E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
patients suffering from Amyotrophic Lateral Sclerosis (ALS) |
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E.1.1.1 | Medical condition in easily understood language |
Amyotrophic Lateral Sclerosis (ALS) |
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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 | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10002026 |
E.1.2 | Term | Amyotrophic lateral sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 masitinib versus placebo in the treatment of patients suffering from Amyotrophic Lateral Sclerosis (ALS). |
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E.2.2 | Secondary objectives of the trial |
- Combined Assessment of Function and Survival
- Survival defined as the time from randomisation to the date of documented death or first tracheotomy
- Time to first tracheotomy
- Change of Forced Vital Capacity from baseline to each time point (week 4, 8, 12, 24, 36, 48)
- Number of failure defined as a 9-point drop in ALSFRS-R or death from baseline
- Change from baseline to each time point (week 4, 8, 12, 24 and 36) in ALSFRS-Revised
- Survival rate defined as the rate of patients alive without tracheotomy at each time point (week 12, 24, 36 and 48)
- Change in cystatin C level from baseline to each time point
- Time to first gastrectomy defined as the time from randomisation to the time of the first gastrectomy
- Absolute and relative change in ALSAQ- 40 at each time point
- Safety: occurrence of Adverse Events (AE), changes on clinical examination including vital signs and weight, ECG and laboratory exams (biochemistry, hematology and urinalysis)
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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 |
PharmacoGenomic (PG) study:
The aim of this study is to determine the genes polymorphisms, including HLA polymorphismsn that could be associated with an increase risk of masitinib-induced severe neutropenia and severe skin toxicity. All samples will be centrally analyzed in the Institut Paoli Calmettes, department de Biopathologie, Marseille, France.
PharmacoKinetic (PK) study:
A Pharmacokinetic study, in up to 10 patients, to evaluate PK parameters of riluzole will be conducted.
All samples will be centrally analysed in the Pharmacology Laboratory, Centre René Huguenin, Saint-Cloud,
France.
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E.3 | Principal inclusion criteria |
INCLUSION CRITERIA:
1. Female or male patient aged between 18 and 75 years of age, with a weight > 50 kg and BMI between 18 and 35 kg/m².
2. Familial or sporadic ALS
3. Patient diagnosed with laboratory supported, clinically probable or definite ALS according to the World Federation of Neurology Revised El Escorial criteria (Brooks, 1994)
4. Disease duration from symptoms onset no longer than 36 months at the screening visit
5. Patient treated with a stable dose of riluzole (100 mg/day) for at least 30 days prior to screening
6. Patient with a FVC (Forced Vital Capacity) equal to or more than 60% predicted normal value for gender, height, and age at the screening visit
7. Patient with life expectancy ≥ 6 months
8. 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/ALT ≤ 3 ULN
• Bilirubin ≤ 1.5 ULN
• Albuminemia > 1 x LLN
• Creatinine clearance > 60 mL/min (Cockcroft and Gault formula)
• Proteinuria < 30 mg/dL (1+) on dipstick; in case of the proteinuria ≥ 1+ on the dipstick, 24 hours proteinuria must be < 1.5g/24 hours
9. Male patient or female patient of child bearing potential, who must agree to use two methods (one for the patient and one for the partner) of medically acceptable forms of contraception (with failure rate < 1%) during the study and for three months after the last treatment intake
10. Female patient of childbearing potential must have a negative pregnancy test at screening and baseline
11. Patient able and willing to comply with study procedures as per protocol
12. Patient able to understand, and willing to sign, and date the written informed consent form at screening visit prior to any protocol-specific procedures
13. Patient 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, during the first two months of treatment
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E.4 | Principal exclusion criteria |
EXCLUSION CRITERIA
1. Patient with history of hematologic, hepatic, respiratory disorder that is clinically significant for his/her participation in the study
2. Patient who underwent tracheotomy and /or gastrostomy
3. Patient with a diagnosis of cancer or evidence of continued disease within five years before starting study treatment
4. Patient with significant sensory abnormalities, dementia, other neurologic diseases, uncompensated medical illness and psychiatric illness
5. Patient who have participated in a clinical trial within 3 months prior to screening
6. Pregnant, or nursing female patient
7. Patient with a known diagnosis of human immunodeficiency virus (HIV) infection
8. Patient with known active hepatitis B, hepatitis C or tuberculosis
9. Patient with any severe and/or uncontrolled medical condition
10. Patient having 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
11. 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
PREVIOUS TREATMENTS WASH OUT
12. Patient treated with any investigational agent within 3 months prior to screening
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoints
Change from baseline to week 48 in Amyotrophic Lateral Sclerosis functional rating scale (ALSFRS)-Revised
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints:
• Combined Assessment of Function and Survival (CAFS)
• Survival defined as the time from randomisation to the date of documented death or first tracheotomy
• Time to first tracheotomy defined as the time from randomisation to the time of the first tracheotomy
• Change of Forced Vital Capacity (FVC) from baseline to each time point (week 4, 8, 12, 24, 36, 48)
• Number of failure defined as a 9-point drop in ALSFRS-R or death from baseline
• Change from baseline to each time point (week 4, 8, 12, 24 and 36) in Amyotrophic Lateral Sclerosis functional rating scale (ALSFRS)-Revised
• Survival rate defined as the rate of patients alive without tracheotomy at each time point (week 12, 24, 36 and 48)
• Change in cystatin C level from baseline to each time point
• Time to first gastrectomy defined as the time from randomisation to the time of the first gastrectomy
• Absolute and relative change in ALSAQ- 40 at each time point
• Safety: occurrence of Adverse Events (AE), changes on clinical examination including vital signs and weight, ECG and laboratory exams (biochemistry, hematology and urinalysis)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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) | Yes |
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 | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
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 | Yes |
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 |
Czech Republic |
France |
Germany |
Greece |
Hungary |
Italy |
Mexico |
Romania |
Serbia |
Slovakia |
Spain |
United Kingdom |
United States |
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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
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Study treatment will be discontinued in case of:
· Informed consent withdrawal
· Adverse or undercurrent event considered intolerable by the patient or incompatible with continuation of
the study according to the investigator
· Protocol violation (e.g., noncompliance with treatment administration, prohibited treatment needed) |
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
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 |