| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Smouldering or Indolent Severe Systemic Mastocytosis with handicap unresponsive to optimal sympomatic treatment |
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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 |
Cumulative response on 3 handicaps (Pruritus, Flush, Depression) from week 8 to week 24.
• Handicaps are defined as: Pruritus score ≥ 9, number of Flushes per week ≥ 8, Depression HAMD score ≥ 19.
• Response on a handicap is defined as an improvement ≥ 75% for Pruritus, Flushes and Depression (HAMD Score).
For all the patients, the response at each study visit (5 visits from week 8 to week 24) will be calculated on each handicap present at Baseline (among pruritus, flushes, depression) as defined above.
Sensitivity analysis will be performed from week 8 to week 48.
In case of rescue medication to manage a handicap, all subsequent measures will be considered as “fail”.
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| E.2.2 | Secondary objectives of the trial |
• Cumulative response on 4 handicaps (Pruritus, Flushes, Depression, FSS) from w 8 to w 24.
• Cumulative response on 4 handicaps (Pruritus, Flushes, Depression, FIS) from w 8 to w24.
• Cumulative response on 2 handicaps (Pruritus, Flush) from w 8 to w24.
• Cumulative response on each of the individual handicaps from w 8 to w 24:
- Response on above mentioned handicaps is defined as an improvement ≥75%.
2. Biological and Skin Parameters:
• Tryptase Level:
- Change from baseline at week 24 in serum tryptase level;
• Urticaria Pigmentosa:
- “Darier Sign” disappearance (Yes/No) (week 12 to week 24);
- Body Surface Area (BSA) (week 12 to week 24).
3. Quality of Life
• MC-QoL Questionnaire (27 questions)
• MC-QoL questionnaire must be completed by patient for quality of
his/her life for past two (2) weeks. |
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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:
• Smouldering Systemic Mastocytosis (SSM)
• Indolent Systemic Mastocytosis (ISM)
2. An excess of mast cells or a presence of abnormal mast cells in at least two organs (among skin, bone-marrow and GI Tract)
3. Patients meet the used classification of SM based on the presence of one of the three criteria:
• Bone marrow biopsy and/or aspirate associated with at least a sign of abnormality of mast cells:
• Abnormal aggregates of mast cells in a sample in bone marrow: The criterion 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;
• ≥25% atypical mast cells in a sample of bone marrow (corresponding to WHO minor criterion);
• c-Kit point mutation at codon 816 in bone marrow (corresponding to WHO minor criterion);
• 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);
• Abnormal immunohistochemistry signs: mast cells in bone marrow express CD2 or/and CD25 present (corresponding to WHO minor criterion);
• Abnormal infiltration of mast cells in the bone marrow: The criterion 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.
• Detection of c-Kit 816 mutation in the bone marrow without evidence of mast cells in bone marrow but with evidence of c-Kit 816 mutation in skin, justifying clonality;
• Excess of mast cells in digestive organs.
4. Patient with severe symptoms of mastocytosis 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
5. Patient with documented treatment failures of his/her handicap(s) (within last two years) with at least two of the symptomatic treatments 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
6. 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.
7. Age between 18 to 75 years (inclusive).
8. Weight > 45 kg and BMI between 18 and 35 kg/m2
9. Contraception:
• The patient and his/her partner must use a highly effective method during the study and for 3 months and 1 week after the last treatment intake.
• Highly effective methods of contraception include:
• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal
• Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable
• Intrauterine device (IUD)
• Intrauterine hormone-releasing system (IUS)
• Bilateral tubal ligation
• Vasectomized male (azoospermia assessed medically)
• Sexual abstinence (Its reliability should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient)
10. Patient must be able and willing to comply with study visits and procedures.
11. Patient able to understand, sign, and date the written informed consent form at the screening visit prior to any protocol-specific procedures.
12. Patient able to 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 |
1. Cutaneous mastocytosis, SM associated with hematological neoplasm, Mast Cell Leukemia and Aggressive SM.
2. Previous treatment with any Tyrosine Kinase Inhibitor within the past 2
months prior to baseline.
3. History of unresponsiveness or intolerance to imatinib or masitinib
4. 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.
5. Treatment with any investigational agent within 8 weeks prior to screening
6. Patients with (an history of) severe cardiovascular disease:
- Myocardial infarction
- Unstable angina pectoris
- Coronary revascularization procedure
- Congestive heart failure of NYHA Class III or IV
- Stroke, including a transient ischemic attack
- Second degree or third-degree atrioventricular block not successfully treated with a pacemaker
- Bi-fascicular block
- QTc Fridericia interval > 450 milliseconds for males and > 470 milliseconds for females
- Drug induced heart failure or ischemic heart disease
- Radiotherapy induced cardiomyopathy
- Family history of unexpected death of cardiovascular origin.
7. Patients, with two or more of the risk factors listed below assessed by cardiologist 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)
- Diabete-
- 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) x T ( number years smoking). Patients who stopped smoking 6 months prior to evaluation are not concerned.
