Hypertrophic Cardiomyopathy
Conditions
Keywords
perhexiline, HCM, Hypertrophic Cardiomyopathy, CPEX
Brief summary
A Study on the Efficacy, Safety, and Tolerability of Perhexiline maleate in Subjects with Hypertrophic Cardiomyopathy and Moderate-To-Severe Heart Failure
Detailed description
This study is an international, multi-center, randomized, double-blind, placebo controlled clinical trial of the effects of perhexiline maleate on a rank-ordered, hierarchical variable consisting of outcome and functional measures in 350 subjects with hypertrophic cardiomyopathy and symptoms of moderate to severe congestive heart failure. The study is designed in four parts: 1) an open-label run-in period of 2 weeks, 2) A blinded, randomized phase of variable duration (anticipated between 6 months and 18 months depending on enrollment rate), 3) an open label period of 3 months, and 4) a randomized withdrawal period of 3 months. Subjects who do not experience an adverse outcome (death or resuscitated ventricular arrhythmia, stroke, need for surgical intervention, cardiovascular hospitalization, occurrence of atrial fibrillation, or study dropout) will undergo cardiopulmonary exercise testing in order to determine change from baseline in maximum oxygen consumption.
Interventions
DRUGPerhexiline
perhexiline maleate, oral, 25mg or 100mg tablets Whenever initiating PHM therapy, subjects will receive a loading regimen of PHM as indicated in in the Heart Metabolics Dose Justification document. Drug levels will be measured first on Day 4 +/- 1 day, with an initial dose adjustment performed on Day 7 +/- 1 day, as needed. The next sampling will occur on Day 21 +/- 1 day for potential dose adjustment, as advised by the DCC, on or about Day 24. Subsequent dosing will be monitored and advised by a Dose Control Center
DRUGPlacebo
Sponsors
Heart Metabolics Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
General Criteria 1. Adult, at least 18 years of age 2. Able and willing to give written informed consent Cardiomyopathy-related Criteria 3. Hypertrophic cardiomyopathy (HCM) with moderate-to-severe heart failure as defined as meeting all of the following criteria: 1. HCM meeting the 2011 ACCF/AHA Criteria for the Diagnosis of Hypertrophic Cardiomyopathy (Gersh et al. 2011) 2. Left ventricular hypertrophy (LVH) with maximum LV wall thickness \> 15 mm by echocardiography or cardiac magnetic resonance imaging without an alternative explanation 3. Left ventricular ejection fraction (LVEF) \> 40% 4. Able to perform exercise testing but unable to exceed 75% of the predicted age-adjusted maximum level(as determined by METs achieved during exercise testing-eligibility is not based on VO2max) 4. Normal sinus rhythm at Screening and Baseline (atrial fibrillation pattern acceptable for subjects with known chronic atrial fibrillation) 5. If taking any medications for the treatment of HCM (including beta-blockers, calcium channel blockers, disopyramide, diuretics), the medication has been taken a stable dose for at least 60 days prior to enrollment and will be continued at the same dose throughout the study
Exclusion criteria
General Criteria 1. Pregnant women, women who intend to become pregnant, or woman who are not practicing contraception, either pharmacologically or with a barrier method 2. Lactating women 3. CYP2D6 Poor Metabolizer (PM) status, based on genotype known prior to Screening, or as predicted by genotype assessed at Screening CYP2D6 Poor Metabolizer (PM) status is defined as having no functional CYP2D6 alleles by genotyping (exclusively having allele combinations of \*3, \*4, \*5, \*6, \*7, \*8, \*12, \*14). 4. Any subject who regularly takes a medication known to be a strong inhibitor of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, or ritonavir) 5. Any concomitant disease, condition, or treatment that could interfere with the conduct of the study, or that would, in the opinion of the investigator or sponsor, pose an unacceptable risk to subjects and/or interfere with the interpretation of study data, including but not limited to: 1. History of a known toxic or inflammatory peripheral neuropathy, such as mononeuritis multiplex, acute or chronic inflammatory demyelinating polyneuropathy (AIDP or CIDP), axonal sensorimotor neuropathies, drug-related neuropathy or neuritis, or diabetic neuropathy (history of a compression neuropathy, such as carpal tunnel syndrome, is acceptable) 2. Poorly controlled diabetes mellitus (e.g., HbA1c \> 8.5%) 3. Clinically severe chronic obstructive pulmonary disease (i.e. COPD requiring home oxygen or history of IV or oral steroid use) 4. History of a known chronic liver disease including cirrhosis of any cause, or chronic hepatitis B or hepatitis C 5. History of porphyria 6. History of recurrent hypoglycemia 7. Active infection requiring antibiotics 8. Life expectancy of less than 2 years 9. Evidence of an active or suspected cancer or a history of malignancy, except for skin squamous cell or basal cell carcinomas that did not require systemic therapy and are considered to be cured 10. History of substance abuse, including alcohol or illicit drugs within the past 12 months 11. Abnormal safety studies of clinical significance at Screening such as: i. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, or lactate dehydrogenase \> 1.5X upper limit of normal (ULN) ii. Glucose \< 70 mg/dL iii. Prolonged QTc (\>450 msec) l. Known hypersensitivity to perhexiline maleate 6. Unable or unwilling to comply with the protocol 7. Enrolled in another therapeutic trial for hypertrophic cardiomyopathy Cardiomyopathy-related
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Subject Outcome Variable | 6 months after randomization | The subject Outcome variable is a rank-ordered, hierarchical classification of outcome variables followed by a rank ordering of change from baseline in Maximum oxygen consumption |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Functional Assessment During Randomized Withdrawal Phase | 6 months after initiation of open label period, and 3 months after randomized withdrawal period initiated | Change of CPEX-VO2max from the beginning of the Randomized Withdrawal phase to the end of the Randomized Withdrawal phase (Part 4). The change in CPEX-VO2max in the placebo group will be compared to the change in CPEX-VO2max in the continued perhexiline (non-withdrawal) group. |
| Functional Assessment During Randomized Phase | 6 months after Randomization | Change in six-minute walk test (6MWT) from baseline (pre-Part 1 run-in, prior to receiving any perhexiline) to 6 months after randomization during the Randomized Treatment (Part 2) |
Outcome results
None listed