Perhexiline Therapy in Heart Failure With Preserved Ejection Fraction Syndrome

Study Overview
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Brief Summary
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Up to half of all patients with clinical features of heart failure are found to have normal heart pumping function. Recently the investigators have shown that a drug called perhexiline markedly improved exercise capacity and symptoms in patients with heart failure associated with impaired cardiac pump function. In this proposal the investigators will assess whether perhexiline has beneficial effects in patients with heart failure and a normal heart pumping function.

Detailed Description
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Up to 50% of patients with symptoms of heart failure have a preserved left ventricular ejection fraction (HFpEF syndrome). Current therapy for systolic heart failure is targeted at inducing vasodilation and counteracting neuro-endocrine activation. There is a lack of a corresponding evidence base for the treatment of HEpEF. We have previously shown that perhexiline, an agent that increases the efficiency of energy production by shifting substrate utilization from free fatty acids towards glucose, was highly effective in improving exercise capacity, symptoms and cardiac function in patients with systolic heart failure. We have also recently shown that energy deficiency plays a major role in the pathophysiology of HFpEF. In this proposal we therefore aim to investigate the effectiveness of perhexiline in 70 HFpEF patients, in a 3 month randomised, double-blind, controlled trial. An interim analysis is planned after 20 patients.

Official Title
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Randomised Double Blind Placebo Controlled Trial of Perhexiline in Heart Failure With Preserved Ejection Fraction Syndrome (HFpEF)

Conditions
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Diastolic Heart Failure

Intervention / Treatment
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* Drug: Perhexiline
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HFpEF will be defined as: Clinical features consistent with heart failure LVEF ≥ 50%, with no evidence of significant valvular disease No hypertrophic cardiomyopathy, and no evidence of pericardial constriction Peak VO2 < 80% predicted, with RER>1 and with a pattern of gas exchange on metabolic exercise testing indicating a cardiac cause for limitation) Patients recruited will be in sinus rhythm Exclusion Criteria: BMI >35 Objective evidence of lung disease on formal lung function testing Reversible myocardial ischaemia on contrast-enhanced myocardial stress Echocardiography, and no evidence of exercise-induced mitral regurgitation (>2+) Impaired hepatic function; known hypersensitivity to perhexiline

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Perhexiline<br>perhexiline 100mg o bd for 3 months | Drug: Perhexiline<br>* 100mg o bd for 3 months<br>* Other names: Pexsig;|
| Placebo Comparator: Placebo<br>Placebo one tablet bd for 3 months | Drug: Placebo<br>* Placebo one tablet bd for 3 months<br>* Other names: Starch Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Peak oxygen consumption (Vo2max) |  | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptomatic Status (Modified Minnesota Living with Heart Failure Questionnaire) |  | 3 Months | 
| Resting myocardial energetics by cardiac MR spectroscopy (MRS) |  | 3 months | 
| Resting and exercise diastolic function (nuclear studies) |  | 3 months | 
| Indirect measures of resting LVEDP (tissue Doppler E/Ea) |  | 3 months | 
| Global LV Ejection Fraction (MRI / nuclear studies) |  | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diastolic dysfunction, cardiac energetics, perhexiline, magnetic resonance spectroscopy