Long QT Syndrome Type 3
Conditions
Keywords
Type 3 long QT syndrome (LQT3), Long QT syndrome, Congenital long QT, Sudden cardiac death
Brief summary
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.
Interventions
DRUGEleclazine
Tablets administered orally
DRUGEleclazine placebo
Tablets administered orally
Sponsors
Gilead Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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; Week 24 | * 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Daytime QTcF Interval (AUC0-6/6) to Week 12 (Lead V5; Standard 12-lead ECG) | Baseline; Week 12 | * 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. |
| Change From Baseline in Mean Daily (Daytime and Nocturnal) QTcF Interval to Week 24 (Lead V5; Holter) | Baseline; Week 24 | * 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. |
| Change From Baseline in Mean Nocturnal QTcF Interval to Week 24 (Lead V5; Holter) | Baseline; Week 24 | * 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. |
Countries
Canada, France, Germany, Israel, Italy, Netherlands, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in North America, Europe, and Asia. The first participant was screened on 17 December 2014. The last study visit occurred on 15 February 2017.
Pre-assignment details
54 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| 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 | 41 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Open-Label (OL) Extension Phase | Lack of Efficacy | 2 |
| Open-Label (OL) Extension Phase | Study Terminated by Sponsor | 29 |
| Open-Label (OL) Extension Phase | Withdrew Consent | 1 |
| Single Blind Phase (24 Weeks) | Study Terminated by Sponsor | 6 |
Baseline characteristics
| Characteristic | Eleclazine |
|---|---|
| Age, Continuous | 46 Years STANDARD_DEVIATION 12.5 |
| Mean Daily QTcF in Lead V5 (Holter) | 514.7 msec STANDARD_DEVIATION 45.76 |
| Mean Daytime QTcF Lead V5 (Standard 12-lead ECG) | 507.5 msec STANDARD_DEVIATION 38.11 |
| Mean Nocturnal QTcF in Lead V5 (Holter) | 530.6 msec STANDARD_DEVIATION 52.25 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 40 Participants |
| Race/Ethnicity, Customized Not Permitted | 1 Participants |
| Race/Ethnicity, Customized Other | 2 Participants |
| Race/Ethnicity, Customized White | 36 Participants |
| Region of Enrollment Canada | 1 Participants |
| Region of Enrollment France | 9 Participants |
| Region of Enrollment Germany | 1 Participants |
| Region of Enrollment Israel | 3 Participants |
| Region of Enrollment Italy | 12 Participants |
| Region of Enrollment Netherlands | 3 Participants |
| Region of Enrollment United Kingdom | 1 Participants |
| Region of Enrollment United States | 11 Participants |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 41 | 0 / 41 | 0 / 41 | 0 / 41 | 0 / 41 |
| other Total, other adverse events | 5 / 41 | 5 / 41 | 17 / 41 | 14 / 41 | 24 / 41 |
| serious Total, serious adverse events | 0 / 41 | 0 / 41 | 1 / 41 | 0 / 41 | 1 / 41 |
Outcome results
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.
Time frame: Baseline; Week 24
Population: 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).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eleclazine | 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) | -8.5 msec | Standard Deviation 18.03 |
Comparison: 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.p-value: 0.0087paired t- test
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.
Time frame: Baseline; Week 24
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Eleclazine | Change From Baseline in Mean Daily (Daytime and Nocturnal) QTcF Interval to Week 24 (Lead V5; Holter) | -1.8 msec |
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.
Time frame: Baseline; Week 12
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Eleclazine | Change From Baseline in Mean Daytime QTcF Interval (AUC0-6/6) to Week 12 (Lead V5; Standard 12-lead ECG) | 2.2 msec |
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.
Time frame: Baseline; Week 24
Population: Participants in the the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Eleclazine | Change From Baseline in Mean Nocturnal QTcF Interval to Week 24 (Lead V5; Holter) | -3.0 msec |