administration
E.5 End points
E.5.1 Primary end point(s): The study has two following primary endpoints:
•	Absolute change from baseline in ADCS-ADL score at week 24
and
•	Absolute change from baseline in ADAS-Cog score at week 24
E.5.1.1 Timepoint(s) of evaluation of this end point: week 24
E.5.2 Secondary end point(s): The key secondary endpoint consists of:
•	Time to severe dementia (MMSE<10)
The secondary endpoints of the study are:
•	Absolute change from baseline in ADAS-Cog score at week 48
•	Absolute change from baseline in ADCS-ADL score at week 48
•	Clinical Responder rate at Week 24.
•	Clinician’s Interview Based Impression of Change-plus (CIBIC-plus) at Week 24
•	Mini-Mental State Examination (MMSE) at Week 24
•	Clinical Dementia Rating (CDR) at Week 24
•	Neuropsychiatric Inventory (NPI) at Week 24
Safety Endpoints
Occurrence of IMP-related and unrelated adverse events (AEs) and serious adverse events (SAEs).
Use of concomitant treatments
Changes in physical examination including vital signs (blood prussure, pulse rate), weight, and ECG
Changes in clinical laboratory tests (biochemistry, haematology, urinalysis).

E.5.2.1 Timepoint(s) of evaluation of this end point: week 24, week 48
E.6 and E.7 Scope of the trial
E.6 Scope of the Trial
E.6.1 Diagnosis: No
E.6.2 Prophylaxis: No
E.6.3 Therapy: Yes
E.6.4 Safety: Yes
E.6.5 Efficacy: Yes
E.6.6 Pharmacokinetic: No
E.6.7 Pharmacodynamic: No
E.6.8 Bioequivalence: No
E.6.9 Dose response: No
E.6.10 Pharmacogenetic: No
E.6.11 Pharmacogenomic: No
E.6.12 Pharmacoeconomic: No
E.6.13 Others: No
E.7 Trial type and phase
E.7.1 Human pharmacology (Phase I): No
E.7.1.1 First administration to humans: No
E.7.1.2 Bioequivalence study: No
E.7.1.3 Other: No
E.7.1.3.1 Other trial type description:
E.7.2 Therapeutic exploratory (Phase II): No
E.7.3 Therapeutic confirmatory (Phase III): Yes
E.7.4 Therapeutic use (Phase IV): No
E.8 Design of the trial
E.8.1 Controlled: Yes
E.8.1.1 Randomised: Yes
E.8.1.2 Open: No
E.8.1.3 Single blind: No
E.8.1.4 Double blind: Yes
E.8.1.5 Parallel group: Yes
E.8.1.6 Cross over: No
E.8.1.7 Other: No
E.8.2 Comparator of controlled trial
E.8.2.1 Other medicinal product(s): Yes
E.8.2.2 Placebo: Yes
E.8.2.3 Other: Yes
E.8.2.3.1 Comparator description: cholinesterase inhibitors (donepezil, rivastigmine, or galantamine), memantine
E.8.2.4 Number of treatment arms in the trial: 2
E.8.3 The trial involves single site in the Member State concerned: Yes
E.8.4 The trial involves multiple sites in the Member State concerned: Yes
E.8.4.1 Number of sites anticipated in Member State concerned: 5
E.8.5 The trial involves multiple Member States: Yes
E.8.5.1 Number of sites anticipated in the EEA: 155
E.8.6 Trial involving sites outside the EEA
E.8.6.1 Trial being conducted both within and outside the EEA: Yes
E.8.6.2 Trial being conducted completely outside of the EEA: No
E.8.6.3 If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned:
Argentina
Canada
Colombia
Israel
Peru
South Africa
United States
Finland
France
Poland
Sweden
Bulgaria
Netherlands
Romania
Spain
Switzerland
Czechia
Germany
Greece
Italy
Belgium
Denmark
Ireland
Norway
Portugal
Russian Federation
Serbia
Slovakia
Slovenia
Ukraine
United Kingdom
E.8.7 Trial has a data monitoring committee: Yes
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: Last Visit Last Subject
E.8.9 Initial estimate of the duration of the trial
E.8.9.1 In the Member State concerned years: 2
E.8.9.1 In the Member State concerned months:
E.8.9.1 In the Member State concerned days:
E.8.9.2 In all countries concerned by the trial years: 2

F. Population of Trial Subjects
F.1 Age Range
F.1.1 Trial has subjects under 18: No
F.1.1.1 In Utero: No
F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No
F.1.1.3 Newborns (0-27 days): No
F.1.1.4 Infants and toddlers (28 days-23 months): No
F.1.1.5 Children (2-11years): No
F.1.1.6 Adolescents (12-17 years): No
F.1.2 Adults (18-64 years): Yes
F.1.2.1 Number of subjects for this age range: 24
F.1.3 Elderly (>=65 years): Yes
F.1.3.1 Number of subjects for this age range: 576
F.2 Gender
F.2.1 Female: Yes
F.2.2 Male: Yes
F.3 Group of trial subjects
F.3.1 Healthy volunteers: No
F.3.2 Patients: Yes
F.3.3 Specific vulnerable populations: Yes
F.3.3.1 Women of childbearing potential not using contraception : No
F.3.3.2 Women of child-bearing potential using contraception: Yes
F.3.3.3 Pregnant women: No
F.3.3.4 Nursing women: No
F.3.3.5 Emergency situation: No
F.3.3.6 Subjects incapable of giving consent personally: No
F.3.3.7 Others: No
F.4 Planned number of subjects to be included
F.4.1 In the member state: 50
F.4.2 For a multinational trial
F.4.2.1 In the EEA: 480
F.4.2.2 In the whole clinical trial: 600
F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): None

G. Investigator Networks to be involved in the Trial


N. Review by the Competent Authority or Ethics Committee in the country concerned
N. Competent Authority Decision: Authorised
N. Date of Competent Authority Decision: 2022-11-02
N. Ethics Committee Opinion of the trial application: Favourable
N. Ethics Committee Opinion: Reason(s) for unfavourable opinion:
N. Date of Ethics Committee Opinion: 2022-06-23

P. End of Trial
P. End of Trial Status: Ongoing

Summary
EudraCT Number: 2021-002179-21
Sponsor's Protocol Code Number: AB21004
National Competent Authority: Poland - Office for Medicinal Products
Clinical Trial Type: EEA CTA
Trial Status: Ongoing
Date on which this record was first entered in the EudraCT database: 2022-06-13
Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-002179-21/PL/

A. Protocol Information
A.1 Member State Concerned: Poland - Office for Medicinal Products
A.2 EudraCT number: 2021-002179-21
A.3 Full title of the trial: A multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 study to evaluate the safety and efficacy of masitinib as add-on therapy in patients with mild to moderate Alzheimer's disease, treated with standard of care
A.3 Full title of the trial (pl): Wieloośrodkowe, randomizowane, prowadzone metodą podwójnie ślepej próby, kontrolowane z użyciem placebo, prowadzone w grupach równoległych badanie fazy III, oceniające bezpieczeństwo i skuteczność masytinibu jako leczenia dodatkowego u pacjentów z chorobą Alzheimera o nasileniu łagodnym do umiarkowanego, leczonych zgodnie ze standardami postępowania
A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: A multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 study to evaluate the safety and efficacy of masitinib as add-on therapy in patients with mild to moderate Alzheimer's disease, treated with standard of care
A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language (pl): Wieloośrodkowe, randomizowane, prowadzone metodą podwójnie ślepej próby, kontrolowane z użyciem placebo, prowadzone w grupach równoległych badanie fazy III, oceniające bezpieczeństwo i skuteczność masytinibu jako leczenia dodatkowego u pacjentów z chorobą Alzheimera o nasileniu łagodnym do umiarkowanego, leczonych zgodnie ze standardami postępowania
A.4.1 Sponsor's protocol code number: AB21004
A.7 Trial is part of a Paediatric Investigation Plan: No
A.8 EMA Decision number of Paediatric Investigation Plan:

