Obstructive Hypertrophic Cardiomyopathy (oHCM)
Conditions
Keywords
mavacamten, obstructive hypertrophic cardiomyopathy, polymorphisms of CYP2C19, CYP3A4/CYP3A5 and CYP2C9
Brief summary
The European Medicines Agency has required pre-treatment genotyping of CYP2C19 to determine the initial and maximum dosage, in order to avoid overexposure to mavacamten associated with a decrease in ventricular ejection fraction below 50% in slow metabolisers of CYP2C19 (AUC multiplied by 3.4). The study is a requalification for the search for DNA samples obtained during treatment in order to genotype the genes of interest.The primary objective of the study is to estimate, for each of the CYP2C19 phenotypes of interest determined by genotyping (ultra-rapid, rapid, normal/extensive and intermediate metabolisers), the proportion of patients who are non-responders to mavacamten at each time point (D0, Week 4, Week 8, Week 12 and Week 24 in the treatment of HCM). This is a multicentre (3 centres which are hospitals of APHP) study aiming to include 300 patients with obstructive hypertrophic cardiomyopathy treated with Mavacamten who underwent or are undergoing CYP2C19 genotyping at the start of treatment. The inclusion period is 36 months and the follow-up period is 6 months. The total duration of the study is 42 months.
Detailed description
Before the arrival of mavacamten, preventive and symptomatic management of patients with obstructive hypertrophic cardiomyopathy relied on the use of non-vasodilating beta-blockers or non-dihydropyridine calcium channel blockers, or the addition of disopyramide in combination therapy with a beta-blocker. When dynamic obstruction of the left ventricular outflow tract (LVOT) persisted, invasive septal reduction treatments were offered, which were associated with significant morbidity and mortality. The introduction of mavacamten, the first reversible and selective inhibitor of cardiac myosin ATPase activity, made it possible to relieve LVOT obstruction and reduce myocardial hypercontractility after a period of titration, which varied in length depending on the patient, guided by echocardiography. The relationship between plasma concentrations of mavacamten and echocardiographic parameters has not been clearly established. However, this new drug is characterised by significant inter-individual pharmacokinetic variability, linked in part to genetic polymorphisms of CYP2C19, the hepatic enzyme responsible for its metabolism. Therefore, to ensure its safe use, the European Medicines Agency has required pre-treatment genotyping of CYP2C19 to determine the initial and maximum dosage, in order to avoid overexposure to mavacamten associated with a decrease in ventricular ejection fraction below 50% in slow metabolisers of CYP2C19 (AUC multiplied by 3.4). The study is a requalification for the search for DNA samples obtained during treatment in order to genotype the genes of interest. The primary objective of the study is to estimate, for each of the CYP2C19 phenotypes of interest determined by genotyping (ultra-rapid, rapid, normal/extensive and intermediate metabolisers), the proportion of patients who are non-responders to mavacamten at each time point (D0, Week 4, Week 8, Week 12 and Week 24 in the treatment of HCM). This is a multicentre (3 centres : La pitie Salpetriere hospital, Bicetre hospital and Ambroise Paré hospital). The study involves 2 non recruiting centres : the Molecular Genetics - Pharmacogenetics Service (which realize the genetic analyses) and the Biological ressources center (which preserves the bioological collection). The study aiming to include 300 patients with obstructive hypertrophic cardiomyopathy treated with Mavacamten who underwent or are undergoing CYP2C19 genotyping at the start of treatment. The inclusion period is 36 months. The recruitment of the patient is retrospective and prospective. The follow-up period is 6 months. The total duration of the study is 42 months.
Interventions
None listed
Sponsors
Assistance Publique - Hôpitaux de Paris
Study design
Observational model
COHORT
Time perspective
OTHER
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* \- Patients aged ≥18 years * Diagnosis of obstructive hypertrophic cardiomyopathy (OHCM), based on the guidelines of the European Society of Cardiology (Arbelo et al. 2023), with unexplained left ventricular hypertrophy and a maximum LVOT gradient ≥ 50 mmHg at rest, or after Valsalva manoeuvre or exercise at the time of diagnosis, and an LVOT gradient with Valsalva manoeuvre ≥ 30 mmHg at selection * With cardiac symptoms defined as NYHA class II/III, persistent despite background treatment (beta-blockers or calcium channel blockers) * LVEF ≥55% at the start of treatment with mavacamten * Initiation of treatment with mavacamten or patient already receiving treatment * Prescription of pre-treatment CYP2C19 genotyping performed * Consent to participate signed by the patient * Beneficiary of health insurance
Exclusion criteria
* Minors * Adults under guardianship (legal guardianship and curatorship) or judicial protection * Pregnant or breastfeeding women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response rate to Mavacamten treatment | Day 0, Week4, Week 8, Week 12, Week 24 | Proportion of patients responding to mavacamten (LVEF \>55% and LVOT gradient at Valsalva \<30 mL/min) according to different CYP2C19 and CYP3A phenotypic groups at 12 and 24 weeks, evaluated by echocardiography |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response rate to Mavacamten treatment in the above-mentioned populations | Day 0, Week4, Week 8, Week 12, Week 24 | Echocardiographic parameters (LVOT gradients at rest and Valsalva, and LVEF) according to different CYP2C19 and CYP3A phenotypic groups at 0, 4, 8, 12 and 24 weeks: 1. Patients who have undergone invasive therapy for obstruction 2. According to NYHA class 3. In patients treated with beta-blockers |
| Response rate to Mavacamten treatment in the general population and in the above-mentioned populations | Day 0, Week4, Week 8, Week 12, Week 24 | Steady-state daily dose of mavacamten in the general population and according to CYP2C19 and CYP3A patient phenotypic groups, at 12 and 24 weekInfluence of steady-state daily dose of mavacamten according to CYP2C19 and CYP3A phenotypic groups and co-treatments: 1. Co-administration of a strong to moderate CYP2C19 inhibitor 2. Co-administration of a strong to moderate CYP3A4 inhibitor 3. Co-administration of a strong to moderate CYP2C9 inhibitor |
| Description of cardiac and other adverse effects (excluding reduced LVEF) in the general population and in the above-mentioned populations | Day 0, Week4, Week 8, Week 12, Week 24 | Description of cardiac and other adverse effects (excluding reduced LVEF) in the general population and in the above-mentioned populations (points 1a, 1b, 1c) according to: 1. Co-administration of a strong to moderate CYP2C19 inhibitor 2. Co-administration of a strong to moderate CYP3A4 inhibitor 3. Co-administration of a strong to moderate CYP2C9 inhibitor |
| Variation in dosage of Mavacamten at weeks 4, week 8, week 12 and week 24 according to the different populations | Weeks 4, week 8, week 12 and week 24 | Variation in dosage of Mavacamten at weeks 4, week 8, week 12 and week 24 according to the different populations : a. Patients who have undergone invasive therapy for obstruction b. According to NYHA class c. In patients treated with beta-blockers |
Countries
France
Contacts
CONTACTPhilippe CHARRON, Pr
CONTACTCéline Verstuyft, Pr
Outcome results
None listed