| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| patients suffering from Amyotrophic Lateral Sclerosis (ALS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Amyotrophic Lateral Sclerosis (ALS) |
|
| 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 | 21.1 |
| 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 |
| The primary objective is to evaluate the efficacy and safety of masitinib 4.5 mg/kg/day as add-on therapy to Riluzole in patients diagnosed with ALS during the prospective Period 2 of the trial |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives are to assess the efficacy and safety of masitinib 4.5 mg/kg/day versus matching placebo in the treatment of patients diagnosed with ALS treated with Riluzole
|
|
| 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 |
Pharmacodynamic/biomarker(s):
-Identification of pharmacodynamic biomarker(s) is needed to fully characterize the potential disease modifying effects of masitinib in ALS patients. The aim is to assess, before and during trial treatment, cerebrospinal fluid (CSF) in up to 30 ALS patients and serum biomarkers in up to all randomized ALS patients known to be associated with the evolution of the disease and potentially modulated by masitinib treatment
Pharmacokinetic:
- Measurement of pharmacokinetic parameters of masitinib and Riluzole in up to 10 ALS patients per group and validate population PK model for masitinib |
|
| E.3 | Principal inclusion criteria |
In order to be eligible to participate in this trial, a patient must fulfil all the following criteria:
1. Patient, male or female, diagnosed with laboratory supported probable, clinically probable or definite ALS according to the World Federation of Neurology Revised El Escorial criteria [52]
2. Patient with a familial or sporadic ALS
3. Patient aged between 18 and 80 years old inclusive at at the time of signing the informed consent
4. Patient treated with a stable dose of Riluzole (100 mg/day) for at least 30 days prior to screening visit
5. Patient with an ALS disease duration from diagnosis no longer than 24 months at screening
6. Patient with onset of first symptom of ALS no longer than 36 months at screening
7. Patient with a ALSFRS-R progression rate of > 0.3 and <1.1 point/month
i) between onset of the disease and screening AND
ii) between any available documented ALSFRS assessment during the period ranging from seven months to two months prior to screening and screening
8. Patient with an ALSFRS-R total score at screening and baseline following rules below:
- at least 3 on item #3 and
- at least 2 on item #12) and
- at least 1 on each of the other 10 items (i.e. item #1, #2, #4, #5a or #5b, #6, #7, #8, #9, #10, and #11)
9. Contraception:
- Female patient of childbearing potential (entering the trial after a menstrual period and who has a negative pregnancy test), who agrees to use a highly effective method of contraception and an effective method of contraception by her male partner during the trial and for 8 months after the last treatment intake
- Male patient with a female partner of childbearing potential who agrees to use a highly effective method of contraception and an effective method of contraception by his female partner during the trial and for 5 months after the last treatment intake OR who agrees to use an effective method of contraception and a highly effective method of contraception by his female partner during the trial and for 5 months after the last treatment intake
Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical trials. Highly effective and effective methods of contraception are detailed in appendix 15.1
10. Patient able to understand, and willing to sign, and date the written informed consent form prior to any protocol-specific procedures. If patients are duly capable of trial consent but are unable to sign by themselves due to aggravation of disease condition, written informed consent can be obtained from a legally authorized representative who can sign on behalf of the patients after confirming the patients' agreement to trial participation
11. Patient able and willing to comply with trial protocol and to come on-site as per protocol visits schedule
12. 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 |
|
| E.4 | Principal exclusion criteria |
A potential patient who meets any of the following criteria will be excluded from trial participation:
1. Patient with dementia or significant neurological, psychiatric, systemic or organic disease, uncontrolled or that may interfere with the conduct of the trial or its results
2. Patient with hypersensitivity to masitinib or its excipients and riluzole or its excipients
3. Patient with an FVC < 70% predicted normal value for gender, height, and age at screening and baseline
4. Patient with a weight < 41 kg and a BMI < 18 or > 35 kg/m² at screening or at baseline
5. Pregnant, or nursing female patient
6. Patient with history (or family history) of severe skin toxicities or reactions
7. Patients treated by drugs known to be at high risk for Stevens-Johnson Syndrome or for Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome
8. Patient 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 :
