Effect of Eleclazine on Shortening of the QT Interval, Safety, and Tolerability in Adults With Long QT Syndrome Type 3

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the effect of oral eleclazine on mean daytime QTcF interval after 24 weeks of treatment with elecalzine in participants with long QT syndrome Type 3. During the single-blind treatment period (24 weeks), participants will receive eleclazine and/or eleclazine placebo. Following the single-blind treatment period, participants who have not permanently discontinued study drug will be eligible, at the discretion of the investigator, to continue receiving eleclazine during an open-label extension (OLE) phase.

Official Title
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A Phase 3, Single-Blind Study to Evaluate the Effect of Eleclazine (GS-6615) on Shortening of the QT Interval, Safety, and Tolerability in Subjects With Long QT Syndrome Type 3

Conditions
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Long QT Syndrome Type 3

Intervention / Treatment
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* Drug: Eleclazine
* Drug: Eleclazine placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Individuals with an established diagnosis of LQT3 (by genotype testing) Mean (of triplicate) QTc interval ≥ 480 msec (or ≥ 460 msec, for individuals who are currently taking ranolazine or Class I antiarrhythmic drugs such as mexiletine) at 3 or more time points, determined by standard 12-lead ECG, at screening Key Exclusion Criteria: Known mutations associated with type 1 long QT syndrome (LQT1) or type 2 long QT syndrome (LQT2) Known or suspected history of seizures or epilepsy History of heart failure defined as New York Heart Association (NYHA) Class IV and/or known left ventricular ejection fraction (EF) ≤ 45% Body mass index (BMI) ≥ 40 kg/m^2 at screening Severe renal impairment at screening (defined as an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m^2, using the 4 Variable Modification of Diet in Renal Disease (MDRD) equation, as determined by the study center) Abnormal liver function tests at screening, defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 x upper limit of normal (ULN), or total bilirubin > 1.5 x ULN An aborted cardiac arrest (ACA), implantable cardioverter-defibrillator (ICD) implantation, syncopal episode, or appropriate ICD therapy within 3 months prior to screening Any other condition or circumstance that in the opinion of the investigator would preclude compliance with the study protocol Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eleclazine (Single-blind treatment phase)<br>Eleclazine and/or eleclazine placebo up to Week 24 | Drug: Eleclazine<br>* Tablets administered orally<br>* Other names: GS-6615;Drug: Eleclazine placebo<br>* Tablets administered orally<br>|
| Experimental: Open-label Extension Phase<br>Eligible participants will continue to receive open-label eleclazine until this drug is commercially available for the treatment of patients with LQT3, or until Gilead terminates development of eleclazine for the treatment of patients with LQT3, or the investigator deems it no longer in the participant's best interest. | Drug: Eleclazine<br>* Tablets administered orally<br>* Other names: GS-6615;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Daytime QT Interval in Lead V5 Corrected for Heart Rate Using the Fridericia Formula (QTcF) Interval to Week 24 (Based on Standard 12-lead ECG Data) | Baseline was the Day 1 value. QTcF is corrected QT interval using Fridericia's formula. QTcF = QT/cube root (RR), where RR is in seconds. AUC0-6 for QTcF was calculated using the trapezoidal rule, mean of triplicate values, and actual time (latest of triplicate times). Mean daytime QTcF (AUC0-6/6) was computed by dividing AUC0-6 by the time from dosing to the 6 hour postdose time point. | Baseline; Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Daytime QTcF Interval (AUC0-6/6) to Week 12 (Lead V5; Standard 12-lead ECG) | Baseline was the Day 1 value. QTcF is corrected QT interval using Fridericia's formula. QTcF = QT/cube root (RR), where RR is in seconds. AUC0-6 for QTcF was calculated using the trapezoidal rule, mean of triplicate values, and actual time (latest of triplicate times) . Mean daytime QTcF (AUC0-6/6) was computed by dividing AUC0-6 by the time from dosing to the 6 hour postdose time point. | Baseline; Week 12 | 
| Change From Baseline in Mean Daily (Daytime and Nocturnal) QTcF Interval to Week 24 (Lead V5; Holter) | Baseline was the Day 1 value. QTcF is corrected QT interval using Fridericia's formula. QTcF = QT/cube root (RR), where RR is in seconds. Mean daytime QTcF (AUC0-6/6) was computed by dividing AUC0-6 by the time from the first nonmissing nominal time point to the last nonmissing nominal time point, from predose to 6 hours postdose. Mean nocturnal QTcF (AUC0-6/6) was computed by dividing AUC0-6 by the time from the first nonmissing nominal time point to the last nonmissing nominal time point, from midnight to 6:00 AM. Daily was computed as the average of daytime (AUC0-6/6) and nocturnal (AUC0-6/6), with both values required to compute the average. | Baseline; Week 24 | 
| Change From Baseline in Mean Nocturnal QTcF Interval to Week 24 (Lead V5; Holter) | Baseline was the Day 1 value. QTcF is corrected QT interval using Fridericia's formula. QTcF = QT/cube root (RR), where RR is in seconds. Mean nocturnal QTcF (AUC0-6/6) was computed by dividing AUC0-6 by the time from the first nonmissing nominal time point to the last nonmissing nominal time point, from midnight to 6:00 AM. | Baseline; Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 3 long QT syndrome (LQT3), Long QT syndrome, Congenital long QT, Sudden cardiac death