- Hypercholesterolemia
- COPD
This assessment is done according to the Systematic Coronary Risk Estimation (SCORE) using the country specific free full version of HeartScore°, the interactive tool for predicting and managing the risk of heart attack and stroke in Europe, available at https://www.heartscore.org/en_GB/access If the country specific version is not available, EU one should be used
8. Patient who had major surgery within 2 weeks prior to screening visit.
9. Known hypersensitivity to masitinib or to any of its excipients
10. Patient taking concomitant treatment or therapies associated with severe drug-induced skin toxicity.
11. Female patients who are pregnant or are breastfeeding.
12. Patient with following laboratory results out of the ranges detailed below at screening:
• Absolute neutrophils count (ANC) ≤ 1.5 x 109/L
• Haemoglobin ≤ 10 g/dL
• Platelets (PLT) ≤ 100 x 109/L
• Albuminemia ≤ 1 x LLN
13. Patient with history of hepatic disorders, recent alcohol abuse or recent history of hepatic impairment defined as hepatic transaminase levels >3 x ULN or total bilirubin level > 1.5 x ULN
14. Patient with severe pre-existing renal impairment, or with abnormal laboratory results from local laboratory assessments at screening:
• Creatinine clearance < 60 mL/min (Cockcroft and Gault formula)
• 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
15. Vulnerable population defined as:
• Life expectancy < 6 months
• Patient with < 5 years free of malignancy.
• Patient with known diagnosis of human immunodeficiency virus (HIV) infection.
16. Patient with history of poor compliance, or current or past psychiatric disease that might interfere with the ability to comply with the study procedures or give informed consent according to the judgment of the investigator or institutionalized by court decision.
17. Patient with any condition that the physician judges could be detrimental to patient participating in this study; including any clinically important deviations from normal clinical laboratory values or concurrent medical conditions.
18. Patients who have received live vaccine within 30 days prior to first IMP administration.
19. Patients treated concomitantly with strong inducers of CYP3A4, substrates of CYP3A4 with a narrow therapeutic index, or inhibitors of CYP2C8.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Cumulative response on 3 handicaps (Pruritus, Flush, Depression) from week 8 to week 24.
• Handicaps are defined as: Pruritus score ≥ 9, number of Flushes per week ≥ 8, Depression HAMD score ≥ 19.
• Response on a handicap is defined as an improvement ≥ 75% for Pruritus, Flushes and Depression (HAMD Score).
• For all the patients, the response at each study visit (5 visits from week 8 to week 24) will be calculated on each handicap present at Baseline (among pruritus, flushes, depression) as defined above.
Sensitivity analysis will be performed from week 8 to week 48.
In case of rescue medication to manage a handicap, all subsequent measures will be considered as “fail”.
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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) |
1. Handicap:
• Cumulative response on 4 handicaps (Pruritus, Flushes, Depression, FSS) from week 8 to week 24. Handicaps for this cumulative response are defined as: Pruritus score ≥ 9, number of Flushes per week ≥ 8, Depression HAMD score ≥ 19, FSS ≥ 36.
• Cumulative response on 4 handicaps (Pruritus, Flushes, Depression, FIS) from week 8 to week 24. Handicaps for this cumulative response are defined as: Pruritus score ≥ 9, number of Flushes per week ≥ 8, Depression HAMD score ≥ 19, FIS ≥ 75.
• Cumulative response on 2 handicaps (Pruritus, Flush) from week 8 to week 24. Handicaps for this cumulative response are defined as: Pruritus score ≥ 9 and number of Flushes per week ≥ 8.
• Cumulative response on each of the individual handicaps from week 8 to week 24:
- Pruritus (Handicap defined as Pruritus Score ≥ 9);
- Flushes (Handicap defined as Flushes ≥ 8);
- Depression (Handicap defined as HAMD ≥ 19);
- Fatigue Severity Scale (FSS) (Handicap defined as FSS ≥ 36);
- Fatigue Impact Scale (FIS) (Handicap defined as FIS ≥ 75).
Response on above mentioned handicaps is defined as an improvement ≥75%.
Sensitivity analysis will be performed from week 8 to week 48.
2. Biological and Skin Parameters:
• Tryptase Level:
- Change from baseline at week 24 in serum tryptase level;
- Response: Defined as a diminution of at least 25% in tryptase level at week 24.
• Urticaria Pigmentosa:
- “Darier Sign” disappearance (Yes/No) (week 12 to week 24);
- Body Surface Area (BSA) (week 12 to week 24).
Sensitivity analysis for “Darier Sign” disappearance (Yes/No) and Body Surface Area (BSA) will be performed from week 12 to week 48.
3. Quality of Life:
• MC-QoL Questionnaire (27 questions)
• MC-QoL questionnaire must be completed by patient for quality of his/her life for past two (2) weeks.
Sensitivity analysis will be performed from week 8 to week 48.
Additional analysis will be elaborated in the Statistical Analysis Plan which will be approved before the Data Base Lock.
Criteria for Safety Occurrence of IMP-related and unrelated Adverse Events (AEs)/Serious Adverse Events (SAEs).
Changes in physical examination including vital signs (blood pressure, pulse rate), weight and ECG.
Changes in clinical laboratory tests (biochemistry, haematology, urinalysis).
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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
| Yes |
| 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 | 2 |
| 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 | Yes |
| 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 |
| Ukraine |
| Canada |
| Russian Federation |
| United Kingdom |
| United States |
| France |
| Germany |
| Italy |
| Lithuania |
| Netherlands |
| Poland |
| Romania |
| Spain |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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