A 96-Week, Prospective, Multicenter, Randomised, Double-Blind, Placebo-Controlled, Phase 3 Study to Compare Efficacy and Safety of Masitinib Dose Titration to 4.5 mg/kg/day versus Placebo in the Treatment of Patients with Primary Progressive or Secondary Progressive Multiple Sclerosis Without Relapse

Prior treatment

• Patients with any known or suspected active infection at screening or baseline or any major episode of infection requiring hospitalization or treatment within 8 weeks prior screening
• Patients who had major surgery within 2 weeks prior to screening visit
• Previous participation in an earlier study with masitinib, assessed at screening
• Patient who has been exposed to an investigational treatment within 3 months or five half-lives of an investigational product, whichever is longer, before the screening visit
• Subjects who have received a live vaccine within 30 days prior to first IMP administration.
• Patients treated with other disease modifying treatments in the time frames and conditions mentioned under previous treatment wash out period, assessed at baseline
• Patients with history (or family history) of severe skin toxicities or reactions at screening or patients taking concomitant treatment or therapies associated with severe drug-induced skin toxicity

Other illness

• Related to the disease: 1. Patients suffering from a disease other than MS that would better explain the patient’s neurological clinical signs and symptoms and/or MRI lesions observed at screening
• Patients, with two or more of the risk factors listed below assessed by a cardiologist 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) - Diabetes - Kidney disease - Smoking (10 pack-year calculated as (packs smoked per day) × (years as a smoker), 20 cigarettes per pack)Hypercholesterolemia, - Chronic obstructive pulmonary disease (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 with active or latent infection detected at screening by usual diagnosis methods: o Tuberculosis: IGRA (Interferon Gamma Release Assay) or identification of Mycobacterium tuberculosis by culture of any biological sample if available, o Viral hepatitis B: HBs antigen positive, o Viral hepatitis C: RT-PCR positive
• Patients with persistent chronic or active or recurring system infection that may adversely affect participation or IMP administration in this study, as judged by the Investigator
• Vulnerable population defined as: • Life expectancy < 6 months • 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 treated concomitantly with Breast Cancer Resistance Protein (BCRP) substrates, inhibitors or inducers (e.g. anthracyclines, mitoxantrone, methotrexate, topotecan, irinotecan)
• Patient with interstitial lung disease or pulmonary fibrosis
• Any medical condition at screening and baseline that, in the opinion of the Investigator, might interfere with the patients’ participation in the trial, poses any added risk for the patients, or confounds the assessment of the patients
• Patients under psychiatric care, patients protected by law under guardianship or curatorship, patients in emergency situations, prisoners and patients without national health insurance at screening and baseline
• Inability to complete screening MRI (contraindications for MRI) and/or any known allergy or hypersensitivity or any contra-indication to gadolinium macrocyclic

Lab values

• 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 or bi-fascicular block, uncontrolled atrial arrhythmia - Repolarisation 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. - Edema of cardiac origin and left ventricular ejection fraction ≤50%
• Patients with lymphocytes <1.0 × 109/L at screening and at baseline
  • Other exclusion criteria: 5. Patients with hypersensitivity masitinib or its excipients at screening
• Patients with history of severe bone marrow disorders such as agranulocytosis or aplasia, or with abnormal laboratory results 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
• Patients 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 × LLN at screening and baseline, or - Patients with concomitant medication known to be associated with severe hepatotoxicity
• Patients with pre-existing severe renal impairment, or with abnormal laboratory results at screening: - Creatinine clearance <60 mL/min (Cockcroft and Gault formula) or 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

Other

• Pregnant, or nursing female patients at screening or baseline

• Related to the disease: 1. Patients with either primary progressive or secondary progressive multiple sclerosis with onset of symptoms at least five years before inclusion and with no relapse diagnosed according to the 2017 revised McDonald’s criteria at least two years before screening
• Patients with Expanded Disability Status Scale (EDSS) score between 3.0 to 6.0 (both inclusive) at screening and baseline
• Patients with an EDSS score progression ≥1 point with no improvement during 2 years before screening
• Absence of T1 Gadolinium-enhancing brain lesions at baseline as measured by MRI at screening
  • Other inclusion criteria: 5. Male or female patients aged between 18 and 65 years at screening
• Weight >45 kg and BMI between 18 and 35 kg/m2 at screening or baseline
• Contraception, to be assessed at screening and baseline: Female patients of childbearing potential (entering the study after a menstrual period and who has a negative pregnancy test), who agree to use a highly effective method of contraception and an effective method of contraception by their male partner during the study and for 8 months after the last treatment intake Male patients with a female partner of childbearing potential who agree to use a highly effective method of contraception and an effective method of contraception by their female partner during the study and for 5 months after the last treatment intake OR who agree to use an effective method of contraception and a highly effective method of contraception by their female partner during the study and for 5 after the last treatment intakePatient able to understand, and willing to sign, and date the written informed consent form prior to any protocol-specific procedures, at screening. 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
• Patients able to understand, and willing to sign, and date the written informed consent form prior to any protocol-specific procedures, at screening. 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
• Patients able and willing to comply with study protocol and to come on-site as per protocol visits schedule, assessed at screening and at baseline.