Evaluating the role of perhexiline (new medication treatment) in patients with abnormally thickened heart muscle (hypertrophic cardiomyopathy)
Randomised controlled trial of pErhexiline on regreSsion Of Left Ventricular hypErtrophy in patients with symptomatic Hypertrophic CardioMyopathy (RESOLVE-HCM)
Flinders Medical Centre
60 participants
Sep 1, 2020
Interventional
Conditions
Summary
Hypertrophic cardiomyopathy (HCM) is an inherited condition that results in an abnormally thickened heart muscle. It is the most common inherited heart muscle condition affecting up to 1 in 200 of the general population. The genetic mutation (or “spelling mistake” in the genes) leads to inefficient heart muscle contraction, and over time it leads to heart muscle thickening. The thickness of the heart muscle is one of the most important predictors of symptoms in patients with HCM. Treatment of HCM has focussed on relief of symptoms by medications which slow the heart rate and improve heart function. However, the symptom relief is incomplete and there is no evidence of medications to reverse abnormal heart muscle thickening. Perhexiline, a drug currently used safely as an anti-anginal agent, increases the energy efficiency of the heart. The principal driver of increased muscle thickness in HCM is energy depletion of cardiac muscle cells. As Perhexiline improves energy efficiency in the heart, there are plausible reasons (not yet tested) that it may reduce heart muscle thickness as well as improve patient symptoms. We aim to study the effects Perhexiline treatment on heart muscle thickness in symptomatic HCM patients. If our study is positive, it would lead to the design of a definitive clinical trial that would address the question whether Perhexiline use reduces heart failure and sudden death events in HCM patients.
Eligibility
Inclusion Criteria4
- a) LVEF =/> 55% by echocardiography or CMR during the screening period or within 6 months prior to study entry
- b) Current / prior symptom(s) of HCM (New York Heart Association [NYHA] functional class II or class III, Canadian Cardiovascular Society [CCS] grade II or grade III) and requiring treatment with ß-blockers and /or non-dihydropyridine calcium antagonists and / or disopyramide for at least 30 days prior to study entry
- c) Structural heart disease as evidenced by interventricular septal thickness of (=/> 15 mm) on echocardiography or CMR in the absence of abnormal loading conditions
- d) Elevated NT-proBNP (>125 pg/ml)
Exclusion Criteria11
- a) Any prior echocardiographic or CMR measurement of LVEF <55%
- b) Current acute decompensated heart failure requiring hospitalisation and / or augmented medical therapy
- c) Cardiac surgery or catheter-based septal reduction therapy planned or having occurred within the past 1 year
- d) Patients with a non-CMR conditional pacemaker / implantable cardioverter-defibrillator device
- e) History of a known chronic liver disease, peripheral neuropathy, recurrent hypoglycemia
- f) Presence of an additional diagnosis that in the opinion of investigator could account for patient's symptoms (e.g. significant pulmonary disease)
- g) Serum bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, or lactate dehydrogenase > 2.0 times upper limit of normal
- h) Previous adverse reaction to perhexiline at therapeutic plasma levels of the drug
- i) Concomitant use of amiodarone, ranolazine or trimetazidine
- j) Life-threatening or uncontrolled dysrhythmia
- k) Contraindications to CMR, gadolinium, adenosine
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Interventions
Interventional Experimental: Perhexiline Control: Placebo Mode of administration: Oral tablets Overall duration of treatment: 12 months All eligible and consented patients will be randomised to initiation of perhexiline 100mg (tablet) once daily or identical placebo. After 4 days of treatment, a blood sample will be collected to determine plasma perhexiline concentrations: timing of the sample need not be “trough” in view of the long-acting nature of perhexiline. Depending on the blood results, patients might require as little as 50mg/week (slow metabolisers) or as much as 600mg/day (ultra-rapid metabolisers). The initial sample will be utilized primarily to detect presence of hydroxylated metabolite: patients in whom perhexiline is detected in the absence of metabolite will be designated “slow metabolisers” and will have their dosage reduced to 50 mg/week in the first instance. In all other patients, a dose of 100mg/day of trial medication will be continued for the first 30 days. Repeat assay on plasma perhexiline concentration at 30 days will be utilized for individual finer dose titration based on dose adjustment table. Dose titration will then be reviewed by cardiologist (study investigators) and pharmacists for all participants at each visit (i.e. Visit 1 month, 3 months, 6 months, 9 months, and 12 months). Compliance will be assessed by pill count. Paired dosage adjustment in placebo-treated patients will be performed to avoid unblinding. Reference for dose adjustments: Lee L, Campbell R, Scheuermann-Freestone M, Taylor R, Gunaruwan P, Williams L, et al. Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment. Circulation. 2005; 112:3280-8.
Locations(5)
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ACTRN12620000785909