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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ab Science

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

2 Feb 2024 → ongoing

Decision date (initial)

2025-01-30

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-516672-16-00

EudraCT number

2021-000639-30

WHO UTN

U1111-1312-3548

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the efficacy and safety of oral masitinib versus placebo in the treatment of patients with primary progressive or secondary progressive multiple sclerosis without relapse.

Secondary objectives 1

1. The secondary objectives of the study are to evaluate the efficacy of masitinib compared with placebo on a range of clinical parameters of multiple sclerosis. The secondary objectives also include the assessment of safety and tolerability of masitinib as compared to placebo in terms of adverse events, vital signs, physical examination, ECG, and clinical laboratory tests.

Conditions and MedDRA coding

Multiple Sclerosis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 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
2. 2. Patients with Expanded Disability Status Scale (EDSS) score between 3.0 to 6.0 (both inclusive) at screening and baseline
3. 3. Patients with an EDSS score progression ≥1 point with no improvement during 2 years before screening
4. 4. Absence of T1 Gadolinium-enhancing brain lesions at baseline as measured by MRI at screening
5. Other inclusion criteria: 5. Male or female patients aged between 18 and 65 years at screening
6. 6. Weight >45 kg and BMI between 18 and 35 kg/m2 at screening or baseline
7. 7. 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
8. 8. 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
9. 9. 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 24

1. 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
2. 2. Inability to complete screening MRI (contraindications for MRI) and/or any known allergy or hypersensitivity or any contra-indication to gadolinium macrocyclic
3. 3. Patients treated with other disease modifying treatments in the time frames and conditions mentioned under previous treatment wash out period, assessed at baseline
4. 4. Patients with lymphocytes <1.0 × 109/L at screening and at baseline
5. Other exclusion criteria: 5. Patients with hypersensitivity masitinib or its excipients at screening
6. 6. 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
7. 7. 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
8. 8. 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
9. 9. 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
10. 10. 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%
11. 11. 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.
12. 12. 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
13. 13. 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
14. 14. 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
15. 15. 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.
16. 16. Patient treated concomitantly with Breast Cancer Resistance Protein (BCRP) substrates, inhibitors or inducers (e.g. anthracyclines, mitoxantrone, methotrexate, topotecan, irinotecan)
17. 17. Patient with interstitial lung disease or pulmonary fibrosis
18. 18. 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
19. 19. 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
20. 20. Patients who had major surgery within 2 weeks prior to screening visit
21. 21. Pregnant, or nursing female patients at screening or baseline
22. 22. Previous participation in an earlier study with masitinib, assessed at screening
23. 23. 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
24. 24. Subjects who have received a live vaccine within 30 days prior to first IMP administration.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is to assess the efficacy of masitinib 3.0 mg/kg/day with a dose escalation to 4.5 mg/kg/day after four weeks on the time to confirmed (12-weeks CDP) EDSS progression. Progression is defined as 1-point worsening when EDSS score ≤5.5, or 0.5-point worsening if baseline score >5.5.

Secondary endpoints 6

1. The secondary endpoints of the study include the following: Expanded Disability Status Scale (EDSS): • Time to confirmed (24-weeks CDP) EDSS progression. Progression is defined as 1-point worsening when EDSS score ≤5.5, or 0.5 if baseline score >5.5) • Expanded Disability Status Scale (EDSS): Absolute and ordinal change from baseline considering all measurements up to Week 96 • Time to EDSS score of 7.0
2. Clinical Global Assessment Tools: • Timed 25-foot walk (T25-FW) from baseline up to Week 96 and 12 weeks confirmed worsening using 20% threshold • Nine-hole peg test (9-HPT), right and left hands sides (finger dexterity) from baseline up to Week 96 and 12 weeks confirmed worsening using 20% threshold • The Symbol Digit Modalities Test (SDMT) from baseline up to Week 96 and 12 weeks confirmed worsening using 4-point threshold
3. Brain MRI Assessments: • Brain Volume and Lesions will be measured and assessed at Baseline, Week 48 and Week 96, or early termination (only if patient discontinues after Week 48 and more than 24 weeks have elapsed since last MRI) for the following endpoints: Brain atrophy - Percent brain volume change (PBVC) from baseline at Week 96 or early termination • New/newly enlarged T2 lesion count (compared with baseline MRI scan) at Week 96 or early termination
4. Quality of Life assessment: • Quality of life assessment: Multiple Sclerosis Quality of Life (MSQOL)-54 instrument from baseline up to Week 96 • Modified Fatigue Impact Scale (MFIS) from baseline up to Week 96 • Hamilton Depression Rating Scale (HAM-D) from baseline up to Week 96 • Disability Impact Profile (DIP) from baseline up to Week 96
5. Relapses: • Occurrence of new or worsening neurological symptoms attributable to MS • Symptoms persisting for >24 hours • Symptoms not attributable to confounding clinical factors (e.g., fever, infection, injury, adverse reactions to medications) • Symptoms immediately preceded by a stable or improving neurological state for at least 30 days • Ssymptoms accompanied by objective neurological worsening consistent with an increase of at least half a step on the EDSS scale
6. Biomarker(s): • Comparison of serum Neurofilament Light Chain (NfL) and Glial Fibrillary Acidic Protein (GFAP) levels at Baseline and Week 96 or early termination (only if patient discontinues after Week 48 and more than 24 weeks have elapsed since last test) These biomarkers are to be tested in a subgroup of 200 patients of pre-selected sites

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ab Science

Sponsor organisation

Ab Science

Address

3 Avenue George V

City

Paris

Postcode

75008

Country

France

Scientific contact point

Organisation

Ab Science

Contact name

Shruti Chatterjee

Public contact point

Organisation

Ab Science

Contact name

Shruti Chatterjee

Third parties 1

Locations

4 EU/EEA countries · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 5 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 18 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications