E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Smouldering Systemic, Indolent Systemic or Cutaneous mastocytosis with handicap |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10026891 |
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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 |
Responder rate at week 24 |
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E.2.2 | Secondary objectives of the trial |
Response in at least two out of three variables among pruritus, flushes, depression or asthenia, at week 12 and week 24 Responder rate at week 12 Pruritus score at week 12 and week 24 Number of flushes per week at week 12 and week 24 Hamilton score at week 12 and week 24 Fatigue Impact Scale at week 12 and week 24 Number of mictions per day at week 12 and week 24 Number of stools per day at week 12 and week 24 QLQ-C30 scores at week 12 and week 24 Overall Patient Assessment (OPA) at week 12 and week 24 AFIRMM V2 score at week 12 and week 24 Percentage of patient without handicap at week 12 and 24 Mast cell infiltration in the skin or bone marrow at week 24 Serum tryptase level at week 24 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient with one of the following documented mastocytosis as per WHO classification: Smouldering Systemic Mastocytosis Indolent Systemic Mastocytosis Cutaneous Mastocytosis 2. Patient with documented mastocytosis and evaluable disease based upon histological criteria: typical infiltrates of mast cells in a multifocal or diffuse pattern in skin and/or bone marrow biopsy 3. Patient with documented treatment failure of his/her handicap(s) with at least one of the following therapy used at optimized dose (refer to table 2): Anti H1 Anti H2 Proton pump inhibitor Osteoclast inhibitor Cromoglycate Sodium Antileukotriene 4. Handicapped status defined as at least two of the following handicaps, including at least one among pruritus, flushes, depression and asthenia: pruritus score ≥ 6 number of flushes per week ≥ 7 Hamilton rating scale (depression) ≥ 10 number of stools per day ≥ 4 , number of mictions per day ≥ 8 , Fatigue Impact Scale total score (asthenia) ≥ 40 5. Patients with OPA > 2 (moderate to intolerable general handicap) 6. ECOG ≤ 2 7. Patient with adequate organ function : absolute neutrophil count (ANC) ≥ 2.0 x 109/L, platelets (PTL) ≥ 100 x 109/L AST/ALT ≤ 2.5x ULN (≤ 5 x ULN in case of liver mast cell involvement), bilirubin ≤ 1.5x ULN creatinin clearance ≥50 mL/min (Cockrot and Gault formula) albumin > 0.75 x LLN urea ≤ 1.5 x ULN proteinuria < 30mg/dL on the dipstick;; in case of proteinuria ≥ 30 mg/dL, 24 hours proteinuria should be < 1.5g/24 hours 8. Male or female patient with age ≥ 18 years 9. Men and women of child bearing potential (entering the study after a confirmed menstrual period and who have a negative pregnancy test) must agree to use 2 methods of medically acceptable forms of contraception during the study. Men and women of childbearing potential must agree upon using contraception for three months following their participation in the study 10. Patient should be able and willing to comply with study visits and procedures per protocol 11. Patient should understand, sign, and date the written voluntary informed consent form at the screening visit prior to any protocol-specific procedures performed 12. Patient must be covered by insurance for routine costs |
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E.4 | Principal exclusion criteria |
1. Patient with one of the following mastocytosis: Systemic Mastocytosis with an Associated clonal Hematologic Non Mast cell lineage Disease (SM-AHNMD) Mast cell leukemia (MCL) Aggressive systemic mastocytosis (ASM) 2. Previous treatment with any Tyrosine Kinase Inhibitor 3. Patient presenting with cardiac disorders defined by at least one of the following condition: a. Ischemic heart disease, defined by at least one of the following condition: i. Medical history of ischemic heart disease ii. Clinical symptoms of ischemic heart disease iii. Q wave > 3 mm on the electrocardiogram iv. ST elevation or depression > 2 mm on the electrocardiogram v. Negative T wave in at least 2 leads of the electrocardiogram b. Cardiac failure, defined by at least one of the following condition: i. Medical history of cardiac failure defined by a previous left ventricular ejection fraction ≤ 50% ii. Clinical symptoms of cardiac failure iii. NT proBNP ≥ 300 pg/mL and/or troponin T > 0.1 ng/mL c. Conduction disorders or arrhythmia, defined by at least one of the following and confirmed by electrocardiogram: i. Severe ventricular arrhythmia (frequent premature ventricular beats) ii. Atrioventricular block at second or third level iii. Left bundle branch block 4. Patient who had major surgery within 2 weeks prior to screening visit 5. 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 6. 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 7. Patient with any condition that the physician judges could be detrimental to subjects participating in this study; including any clinically important deviations from normal clinical laboratory values or concurrent medical events Previous treatment 8. Change in the symptomatic treatment of mastocytosis or administration of any new treatment of mastocytosis within 4 weeks prior to baseline 9. 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) |
The primary endpoint is the percentage of responders at week 24. A patient is classified as responder if he/she presents an improvement of ≥ 50% in at least one handicap, handicap being defined as a score above the cut in any of the 4 variables: - pruritus score ≥ 6, - number of flushes per week ≥ 7, - Hamilton score ≥ 10 - Fatigue Impact Scale score ≥ 40 Any patient with a worsening of more than 50% of any handicap, and/or with emergence of a new handicap with an increase of more than 50% from baseline, will be considered a non responder. Superiority of 6 mg/kg masitinib daily over placebo in patients suffering from mastocytosis with regard to the primary variable as given above will be tested with the following hypotheses, where � denotes the percentage of responders at week 24: H0: �6mg/kg masitinib bid ≤ �placebo bid H1: �6mg/kg masitinib bid > �placebo bid This means that a test for superiority will be performed in percentage of responders in the group treated with 6mg/kg/day masitinib compared to the one treated with placebo. Superiority will be tested using the Pearson Chi-square. |
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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 | No |
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.8.3 |
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 | Information not present in EudraCT |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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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Fino a progressione di malattia. |
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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 | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
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 |