| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with primary progressive or secondary progressive multiple sclerosis without relapse |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063400 |
| E.1.2 | Term | Secondary progressive multiple sclerosis |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063401 |
| E.1.2 | Term | Primary progressive multiple sclerosis |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to evaluate whether masitinib treatment will show a significant delay on three-month confirmed disease progression versus placebo in the study patients. |
|
| E.2.2 | Secondary objectives of the trial |
| 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. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A patient must fulfil all of the following inclusion criteria to be eligible to participate in the study:
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. Patients with Expanded Disability Status Scale (EDSS) score between 3.0 to 6.0 (both inclusive) at screening and baseline
3. Patients with an EDSS score progression ≥1 point with no improvement during 2 years before screening
4. 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
6. Weight >45 kg and BMI between 18 and 35 kg/m2 at screening or baseline
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 both at screening and at baseline), 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 3 months and a half after the last treatment intake
- Male patients 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 3 months and 2 weeks 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 3 months and 2 weeks after the last treatment intake
Highly effective and effective methods of contraception are detailed in the appendix 14.1 of the protocol
8. Patient 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. Patient able and willing to comply with study protocol and to come on-site as per protocol visits schedule, assessed at screening and at baseline
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|
| E.4 | Principal exclusion criteria |
Related to the disease:
1. Patients suffering from a disease other than MS that would better explain the neurological clinical signs and symptoms and/or MRI lesions observed at screening
2. Inability to complete screening MRI (contraindications for MRI) and/or any known allergy/hypersensitivity/any contra-indication to gadolinium macrocyclic
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. Patients with lymphocytes <1.0 × 109/L at screening and baseline
Other exclusion criteria:
5. Patients with hypersensitivity masitinib/its excipients at screening
6. Patients with history/family history of severe skin toxicities or reactions at screening or patients taking concomitant treatment/therapies associated with severe drug-induced skin toxicity
7. Patients with history of severe bone marrow disorders e.g. agranulocytosis or aplasia, or with abnormal laboratory results at screening and baseline:
- Neutropenia with ANC <1.5 × 109/L
- Anemia with Hgb <10 g/dl
- Thrombocytopenia with platelet counts <75 × 109/L
8. Patients with history of severe hepatic disorders, e.g. viral hepatitis or steatohepatitis, and alcohol steatosis, or with abnormal laboratory results:
- 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. Patients with pre-existing severe renal impairment, or with abnormal laboratory results at screening:
- Creatinine clearance <60 mL/min (Cockcroft and Gault formula) or
- Proteinuria >30 mg/dL (1+) on dipstick; if the proteinuria ≥1+ on the dipstick, 24 hours proteinuria must be >1.5 g/24 hours
10. Patients with current or history of severe cardiovascular disease, assessed at screening:
- Myocardial infarction
- Unstable angina pectoris
- Coronary revascularization procedure
- Congestive heart failure of NYHA Class III or IV
- Stroke, including a transient ischemic attack
- 2nd or 3rd degree atrioventricular block not successfully treated with a pacemaker
- Bi-fascicular block
- QTc Fridericia interval > 450 millisec. for males and > 470 millisec. for females
- 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 ejaculation fraction ≤50%
11. Patients with ≥2 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
- Current tabagism (≥10 Pack-year: equivalent to 1 pack of 20 cigarettes for 10 years with the formula N (number of packs of 20 cigarettes smoked daily) × T (number years smoking)). Patients who stopped smoking 6 months prior to the evaluation, are not concerned.
- Hypercholesterolemia,
- Chronic obstructive pulmonary disease (COPD)
* acc. to the Systematic Coronary Risk Estimation (SCORE) using the country specific free full version of HeartScore®, available at https://www.heartscore.org/en_GB/access
If the country specific version is not available, EU one should be used.
12. Patients with active severe infection e.g. tuberculosis, viral hepatitis, human immunodeficiency virus infection, syphilis or COVID-19 (confirmed by positive RT-PCR and/or other applicable methods), from medical files assessed at screening or baseline
13. Patient treated concomitantly with known substrates of P-gp and/or BCRP with narrow therapeutic index
14. 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
15. Patients under psychiatric care, protected by law under guardianship or curatorship, in emergency situations, prisoners and patients without national health insurance at screening and baseline
16. Patients who had major surgery within 2 weeks prior to screening visit
17. Pregnant/nursing female patients at screening or baseline
18. Patients with a diagnosis of cancer or evidence of continued disease within five years before screening
19. Previous participation in an earlier study with masitinib, assessed at screening
20. Patient who has been exposed to an investigational treatment within 3 months or 5 half-lives of an investigational product, whichever is longer, before the screening visit
21. Subjects who have received a live vaccine within 30 days prior to first IMP administration. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
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
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
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
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
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
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
Elevated blood concentrations of Comparison of serum Neurofilament Light Chain (NfL) were found to correlate with an increase in the number of relapses, disability worsening, MRI disease activity and brain volume loss in Multiple Sclerosis (MS). Glial Fibrilliary Acidic Protein (GFAP) is the major intermediate cytoskeletal protein of astrocytes and that of axons may be released into the cerebrospinal fluid (CSF) during pathological processes in the central nervous system (CNS). GFAP, is a marker for astrogliosis and a potential biomarker for MS progression.
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Israel |
| South Africa |
| United States |
| Finland |
| France |
| Poland |
| Sweden |
| Bulgaria |
| Romania |
| Spain |
| Germany |
| Greece |
| Italy |
| Hungary |
| Portugal |
| Russian Federation |
| Ukraine |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of study is defined as the date of the last visit of the last patient undergoing the trial. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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