Open-Label Study of Perhexiline in Patients With Hypertrophic Cardiomyopathy and Moderate to Severe Heart Failure

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effect of perhexiline on exercise performance (efficacy) and safety in patients with hypertrophic cardiomyopathy and moderate-to-severe heart failure following dosing for 16 weeks.

Detailed Description
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Patients with hypertrophic cardiomyopathy and symptoms without severe outflow obstruction will be eligible to participate. Enrollment will be limited to subjects who are unable to attain 75% of their maximum predicted MVO2 at cardiopulmonary exercise testing. Subjects with genetic evidence of CYP2D6 poor metabolizer status will be excluded. Subjects will undergo functional testing at baseline with CPEX testing and 6 minute walk distance testing. They will begin perhexiline orally, and the dose will be adjusted according to plasma level testing. For the first 8 week period, the target therapeutic range will be 100-300 ng/mL, and for the second 8 week period, the range will be 300-500 ng/mL. Functional testing will be repeated at the end of both periods.

Official Title
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A Phase 2, Multi-Center, Open-Label, Ascending Dose Study on the Efficacy, Safety and Tolerability of Perhexiline in Patients With Hypertrophic Cardiomyopathy and Moderate to Severe Heart Failure With Preserved Left Ventricular Function

Conditions
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Cardiomyopathy, Hypertrophic, Cardiomyopathy, Hypertrophic, Familial

Intervention / Treatment
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* Drug: Perhexiline
* Device: Use of bioanalytical assay to monitor plasma levels of perhexiline


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Hypertrophic cardiomyopathy with symptoms of moderate-to-severe heart failure Left ventricular hypertrophy with maximum LV wall thickness ≥ 15 mm Left ventricular ejection fraction ≥ 50% Able to perform exercise testing but unable to exceed 75% of the predicted age-adjusted maximum level Key Exclusion Criteria: CYP2D6 Poor Metabolizer (PM) status History of a known chronic liver disease ALT, AST, alkaline phosphatase, or LDH > 1.5 x upper limit of normal Total Bilirubin > 2.0 x upper limit of normal Severe LV outflow obstruction Asymptomatic patients or cardiomyopathy-related criteria as per protocol QT interval related criteria as per protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Open-label, 2 period, dose escalation study of perhexiline in symptomatic patients with hypertrophic cardiomyopathy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Perhexiline<br>Perhexiline will be administered orally. Dosing will be determined based on plasma level monitoring. For the first 8 week period, the target range will be 100-300 ng/mL, for the second 8 week period, the target range will be 300-500 ng/mL. | Drug: Perhexiline<br>* Period 1 (Weeks 1-8) and Period 2 (Weeks 9-16): dose titrated to two different plasma levels of perhexiline<br>Device: Use of bioanalytical assay to monitor plasma levels of perhexiline<br>* The bioanalytical assay is the device under investigation. It will be used to monitor plasma levels of perhexiline. The data obtained from this analysis will be used to guide dose adjustments of perhexiline.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline of VO2MAX at 16 Weeks | At the conclusion of 16 weeks of perhexiline treatment, MVO2 was measured using CPEX and compared to MVO2 measured at baseline. | end of Period 2 (Week 16) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline of VO2MAX at End of Period 1 | At the conclusion of 8 weeks of perhexiline treatment, MVO2 was measured using CPEX and compared to MVO2 measured at baseline. | end of Period 1 (Week 8) | 
| Change From Baseline in the Six-minute Walk Test at the End of Period 2 | At the conclusion of 16 weeks of perhexiline treatment, 6MWD was measured and compared to 6MWD measured at baseline. | end of Period 2 (Week 16) | 
| Change From Baseline in the Six-minute Walk Test at the End of Period 1 | At the conclusion of 8 weeks of perhexiline treatment, 6MWD was measured and compared to 6MWD measured at baseline. | end of Period 1 (Week 8) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hypertrophic cardiomyopathy, heart failure, cardiopulmonary exercise testing, 6 minute walk test, perhexiline, carnitine palmitoyltransferase, mixed ion channel effects, late sodium current inhibitor, calcium channel inhibition