Role of Perhexiline in Hypertrophic Cardiomyopathy

NCT04426578 | Unknown Phase 2 DMC

• 1 other identifier: HCM2020-01
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

Hypertrophic Cardiomyopathy (HCM) is the most common inherited heart muscle condition affecting up to 1 in 200 of the general population. It results from mutations in genes encoding components of the contractile apparatus in the heart muscle cell (myocyte). These mutations result in increased energy cost of force production for the myocyte which then cumulatively causes a myocardial energy deficit. This myocardial energy deficit is then thought to lead to cardiac hypertrophy ('left ventricular hypertrophy' or LVH) in HCM. LVH leads to impairments in heart muscle function, heart muscle oxygenation and microvascular blood flow and is the chief driver of patient symptoms in HCM. These symptoms consist of chest pain, shortness of breath, dizziness, fainting episodes or palpitations. Occasionally, the disease may cause sudden cardiac death (SCD). HCM is the most common cause of SCD in young people including competitive athletes. In addition, HCM has been found to result in significant global deterioration in health-related quality of life. Treatment of HCM has focused on relief of symptoms by drugs such as ß-blockers which slow the heart rate and improve heart function. However, symptom relief is often incomplete and there is no evidence on the benefit of ß-blockers or related medications to reverse LVH. Perhexiline, a potent carnitine palmitoyl transferase-1 (CPT-1) inhibitor shifts myocardial metabolism to more efficient glucose utilisation and rectifies impaired myocardial energetics. It is currently used to treat angina in patients with coronary artery disease. There is some preliminary evidence that Perhexiline may aid in the improvement of symptoms in patients with HCM. However, the effect of any form of therapy on potential regression of LVH in HCM remains unexplored. In this randomised double-blind placebo-controlled trial, the investigators will use state of the art cardiac imaging, principally advanced echocardiography and Cardiovascular Magnetic Resonance (CMR) to study the effects of perhexiline on LVH, cardiac function, and oxygenation in symptomatic patients with HCM. The investigators hypothesize that perhexiline will favourably reduce LVH and improve myocardial oxygenation by improving myocardial energetics, and that these putative morphological and functional changes can be accurately measured utilizing echocardiography and CMR. If this pilot study supports the hypothesis, then it will pave the way for a major randomised controlled trial to definitely determine the role of Perhexiline in HCM.

Conditions

Hypertrophic Cardiomyopathy

Keywords

Heart function and structure; Hypertrophy; Heart Failure; Medication; Imaging

Outcome Measures

Primary Outcomes (1)

• Change in Left Ventricular Hypertrophy (LVH)

  Change in LVH (septal thickness) in symptomatic at 12 months following perhexiline therapy in HCM patients assessed by CMR

  12 months post baseline

Secondary Outcomes (10)

• Change in Left Ventricular (LV) mass

  12 months post baseline

• Change in oxygen-sensitive Cardiac Magnetic Resonance

  12 months post baseline

• Change in left ventricular diastolic function

  12 months post baseline

• New York Heart Association (NYHA) functional classification

  12 months post baseline

• Canadian Cardiovascular Society (CCS) functional class

  12 months post baseline

Study Arms (2)

Perhexiline

EXPERIMENTAL

Drug: Perhexiline

Placebo

PLACEBO COMPARATOR

Other: Placebo

Interventions

Perhexiline DRUG

All eligible and consented patients will be randomised to initiation of perhexiline 100mg 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. Repeat assay at 30 days will be utilized for individual finer dose titration based on dose adjustment table. Paired dosage adjustment in placebo-treated patients will be performed to avoid unblinding. Compliance will be assessed by capsule count.

Also known as: Pexsig

Perhexiline

Placebo OTHER

All eligible and consented patients will be randomised to initiation of perhexiline 100mg 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. Repeat assay at 30 days will be utilized for individual finer dose titration based on dose adjustment table. Paired dosage adjustment in placebo-treated patients will be performed to avoid unblinding. Compliance will be assessed by capsule count.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Left Ventricular Ejection Fraction (LVEF) =/\> 55% by echocardiography or CMR during the screening period or within 6 months prior to study entry
• 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
• Structural heart disease as evidenced by interventricular septal thickness of (= 15 mm) on echocardiography or CMR in the absence of abnormal loading conditions
• Elevated N terminal pro-brain natriuretic peptide (NT-proBNP), \>125 pg/ml

You may not qualify if:

• Any prior echocardiographic or CMR measurement of LVEF \<55%
• Current acute decompensated heart failure requiring hospitalisation and / or augmented medical therapy
• Cardiac surgery or catheter-based septal reduction therapy planned or having occurred within the past 1 year
• Patients with a non-CMR conditional pacemaker / implantable cardioverter-defibrillator device
• History of a known chronic liver disease, peripheral neuropathy, recurrent hypoglycemia
• Serum bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, or lactate dehydrogenase \> 2.0 times upper limit of normal
• Previous adverse reaction to perhexiline at therapeutic plasma levels of the drug
• Concomitant use of amiodarone, ranolazine or trimetazidine
• Life-threatening or uncontrolled dysrhythmia
• Contraindications to CMR, gadolinium, adenosine

Sponsors & Collaborators

• Flinders University: lead

Study Sites (1)

Flinders Medical Centre

Adelaide, South Australia, 5042, Australia

RECRUITING

MeSH Terms

Conditions

Cardiomyopathy, Hypertrophic; Hypertrophy; Heart Failure

Interventions

Perhexiline

Condition Hierarchy (Ancestors)

Cardiomyopathies; Heart Diseases; Cardiovascular Diseases; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Aortic Valve Disease; Heart Valve Diseases; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Joseph Selvanayagam

  Flinders Medical Centre

  STUDY CHAIR

• Rajiv Ananthakrishna

  Flinders Medical Centre

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Joseph Selvanayagam

CONTACT

+61882045619; joseph.selva@sa.gov.au

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: May 14, 2020
• First Posted: June 11, 2020
• Study Start: December 1, 2020
• Primary Completion: August 1, 2022
• Study Completion: August 1, 2022
• Last Updated: March 11, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)