B. Sponsor Information
Sponsor 1
B.1.1 Name of Sponsor: AB Science
B.1.3.4	Country: France
B.3.1 and B.3.2	Status of the sponsor: Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1 Name of organisation providing support: AB Science
B.4.2 Country: France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1 Name of organisation: AB Science
B.5.2 Functional name of contact point: Alain Moussy
B.5.3 Address
B.5.3.1 Street Address: 3 avenue George V
B.5.3.2 Town/ city: Paris
B.5.3.3 Post code: 75008
B.5.3.4 Country: France
B.5.4 Telephone number: 0033147202311
B.5.5 Fax number: 0033147202411
B.5.6 E-mail: regulatoryaffairs@ab-science.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3 IMP Role: Test
D.2 Status of the IMP to be used in the clinical trial
D.2.1 IMP to be used in the trial has a marketing authorisation: No
D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No
D.2.5.1 Orphan drug designation number:
D.3 Description of the IMP
D.3.1 Product name: Masitinib
D.3.2 Product code: AB1010
D.3.4 Pharmaceutical form: Film-coated tablet
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8 INN - Proposed INN: Masitinib mesilate
D.3.9.1 CAS number: 790299-79-5
D.3.9.2 Current sponsor code: AB1010
D.3.9.4 EV Substance Code: SUB32266
D.3.10 Strength
D.3.10.1 Concentration unit: mg milligram(s)
D.3.10.2 Concentration type: equal
D.3.10.3 Concentration number: 100
D.3.11 The IMP contains an
D.3.11.1 Active substance of chemical origin: Yes
D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No
D.3.11.3 Advanced Therapy IMP (ATIMP): No
D.3.11.3.1 Somatic cell therapy medicinal product: No
D.3.11.3.2 Gene therapy medical product: No
D.3.11.3.3 Tissue Engineered Product: No
D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No
D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No
D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No
D.3.11.5 Radiopharmaceutical medicinal product: No
D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No
D.3.11.7 Plasma derived medicinal product: No
D.3.11.8 Extractive medicinal product: No
D.3.11.9 Recombinant medicinal product: No
D.3.11.10 Medicinal product containing genetically modified organisms: No
D.3.11.11 Herbal medicinal product: No
D.3.11.12 Homeopathic medicinal product: No
D.3.11.13 Another type of medicinal product: No
D.IMP: 2
D.1.2 and D.1.3 IMP Role: Test
D.2 Status of the IMP to be used in the clinical trial
D.2.1 IMP to be used in the trial has a marketing authorisation: No
D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No
D.2.5.1 Orphan drug designation number:
D.3 Description of the IMP
D.3.1 Product name: Masitinib
D.3.2 Product code: AB1010
D.3.4 Pharmaceutical form: Film-coated tablet
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8 INN - Proposed INN: Masitinib mesilate
D.3.9.1 CAS number: 790299-79-5
D.3.9.4 EV Substance Code: SUB32266
D.3.10 Strength
D.3.10.1 Concentration unit: mg milligram(s)
D.3.10.2 Concentration type: equal
D.3.10.3 Concentration number: 200
D.3.11 The IMP contains an
D.3.11.1 Active substance of chemical origin: Yes
D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No
D.3.11.3 Advanced Therapy IMP (ATIMP): No
D.3.11.3.1 Somatic cell therapy medicinal product: No
D.3.11.3.2 Gene therapy medical product: No
D.3.11.3.3 Tissue Engineered Product: No
D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No
D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No
D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No
D.3.11.5 Radiopharmaceutical medicinal product: No
D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No
D.3.11.7 Plasma derived medicinal product: No
D.3.11.8 Extractive medicinal product: No
D.3.11.9 Recombinant medicinal product: No
D.3.11.10 Medicinal product containing genetically modified organisms: No
D.3.11.11 Herbal medicinal product: No
D.3.11.12 Homeopathic medicinal product: No
D.3.11.13 Another type of medicinal product: No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1 Is a Placebo used in this Trial? Yes
D.8.3 Pharmaceutical form of the placebo: Film-coated tablet
D.8.4 Route of administration of the placebo: Oral use
D.8 Placebo: 2
D.8.1 Is a Placebo used in this Trial? Yes
D.8.3 Pharmaceutical form of the placebo: Film-coated tablet
D.8.4 Route of administration of the placebo: Oral use

E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1 Medical condition(s) being investigated:
E.1.1.1 Medical condition in easily understood language: Alzheimer's disease
E.1.1.2 Therapeutic area: Diseases [C] - Nervous System Diseases [C10]
MedDRA Classification
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 20.0
E.1.2 Level: HLT
E.1.2 Classification code: 10001897
E.1.2 Term: Alzheimer's disease (incl subtypes)
E.1.2 System Organ Class: 100000004852
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 20.0
E.1.2 Level: LLT
E.1.2 Classification code: 10001896
E.1.2 Term: Alzheimer's disease
E.1.2 System Organ Class: 100000004852
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 24.1
E.1.2 Level: LLT
E.1.2 Classification code: 10086384
E.1.2 Term: Early onset Alzheimer's disease
E.1.2 System Organ Class: 100000004852
E.1.3 Condition being studied is a rare disease: No
E.2 Objective of the trial
E.2.1 Main objective of the trial: The primary objective of the study is to evaluate whether masitinib treatment will show a significant improvement ADCS-ADL and ADAS-Cog versus placebo in the study patients.
E.2.2 Secondary objectives of the trial: The secondary objectives of the study are to evaluate the efficacy of masitinib compared with placebo on a range of clinical parameters of Alzheimer's disease.  The secondary objectives also include the assessment of safety and tolerability of masitinib as compared to placebo in terms of adverse events, vital signs, physical examination, ECG, and clinical laboratory tests.
E.2.3 Trial contains a sub-study: No
E.3 Principal inclusion criteria: 1.	Patient with clinical diagnosis of Alzheimer's disease based on criteria defined by IWG (International Working Group) on Alzheimer’s disease at screening visit

2.	Patients with ADCS-ADL score at screening visit and baseline visit < 73

3.	Patient with MMSE ≥ 14 and ≤ 25 at screening visit and baseline visit

4.	Patient with Alzheimer’s Disease biomarker profile at screening visit:
- A positive amyloid PET scan
- Alternatively, positive a-beta AND p-tau OR an abnormal p-tau/a-beta ratio  in CSF analyses.
Before randomization, the results will be verified centrally.

5.	If patients are treated with :
•	 cholinesterase inhibitors (donepezil, rivastigmine or galantamine)
•	And/or memantine.
They should have been at stable dose for a minimum of 6 months at baseline visit, with no changes foreseen in therapy throughout the study

6.	If receiving a supplement for cognition (eg, gingko biloba, omega-3 polyunsaturated fatty acid, vitamin E, curcumin, souvenaid) patients must have been taking it at stable dose for at least 4 months prior to screening visit

7.	Patients with a caregiver who, at screening visit and baseline visit:
o	 Agrees to accompany the participant to all study visits and able to supervise the participant's compliance with the study procedures and provide detailed information about the participant.
o	 Either lives with the participant or sees the participant on average for ≥1 hours/day ≥3 days/week, or in the Investigator's opinion, the extent of contact is sufficient to provide meaningful assessment of changes in participant behaviour and function over time and provide information on safety and tolerability.
o	 Is able to read, understand, and speak the designated language at the study centre.
o	 Caregiver must be cognitively able to fulfil the requirements of the study.
Other inclusion criteria
8.	Male or non-pregnant female adult ≥50 years of age at time of enrolment at screening visit

9.	Patients with bodyweight >45 kg and BMI between 18 and 35 kg/m2 at screening visit or baseline visit

10.	Contraception, at screening and baseline visit:
Female patients of childbearing potential (entering the study after a menstrual period and who has a negative pregnancy test), who agree to use a highly effective method of contraception and an effective method of contraception by their male partner during the study and for 8 months after the last treatment intake
Male patients with a female partner of childbearing potential who agree to use a highly effective method of contraception and an effective method of contraception by their female partner during the study and for 3 months and a half after the last treatment intake OR who agree to use an effective method of contraception and a highly effective method of contraception by their female partner during the study and for 5 months after the last treatment intake.

Highly effective and effective methods of contraception are detailed in the Appendix 14.1 of the protocol.

11.	Subjects must be able and willing to comply, both at screening visit and at baseline visit, with study visits and procedures

12.	Subjects able to understand, sign, and date the written informed consent form at screening visit prior to any protocol-specific procedures

13.	Subjects able to understand, and willing to follow the safety procedures mentioned on the patient card in case of signs or symptoms of severe neutropenia or severe cutaneous toxicity, at screening and baseline visit. Patient card will be provided at baseline visit


E.4 Principal exclusion criteria: 1.	Patients with any other cause of dementia shown by MRI findings and neurological examination.

2.	Systemic conditions known to cause dementia, e.g., hypothyroidism, untreated vitamin B12 or folic acid deficiency, niacin deficiency, neurosyphilis, HIV infection at screening visit

3.	Patients with substance-induced dementia at screening visit

4.	Patients with Alzheimer’s disease with delirium at screening visit

5.	Patients with severe forms of delusions (e.g, NPI delusion score of 4 or more) at screening visit

6.	Patients with evidence of psychosis and/or use of antipsychotic drugs at screening, or history of significant psychiatric disorder at screening visit

7.	ADAS-Cog and ADCS-ADL scores at screening and baseline not in line with medical history and/or unexplained significant improvement or decline in overall status on ADAS-Cog and ADCS-ADL at screening and baseline compared with previous status

8.	Patients with hypersensitivity to masitinib or its excipients at screening

9.	Patients with history (or family history) of drug-induced severe skin toxicities or reactions at screening or patients taking concomitant treatment or therapies associated with severe drug-induced skin toxicity

10.	Patients with history of severe bone marrow disorders such as agranulocytosis or aplasia, or with abnormal laboratory results from local laboratory assessments at screening and baseline defined as:
o	Neutropenia with ANC <1.5 × 109/L
o	Anemia with Hgb <10 g/dl
o	Thrombocytopenia with platelet counts <75 × 109/L

11.	Patients with history of severe hepatic disorders, such as viral hepatitis or steatohepatitis, and alcoholic steatosis, or with abnormal laboratory results defined as:
o	Hepatic transaminase levels >2 ULN at baseline, or
o	Total bilirubin level >1.5 ULN at baseline, or
o	Both hepatic transaminase levels and total bilirubin level outside of the normal ranges at screening and baseline, or
o	Albuminemia <1 × LLN at screening and baseline, or
o	Patients with concomitant medication known to be associated with severe hepatotoxicity

12.	Patients with pre-existing severe renal impairment, or with abnormal laboratory results at screening:
o	Creatinine clearance <60 mL/min (Cockcroft and Gault formula) or
o	Proteinuria >30 mg/dL (1+) on dipstick; in case of the proteinuria ≥1+ on the dipstick, 24 hours proteinuria must be >1.5 g/24 hours

13.	Patients with current or history of severe cardiovascular disease, assessed at screening:
o	Myocardial infarction
o	Unstable angina pectoris
o	Coronary revascularization procedure
o	Congestive heart failure of NYHA Class III or IV
o	Stroke, including a transient ischemic attack
o	Second degree or third-degree atrioventricular block not successfully treated with a pacemaker
o	Bi-fascicular block
o	QTc Fridericia interval > 450 milliseconds for males and > 470 milliseconds for females
o	Drug induced heart failure or ischemic heart disease
o	Radiotherapy induced cardiomyopathy
o	Family history of unexpected death of cardiovascular origin
o	Edema of cardiac origin and left ventricular ejaculation fraction ≤50%

14.	Patients, with two or more of the risk factors listed below assessed by a cardiologist at screening as Very High Risk (calculated SCORE* ≥10%.) according to the Systematic Coronary Risk Estimation (SCORE*):
o	Hypertension (uncontrolled)
o	Diabetes
o	Kidney disease
o	Current smoking (≥ 10 Pack-year: equivalent to 1 pack of 20 cigarettes for 10 years with the formula N (number of packs of 20 cigarettes smoked daily) × T (number years smoking)) Patients who stopped smoking 6 months prior to the evaluation, are not concerned.
o	Hypercholesterolemia,
o	COPD
* This assessment is done according to the Systematic Coronary Risk Estimation (SCORE) using the country specific free full version of HeartScore®, the interactive tool for predicting and managing the risk of heart attack and stroke in Europe, available at https://www.heartscore.org/en_GB/access
If the country specific version is not available, EU one should be used.

