| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| severe mast cell activation syndrome (MCAS) with handicap unresponsive to optimal symptomatic treatment |
|
| E.1.1.1 | Medical condition in easily understood language |
| severe mast cell activation syndrome (MCAS) |
|
| 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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10075217 |
| E.1.2 | Term | Mast cell activation syndrome |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| 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 |
| The primary objective is to evaluate the masitinib treatment will show a significant trend on response at 50% on 3 handicaps (pruritus, flush, depression) at week 24. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of the study are to evaluate the efficacy of masitinib compared with placebo efficacy on cumulative response on handicaps, reducing symptom severity and quality of life. The secondary objectives also include the assessment of safety and tolerability of masitinib as compared to placebo in terms of adverse events, vital signs, physical examination, ECG, and clinical laboratory tests. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient with Mast cell activation syndrome (MCAS)
For diagnosis of MCAS, the patients must fulfil the following criteria:
a) Clinical Criteria:
Episodic occurrence of typical MCAS-related clinical symptoms (urticaria, angioedema, flushing, pruritus, nausea, hoarseness, vomiting, diarrhea, abdominal cramping, hypotensive syncope, tachycardia, wheezing, conjunctival injection, nasal congestion, and headache) affecting 2 or more organ systems.
b) Biomarker Criteria:
Increase in serum total tryptase by at least 20% above baseline plus 2 ng/ml during or within 4 h after a symptomatic period.
Or
Documented evidence of above-normal levels for one of the following MC mediators according to local laboratory criteria:
- Random serum tryptase, prostaglandin D2, histamine;
- Random urinary histamine, N-methylhistamine, prostaglandin D2 and its metabolite 11F2 alpha;
- 24-hour urinary histamine, N-methylhistamine, prostaglandin D2 and its metabolite 11F2 alpha
2. 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
-Fatigue scales FSS ≥ 36 and/or FIS ≥ 75
Patients with depression should receive a psychiatric assessment in order to confirm the failure of standard treatment
3. 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
- Corticosteroids
- Antidepressants
- Cromoglycate Sodium
- Antileukotriene
4. 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 Antileukotriene, the treatment must have started at least 4 weeks before Screening and must be
stable throughout the study.
5. Age between 18 to 75 years (inclusive).
6. Weight > 45 kg and BMI between 18 and 35 kg/m2
7. Contraception:
* The patient and his/her partner must use a highly effective method during the study and for 6 months 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)
8. Patient must be able and willing to comply with study visits and procedures.
9. Patient able to understand, sign, and date the written informed consent form at the screening visit prior to any protocol-specific procedures.
10. 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. |
|
| E.4 | Principal exclusion criteria |
1. Previous treatment with any Tyrosine Kinase Inhibitor.
2. 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.
3. Treatment with any investigational agent within 8 weeks prior to screening.
4. Patients with current or 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.
- Edema of cardiac origin and left ventricular ejection fraction ≤50%
5. 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)
- Diabetes
- Kidney disease,
- Current tabagism (≥ 10 Pack-year: equivalent to 1 pack of 20 cigarettes per 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
6. Patient with systemic indolent mastocytosis.
7. Patient who had major surgery within 2 weeks prior to screening visit
8. Known hypersensitivity to masitinib or to any of its excipients
9. Patient with concomitant treatment or therapies associated with severe drug-induced skin toxicity.
10.Female patients who are pregnant or are breastfeeding.
11. 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
12.Patient with history of hepatic disorders, recent alcohol abuse or recent history of hepatic impairment defined as hepatic transaminase levels >1.5 x ULN or total bilirubin level > 1 x ULN
13.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
14. 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.
15.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.
16.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.
17. Patients who have received live vaccine within 30 days prior to first IMP administration.
18. Taking part in another research study at the same time and until 30 days after the last study medication intake.
19. Patients treated concomitantly with strong inducers of CYP3A4, substrates of CYP3A4 with a narrow therapeutic index, or inhibitors of CYP2C8.
20.Patients with active severe infection such as tuberculosis, viral hepatitis, human immunodeficiency virus infection, syphilis or COVID-19 (confirmed by positive RT-PCR and/or other applicable methods), from medical files assessed at screening or baseline
21. Patients with any known or suspected active infection at screening or baseline or any major
episode of infection requiring hospitalization or treatment within 8 weeks prior screening
22. Patients with a history of active or latent tuberculosis (TB)
23. Patients with persistent chronic or active or recurring system infection that may adversely affect participation or IMP administration in this study, as judged by the Investigator
24. Patients at risk of developing or having reactivation of hepatitis: results at screening for serological markers for hepatitis B and C indicating acute or chronic infection |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is confirmed response at 50% at week 24 using stratified Cochran Mantel-Haenszel (CMH) test on 3 handicap scores (pruritus, flush, depression). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints of the study are:
- Cumulative and every four weeks (every patient’s visit) response at 75% on 3 handicaps (pruritus, flush, depression) from week 8 to week 24.
- Confirmed response (CR) at 75% at week 24
Two evaluations will be done for each of the following end points as an improvement of response >50% and ≥75%
- Cumulative and every four weeks (every patient’s visit) response on 4 handicaps (pruritus, flushes, depression, fatigue by FSS) from week 8 to week 24.
- Cumulative and every four weeks (every patient’s visit) response on 4 handicaps (pruritus, flush, depression, fatigue by FIS) from week 8 to week 24.
- Cumulative and every four weeks (every patient’s visit) response on 2 handicaps (pruritus, flush) from week 8 to week 24.
- Cumulative and every four weeks (every patient’s visit) 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-17 score ≥ 19)
* Fatigue by FSS (handicap defined as FSS ≥ 36)
* Fatigue by FIS (handicap defined as FIS ≥ 75).
- Confirmed response (CR) at week 24:
* Pruritus (handicap defined as pruritus score ≥ 9)
* Flushes (handicap defined as flushes ≥ 8)
* Depression (handicap defined as HAMD-17 score ≥ 19)
* Fatigue by FSS (handicap defined as FSS ≥ 36)
* Fatigue by FIS (handicap defined as FIS ≥ 75). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 |
| United States |
| France |
| Poland |
| Switzerland |
| Germany |
| Italy |
| Belgium |
|
| 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
|
|
| 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 | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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