A 24-week, multicenter, randomized, double blind, placebo-controlled, dose-range finding phase II study to compare efficacy and safety of oral masitinib to placebo in treatment of patients with severe mast cell activation syndrome (MCAS) with handicap unresponsive to optimal symptomatic treatment

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ab Science

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

19 Sep 2024 → ongoing

Decision date (initial)

2024-09-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AB Science

External identifiers

EU CT number

2024-515193-27-00

EudraCT number

2021-005406-96

WHO UTN

U1111-1310-5431

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Safety

The objective of the study to evaluate the efficacy and safety of two titration schemes of oral masitinib versus placebo in the treatment of patients with severe mast cell activation syndrome (MCAS) with handicap unresponsive to optimal symptomatic treatment.

Secondary objectives 1

1. 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.

Conditions and MedDRA coding

Mast cell activation syndrome

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 1. Patient with severe 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. 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 Patients with depression should receive a psychiatric assessment in order to confirm the failure of standard treatment.
3. 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. 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. 5. Age between 18 to 75 years (inclusive).
6. 6. Weight > 45 kg and BMI between 18 and 35 kg/m2
7. 7. Contraception: • Female patients of childbearing potential (entering the study after a menstrual period and who has a negative pregnancy test), who agree to use a highly effective method of contraception and an effective method of contraception by their male partner during the study and for 8 months after the last treatment intake • Male patients with a female partner of childbearing potential who agree to use a highly effective method of contraception and an effective method of contraception by their female partner during the study and for 5 months after the last treatment intake OR who agree to use an effective method of contraception and a highly effective method of contraception by their female partner during the study and for 5 after the last treatment intake. - Highly effective and effective methods of contraception are detailed in the Appendix 15.3 of the protocol.
8. 8. Patient must be able and willing to comply with study visits and procedures.
9. 9. Patient able to understand, sign, and date the written informed consent form at the screening visit prior to any protocol-specific procedures.
10. 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.

Exclusion criteria 25

1. 1. Previous treatment with any Tyrosine Kinase Inhibitor.
2. 2. Any change in the symptomatic treatment of MCAS, including the systemic corticosteroids, or administration of any new treatment for MCAS within 4 weeks prior to screening.
3. 3. Treatment with any investigational agent within 8 weeks prior to screening.
4. 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. 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 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 country specific version is not available, EU one should be used.
6. 6. Patient with systemic indolent mastocytosis.
7. 7. Patient who had major surgery within 2 weeks prior to screening visit.
8. 8. Known hypersensitivity to masitinib or to any of its excipients
9. 9. Patient with concomitant treatment or therapies associated with severe drug-induced skin toxicity.
10. 10. Female patients who are pregnant or are breastfeeding.
11. 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
12. 12. Patients with history of severe bone marrow disorders such as agranulocytosis or aplasia
13. 13. Patient with history of hepatic disorders with a known liver disease or recent alcohol abuse or with abnormal laboratory results from local laboratory assessments defined as: o hepatic transaminase levels >2 x ULN at baseline, or o total bilirubin level > 1 x ULN at baseline, or o Both hepatic transaminase levels and total bilirubin level outside of the normal ranges at screening and baseline, or o Albuminemia ≤ 1 x LLN at screening and baseline, or o Patients with concomitant medication known to be associated with severe hepatotoxicity
14. 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. 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. 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. 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. 18. Patients who have received live vaccine within 30 days prior to first IMP administration.
19. 19. Taking part in another clinical trial or in another clinical study whose primary objective may interfere with the present study, at the same time and until 30 days after the last study medication intake.
20. 20. Patients treated concomitantly with strong inducers of CYP3A4, substrates of CYP3A4 with a narrow therapeutic index.
21. 21. 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
22. 22. 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
23. 23. Patients with a history of active or latent tuberculosis (TB)
24. 24. 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
25. 25. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is confirmed response at 50% at week 24 using stratified Cochran Mantel-Haenszel (CMH) test on 4 handicap scores (pruritus, flush, depression, fatigue).

Secondary endpoints 3

1. • Cumulative and every four weeks (every patient’s visit) response at 75% on 4 handicaps (pruritus, flush, depression, fatigue) from week 8 to week 24.
2. • Confirmed response (CR) at 75% at week 24
3. 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 (

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ab Science

Sponsor organisation

Ab Science

Address

3 Avenue George V

City

Paris

Postcode

75008

Country

France

Scientific contact point

Organisation

Ab Science

Contact name

Shruti Chatterjee

Public contact point

Organisation

Ab Science

Contact name

Alain Moussy

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications