Trimetazidine Therapy in Hypertrophic Cardiomyopathy

A Phase 2b Randomised, Double Blind, Placebo-controlled Trial of Trimetazidine Therapy in Patients With Non-obstructive Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a common inherited heart condition that causes breathlessness, chest pain and fatigue. There are few treatments available. The investigators have recently shown that a drug called perhexiline reduced symptoms and improved exercise capacity in patients with HCM. This change appears to be driven by alterations in myocardial energy metabolism. The aim of this trial is to test a similar drug, trimetazidine, in a group of symptomatic patients with non-obstructive HCM.

HYPOTHESIS: trimetazidine will improve symptoms, peak oxygen consumption, cardiac function and arrhythmia burden in medically refractory symptomatic patients with non-obstructive HCM.

Study Overview

• Status: Unknown
• Conditions: Hypertrophic Cardiomyopathy
• Intervention / Treatment: Drug: Trimetazidine; Other: Placebo capsule

Detailed Description

BACKGROUND:

Hypertrophic cardiomyopathy (HCM) is a common inherited disorder of heart muscle affecting 1 in 500 individuals worldwide. It is associated with arrhythmias, heart failure and sudden death in young people. In the majority of patients, HCM is caused by mutations in genes encoding cardiac contractile proteins. It has been hypothesised that excessive sarcomeric energy consumption is an important and early factor in the pathophysiology of HCM. Therefore modulation of myocardial metabolism presents a novel target for improving myocardial performance and symptoms in patients with HCM. Trimetazidine is an anti-anginal agent which like perhexiline reduces fatty acid oxidation and increases glucose oxidation, thus increasing the efficiency of energy production. Trimetazidine has been shown to significantly improve exercise performance in patients with stable angina, ischaemic and non ischaemic cardiomyopathy, either as monotherapy or in combination with beta-blockers or calcium channel blockers,

DESIGN: A single centre prospective randomised, double blind, placebo-controlled, trial of trimetazidine therapy.

DOSING: 20 mg Trimetazidine or Placebo three times daily for three months

METHODS: The following assessments will be made at baseline and after 3 months treatment: history and physical examination, Minnesota heart failure questionnaire, fasting blood tests, electrocardiogram, echocardiogram, cardiopulmonary exercise test, six minute walk test, 24 hour ECG Holter monitor.

• Study Type: Interventional
• Enrollment (Anticipated): 90
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, W1G 8PH
    • Recruiting
    • The Heart Hospital, UCLH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Non-obstructive hypertrophic cardiomyopathy (gradient <30 mmHg at rest)
• NYHA (New York Heart Association) Class ≥ 2
• Peak VO2 (maximal oxygen consumption) ≤80% predicted for age and gender
• Heart rate < 90/minute at rest

Exclusion Criteria:

• Diabetes Mellitus
• Abnormal renal function (GFR<60ml/min) or hepatic impairment
• Female who is pregnant, lactating or planning pregnancy during the course of the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo capsule	Other: Placebo capsule; one capsule three times per day for 3 months
Active Comparator: Trimetazidine	Drug: Trimetazidine; Trimetazidine 20mg three times per day for 3 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Peak oxygen consumption	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left ventricular function	TDI and 2D strain	3 months
Symptom status	questionnaire	3 months
Arrhythmia	24 Hour Holter	3 months
Cardiac biomarkers		3 months
Exercise capacity	6 minute walk test	3 months

Collaborators and Investigators

• Sponsor: University College, London
• Collaborators: British Heart Foundation
• Investigators: Principal Investigator: Perry M Elliott, MBBS MD, University College, London

Publications and helpful links

General Publications

• Coats CJ, Pavlou M, Watkinson OT, Protonotarios A, Moss L, Hyland R, Rantell K, Pantazis AA, Tome M, McKenna WJ, Frenneaux MP, Omar R, Elliott PM. Effect of Trimetazidine Dihydrochloride Therapy on Exercise Capacity in Patients With Nonobstructive Hypertrophic Cardiomyopathy: A Randomized Clinical Trial. JAMA Cardiol. 2019 Mar 1;4(3):230-235. doi: 10.1001/jamacardio.2018.4847.

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Anticipated): April 1, 2014
• Study Completion (Anticipated): April 1, 2014

Study Registration Dates

• First Submitted: September 27, 2012
• First Submitted That Met QC Criteria: September 28, 2012
• First Posted (Estimate): October 1, 2012

Study Record Updates

• Last Update Posted (Estimate): February 28, 2013
• Last Update Submitted That Met QC Criteria: February 27, 2013
• Last Verified: August 1, 2011

More Information

Terms related to this study

• Keywords: Trimetazidine
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Hypertrophy; Cardiomyopathies; Cardiomyopathy, Hypertrophic; Vasodilator Agents; Trimetazidine
• Other Study ID Numbers: 10/0216