CYPRO-MR: Blocking the Effects of Serotonin to Prevent Ischemic Mitral Regurgitation: a Randomized Trial

Sponsor

Laval University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05469165

Collaborator

Canadian Institutes of Health Research (CIHR) (Other)

214

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Ischemic Mitral Regurgitation	Drug: Cyproheptadine 4 Mg Oral Tablet Other: Placebo	Phase 2

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, we 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 Design

Study Type:

Interventional

Anticipated Enrollment :

214 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

Blocking the Effects of Serotonin to Prevent Ischemic Mitral Regurgitation: a Randomized Trial (CYPRO-MR)

Anticipated Study Start Date :

Sep 1, 2022

Anticipated Primary Completion Date :

Sep 1, 2026

Anticipated Study Completion Date :

Sep 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Cyproheptadine 4 Mg Oral Tablet Cyproheptadine treatment for 3 months Other Names: Cyproheptadine
Placebo Comparator: Placebo Participants will receive a matched placebo orally three times a day for 3 months. Daily titration similar to the treatment arm.	Other: Placebo Placebo administration for 3months

Arm

Intervention/Treatment

Experimental: 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.

Drug: Cyproheptadine 4 Mg Oral Tablet

Cyproheptadine treatment for 3 months

Other Names:

Cyproheptadine

Placebo Comparator: Placebo

Participants will receive a matched placebo orally three times a day for 3 months. Daily titration similar to the treatment arm.

Other: Placebo

Placebo administration for 3months

Outcome Measures

Primary Outcome Measures

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

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)
Change in left ventricle size [Baseline, 3 months]
Left ventricle size (measured by MRI )
Change in left ventricle function [Baseline, 3 months]
Left ventricle function (measured by MRI )
Incidence of other valve regurgitation [3 months]
Incidence of other valve regurgitation (more than mild) (measured by echocardiography)
Change in mitral valve thickness [Baseline, 3 months]
Mitral valve thickness (measured by echocardiography)
Adverse events [3 months and 1 year]
Composite of: Mortality, Heart failure requiring hospital admission, Mitral valve intervention (surgical/percutaneous)
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 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)
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 depression score [Baseline, 3 months]
Self-administered questionnaire: Patient Health Questionnaire (PHQ-9)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients 18-80 years old with a 1st episode of STEMI with documented coronary obstruction.
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:

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