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

• Sponsor: Gilead Sciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02365506
• Collaborator: (none)
• Enrollment: 13
• Location: 1
• Arms: 3
• Actual Duration (Months): 10.8
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
LQT2 Syndrome	Drug: Eleclazine; Drug: Placebo	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-blind, Placebo-controlled Study to Evaluate the Effect of GS-6615 on QT, Safety and Tolerability in Subjects With Long QT2 Syndrome
• Actual Study Start Date: Jul 20, 2015
• Actual Primary Completion Date: May 13, 2016
• Actual Study Completion Date: Jun 13, 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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 [Baseline (Day 1), Day 3]

   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.

2. Change From Baseline in Standard 12-Lead ECG Daytime QTcF (AUC0-8)/8 at Day 3: Lead II [Baseline (Day 1), Day 3]

   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.

3. Change From Baseline in Standard 12-Lead ECG Daytime QTcF (AUC0-8)/8 at Day 3: Global Lead [Baseline (Day 1), Day 3]

   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.

Secondary Outcome Measures

1. Change From Baseline in Holter Daily QTcF Interval (Daytime and Nocturnal) at Day 3 : Lead V5 [Baseline (Day 1), Day 3]

   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.

2. Change From Baseline in Holter Daily QTcF Interval (Daytime and Nocturnal) at Day 3 : Global Lead [Baseline (Day 1), Day 3]

   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.

3. Maximum Reduction From Predose in Standard 12-Lead QTcF on Days 2 and 3: Lead V5 [Predose, Days 2 and 3]

   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.

4. Maximum Reduction From Predose in Standard 12-Lead QTcF on Days 2 and 3: Lead II [Predose, Days 2 and 3]

   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.

5. Maximum Reduction From Predose in Standard 12-Lead QTcF on Days 2 and 3: Global Lead [Predose, Days 2 and 3]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Rochester Medical Center/Strong Memorial Hospital	Rochester	New York	United States	14620

Sponsors and Collaborators

• Gilead Sciences

Investigators

• Study Director: Gilead Study Director, Gilead Sciences

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT02365506
• Other Study ID Numbers: GS-US-394-1658
• First Posted: Feb 19, 2015
• Last Update Posted: Dec 30, 2020
• Last Verified: Dec 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Gilead Sciences: Congenital Long QT Syndrome; LQTS; Sudden Cardiac Death
• Additional relevant MeSH terms: Long QT Syndrome; Syndrome

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at 1 study site in the United States. The first participant was screened on 20 July 2015. The last study visit occurred on 13 June 2016.
Pre-assignment Detail	15 participants were screened.

Arm/Group Title	Eleclazine 24 mg + Eleclazine 48 mg + Placebo	Eleclazine 48 mg + Placebo	Placebo
Arm/Group Description	Participants received single oral dose of placebo to match eleclazine tablet on Days 1 and 4, a single oral dose of eleclazine 24 mg (4 x 6 mg) tablets on Day 2 and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received single oral dose of placebo to match eleclazine tablet on Days 1, 2 and 4, and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received placebo to match eleclazine tablets on Days 1 to 4.
Period Title: Overall Study
STARTED	4	4	5
COMPLETED	4	4	4
NOT COMPLETED	0	0	1

Baseline Characteristics

Arm/Group Title	Eleclazine 24 mg + Eleclazine 48 mg + Placebo	Eleclazine 48 mg + Placebo	Placebo	Total
Arm/Group Description	Participants received single oral dose of placebo to match eleclazine tablet on Days 1 and 4, a single oral dose of eleclazine 24 mg (4 x 6 mg) tablets on Day 2 and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received single oral dose of placebo to match eleclazine tablet on Days 1, 2 and 4, and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received placebo to match eleclazine tablets on Days 1 to 4.	Total of all reporting groups
Overall Participants	4	4	5	13
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41 (15.3)	40 (13.9)	48 (11.0)	43 (12.8)
Sex: Female, Male (Count of Participants)
Female	3 75%	3 75%	3 60%	9 69.2%
Male	1 25%	1 25%	2 40%	4 30.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	4 100%	4 100%	5 100%	13 100%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	4 100%	4 100%	5 100%	13 100%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	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
Description	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.
Time Frame	Baseline (Day 1), Day 3

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set (included all participants who took at least 1 dose of study drug and had standard 12-lead Day 3 QT measurements recorded) with available data were analyzed.

Arm/Group Title	Eleclazine 24 mg + Eleclazine 48 mg + Placebo	Eleclazine 48 mg + Placebo	Placebo
Arm/Group Description	Participants received single oral dose of placebo to match eleclazine tablet on Days 1 and 4, a single oral dose of eleclazine 24 mg (4 x 6 mg) tablets on Day 2 and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received single oral dose of placebo to match eleclazine tablet on Days 1, 2 and 4, and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received placebo to match eleclazine tablets on Days 1 to 4.
Measure Participants	4	3	4
Baseline	447.2 (5.32)	468.3 (26.20)	464.3 (20.50)
Change at Day 3	-5.3 (8.31)	0.4 (15.20)	2.1 (7.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eleclazine 24 mg + Eleclazine 48 mg + Placebo, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.358
	Comments
	Method	Mixed Models Analysis
	Comments	p-value is from a mixed model with fixed effect for treatment, day, and treatment by day with baseline daytime QTcF as a covariate.
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	-7.7
	Confidence Interval	(2-Sided) 95%; -26.0 to 10.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.92
	Estimation Comments	Least Square mean (LSM) and 95% confidence interval (CI) is from a mixed model with fixed effect for treatment, day, and treatment by day with baseline daytime QTcF as a covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Eleclazine 48 mg + Placebo, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.840
	Comments
	Method	Mixed Models Analysis
	Comments	p-value is from a mixed model with fixed effect for treatment, day, and treatment by day with baseline daytime QTcF as a covariate.
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	-1.7
	Confidence Interval	(2-Sided) 95%; -20.0 to 16.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.96
	Estimation Comments	LSM and 95% CI are from a mixed model with fixed effect for treatment, day, and treatment by day with baseline daytime QTcF as a covariate.

2. Primary Outcome

Title	Change From Baseline in Standard 12-Lead ECG Daytime QTcF (AUC0-8)/8 at Day 3: Lead II
Description	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.
Time Frame	Baseline (Day 1), Day 3

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set with available data were analyzed.

Arm/Group Title	Eleclazine 24 mg + Eleclazine 48 mg + Placebo	Eleclazine 48 mg + Placebo	Placebo
Arm/Group Description	Participants received single oral dose of placebo to match eleclazine tablet on Days 1 and 4, a single oral dose of eleclazine 24 mg (4 x 6 mg) tablets on Day 2 and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received single oral dose of placebo to match eleclazine tablet on Days 1, 2 and 4, and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received placebo to match eleclazine tablets on Days 1 to 4.
Measure Participants	4	3	4
Baseline	447.7 (5.48)	464.7 (34.00)	461.2 (20.01)
Change at Day 3	-3.4 (7.72)	8.7 (8.96)	3.3 (7.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eleclazine 24 mg + Eleclazine 48 mg + Placebo, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.338
	Comments
	Method	Mixed Models Analysis
	Comments	p-value is from a mixed model with fixed effect for treatment, day, and treatment by day with baseline daytime QTcF as a covariate.
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	-6.0
	Confidence Interval	(2-Sided) 95%; -19.8 to 7.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.83
	Estimation Comments	LSM and 95% CI are from a mixed model with fixed effect for treatment, day, and treatment by day with baseline daytime QTcF as a covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Eleclazine 48 mg + Placebo, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.425
	Comments
	Method	Mixed Models Analysis
	Comments	p-value is from a mixed model with fixed effect for treatment, day, and treatment by day with baseline daytime QTcF as a covariate.
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	5.3
	Confidence Interval	(2-Sided) 95%; -9.4 to 19.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.21
	Estimation Comments	LSM and 95% CI are from a mixed model with fixed effect for treatment, day, and treatment by day with baseline daytime QTcF as a covariate.

3. Primary Outcome

Title	Change From Baseline in Standard 12-Lead ECG Daytime QTcF (AUC0-8)/8 at Day 3: Global Lead
Description	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.
Time Frame	Baseline (Day 1), Day 3

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set with available data were analyzed.

Arm/Group Title	Eleclazine 24 mg + Eleclazine 48 mg + Placebo	Eleclazine 48 mg + Placebo	Placebo
Arm/Group Description	Participants received single oral dose of placebo to match eleclazine tablet on Days 1 and 4, a single oral dose of eleclazine 24 mg (4 x 6 mg) tablets on Day 2 and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received single oral dose of placebo to match eleclazine tablet on Days 1, 2 and 4, and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received placebo to match eleclazine tablets on Days 1 to 4.
Measure Participants	4	4	4
Baseline	453.3 (8.11)	471.2 (41.88)	477.9 (32.80)
Change at Day 3	-7.8 (7.55)	0.5 (9.68)	-3.5 (3.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eleclazine 24 mg + Eleclazine 48 mg + Placebo, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.174
	Comments
	Method	Mixed Models Analysis
	Comments	p-value is from a mixed model with fixed effect for treatment, day, and treatment by day with baseline daytime QTcF as a covariate.
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	-6.5
	Confidence Interval	(2-Sided) 95%; -16.5 to 3.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.42
	Estimation Comments	LSM and 95% CI are from a mixed model with fixed effect for treatment, day, and treatment by day with baseline daytime QTcF as a covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Eleclazine 48 mg + Placebo, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.448
	Comments
	Method	Mixed Models Analysis
	Comments	p-value is from a mixed model with fixed effect for treatment, day, and treatment by day with baseline daytime QTcF as a covariate.
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	3.4
	Confidence Interval	(2-Sided) 95%; -6.3 to 13.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.28
	Estimation Comments	LSM and 95% CI are from a mixed model with fixed effect for treatment, day, and treatment by day with baseline daytime QTcF as a covariate.

4. Secondary Outcome

Title	Change From Baseline in Holter Daily QTcF Interval (Daytime and Nocturnal) at Day 3 : Lead V5
Description	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.
Time Frame	Baseline (Day 1), Day 3

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set with available data were analyzed.

Arm/Group Title	Eleclazine 24 mg + Eleclazine 48 mg + Placebo	Eleclazine 48 mg + Placebo	Placebo
Arm/Group Description	Participants received single oral dose of placebo to match eleclazine tablet on Days 1 and 4, a single oral dose of eleclazine 24 mg (4 x 6 mg) tablets on Day 2 and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received single oral dose of placebo to match eleclazine tablet on Days 1, 2 and 4, and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received placebo to match eleclazine tablets on Days 1 to 4.
Measure Participants	3	3	4
Baseline	461.6 (6.89)	466.6 (20.00)	481.2 (28.12)
Change at Day 3	3.5 (10.37)	7.8 (2.20)	-4.1 (13.77)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eleclazine 24 mg + Eleclazine 48 mg + Placebo, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.339
	Comments
	Method	Mixed Models Analysis
	Comments	p-value is from a mixed model with fixed effect for treatment, day, and treatment by day with baseline daytime QTcF as a covariate.
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	8.8
	Confidence Interval	(2-Sided) 95%; -12.0 to 29.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.50
	Estimation Comments	LSM and 95% CI are from a mixed model with fixed effect for treatment, day, and treatment by day with baseline daytime QTcF as a covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Eleclazine 48 mg + Placebo, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.178
	Comments
	Method	Mixed Models Analysis
	Comments	p-value is from a mixed model with fixed effect for treatment, day, and treatment by day with baseline daytime QTcF as a covariate.
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	12.8
	Confidence Interval	(2-Sided) 95%; -7.7 to 33.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.40
	Estimation Comments	LSM and 95% CI are from a mixed model with fixed effect for treatment, day, and treatment by day with baseline daytime QTcF as a covariate.

