Efficacy and Safety of Masitinib Plus Riluzole Versus Placebo Plus Riluzole in Amyotrophic Lateral Sclerosis: A Phase 3 Randomized Controlled Trial
- Trial ID
- 2024-516671-33-00
- Protocol
- AB19001
- Sponsor
- Ab Science
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** and **safety** of two doses of masitinib as an add-on therapy to Riluzole in patients diagnosed with **Amyotrophic Lateral Sclerosis (ALS)**. This is clinically relevant as ALS is a progressive neurodegenerative disease with limited treatment options, and improving therapeutic strategies could significantly impact patient outcomes.
Secondary objectives include assessing the efficacy and safety of two doses of masitinib versus matching placebo in the treatment of patients with ALS treated with Riluzole. This will involve clinical assessments, quality of life assessment, Clinical Global Impression assessment, safety evaluations, and pharmacodynamic/biomarker and pharmacokinetic analyses.
Participants
The clinical trial involves participants diagnosed with **Amyotrophic Lateral Sclerosis** (ALS), both male and female, aged between 18 and 80 years. The sponsor has not provided the total number of participants. The study population includes individuals with either familial or sporadic ALS, who have been on a stable dose of Riluzole (100 mg/day) for at least 12 weeks prior to the baseline visit. Participants are required to have an ALS disease duration from diagnosis of no longer than 24 months at screening. The trial includes individuals with an ALSFRS-R total score of at least 26 at screening and at least 25 at randomization, with specific item score requirements. The trial population was selected based on their ability to understand and comply with the study protocol, including safety procedures, and to attend on-site visits as per the protocol schedule. Participants are expected to adhere to specific contraception guidelines if applicable. The study involves a vulnerable population, and informed consent is obtained from participants or their legally authorized representatives if necessary.
Plans and Procedures
The clinical trial is a **randomized**, double-blind, placebo-controlled, phase 3 study designed to evaluate the efficacy and safety of **masitinib** in combination with Riluzole compared to placebo in combination with Riluzole for the treatment of patients with **Amyotrophic Lateral Sclerosis (ALS)**. The trial is structured with parallel groups and is conducted across multiple centers. The estimated duration of the trial is from October 2019 to December 2025, with a maximum treatment period 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 stable Riluzole treatment. Following successful screening, participants will be randomized to receive either masitinib or placebo, both administered orally in the form of coated tablets. The primary endpoint is the absolute change from baseline in the ALS Functional Rating Scale-Revised (ALSFRS-R) score at week 48, analyzed using a multiple imputation model. Secondary endpoints include progression-free survival, changes in ALSAQ-40 and forced vital capacity, muscle strength assessments, and safety evaluations.
Study visits will include regular follow-up assessments to monitor efficacy and safety, with specific attention to adverse events, physical examinations, and laboratory tests. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of the treatment's impact. Participants are expected to remain in the study for the full 48-week treatment period unless conditions such as severe adverse reactions or non-compliance with the study protocol necessitate early termination. The trial aims to provide robust data on the potential benefits of masitinib as an add-on therapy for ALS, contributing to the understanding and management of this rare disease.
Treatment
The clinical trial involves the administration of **masitinib**, a tyrosine kinase inhibitor, as the experimental medication. Masitinib is provided in the form of a coated tablet and is administered orally. The maximum daily dose is 6 tablets, with a total maximum dose of 288 tablets over a treatment period of 48 weeks. The active substance, masitinib, is of chemical origin and is produced by AB Science. The trial aims to evaluate the efficacy and safety of masitinib in combination with Riluzole for the treatment of patients with Amyotrophic Lateral Sclerosis (ALS).
In addition to masitinib, the study includes a **placebo** treatment to serve as a comparator. The placebo is designed to match the 200mg and 100mg masitinib doses and is administered in a similar manner, orally, to maintain the double-blind nature of the trial. The placebo does not contain any active substance and is used to assess the efficacy of masitinib by comparison.
Participants in the trial will also receive **Riluzole**, a standard-of-care therapy for ALS, as part of the treatment regimen. Riluzole is administered according to standard dosing guidelines and is not considered an experimental treatment in this study. Compliance with the dosing schedule for both masitinib and Riluzole will be monitored throughout the trial to ensure adherence to the protocol.
Efficacy
The efficacy of masitinib in combination with Riluzole for the treatment of patients with **Amyotrophic Lateral Sclerosis (ALS)** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the absolute change from baseline in the ALS Functional Rating Scale-Revised (ALSFRS-R) score at week 48. This will be analyzed using a multiple imputation model to account for missing data. Secondary endpoints include progression-free survival (PFS), which will be analyzed using the log-rank test with Kaplan-Meier plots provided for visualization. Changes in the ALS Assessment Questionnaire-40 (ALSAQ-40) and forced vital capacity (FVC) from baseline will also be evaluated using the primary model and an Analysis of Covariance (ANCOVA) model, incorporating stratification factors, treatment, and baseline scores.
