A prospective, multicenter, randomised, double-blind, placebo-controlled, parallel groups, phase 3 study to compare the efficacy and safety of masitinib in combination with Riluzole versus placebo in combination with Riluzole in the treatment of patients suffering from Amyotrophic Lateral Sclerosis (ALS)

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

24 May 2021 → ongoing

Decision date (initial)

2025-01-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-516671-33-00

EudraCT number

2019-001862-13

WHO UTN

U1111-1312-2656

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate the efficacy and safety of two doses of masitinib as add-on therapy to Riluzole in patients diagnosed with ALS.

Secondary objectives 1

1. Secondary objectives are to assess the efficacy and safety of two doses of masitinib versus matching placebo in the treatment of patients diagnosed with ALS treated with Riluzole: Clinical assessments, Quality of Life assessment, Clinical Global Impression assessment, Safety, Pharmacodynamic/biomarker, Pharmacokinetic.

Conditions and MedDRA coding

Amyotrophic Lateral Sclerosis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 1. 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]
2. 2. Patient with a familial or sporadic ALS
3. 3. Patient aged between 18 and 80 years old inclusive at screening
4. 4. Patient treated with a stable dose of Riluzole (100 mg/day) for at least 12 weeks prior to baseline visit
5. 5. Patient with an ALS disease duration from diagnosis no longer than 24 months at screening
6. 6. Patient with an ALSFRS-R total score progression between onset of the disease and screening of > 0.3 and <1.1 point/month
7. 7. Patient with an ALSFRS-R total score decrease of ≥ 1 point between screening and baseline
8. 8. 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)
9. 9. 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)
10. 10. 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
11. 11. 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.
12. 12. Patient able and willing to comply with study protocol and to come on-site as per protocol visits schedule
13. 13. 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 25

1. 1. 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
2. 10. 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.
3. 11. 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.
4. 12. Patient with interstitial lung disease or pulmonary fibrosis.
5. 13. Patient with active severe infection such as herpes, tuberculosis, viral hepatitis, human immunodeficiency virus infection
6. 14. Patient with autoimmune conditions such as systemic lupus erythematosus
7. 15. Patient with a diagnosis of cancer or evidence of continued disease within five years before screening
8. 16. 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%
9. 17. 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.
10. 18. 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
11. 19. Patient who has been treated to Edaravone within 30 days prior to screening
12. 2. Patient with hypersensitivity to masitinib or its excipients and riluzole or its excipients
13. 20. Patients treated concomitantly with Breast Cancer Resistance Protein (BCRP) substrates, inhibitors or inducers (e.g. anthracyclines, mitoxantrone, methotrexate, topotecan, irinotecan).
14. 21. 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
15. 22. Previous participation in an earlier study with masitinib
16. 23. 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.
17. 24. Patient under psychiatric, patient protected by law under guardianship or curatorship, patient in emergency situations, prisoners and patient without National health insurance
18. 3. Patient with an FVC < 60% predicted normal value for gender, height, and age at screening
19. 4. Patient with a weight < 41 kg and a BMI < 18 or > 35 kg/m² at screening or at baseline
20. 5. Pregnant, or nursing female patient
21. 6. Patient with history (or family history) of severe skin toxicities or reactions
22. 7. 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
23. 8. 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
24. 9. 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
25. 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. Absolute change from baseline at week 48 in ALSFRS-R score will be analysed using multiple imputation model.

Secondary endpoints 9

1. - PFS will be analysed using the log rank test. Kaplan-Meier Plots will be provided.
2. - ALSAQ-40 change will be analyzed using the same primary model. In addition, an Analysis of Covariance model (ANCOVA) with stratification factors, treatment and baseline ALSAQ-40 score will be performed.
3. - FVC change from baseline will be analysed using the same model as primary. In addition, an ANCOVA with stratification factors, treatment and baseline ALSAQ-40 score will be performed.
4. - Upper- and lower-limb muscle strength using HHD will be summarized by treatment arm.
5. - Clinician-rated CGI will be summarized by treatment arm.
6. - CAFS will be analysed using the Generalised GehanWilcoxon rank test.
7. - OS will be analysed using the log rank test. Kaplan-Meier Plots will be provided.
8. - EFS will be analysed using the log rank test. Kaplan-Meier Plots will be provided.
9. - Safety: Occurrence of Adverse Events (AE), changes on physical examination, vital signs (blood pressure, heart rate, weight and temperature), ECG and clinical laboratory tests (haematology, biochemistry, urinalysis, urinary cytology)

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

Christian Fassotte

Public contact point

Organisation

Ab Science

Contact name

Alain Moussy

Third parties 2

Locations

5 EU/EEA countries · 19 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 34 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