Serotonin Receptor Blockers in Ischemic Mitral Regurgitation (CYPRO-MR)

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

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

Study Overview

• Status: Recruiting
• Conditions: Ischemic Mitral Regurgitation
• Intervention / Treatment: Drug: Cyproheptadine 4 Mg Oral Tablet; Other: Placebo

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 Type: Interventional
• Enrollment (Estimated): 214
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jonathan Beaudoin, MD; Phone Number: 2943 (418) 656-8711; Email: jonathan.beaudoin@criucpq.ulaval.ca
• Study Contact Backup: Name: Ons Marsit, PhD; Phone Number: 5773 (418) 656-8711; Email: ons.marsit.1@ulaval.ca

Study Locations

• Canada
  • Québec, Canada, G1V 4G5
    • Recruiting
    • Institut Universitaire de Cardiologie et de Pneumologie de Quebec - Université Laval
    • Contact: Jonathan Beaudoin, MD; Phone Number: 2943 418 656-8711

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in mitral leaflet size	Mitral leaflet size (3D echo) and its variation vs baseline (measured by echocardiography)	Baseline, 3 months
Change in left ventricle size	Left ventricle size (measured by MRI )	Baseline, 3 months
Change in left ventricle function	Left ventricle function (measured by MRI )	Baseline, 3 months
Incidence of other valve regurgitation	Incidence of other valve regurgitation (more than mild) (measured by echocardiography)	3 months
Change in mitral valve thickness	Mitral valve thickness (measured by echocardiography)	Baseline, 3 months
Adverse events	Composite of: Mortality, Heart failure requiring hospital admission, Mitral valve intervention (surgical/percutaneous)	3 months and 1 year
Ischemic events	stroke and myocardial infarction	3 months and 1 year
Bleeding events	Bleeding Academic Research Consortium (BARC) definition	3 months and 1 year
Change in weight of participants	Weight gain during therapy (self-assessment by participants)	Baseline, 3 months
Change in the functional capacity of participants	6-minutes walk test	3 months, 1 year
Incidence of sedation	Incidence of sedation (reported by participants)	Baseline, 3 months
Change in mitral regurgitation grade	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.	Baseline, 3 months
Change in the patient's perception of their health status	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).	Baseline, 3 months
Change in depression score	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.	Baseline, 3 months

Collaborators and Investigators

• Sponsor: Laval University
• Collaborators: Canadian Institutes of Health Research (CIHR)

Study record dates

Study Major Dates

• Study Start (Actual): June 20, 2023
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): September 1, 2027

Study Registration Dates

• First Submitted: July 19, 2022
• First Submitted That Met QC Criteria: July 19, 2022
• First Posted (Actual): July 21, 2022

Study Record Updates

• Last Update Posted (Actual): November 15, 2023
• Last Update Submitted That Met QC Criteria: November 13, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Myocardial infarction; Serotonin; Mitral valve; Cyproheptadine; Ischemic mitral regurgitation
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Heart Valve Diseases; Ischemia; Mitral Valve Insufficiency; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Dermatologic Agents; Serotonin Agents; Serotonin Antagonists; Anti-Allergic Agents; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Antipruritics; Cyproheptadine
• Other Study ID Numbers: 22229

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No