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Trial record 49 of 74 for:    "Andersen-Tawil syndrome" OR "Long QT Syndrome"

Ability of Late Sodium or Calcium Current Block to Balance the ECG Effects of Potassium Current Block

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02308748
Recruitment Status : Completed
First Posted : December 4, 2014
Results First Posted : June 8, 2016
Last Update Posted : June 8, 2016
Sponsor:
Collaborator:
Spaulding Clinical Research LLC
Information provided by (Responsible Party):
Food and Drug Administration (FDA)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Basic Science
Conditions Drug-induced QT Prolongation
Pharmacokinetics
Pharmacodynamics
Interventions Drug: Dofetilide
Drug: Mexiletine
Drug: Lidocaine
Drug: Moxifloxacin
Drug: Diltiazem
Drug: Placebo
Enrollment 22
Recruitment Details  
Pre-assignment Details 44 healthy volunteers were assessed for eligibility. 15 subjects were excluded because they did not meet the inclusion criteria. 22 of 29 subjects who met the inclusion criteria were randomized and allocated to receive crossed-over intervention. Williams Latin square design balanced for first-order carryover effects was used for randomization.
Arm/Group Title A-D-E-C-B B-C-E-D-A C-D-B-A-E D-C-A-B-E E-A-B-D-C D-A-C-E-B E-B-A-C-D A-E-D-B-C B-E-C-A-D C-B-D-E-A
Hide Arm/Group Description

All subjects received the same 5 treatments, separated by 6 days of washout, but were randomized to receive them in different orders. Subjects in this arm received them in the following order:

Treatment A (dofetilide) Treatment D (moxifloxacin + diltiazem) Treatment E (placebo) Treatment C (dofetilide + mexiletine) Treatment B (dofetilide + lidocaine)

All subjects received the same 5 treatments, separated by 6 days of washout, but were randomized to receive them in different orders. Subjects in this arm received them in the following order:

Treatment B (dofetilide + lidocaine) Treatment C (dofetilide + mexiletine) Treatment E (placebo) Treatment D (moxifloxacin + diltiazem) Treatment A (dofetilide)

All subjects received the same 5 treatments, separated by 6 days of washout, but were randomized to receive them in different orders. Subjects in this arm received them in the following order:

Treatment C (dofetilide + mexiletine) Treatment D (moxifloxacin + diltiazem) Treatment B (dofetilide + lidocaine) Treatment A (dofetilide) Treatment E (placebo)

All subjects received the same 5 treatments, separated by 6 days of washout, but were randomized to receive them in different orders. Subjects in this arm received them in the following order:

Treatment D (moxifloxacin + diltiazem) Treatment C (dofetilide + mexiletine) Treatment A (dofetilide) Treatment B (dofetilide + lidocaine) Treatment E (placebo)

All subjects received the same 5 treatments, separated by 6 days of washout, but were randomized to receive them in different orders. Subjects in this arm received them in the following order:

Treatment E (placebo) Treatment A (dofetilide) Treatment B (dofetilide + lidocaine) Treatment D (moxifloxacin + diltiazem) Treatment C (dofetilide + mexiletine)

All subjects received the same 5 treatments, separated by 6 days of washout, but were randomized to receive them in different orders. Subjects in this arm received them in the following order:

Treatment D (moxifloxacin + diltiazem) Treatment A (dofetilide) Treatment C (dofetilide + mexiletine) Treatment E (placebo) Treatment B (dofetilide + lidocaine)

All subjects received the same 5 treatments, separated by 6 days of washout, but were randomized to receive them in different orders. Subjects in this arm received them in the following order:

Treatment E (placebo) Treatment B (dofetilide + lidocaine) Treatment A (dofetilide) Treatment C (dofetilide + mexiletine) Treatment D (moxifloxacin + diltiazem)

All subjects received the same 5 treatments, separated by 6 days of washout, but were randomized to receive them in different orders. Subjects in this arm received them in the following order:

Treatment A (dofetilide) Treatment E (placebo) Treatment D (moxifloxacin + diltiazem) Treatment B (dofetilide + lidocaine) Treatment C (dofetilide + mexiletine)

