|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Subjects with symptoms (NYHA Class ≥ II dyspnea or CCS Class ≥ II angina) due to hypertrophic cardiomyopathy (defined by standard criteria as a maximal LV wall thickness of ≥ 15 mm in the absence of other causative loading abnormalities capable of producing the magnitude of hypertrophy observed)
|Medical condition in easily understood language
|Subjects with symptomatic hypertrophic cardiomyopathy.
|Diseases [C] - Cardiovascular Diseases [C14]
|E.1.2 Medical condition or disease under investigation
|System Organ Class
|10010331 - Congenital, familial and genetic disorders
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|The primary objective of this study is to evaluate the effect of GS-6615 on exercise capacity, as measured by Peak VO2 achieved during cardiopulmonary exercise testing (CPET), in subjects with symptomatic hypertrophic cardiomyopathy.
|Secondary objectives of the trial
|The secondary objectives of this study are to:
• Evaluate the safety and tolerability of GS-6615 in subjects with symptomatic hypertrophic cardiomyopathy.
• Evaluate the effect of GS-6615 on quality of life as measured by the Minnesota Living With Heart Failure Questionnaire (MLHFQ).
• Evaluate the effect of GS-6615 on treadmill exercise time during CPET.
|Trial contains a sub-study
|Principal inclusion criteria
|1) Have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures
2) Males and females 18 to 65 years old, inclusive
3) Established diagnosis of Hypertrophic Cardiomyopathy defined by standard criteria as a maximal LV wall thickness ≥ 15mm at initial diagnosis in the absence of other causative loading abnormalities capable of producing the magnitude of hypertrophy observed
4) Exertional symptoms including at least one of the following:
a) New York Heart Association (NYHA) Class ≥ II Dyspnea
b) Canadian Cardiovascular Society (CCS) Class ≥ II Angina
5) Screening (baseline) Peak VO2 < 80% of predicted for age, sex, and weight-adjusted equations, as confirmed by the investigator
6) Ability to perform an upright treadmill cardiopulmonary exercise test (CPET)
7) Hemodynamically stable at both Screening and Randomization visits defined as: systolic blood pressure ≥ 90 mmHg, HR ≤ 100 beats/min, and not requiring mechanical circulatory support or intravenous treatment with diuretics or vasoactive drugs
8) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to utilize protocol-specified method(s) of contraception
|Principal exclusion criteria
|1) Known aortic valve stenosis (moderate or severe) confirmed by echocardiogram
2) Known coronary artery disease (defined as ≥ 50% stenosis in ≥ 1 epicardial coronary artery)
3) Left ventricular systolic dysfunction (ejection fraction < 50%), known or detected during Screening visit
4) Known moderate or severe Chronic Obstructive Pulmonary Disease (defined as FEV1 < 80% predicted)
5) Known moderate or severe restrictive lung disease (defined as total lung capacity < 70% predicted)
6) 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
7) Atrial fibrillation on 12-lead ECG at Screening or detected during Randomization visit. Subjects with paroxysmal atrial fibrillation in whom sinus rhythm is restored may be re-screened at a later date.
8) Known or suspected infiltrative myocardial disease or glycogen storage disorder
9) Body mass index (BMI) ≥ 36 kg/m2
10) Severe renal impairment at Screening (defined as an estimated GFR < 30 mL/min/1.73m2 as calculated by the Modification of Diet in Renal Disease [MDRD] equation by the central laboratory)
11) Abnormal liver function tests at Screening, defined as ALT or AST > 2xULN, or total bilirubin > 1.5xULN
12) Known or suspected history of seizures or epilepsy
13) Use of Class I antiarrhythmic drugs, including disopyramide, within 7 days prior to Screening
14) Use of ranolazine within 7 days prior to Screening
15) Use of concomitant treatment with drugs or products that are strong inhibitors or inducers of CYP3A within 5- half-lives prior to Screening
16) Known hypersensitivity to study drug (GS-6615 or placebo), its metabolites, or formulation excipient
17) Females who are pregnant or breastfeeding. Lactating females must agree to discontinue nursing before the study drug is administered. A negative serum pregnancy test at Screening and a negative urine pregnancy test at Randomization visit are required for female subjects of childbearing potential.
18) In the judgment of the investigator, any clinically significant ongoing medical condition that might jeopardize the subject’s safety or interfere with the study, including participation in another investigational drug or investigational device study within the 30 days prior to Screening with potential residual effects that might confound the results of this study
19) Any condition that in the opinion of the investigator would preclude compliance with the study protocol
|E.5 End points
|Primary end point(s)
|The primary efficacy endpoint is the change in Peak VO2 from baseline (Screening) to Week 24.
|Timepoint(s) of evaluation of this end point
|Monitoring will be conducted on subject in the clinic at Screening and Week 24.
|Secondary end point(s)
|The secondary efficacy endpoints are:
• Change in MLHFQ from baseline to Week 24.
• Change in treadmill exercise time from baseline to Week 24.
• Change in Peak VO2 from baseline to Week 12.
• Change in the MLHFQ from baseline to Week 12.
• Change in treadmill exercise time from baseline to Week 12.
The safety endpoints include mortality and appropriate ICD interventions (shock or anti-tachycardia pacing), AEs, vital signs, clinical laboratory tests, and ECG data (PR, RR, QRS, QT and QTc interval).
|Timepoint(s) of evaluation of this end point
|Monitoring will be conducted on subject in the clinic at Screening, Randomization (Day 1 of the Treatment period), during the treatment period at Week 2, Week 6, Week 12, Week 18, Week 24, and every 12 weeks after Week 24 through End of Double-Blind Treatment visit.
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Other scope of the trial description
|Biomarkers NT-proBNP and high-sensitivity Troponin T analysis
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days