Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of Masitinib and Riluzole in Amyotrophic Lateral Sclerosis Patients
- Trial ID
- 2024-511244-12-01
- Protocol
- AB23005
- Sponsor
- Ab Science
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to evaluate the **efficacy** and **safety** of masitinib at a dosage of 4.5 mg/kg/day as an add-on therapy to the standard of care in patients diagnosed with **Amyotrophic Lateral Sclerosis (ALS)**. This objective is clinically relevant as it aims to determine whether masitinib can provide additional therapeutic benefits in managing ALS, a progressive neurodegenerative disease with limited treatment options.
Secondary objectives include:
- Progression-Free Survival (PFS) defined as the time from randomization to progression (a decline of more than 9 points in the ALSFRS-R score from baseline) or death.
- Change in ALSAQ-40 from baseline to week 48.
- Change in the percentage of Forced Vital Capacity (FVC) from baseline to week 48.
- Changes in upper- and lower-limb muscle strength using Hand-Held Dynamometry (HHD) from baseline to week 48.
- Change in each component of clinician-rated Clinical Global Impression (CGI) from baseline to week 48.
- Change in Combined Assessment of Function and Survival (CAFS) from baseline to week 48 (outside of FDA scope).
- Overall Survival (OS) defined as the time from randomization to the date of documented death.
- Tracheostomy Free Survival (TFS) defined as the time from randomization to the first occurrence of either death or tracheostomy.
These secondary objectives are crucial for understanding the broader impact of masitinib on various clinical outcomes in ALS, potentially guiding future therapeutic strategies.
Participants
The clinical trial involves a total of **192 participants** diagnosed with **Amyotrophic Lateral Sclerosis** (ALS). The study population includes both male and female subjects, aged between 18 and 80 years. Participants were selected based on specific criteria, including a diagnosis of familial or sporadic ALS, and must have been treated with a stable dose of Riluzole for at least 30 days prior to the screening visit. The trial also considers lifestyle factors such as the use of Edaravone, which, if applicable, must have been administered at a stable dose for at least 30 days before screening. The population includes individuals who are not candidates for QALSODY® Tofersen treatment. Participants are required to have an ALSFRS-R progression rate between 0.3 and 1.1 points per month and must meet specific ALSFRS-R total score criteria at screening and baseline. The trial includes a vulnerable population, and all participants must be able to understand and comply with the trial protocol, including safety procedures for severe neutropenia or cutaneous toxicity. Contraceptive measures are mandated for participants of childbearing potential, consistent with local regulations.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy and safety of **masitinib** in combination with standard care for patients diagnosed with **Amyotrophic Lateral Sclerosis (ALS)**. The trial is structured as a phase 3 study with parallel groups, aiming to compare the outcomes of masitinib against a placebo. The trial is expected to commence recruitment on September 2, 2024, and conclude by September 2, 2026, with a total duration of 48 weeks for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, ALS diagnosis, and current treatment regimen. Following successful screening, participants will be randomized to receive either masitinib or a placebo, both administered orally. The trial includes regular follow-up visits to monitor the participants' health, adherence to the treatment protocol, and any adverse events. These visits will also involve assessments of primary and secondary endpoints, such as changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) score, progression-free survival (PFS), and overall survival (OS).
The end-of-study visit will mark the completion of the trial for each participant, where final assessments will be conducted to evaluate the long-term effects of the treatment. Participants are expected to be involved in the study for the entire 48-week period unless conditions arise that necessitate early termination, such as severe adverse reactions or non-compliance with the study protocol. The trial's primary endpoint focuses on the absolute change from baseline in the ALSFRS-R score at week 48, analyzed using a multiple imputation model. Secondary endpoints include various clinical and safety assessments, ensuring a comprehensive evaluation of masitinib's therapeutic potential in ALS treatment.
Treatment
The clinical trial involves the administration of several treatments to evaluate their efficacy and safety in patients with **Amyotrophic Lateral Sclerosis (ALS)**. The experimental medication **Riluzole** is provided in the form of film-coated tablets, specifically under the brand names RILUTEK and Riluzole Zentiva, each containing 50 mg of the active substance. The tablets are administered orally with a maximum daily dose of 100 mg, equating to two tablets per day. The treatment period extends up to 48 weeks. Riluzole is a chemical substance with the ATC code N07XX02, and it is manufactured by SANOFI WINTHROP INDUSTRIE and ZENTIVA, K.S.
Another experimental treatment in the trial is **Masitinib**, a tyrosine kinase inhibitor, available as coated tablets. The administration of masitinib is oral, with a dosage of 4.5 mg/kg/day. The maximum total dose over the treatment period is 1512 mg, and the treatment duration is also up to 48 weeks. Masitinib is produced by AB SCIENCE and is designated as an orphan drug with the code EMA/OD/081/16. The chemical nature of masitinib is confirmed, and it is identified by the ATC code L01EX06.
The trial also includes a placebo group to compare the efficacy of masitinib. The placebo is designed to match the 200 mg and 100 mg masitinib tablets, ensuring blinding in the study. The placebo is administered orally, and its role is to serve as a control in the double-blind, placebo-controlled trial design. The placebo does not contain any active substance and is used to assess the true effect of the experimental treatment.
Throughout the trial, participant compliance with the dosing schedule is monitored to ensure adherence to the treatment protocol. The study is structured as a prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial, aiming to provide robust data on the safety and efficacy of masitinib in combination with standard care for ALS patients.
Efficacy
The efficacy of the investigational treatment in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the absolute change from baseline at week 48 in the **ALSFRS-R** (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised) score. This will be analyzed using a multiple imputation model in the intention-to-treat (ITT) population.
Secondary endpoints include several measures: Progression-Free Survival (PFS) will be analyzed using the log-rank test with Kaplan-Meier plots; changes in ALSAQ-40 scores will be analyzed using the same model as the primary endpoint; changes in Forced Vital Capacity (FVC) from baseline will also be analyzed using the same model. Upper- and lower-limb muscle strength will be summarized by treatment arm using Hand-Held Dynamometry (HHD). Clinician-rated Clinical Global Impression (CGI) scores will be summarized by treatment arm. The Combined Assessment of Function and Survival (CAFS) will be analyzed using the Generalized Gehan-Wilcoxon rank test. Overall Survival (OS) and Time to Functional Decline (TFS) will be analyzed using the log-rank test and Kaplan-Meier plots. Safety assessments will include the occurrence of adverse events, changes in physical examination, vital signs, ECG, and clinical laboratory tests. Additionally, pharmacodynamic biomarkers and pharmacokinetic parameters of Masitinib will be identified and measured.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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] at screening
- At screening visit patient is 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.
- At screening visit patient is able and willing to comply with trial protocol and to come on-site as per protocol visits schedule
- At screening visit patient is 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
- Patient with a familial or sporadic ALS at screening
- Patient aged between 18 and 80 years old inclusive at screening
- Patient treated with a stable dose of Riluzole (100 mg/day) for at least 30 days prior to screening visit and baseline visit
- Patient receiving or not Edaravone. If receiving Edaravone (oral suspension only), patients must have been taking it at stable dose for at least 30 days prior to screening visit
- Patient with onset of first symptom of ALS no longer than 36 months at screening
- Patient with a ALSFRS-R progression rate of > 0.3 and <1.1 point/month at screening visit i) as measured between onset of the disease and screening
- 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)
- Contraception at screening and baseline: - 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 16.1.
- Patients who are not a candidate for QALSODY® Tofersen treatment
Exclusion Criteria
- 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 at screening visit
- 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
- Patient with active tuberculosis infection, viral hepatitis, human immunodeficiency virus infection at screening
- Patient with a diagnosis of cancer or evidence of continued disease within five years before screening
- 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%
- Patients, with two or more of the risk factors listed below assessed, at screening, 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 - Chronic 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.
- Patient treated concomitantly with substrates, inhibitors or inducers of BCRP at screening and baseline
- Participants with a significant pulmonary disorder not attributed to ALS or who require treatments that might complicate the evaluation of the effect of ALS on respiratory function at screening visit
- Previous treatments with masitinib
- Any medical condition that, in the opinion of the Investigator, might interfere with the patient’s participation in the trial, poses any added risk for the patient, or confounds the assessment of the patient at screening visit
- Patient under psychiatric care, patient protected by law under guardianship or curatorship, patient in emergency situations, prisoners and patient without National health insurance at screening visit
- Patient with hypersensitivity to masitinib excipients or riluzole at screening visit
- Patient with an FVC < 70%, predicted normal value for gender, height, and age, at screening and baseline
- Patient with a weight < 41 kg and a BMI < 18 or > 35 kg/m² at screening and baseline visit
- Pregnant, or nursing female patient at screening and baseline
- Patient with history (or family history) of severe skin toxicities or reactions at screening
- 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 at screening and baseline
- 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, or - Anemia with Hgb < LLN or red blood cell count below the LLN, or - Thrombocytopenia with platelets counts < 150 x 109/L
- Patient with history of hepatic disorders, with a known liver disease or recent alcohol abuse, or with abnormal laboratory results from local laboratory assessments, at screening and baseline, defined as: - Hepatic transaminase levels > 2 ULN, or - Total bilirubin level > 1.5 ULN, or - Both hepatic transaminase levels and total bilirubin level outside of the normal ranges, or - Albuminemia < 1 x LLN - Patients with concomitant medication known to be associated with severe hepatotoxicity
- Patients who have received a live vaccine within 30 days before the first administration of the investigational medicinal product
- Patient with interstitial lung disease or pulmonary fibrosis.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Yet Recruiting | 02 Sept 2024 | 20 |
 Germany | Not Yet Recruiting | 02 Sept 2024 | 20 |
 Greece | Not Yet Recruiting | 02 Sept 2024 | 20 |
 Latvia | Not Yet Recruiting | 02 Sept 2024 | 15 |
 Slovenia | Not Yet Recruiting | 02 Sept 2024 | 20 |
 Spain | Not Yet Recruiting | 02 Sept 2024 | 20 |
 Sweden | Not Yet Recruiting | 02 Sept 2024 | 20 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
RILUTEK 50 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 100 | 48 | PRD3139261 |
masitinib | Test | COATED TABLET | ORAL | 4.5 | 48 | PRD10419816 |
Placebo to 200mg masitinib | Placebo | N/A | — | — | — | N/A |
masitinib | Test | COATED TABLET | ORAL | 4.5 | 48 | PRD110277 |
Riluzole Zentiva 50 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 100 | 48 | PRD6640737 |
Placebo to 100mg masitinib | Placebo | N/A | ORAL | 4.5 | 48 | N/A |