All subjects received the same 5 treatments, separated by 6 days of washout, but were randomized to receive them in different orders. Subjects in this arm received them in the following order:

Treatment B (dofetilide + lidocaine) Treatment E (placebo) Treatment C (dofetilide + mexiletine) Treatment A (dofetilide) Treatment D (moxifloxacin + diltiazem)

All subjects received the same 5 treatments, separated by 6 days of washout, but were randomized to receive them in different orders. Subjects in this arm received them in the following order:

Treatment C (dofetilide + mexiletine) Treatment B (dofetilide + lidocaine) Treatment D (moxifloxacin + diltiazem) Treatment E (placebo) Treatment A (dofetilide)

Period Title: Period 1
Started 2 2 2 2 2 3 2 2 2 3
Completed 2 2 1 [1] 2 2 3 2 2 2 3
Not Completed 0 0 1 0 0 0 0 0 0 0
Reason Not Completed
Withdrawal by Subject             0             0             1             0             0             0             0             0             0             0
[1]
One subject withdraw consent before starting Period 2
Period Title: Period 2
Started 2 2 1 2 2 3 2 2 2 3
Completed 2 2 1 2 2 3 2 1 2 3
Not Completed 0 0 0 0 0 0 0 1 0 0
Reason Not Completed
Adverse Event             0             0             0             0             0             0             0             1             0             0
Period Title: Period 3
Started 2 2 1 2 2 3 2 1 2 3
Completed 2 2 1 2 2 3 2 1 2 2
Not Completed 0 0 0 0 0 0 0 0 0 1
Reason Not Completed
Protocol Violation             0             0             0             0             0             0             0             0             0             1
Period Title: Period 4
Started 2 2 1 2 2 3 2 1 2 2
Completed 2 2 1 2 2 3 2 1 2 2
Not Completed 0 0 0 0 0 0 0 0 0 0
Period Title: Period 5
Started 2 2 1 2 2 3 2 1 2 2
Completed 1 2 1 2 2 3 2 1 1 2
Not Completed 1 0 0 0 0 0 0 0 1 0
Reason Not Completed
Adverse Event             1             0             0             0             0             0             0             0             1             0
Arm/Group Title All Study Participants
Hide Arm/Group Description Participants who were randomized to receive either dofetilide alone, dofetilide + mexiletine, dofetilide + lidocaine, moxifloxacin + diltiazem or placebo.
Overall Number of Baseline Participants 22
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 22 participants
26.1  (4.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants
Female
9
  40.9%
Male
13
  59.1%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants
Hispanic or Latino
2
   9.1%
Not Hispanic or Latino
20
  90.9%
Unknown or Not Reported
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants
American Indian or Alaska Native
1
   4.5%
Asian
1
   4.5%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
10
  45.5%
White
10
  45.5%
More than one race
0
   0.0%
Unknown or Not Reported
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 22 participants
22
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 22 participants
69.9  (9.0)
Systolic blood pressure  
Mean (Standard Deviation)
Unit of measure:  Mm Hg
Number Analyzed 22 participants
109.5  (5.5)
Diastolic blood pressure  
Mean (Standard Deviation)
Unit of measure:  Mm Hg
Number Analyzed 22 participants
60.2  (3.5)
Heart rate  
Mean (Standard Deviation)
Unit of measure:  Beats per minute (bpm)
Number Analyzed 22 participants
61.3  (6.7)
PR interval  
Mean (Standard Deviation)
Unit of measure:  Ms
Number Analyzed 22 participants
160.8  (19.1)
QRS duration  
Mean (Standard Deviation)
Unit of measure:  Ms
Number Analyzed 22 participants
86.7  (8.5)
J-Tpeakc (heart rate corrected J-Tpeak interval)  
Mean (Standard Deviation)
Unit of measure:  Ms
Number Analyzed 22 participants
229.5  (19.0)
Tpeak-Tend interval  
Mean (Standard Deviation)
Unit of measure:  Ms
Number Analyzed 22 participants
81.9  (6.4)
QTc (Fridericia's heart rate corrected QT interval)  
Mean (Standard Deviation)
Unit of measure:  Ms
Number Analyzed 22 participants
397.8  (14.2)
1.Primary Outcome
Title Change in Placebo Corrected Change From Baseline QTc and J-Tpeakc Intervals on the ECG Measured in Milliseconds When Dofetilide is Administered With Mexiletine or Lidocaine Compared to When Dofetilide is Administered Alone at Evening Dose on Treatment Day
Hide Description After 3rd dose of mexiletine or lidocaine (evening dose) on treatment day when combined with dofetilide to evening dose on dofetilide alone day.
Time Frame 5 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All study participants that completed placebo and dofetilide alone as well as dofetilide + mexiletine and/or dofetilide + lidocaine
Arm/Group Title Dofetilide Alone Dofetilide + Mexiletine Dofetilide + Lidocaine
Hide Arm/Group Description:
Subjects that completed placebo and dofetilide alone interventions
Subjects that completed placebo and dofetilide + mexiletine interventions
Subjects that completed placebo and dofetilide + lidocaine interventions
Overall Number of Participants Analyzed 20 20 18
Mean (95% Confidence Interval)
Unit of Measure: ms
Placebo corrected change from baseline in QTc
37.9
(32.6 to 43.1)
20.4
(15.1 to 25.6)
18
(12.7 to 23.3)
Placebo corrected change from baseline in J-Tpeakc
24.0
(19.2 to 28.9)
0.8
(-4.0 to 5.6)
3.5
(-1.4 to 8.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dofetilide Alone, Dofetilide + Mexiletine
Comments Change in QTc interval on the ECG measured in milliseconds when dofetilide is administered with mexiletine compared to when dofetilide is administered alone at evening dose on treatment day.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.025
Comments Adjustment for multiple comparisons was performed according to the Bonferroni method.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -19.8
Confidence Interval (2-Sided) 95%
-25.2 to -14.3
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Dofetilide Alone, Dofetilide + Lidocaine
Comments Change in QTc interval on the ECG measured in milliseconds when dofetilide is administered with lidocaine compared to when dofetilide is administered alone at evening dose on treatment day.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.025
Comments Adjustment for multiple comparisons was performed according to the Bonferroni method.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -19.7
Confidence Interval (2-Sided) 95%
-25.2 to -14.1
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Dofetilide Alone, Dofetilide + Mexiletine
Comments Change in J-Tpeakc interval on the ECG measured in milliseconds when dofetilide is administered with mexiletine compared to when dofetilide is administered alone at evening dose on treatment day.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.025
Comments Adjustment for multiple comparisons was performed according to the Bonferroni method.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -23.2
Confidence Interval (2-Sided) 95%
-28.0 to -18.3
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Dofetilide Alone, Dofetilide + Lidocaine
Comments Change in J-Tpeakc interval on the ECG measured in milliseconds when dofetilide is administered with lidocaine compared to when dofetilide is administered alone at evening dose on treatment day.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.025
Comments Adjustment for multiple comparisons was performed according to the Bonferroni method.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -20.5
Confidence Interval (2-Sided) 95%
-25.5 to -15.5
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change in Placebo Corrected Change From Baseline QTc Interval on the ECG Measured in Milliseconds When Moxifloxacin is Administered With Diltiazem at the Evening Dose Compared to When Moxifloxacin is Administered Alone at Afternoon Dose on Treatment Day.
Hide Description Evening dose (moxifloxacin+diltiazem) versus afternoon dose (diltiazem alone).
Time Frame 5 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All study participants that completed placebo, moxifloxacin and moxifloxacin + diltiazem
Arm/Group Title Moxifloxacin Alone Moxifloxacin + Diltiazem
Hide Arm/Group Description:
Subjects that completed placebo and moxifloxacin alone interventions
Subjects that completed placebo and moxifloxacin + diltiazem interventions
Overall Number of Participants Analyzed 19 19
Mean (95% Confidence Interval)
Unit of Measure: ms
29.9
(24.6 to 35.2)
31.3
(26.0 to 36.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Moxifloxacin Alone, Moxifloxacin + Diltiazem
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.025
Comments Adjustment for multiple comparisons was performed according to the Bonferroni method.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2.9
Confidence Interval (2-Sided) 95%
-1 to 6.7
Estimation Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Dofetilide Dofetilide + Lidocaine Dofetilide + Mexiletine Moxifloxacin + Diltiazem Placebo
Hide Arm/Group Description

