Smouldering or Indolent Severe Systemic mastocytosis
Conditions
Interventions
Product Name: Masitinib
Product Code: AB1010
Pharmaceutical Form: Film-coated tablet
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use
Product Na
Sponsors
AB SCIENCE
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patient with one of the following documented mastocytosis: ? Smouldering Systemic Mastocytosis (SSM) ? Indolent Systemic Mastocytosis (ISM) 2. Patients meet the retained classification of SM based on the presence of one of the three criteria and an excess of mast cells or a presence of abnormal mast cells in at least two organs (first one is skin and the second being bone-marrow or GI Tract): I. Bone marrow biopsy and/or aspirate associated with at least a sign of abnormality of mast cells: 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. 3. Patient with severe symptoms over the 14-day run-in period defined as at least one of the following: ? Pruritus score = 9 ? Number of flushes per week = 8 ? Hamilton rating scale for depression (HAMD-17) score = 19 4. Patient with documented treatment failure of his/her symptom (s) (within last two years) with at least two of the failure symptomatic treatment used at optimized dose (Minimal duration of each treatment should be at least 8 weeks): ? Anti H1 ? Anti H2 ? Proton pump inhibitor ? Antidepressants ? Cromoglycate Sodium ? Antileukotriene 5. Patients must be on a stable dose of Anti-H1 for a minimum of 4 weeks before screening and should remain at a stable dose throughout the study period. For other symptomatic treatments, if the patient takes corticosteroids, Anti-H2 or PPI or Antidepressants or Cromoglycate Sodium or Antileucotriene, the treatment must have started at least 4 weeks before Screening and must be stable throughout the study. 6. Documented age between 18 to 75 years (inclusive). Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 112 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 28
Exclusion criteria
Exclusion criteria: 1. Cutaneous mastocytosis, SM associated with hematological neoplasm, Mast Cell Leukemia and Aggressive SM. 2. Previous treatment with any Tyrosine Kinase Inhibitor. 3. Any change in the symptomatic treatment of SM, including the systemic corticosteroids, or administration of any new treatment for SM within 4 weeks prior to screening.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The study objective is 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 unresponsive to optimal symptomatic treatment;Secondary Objective: Not applicable ;Primary end point(s): Cumulative response on 3 severe symptoms (Pruritus, Flush, Depression) from week 8 to week 24. Severe symptomd for primary objective is defined as: Pruritus score = 9, number of Flushes per week = 8, Depression = 19. Response on a severe symptoms is defined as an improvement = 75% for Pruritus, Flushes and Depression. In case of rescue medication to manage a severe symptom, all subsequent measures will be considered as “fail”. ;Timepoint(s) of evaluation of this end point: Every 4 weeks from week 8 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1) Severe symptom The following secondary endpoints will be analysed using a Generalized Estimating Equations (GEE) model using Logit as link function. This statistical model will include all the responses (Yes/No) on handicaps observed from week 8 to week 24. This model will include treatment, handicap and visit as factors and all stratification factors as covariates: • Response on 4 severe symptoms (version 1) from week 8 to week 24. This analysis will include FSS score in addition to the three severe symptoms included in the primary endpoint. • Response on 4 severe symptoms (version 2) from W8 to W24. This analysis will include FIS score in addition to the three severe symptoms included in the primary endpoint. • Response 2 on severe symptoms from W8 to W24. This analysis will include pruritus and flush at Baseline. • Each individual severe symptoms (Pruritus, Flushes, Depression, fatigue (FIS), fatigue (FSS). Sensitivity analysis will be performed on the week 8 to week 48. 2) Biological and Skin Parameters: • Tryptase: Tryptase will be analysed for patients with a baseline level higher than 20 µg/L. - Change from baseline in serum tryptase level at week 24 will be analyzed using Analysis of Covariance (ANCOVA) with baseline value as covariate for the absolute change from baseline and Wilcoxon’s non-parametric exact test for ranks for relative change from baseline. - Response: Defined as a diminution of at least 25% in tryptase level from baseline to week 24 will be analyzed using logistic regression. If logistic regression fails to estimate the treatment effects, Chi-Square test or Fisher’s exact test (depending the observations). • Urticaria Pigmentosa: a) “Darier Sign” disappearance: “Darier Sign” disappearance (Yes/No) for patients with “Darier’s sign” at baseline from W8 to W24 will be analyzed using Generalized Estimating Equation (GEE) with logit as link function. The model will include treatment and v | — |
Countries
Canada, France, Germany, Italy, Lithuania, Netherlands, Poland, Romania, Russian Federation, Spain, Ukraine, United Kingdom, United States
Contacts
Public ContactAlain Moussy
AB SCIENCE
Outcome results
None listed