Clinical Trial Results:
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
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Summary
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EudraCT number |
2014-000042-30 |
Trial protocol |
GB DE NL ES FI IT |
Global end of trial date |
15 Feb 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Dec 2017
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First version publication date |
30 Dec 2017
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
GS-US-372-1234
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02300558 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Gilead Sciences
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Sponsor organisation address |
333 Lakeside Drive , Foster City, CA, United States, 94404
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Public contact |
Clinical Trials Mailbox
, Gilead Sciences International Ltd
, ClinicalTrialDisclosures@gilead.com
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Scientific contact |
Clinical Trials Mailbox
, Gilead Sciences International Ltd
, ClinicalTrialDisclosures@gilead.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
15 Feb 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
12 Dec 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
15 Feb 2017
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The primary objective of this study was 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 received eleclazine placebo on Day 1 and eleclazine from Day 2 to Week 24. Following the single-blind treatment period, participants who didn't permanently discontinue study drug were be eligible, at the discretion of the investigator, to continue receiving eleclazine during an open-label extension phase (OLE).
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Protection of trial subjects |
The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements.
This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
17 Dec 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 3
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
France: 9
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Country: Number of subjects enrolled |
Germany: 1
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Country: Number of subjects enrolled |
Italy: 12
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Country: Number of subjects enrolled |
United States: 11
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Country: Number of subjects enrolled |
Israel: 3
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Country: Number of subjects enrolled |
Canada: 1
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Worldwide total number of subjects |
41
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EEA total number of subjects |
26
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
38
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From 65 to 84 years |
3
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85 years and over |
0
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Recruitment
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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. | ||||||||||||||
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Pre-assignment
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Screening details |
54 participants were screened. | ||||||||||||||
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Period 1
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Period 1 title |
Single Blind Phase (24 Weeks)
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Single blind | ||||||||||||||
Roles blinded |
Subject | ||||||||||||||
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Arms
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Arm title
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Eleclazine (Single-Blind Treatment Period) | ||||||||||||||
Arm description |
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 | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Eleclazine
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Investigational medicinal product code |
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Other name |
GS-6615
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
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
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Period 2
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Period 2 title |
Open-Label Extension
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Is this the baseline period? |
No | ||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||
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Arms
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Arm title
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Eleclazine | ||||||||||||||
Arm description |
Eleclazine 6 mg or 3 mg tablets orally once daily | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Eleclazine
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Investigational medicinal product code |
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Other name |
GS-6615
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
6 mg or 3 mg tablets orally once daily
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| Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: 3 participants completed the single-blind phase (24 weeks) but did not continue to open-label extension phase. |
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Baseline characteristics reporting groups
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Reporting group title |
Single Blind Phase (24 Weeks)
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Reporting group description |
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End points reporting groups
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Reporting group title |
Eleclazine (Single-Blind Treatment Period)
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Reporting group description |
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 | ||
Reporting group title |
Eleclazine
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Reporting group description |
Eleclazine 6 mg or 3 mg tablets orally once daily | ||
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End point title |
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) [1] | ||||||||
End point description |
1) Baseline was the Day 1 value.
2) QTcF is corrected QT interval using Fridericia's formula. QTcF = QT/cube root (RR), where RR is in seconds.
3) AUC0-6 for QTcF was calculated using the trapezoidal rule, mean of triplicate values, and actual time (latest of triplicate times).
4) Mean daytime QTcF (AUC0-6/6) was computed by dividing AUC0-6 by the time from dosing to the 6 hour postdose time point.
5) Participants in Full Analysis Set (FAS) with available data were analyzed. Full Analysis Set 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).
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End point type |
Primary
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End point timeframe |
Baseline; Week 24
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The statistical analysis of this primary endpoint is provided in the attachment. |
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Attachments |
Untitled (Filename: Primary_Endpoint_StatsAnalysis.pdf) |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Mean Daytime QTcF Interval (AUC0-6/6) to Week 12 (Lead V5; Standard 12-Lead ECG) | ||||||||
End point description |
1) Baseline was the Day 1 value.
2) QTcF is corrected QT interval using Fridericia's formula. QTcF = QT/cube root (RR), where RR is in seconds.
3) AUC0-6 for QTcF was calculated using the trapezoidal rule, mean of triplicate values, and actual time (latest of triplicate times) .
4) Mean daytime QTcF (AUC0-6/6) was computed by dividing AUC0-6 by the time from dosing to the 6 hour postdose time point.
5) Participants in the Full Analysis Set with available data were analyzed.
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End point type |
Secondary
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End point timeframe |
Baseline; Week 12
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline Mean Daily (Daytime and Nocturnal) QTcF interval to Week 24 (Lead V5; Holter) | ||||||||
End point description |
1) Baseline was the Day 1 value.
