Effect of Eleclazine on Shortening of the QT Interval, Sa... | NCT02300558

ID	Type	Description	Link
2014-000042-30	EudraCT Number

Label	Type	Description	Intervention Names
Eleclazine (Single-blind treatment phase)	Experimental	Eleclazine and/or eleclazine placebo up to Week 24	Drug: Eleclazine Drug: Eleclazine placebo
Open-label Extension Phase	Experimental	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

Name	Type	Description	Arm Group Labels	Other Names
Eleclazine	Drug	Tablets administered orally	Eleclazine (Single-blind treatment phase) Open-label Extension Phase

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

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.

Eligibility Module

Eligibility Criteria

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.

Name	Affiliation	Role
Gilead Study Director	Gilead Sciences	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Mayo Clinic Rochester		Rochester	Minnesota	55905	United States
NYU Langone Medical Center

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Eleclazine	Single-Blind Treatment Period: Single oral loading dose of placebo to match eleclazine loading dose (8 x 6 mg placebo to match tablets) on Day 1; eleclazine 48 mg ( 8 x 6 mg tablets) on Day 2; followed by eleclazine 3 mg (1 x 3 mg tablet) once daily from Day 3 to the Week 12 Visit; then once daily maintenance dose of eleclazine 6 mg (1 x 6 mg tablet) from the day after the Week 12 Visit through Week 24 Open-label Extension (OLE): Eleclazine 6 mg or 3 mg tablets orally once daily

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

ID	Title	Description
BG000	Eleclazine	Single-Blind Treatment Period: Single oral loading dose of placebo to match eleclazine loading dose (8 x 6 mg placebo to match tablets) on Day 1; eleclazine 48 mg ( 8 x 6 mg tablets) on Day 2; followed by eleclazine 3 mg (1 x 3 mg tablet) once daily from Day 3 to the Week 12 Visit; then once daily maintenance dose of eleclazine 6 mg (1 x 6 mg tablet) from the day after the Week 12 Visit through Week 24 OLE: Eleclazine 6 mg or 3 mg tablets orally once daily

Units	Counts
Participants	BG00041

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

Years

Title

Denominators

Categories

Title	Measurements
	BG00046± 12.5

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00024
Male	BG00017

Race/Ethnicity, Customized

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0001
Asian	BG0001

Race/Ethnicity, Customized

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Hispanic or Latino	BG0000
Not Hispanic or Latino	BG00040

Region of Enrollment

Count of Participants

Participants

Title

Denominators

Categories

Canada

Title	Measurements
	BG0001

Netherlands

Title	Measurements
	BG000

Mean Daytime QTcF Lead V5 (Standard 12-lead ECG)

QTcF refers to QT interval corrected for heart rate using the Fridericia 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.

Mean

Standard Deviation

msec

Title

Denominators

Categories

Title	Measurements
	BG000507.5± 38.11

Mean Daily QTcF in Lead V5 (Holter)

AUC (0-6) was calculated using the trapezoidal rule, mean of triplicate vales, and nominal time.
Mean daytime QTcF (AUC 0-6/6) was computed by dividing AUC(0-6) by the time from the first nonmissing time^ to the last nonmissing time^, from predose to 6 hours postdose.
Mean nocturnal QTcF (AUC 0-6/6) was computed by dividing AUC(0-6) by the time from the first nonmissing time^ to the last nonmissing time^, from midnight to 6:00 AM.
Daily was computed as the average of daytime AUC(0-6/6) and nocturnal AUC (0-6/6), when both values are not missing.
^ = nominal time point

Mean

Standard Deviation

msec

Title

Denominators

Categories

Title	Measurements
	BG000514.7± 45.76

Mean Nocturnal QTcF in Lead V5 (Holter)

AUC(0-6) for QTcF was calculated using the trapezoidal rule, mean of triplicate values, and nominal time.

