Serotonin Receptor Blockers in Ischemic Mitral Regurgitation

Phase 2

Recruiting

• Conditions: Ischemic Mitral Regurgitation
• Interventions: Drug: Cyproheptadine 4 Mg Oral Tablet; Other: Placebo

• Registration Number: NCT05469165
• Lead Sponsor: Laval University

Brief Summary

This study is intended to investigate the effect of cyproheptadine (a 5HT2B receptor blocker) on mitral regurgitation severity.

Detailed Description

Ischemic mitral regurgitation (MR) is a common and morbid complication of myocardial infarction (MI), doubling heart failure and mortality with currently limited therapies. Its mechanisms have been previously linked to left ventricle (LV) remodeling with secondary deformation of otherwise normal mitral leaflets. Recent studies are introducing new mechanistic elements, allowing possibilities for potential pharmacotherapeutic approaches. Normal mitral leaflets have the capacity to enlarge and adapt to even the largest LV dilatation to prevent MR. However, this compensatory mechanism is insufficient after MI, and the leaflets are abnormally thick with fibrotic changes. Those fibrotic changes could be related to a variation in blood serotonin (5-HT) levels after MI, which has been previously reported. Serotonin is a known cause of valve fibrosis through its 5HT type 2B receptor. In sheep models, the investigators have tested the hypothesis that a 5HT type 2B receptor blocker (cyproheptadine) can prevent adverse remodeling in the valve after MI. Cyproheptadine treatment was associated with increased valve leaflet surface, attenuated leaflet thickening and collagen deposition. Importantly, treated animals had less MR compared to non-treated animals.

Thus the present study is a double-blind randomized trial to assess the effect of cyproheptadine on MR severity, mitral valve surface variation, and left ventricular size following MI. Serial imaging (3D echo and MRI) will assess valve adaptation, LV remodeling and MR.

Study Timeline

• Study First Submitted: 2022-07-19
• Study First Submitted QC: 2022-07-19
• Study First Posted: 2022-07-21
• Study Start: 2023-06-20
• Status Verified: 2023-11
• Last Update Submitted: 2023-11-13
• Last Update Posted: 2023-11-15
• Primary Completion: 2026-09
• Study Completion: 2027-09

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 214

Inclusion Criteria

1. Patients 18-80 years old with a 1st episode of STEMI with documented coronary obstruction.
2. Left ventricle ejection fraction (LVEF)<50% and mitral tenting area ≥ 4 cm2, OR LVEF ≤ 40% and inferior/posterior wall motion anomaly, OR LVEF≤30% and wall motion in any territory.

Exclusion Criteria

1. Inability to provide informed consent
2. Hemodynamic instability / cardiogenic shock / papillary muscle rupture
3. Prior mitral valve procedure/surgery
4. Permanent atrial fibrillation (limiting imaging and MR quantification)
5. Primary mitral disease (endocarditis, rheumatic, degenerative or congenital)
6. More than mild valvular disease (other than mitral) at baseline
7. Planned cardiac surgery (CABG or valve intervention) within 3 months
8. Contraindications for MRI
9. Ongoing treatment with selective serotonin reuptake inhibitor (SSRI)
10. Chronic use of sedative medication
11. Ongoing or planned pregnancy
12. Chronic renal failure with Estimated Glomerular Filtration Rate (eGFR) < 30 mL/min
13. Neurocognitive disorder
14. Symptom or prior episode of urinary obstruction or glaucoma (relative contraindications for cyproheptadine)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cyproheptadine 4 Mg Oral Tablet	Cyproheptadine 4 Mg Oral Tablet	Participants will receive cyproheptadine 4mg tablet orally three times a day for three months, with a daily increase of 4mg/dose if the previous dose was well tolerated, up to 0.5 mg/kg/day.
Placebo	Placebo	Participants will receive a matched placebo orally three times a day for 3 months. Daily titration similar to the treatment arm.

Primary Outcome Measures

Name	Time	Method
Change in mitral regurgitation severity	Baseline, 3 months	Incidence of more than mild MR (MRI regurgitant fraction ≥ 20%) at 3 months (measured by MRI)

Secondary Outcome Measures

Name	Time	Method
Ischemic events	3 months and 1 year	stroke and myocardial infarction
Bleeding events	3 months and 1 year	Bleeding Academic Research Consortium (BARC) definition
Change in mitral valve thickness	Baseline, 3 months	Mitral valve thickness (measured by echocardiography)
Change in left ventricle function	Baseline, 3 months	Left ventricle function (measured by MRI )
Change in weight of participants	Baseline, 3 months	Weight gain during therapy (self-assessment by participants)
Change in the patient's perception of their health status	Baseline, 3 months	Self-administered questionnaire : Kansas City Cardiomyopathy Questionnaire (KCCQ). All score are represented on a 0-to-100-point scale (lower scores represent more severe symptoms and/or limitations and scores of 100 indicate no symptoms, no limitations, and excellent quality of life).
Change in the functional capacity of participants	3 months, 1 year	6-minutes walk test
Incidence of sedation	Baseline, 3 months	Incidence of sedation (reported by participants)
Change in mitral leaflet size	Baseline, 3 months	Mitral leaflet size (3D echo) and its variation vs baseline (measured by echocardiography)
Change in mitral regurgitation grade	Baseline, 3 months	Mitral regurgitation grade (measured by echocardiography). Mitral regurgitation is graded on a scale of I-IV (grade I (mild MR), grade II (moderate MR), grade III (moderate-to-severe MR) and grade IV (severe MR)). A higher mitral regurgitation grade is generally associated with a worse outcome for the patient.
Change in left ventricle size	Baseline, 3 months	Left ventricle size (measured by MRI )
Incidence of other valve regurgitation	3 months	Incidence of other valve regurgitation (more than mild) (measured by echocardiography)
Adverse events	3 months and 1 year	Composite of: Mortality, Heart failure requiring hospital admission, Mitral valve intervention (surgical/percutaneous)
Change in depression score	Baseline, 3 months	Self-administered questionnaire: Patient Health Questionnaire (PHQ-9). The Patient Health Questionnaire has a scale of 0-27, with higher scores indicating a worse outcome for the patient, with more severe depression symptoms.

Trial Locations

Locations (1)

Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval; 🇨🇦 Québec, Canada