Effect of Eleclazine (GS-6615) on Exercise Capacity in Subjects With Symptomatic Hypertrophic Cardiomyopathy

• Eleclazine (Drug), also known as GS-6615: Tablet (s) administered orally once daily
• Placebo (Drug): Placebo to match eleclazine administered orally once daily

Primary outcomes

• Change in Peak Oxygen Uptake (VO2) Achieved During Cardiopulmonary Exercise Testing (CPET) From Baseline to Week 24 [Baseline to Week 24]

Secondary outcomes

• Change in Peak Oxygen Uptake (VO2) Achieved During Cardiopulmonary Exercise Testing (CPET) From Baseline to Week 12 [Baseline to Week 12]
• Change in Minnesota Living With Heart Failure Questionnaire (MLHFQ) From Baseline to Week 24 [Baseline to Week 24]: The MLHFQ is a 21-item quality of life (QoL) questionnaire that measures the effects of symptoms, functional limitations, and psychological distress on an individual. Each item is measured on a 6-point Likert scale (0 to 5) and is scored by summing the responses to all 21 questions. Scores range from 0 to 105, with lower scores indicating a better quality of life.
• Change in Minnesota Living With Heart Failure Questionnaire (MLHFQ) From Baseline to Week 12 [Baseline to Week 12]: The MLHFQ is a 21-item quality of life (QoL) questionnaire that measures the effects of symptoms, functional limitations, and psychological distress on an individual. Each item is measured on a 6-point Likert scale (0 to 5) and is scored by summing the responses to all 21 questions. Scores range from 0 to 105, with lower scores indicating a better quality of life.
• Change in Treadmill Exercise Time From Baseline to Week 24 [Baseline to Week 24]: Treadmill exercise time is the time to peak exercise.
• Change in Treadmill Exercise Time From Baseline to Week 12 [Baseline to Week 12]: Treadmill exercise time is the time to peak exercise.

Sex: All, ages: 18 Years to 65 Years

Key Inclusion Criteria:

* Established diagnosis of hypertrophic cardiomyopathy defined by standard criteria as a maximal left ventricular wall thickness ≥ 15 mm at initial diagnosis
* Exertional symptoms including at least one of the following:

  * New York Heart Association (NYHA) Class ≥ II dyspnea
  * Canadian Cardiovascular Society (CCS) Class ≥ II angina
* Screening (baseline) peak VO2 < 80% of predicted for age, sex, and weight
* Ability to perform an upright treadmill cardiopulmonary exercise test (CPET)

Key Exclusion Criteria:

* Known aortic valve stenosis (moderate or severe)
* Known coronary artery disease
* Left ventricular systolic dysfunction (ejection fraction < 50%)
* Recent septal reduction procedure (ie, surgical myectomy or alcohol septal ablation) within six months prior to screening or such a procedure scheduled to occur during the study

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Participant flow

Outcome results

• Change in Peak Oxygen Uptake (VO2) Achieved During Cardiopulmonary Exercise Testing (CPET) From Baseline to Week 24 (Primary), Mean, mL/kg/min: Eleclazine 30/3/6 mg 0.15 +/- 4.312; Placebo 0.48 +/- 4.143 (p 0.416)
• Change in Peak Oxygen Uptake (VO2) Achieved During Cardiopulmonary Exercise Testing (CPET) From Baseline to Week 12 (Secondary), Mean, mL/kg/min: Eleclazine 30/3/6 mg 0.28 +/- 4.028; Placebo 0.57 +/- 4.314 (p 0.517)
• Change in Minnesota Living With Heart Failure Questionnaire (MLHFQ) From Baseline to Week 24 (Secondary), Mean, Score: Eleclazine 30/3/6 mg 40.22 +/- 25.544; Placebo 38.80 +/- 23.177 (p 0.513)
• Change in Minnesota Living With Heart Failure Questionnaire (MLHFQ) From Baseline to Week 12 (Secondary), Mean, Score: Eleclazine 30/3/6 mg 40.22 +/- 25.544; Placebo 38.80 +/- 23.177 (p 0.964)
• Change in Treadmill Exercise Time From Baseline to Week 24 (Secondary), Mean, min: Eleclazine 30/3/6 mg 12.88 +/- 4.641; Placebo 13.60 +/- 4.317 (p 0.944)
• Change in Treadmill Exercise Time From Baseline to Week 12 (Secondary), Mean, min: Eleclazine 30/3/6 mg 12.88 +/- 4.641; Placebo 13.60 +/- 4.317 (p 0.993)

Adverse events

Time frame: Baseline up to the last dose date plus 30 days (maximum exposure: 668 days)

Serious adverse events by term

Other adverse events by term

Limitations and caveats: The totality of the data did not support continuation of the eleclazine development program. So, this study was terminated prior to the end of the double-blind phase, and therefore no participants entered the open-label extension (OLE) period.

• Olivotto I, Hellawell JL, Farzaneh-Far R, Blair C, Coppini R, Myers J, Belardinelli L, Maron MS. Novel Approach Targeting the Complex Pathophysiology of Hypertrophic Cardiomyopathy: The Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) Trial. Circ Heart Fail. 2016 Mar;9(3):e002764. doi: 10.1161/CIRCHEARTFAILURE.115.002764. PMID 26915375

• Study Protocol: Original (PDF, 2014-04-01)
• Study Protocol: Amendment 1 (PDF, 2014-10-10)
• Study Protocol: Amendment 2 (PDF, 2015-02-10)
• Study Protocol: Amendment 3 (PDF, 2016-08-12)
• Statistical Analysis Plan (PDF, 2017-05-10)

• Gilead Study Director, Study director, Gilead Sciences