- Neutropenia with ANC < 1.5x109/L
- Anemia with Hgb < LLN or red blood cell count below the LLN
- Thrombocytopenia with platelets counts < 150 x 109/L
9. Patient with history of hepatic disorders, with a known liver disease or recent alcohol abuse, or with abnormal laboratory results from local laboratory assessments 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 x LLN at screening and baseline
- Patients with concomitant medication known to be associated with severe hepatotoxicity
10. Patient with pre-existing severe renal impairment, or with abnormal laboratory results from local laboratory assessments at screening and baseline :
- 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 > 1.5g/24 hours
11. Patient with active severe infection such as herpes, tuberculosis, viral hepatitis, human immunodeficiency virus infection
12. Patient with autoimmune conditions such as systemic lupus erythematosus
13. Patient with a diagnosis of cancer or evidence of continued disease within five years before screening
14. 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
- oedema of cardiac origin and left ventricular ejection fraction ≤ 50%
15. Patients, with two or more of the risk factors listed below assessed by a cardiologist as Very High Risk (calculated SCORE ≥10%.) or High Risk calculated SCORE ≥5% and <10%) according to the Systematic Coronary Risk Estimation (SCORE):
- Hypertension (uncontrolled)
- Diabete
- Kidney disease
- Current tabagism (≥ 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) x 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. HeartScore is calculated for patients up to age 65. Patients older than this may be at a higher risk level than stated
16. Patient who has been exposed to an investigational treatment within 3 months or five half-lives of the investigational product, whichever is longer, before the screening visit
17. Patient who has been treated to Edaravone within 30 days prior to screening
18. Patient treated concomitantly with known substrates of P-gp and BCRP with narrow therapeutic index
19. Patient treated concomitantly with clinical strong or moderate inhibitors of CYP2C8
20. Patient treated concomitantly with clinical strong or moderate inhibitors or inducers of CYP1A2
(...) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Absolute change from baseline at week 48 in ALSFRS-R score will be analysed using multiple imputation model. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints:
- PFS will be analysed using the log rank test. Kaplan-Meier Plots will be provided.
- ALSAQ-40 change will be analyzed using the same primary model. In addition, an Analysis of Covariance model (ANCOVA) with stratification factors, drug and baseline ALSAQ-40 score will be performed.
- FVC change from baseline will be analysed using the same model as primary. In addition, an ANCOVA with stratification factors, treatment and baseline ALSAQ-40 score will be performed.
- Upper- and lower-limb muscle strength using HHD will be summarized by treatment arm.
- Clinician-rated CGI will be summarized by treatment arm.
- CAFS will be analysed using the Generalised GehanWilcoxon rank test.
- OS will be analysed using the log rank test. Kaplan-Meier Plots will be provided.
- EFS will be analysed using the log rank test. Kaplan-Meier Plots will be provided.
- Safety: Occurrence of Adverse Events (AE), changes on physical examination, vital signs (blood pressure, heart rate, weight and temperature), ECG and clinical laboratory tests (haematology, biochemistry, urinalysis, urinary cytology)
Analysis will be performed in patients randomized during Period 2 of the trial.
Group 4 versus Group 5 comparisonwill be tested at 5% level of significance a two-sided test.
If there is a statistically significant difference observed between Group 4 and Group 5 for the change from baseline at W48 in ALSFRS-R score then efficacy claim will be made with masitinib dose titration to 4.5 mg/kg/day
Patients randomized in Group 1 and Group 3 during Period 1 of the trial and fitting the inclusion criteria of the present protocol amendment will then be added for sensitivity analysis
Exploratory analyses will be performed for other patients (i.e. Fast Progressors, and 6 mg/kg day dosing).
Interim analysis:
It will be performed once 225 patients have been randomized in Period 2 and could have reached the 48-week treatment time point. This represents 75% of the patient population in each group. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| at W48 or event occurence (death) depending on secondary endpoint |
|
| 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 | Yes |
| 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) | 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 | 29 |
| 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 |
| Ukraine |
| Canada |
| Israel |
| Russian Federation |
| United Kingdom |
| United States |
| Belgium |
| Denmark |
| France |
| Italy |
| Norway |
| Poland |
| Portugal |
| Slovenia |
| Spain |
| Sweden |
|
| 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 | 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 |
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