Mean nocturnal QTcF (AUC 0-6/6) was computed by dividing AUC(0-6) by the time from the first nonmissing nominal time point to the last nonmissing nominal time point, from midnight to 6:00 AM.

Mean

Standard Deviation

msec

Title

Denominators

Categories

Title	Measurements
	BG000530.6± 52.25

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

Participants in Full Analysis Set (FAS) with available data were analyzed. FAS was defined as all enrolled participants who have confirmed LQT3 genotype, do not have confirmed LQT1 or LQT2 mutations, received at least 1 dose of active eleclazine, and have both a baseline and at least 1 postbaseline mean daytime QTcF interval (standard 12-lead).

Posted

Mean

Standard Deviation

msec

Baseline; Week 24

ID	Title	Description
OG000	Eleclazine	Single-Blind Treatment Period: Single oral loading dose of placebo to match eleclazine loading dose (8 x 6 mg placebo to match tablets) on Day 1; eleclazine 48 mg ( 8 x 6 mg tablets) on Day 2; followed by eleclazine 3 mg (1 x 3 mg tablet) once daily from Day 3 to the Week 12 Visit; then once daily maintenance dose of eleclazine 6 mg (1 x 6 mg tablet) from the day after the Week 12 Visit through Week 24 OLE: Eleclazine 6 mg or 3 mg tablets orally once daily

Units	Counts
Participants	OG00035

Title

Denominators

Categories

Title	Measurements
	OG000-8.5± 18.03

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000	Based on a 2-sided, paired t-test ( α = 0.05), and a standard deviation (SD) of 30 msec, a sample size of 40 participants provided greater than 95% power assuming a difference in mean daytime QTcF interval (AUC0-6/6) as measured by standard 12-lead ECG between baseline and Week 24 of 20 msec. The null hypothesis was that the mean difference between the baseline and Week 24 mean daytime QTcF interval was zero.	paired t- test		0.0087														Other

Secondary

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.

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

Posted

Mean

95% Confidence Interval

msec

Baseline; Week 12

ID	Title	Description
OG000	Eleclazine	Single-Blind Treatment Period: Single oral loading dose of placebo to match eleclazine loading dose (8 x 6 mg placebo to match tablets) on Day 1; eleclazine 48 mg ( 8 x 6 mg tablets) on Day 2; followed by eleclazine 3 mg (1 x 3 mg tablet) once daily from Day 3 to the Week 12 Visit; then once daily maintenance dose of eleclazine 6 mg (1 x 6 mg tablet) from the day after the Week 12 Visit through Week 24 OLE: Eleclazine 6 mg or 3 mg tablets orally once daily

Units	Counts
Participants	OG000

Secondary

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.

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

Posted

Mean

95% Confidence Interval

msec

Baseline; Week 24

ID	Title	Description
OG000	Eleclazine	Single-Blind Treatment Period: Single oral loading dose of placebo to match eleclazine loading dose (8 x 6 mg placebo to match tablets) on Day 1; eleclazine 48 mg ( 8 x 6 mg tablets) on Day 2; followed by eleclazine 3 mg (1 x 3 mg tablet) once daily from Day 3 to the Week 12 Visit; then once daily maintenance dose of eleclazine 6 mg (1 x 6 mg tablet) from the day after the Week 12 Visit through Week 24 OLE: Eleclazine 6 mg or 3 mg tablets orally once daily

Units	Counts

Secondary

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.

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

Posted

Mean

95% Confidence Interval

msec

Baseline; Week 24

ID	Title	Description
OG000	Eleclazine	Single-Blind Treatment Period: Single oral loading dose of placebo to match eleclazine loading dose (8 x 6 mg placebo to match tablets) on Day 1; eleclazine 48 mg ( 8 x 6 mg tablets) on Day 2; followed by eleclazine 3 mg (1 x 3 mg tablet) once daily from Day 3 to the Week 12 Visit; then once daily maintenance dose of eleclazine 6 mg (1 x 6 mg tablet) from the day after the Week 12 Visit through Week 24 OLE: Eleclazine 6 mg or 3 mg tablets orally once daily

