| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| mild to moderate Alzheimer’s disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| mild to moderate 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 | LLT |
| E.1.2 | Classification code | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012271 |
| E.1.2 | Term | Dementia Alzheimer's type |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| 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 objective is to compare the efficacy and safety of oral masitinib 3, 4,5 mg/kg/day or 4.5 mg/kg/day with a switch after 12 weeks of treatment to 6 mg/kg/day in combination with cholinesterase inhibitors and/or memantine to placebo in combination with cholinesterase inhibitors and/or memantine in patients with mild-to moderate Alzheimer’s disease.
• Co-primary endpoints:
- Effect on self-care and activities of daily living assessed by Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) from Week 8 to Week 24.
- Effect on cognition and memory assessed by Alzheimer’s disease Assessment Scale (ADAS-Cog) from Week 8 to Week 24.
The treatment effect needs to be established in at least one of the endpoints and both the endpoints will be simultaneously tested at 2.5% level of significance with a fallback procedure. While the changes in ADAS-Cog is aimed to demonstrate the treatment effect on cognitive impairment, ADCS-ADL is designed to capture the change on the |
|
| E.2.2 | Secondary objectives of the trial |
• Secondary endpoints:
-
- 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
- Clinical responder rate at Week 24
- MRI assessment at Week 24
- Safety: occurrence of Adverse Events (AE), changes on clinical examination including vital signs (blood pressure, pulse rate) and weight, ECG and laboratory exams (biochemistry, hematology and urinalysis)
- Pharmacogenomic assessment: relationship between genomic data and safety
- Pharmacokinetic (PK) analysis in some patients randomized in masitinib group
Objectives of the extension period
- First objective: to evaluate the sustainability of masitinib efficacy in long term therapy for Alzheimer disease assessed by ADCS-ADL and ADAS-Cog every 12-weeks from W24 to W96. Only a descriptive analysis of those ADCS-ADL and ADAS-Cog scores will be performed.
- Second objective: safety |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
There are four sub studies
1. Pharmacogenomic study in order to define efficacy or safety genomic predictive criteria.
2. MRI study: to define a new precoce marker of Alzheimer‘s disease
3. A pharmacogenomic sub study is also proposed in order to define efficacy or safety genomic predictive criteria if a patient experiences severe neutropenia/skin toxicity
4. A pharmacokinetic (PK) analysis will be performed in patients who agreed to participate in the PK study and were randomized in the trial.
Pharmacogenomic study: The objectives of this genomic study are to evaluate potential relationships between the genes, efficacy and safety of the study treatment. Participation to this additional study will require additional laboratory samplings.
MRI study: The objective of this study is to define a new precocious marker of Alzheimer's disease. Participation to this additional study will require two additional MRIs.
A pharmacogenomic sub study is also proposed in order to define efficacy or safety genomic predictive criteria. A blood sample will be
collected if a patient experiences either severe skin toxicity or severe neutropenia. The objectives of this genomic study are to evaluate potential relationships between the genes, efficacy and safety of the study treatment. Participation to this additional study will require additional blood samples and a separate consent will be required.
For a given patient, masitinib pharmacokinetics parameters will first be determined at week 4, week 12 and week 24 visits.
These sub studies are optional. Patients can agree to participate to the principal study only or to both principal and sub studies. Participation in one or all the studies will mean they will only have to provide additional blood samples and or undergo additional MRI scans respectively. For this separate consents will be provided. |
|
| E.3 | Principal inclusion criteria |
1. Male or female patient
2. Age ≥ 50 years, weight >50 kg and with a Body Mass Index (BMI) >18 kg/m² at screening
3. Patient and/ or caregiver able to understand the patient card and to follow the patient card procedures in case of signs or symptoms of severe neutropenia or severe cutaneous toxicity, during the first 2 months of treatment
4. Menopause ≥ 2 years for female patient
5. Patient with dementia of Alzheimer's type, according to DSM-IV criteria
6. Patient with probable Alzheimer' disease according to NINCDS-ADRDA criteria
7. Patient with MMSE ≥ 12 and ≤ 25 at baseline
8. Patient treated for a minimum of 6 months with a stable dose of cholinesterase inhibitors (donepezil, rivastigmine or galantamine) at baseline, and/or a stable dose of memantine for a minimum of 6 months at baseline, with no changes foreseen in therapy throughout the study
9. Patient with adequate organ function at screening and baseline:
• Absolute Neutrophils Count (ANC) ≥ 2 x 109/L
• Hemoglobin ≥ 10 g/dL
• Platelets (PTL) ≥ 100 x 109/L
• AST and ALT ≤ 3 ULN
• Bilirubin ≤ 1.5 ULN
• Albuminemia > 1 x LLN
• Creatinine clearance ≥ 60 mL/min. Calculated with both Cockcroft-Gault formula and MDDR (Modification of Diet in Renal Disease) formulae.
