E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary progressive or relapse-free secondary progressive multiple sclerosis |
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E.1.1.1 | Medical condition in easily understood language |
Primary progressive or relapse-free secondary progressive multiple sclerosis |
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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 | 20.1 |
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 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
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.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The objective of the study is to compare the safety and efficacy of masitinib at 4.5 mg/kg/day or masitinib at 4.5 mg/kg/day with a dose escalation to 6 mg/kg/day after three month of treatment versus placebo in the treatment of patients with primary progressive multiple sclerosis or relapse-free secondary progressive multiple sclerosis.
Primary endpoint: Multiple Sclerosis Functional Composite (MSFC) from week 12 to week 96 |
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E.2.2 | Secondary objectives of the trial |
Clinical assessment: • EDSS at weeks 12, 24, 36, 48, 60, 72, 84 and 96 • Quality of Life assessment: MSQOL-54 at weeks 12, 24, 36,48, 60, 72, 84 and 96 • Timed 25-foot walk at weeks 12, 24, 36, 48, 60, 72, 84 and 96 • Nine-hole peg test, right and left hands sides (finger dexterity) at weeks 12, 24, 36, 48, 60, 72, 84 and 96 • PASAT 3 at weeks 12, 24, 36, 48, 60, 72, 84 and 96 • Modified Fatigue Impact Scale at weeks 12, 24, 36, 48, 60, 72, 84 and 96 • Hamilton Rating Scale for Depression at weeks 12, 24, 36, 48, 60, 72, 84 and 96 • Disability Impact Profile at weeks 12, 24, 36, 48, 60, 72, 84 and 96 • Health state Visual Analogue Scale (EQ-VAS) at weeks 12, 24, 36, 48, 60, 72, 84 and 96 • Use of corticosteroids for MS • Number of hospitalizations for relapse • Clinical and biological safety profile: occurrence of Adverse Events, potential changes in vital signs, ECG, and biological parameters.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PharmacoKinetic (PK) study
A Pharmacokinetic study, in up to 10 MS patients, will be conducted to evaluate PK parameters of study treatment.
PharmacoGenomic (PG) study
The aim of this study is to determine the genes polymorphisms, including HLA polymorphismsn that could be associated with an increase risk of masitinib-induced severe neutropenia and severe skin toxicity. All samples will be centrally analyzed in the Institut Paoli Calmettes, department de Biopathologie, Marseille, France. |
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E.3 | Principal inclusion criteria |
1. Patient suffering from either primary progressive or secondary progressive multiple sclerosis without relapse within 2 years before inclusion according to the revised McDonald’s criteria 2. Patient with EDSS score of [2.0 to 6.0] inclusive at baseline 3. Patient who had an EDSS score progression ≥ 1 point within 2 years before inclusion 4. Patient with normal organ function defined as: • Absolute neutrophils count (ANC) ≥ 2 x 109/L • Hemoglobin ≥ 10 g/dL • Platelets (PTL) ≥ 100 x 109/L • AST/ALT ≤ 3 ULN • Bilirubin ≤ 1.5x ULN • Creatinine clearance > 60 mL/min (Cockcroft and Gault formula) • Albuminemia > 1 x LLN • Proteinuria < 30 mg/dL (1+) on dipstick; in case of the proteinuria ≥1+ on the dipstick 24 hours proteinuria must be < 1.5g/24 hours 5. Male or female patient aged between 18 and 75 years old, with a weight > 50 kg and BMI between 18 and 35 kg/m². 6. Patient able to understand the patient card and to follow the patient card procedures in case of signs or symptoms of severe neutropenia or severe cutaneous toxicity, during the first 2 months of treatment. 7. Female patient of childbearing potential (entering the study after a menstrual period and who have a negative pregnancy test), who agrees to use two highly effective methods (one for the patient and one for the partner) of medically acceptable forms of contraception during the study and for 3 months after the last treatment intake. Acceptable forms of contraception include: 8. Male patients must use medically acceptable methods of contraception if your female partner is pregnant, from the time of the first administration of the study drug until three months following administration of the last dose of study drug. Acceptable methods include: 9. Patient able and willing to comply with study procedures as per protocol 10. Patient able to understand, sign, and date the written informed consent form at screening visit prior to any protocol-specific procedures