Units	Counts
Participants	OG000

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo	Single oral loading dose of placebo to match eleclazine loading dose (8 x 6 mg placebo to match tablets) on Day 1	41	0	41	5	41
EG001	Eleclazine Loading Dose (LD) 48 mg	Eleclazine 48 mg ( 8 x 6 mg tablets) administered orally on Day 2	41	0	41	5	41
EG002	Eleclazine Maintenance Dose (MD) 3 mg	Eleclazine 3 mg (1 x 3 mg tablet) administered once daily from Day 3 to the Week 12 Visit	41	1	41	17	41
EG003	Eleclazine MD 6 mg	Eleclazine 6 mg (1 x 6 mg tablet) administered orally from the day after the Week 12 Visit through Week 24 and open-label extension.	41	0	41	14	41
EG004	All Eleclazine	Loading Dose: Eleclazine 48 mg ( 8 x 6 mg tablets) administered on Day 2 and 3 mg (1 x 3 mg tablet) once daily from Day 3 to the Week 12 Visit Maintenance dose: Eleclazine 6 mg (1 x 6 mg tablet) from the day after the Week 12 Visit through Week 24 and open-label extension. Adverse events in this reporting group include those that occurred any time during the study by participants while receiving loading dose or maintenance dose of eleclazine.	41	1	41	24	41

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Vertigo	Ear and labyrinth disorders	MedDRA 19.1	Systematic Assessment	EG0001 affected41 at risk EG0012 affected41 at risk EG0020 affected41 at risk EG0032 affected41 at risk EG0043 affected41 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 19.1	Systematic Assessment	EG0000 affected41 at risk EG0010 affected41 at risk EG0023 affected41 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA 19.1	Systematic Assessment	EG0000 affected41 at risk EG0011 affected41 at risk EG0023 affected41 at risk EG003
Asthenia	General disorders	MedDRA 19.1	Systematic Assessment	EG0001 affected41 at risk EG0010 affected41 at risk EG0022 affected41 at risk EG003
Fatigue	General disorders	MedDRA 19.1	Systematic Assessment	EG0000 affected41 at risk EG0010 affected41 at risk EG0023 affected41 at risk EG003
Influenza	Infections and infestations	MedDRA 19.1	Systematic Assessment	EG0000 affected41 at risk EG0010 affected41 at risk EG0023 affected41 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA 19.1	Systematic Assessment	EG0000 affected41 at risk EG0010 affected41 at risk EG0022 affected41 at risk EG003
Weight increased	Investigations	MedDRA 19.1	Systematic Assessment	EG0000 affected41 at risk EG0010 affected41 at risk EG0021 affected41 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 19.1	Systematic Assessment	EG0001 affected41 at risk EG0010 affected41 at risk EG0020 affected41 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 19.1	Systematic Assessment	EG0000 affected41 at risk EG0010 affected41 at risk EG0023 affected41 at risk EG003
Dizziness	Nervous system disorders	MedDRA 19.1	Systematic Assessment	EG0000 affected41 at risk EG0012 affected41 at risk EG0022 affected41 at risk EG003
Headache	Nervous system disorders	MedDRA 19.1	Systematic Assessment	EG0002 affected41 at risk EG0011 affected41 at risk EG0022 affected41 at risk EG003

ID	Term
C537034	Long QT syndrome type 3
D008133	Long QT Syndrome
D016757	Death, Sudden, Cardiac

ID	Term
D001145	Arrhythmias, Cardiac
D006331	Heart Diseases
D002318	Cardiovascular Diseases
D000075224	Cardiac Conduction System Disease
D006330	Heart Defects, Congenital
D018376	Cardiovascular Abnormalities
D000013	Congenital Abnormalities
D009358	Congenital, Hereditary, and Neonatal Diseases and Abnormalities
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms
D006323	Heart Arrest
D003645	Death, Sudden
D003643	Death