E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with an ICD or CRT-D implanted for primary or secondary prevention |
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E.1.1.1 | Medical condition in easily understood language |
Subjects with Implantable Cardioverter Defibrillator (ICD) or Cardiac Resynchronization Therapy-Defibrillator (CRT D) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10047281 |
E.1.2 | Term | Ventricular arrhythmia |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the effect of GS-6615 compared to placebo on the overall occurrence of appropriate ICD interventions (antitachycardia pacing [ATP] or shock) in subjects with ICD or CRT-D during the first 24 weeks of treatment |
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E.2.2 | Secondary objectives of the trial |
The overall occurrence of appropriate ICD interventions in subjects with ICD or CRT-D through the end of the study Premature ventricular complex count/48 hours after 12 weeks of treatment Nonsustained ventricular tachycardia episodes/48 hours after 12 weeks of treatment The overall occurrence of ventricular tachycardia/ventricular fibrillation, (treated and untreated) during the first 24 weeks and through the end of the study The time from randomization to the first occurrence of appropriate ICD interventions (ATP or shock) or cardiovascular (CV) death The overall occurrence of electrical storm during the first 24 weeks and through the end of the study The occurrence of inappropriate ICD interventions during the first 24 weeks and through the end of the study Time from randomization to the first CV hospitalization, CV emergency room (ER) visit, or CV death Left ventricular (LV) systolic and diastolic function as assessed by echocardiography (ECHO) Safety and tolerability |
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E.2.3 | Trial contains a sub-study | No |
E.3 | 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) Between 18 and 80 years of age (inclusive) 3) Implanted ICD or CRT-D for primary or secondary prevention a) ICD or CRT-D must have capabilities of counting device interventions and storing electrograms b) Subjects with ICD or CRT-D implanted for primary prevention must have at least one ICD intervention for VT/VF (shock or ATP) within 60 days prior to Screening c) Subjects with ICD or CRT-D implanted for secondary prevention must have at least one ICD intervention for VT/VF (shock or ATP) or a documented VT/VF episode (prior to implantation) within 60 days prior to Screening 4) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use the protocol specified method(s) of contraception as described in Appendix 3 5) Subjects must be hemodynamically stable at both Screening and Randomization visits as defined by: systolic blood pressure ≥ 90 mmHg, HR ≤ 100 beats/min, and not requiring mechanical circulatory support (intra-aortic balloon pump or LV assist device), or treatment with IV inotropic drugs, IV vasodilators, or IV diuretics. |
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E.4 | Principal exclusion criteria |
1) New York Heart Association (NYHA) Class IV heart failure 2) Myocardial infarction, unstable angina, coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI) within 4 weeks prior to Screening or during the screening period before Randomization 3) Hemodynamically significant primary obstructive valvular disease 4) History of congenital heart disease 5) Inherited arrhythmia such as Brugada syndrome. Subjects with LQT-3 or HCM may be considered. 6) Subjects who are being considered for cardiac transplantation and are on a cardiac transplant list. Subjects who are not expected to have a transplant during the study can be considered for the study after consultation with the Gilead Medical Monitor. 7) Known or suspected history of seizures or epilepsy 8) Cardiac ablation within 3 months prior to Screening or planned cardiac ablation during the course of the study 9) Severe renal impairment at Screening (defined as an estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease [MDRD] equation by the central laboratory) 10) Abnormal liver function test defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2xULN at Screening, or bilirubin > 1.5xULN at Screening 11) Current use of Class I and Class III antiarrhythmic drugs; such medications should be discontinued > 5 half-lives (or > 28 days for chronic use of amiodarone) prior to Randomization. 12) Current use of concomitant treatment with drugs or products that are strong inhibitors or inducers of CYP3A; such medications should be discontinued at least 5 half-lives prior to Randomization. 13) Current use of concomitant treatment with ranolazine. Ranolazine should be discontinued at least 7 days prior to Randomization. 14) Previous exposure to GS-6615 15) Known hypersensitivity to the study drug, its metabolites, or formulation excipient 16) Females who are pregnant or are 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 are required for female subjects of childbearing potential 17) Subjects with a subcutaneous ICD 18) Any ICD/CRT-D -related technical issue, malfunction, or potential malfunction which in the judgment of the investigator would disrupt adequate data collection or interpretation 19) 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 previous 30 days with potential residual effects that might confound the results of this study 20) Any condition that in the opinion of the investigator would preclude compliance with the study protocol 21) Body mass index (BMI) ≥ 36 kg/m2 |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the overall occurrence (total number) of appropriate ICD interventions (ATP or shock) through Week 24. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Monitoring will be conducted on subject in the clinic at Randomization (Day 1 of the Treatment period), Week 2, Week 4, Week 12, Week 24, and every 12 weeks thereafter until the last subject randomized is followed up for approximately 24 weeks |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints are: - Overall occurrence (total number) of appropriate ICD interventions (ATP or shock) through the end of the study - The change in PVC (count/48 hours) from Screening to Week 12 - The change in nsVT (number of episodes/48 hours) from Screening to Week 12 - Overall occurrence (total number) of VT/VF (treated or untreated) through Week 24 and through the end of the study - The time from randomization to the first occurrence of appropriate ICD interventions (ATP or shock) or CV death - Overall occurrence (total number) of electrical storm through Week 24 and through the end of the study - Overall occurrence (total number) of inappropriate ICD interventions through Week 24 and through the end of the study - Time from randomization to the first occurrence of CV hospitalization, CV ER visit, or CV death - Change in LV systolic and diastolic function as assessed by ECHO at Week 12 and Week 24 Safety will be assessed by collecting AEs, vital signs, clinical laboratory tests, PE findings, and ECG data (PR, RR, QRS, and QT interval) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Monitoring will be conducted on subject in the clinic at Randomization (Day 1 of the Treatment period), Week 4, Week 12, Week 24, and every 12 weeks thereafter until the end of the study. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 38 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Czech Republic |
Denmark |
Germany |
Hungary |
Israel |
Netherlands |
Poland |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 10 |