• Proteinuria < 30 mg/dL (1+) on the dipstick. If proteinuria ≥ 1+ on the dipstick, 24 hours proteinuria must be < 1.5g/24 hours
10. Patient with a regular and reliable caregiver. The designated caregiver must be sufficiently familiar with the patient (as determined by the investigator) to provide accurate data. The caregiver must have regular contact with the patient (i.e., an average of 10 or more hours per week), must be able to observe for possible adverse events, must be able to oversee patient’s compliance with the study treatment and to report on the patient’s status and must be able to accompany the patient to all visits
11. Patient, identified caregiver and, if applicable, patient surrogate able and willing to comply with study visits and procedures per protocol, understand, sign, and date the informed consent form at screening visit prior to any protocol-specific procedures performed
12. Male patient with a female partner of childbearing potential who agrees to use a highly effective method of contraception and an acceptable method of contraception by his female partner during the study and for 3 months after the last treatment intake or who agrees to use an acceptable method of contraception and a highly effective method of contraception by his female partner during the study and for 3 months after the last treatment intake.
Highly effective methods of contraception include:
- Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal
- Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable
- Intrauterine device (IUD)
- Intrauterine hormone-releasing system (IUS)
- Bilateral tubal occlusion
- Vasectomized male (azoospermia assessed medically)
- Sexual abstinence (Its reliability should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient)
Acceptable methods of contraception include:
- Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action
- Male or female condom with or without spermicide
- Cap, diaphragm, or sponge with spermicide |
|
| E.4 | Principal exclusion criteria |
1. Patient with any other cause of dementia not due to Alzheimer's disease. If a specific examination including a brain neuro-imagery exam had been performed within the last 6 months that shows the following, the patient cannot be enrolled;
• Other central nervous condition causing progressive deficits in memory and cognition, e.g. cerebrovascular disease (patient with not more than 4 microbleeds and not more than 2 lacunes at the MRI could be enrolled in the study), Parkinson's disease, Huntington's disease and brain tumor
• Systemic conditions known to cause dementia, e.g., hypothyroidism, untreated vitamin B12 or folic acid deficiency, niacin deficiency, neurosyphilis, HIV infection…
• Substance-induced dementia
2. Patient with Alzheimer disease with severe forms of delusions or delirium (patients with light and mild forms of delusions and delirium will be allowed in the study)
3. Patient treated with any registered or putative cognitive/memory enhancer or disease modifier other than donepezil, galantamine, rivastigmine or memantine. (Patient taking Ginkgo Biloba can be enrolled providing it has been taken at a stable dose for at least 6 months).
4. Patient with evidence of psychosis and/or use of antipsychotic drugs at screening, or history of significant psychiatric disorder
5. Patient with active current bacterial, viral (including hepatitis B and C, HIV, EBV, CMV, herpes zoster), fungal, mycobacterium, protozoan, or other infection
6. Patient with history of infection requiring hospitalization within 2 weeks of screening
7. Patient presenting with cardiac disorders defined by at least one of the following conditions:
• Patient with recent cardiac history (within 6 months) of:
- Acute coronary syndrome
- Acute heart failure (class III or IV of the NYHA classification)
- Significant ventricular arrhythmia (persistent ventricular tachycardia, ventricular fibrillation, resuscitated sudden death)
• Patient with cardiac failure class III or IV of the NYHA classification
• Patient with severe conduction disorders which are not prevented by permanent pacing (atrio-ventricular block 2 and 3, sino-atrial block)
• Syncope without known aetiology within 3 months
• Uncontrolled severe hypertension, according to the judgment of the investigator, or symptomatic hypertension
8. Patient with history of poor compliance or history of drug/alcohol abuse, or excessive alcohol beverage consumption that would interfere with the ability to comply with the study protocol, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent
9. Patient with life expectancy < 1 year
Previous medications:
10. Patient treated with any investigational agent within 4 weeks of screening |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Co-primary endpoints:
- Effect on self-care and activities of daily living assessed by Alzheimer’s Disease Cooperative Study
Activities of Daily Living (ADCS-ADL) from Week 8 to Week 24.
- Effect on cognition and memory assessed by Alzheimer’s disease Assessment Scale (ADAS-Cog) from
Week 8 to Week 24.
The treatment effect needs to be established in at least one of the endpoints and both the endpoints will be
simultaneously tested at 2.5% level of significance with a fallback procedure. While the changes in ADASCog
is aimed to demonstrate the treatment effect on cognitive impairment, ADCS-ADL is designed to
capture the change on the functional scale.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
-
- 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.
- Clinical responder rate at Week 24.
- MRI assessment at Week 24
- Safety: occurrence of Adverse Events (AE), changes on clinical examination including vital signs (blood pressure, pulse rate) and weight, ECG and laboratory exams (biochemistry, haematology and urinalysis)
- Pharmacogenomic assessment: relationship between genomic data and safety
- Pharmacokinetic (PK) analysis in some patients randomized in masitinib group
Objectives of the extension period
- First objective: to evaluate the sustainability of masitinib efficacy in long term therapy for Alzheimer disease assessed by ADCS-ADL and ADAS-Cog every 12-weeks from W24 to W96. Only a descriptive analysis of those ADCS-ADL and ADAS-Cog scores will be performed.
- Second objective: safety of masitinib in long term use in patients with mild-to-moderate Alzheimer’s disease |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
| Bulgaria |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Romania |
| Slovakia |
| South Africa |
| Spain |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 29 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 29 |
Print
