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Effect of Eleclazine on Shortening of the QT Interval, Safety, and Tolerability in Adults With Long QT Syndrome Type 3

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ClinicalTrials.gov Identifier: NCT02300558
Recruitment Status : Terminated
First Posted : November 25, 2014
Results First Posted : January 12, 2018
Last Update Posted : January 12, 2018
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: Single (Participant);   Primary Purpose: Treatment
Condition Long QT Syndrome Type 3
Interventions Drug: Eleclazine
Drug: Eleclazine placebo
Enrollment 41
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.
Arm/Group Title Eleclazine
Hide Arm/Group Description
  • 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
Period Title: Single Blind Phase (24 Weeks)
Started 41
Completed 35
Not Completed 6
Reason Not Completed
Study Terminated by Sponsor             6
Period Title: Open-Label (OL) Extension Phase
Started [1] 32
Completed 0
Not Completed 32
Reason Not Completed
Lack of Efficacy             2
Withdrew Consent             1
Study Terminated by Sponsor             29
[1]
3 participants completed the single-blind phase (24 weeks) but did not continue to OL Extension.
Arm/Group Title Eleclazine
Hide Arm/Group Description
  • 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
Overall Number of Baseline Participants 41
Hide Baseline Analysis Population Description
Safety Analysis Set: participants who received at least 1 dose of study drug (either active or placebo).
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 41 participants
46  (12.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 41 participants
Female
24
  58.5%
Male
17
  41.5%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 41 participants
American Indian or Alaska Native
1
   2.4%
Asian
1
   2.4%
Black or African American
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
White
36
  87.8%
Not Permitted
1
   2.4%
Other
2
   4.9%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 41 participants
Hispanic or Latino
0
   0.0%
Not Hispanic or Latino
40
  97.6%
Not Permitted
1
   2.4%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 41 participants
Canada
1
   2.4%
Netherlands
3
   7.3%
United States
11
  26.8%
Italy
12
  29.3%
United Kingdom
1
   2.4%
Israel
3
   7.3%
France
9
  22.0%
Germany
1
   2.4%
Mean Daytime QTcF Lead V5 (Standard 12-lead ECG)   [1] 
Mean (Standard Deviation)
Unit of measure:  Msec
Number Analyzed 41 participants
507.5  (38.11)
[1]
Measure Description:
  • 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 Daily QTcF in Lead V5 (Holter)   [1] 
Mean (Standard Deviation)
Unit of measure:  Msec
Number Analyzed 41 participants
514.7  (45.76)
[1]
Measure Description:
  • 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 Nocturnal QTcF in Lead V5 (Holter)   [1] 
Mean (Standard Deviation)
Unit of measure:  Msec
Number Analyzed 41 participants
530.6  (52.25)
[1]
Measure Description:

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.

1.Primary Outcome
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)
Hide Description
  • 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Eleclazine
Hide Arm/Group Description:
  • 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
Overall Number of Participants Analyzed 35
Mean (Standard Deviation)
Unit of Measure: msec
-8.5  (18.03)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Eleclazine
Comments 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.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0087
Comments [Not Specified]
Method paired t- test
Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline in Mean Daytime QTcF Interval (AUC0-6/6) to Week 12 (Lead V5; Standard 12-lead ECG)
Hide Description
  • 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
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Full Analysis Set with available data were analyzed.
Arm/Group Title Eleclazine
Hide Arm/Group Description:
  • 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
Overall Number of Participants Analyzed 40
Mean (95% Confidence Interval)
Unit of Measure: msec
2.2
(-4.7 to 9.2)
3.Secondary Outcome
Title Change From Baseline in Mean Daily (Daytime and Nocturnal) QTcF Interval to Week 24 (Lead V5; Holter)
Hide Description
  • 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
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Full Analysis Set with available data were analyzed.
Arm/Group Title Eleclazine
Hide Arm/Group Description:
  • 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
Overall Number of Participants Analyzed 30
Mean (95% Confidence Interval)
Unit of Measure: msec
-1.8
(-13.6 to 10.0)
4.Secondary Outcome
Title Change From Baseline in Mean Nocturnal QTcF Interval to Week 24 (Lead V5; Holter)
Hide Description
  • 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
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the the Full Analysis Set with available data were analyzed.
Arm/Group Title Eleclazine
Hide Arm/Group Description:
  • 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
Overall Number of Participants Analyzed 31
Mean (95% Confidence Interval)
Unit of Measure: msec
-3.0
(-17.1 to 11.0)
Time Frame Day 1 to the last dose date plus 30 days (median exposure to eleclazine: 396 days)
Adverse Event Reporting Description Safety Analysis Set
 
Arm/Group Title Placebo Eleclazine Loading Dose (LD) 48 mg Eleclazine Maintenance Dose (MD) 3 mg Eleclazine MD 6 mg All Eleclazine
Hide Arm/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) administered orally on Day 2 Eleclazine 3 mg (1 x 3 mg tablet) administered once daily from Day 3 to the Week 12 Visit 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.
  • 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.

All-Cause Mortality
Placebo Eleclazine Loading Dose (LD) 48 mg Eleclazine Maintenance Dose (MD) 3 mg Eleclazine MD 6 mg All Eleclazine
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/41 (0.00%)   0/41 (0.00%)   0/41 (0.00%)   0/41 (0.00%)   0/41 (0.00%) 
Hide Serious Adverse Events
Placebo Eleclazine Loading Dose (LD) 48 mg Eleclazine Maintenance Dose (MD) 3 mg Eleclazine MD 6 mg All Eleclazine
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/41 (0.00%)   0/41 (0.00%)   1/41 (2.44%)   0/41 (0.00%)   1/41 (2.44%) 
Renal and urinary disorders           
Nephrolithiasis  1  0/41 (0.00%)  0/41 (0.00%)  1/41 (2.44%)  0/41 (0.00%)  1/41 (2.44%) 
1
Term from vocabulary, MedDRA 19.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Eleclazine Loading Dose (LD) 48 mg Eleclazine Maintenance Dose (MD) 3 mg Eleclazine MD 6 mg All Eleclazine
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   5/41 (12.20%)   5/41 (12.20%)   17/41 (41.46%)   14/41 (34.15%)   24/41 (58.54%) 
Ear and labyrinth disorders           
Vertigo  1  1/41 (2.44%)  2/41 (4.88%)  0/41 (0.00%)  2/41 (4.88%)  3/41 (7.32%) 
Gastrointestinal disorders           
Diarrhoea  1  0/41 (0.00%)  0/41 (0.00%)  3/41 (7.32%)  1/41 (2.44%)  4/41 (9.76%) 
Nausea  1  0/41 (0.00%)  1/41 (2.44%)  3/41 (7.32%)  0/41 (0.00%)  4/41 (9.76%) 
General disorders           
Asthenia  1  1/41 (2.44%)  0/41 (0.00%)  2/41 (4.88%)  1/41 (2.44%)  3/41 (7.32%) 
Fatigue  1  0/41 (0.00%)  0/41 (0.00%)  3/41 (7.32%)  2/41 (4.88%)  5/41 (12.20%) 
Infections and infestations           
Influenza  1  0/41 (0.00%)  0/41 (0.00%)  3/41 (7.32%)  3/41 (7.32%)  6/41 (14.63%) 
Nasopharyngitis  1  0/41 (0.00%)  0/41 (0.00%)  2/41 (4.88%)  2/41 (4.88%)  4/41 (9.76%) 
Investigations           
Weight increased  1  0/41 (0.00%)  0/41 (0.00%)  1/41 (2.44%)  2/41 (4.88%)  3/41 (7.32%) 
Musculoskeletal and connective tissue disorders           
Arthralgia  1  1/41 (2.44%)  0/41 (0.00%)  0/41 (0.00%)  2/41 (4.88%)  2/41 (4.88%) 
Back pain  1  0/41 (0.00%)  0/41 (0.00%)  3/41 (7.32%)  0/41 (0.00%)  3/41 (7.32%) 
Nervous system disorders           
Dizziness  1  0/41 (0.00%)  2/41 (4.88%)  2/41 (4.88%)  0/41 (0.00%)  4/41 (9.76%) 
Headache  1  2/41 (4.88%)  1/41 (2.44%)  2/41 (4.88%)  4/41 (9.76%)  6/41 (14.63%) 
1
Term from vocabulary, MedDRA 19.1
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Clinical Trial Disclosures
Organization: Gilead Sciences
EMail: ClinicalTrialDisclosures@gilead.com
Layout table for additonal information
Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT02300558    
Other Study ID Numbers: GS-US-372-1234
2014-000042-30 ( EudraCT Number )
First Submitted: November 21, 2014
First Posted: November 25, 2014
Results First Submitted: December 12, 2017
Results First Posted: January 12, 2018
Last Update Posted: January 12, 2018