E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Smouldering or Indolent Severe Systemic Mastocytosis with handicap |
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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] - Blood and lymphatic diseases [C15] |
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 | 10042949 |
E.1.2 | Term | Systemic mastocytosis |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10026891 |
E.1.2 | Term | Mastocytosis |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10056452 |
E.1.2 | Term | Indolent systemic mastocytosis |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary objective: to compare the efficacy and safety of oral masitinib versus placebo in the treatment of patients suffering from documented Smouldering or Indolent Severe Systemic mastocytosis with handicap after failure of symptomatic treatment. Primary endpoint: - Response on 3 handicaps: cumulative response by patient*handicap (pruritus and/or flushes and/or depression) from Week 8 to Week 24.
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E.2.2 | Secondary objectives of the trial |
Secondary objectives: - Response on 4 handicaps: cumulative response by patient*handicap (pruritus and/or flushes and/or depression and/or FSS) from W8 to W24. - Response on 4 handicaps: response by patient*handicap (pruritus and/or flushes and/or depression and/or FIS) from W8 to W24. - Response on 2 handicaps: response by patient*handicap (pruritus and/or flushes) from W8 to W24. - Long-term response on 3 handicaps: response by patient*handicap (pruritus and/or flushes and/or depression) from W8 to W96. - Long-term response on 4 handicaps: response by patient*handicap (pruritus and/or flushes and/or depression and/or FSS) from W8 to W96. - Long-term response on 4 handicaps: response by patient*handicap (pruritus and/or flushes and/or depression and/or FIS) from 8 to W96 . - Long-term response on 2 handicaps: response by patients*handicap (pruritus and/or flushes) from W8 to W96.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria: 1. Patients with one of the following documented mastocytosis: Smouldering Systemic Mastocytosis Indolent Systemic Mastocytosis The retained classification of systemic mastocytosis is based on an excess of mast cells or a presence of abnormal mast cells in at least two organs. The criteria used will be as follows: i. Bone marrow biopsy and/or aspirate associated with at least a sign of abnormality of mast cells: Signs of abnormality of mast cells are: a) Abnormal aggregates of mast cells in a sample in bone marrow: The criteria is deemed satisfied if the aggregate i) is quantified and is strictly above 15 mast cells per aggregated (corresponding to WHO major criterion), or ii) is not quantified but is described as nodule, seat, cluster, focus, or granuloma and therefore pathological b) ≥25% atypical mast cells in a sample of bone marrow (corresponding to WHO minor criterion) c) c-Kit point mutation at codon 816 in bone marrow (corresponding to WHO minor criterion) d) Abnormal mast cells in the sample of bone marrow while microscopic testing that can be described by the following words: Spindled; Abnormal; Atypical; Fusiform; Dystrophic; Pathologic; Dysmorphic (corresponding to WHO minor criterion) e) Abnormal immunohistochemistry signs: mast cells in bone marrow express CD2 or/and CD25 present (corresponding to WHO minor criterion) f) Abnormal infiltration of mast cells in the bone marrow The criteria is deemed satisfied if the infiltration i) is quantified and is strictly above 3% in the biopsy, or ii) is not quantified but is abnormal as described with infiltration, contingent of mast cells, or proliferation and therefore pathological. ii. Detection of c-kit 816 in the bone marrow without evidence of mast cells in bone marrow but with evidence of c-Kit 816 in skin, justifying clonality iii. Excess of mast cells in digestive organs
2. Patient with documented treatment failure of his/her handicap(s) with at least one of the following therapy used at optimized dose (Table S1): Anti H1 Anti H2 Proton pump inhibitor Osteoclast inhibitor Cromoglycate Sodium Antileukotriene 3. Handicapped status defined as at least one of the following handicaps: Pruritus score ≥ 9 Number of flushes per week ≥ 8 Hamilton rating scale for depression(HAMD-17) score ≥ 19 4. Patients with adequate organ function: - Absolute neutrophils count (ANC) ≥ 2.0 x 109/L, - Haemoglobin ≥ 10 g/dL - Platelets (PLT) ≥ 100 x 109/L - AST and ALT ≤ 3x ULN - Bilirubin ≤ 1.5x ULN - Creatinine clearance > 60mL/min (Cockcroft and Gault formula) - Albuminemia >1 x LLN - Proteinuria at screening < 30 mg/mL (1+) on the dipstick. If proteinuria is > 1+ on the dipstick, 24 hours proteinuria must be < 1.5g/24 hours 5. Male or female patient aged 18 to 75 years, weight > 41 kg and BMI between 18 and 35 kg/m2 6. 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 acceptable method of contraception by her male partner during the study and for 3 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 acceptable method of contraception by his female partner during the study and for 3 months after the last treatment intake or who agrees to use an acceptable method of contraception and a highly effective method of contraception by his female partner during the study and for 3 months after the last treatment intake. 7. Female patient of childbearing potential must have a negative serum pregnancy test at screening and baseline 8. Patient must be able and willing to comply with study visits and procedures per protocol 9. Patient must understand, sign, and date the written voluntary informed consent form at the screening visit prior to any protocol-specific procedures performed 10. Patient must understand the patient card and follow the patient card procedures in case of signs or symptoms of severe neutropenia or severe cutaneous toxicity |