15.	Patients with active severe infection such as tuberculosis, viral hepatitis, human immunodeficiency virus infection, syphilis or COVID-19 (confirmed by positive RT-PCR and/or other applicable methods), from medical files assessed at screening or baseline

16.	Patient treated concomitantly with known substrates of Permeability-GlycoProtein (P-gp) and/or Breast Cancer Resistance Protein (BCRP) with narrow therapeutic index
[...]







E.5 End points
E.5.1 Primary end point(s): The study has two following primary endpoints:
•	Absolute change from baseline in ADCS-ADL score at week 24
and
•	Absolute change from baseline in ADAS-Cog score at week 24
E.5.1.1 Timepoint(s) of evaluation of this end point: week 24
E.5.2 Secondary end point(s): The key secondary endpoint consists of:
•	Time to severe dementia (MMSE<10)
The secondary endpoints of the study are:
•	Absolute change from baseline in ADAS-Cog score at week 48
•	Absolute change from baseline in ADCS-ADL score at week 48
•	Clinical Responder rate at Week 24.
•	Clinician’s Interview Based Impression of Change-plus (CIBIC-plus) at Week 24
•	Mini-Mental State Examination (MMSE) at Week 24
•	Clinical Dementia Rating (CDR) at Week 24
•	Neuropsychiatric Inventory (NPI) at Week 24
Safety Endpoints
Occurrence of IMP-related and unrelated adverse events (AEs) and serious adverse events (SAEs).
Use of concomitant treatments
Changes in physical examination including vital signs (blood prussure, pulse rate), weight, and ECG
Changes in clinical laboratory tests (biochemistry, haematology, urinalysis).

E.5.2.1 Timepoint(s) of evaluation of this end point: week 24, week 48
E.6 and E.7 Scope of the trial
E.6 Scope of the Trial
E.6.1 Diagnosis: No
E.6.2 Prophylaxis: No
E.6.3 Therapy: Yes
E.6.4 Safety: Yes
E.6.5 Efficacy: Yes
E.6.6 Pharmacokinetic: No
E.6.7 Pharmacodynamic: No
E.6.8 Bioequivalence: No
E.6.9 Dose response: No
E.6.10 Pharmacogenetic: No
E.6.11 Pharmacogenomic: No
E.6.12 Pharmacoeconomic: No
E.6.13 Others: No
E.7 Trial type and phase
E.7.1 Human pharmacology (Phase I): No
E.7.1.1 First administration to humans: No
E.7.1.2 Bioequivalence study: No
E.7.1.3 Other: No
E.7.1.3.1 Other trial type description:
E.7.2 Therapeutic exploratory (Phase II): No
E.7.3 Therapeutic confirmatory (Phase III): Yes
E.7.4 Therapeutic use (Phase IV): No
E.8 Design of the trial
E.8.1 Controlled: Yes
E.8.1.1 Randomised: Yes
E.8.1.2 Open: No
E.8.1.3 Single blind: No
E.8.1.4 Double blind: Yes
E.8.1.5 Parallel group: Yes
E.8.1.6 Cross over: No
E.8.1.7 Other: No
E.8.2 Comparator of controlled trial
E.8.2.1 Other medicinal product(s): Yes
E.8.2.2 Placebo: Yes
E.8.2.3 Other: Yes
E.8.2.3.1 Comparator description: Standard of care
E.8.2.4 Number of treatment arms in the trial: 2
E.8.3 The trial involves single site in the Member State concerned: Yes
E.8.4 The trial involves multiple sites in the Member State concerned: Yes
E.8.4.1 Number of sites anticipated in Member State concerned: 5
E.8.5 The trial involves multiple Member States: Yes
E.8.5.1 Number of sites anticipated in the EEA: 155
E.8.6 Trial involving sites outside the EEA
E.8.6.1 Trial being conducted both within and outside the EEA: Yes
E.8.6.2 Trial being conducted completely outside of the EEA: No
E.8.6.3 If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned:
Argentina
Colombia
Peru
Switzerland
Ukraine
Ireland
Belgium
Bulgaria
Canada
Czechia
Denmark
Finland
France
Germany
Greece
Israel
Italy
Netherlands
Norway
Poland
Portugal
Romania
Russian Federation
Serbia
Slovakia
Slovenia
South Africa
Spain
Sweden
United Kingdom
United States
E.8.7 Trial has a data monitoring committee: Yes
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: Last Visit Last Subject
E.8.9 Initial estimate of the duration of the trial
E.8.9.1 In the Member State concerned years: 2
E.8.9.1 In the Member State concerned months:
E.8.9.1 In the Member State concerned days:
E.8.9.2 In all countries concerned by the trial years: 2

F. Population of Trial Subjects
F.1 Age Range
F.1.1 Trial has subjects under 18: No
F.1.1.1 In Utero: No
F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No
F.1.1.3 Newborns (0-27 days): No
F.1.1.4 Infants and toddlers (28 days-23 months): No
F.1.1.5 Children (2-11years): No
F.1.1.6 Adolescents (12-17 years): No
F.1.2 Adults (18-64 years): Yes
F.1.2.1 Number of subjects for this age range: 24
F.1.3 Elderly (>=65 years): Yes
F.1.3.1 Number of subjects for this age range: 576
F.2 Gender
F.2.1 Female: Yes
F.2.2 Male: Yes
F.3 Group of trial subjects
F.3.1 Healthy volunteers: No
F.3.2 Patients: Yes
F.3.3 Specific vulnerable populations: Yes
F.3.3.1 Women of childbearing potential not using contraception : No
F.3.3.2 Women of child-bearing potential using contraception: Yes
F.3.3.3 Pregnant women: No
F.3.3.4 Nursing women: No
F.3.3.5 Emergency situation: No
F.3.3.6 Subjects incapable of giving consent personally: No
F.3.3.7 Others: No
F.4 Planned number of subjects to be included
F.4.1 In the member state: 50
F.4.2 For a multinational trial
F.4.2.1 In the EEA: 480
F.4.2.2 In the whole clinical trial: 600
F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): None

G. Investigator Networks to be involved in the Trial


N. Review by the Competent Authority or Ethics Committee in the country concerned
N. Competent Authority Decision: Authorised
N. Date of Competent Authority Decision: 2022-11-02
N. Ethics Committee Opinion of the trial application: Favourable
N. Ethics Committee Opinion: Reason(s) for unfavourable opinion:
N. Date of Ethics Committee Opinion: 2022-06-23

P. End of Trial
P. End of Trial Status: Ongoing

Summary
EudraCT Number: 2021-002179-21
Sponsor's Protocol Code Number: AB21004
National Competent Authority: Portugal - INFARMED
Clinical Trial Type: EEA CTA
Trial Status: Ongoing
Date on which this record was first entered in the EudraCT database: 2022-06-20
Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-002179-21/PT/

A. Protocol Information
A.1 Member State Concerned: Portugal - INFARMED
A.2 EudraCT number: 2021-002179-21
A.3 Full title of the trial: A multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 study to evaluate the safety and efficacy of masitinib as add-on therapy in patients with mild to moderate Alzheimer's disease, treated with standard of care : cholinesterase inhibitors, memantine
A.3 Full title of the trial (pt): Estudo clínico de fase 3, multicêntrico, aleatorizado, duplamente cego, controlado por placebo, de grupos paralelos para avaliar a segurança e a eficácia do Masitinib como terapêutica adjuvante em doentes que apresentam doença de Alzheimer leve a moderada, a fazer a terapêutica farmacológica padrão: inibidores de colinesterase, memantina
A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: A phase 3 study to evaluate the safety and efficacy of masitinib as add-on therapy in patients with mild to moderate Alzheimer's disease treated with standard of care: cholinesterase inhibitors, memantine
A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language (pt): Estudo de fase 3, aleatorizado, duplamente cego, controlado por placebo, de grupos paralelos, para avaliar a segurança e a eficácia do Masitinib como terapêutica adjuvante em doentes que apresentam doença de Alzheimer leve a moderada.
A.3.2 Name or abbreviated title of the trial where available: Alzheimer
A.3.2 Name or abbreviated title of the trial where available (pt): Alzheimer
A.4.1 Sponsor's protocol code number: AB21004
A.7 Trial is part of a Paediatric Investigation Plan: No
A.8 EMA Decision number of Paediatric Investigation Plan:

B. Sponsor Information
Sponsor 1
B.1.1 Name of Sponsor: ABScience
B.1.3.4	Country: France
B.3.1 and B.3.2	Status of the sponsor: Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1 Name of organisation providing support: ABScience
B.4.2 Country: France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1 Name of organisation: ABScience
B.5.2 Functional name of contact point: Alain Moussy
B.5.3 Address
B.5.3.1 Street Address: 3 avenue George V
B.5.3.2 Town/ city: Paris
B.5.3.3 Post code: 75008
B.5.3.4 Country: France
B.5.4 Telephone number: 0033147202311
B.5.5 Fax number: 0033147202411
B.5.6 E-mail: regulatoryaffairs@ab-science.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3 IMP Role: Test
D.2 Status of the IMP to be used in the clinical trial
D.2.1 IMP to be used in the trial has a marketing authorisation: No
D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No
D.2.5.1 Orphan drug designation number:
D.3 Description of the IMP
D.3.1 Product name: Masitinib
D.3.2 Product code: AB1010
D.3.4 Pharmaceutical form: Film-coated tablet
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8 INN - Proposed INN: Masitinib mesilate
D.3.9.1 CAS number: 790299-79-5
D.3.9.2 Current sponsor code: AB1010
D.3.9.4 EV Substance Code: SUB32266
D.3.10 Strength
D.3.10.1 Concentration unit: mg milligram(s)
D.3.10.2 Concentration type: equal
D.3.10.3 Concentration number: 100
D.3.11 The IMP contains an
D.3.11.1 Active substance of chemical origin: Yes
D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No
D.3.11.3 Advanced Therapy IMP (ATIMP): No
D.3.11.3.1 Somatic cell therapy medicinal product: No
D.3.11.3.2 Gene therapy medical product: No
D.3.11.3.3 Tissue Engineered Product: No
D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No
D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No
D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No
D.3.11.5 Radiopharmaceutical medicinal product: No
D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No
D.3.11.7 Plasma derived medicinal product: No
D.3.11.8 Extractive medicinal product: No
D.3.11.9 Recombinant medicinal product: No
D.3.11.10 Medicinal product containing genetically modified organisms: No
D.3.11.11 Herbal medicinal product: No
D.3.11.12 Homeopathic medicinal product: No
D.3.11.13 Another type of medicinal product: No
D.IMP: 2
D.1.2 and D.1.3 IMP Role: Test
D.2 Status of the IMP to be used in the clinical trial
D.2.1 IMP to be used in the trial has a marketing authorisation: No
D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No
D.2.5.1 Orphan drug designation number:
D.3 Description of the IMP
D.3.1 Product name: Masitinib
D.3.2 Product code: AB1010
D.3.4 Pharmaceutical form: Film-coated tablet
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8 INN - Proposed INN: Masitinib mesilate
D.3.9.1 CAS number: 790299-79-5
D.3.9.4 EV Substance Code: SUB32266
D.3.10 Strength
D.3.10.1 Concentration unit: mg milligram(s)
D.3.10.2 Concentration type: equal
D.3.10.3 Concentration number: 200
D.3.11 The IMP contains an
D.3.11.1 Active substance of chemical origin: Yes
D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No
D.3.11.3 Advanced Therapy IMP (ATIMP): No
D.3.11.3.1 Somatic cell therapy medicinal product: No
D.3.11.3.2 Gene therapy medical product: No
D.3.11.3.3 Tissue Engineered Product: No
D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No
D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No
D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No
D.3.11.5 Radiopharmaceutical medicinal product: No
D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No
D.3.11.7 Plasma derived medicinal product: No
D.3.11.8 Extractive medicinal product: No
D.3.11.9 Recombinant medicinal product: No
D.3.11.10 Medicinal product containing genetically modified organisms: No
D.3.11.11 Herbal medicinal product: No
D.3.11.12 Homeopathic medicinal product: No
D.3.11.13 Another type of medicinal product: No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1 Is a Placebo used in this Trial? Yes
D.8.3 Pharmaceutical form of the placebo: Film-coated tablet
D.8.4 Route of administration of the placebo: Oral use
D.8 Placebo: 2
D.8.1 Is a Placebo used in this Trial? Yes
D.8.3 Pharmaceutical form of the placebo: Film-coated tablet
D.8.4 Route of administration of the placebo: Oral use

E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1 Medical condition(s) being investigated: Alzheimer's disease
E.1.1 Medical condition(s) being investigated (pt): Doença de Alzheimer
E.1.1.1 Medical condition in easily understood language: Alzheimer's disease
E.1.1.1 Medical condition in easily understood language (pt): Doença de Alzheimer
E.1.1.2 Therapeutic area: Diseases [C] - Nervous System Diseases [C10]
MedDRA Classification
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 20.0
E.1.2 Level: HLT
E.1.2 Classification code: 10001897
E.1.2 Term: Alzheimer's disease (incl subtypes)
E.1.2 System Organ Class: 100000004852
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 20.0
E.1.2 Level: LLT
E.1.2 Classification code: 10001896
E.1.2 Term: Alzheimer's disease
E.1.2 System Organ Class: 100000004852
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 24.1
E.1.2 Level: LLT
E.1.2 Classification code: 10086384
E.1.2 Term: Early onset Alzheimer's disease
E.1.2 System Organ Class: 100000004852
E.1.3 Condition being studied is a rare disease: No
E.2 Objective of the trial
E.2.1 Main objective of the trial: The primary objective of the study is to evaluate whether masitinib treatment will show a significant improvement ADCS-ADL and ADAS-Cog versus placebo in the study patients.
E.2.1 Main objective of the trial (pt): O objetivo principal do estudo é avaliar se o tratamento com masitinib demonstra uma melhoria significativa nas escalas ADCS-ADL e ADAS-Cog versus o placebo nos doentes do estudo.
E.2.2 Secondary objectives of the trial: The secondary objectives of the study are to evaluate the efficacy of masitinib compared with placebo on a range of clinical parameters of Alzheimer's disease.  The secondary objectives also include the assessment of safety and tolerability of masitinib as compared to placebo in terms of adverse events, vital signs, physical examination, ECG, and clinical laboratory tests.
E.2.2 Secondary objectives of the trial (pt): Os objetivos secundários do estudo são avaliar a eficácia do masitinib em comparação com o placebo numa série de parâmetros clínicos da doença de Alzheimer. Os objetivos secundários incluem igualmente a avaliação da segurança e da tolerabilidade do masitinib em comparação com o placebo em termos de acontecimentos adversos, sinais vitais, exame físico, ECG e testes clínicos laboratoriais.
E.2.3 Trial contains a sub-study: No
E.3 Principal inclusion criteria: 1.	Patient with clinical diagnosis of Alzheimer's disease based on cognitive impairment and daily functional dependency at screening visit
2.	Patient with ADCS-ADL score at screening visit and baseline visit <73
3.	Patient with MMSE ≥ 14 and ≤ 25 at screening visit and baseline visit
4.	Patient with Alzheimer’s Disease biomarker profile at screening visit:
- A positive amyloid PET scan
- Alternatively, a-beta 1-42 <1000pg/ml AND p-tau >19pg/ml OR a p-tau/a-beta ratio > 0.024, as measured by a central laboratory according to the Elecsys assay for CSF biomarkers
5.	Patients treated for a minimum of 6 months with a stable dose of cholinesterase inhibitors (donepezil, rivastigmine or galantamine) at baseline visit, and/or a stable dose of memantine for a minimum of 6 months at baseline visit, with no changes foreseen in therapy throughout the study
6.	If receiving a supplement for cognition (eg, gingko biloba, omega-3 polyunsaturated fatty acid, vitamin E, curcumin, souvenaid) must be taking a stable dose for at least 4 months prior to screening visit
7.	Patients with a caregiver who, at screening visit and baseline visit:
-	Agrees to accompany the participant to all study visits and able to supervise the participant's compliance with the study procedures and provide detailed information about the participant.
-	Either lives with the participant or sees the participant on average for ≥1 hours/day ≥3 days/week, or in the Investigator's opinion, the extent of contact is sufficient to provide meaningful assessment of changes in participant behaviour and function over time and provide information on safety and tolerability.
-	Is able to read, understand, and speak the designated language at the study centre.
-	Caregiver must be cognitively able to fulfil the requirements of the study.

Other inclusion criteria
8.	Male or non-pregnant female adult ≥50 years of age at time of enrolment at screening visit
9.	Patients with bodyweight >45 kg and BMI between 18 and 35 kg/m2 at screening visit or baseline visit
10.	Contraception, at screening and baseline visit:
Female patients of childbearing potential (entering the study after a menstrual period and who has a negative pregnancy test), who agree to use a highly effective method of contraception and an effective method of contraception by their male partner during the study and for 3 months and a half after the last treatment intake
Male patients with a female partner of childbearing potential who agree to use a highly effective method of contraception and an effective method of contraception by their female partner during the study and for 3 months and a half after the last treatment intake OR who agree to use an effective method of contraception and a highly effective method of contraception by their female partner during the study and for 3 months and a half after the last treatment intake.

Highly effective and effective methods of contraception are detailed in the Appendix 14.1 of the protocol.
11.	Subjects must be able and willing to comply, both at screening visit and at baseline visit, with study visits and procedures
12.	Subjects able to understand, sign, and date the written informed consent form at screening visit prior to any protocol-specific procedures
13.	Subjects able to understand, and willing to follow the safety procedures mentioned on the patient card in case of signs or symptoms of severe neutropenia or severe cutaneous toxicity, at screening and baseline visit. Patient card will be provided at baseline visit
E.3 Principal inclusion criteria (pt): 1. O doente com diagnóstico clínico de doença de Alzheimer com base em perturbação cognitiva e dependência funcional diária na visita de triagem
2.      Doentes com uma classificação ADCS-ADL nas visitas de triagem e baseline < 73
3.      Doente com MMSE ≥ 14 e ≤ 25 nas visitas de triagem e de baseline
4.      Doente com perfil de biomarcador da Doença de Alzheimer na visita de triagem:
- A imagem PET amilóide positiva
- Alternativamente, a-beta 1-42 <1000pg/ml E p-tau >19pg/ml OU um rácio p-tau/a-beta > 0,024, conforme a medição por um laboratório central de acordo com a análise Elecsys para biomarcadores CSF
5.      Os doentes tratados durante um período mínimo de 6 meses com uma dose estável de inibidores da colinesterase (donepezilo, rivastigmina ou galantamina) na visita de baseline e/ou uma dose estável de memantina durante um mínimo de 6 meses na visita de baseline, sem alterações previstas na terapêutica durante o estudo
6.      Se estiver a receber um suplemento alimentar para a cognição (por ex., gingko biloba, ácidos gordos poli-insaturados omega-3, vitamina E, curcumina, souvenaid), deve tomar uma dose estável durante pelo menos 4 meses antes da visita de triagem
7.      Doentes com um cuidador que, na visita de triagem e na visita de baseline:
o        Concorde em acompanhar o participante a todas as visitas de estudo e sejam capazes de supervisionar a conformidade do participante com os procedimentos do estudo e de fornecer informação detalhada sobre o participante.
o        Viva com o participante ou vêm o participante em média ≥1 hora/dia ≥3 dias/semana, ou na opinião do Investigador, o âmbito do contacto é suficiente para providenciar uma avaliação relevante das alterações no comportamento do participante e da função com o tempo e de fornecer informação sobre a segurança e tolerabilidade.
o        Seja capaz de ler, perceber e falar o idioma utilizado no centro do estudo.
o        Seja cognitivamente capaz de preencher os requisitos do estudo.
8.      Adulto do sexo feminino não grávida ou do sexo masculino ≥ 50 anos de idade na altura da visita de rastreio
9.      Doentes com peso corporal >45 kg e IMC entre 18 e 35 kg/m2 na visita de triagem ou visita de baseline
10.     Contraceção, na triagem e na visita da baseline:
Os doentes do sexo feminino com potencial para engravidar (que entrem no estudo após um período menstrual e que tenham um teste de gravidez negativo), que concordem em usar um método de contraceção altamente eficaz e o parceiro do sexo masculino um método de contraceção efetivo durante o estudo e nos 3 meses e meio após a última toma do medicamento.
Os doentes do sexo masculino com uma parceira de sexo feminino potencialmente fértil que aceite utilizar um método de contraceção altamente eficaz durante o estudo e durante os 3 meses após a última ingestão do tratamento OU que aceite utilizar um método de contraceção durante o estudo e que a sua parceira do sexo feminino utilize um método de contraceção altamente eficaz durante o estudo e durante 3 meses e meio após a última toma  do medicamento.



E.4 Principal exclusion criteria: 1.	Patients with any other cause of dementia shown by MRI findings and neurological examination in the last 12 months prior to screening visit
2.	Systemic conditions known to cause dementia, e.g., hypothyroidism, untreated vitamin B12 or folic acid deficiency, niacin deficiency, neurosyphilis, HIV infection at screening visit
3.	Patients with substance-induced dementia at screening visit
4.	Patients with Alzheimer’s disease with delirium at screening visit
5.	Patients with severe forms of delusions (e.g, NPI delusion score of 4 or more) at screening visit
6.	Patients with evidence of psychosis and/or use of antipsychotic drugs at screening, or history of significant psychiatric disorder at screening visit
7.	Patients with hypersensitivity to masitinib or its excipients at screening
8.	Patients with history (or family history) of drug-induced severe skin toxicities or reactions at screening or patients taking concomitant treatment or therapies associated with severe drug-induced skin toxicity

9.	Patients with history of severe bone marrow disorders such as agranulocytosis or aplasia, or with abnormal laboratory results from local laboratory assessments at screening and baseline defined as:
-	Neutropenia with ANC <1.5 × 109/L
-	Anemia with Hgb <10 g/dl
-	Thrombocytopenia with platelet counts <75 × 109/L

10.	Patients with history of severe hepatic disorders, such as viral hepatitis or steatohepatitis, and alcoholic steatosis, or with abnormal laboratory results defined as:
-	Hepatic transaminase levels >2 ULN at baseline, or
-	Total bilirubin level >1.5 ULN at baseline, or
-	Both hepatic transaminase levels and total bilirubin level outside of the normal ranges at screening and baseline, or
-	Albuminemia <1 × LLN at screening and baseline, or
-	Patients with concomitant medication known to be associated with severe hepatotoxicity

11.	Patients with pre-existing severe renal impairment, or with abnormal laboratory results at screening:
-	Creatinine clearance <60 mL/min (Cockcroft and Gault formula) or
-	Proteinuria >30 mg/dL (1+) on dipstick; in case of the proteinuria ≥1+ on the dipstick, 24 hours proteinuria must be >1.5 g/24 hours

12.	Patients with current or history of severe cardiovascular disease, assessed at screening:
-	Myocardial infarction
-	Unstable angina pectoris
-	Coronary revascularization procedure
-	Congestive heart failure of NYHA Class III or IV
-	Stroke, including a transient ischemic attack
-	Second degree or third-degree atrioventricular block not successfully treated with a pacemaker
-	Bi-fascicular block
-	QTc Fridericia interval > 450 milliseconds for males and > 470 milliseconds for females
-	Drug induced heart failure or ischemic heart disease
-	Radiotherapy induced cardiomyopathy
-	Family history of unexpected death of cardiovascular origin
-	Edema of cardiac origin and left ventricular ejaculation fraction ≤50%

13.	Patients, with two or more of the risk factors listed below assessed by a cardiologist at screening as Very High Risk (calculated SCORE* ≥10%.) according to the Systematic Coronary Risk Estimation (SCORE*):
-	Hypertension (uncontrolled)
-	Diabetes
-	Kidney disease
-	Current smoking (≥ 10 Pack-year: equivalent to 1 pack of 20 cigarettes for 10 years with the formula N (number of packs of 20 cigarettes smoked daily) × T (number years smoking)) Patients who stopped smoking 6 months prior to the evaluation, are not concerned.
-	Hypercholesterolemia,
-	COPD
* This assessment is done according to the Systematic Coronary Risk Estimation (SCORE) using the country specific free full version of HeartScore®, the interactive tool for predicting and managing the risk of heart attack and stroke in Europe, available at https://www.heartscore.org/en_GB/access
If the country specific version is not available, EU one should be used.


19.	Pregnant, or nursing female patients at screening or baseline

20.	Patients with a diagnosis of cancer or evidence of continued disease within five years before screening
22.	Patient who has been exposed to an investigational treatment within 3 months (9 months for immunotherapies) or five half-lives of an investigational product, whichever is longer, before the screening visit
23.	Subjects who have received a live vaccine within 30 days prior to first IMP administration
E.4 Principal exclusion criteria (pt): 1. Doentes com qualquer outra causa de demência comprovada por resultados de uma RMI e exame neurológico nos últimos 12 meses antes da visita de triagem; 2-Condições sistémicas que se sabe causarem demência, como hipotiroidismo, deficiência não tratada de vitamina B12 ou ác. fólico, deficiência de niacina, neurossífilis, infeção por VIH na visita de triagem;
3-Doentes com demência induzida por substâncias na visita de triagem;
4-Doentes com doença de Alzheimer com delírios na visita de triagem; 5-Doentes com formas graves de delírio na visita de triagem; 6-Doentes com evidência de psicose e/ou uso de medicamentos antipsicóticos na triagem, ou historial de perturbação psiquiátrica significativa na visita de triagem; 7-Doentes com hipersensibilidade ao masitinib ou aos seus excipientes na visita de rastreio; 8-Doentes com um historial (ou história familiar) de toxicidades cutâneas graves ou reações na triagem ou doentes que façam um tratamento concomitante ou terapêuticas associadas com uma toxicidade da pele induzida por medicamentos na triagem e baseline; 9-Doentes com história de perturbações graves da medula óssea tais como agranulocitose ou aplasia, ou com resultados de análises anormais das avaliações de laboratório local na triagem e na baseline definidos como:
Neutropenia com ANC <1,5 × 109/L,        Anemia com Hgb <10 g/dl,       Trombocitopenia com contagem de plaquetas <75 × 109/L; 10-Doentes com história de distúrbios hepáticos graves, tais como hepatite viral ou esteatohepatite, e esteatose hepática ou com resultados de análises anormais definidos como:
Níveis de transaminase hepática >2 ULN na baseline ou Nível total de bilirrubina >1,5 ULN na baseline, ou
Níveis de transaminase hepática e nível total de bilirrubina fora dos intervalos de referência na triagem e baseline, ou Albuminémia <1 × LLN na triagem e baseline ou com medicação concomitante que se sabe estar associada a toxicidade hepática grave; 11-Doentes com perturbações renais graves pré-existentes ou com resultados laboratoriais anormais na triagem:
Depuração de creatinina <60 mL/min (fórmula de Cockcroft e Gault) ou
Proteinúria >30 mg/dL (1+) na vareta; no caso de proteinúria ≥1+ na vareta, a proteinúria a 24 horas deve ser de >1,5 g/24 horas; 12-Os doentes com um história atual de doença cardiovascular grave, avaliada na triagem: Enfarte do miocárdio, Angina de peito instável,        Intervenção de revascularização coronária, Insuficiência cardíaca congestiva e Classe III ou IV da NYHA, AVC, incluindo um ataque isquémico transitório, Bloqueio atrioventricular de segundo grau ou terceiro grau não tratado com êxito com um pacemaker,        Bloqueio bifascicular, Intervalo QTc >450 ms para homens e >470 ms para mulheres (fórmula de Fridericia), Insuficiência cardíaca induzida por medicamentos ou doença cardíaca isquémica, Miocardiopatia induzida por radioterapia, História familiar de morte inesperada de origem cardiovascular, Edema de origem cardíaca e fração da ejeção ventricular esquerda ≤50%; 13-Doentes, com 2 ou mais dos fatores de risco enumerados em baixo avaliados por um cardiologista na triagem como sendo de Muito Alto Risco segundo a avaliação do risco cardiovascular (SCORE): Hipertensão (não controlada), Diabetes, Doença renal, Tabagismo (≥ ano de 10 maços: equivalente a 1 maço de cigarros durante 10 anos com a fórmula N (número de maços de 20 cigarros fumados por dia) × T (número de anos a fumar)). Os doentes que tenham deixado de fumar 6 meses antes da avaliação não são incluídos;
14-Os doentes com uma infeção grave ativa como tuberculose, hepatite viral, infeção pelo vírus da imunodeficiência humana, sífilis ou COVID-19; 15- Doente tratado concomitantemente com substratos de glicoproteína P e/ou proteína de resistência ao cancro da mama (BCRP) com índice terapêutico estreito;
16-Qualquer condição médica na triagem e na linha de base que, na opinião do Investigador, possa interferir com a participação dos doentes no estudo, representando um risco acrescido , ou que possa confundir a avaliação dos doentes; 17-Os doentes em cuidado psiquiátrico, doentes protegidos pela lei sob tutoria ou curadoria, doentes em situações de emergência, prisioneiros e doentes sem segurança social nacional na triagem e baseline;
18-Doentes que tenham sido submetidos a uma grande cirurgia nas 2 semanas que antecedem a visita de triagem; 19-Doentes do sexo feminino grávidas ou em aleitamento na triagem ou baseline; 20-Doentes com um diagnóstico de cancro ou evidência de doença continuada nos cinco anos que antecedem a triagem; 21- Participação prévia num estudo anterior com masitinib, avaliada na triagem; 22-Doentes expostos a um tratamento de investigação nos 3 meses (9 meses para imunoterapias) ou 5 semividas de um produto em investigação, conforme o mais longo, antes da visita de triagem; 23- Os participantes que tenham recebido uma vacina viva nos 30 dias que antecedem a primeira administração do medicamento experimental.
E.5 End points
E.5.1 Primary end point(s): The study has two following primary endpoints:
•	Absolute change from baseline in ADCS-ADL score at week 24
and
•	Absolute change from baseline in ADAS-Cog score at week 24
E.5.1 Primary end point(s) (pt): •        Alteração inequívoca da escala ADCS-ASL da visita baseline para a semana 24
e
• Alteração inequívoca da escala ADAS-Cog da visita baseline para a semana 24