Additional secondary endpoints involve the assessment of upper- and lower-limb muscle strength using hand-held dynamometry (HHD), clinician-rated Clinical Global Impression (CGI), and Combined Assessment of Function and Survival (CAFS), which will be analyzed using the Generalized Gehan-Wilcoxon rank test. Overall survival (OS) and event-free survival (EFS) will be analyzed using the log-rank test, with Kaplan-Meier plots provided. Safety assessments will include the occurrence of adverse events, changes in physical examination, vital signs, electrocardiogram (ECG) results, and clinical laboratory tests, including hematology, biochemistry, urinalysis, and urinary cytology. These efficacy and safety parameters will be measured and collected at specified time points throughout the trial to ensure comprehensive evaluation of the treatment's impact on ALS patients.
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]
- Patient with a familial or sporadic ALS
- 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 12 weeks prior to baseline visit
- Patient with an ALS disease duration from diagnosis no longer than 24 months at screening
- Patient with an ALSFRS-R total score progression between onset of the disease and screening of > 0.3 and <1.1 point/month
- Patient with an ALSFRS-R total score decrease of ≥ 1 point between screening and baseline
- Patient with an ALSFRS-R total score of at least 26 at screening following rules below: - at least 3 on item #3 and - at least 2 on each of the other 11 items (i.e. item #1, #2, #4, #5a or #5b, #6, #7, #8, #9, #10, #11 and #12)
- Patient with an ALSFRS-R total score of at least 25 at randomization following rules below: - at least 3 on item #3 and - at least 2 on each of the other 11 items (i.e. item #1, #2, #4, #5a or #5b, #6, #7, #8, #9, #10, #11 and #12)
- Contraception: - Female patient of childbearing potential (entering the study 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 study 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 study 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 study and for 5 months after the last treatment intake. Highly effective and effective methods of contraception are detailed in appendix 15.1
- 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 study 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 study participation.
- Patient able and willing to comply with study protocol and to come on-site as per protocol visits schedule
- 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
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
- Patient with pre-existing severe renal impairment, or with abnormal laboratory results from local laboratory assessments at screening: - Creatinine clearance < 60 mL/min (Cockcroft and Gault formula) - In case of proteinuria ≥1+ on the dipstick, proteinuria to creatininuria ratio will be assessed on urine sampled in the morning. If this ratio > 20 mg/mmol, the patient should be excluded.
- Vulnerable population defined as: - Patients with a diagnosis of cancer within five years before screening except for basal cell carcinoma. - Patients with known diagnosis of human immunodeficiency virus (HIV) infection.
- Patient with interstitial lung disease or pulmonary fibrosis.
- Patient with active severe infection such as herpes, tuberculosis, viral hepatitis, human immunodeficiency virus infection
- Patient with autoimmune conditions such as systemic lupus erythematosus
- 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 - Ischemic heart disease (Myocardial infarction, unstable angina pectoris, acute coronary syndrome, coronary revascularization procedure)Congestive heart failure of NYHA Class III or IV - Stroke, including a transient ischemic attack, - Conduction disorders such as second degree or third-degree atrioventricular block not successfully treated with a pacemaker, Bi-fascicular block, uncontrolled atrial arrhythmia - Repolarization disorders such as QTc Fridericia interval > 450 milliseconds for males and > 470 milliseconds for females, torsades de pointe, ventricular tachycardia - 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 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, - Smoking (10 pack-year calculated as (packs smoked per day) × (years as a smoker), 20 cigarettes per pack)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.
- 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
- Patient who has been treated to Edaravone within 30 days prior to screening
- Patient with hypersensitivity to masitinib or its excipients and riluzole or its excipients
- Patients treated concomitantly with Breast Cancer Resistance Protein (BCRP) substrates, inhibitors or inducers (e.g. anthracyclines, mitoxantrone, methotrexate, topotecan, irinotecan).
- Subjects 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
- Previous participation in an earlier study 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.
- Patient under psychiatric, patient protected by law under guardianship or curatorship, patient in emergency situations, prisoners and patient without National health insurance
- Patient with an FVC < 60% predicted normal value for gender, height, and age at screening
- Patient with a weight < 41 kg and a BMI < 18 or > 35 kg/m² at screening or at baseline
- Pregnant, or nursing female patient
- Patient with history (or family history) of severe skin toxicities or reactions
- 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
- Patients 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 defined as: -Neutropenia with ANC <1.5 × 109/L - Anemia with Hgb <10 g/dl - Thrombocytopenia with platelet counts <150 × 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 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, or - Patients with concomitant medication known to be associated with severe hepatotoxicity
- Subjects who have received a live vaccine within 30 days prior to first IMP administration.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Yet Recruiting | 01 Oct 2019 | 30 |
 France | Not Yet Recruiting | 01 Oct 2019 | 60 |
 Greece | Not Yet Recruiting | 01 Oct 2019 | 40 |
 Norway | Not Yet Recruiting | 01 Oct 2019 | 15 |
 Sweden | Not Recruiting | 01 Oct 2019 | 10 |
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 |
|---|---|---|---|---|---|---|
masitinib | Test | COATED TABLET | ORAL | 6 | 48 | PRD110277 |
Placebo to 200mg masitinib | Placebo | N/A | — | — | — | N/A |
Placebo to 100mg masitinib | Placebo | N/A | ORAL USE | 6 | 48 | N/A |
masitinib | Test | COATED TABLET | ORAL | 6 | 48 | PRD10419816 |