Serotonin Receptor Blockers in Ischemic Mitral Regurgitation

Ischemic Mitral Regurgitation Clinical Trial

— CYPRO-MR  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05469165
• Other study ID #: 22229
• Status: Recruiting
• Phase: Phase 2
• Start date: June 20, 2023
• Est. completion date: September 2027

Study information

• Verified date: November 2023
• Source: Laval University
• Contact: Jonathan Beaudoin, MD
• Phone: (418) 656-8711
• Email: jonathan.beaudoin[@]criucpq.ulaval.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 214
• Est. completion date: September 2027
• Est. primary completion date: September 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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)

Related Conditions & MeSH terms

• Ischemia
• Ischemic Mitral Regurgitation
• Mitral Valve Insufficiency

Intervention

Drug:
• Cyproheptadine 4 Mg Oral Tablet
Cyproheptadine treatment for 3 months

Other:
• Placebo
Placebo administration for 3months

Locations

Country	Name	City	State
Canada	Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval	Québec

Sponsors (2)

Lead Sponsor	Collaborator
Laval University	Canadian Institutes of Health Research (CIHR)

Country where clinical trial is conducted

Canada, 

Outcome

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