Study to Evaluate the Effect of Eleclazine on QT, Safety, and Tolerability in Participants With Long QT2 Syndrome

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the effect of oral eleclazine (formerly GS-6615) on corrected QT (QTc) interval in participants with long QT2 syndrome.

Official Title
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A Double-blind, Placebo-controlled Study to Evaluate the Effect of GS-6615 on QT, Safety and Tolerability in Subjects With Long QT2 Syndrome

Conditions
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LQT2 Syndrome

Intervention / Treatment
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* Drug: Eleclazine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Participants with an established diagnosis of LQT2 (by genotype testing) Mean (of triplicate) QTc interval ≥ 480 msec for at least four out of seven time points, determined by standard 12-lead electrocardiogram (ECG), at screening Key Exclusion Criteria: Known mutations associated with long QT syndrome type 1 or long QT syndrome type 3 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) ≥ 36 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: 65 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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eleclazine 24 mg + Eleclazine 48 mg + Placebo<br>Participants will receive placebo to match eleclazine on Days 1 and 4, eleclazine 24 mg on Day 2 and eleclazine 48 mg on Day 3. | Drug: Eleclazine<br>* Tablets administered orally in a single dose<br>* Other names: GS-6615;Drug: Placebo<br>* Placebo to match tablets administered orally in a single dose<br>|
| Experimental: Eleclazine 48 mg + Placebo<br>Participants will receive placebo to match eleclazine on Days 1, 2 and 4, and eleclazine 48 mg on Day 3. | Drug: Eleclazine<br>* Tablets administered orally in a single dose<br>* Other names: GS-6615;Drug: Placebo<br>* Placebo to match tablets administered orally in a single dose<br>|
| Placebo Comparator: Placebo<br>Participants will receive placebo to match eleclazine on Days 1 to 4. | Drug: Placebo<br>* Placebo to match tablets administered orally in a single dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Standard 12-Lead Electrocardiogram (ECG) Daytime QT Interval Corrected For Heart Rate Using The Fridericia Formula (QTcF) (AUC0-8)/8 at Day 3: Lead V5 | Daytime (AUC0-8)/8 was defined as the area under the QTc curve during the 8 hours postdose, where 0 was defined as the time of dosing (i.e., T = 0) on a given day. Daytime (AUC0-8)/8 was computed by dividing AUC0-8 by the time from dosing to the 8 hour postdose time point. QTcF is corrected QT interval using Fridericia's formula. | Baseline (Day 1), Day 3 | 
| Change From Baseline in Standard 12-Lead ECG Daytime QTcF (AUC0-8)/8 at Day 3: Lead II | Daytime (AUC0-8)/8 was defined as the area under the QTc curve during the 8 hours postdose, where 0 was defined as the time of dosing (i.e.,T = 0) on a given day. Daytime (AUC0-8)/8 was computed by dividing AUC0-8 by the time from dosing to the 8 hour postdose time point. QTcF is corrected QT interval using Fridericia's formula. | Baseline (Day 1), Day 3 | 
| Change From Baseline in Standard 12-Lead ECG Daytime QTcF (AUC0-8)/8 at Day 3: Global Lead | Daytime (AUC0-8)/8 was defined as the area under the QTc curve during the 8 hours postdose, where 0 was defined as the time of dosing (i.e., T = 0) on a given day. Daytime (AUC0-8)/8 was computed by dividing AUC0-8 by the time from dosing to the 8 hour postdose time point. QTcF is corrected QT interval using Fridericia's formula. | Baseline (Day 1), Day 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Holter Daily QTcF Interval (Daytime and Nocturnal) at Day 3 : Lead V5 | Daily Holter QTcF interval was calculated as the average of the daytime QTcF interval (AUC0-6)/6 and nocturnal QTcF interval (AUC0-6)/6. Daytime AUC0-6 was defined as the area under the QTc curve during the 6 hours postdose and nocturnal AUC0-6 was defined as the area under the QTc curve from midnight to 6am. (AUC0-6)/6 was computed by dividing AUC0-6 by the time difference over the 6 hours. QTcF is corrected QT interval using Fridericia's formula. | Baseline (Day 1), Day 3 | 
| Change From Baseline in Holter Daily QTcF Interval (Daytime and Nocturnal) at Day 3 : Global Lead | Daily Holter QTcF interval was calculated as the average of the daytime QTcF interval (AUC0-6)/6 and nocturnal QTcF interval (AUC0-6)/6. Daytime AUC0-6 was defined as the area under the QTc curve during the 6 hours postdose and nocturnal AUC0-6 was defined as the area under the QTc curve from midnight to 6am. (AUC0-6)/6 was computed by dividing AUC0-6 by the time difference over the 6 hours. QTcF is corrected QT interval using Fridericia's formula. | Baseline (Day 1), Day 3 | 
| Maximum Reduction From Predose in Standard 12-Lead QTcF on Days 2 and 3: Lead V5 | Maximal reduction from predose (0 hour) is the maximum decrease from predose of the QTc interval (QTcF) at any time point from 1 to 8 hours postdose for Days 2 and 3. QTcF is corrected QT interval using Fridericia's formula. Predose was defined as the Day 2 predose value. | Predose, Days 2 and 3 | 
| Maximum Reduction From Predose in Standard 12-Lead QTcF on Days 2 and 3: Lead II | Maximal reduction from predose is the maximum decrease from predose of the QTc interval (QTcF) at any time point from 1 to 8 hours postdose for Days 2 and 3. QTcF is corrected QT interval using Fridericia's formula. Predose was defined as the Day 2 predose value. | Predose, Days 2 and 3 | 
| Maximum Reduction From Predose in Standard 12-Lead QTcF on Days 2 and 3: Global Lead | Maximal reduction from predose is the maximum decrease from predose of the QTc interval (QTcF) at any time point from 1 to 8 hours postdose for Days 2 and 3. QTcF is corrected QT interval using Fridericia's formula. Predose was defined as the Day 2 predose value. | Predose, Days 2 and 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Congenital Long QT Syndrome, LQTS, Sudden Cardiac Death