E.5.1.1 Timepoint(s) of evaluation of this end point: week 24
E.5.1.1 Timepoint(s) of evaluation of this end point (pt): Semana 24
E.5.2 Secondary end point(s): The key secondary endpoint consists of:
 Time to severe dementia (MMSE<10)
The secondary endpoints of the study are:
 Absolute change from baseline in ADAS-Cog score at week 48
 Absolute change from baseline in ADCS-ADL score at week 48
 Clinical Responder rate at Week 24.
 Clinician’s Interview Based Impression of Change-plus (CIBIC-plus) at Week 24
 Absolute change from baseline in Mini-Mental State Examination (MMSE) at Week 24
 Absolute change from baseline in Clinical Dementia Rating (CDR) at Week 24
 Absolute change from baseline in Neuropsychiatric Inventory (NPI) at Week 24
E.5.2 Secondary end point(s) (pt): •    Tempo até à demência grave (MMSE<10)
• Alteração inequívoca da escala ADAS-Cog da visita baseline para a semana  48
• Alteração inequívoca da escala ADCS-ASL da visita baseline para a semana 48
• Taxa de resposta clínica na semana 24.
• Impressão de Alteração Baseada na Entrevista com o Médico (CIBIC-plus) na semana 24
• Alteração inequívoca em relação à visita baseline no MMSE (mini-exame do estado mental) na semana 24
• A alteração inequívoca em relação à visita baseline da Avaliação clínica da demência (CDR) na semana 24
• Alteração inequívoca em relação à visita baseline do Inventário Neuropsiquiátrico (NPI) na semana 24


E.5.2.1 Timepoint(s) of evaluation of this end point: week 24, week 48
E.5.2.1 Timepoint(s) of evaluation of this end point (pt): Semana 24, semana 48
E.6 and E.7 Scope of the trial
E.6 Scope of the Trial
E.6.1 Diagnosis: No
E.6.2 Prophylaxis: No
E.6.3 Therapy: Yes
E.6.4 Safety: Yes
E.6.5 Efficacy: Yes
E.6.6 Pharmacokinetic: No
E.6.7 Pharmacodynamic: No
E.6.8 Bioequivalence: No
E.6.9 Dose response: No
E.6.10 Pharmacogenetic: No
E.6.11 Pharmacogenomic: No
E.6.12 Pharmacoeconomic: No
E.6.13 Others: No
E.7 Trial type and phase
E.7.1 Human pharmacology (Phase I): No
E.7.1.1 First administration to humans: No
E.7.1.2 Bioequivalence study: No
E.7.1.3 Other: No
E.7.1.3.1 Other trial type description:
E.7.2 Therapeutic exploratory (Phase II): No
E.7.3 Therapeutic confirmatory (Phase III): Yes
E.7.4 Therapeutic use (Phase IV): No
E.8 Design of the trial
E.8.1 Controlled: Yes
E.8.1.1 Randomised: Yes
E.8.1.2 Open: No
E.8.1.3 Single blind: No
E.8.1.4 Double blind: Yes
E.8.1.5 Parallel group: Yes
E.8.1.6 Cross over: No
E.8.1.7 Other: No
E.8.2 Comparator of controlled trial
E.8.2.1 Other medicinal product(s): Yes
E.8.2.2 Placebo: Yes
E.8.2.3 Other: Yes
E.8.2.3.1 Comparator description: cholinesterase inhibitors (donestigmpezil, rivaine, or galantamine), and/or memantine
E.8.2.3.1 Comparator description (pt): inibidores da colinesterase (donepezilo, rivastigmina ou galantamina) e/ou memantina
E.8.2.4 Number of treatment arms in the trial: 2
E.8.3 The trial involves single site in the Member State concerned: Yes
E.8.4 The trial involves multiple sites in the Member State concerned: Yes
E.8.4.1 Number of sites anticipated in Member State concerned: 1
E.8.5 The trial involves multiple Member States: Yes
E.8.5.1 Number of sites anticipated in the EEA: 155
E.8.6 Trial involving sites outside the EEA
E.8.6.1 Trial being conducted both within and outside the EEA: Yes
E.8.6.2 Trial being conducted completely outside of the EEA: No
E.8.6.3 If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned:
Argentina
Canada
Colombia
Israel
Peru
South Africa
United States
Finland
France
Poland
Sweden
Bulgaria
Netherlands
Romania
Spain
Switzerland
Czechia
Germany
Greece
Italy
Belgium
Denmark
Ireland
Norway
Portugal
Russian Federation
Serbia
Slovakia
Slovenia
Ukraine
United Kingdom
E.8.7 Trial has a data monitoring committee: Yes
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: Last Visit Last Subject
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial (pt): Última visita do último doente
E.8.9 Initial estimate of the duration of the trial
E.8.9.1 In the Member State concerned years: 2
E.8.9.1 In the Member State concerned months:
E.8.9.1 In the Member State concerned days:
E.8.9.2 In all countries concerned by the trial years: 2

F. Population of Trial Subjects
F.1 Age Range
F.1.1 Trial has subjects under 18: No
F.1.1.1 In Utero: No
F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No
F.1.1.3 Newborns (0-27 days): No
F.1.1.4 Infants and toddlers (28 days-23 months): No
F.1.1.5 Children (2-11years): No
F.1.1.6 Adolescents (12-17 years): No
F.1.2 Adults (18-64 years): Yes
F.1.2.1 Number of subjects for this age range: 24
F.1.3 Elderly (>=65 years): Yes
F.1.3.1 Number of subjects for this age range: 576
F.2 Gender
F.2.1 Female: Yes
F.2.2 Male: Yes
F.3 Group of trial subjects
F.3.1 Healthy volunteers: No
F.3.2 Patients: Yes
F.3.3 Specific vulnerable populations: Yes
F.3.3.1 Women of childbearing potential not using contraception : No
F.3.3.2 Women of child-bearing potential using contraception: Yes
F.3.3.3 Pregnant women: No
F.3.3.4 Nursing women: No
F.3.3.5 Emergency situation: No
F.3.3.6 Subjects incapable of giving consent personally: No
F.3.3.7 Others: No
F.4 Planned number of subjects to be included
F.4.1 In the member state: 50
F.4.2 For a multinational trial
F.4.2.1 In the EEA: 550
F.4.2.2 In the whole clinical trial: 600
F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): None

G. Investigator Networks to be involved in the Trial


N. Review by the Competent Authority or Ethics Committee in the country concerned
N. Competent Authority Decision: Authorised
N. Date of Competent Authority Decision: 2023-04-10
N. Ethics Committee Opinion of the trial application: Favourable
N. Ethics Committee Opinion: Reason(s) for unfavourable opinion:
N. Date of Ethics Committee Opinion: 2023-01-13

P. End of Trial
P. End of Trial Status: Ongoing

Summary
EudraCT Number: 2021-002179-21
Sponsor's Protocol Code Number: AB21004
National Competent Authority: Hungary - National Institute of Pharmacy
Clinical Trial Type: EEA CTA
Trial Status: Ongoing
Date on which this record was first entered in the EudraCT database: 2022-07-25
Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-002179-21/HU/

