Efficacy and Safety of Masitinib Dose Titration in Primary and Secondary Progressive Multiple Sclerosis: A 96-Week Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2024-516672-16-00
- Protocol
- AB20009
- Sponsor
- Ab Science
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** and **safety** of oral masitinib compared to placebo in the treatment of patients with primary progressive or secondary progressive **multiple sclerosis** without relapse. This is clinically relevant as it aims to provide insights into a potential therapeutic option for a condition with limited treatment alternatives, potentially improving patient outcomes and quality of life.
The secondary objectives of the study are to assess the efficacy of masitinib compared with placebo on a range of clinical parameters of multiple sclerosis. Additionally, the study aims to evaluate the safety and tolerability of masitinib in comparison to placebo, focusing on adverse events, vital signs, physical examination, ECG, and clinical laboratory tests. These assessments are crucial for understanding the broader impact of masitinib on patient health and its potential role in clinical practice.
Participants
The clinical trial involves participants diagnosed with **Multiple Sclerosis**, specifically targeting those with primary progressive or secondary progressive forms without relapse. The study population includes both male and female subjects aged between 18 and 65 years, with a weight greater than 45 kg and a body mass index (BMI) ranging from 18 to 35 kg/m². Participants are required to have an Expanded Disability Status Scale (EDSS) score between 3.0 and 6.0 at screening and baseline, and must have experienced an EDSS score progression of at least 1 point without improvement over the two years prior to screening. The absence of T1 Gadolinium-enhancing brain lesions at baseline, as measured by MRI, is also a criterion. The trial population was selected based on these specific inclusion criteria, ensuring that participants are able and willing to comply with the study protocol and attend scheduled visits. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as contraception are assessed, with requirements for effective methods of contraception for both male and female participants during the study and for a specified period after the last treatment intake. The trial includes 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 patients with primary progressive or secondary progressive **multiple sclerosis** without relapse. The trial will span a duration of 96 weeks, with participants receiving either masitinib or a placebo. The primary objective is to assess the time to confirmed Expanded Disability Status Scale (EDSS) progression, with secondary endpoints including various clinical assessments, brain MRI evaluations, and quality of life measures. Participants will be required to attend several study visits, beginning with a screening visit to confirm eligibility based on criteria such as an EDSS score between 3.0 and 6.0, absence of T1 Gadolinium-enhancing brain lesions, and other health parameters.
Following the screening, eligible participants will be randomized to receive either masitinib or placebo, with the initial dose of masitinib set at 3.0 mg/kg/day, escalating to 4.5 mg/kg/day after four weeks. Study visits will occur at regular intervals to monitor safety, efficacy, and adherence to the protocol. These visits will include assessments such as the Timed 25-foot walk, Nine-hole peg test, and Symbol Digit Modalities Test, alongside MRI scans at baseline, Week 48, and Week 96. The end-of-study visit will conclude the trial, with final assessments and data collection. Participants are expected to be involved for the full 96-week duration unless early termination is warranted due to adverse events, non-compliance, or withdrawal of consent. The trial aims to provide comprehensive data on the potential benefits of masitinib in managing progressive forms of multiple sclerosis.
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 dosage is titrated to a maximum of 4.5 mg/kg/day, with the treatment period extending up to 96 weeks. The active substance, masitinib, is of chemical origin and is manufactured by AB Science. The trial aims to evaluate the efficacy and safety of masitinib in patients with primary progressive or secondary progressive multiple sclerosis without relapse.
In addition to the experimental treatment, the study includes the use of a placebo as a comparator. The placebo is designed to match the 200 mg and 100 mg masitinib tablets, although it does not contain any active substance. The placebo is utilized to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo administration follows the same oral route and dosing schedule as the masitinib treatment, facilitating a direct comparison of outcomes between the experimental and control groups.
Efficacy
The efficacy of **masitinib** in the treatment of patients with primary progressive or secondary progressive multiple sclerosis without relapse will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the time to confirmed 12-week Expanded Disability Status Scale (EDSS) progression. This progression is defined as a 1-point worsening when the EDSS score is ≤5.5, or a 0.5-point worsening if the baseline score is >5.5. The dose of masitinib will be titrated from 3.0 mg/kg/day to 4.5 mg/kg/day after four weeks.
Secondary endpoints include several measures: the time to confirmed 24-week EDSS progression, absolute and ordinal changes in EDSS from baseline up to Week 96, and the time to reach an EDSS score of 7.0. Clinical Global Assessment Tools will be utilized, including the Timed 25-foot walk (T25-FW), Nine-hole peg test (9-HPT), and the Symbol Digit Modalities Test (SDMT), with assessments conducted from baseline up to Week 96. Brain MRI assessments will measure brain volume and lesions at baseline, Week 48, and Week 96, or upon early termination, focusing on percent brain volume change and new/enlarged T2 lesion count.
Quality of life will be evaluated using the Multiple Sclerosis Quality of Life (MSQOL)-54 instrument, Modified Fatigue Impact Scale (MFIS), Hamilton Depression Rating Scale (HAM-D), and Disability Impact Profile (DIP), all assessed from baseline up to Week 96. Relapse occurrences will be monitored, defined by new or worsening neurological symptoms persisting for over 24 hours, not attributable to confounding factors, and accompanied by objective neurological worsening. Biomarker analysis will compare serum Neurofilament Light Chain (NfL) and Glial Fibrillary Acidic Protein (GFAP) levels at baseline and Week 96 or early termination in a subgroup of 200 patients.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
Exclusion Criteria
- 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
- Inability to complete screening MRI (contraindications for MRI) and/or any known allergy or hypersensitivity or any contra-indication to gadolinium macrocyclic
- 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 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 (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
- 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
- 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 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 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 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
- Patients who had major surgery within 2 weeks prior to screening visit
- Pregnant, or nursing female patients at screening or baseline
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 01 Feb 2022 | 30 |
 Greece | Not Recruiting | 01 Feb 2022 | 10 |
 Poland | Not Recruiting | 01 Feb 2022 | 80 |
 Spain | Not Recruiting | 01 Feb 2022 | 25 |
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 | 4.5 | 96 | PRD110277 |
Placebo to 200mg masitinib | Placebo | N/A | — | — | — | N/A |
Placebo to 100mg masitinib | Placebo | N/A | — | — | — | N/A |
masitinib | Test | COATED TABLET | ORAL | 4.5 | 96 | PRD10419816 |