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E.4 | Principal exclusion criteria |
1. Patient suffering from a disease other than MS that would better explain the patient’s neurological clinical signs and symptoms and/or MRI lesions 2. Patient who had a major surgery within 2 weeks of study entry 3. Patient with life expectancy < 6 months 4. Patient with history of primary malignancy < 5 years, except treated basal cell skin cancer or cervical carcinoma in situ 5. Patient presenting with cardiac disorders defined by at least one of the following conditions: • Patient with recent cardiac history (within 6 months) of: - Acute coronary syndrome - Acute heart failure (class III or IV of the NYHA classification) - Significant ventricular arrhythmia (persistent ventricular tachycardia, ventricular fibrillation, resuscitated sudden death) • Patient with cardiac failure class III or IV of the NYHA classification • Patient with severe conduction disorders which are not prevented by permanent pacing (atrio-ventricular block 2 and 3, sino-atrial block) • Syncope without known aetiology within 3 months • Uncontrolled severe hypertension, according to the judgment of the investigator, or symptomatic hypertension 6. Patient with any severe and/or uncontrolled medical condition 7. Patient with a known diagnosis of human immunodeficiency virus (HIV) infection 8. Patient with known hepatitis B, hepatitis C or tuberculosis 9. Pregnant or nursing female 10. Patient with history of poor compliance or history of drug/alcohol abuse, or excessive alcohol beverage consumption that would interfere with the ability to comply with the study protocol, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent 11. Patient with any condition or concurrent medical events, including any clinically significant deviations from reference ranges in laboratory test, that on the opinion of the physician could be detrimental to the subjects 12. Patients requiring medication, which are prohibited in the current protocol, including corticosteroids used other than defined by the protocol, chemotherapies, immunomodulators or immunosuppressors, investigational drugs, live attenuated vaccines, drugs known to be at high risk of Stevens-Johnson syndrome.
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E.5 End points |
E.5.1 | Primary end point(s) |
Multiple Sclerosis Functional Composite (MSFC) from week 12 to week 96 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Clinical assessment: • EDSS at weeks 12, 24, 36, 48, 60, 72, 84 and 96 • Quality of Life assessment: MSQOL-54 at weeks 12, 24, 36,48, 60, 72, 84 and 96 • Timed 25-foot walk at weeks 12, 24, 36, 48, 60, 72, 84 and 96 • Nine-hole peg test, right and left hands sides (finger dexterity) at weeks 12, 24, 36, 48, 60, 72, 84 and 96 • PASAT 3 at weeks 12, 24, 36, 48, 60, 72, 84 and 96 • Modified Fatigue Impact Scale at weeks 12, 24, 36, 48, 60, 72, 84 and 96 • Hamilton Rating Scale for Depression at weeks 12, 24, 36, 48, 60, 72, 84 and 96 • Disability Impact Profile at weeks 12, 24, 36, 48, 60, 72, 84 and 96 • Health state Visual Analogue Scale (EQ-VAS) at weeks 12, 24, 36, 48, 60, 72, 84 and 96 • Use of corticosteroids for MS • Number of hospitalizations for relapse • Clinical and biological safety profile: occurrence of Adverse Events, potential changes in vital signs, ECG, and biological parameters.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
week 12, 24, 36, 48, 60, 72, 84 and 96 |
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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 | Yes |
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 | Yes |
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 | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 90 |
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 |
Argentina |
Bosnia and Herzegovina |
Brazil |
Bulgaria |
France |
Germany |
Greece |
Hungary |
Italy |
Mexico |
Morocco |
Poland |
Romania |
Russian Federation |
Serbia |
Slovakia |
South Africa |
Spain |
Tunisia |
Ukraine |
United Kingdom |
United States |
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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
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last visit of the last subject 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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |