| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Amyotrophic lateral Sclerosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| A rare disorder of nerve cells (motor neurone disease) located in the brain and connected tissue. ALS causes the nerve cells to die and stops messages being sent to the muscles in the body. |
|
| 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 | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028003 |
| E.1.2 | Term | Motor neurone disease |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| 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 |
|
| 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 compare the Efficacy and safety of the study drug (Masitinib) as add-on therapy in combination with the drug Riluzole in the treatment of patients suffering from Amyotrophic Lateral Sclerosis(ALS). Riluzole is currently the only approved drug for the treatment of ALS.
The primary endpoint for this study is the comparison of the Revised ALS Functional Rating Scale (ALSFRS -revised) from baseline to week 48. ALSFRS-revised is a validated rating system for monitoring the progression of disability in ALS patients.
Extension period:
Given that a favourable benefice/risk balance has been documented and approved, the objective of the extension phase is to evaluate the maintenance of the clinical benefit of patients at each extension visit through the same efficacy and safety measures implemented from baseline to week 48. |
|
| E.2.2 | Secondary objectives of the trial |
- 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 and at each patient visit from the date of entry in the extension period).
- 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, 36 and at each patient visit from the date of entry in the extension period) 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, 48 and at each patient visit from the date of entry in the extension period)
- Change in cystatin C level from baseline to each time point
- Time to fi |
|
| 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 |
The protocol allows for an 2 optional studies.
- A pharmacogenomic sub-study 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.
- pharmacokinetic sub-study, Additional blood samples will be collected at week 0 and week 1 to investigate the pharmacokinetic profile of Riluzole used in conjunction with Masitinib. Participation to this additional study will require additional blood samples and a separate consent will be required. |
|
| E.3 | Principal inclusion criteria |
1.Female or male patient aged between 18 and 75 years of age, with a weight > 50 kg and BMI (body mass index) 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 and Female patient of childbearing potential (entering the study after a menstrual period and who have a negative pregnancy test), who agrees to use two highly effective 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 3 months after the last treatment intake. Acceptable forms of contraception include:
- combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
o oral
o intravaginal
o transferral
- progestogen-only hormonal contraception associated with inhibition of ovulation:
o oral
o inject able hormonal contraception
o implantable hormonal contraception
- placement of an intrauterine device (IUD)
- placement of an intrauterine hormone-releasing system ( IUS)
- bilateral tubal occlusion
- vasectomised partner
- sexual abstinence
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 |
|
| E.4 | Principal 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Compare the efficacy and safety of masitinib combined with Riluzole as add-on therapy versus placebo combined with Riluzole as add-on therapy in the treatment of patients suffering from Amyotrophic Lateral Sclerosis (ALS).
Primary Objective is stated as: Amyotrophic Lateral Sclerosis functional rating scale (ALSFRS) - Revised from baseline to week 48. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
All data will be analysed at Week 48.
In addition safety, futility and an interim analysis is planned during the study. An Independent Data Monitoring Committee without direct involvement in the conduct of the study, will monitor safety data throughout the duration of the study to determine if continuation is appropriate both scientifically and ethically.
Futility analysis:
The IDMC will review the different efficacy criteria about 48 weeks after the 60-75th patient is randomized.
Interim analysis:
An independent statistical center will be responsible for carrying out the planned interim analysis after about 50% of patients are randomised. |
|
| E.5.2 | Secondary end point(s) |
- 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 and at each patient visit from the date of entry in the extension period)
- Number of failure defined as a 9-point drop in ALSFRS-R from baseline or death
- Change from baseline to each time point (week 4, 8, 12, 24, 36, and at each patient visit from the date of entry in the extension period) 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, 48, and at each patient visit from the date of entry in the extension period)
- Change in cystatin C level from baseline to each time point
- Time to first gastrostomy defined as the time from randomisation to the time of the first gastrostomy
- Absolute and relative change from baseline 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) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Full analysis will be performed at 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 | 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) | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | 40 |
| 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 |
| Belgium |
| Colombia |
| France |
| Germany |
| Greece |
| Hungary |
| Ireland |
| Italy |
| Mexico |
| Netherlands |
| Portugal |
| Romania |
| Slovakia |
| Spain |
| Switzerland |
| 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 W48. After W48 the patient may enter the extension if approved by the Investigator, patient, available study data and competent authority. After 96 weeks of exposure patients will need to re-sign consent. |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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