A. Protocol Information
A.1 Member State Concerned: Hungary - National Institute of Pharmacy
A.2 EudraCT number: 2021-002179-21
A.3 Full title of the trial: A multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 study to evaluate the safety and efficacy of masitinib as add-on therapy in patients with mild to moderate Alzheimer's disease, treated with standard of care : cholinesterase inhibitors, memantine
A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: A phase 3 study to evaluate the safety and efficacy of masitinib as add-on therapy in patients with mild to moderate Alzheimer's disease treated with standard of care: cholinesterase inhibitors, memantine
A.4.1 Sponsor's protocol code number: AB21004
A.7 Trial is part of a Paediatric Investigation Plan: No
A.8 EMA Decision number of Paediatric Investigation Plan:

B. Sponsor Information
Sponsor 1
B.1.1 Name of Sponsor: AB Science
B.1.3.4	Country: France
B.3.1 and B.3.2	Status of the sponsor: Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1 Name of organisation providing support: AB Science
B.4.2 Country: France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1 Name of organisation: AB Science
B.5.2 Functional name of contact point: Alain Moussy
B.5.3 Address
B.5.3.1 Street Address: 3 avenue George V
B.5.3.2 Town/ city: Paris
B.5.3.3 Post code: 75008
B.5.3.4 Country: France
B.5.4 Telephone number: 0033147202311
B.5.5 Fax number: 0033147202411
B.5.6 E-mail: regulatoryaffairs@ab-science.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3 IMP Role: Test
D.2 Status of the IMP to be used in the clinical trial
D.2.1 IMP to be used in the trial has a marketing authorisation: No
D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No
D.2.5.1 Orphan drug designation number:
D.3 Description of the IMP
D.3.1 Product name: Masitinib
D.3.2 Product code: AB1010
D.3.4 Pharmaceutical form: Film-coated tablet
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8 INN - Proposed INN: Masitinib mesilate
D.3.9.1 CAS number: 790299-79-5
D.3.9.2 Current sponsor code: AB1010
D.3.9.4 EV Substance Code: SUB32266
D.3.10 Strength
D.3.10.1 Concentration unit: mg milligram(s)
D.3.10.2 Concentration type: equal
D.3.10.3 Concentration number: 100
D.3.11 The IMP contains an
D.3.11.1 Active substance of chemical origin: Yes
D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No
D.3.11.3 Advanced Therapy IMP (ATIMP): No
D.3.11.3.1 Somatic cell therapy medicinal product: No
D.3.11.3.2 Gene therapy medical product: No
D.3.11.3.3 Tissue Engineered Product: No
D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No
D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No
D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No
D.3.11.5 Radiopharmaceutical medicinal product: No
D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No
D.3.11.7 Plasma derived medicinal product: No
D.3.11.8 Extractive medicinal product: No
D.3.11.9 Recombinant medicinal product: No
D.3.11.10 Medicinal product containing genetically modified organisms: No
D.3.11.11 Herbal medicinal product: No
D.3.11.12 Homeopathic medicinal product: No
D.3.11.13 Another type of medicinal product: No
D.IMP: 2
D.1.2 and D.1.3 IMP Role: Test
D.2 Status of the IMP to be used in the clinical trial
D.2.1 IMP to be used in the trial has a marketing authorisation: No
D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No
D.2.5.1 Orphan drug designation number:
D.3 Description of the IMP
D.3.1 Product name: Masitinib
D.3.2 Product code: AB1010
D.3.4 Pharmaceutical form: Film-coated tablet
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8 INN - Proposed INN: Masitinib mesilate
D.3.9.1 CAS number: 790299-79-5
D.3.9.4 EV Substance Code: SUB32266
D.3.10 Strength
D.3.10.1 Concentration unit: mg milligram(s)
D.3.10.2 Concentration type: equal
D.3.10.3 Concentration number: 200
D.3.11 The IMP contains an
D.3.11.1 Active substance of chemical origin: Yes
D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No
D.3.11.3 Advanced Therapy IMP (ATIMP): No
D.3.11.3.1 Somatic cell therapy medicinal product: No
D.3.11.3.2 Gene therapy medical product: No
D.3.11.3.3 Tissue Engineered Product: No
D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No
D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No
D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No
D.3.11.5 Radiopharmaceutical medicinal product: No
D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No
D.3.11.7 Plasma derived medicinal product: No
D.3.11.8 Extractive medicinal product: No
D.3.11.9 Recombinant medicinal product: No
D.3.11.10 Medicinal product containing genetically modified organisms: No
D.3.11.11 Herbal medicinal product: No
D.3.11.12 Homeopathic medicinal product: No
D.3.11.13 Another type of medicinal product: No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1 Is a Placebo used in this Trial? Yes
D.8.3 Pharmaceutical form of the placebo: Film-coated tablet
D.8.4 Route of administration of the placebo: Oral use
D.8 Placebo: 2
D.8.1 Is a Placebo used in this Trial? Yes
D.8.3 Pharmaceutical form of the placebo: Film-coated tablet
D.8.4 Route of administration of the placebo: Oral use

E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1 Medical condition(s) being investigated:
E.1.1.1 Medical condition in easily understood language: Alzheimer's disease
E.1.1.2 Therapeutic area: Diseases [C] - Nervous System Diseases [C10]
MedDRA Classification
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 20.0
E.1.2 Level: HLT
E.1.2 Classification code: 10001897
E.1.2 Term: Alzheimer's disease (incl subtypes)
E.1.2 System Organ Class: 100000004852
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 20.0
E.1.2 Level: LLT
E.1.2 Classification code: 10001896
E.1.2 Term: Alzheimer's disease
E.1.2 System Organ Class: 100000004852
E.1.2 Medical condition or disease under investigation:
E.1.2 Version: 24.1
E.1.2 Level: LLT
E.1.2 Classification code: 10086384
E.1.2 Term: Early onset Alzheimer's disease
E.1.2 System Organ Class: 100000004852
E.1.3 Condition being studied is a rare disease: No
E.2 Objective of the trial
E.2.1 Main objective of the trial: The primary objective of the study is to evaluate whether masitinib treatment will show a significant improvement ADCS-ADL and ADAS-Cog versus placebo in the study patients.
E.2.2 Secondary objectives of the trial: The secondary objectives of the study are to evaluate the efficacy of masitinib compared with placebo on a range of clinical parameters of Alzheimer's disease.  The secondary objectives also include the assessment of safety and tolerability of masitinib as compared to placebo in terms of adverse events, vital signs, physical examination, ECG, and clinical laboratory tests.
E.2.3 Trial contains a sub-study: No
E.3 Principal inclusion criteria: 1.	Patient with clinical diagnosis of Alzheimer's disease based on cognitive impairment and daily functional dependency at screening visit
2.	Patient with ADCS-ADL score at screening visit and baseline visit <73

3.	Patient with MMSE ≥ 14 and ≤ 25 at screening visit and baseline visit

4.	Patient with Alzheimer’s Disease biomarker profile at screening visit:
- A positive amyloid PET scan
- Alternatively, a-beta 1-42 <1000pg/ml AND p-tau >19pg/ml OR a p-tau/a-beta ratio > 0.024, as measured by a central laboratory according to the Elecsys assay for CSF biomarkers

5.	Patients treated for a minimum of 6 months with a stable dose of cholinesterase inhibitors (donepezil, rivastigmine or galantamine) at baseline visit, and/or a stable dose of memantine for a minimum of 6 months at baseline visit, with no changes foreseen in therapy throughout the study

6.	If receiving a supplement for cognition (eg, gingko biloba, omega-3 polyunsaturated fatty acid, vitamin E, curcumin, souvenaid) must be taking a stable dose for at least 4 months prior to screening visit

7.	Patients with a caregiver who, at screening visit and baseline visit:
-	Agrees to accompany the participant to all study visits and able to supervise the participant's compliance with the study procedures and provide detailed information about the participant.
-	Either lives with the participant or sees the participant on average for ≥1 hours/day ≥3 days/week, or in the Investigator's opinion, the extent of contact is sufficient to provide meaningful assessment of changes in participant behaviour and function over time and provide information on safety and tolerability.
-	Is able to read, understand, and speak the designated language at the study centre.
-	Caregiver must be cognitively able to fulfil the requirements of the study.

Other inclusion criteria
8.	Male or non-pregnant female adult ≥50 years of age at time of enrolment at screening visit

9.	Patients with bodyweight >45 kg and BMI between 18 and 35 kg/m2 at screening visit or baseline visit

10.	Contraception, at screening and baseline visit:
Female patients of childbearing potential (entering the study after a menstrual period and who has a negative pregnancy test), who agree to use a highly effective method of contraception and an effective method of contraception by their male partner during the study and for 3 months and a half after the last treatment intake
Male patients with a female partner of childbearing potential who agree to use a highly effective method of contraception and an effective method of contraception by their female partner during the study and for 3 months and a half after the last treatment intake OR who agree to use an effective method of contraception and a highly effective method of contraception by their female partner during the study and for 3 months and a half after the last treatment intake.

Highly effective and effective methods of contraception are detailed in the Appendix 14.1 of the protocol.

11.	Subjects must be able and willing to comply, both at screening visit and at baseline visit, with study visits and procedures

12.	Subjects able to understand, sign, and date the written informed consent form at screening visit prior to any protocol-specific procedures

13.	Subjects able to understand, and willing to follow the safety procedures mentioned on the patient card in case of signs or symptoms of severe neutropenia or severe cutaneous toxicity, at screening and baseline visit. Patient card will be provided at baseline visit

E.4 Principal exclusion criteria: 1.	Patients with any other cause of dementia shown by MRI findings and neurological examination in the last 12 months prior to screening visit
2.	Systemic conditions known to cause dementia, e.g., hypothyroidism, untreated vitamin B12 or folic acid deficiency, niacin deficiency, neurosyphilis, HIV infection at screening visit
3.	Patients with substance-induced dementia at screening visit
4.	Patients with Alzheimer’s disease with delirium at screening visit
5.	Patients with severe forms of delusions (e.g, NPI delusion score of 4 or more) at screening visit
6.	Patients with evidence of psychosis and/or use of antipsychotic drugs at screening, or history of significant psychiatric disorder at screening visit
7.	Patients with hypersensitivity to masitinib or its excipients at screening
8.	Patients with history (or family history) of drug-induced severe skin toxicities or reactions at screening or patients taking concomitant treatment or therapies associated with severe drug-induced skin toxicity

9.	Patients with history of severe bone marrow disorders such as agranulocytosis or aplasia, or with abnormal laboratory results from local laboratory assessments at screening and baseline defined as:
-	Neutropenia with ANC <1.5 × 109/L
-	Anemia with Hgb <10 g/dl
-	Thrombocytopenia with platelet counts <75 × 109/L

10.	Patients with history of severe hepatic disorders, such as viral hepatitis or steatohepatitis, and alcoholic steatosis, or with abnormal laboratory results defined as:
-	Hepatic transaminase levels >2 ULN at baseline, or
-	Total bilirubin level >1.5 ULN at baseline, or
-	Both hepatic transaminase levels and total bilirubin level outside of the normal ranges at screening and baseline, or
-	Albuminemia <1 × LLN at screening and baseline, or
-	Patients with concomitant medication known to be associated with severe hepatotoxicity

11.	Patients with pre-existing severe renal impairment, or with abnormal laboratory results at screening:
-	Creatinine clearance <60 mL/min (Cockcroft and Gault formula) or
-	Proteinuria >30 mg/dL (1+) on dipstick; in case of the proteinuria ≥1+ on the dipstick, 24 hours proteinuria must be >1.5 g/24 hours

12.	Patients with current or history of severe cardiovascular disease, assessed at screening:
-	Myocardial infarction
-	Unstable angina pectoris
-	Coronary revascularization procedure
-	Congestive heart failure of NYHA Class III or IV
-	Stroke, including a transient ischemic attack
-	Second degree or third-degree atrioventricular block not successfully treated with a pacemaker
-	Bi-fascicular block
-	QTc Fridericia interval > 450 milliseconds for males and > 470 milliseconds for females
-	Drug induced heart failure or ischemic heart disease
-	Radiotherapy induced cardiomyopathy
-	Family history of unexpected death of cardiovascular origin
-	Edema of cardiac origin and left ventricular ejaculation fraction ≤50%

13.	Patients, with two or more of the risk factors listed below assessed by a cardiologist at screening as Very High Risk (calculated SCORE* ≥10%.) according to the Systematic Coronary Risk Estimation (SCORE*):
-	Hypertension (uncontrolled)
-	Diabetes
-	Kidney disease
-	Current smoking (≥ 10 Pack-year: equivalent to 1 pack of 20 cigarettes for 10 years with the formula N (number of packs of 20 cigarettes smoked daily) × T (number years smoking)) Patients who stopped smoking 6 months prior to the evaluation, are not concerned.
-	Hypercholesterolemia,
-	COPD
* This assessment is done according to the Systematic Coronary Risk Estimation (SCORE) using the country specific free full version of HeartScore®, the interactive tool for predicting and managing the risk of heart attack and stroke in Europe, available at https://www.heartscore.org/en_GB/access
If the country specific version is not available, EU one should be used.


19.	Pregnant, or nursing female patients at screening or baseline

20.	Patients with a diagnosis of cancer or evidence of continued disease within five years before screening
22.	Patient who has been exposed to an investigational treatment within 3 months (9 months for immunotherapies) or five half-lives of an investigational product, whichever is longer, before the screening visit
23.	Subjects who have received a live vaccine within 30 days prior to first IMP administration
E.5 End points
E.5.1 Primary end point(s): The study has two following primary endpoints:
•	Absolute change from baseline in ADCS-ADL score at week 24
and
•	Absolute change from baseline in ADAS-Cog score at week 24
E.5.1.1 Timepoint(s) of evaluation of this end point: week 24
E.5.2 Secondary end point(s): The key secondary endpoint consists of:
•	Time to severe dementia (MMSE<10)
The secondary endpoints of the study are:
•	Absolute change from baseline in ADAS-Cog score at week 48
•	Absolute change from baseline in ADCS-ADL score at week 48
•	Clinical Responder rate at Week 24.
•	Clinician’s Interview Based Impression of Change-plus (CIBIC-plus) at Week 24
•	Mini-Mental State Examination (MMSE) at Week 24
•	Clinical Dementia Rating (CDR) at Week 24
•	Neuropsychiatric Inventory (NPI) at Week 24

E.5.2.1 Timepoint(s) of evaluation of this end point: week 24, week 48
E.6 and E.7 Scope of the trial
E.6 Scope of the Trial
E.6.1 Diagnosis: No
E.6.2 Prophylaxis: No
E.6.3 Therapy: Yes
E.6.4 Safety: Yes
E.6.5 Efficacy: Yes
E.6.6 Pharmacokinetic: No
E.6.7 Pharmacodynamic: No
E.6.8 Bioequivalence: No
E.6.9 Dose response: No
E.6.10 Pharmacogenetic: No
E.6.11 Pharmacogenomic: No
E.6.12 Pharmacoeconomic: No
E.6.13 Others: No
E.7 Trial type and phase
E.7.1 Human pharmacology (Phase I): No
E.7.1.1 First administration to humans: No
E.7.1.2 Bioequivalence study: No
E.7.1.3 Other: No
E.7.1.3.1 Other trial type description:
E.7.2 Therapeutic exploratory (Phase II): No
E.7.3 Therapeutic confirmatory (Phase III): Yes
E.7.4 Therapeutic use (Phase IV): No
E.8 Design of the trial
E.8.1 Controlled: Yes
E.8.1.1 Randomised: Yes
E.8.1.2 Open: No
E.8.1.3 Single blind: No
E.8.1.4 Double blind: Yes
E.8.1.5 Parallel group: Yes
E.8.1.6 Cross over: No
E.8.1.7 Other: No
E.8.2 Comparator of controlled trial
E.8.2.1 Other medicinal product(s): Yes
E.8.2.2 Placebo: Yes
E.8.2.3 Other: Yes
E.8.2.3.1 Comparator description: cholinesterase inhibitors (donepezil, rivastigmine, or galantamine), memantine
E.8.2.4 Number of treatment arms in the trial: 2
E.8.3 The trial involves single site in the Member State concerned: Yes
E.8.4 The trial involves multiple sites in the Member State concerned: Yes
E.8.4.1 Number of sites anticipated in Member State concerned: 5
E.8.5 The trial involves multiple Member States: Yes
E.8.5.1 Number of sites anticipated in the EEA: 155
E.8.6 Trial involving sites outside the EEA
E.8.6.1 Trial being conducted both within and outside the EEA: Yes
E.8.6.2 Trial being conducted completely outside of the EEA: No
E.8.6.3 If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned:
Argentina
Canada
Colombia
Israel
Peru
South Africa
United States
Finland
France
Poland
Sweden
Bulgaria
Netherlands
Romania
Spain
Switzerland
Czechia
Germany
Greece
Italy
Belgium
Denmark
Ireland
Norway
Portugal
Russian Federation
Serbia
Slovakia
Slovenia
Ukraine
United Kingdom
E.8.7 Trial has a data monitoring committee: Yes
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: Last Visit Last Subject
E.8.9 Initial estimate of the duration of the trial
E.8.9.1 In the Member State concerned years: 2
E.8.9.1 In the Member State concerned months:
E.8.9.1 In the Member State concerned days:
E.8.9.2 In all countries concerned by the trial years: 2

F. Population of Trial Subjects
F.1 Age Range
F.1.1 Trial has subjects under 18: No
F.1.1.1 In Utero: No
F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No
F.1.1.3 Newborns (0-27 days): No
F.1.1.4 Infants and toddlers (28 days-23 months): No
F.1.1.5 Children (2-11years): No
F.1.1.6 Adolescents (12-17 years): No
F.1.2 Adults (18-64 years): Yes
F.1.2.1 Number of subjects for this age range: 24
F.1.3 Elderly (>=65 years): Yes
F.1.3.1 Number of subjects for this age range: 576
F.2 Gender
F.2.1 Female: Yes
F.2.2 Male: Yes
F.3 Group of trial subjects
F.3.1 Healthy volunteers: No
F.3.2 Patients: Yes
F.3.3 Specific vulnerable populations: Yes
F.3.3.1 Women of childbearing potential not using contraception : No
F.3.3.2 Women of child-bearing potential using contraception: Yes
F.3.3.3 Pregnant women: No
F.3.3.4 Nursing women: No
F.3.3.5 Emergency situation: No
F.3.3.6 Subjects incapable of giving consent personally: No
F.3.3.7 Others: No
F.4 Planned number of subjects to be included
F.4.1 In the member state: 30
F.4.2 For a multinational trial
F.4.2.1 In the EEA: 480
F.4.2.2 In the whole clinical trial: 600
F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): None

G. Investigator Networks to be involved in the Trial


N. Review by the Competent Authority or Ethics Committee in the country concerned
N. Competent Authority Decision: Authorised
N. Date of Competent Authority Decision: 2022-09-22
N. Ethics Committee Opinion of the trial application: Favourable
N. Ethics Committee Opinion: Reason(s) for unfavourable opinion:
N. Date of Ethics Committee Opinion: 2022-09-20

P. End of Trial
P. End of Trial Status: Ongoing

