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

• ClinicalTrials.gov Identifier: NCT02862600
• Recruitment Status: Terminated
• First Posted: August 11, 2016
• Results First Posted: August 31, 2017
• Last Update Posted: August 31, 2017
• Sponsor: Heart Metabolics Limited
• Information provided by (Responsible Party): Heart Metabolics Limited

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Cardiomyopathy, Hypertrophic; Cardiomyopathy, Hypertrophic, Familial
• Interventions: Drug: Perhexiline; Device: Use of bioanalytical assay to monitor plasma levels of perhexiline
• Enrollment: 35

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.

Arm/Group Title	Perhexiline
Arm/Group Description	Perhexiline: Period 1 (Weeks 1-8) and Period 2 (Weeks 9-16): dose titrated to two different plasma levels of perhexiline
Period Title: Period 1--Perhexiline-low Target Range
Started [1]	35 [2]
Completed [3]	22 [4]
Not Completed	13
Reason Not Completed
Lack of Efficacy	9
Protocol Violation	3
Withdrawal by Subject	1
[1] Target range 100-300 ng/mL; [2] First subject underwent baseline functional assessment and perhexiline dosing on August 22, 2016; [3] Period and study terminated; [4] Study terminated on April 26, 2017 due to lack of efficacy.
Period Title: Period 2--Perhexiline-high Target Range
Started [1]	22 [2]
Completed [3]	15 [4]
Not Completed	7
Reason Not Completed
Lack of Efficacy	7
[1] Target range 300-500 ng/mL; [2] First subject completed Period 1 and moved into Period 2 perhexiline dosing on October 17, 2016; [3] Period and study termination; [4] Study terminated on April 26, 2017 due to lack of efficacy in first 15 subjects completing Period 2.

Baseline Characteristics

Arm/Group Title		Perhexiline
Arm/Group Description		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.
Overall Number of Baseline Participants		35
Baseline Analysis Population Description		Baseline data was collected on all enrolled subjects on Day 0.
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	35 participants
		50; (26 to 72)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	35 participants
	Female	16 45.7%
	Male	19 54.3%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	35 participants
	Hispanic or Latino	2 5.7%
	Not Hispanic or Latino	33 94.3%
	Unknown or Not Reported	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	35 participants
	American Indian or Alaska Native	0 0.0%
	Asian	1 2.9%
	Native Hawaiian or Other Pacific Islander	0 0.0%
	Black or African American	5 14.3%
	White	29 82.9%
	More than one race	0 0.0%
	Unknown or Not Reported	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	35 participants
		35

Outcome Measures

1. Primary Outcome

Title	Change From Baseline of VO2MAX at 16 Weeks
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Perhexiline--16 Weeks
Arm/Group Description:	Subjects completing 8 weeks of perhexiline at target range 100-300 ng/ml, and an additional 8 weeks of perhexiline at target range 300-500 ng/ml.
Overall Number of Participants Analyzed	15
Mean (Standard Deviation); Unit of Measure: ml/kg/min
	-0.2 (2.7)

2. Secondary Outcome

Title	Change From Baseline of VO2MAX at End of Period 1
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Perhexiline--8 Weeks
Arm/Group Description:	Subjects completing 8 weeks of perhexiline at target range 100-300 ng/ml.
Overall Number of Participants Analyzed	22
Mean (Standard Deviation); Unit of Measure: ml/kg/min
	0.3 (1.8)

3. Secondary Outcome

Title	Change From Baseline in the Six-minute Walk Test at the End of Period 2
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Perhexiline--16 Weeks
Arm/Group Description:	Subjects completing 8 weeks of perhexiline at target range 100-300 ng/ml, and an additional 8 weeks of perhexiline at target range 300-500 ng/ml.
Overall Number of Participants Analyzed	15
Mean (Standard Deviation); Unit of Measure: meters
	27 (46)

4. Secondary Outcome

Title	Change From Baseline in the Six-minute Walk Test at the End of Period 1
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Perhexiline--8 Weeks
Arm/Group Description:	Subjects completing 8 weeks of perhexiline at target range 100-300 ng/ml
Overall Number of Participants Analyzed	22
Mean (Standard Deviation); Unit of Measure: meters
	16 (50)

Adverse Events

Time Frame	Adverse events were collected from the time of enrollment (Day 0) until 30 days after study drug termination.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Perhexiline
Arm/Group Description	All enrolled subjects
All-Cause Mortality
	Perhexiline
	Affected / at Risk (%)
Total	0/35 (0.00%)
Serious Adverse Events
	Perhexiline
	Affected / at Risk (%)
Total	5/35 (14.29%)
Cardiac disorders
Exacerbation of congestive heart failure * [1]	1/35 (2.86%)
atrial fibrillation recurrence * [2]	1/35 (2.86%)
recurrence of atrial fibrillation * [2]	1/35 (2.86%)
Musculoskeletal and connective tissue disorders
Non-cardiac chest pain *	1/35 (2.86%)
Respiratory, thoracic and mediastinal disorders
Pneumonia *	1/35 (2.86%)
* Indicates events were collected by non-systematic assessment; [1] The subject had a history of CHF which was exacerbated during the study. The investigator classified the event as unrelated to study drug.; [2] A subject with a history of AF had a recurrent event during the trial. The subject was admitted and the condition resolved. The investigator classified the event as unrelated to study drug.
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Perhexiline
	Affected / at Risk (%)
Total	19/35 (54.29%)
Gastrointestinal disorders
Nausea *	3/35 (8.57%)
General disorders
Fatigue *	4/35 (11.43%)
Influenza like illness *	3/35 (8.57%)
Infections and infestations
Nasopharyngitis *	3/35 (8.57%)
Metabolism and nutrition disorders
Decreased appetite *	2/35 (5.71%)
Nervous system disorders
Dizziness *	2/35 (5.71%)
Headache *	2/35 (5.71%)
Psychiatric disorders
Insomnia *	3/35 (8.57%)
Respiratory, thoracic and mediastinal disorders
Dyspnea *	2/35 (5.71%)
* Indicates events were collected by non-systematic assessment

Limitations and Caveats

Early termination due to lack of efficacy in the first 15 subjects completing the study. Any conclusions regarding safety or efficacy a challenging in light of the small numbers of subjects studied.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Mark G. Midei, MD, Executive Director and Head of Cardiology
• Organization: Heart Metabolics, Ltd.
• Phone: 4103715357 ext 410
• EMail: markgmidei@gmail.com

• Responsible Party: Heart Metabolics Limited
• ClinicalTrials.gov Identifier: NCT02862600
• Other Study ID Numbers: HML-PHX-005
• First Submitted: August 8, 2016
• First Posted: August 11, 2016
• Results First Submitted: June 25, 2017
• Results First Posted: August 31, 2017
• Last Update Posted: August 31, 2017