Metabolic Manipulation in Chronic Heart Failure

Phase 2

Completed

• Conditions: Chronic Heart Failure
• Interventions: Drug: Placebo; Drug: Perhexiline

• Registration Number: NCT00841139
• Lead Sponsor: University Hospital Birmingham NHS Foundation Trust

Brief Summary

Conventional measures used for the treatment of chronic heart failure act predominantly by reducing the work performed by the heart. In a recent study, the investigators showed that one drug (perhexiline) substantially improved symptoms and cardiac function in heart failure. The investigators wish to confirm these findings and test whether or not this drug acts by altering the heart's energy source thus augmenting the energetic status and work efficiency of the heart.

Detailed Description

Perhexiline maleate is an antianginal agent which increases the efficiency of energy production by shifting substrate utilisation from free fatty acids towards glucose. We showed that perhexiline therapy was highly effective in improving exercise capacity, symptoms and cardiac function in patients with systolic heart failure of both ischaemic and non ischaemic aetiology. Perhexiline acts by inhibiting both carnitine palmitoyl transferase-1 (CPT-1) and CPT-2, which are key enzymes in mitochondrial free fatty acid uptake. This leads to increased myocardial glucose substrate utilization. Further we wish to ascertain whether or not this drug improves cardiac energetics and efficiency by altering substrate utilization. In this proposal we will assess the cardiac function (by cardiac Magnetic Resonance Imaging MRI), cardiac energetic status (by cardiac Magnetic Resonance Spectroscopy MRS), cardiac efficiency (via pressure-volume loops) and substrate utilization (via left and right heart catheterization), following one month of perhexiline therapy or placebo in patients with symptomatic idiopathic dilated cardiomyopathy on optimal conventional heart failure medications. An interim analysis is planned after 20 patients.

Study Timeline

• Study Start: 2009-02
• Study First Submitted: 2009-02-06
• Study First Submitted QC: 2009-02-10
• Study First Posted: 2009-02-11
• Primary Completion: 2011-09
• Study Completion: 2011-09
• Status Verified: 2011-11
• Last Update Submitted: 2011-11-25
• Last Update Posted: 2011-11-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 50

Inclusion Criteria

• Optimally-medicated idiopathic dilated cardiomyopathy
• Symptomatic ( NYHA IIb-III)
• Impaired left ventricular systolic function (EF < 40%)

Exclusion Criteria

• Abnormal liver function tests (defined as above twice the upper limit of normal (ULN))
• Concomitant use of Amiodarone , Quinidine , Haloperidol or Selective serotonin (5HT) uptake inhibitors such as Fluoxetine and Paroxetine which may inhibit the CYP2D6 enzyme.
• Pre-existing evidence of peripheral neuropathy.
• Women of childbearing potential.
• Patients with implantable cardiac devices (or any other contraindication to MRI).
• Obesity ( BMI > 32)
• Obstructive sleep apnea syndrome
• Patients with known hypersensitivity to perhexiline
• Patients with impaired renal function (Creatinine > 250 µmol/L)
• Valvular heart disease defined as more than moderate valvular stenosis or regurgitation.
• Atrial Fibrillation

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	placebo one tablet bd for 1 month duration
Perhexiline	Perhexiline	perhexiline 100mg bd for 1 month duration

Primary Outcome Measures

Name	Time	Method
Change in cardiac energetics as demonstrated by resting myocardial PCr/ATP ratio from cardiac MRS	1 Month

Secondary Outcome Measures

Name	Time	Method
Change in respiratory quotient	1 Month
Change in mechanical efficiency (external work / MVO2)	1 Month

Trial Locations

Locations (2)

University Hospitals Brimingham NHS Foundation Trust; 🇬🇧 Birmingham, West Midlands, United Kingdom

University of Birmingham; 🇬🇧 Birmingham, West Midlands, United Kingdom