Efficacy and Safety of Oral Masitinib in Severe Mast Cell Activation Syndrome: A 24-Week, Randomized, Double-Blind, Placebo-Controlled Phase II Study
- Trial ID
- 2024-515193-27-00
- Protocol
- AB20006
- Sponsor
- Ab Science
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is 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. This is clinically relevant as MCAS is a condition characterized by inappropriate mast cell activation, leading to a range of symptoms that can significantly impair quality of life. Effective management of this syndrome is crucial for improving patient outcomes and reducing the burden of symptoms.
The secondary objectives of the study are to assess the efficacy of masitinib compared with placebo on cumulative response on handicaps, reducing symptom severity, and improving quality of life. Additionally, the study aims to evaluate the safety and tolerability of masitinib compared to placebo, focusing on adverse events, vital signs, physical examination, ECG, and clinical laboratory tests. These assessments are important for understanding the broader impact of masitinib on patient health and its potential as a therapeutic option for MCAS.
Participants
The clinical trial focuses on evaluating the efficacy and safety of oral masitinib in patients with **mast cell activation syndrome** (MCAS) who have not responded to optimal symptomatic treatment. The study population includes both male and female participants aged between 18 to 75 years, with a weight greater than 45 kg and a body mass index (BMI) ranging from 18 to 35 kg/m². Participants are required to have severe MCAS, characterized by symptoms affecting two or more organ systems and documented treatment failures with at least two optimized symptomatic treatments. The trial includes individuals who are able to comply with study procedures and have provided informed consent. Participants must maintain stable doses of certain medications, such as Anti-H1, for a specified period before and during the study. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on specific inclusion criteria, including the ability to understand and follow study procedures, and adherence to contraception requirements for those of childbearing potential. The study involves a vulnerable population, as indicated by the inclusion of individuals with severe symptoms and treatment-resistant conditions.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy and safety of oral **masitinib** in patients with severe **mast cell activation syndrome** (MCAS) who are unresponsive to optimal symptomatic treatment. The trial will span a duration of 24 weeks, during which participants will be randomly assigned to receive either masitinib or a placebo. The primary objective is to assess the confirmed response at 50% at week 24 using the stratified Cochran Mantel-Haenszel test on four handicap scores: pruritus, flush, depression, and fatigue. Secondary endpoints include cumulative and every four weeks response at 75% on the same four handicaps from week 8 to week 24.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, weight, and documented treatment failures. The inclusion criteria require patients to have severe MCAS symptoms affecting two or more organ systems and a documented increase in serum total tryptase or other MC mediators. Following the screening, participants will enter a 14-day run-in period to assess the severity of symptoms. Subsequent visits will occur every four weeks to monitor response and safety, with the final visit at the end of the 24-week period to evaluate the primary and secondary endpoints.
The expected length of participant involvement is approximately 24 weeks, with conditions for early termination including severe adverse events or non-compliance with study procedures. Participants must maintain stable doses of certain medications throughout the study and adhere to contraception requirements if applicable. The trial aims to provide valuable insights into the therapeutic potential of masitinib for patients with severe MCAS, contributing to the understanding of its efficacy and safety profile.
Treatment
The clinical trial involves the administration of **masitinib**, a tyrosine kinase inhibitor, as the experimental medication. Masitinib is provided in the form of a **coated tablet** and is administered orally. The dosage is calculated based on body weight, with a maximum daily dose of 4.5 mg/kg. The total maximum dose is capped at 756 mg per day. The treatment period extends up to 24 weeks. The active substance, masitinib, is of chemical origin and is manufactured by AB Science. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the prescribed treatment schedule.
In addition to the experimental treatment, the study includes the use of a **placebo** as a comparator. The placebo is designed to match the appearance of the masitinib tablets but contains no active pharmaceutical ingredient. Two variations of the placebo are used, corresponding to the 100 mg and 200 mg masitinib doses. The placebo is administered orally, following the same schedule as the active treatment, to maintain the double-blind nature of the trial. The use of placebo allows for the assessment of the efficacy and safety of masitinib in comparison to a non-active treatment.
Efficacy
The efficacy of the clinical trial will be assessed through a series of predefined endpoints. The primary endpoint is the confirmed response at 50% at week 24, evaluated using the stratified Cochran Mantel-Haenszel (CMH) test on four handicap scores: pruritus, flush, depression, and fatigue. Secondary endpoints include cumulative and every four weeks response at 75% on the same four handicaps from week 8 to week 24, as well as a confirmed response at 75% at week 24. These assessments will be conducted at regular intervals throughout the trial to monitor the efficacy of the treatment.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- 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.
- 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
- 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.
- Age between 18 to 75 years (inclusive).
- Weight > 45 kg and BMI between 18 and 35 kg/m2
- 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.
- Patient must be able and willing to comply with study visits and procedures.
- Patient able to understand, sign, and date the written informed consent form at the screening visit prior to any protocol-specific procedures.
- 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
- Previous treatment with any Tyrosine Kinase Inhibitor.
- 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.
- Treatment with any investigational agent within 8 weeks prior to screening.
- 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%
- 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.
- Patient with systemic indolent mastocytosis.
- Patient who had major surgery within 2 weeks prior to screening visit.
- Known hypersensitivity to masitinib or to any of its excipients
- Patient with concomitant treatment or therapies associated with severe drug-induced skin toxicity.
- Female patients who are pregnant or are breastfeeding.
- 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
- Patients with history of severe bone marrow disorders such as agranulocytosis or aplasia
- 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
- 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
- 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.
- 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.
- 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.
- Patients who have received live vaccine within 30 days prior to first IMP administration.
- 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.
- Patients treated concomitantly with strong inducers of CYP3A4, substrates of CYP3A4 with a narrow therapeutic index.
- 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
- 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
- Patients with a history of active or latent tuberculosis (TB)
- 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
- 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 18 Apr 2023 | 5 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
masitinib | Test | COATED TABLET | ORAL | 4.5 | 24 | PRD110277 |
masitinib | Test | COATED TABLET | ORAL | 4.5 | 24 | PRD10419816 |
Placebo to 100mg masitinib | Placebo | N/A | — | — | — | N/A |
Placebo to 200mg masitinib | Placebo | N/A | — | — | — | N/A |