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Trial registered on ANZCTR
Registration number
ACTRN12620000785909
Ethics application status
Approved
Date submitted
14/05/2020
Date registered
3/08/2020
Date last updated
3/08/2020
Date data sharing statement initially provided
3/08/2020
Type of registration
Prospectively registered
Titles & IDs
Public title
Evaluating the role of perhexiline (new medication treatment) in patients with abnormally thickened heart muscle (hypertrophic cardiomyopathy)
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Scientific title
Randomised controlled trial of pErhexiline on regreSsion Of Left Ventricular hypErtrophy in patients with symptomatic Hypertrophic CardioMyopathy (RESOLVE-HCM)
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Secondary ID [1]
301209
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Nil known
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Universal Trial Number (UTN)
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Trial acronym
RESOLVE-HCM
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Chest pain
317358
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Shortness of breath
317610
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Abnormally thickened heart muscle
317611
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Condition category
Condition code
Cardiovascular
315465
315465
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0
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Other cardiovascular diseases
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Human Genetics and Inherited Disorders
315687
315687
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0
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Other human genetics and inherited disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
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.
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Intervention code [1]
317511
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Treatment: Drugs
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Comparator / control treatment
Placebo lactose tablet
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Control group
Placebo
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Outcomes
Primary outcome [1]
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Change in left ventricular hypertrophy (septal thickness) in symptomatic HCM patients at 12 months following perhexiline therapy as assessed by CMR
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Assessment method [1]
323705
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Timepoint [1]
323705
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At 12 months post baseline
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Secondary outcome [1]
382681
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Change in left ventricular mass in symptomatic HCM patients at 12 months following perhexiline therapy via CMR assessment in HCM patients
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Assessment method [1]
382681
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Timepoint [1]
382681
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At 12 months post baseline
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Secondary outcome [2]
382682
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Change in oxygen-sensitive CMR in symptomatic HCM patients at 12 months following perhexiline therapy in HCM patients
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Assessment method [2]
382682
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Timepoint [2]
382682
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At 12 months post baseline
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Secondary outcome [3]
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Change in echocardiographic left ventricular diastolic function in HCM patients at 12 months following perhexiline therapy.
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Assessment method [3]
382684
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Timepoint [3]
382684
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At 12 months post baseline
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Secondary outcome [4]
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Change in NYHA at 12 months in HCM patients
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Assessment method [4]
382686
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Timepoint [4]
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At 1, 6, 12 months post baseline
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Secondary outcome [5]
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Change in CCS functional class
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Assessment method [5]
383374
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Timepoint [5]
383374
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At 1, 6, 12 months post baseline
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Secondary outcome [6]
383375
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Change in physical activity domain score of SF36
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Assessment method [6]
383375
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Timepoint [6]
383375
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At 1, 6, 12 months post baseline
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Secondary outcome [7]
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Major adverse event on heart failure related hospitalisations
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Assessment method [7]
383640
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Timepoint [7]
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Monitored over the 12 months period, assessed via patient medical records
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Secondary outcome [8]
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Major adverse event on arrhythmic events
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Assessment method [8]
383641
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Timepoint [8]
383641
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Monitored over the 12 months period, assessed via patient medical records
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Secondary outcome [9]
383642
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Major adverse event on abnormal liver function test
(Number of HCM patients receiving perhexiline with deranged liver function tests during the study period)
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Assessment method [9]
383642
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Timepoint [9]
383642
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Liver function tests at baseline, 1 month, 6 months and 12 months
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Secondary outcome [10]
383643
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Major adverse event on sudden cardiac death
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Assessment method [10]
383643
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Timepoint [10]
383643
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Monitored over the 12 months period, assessed via patient medical records
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Secondary outcome [11]
384556
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Change in strain parameters at 12 months following perhexiline therapy via echochardiography assessment in HCM patients
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Assessment method [11]
384556
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Timepoint [11]
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Monitored over the 12 months period
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Eligibility
Key inclusion criteria
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)
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
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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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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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
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2
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Type of endpoint/s
Efficacy
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Statistical methods / analysis
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
1/09/2020
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Actual
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Date of last participant enrolment
Anticipated
1/09/2021
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Actual
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Date of last data collection
Anticipated
31/12/2022
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Actual
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Sample size
Target
60
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA
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Recruitment hospital [1]
16610
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Flinders Medical Centre - Bedford Park
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Recruitment hospital [2]
16611
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The Queen Elizabeth Hospital - Woodville
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Recruitment hospital [3]
16613
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Royal Prince Alfred Hospital - Camperdown
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Recruitment hospital [4]
16614
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Royal Brisbane & Womens Hospital - Herston
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Recruitment hospital [5]
16615
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Lyell McEwin Hospital - Elizabeth Vale
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Recruitment postcode(s) [1]
30206
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5042 - Bedford Park
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Recruitment postcode(s) [2]
30207
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5011 - Woodville
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Recruitment postcode(s) [3]
30209
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2050 - Camperdown
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Recruitment postcode(s) [4]
30210
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4029 - Herston
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Recruitment postcode(s) [5]
30211
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5112 - Elizabeth Vale
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Funding & Sponsors
Funding source category [1]
305721
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Other
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Name [1]
305721
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SAHMRI
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Address [1]
305721
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SAHMRI (South Australian Health and Medical Research Institute)
North Terrace, Adelaide SA 5000
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Country [1]
305721
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Australia
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Primary sponsor type
Hospital
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Name
Flinders Medical Centre
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Address
1, Flinders Drive
Bedford Park
SA 5042
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Country
Australia
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Secondary sponsor category [1]
306855
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None
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Name [1]
306855
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Address [1]
306855
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Country [1]
306855
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
305942
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The Southern Adelaide Local Health Network
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Ethics committee address [1]
305942
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Flinders Medical Centre, Bedford Park SA 5042
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Ethics committee country [1]
305942
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Australia
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Date submitted for ethics approval [1]
305942
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23/03/2020
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Approval date [1]
305942
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09/06/2020
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Ethics approval number [1]
305942
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Summary
Brief 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.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Prof Joseph Selvanayagam
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Address
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Flinders Medical Centre
1, Flinders Drive
Bedford Park
SA 5042
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Country
102150
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Australia
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Phone
102150
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+61 8 8204 5619
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Fax
102150
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+61 8 8204 5625
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Email
102150
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[email protected]
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Contact person for public queries
Name
102151
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Prof Joseph Selvanayagam
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Address
102151
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Flinders Medical Centre
1, Flinders Drive
Bedford Park
SA 5042
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Country
102151
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Australia
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Phone
102151
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+61 8 8204 5619
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Fax
102151
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+61 8 8204 5625
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Email
102151
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[email protected]
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Contact person for scientific queries
Name
102152
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Prof Joseph Selvanayagam
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Address
102152
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Flinders Medical Centre
1, Flinders Drive
Bedford Park
SA 5042
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Country
102152
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Australia
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Phone
102152
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+61 8 8204 5619
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Fax
102152
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+61 8 8204 5625
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Email
102152
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[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
Documents added manually
No documents have been uploaded by study researchers.
Documents added automatically
Source
Title
Year of Publication
DOI
Embase
Randomized controlled trial of perhexiline on regression of left ventricular hypertrophy in patients with symptomatic hypertrophic cardiomyopathy (RESOLVE-HCM trial).
2021
https://dx.doi.org/10.1016/j.ahj.2021.06.010
N.B. These documents automatically identified may not have been verified by the study sponsor.
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