5. Secondary Outcome

Title	Change From Baseline in Holter Daily QTcF Interval (Daytime and Nocturnal) at Day 3 : Global Lead
Description	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.
Time Frame	Baseline (Day 1), Day 3

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set with available data were analyzed.

Arm/Group Title	Eleclazine 24 mg + Eleclazine 48 mg + Placebo	Eleclazine 48 mg + Placebo	Placebo
Arm/Group Description	Participants received single oral dose of placebo to match eleclazine tablet on Days 1 and 4, a single oral dose of eleclazine 24 mg (4 x 6 mg) tablets on Day 2 and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received single oral dose of placebo to match eleclazine tablet on Days 1, 2 and 4, and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received placebo to match eleclazine tablets on Days 1 to 4.
Measure Participants	3	4	4
Baseline	461.6 (7.85)	483.3 (33.11)	486.4 (28.03)
Change at Day 3	3.2 (8.02)	2.0 (3.81)	-0.6 (14.67)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eleclazine 24 mg + Eleclazine 48 mg + Placebo, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.564
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	4.9
	Confidence Interval	(2-Sided) 95%; -14.1 to 23.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.03
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Eleclazine 48 mg + Placebo, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.721
	Comments
	Method	Mixed Models Analysis
	Comments	p-value is from a mixed model with fixed effect for treatment, day, and treatment by day with baseline daytime QTcF as a covariate.
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	2.7
	Confidence Interval	(2-Sided) 95%; -14.7 to 20.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.38
	Estimation Comments	LSM and 95% CI are from a mixed model with fixed effect for treatment, day, and treatment by day with baseline daytime QTcF as a covariate.

6. Secondary Outcome

Title	Maximum Reduction From Predose in Standard 12-Lead QTcF on Days 2 and 3: Lead V5
Description	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.
Time Frame	Predose, Days 2 and 3

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set with available data were analyzed.

Arm/Group Title	Eleclazine 24 mg + Eleclazine 48 mg + Placebo	Eleclazine 48 mg + Placebo	Placebo
Arm/Group Description	Participants received single oral dose of placebo to match eleclazine tablet on Days 1 and 4, a single oral dose of eleclazine 24 mg (4 x 6 mg) tablets on Day 2 and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received single oral dose of placebo to match eleclazine tablet on Days 1, 2 and 4, and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received placebo to match eleclazine tablets on Days 1 to 4.
Measure Participants	4	3	4
Predose	450.6 (13.00)	481.6 (33.28)	453.9 (20.31)
Day 2	-14.3 (7.82)	-40.3 (20.85)	-9.4 (14.11)
Day 3	-16.3 (5.80)	-64.4 (75.73)	2.8 (15.57)

7. Secondary Outcome

Title	Maximum Reduction From Predose in Standard 12-Lead QTcF on Days 2 and 3: Lead II
Description	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.
Time Frame	Predose, Days 2 and 3

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set with available data were analyzed.

Arm/Group Title	Eleclazine 24 mg + Eleclazine 48 mg + Placebo	Eleclazine 48 mg + Placebo	Placebo
Arm/Group Description	Participants received single oral dose of placebo to match eleclazine tablet on Days 1 and 4, a single oral dose of eleclazine 24 mg (4 x 6 mg) tablets on Day 2 and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received single oral dose of placebo to match eleclazine tablet on Days 1, 2 and 4, and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received placebo to match eleclazine tablets on Days 1 to 4.
Measure Participants	4	3	4
Predose	458.3 (11.54)	482.1 (37.67)	455.8 (21.61)
Day 2	-16.5 (9.34)	-37.1 (37.79)	-9.1 (18.40)
Day 3	-21.5 (6.14)	-35.8 (24.15)	-1.7 (18.06)

8. Secondary Outcome

Title	Maximum Reduction From Predose in Standard 12-Lead QTcF on Days 2 and 3: Global Lead
Description	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.
Time Frame	Predose, Days 2 and 3

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set with available data were analyzed.

Arm/Group Title	Eleclazine 24 mg + Eleclazine 48 mg + Placebo	Eleclazine 48 mg + Placebo	Placebo
Arm/Group Description	Participants received single oral dose of placebo to match eleclazine tablet on Days 1 and 4, a single oral dose of eleclazine 24 mg (4 x 6 mg) tablets on Day 2 and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received single oral dose of placebo to match eleclazine tablet on Days 1, 2 and 4, and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.	Participants received placebo to match eleclazine tablets on Days 1 to 4.
Measure Participants	4	4	4
Predose	458.8 (14.60)	473.5 (42.27)	461.7 (24.49)
Day 2	-18.3 (8.31)	-13.5 (6.92)	-4.6 (17.12)
Day 3	-23.3 (6.10)	-15.7 (14.01)	2.1 (11.29)

Adverse Events

Time Frame	First dose date up to 30 days after last dose of study drug (up to Day 34)
Adverse Event Reporting Description	The Safety Analysis Set included all participants who took at least 1 dose of study drug.
Arm/Group Title	Eleclazine 24 mg + Eleclazine 48 mg + Placebo		Eleclazine 48 mg + Placebo		Placebo
Arm/Group Description	Participants received single oral dose of placebo to match eleclazine tablet on Days 1 and 4, a single oral dose of eleclazine 24 mg (4 x 6 mg) tablets on Day 2 and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.		Participants received single oral dose of placebo to match eleclazine tablet on Days 1, 2 and 4, and a single oral dose of eleclazine 48 mg (8 x 6 mg) tablets on Day 3.		Participants received placebo to match eleclazine tablets on Days 1 to 4.
All Cause Mortality
	Eleclazine 24 mg + Eleclazine 48 mg + Placebo		Eleclazine 48 mg + Placebo		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/4 (0%)		0/5 (0%)
Serious Adverse Events
	Eleclazine 24 mg + Eleclazine 48 mg + Placebo		Eleclazine 48 mg + Placebo		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/4 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Eleclazine 24 mg + Eleclazine 48 mg + Placebo		Eleclazine 48 mg + Placebo		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/4 (25%)		2/4 (50%)		4/5 (80%)
Cardiac disorders
Palpitations	0/4 (0%)		0/4 (0%)		1/5 (20%)
Pericarditis	0/4 (0%)		0/4 (0%)		1/5 (20%)
Gastrointestinal disorders
Abdominal pain	1/4 (25%)		0/4 (0%)		0/5 (0%)
Dry mouth	0/4 (0%)		0/4 (0%)		1/5 (20%)
Nausea	1/4 (25%)		0/4 (0%)		1/5 (20%)
General disorders
Chest discomfort	0/4 (0%)		0/4 (0%)		1/5 (20%)
Chest pain	0/4 (0%)		0/4 (0%)		1/5 (20%)
Fatigue	0/4 (0%)		0/4 (0%)		1/5 (20%)
Oedema peripheral	0/4 (0%)		0/4 (0%)		1/5 (20%)
Metabolism and nutrition disorders
Dehydration	0/4 (0%)		0/4 (0%)		1/5 (20%)
Hypovolaemia	0/4 (0%)		0/4 (0%)		1/5 (20%)
Nervous system disorders
Dizziness	0/4 (0%)		1/4 (25%)		1/5 (20%)
Headache	1/4 (25%)		1/4 (25%)		3/5 (60%)
Migraine with aura	0/4 (0%)		1/4 (25%)		0/5 (0%)
Syncope	0/4 (0%)		0/4 (0%)		1/5 (20%)
Psychiatric disorders
Insomnia	0/4 (0%)		0/4 (0%)		1/5 (20%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/4 (0%)		0/4 (0%)		1/5 (20%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or The study has been completed at all study sites for at least 2 years