Dofetilide alone arm

Dofetilide: • 8 am: Placebo

  • 12 pm (noon): 250 µg
  • 5:30 pm: 250 µg

Dofetilide combined with lidocaine

Dofetilide: • 8 am: Placebo

  • 12 pm (noon): 250 µg
  • 5:30 pm: 250 µg

Lidocaine: • 9 am : 30 µg/min per kg (loading) for 60 minutes and 10 µg/min per kg (maintenance) for 30 minutes

  • 2 pm: 55 µg/min per kg (loading) for 60 minutes and 20 µg/min per kg (maintenance) for 30 minutes
  • 7:30 pm: 52 µg/min per kg (loading) for 60 minutes and 20 µg/min per kg (maintenance) for 30 minutes

Dofetilide combined with mexiletine

Dofetilide: • 8 am: Placebo

  • 12 pm (noon): 250 µg
  • 5:30 pm: 250 µg

Mexiletine: • 8 am: weight x 4 mg/kg

  • 12 pm (noon): Same as at 8 am
  • 5:30 pm: Same as at 8 am

Moxifloxacin with and without diltiazem.

Moxifloxacin: • 9 am: 5.63 mg/h per kg (loading) for 1 hour and 0.26 mg/h per kg (maintenance for 30 minutes)

  • 2 pm: 6.14 mg/h per kg (loading) for 1 hour and 0.49 mg/h per kg (maintenance for 30 minutes)
  • 7:30 pm: 2.23 mg/h per kg (loading) for 1 hour and 0.49 mg/h per kg (maintenance for 30 minutes)

Diltiazem: • 7:30 pm: 330 µg/h per kg (loading) for 60 minutes and 61 µg/h per kg (maintenance) for 30 minutes

Placebo (#2 gelcap and intravenous saline)

Placebo: Placebo (#2 Gelcap or IV saline)

All-Cause Mortality
Dofetilide Dofetilide + Lidocaine Dofetilide + Mexiletine Moxifloxacin + Diltiazem Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Dofetilide Dofetilide + Lidocaine Dofetilide + Mexiletine Moxifloxacin + Diltiazem Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/20 (0.00%)      0/19 (0.00%)      0/21 (0.00%)      0/20 (0.00%)      0/20 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Dofetilide Dofetilide + Lidocaine Dofetilide + Mexiletine Moxifloxacin + Diltiazem Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/20 (15.00%)      1/19 (5.26%)      11/21 (52.38%)      6/20 (30.00%)      3/20 (15.00%)    
Gastrointestinal disorders           
Nausea * 1  1/20 (5.00%)  1 0/19 (0.00%)  4/21 (19.05%)  4 3/20 (15.00%)  3 2/20 (10.00%)  2
Vomiting * 1  1/20 (5.00%)  1 0/19 (0.00%)  1/21 (4.76%)  1 1/20 (5.00%)  1 0/20 (0.00%) 
Nervous system disorders           
Dizzines * 1  1/20 (5.00%)  1 1/19 (5.26%)  1 6/21 (28.57%)  6 2/20 (10.00%)  2 1/20 (5.00%)  1
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (10.0)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT 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.
Results Point of Contact
Name/Title: David G Strauss, MD, PhD
Organization: U.S. Food and Drug Administration
Phone: 301-796-6323
Responsible Party: Food and Drug Administration (FDA)
ClinicalTrials.gov Identifier: NCT02308748     History of Changes
Other Study ID Numbers: 14-022D
SCR-003 ( Other Identifier: Spaulding Clinical Research )
First Submitted: November 6, 2014
First Posted: December 4, 2014
Results First Submitted: January 13, 2016
Results First Posted: June 8, 2016
Last Update Posted: June 8, 2016