2) QTcF is corrected QT interval using Fridericia's formula. QTcF = QT/cube root (RR), where RR is in seconds.
3) 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.
4) 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.
4) Participants in the the Full Analysis Set with available data were analyzed.
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End point type |
Secondary
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End point timeframe |
Baseline; Week 24
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Mean Nocturnal QTcF Interval to Week 24 (Lead V5; Holter) | ||||||||
End point description |
1) Baseline was the Day 1 value.
2) QTcF is corrected QT interval using Fridericia's formula. QTcF = QT/cube root (RR), where RR is in seconds.
3) 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.
4) Participants in the the Full Analysis Set with available data were analyzed.
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End point type |
Secondary
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End point timeframe |
Baseline; Week 24
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Day 1 to the last dose date plus 30 days (median exposure to eleclazine: 396 days)
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Adverse event reporting additional description |
Safety Analysis Set: participants who received at least 1 dose of study drug (either active or placebo).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.1
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Single oral loading dose of placebo to match eleclazine loading dose (8 x 6 mg placebo to match tablets) on Day 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Eleclazine Loading Dose (LD) 48 mg
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Reporting group description |
Eleclazine 48 mg ( 8 x 6 mg tablets) administered orally on Day 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Eleclazine Maintenance Dose (MD) 3 mg
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Reporting group description |
Eleclazine 3 mg (1 x 3 mg tablet) administered once daily from Day 3 to the Week 12 Visit | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Eleclazine MD 6 mg
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Reporting group description |
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
All Eleclazine
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Reporting group description |
• 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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31 Oct 2014 |
1) Updated information from phase 1 studies in healthy volunteers and subjects with LQT3.
2) Revised Inclusion Criteria 4 to include QTc interval measurement criteria for subjects who are currently taking ranolazine or Class I antiarrhythmic drugs such as mexiletine.
3) Revised Exclusion Criteria 2 to strengthen language regarding seizures.
4) Revised Exclusion Criteria 11 to reflect the ranolazine half-life.
5) Revised the study design and study procedures to incorporate the addition of Week 2 Monitoring, the Week 18 Visit, and the open-label extension.
6) Revised the duration (length), windows, and timing of study visits.
7) Revised to clarify that subjects taking ranolazine or Class I antiarrhythmic drugs such as mexiletine may be hospitalized, at the discretion of the investigator, to allow for washout of the aforementioned medications.
8) Revised collection of DNA for the LQTS sequencing test to only occur on Day 1 of the Enrollment Visit.
9) Specified guidance to investigators for subjects who may experience a
seizure.
10) Added use of a cardiac rhythm monitoring device (eg, ZIO® XT Patch).
11) Added predose urine PK collection from Day 1 through the OLE, and also
at the Follow-up and Early Termination Visits.
12) Revised the dosing regimen of the single-blind treatment period; initiating the maintenance dose of 3 mg GS-6615 once daily for 12 weeks, followed by a fixed up-titration to 6 mg GS-6615 once daily for the next 12 weeks.
13) Added the formulation of 6 mg GS-6615 supplied during the single blind treatment period and also the formulation of GS-6615 supplied during the open-label extension.
14) Added guidance regarding review of safety data and consultation with the Gilead medical monitor regarding dose adjustment for subjects who turn 66 years of age during the study.
15) Revised the instructions for dose modification.
16) Updated to reflect change of primary endpoint to Week 24, consistent with revised dosing regimen.
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13 Nov 2015 |
1) Updated the protocol title to reflect the name change of GS-6615 to eleclazine
5) Updated objectives and study endpoints to align with what was agreed
to with the FDA and in the current Statistical Analysis Plan dated 06 February 2015
6) Revised Inclusion Criteria 2 to increase the age limit to 70 (inclusive)
7) Revised Inclusion Criteria 3 to remove the 6 month genotype requirement
8) Revised Inclusion Criterion 4 to reflect the decreased ECG collection time points
9) Added new exclusion criteria to exclude subjects with known severe obstructive sleep apnea that is not treated
10) Revised Exclusion Criteria 5 to increase the BMI to 40 kg/m2 (inclusive)
11) Revised Exclusion Criteria 17 to clarify that clinically significant planned elective invasive surgeries or procedures should be avoided during the single blind treatment period only
12) Modified the number of ECG collection time points at the screening visit
13) Updated Holter monitor recording requirements from 48 hours to 24 hours for each study visit
14) Revised the window for when plasma predose PK sample is to be collected for each visit
15) Revised PK sampling time points at each visit
16) Revised language in Section 8 regarding presentation of PK parameters
in population PK report
17) Removed language referencing ZIO® XT Patch country restrictions
18) Corrected GFR MDRD equation in Appendix 6
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| None reported | |||||||