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E.4 | Principal exclusion criteria |
Exclusion criteria: 1. Previous treatment with any Tyrosine Kinase Inhibitor. 2. 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 3. Patient who had major surgery within 2 weeks prior to screening visit 4. Patient presenting with edema of cardiac origin and left ventricular ejection fraction ≤ 50% 5. Patient with chronic diarrhea defined as an episode that lasts longer than 14 days. 6. Vulnerable population defined as: • Life expectancy < 6 months • Patient with < 5 years free of malignancy, except treated basal cell skin cancer or cervical carcinoma in situ • Patient with any severe and/or uncontrolled medical condition • Patient with known diagnosis of human immunodeficiency virus (HIV) infection 7. 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 according to the judgment of the investigator , or institutionalized by court decision 8. Patient with any condition that the physician judges could be detrimental to patients participating in this study; including any clinically important deviations from normal clinical laboratory values or concurrent medical events Previous treatment 9. Change in the symptomatic treatment of systemic mastocytosis, including the systemic corticosteroids,or administration of any new treatment for systemic mastocytosis (including any Tyrosine Kinase Inhibitor) within 4 weeks prior to baseline 10. Treatment with any investigational agent within 4 weeks prior to baseline
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary objective: Primary endpoint: - Response on 3 handicaps: cumulative response by patient*handicap (pruritus and/or flushes and/or depression) from Week 8 to Week 24.
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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) |
Secondary objectives: Secondary endpoints:
Mast cells activation symptoms:
- Response on 4 handicaps: cumulative response by patient*handicap (pruritus and/or flushes and/or depression and/or FSS) from Week 8 to Week 24 (version 1). - Response on 4 handicaps: cumulative response by patient*handicap (pruritus and/or flushes and/or depression and/or FIS) from Week 8 to Week 24 (version 2). - Response on 2 handicaps: cumulative response by patient*handicap (pruritus and/or flushes) from Week 8 to Week 24. - Long-term response on 3 handicaps: cumulative response by patient*handicap (pruritus and/or flushes and/or depression) from Week 8 to Week 96. - Long-term response on 4 handicaps: cumulative response by patient*handicap (pruritus and/or flushes and/or depression and/or FSS) from Week 8 to Week 96 (version 1). - Long-term response on 4 handicaps: cumulative response by patient*handicap (pruritus and/or flushes and/or depression and/or FIS) from Week 8 to Week 96 (version 2). - Long-term response on 2 handicaps: cumulative response by patients*handicap (pruritus and/or flushes) from Week 8 to Week 96.
Biological and skin parameters:
- Tryptase response –change from baseline at week 12, 24 and then every 12 weeks - Urticaria Pigmentosa (UP) evaluation: o percentage of patients with improvement Darrier sign among UP patients at week 8, 12, 24 and then every 12 weeks o change from baseline in the Body Surface Area (BSA) covered by UP
Other symptomatic endpoints: - Cumulative response on pruritus from Week 8 to Week 24 among patients with the handicap at Baseline. - Cumulative response on flushes from Week 8 to Week 24 among patients with the handicap at Baseline. - Cumulative response on depression from Week 8 to Week 24 among patients with the handicap at Baseline (Hamilton rating scale for depression (HAMD-17) score ≥ 19) - Cumulative response on Fatigue Severity Scale (FSS) from Week 8 to Week 24 among patients with the handicap at Baseline (FSS score ≥ 36) - Cumulative response on Fatigue Impact Scale (FIS) from Week 8 to Week 24 among patients with the handicap at Baseline (FIS score ≥ 75) - In addition, long-term response (Week 8 to Week 96) for each endpoint in this section
Quality of Life (QOL) – valid for the sites for which questionnaire is validated in local language: - Change from baseline to week 24 and every 24 weeks in MC-QoL questionnaire; in addition, long-term response (W8 to W96) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | 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 | 2 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
United States |
France |
Poland |
Bulgaria |
Romania |
Spain |
Switzerland |
Czechia |
Germany |
Italy |
Hungary |
Russian Federation |
Slovakia |
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
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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |