Cardiomyopathy, Hypertrophic, Cardiomyopathy, Hypertrophic, Familial
Conditions
Keywords
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
Brief summary
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
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.
Interventions
DRUGPerhexiline
Period 1 (Weeks 1-8) and Period 2 (Weeks 9-16): dose titrated to two different plasma levels of perhexiline
DEVICEUse of bioanalytical assay to monitor plasma levels of perhexiline
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.
Sponsors
Heart Metabolics Limited
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label, 2 period, dose escalation study of perhexiline in symptomatic patients with hypertrophic cardiomyopathy
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline of VO2MAX at 16 Weeks | end of Period 2 (Week 16) | At the conclusion of 16 weeks of perhexiline treatment, MVO2 was measured using CPEX and compared to MVO2 measured at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline of VO2MAX at End of Period 1 | end of Period 1 (Week 8) | At the conclusion of 8 weeks of perhexiline treatment, MVO2 was measured using CPEX and compared to MVO2 measured at baseline. |
| Change From Baseline in the Six-minute Walk Test at the End of Period 2 | end of Period 2 (Week 16) | At the conclusion of 16 weeks of perhexiline treatment, 6MWD was measured and compared to 6MWD measured at baseline. |
| Change From Baseline in the Six-minute Walk Test at the End of Period 1 | end of Period 1 (Week 8) | At the conclusion of 8 weeks of perhexiline treatment, 6MWD was measured and compared to 6MWD measured at baseline. |
Countries
United States
Participant flow
Recruitment details
Fifty subjects were screened at 13 US centers. Of these, 36 were found suitable for enrollment, and 35 were enrolled prior to study termination.
Pre-assignment details
The principal reason for screen failure was attainment of \> 75% of the maximum predicted MVO2 on CPEX testing. One subject was found to be a CYP2D6 poor metabolizer.
Participants by arm
| Arm | Count |
|---|---|
| Perhexiline 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.
Perhexiline: Period 1 (Weeks 1-8) and Period 2 (Weeks 9-16): dose titrated to two different plasma levels of perhexiline
Use of bioanalytical assay to monitor plasma levels of perhexiline: 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. | 35 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Period 1--Perhexiline-low Target Range | Lack of Efficacy | 9 |
| Period 1--Perhexiline-low Target Range | Protocol Violation | 3 |
| Period 1--Perhexiline-low Target Range | Withdrawal by Subject | 1 |
| Period 2--Perhexiline-high Target Range | Lack of Efficacy | 7 |
Baseline characteristics
| Characteristic | Perhexiline |
|---|---|
| Age, Continuous | 50 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 29 Participants |
| Region of Enrollment United States | 35 participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 35 |
| other Total, other adverse events | 19 / 35 |
| serious Total, serious adverse events | 5 / 35 |
Outcome results
Primary
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.
Time frame: end of Period 2 (Week 16)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Perhexiline--16 Weeks | Change From Baseline of VO2MAX at 16 Weeks | -0.2 ml/kg/min | Standard Deviation 2.7 |
Secondary
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.
Time frame: end of Period 1 (Week 8)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Perhexiline--16 Weeks | Change From Baseline in the Six-minute Walk Test at the End of Period 1 | 16 meters | Standard Deviation 50 |
Secondary
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.
Time frame: end of Period 2 (Week 16)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Perhexiline--16 Weeks | Change From Baseline in the Six-minute Walk Test at the End of Period 2 | 27 meters | Standard Deviation 46 |
Secondary
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.
Time frame: end of Period 1 (Week 8)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Perhexiline--16 Weeks | Change From Baseline of VO2MAX at End of Period 1 | 0.3 ml/kg/min | Standard Deviation 1.8 |