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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04426578




Registration number
NCT04426578
Ethics application status
Date submitted
14/05/2020
Date registered
11/06/2020
Date last updated
11/03/2021

Titles & IDs
Public title
Role of Perhexiline in Hypertrophic Cardiomyopathy
Scientific title
Randomised Controlled Trial of pErhexiline on regreSsion Of Left Ventricular hypErtrophy (LVH) in Patients With Symptomatic Hypertrophic CardioMyopathy (RESOLVE-HCM)
Secondary ID [1] 0 0
HCM2020-01
Universal Trial Number (UTN)
Trial acronym
RESOLVE-HCM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hypertrophic Cardiomyopathy 0 0
Condition category
Condition code
Cardiovascular 0 0 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Perhexiline
Other interventions - Placebo

Experimental: Perhexiline -

Placebo comparator: Placebo -


Treatment: Drugs: Perhexiline
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.

Other interventions: Placebo
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.
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Change in Left Ventricular Hypertrophy (LVH)
Timepoint [1] 0 0
12 months post baseline
Secondary outcome [1] 0 0
Change in Left Ventricular (LV) mass
Timepoint [1] 0 0
12 months post baseline
Secondary outcome [2] 0 0
Change in oxygen-sensitive Cardiac Magnetic Resonance
Timepoint [2] 0 0
12 months post baseline
Secondary outcome [3] 0 0
Change in left ventricular diastolic function
Timepoint [3] 0 0
12 months post baseline
Secondary outcome [4] 0 0
New York Heart Association (NYHA) functional classification
Timepoint [4] 0 0
12 months post baseline
Secondary outcome [5] 0 0
Canadian Cardiovascular Society (CCS) functional class
Timepoint [5] 0 0
12 months post baseline
Secondary outcome [6] 0 0
Quality of life assessment
Timepoint [6] 0 0
12 months post baseline
Secondary outcome [7] 0 0
Major adverse event on heart failure related hospitalisations
Timepoint [7] 0 0
Monitored over the 12 months period
Secondary outcome [8] 0 0
Major adverse event on arrhythmic events
Timepoint [8] 0 0
Monitored over the 12 months period
Secondary outcome [9] 0 0
Major adverse event on abnormal liver function test
Timepoint [9] 0 0
Liver function tests at baseline, 1 month, 6 months and 12 months
Secondary outcome [10] 0 0
Major adverse event on sudden cardiac death
Timepoint [10] 0 0
Monitored over the 12 months period

Eligibility
Key inclusion criteria
1. Left Ventricular Ejection Fraction (LVEF) =/> 55% by echocardiography or CMR during the screening period or within 6 months prior to study entry
2. 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
3. Structural heart disease as evidenced by interventricular septal thickness of (= 15 mm) on echocardiography or CMR in the absence of abnormal loading conditions
4. Elevated N terminal pro-brain natriuretic peptide (NT-proBNP), >125 pg/ml
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Any prior echocardiographic or CMR measurement of LVEF <55%
2. Current acute decompensated heart failure requiring hospitalisation and / or augmented medical therapy
3. Cardiac surgery or catheter-based septal reduction therapy planned or having occurred within the past 1 year
4. Patients with a non-CMR conditional pacemaker / implantable cardioverter-defibrillator device
5. History of a known chronic liver disease, peripheral neuropathy, recurrent hypoglycemia
6. Serum bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, or lactate dehydrogenase > 2.0 times upper limit of normal
7. Previous adverse reaction to perhexiline at therapeutic plasma levels of the drug
8. Concomitant use of amiodarone, ranolazine or trimetazidine
9. Life-threatening or uncontrolled dysrhythmia
10. Contraindications to CMR, gadolinium, adenosine

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
UNKNOWN
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/12/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/08/2022
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 0 0
Flinders Medical Centre - Adelaide
Recruitment postcode(s) [1] 0 0
5042 - Adelaide

Funding & Sponsors
Primary sponsor type
Other
Name
Flinders University
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT04426578
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Joseph Selvanayagam
Address 0 0
Flinders Medical Centre
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Joseph Selvanayagam
Address 0 0
Country 0 0
Phone 0 0
+61882045619
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT04426578