Trial Outcomes & Findings for Ability of Late Sodium or Calcium Current Block to Balance the ECG Effects of Potassium Current Block (NCT NCT02308748)
NCT ID: NCT02308748
Last Updated: 2016-06-08
Results Overview
After 3rd dose of mexiletine or lidocaine (evening dose) on treatment day when combined with dofetilide to evening dose on dofetilide alone day.
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
22 participants
Primary outcome timeframe
5 weeks
Results posted on
2016-06-08
Participant Flow
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.
Participant milestones
| Measure |
A-D-E-C-B
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)
|
B-C-E-D-A
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)
|
C-D-B-A-E
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)
|
D-C-A-B-E
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)
|
E-A-B-D-C
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)
|
D-A-C-E-B
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)
|
E-B-A-C-D
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)
|
A-E-D-B-C
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)
|
B-E-C-A-D
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)
|
C-B-D-E-A
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)
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|---|---|---|---|---|---|---|---|---|---|---|
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Period 1
STARTED
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2
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2
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Period 1
COMPLETED
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2
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2
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1
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2
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2
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2
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2
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Period 1
NOT COMPLETED
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0
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0
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1
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0
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0
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0
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0
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0
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0
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0
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Period 2
STARTED
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2
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Period 2
COMPLETED
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2
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2
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1
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Period 2
NOT COMPLETED
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0
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0
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0
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0
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0
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0
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0
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1
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0
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0
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Period 3
STARTED
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2
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1
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2
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Period 3
COMPLETED
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2
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2
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1
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2
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2
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2
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1
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2
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2
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Period 3
NOT COMPLETED
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0
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0
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0
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0
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0
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0
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0
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0
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0
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1
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Period 4
STARTED
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1
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2
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Period 4
COMPLETED
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2
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2
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1
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2
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2
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3
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2
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1
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2
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2
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Period 4
NOT COMPLETED
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0
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0
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0
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0
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0
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0
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0
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0
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0
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0
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Period 5
STARTED
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2
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2
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1
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2
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1
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2
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Period 5
COMPLETED
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1
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2
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1
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2
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2
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3
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2
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1
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1
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2
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Period 5
NOT COMPLETED
|
1
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0
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0
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0
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0
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0
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0
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0
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1
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0
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Reasons for withdrawal
| Measure |
A-D-E-C-B
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)
|
B-C-E-D-A
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)
|
C-D-B-A-E
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)
|
D-C-A-B-E
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)
|
E-A-B-D-C
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)
|
D-A-C-E-B
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)
|
E-B-A-C-D
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)
|
A-E-D-B-C
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)
|
B-E-C-A-D
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)
|
C-B-D-E-A
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 1
Withdrawal by Subject
|
0
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0
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1
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0
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0
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0
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0
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0
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0
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0
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Period 2
Adverse Event
|
0
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0
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0
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0
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0
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0
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0
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1
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0
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0
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Period 3
Protocol Violation
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0
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0
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0
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0
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0
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0
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0
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0
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0
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1
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Period 5
Adverse Event
|
1
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0
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0
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0
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0
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0
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0
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0
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1
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0
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Baseline Characteristics
Ability of Late Sodium or Calcium Current Block to Balance the ECG Effects of Potassium Current Block
Baseline characteristics by cohort
| Measure |
All Study Participants
n=22 Participants
Participants who were randomized to receive either dofetilide alone, dofetilide + mexiletine, dofetilide + lidocaine, moxifloxacin + diltiazem or placebo.
|
|---|---|
|
Age, Continuous
|
26.1 years
STANDARD_DEVIATION 4.9 • n=5 Participants
|
|
Sex: Female, Male
Female
|
9 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
13 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
2 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
20 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
1 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
|
1 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Black or African American
|
10 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
10 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
|
Region of Enrollment
United States
|
22 participants
n=5 Participants
|
|
Weight
|
69.9 kg
STANDARD_DEVIATION 9.0 • n=5 Participants
|
|
Systolic blood pressure
|
109.5 mm Hg
STANDARD_DEVIATION 5.5 • n=5 Participants
|
|
Diastolic blood pressure
|
60.2 mm Hg
STANDARD_DEVIATION 3.5 • n=5 Participants
|
|
Heart rate
|
61.3 beats per minute (bpm)
STANDARD_DEVIATION 6.7 • n=5 Participants
|
|
PR interval
|
160.8 ms
STANDARD_DEVIATION 19.1 • n=5 Participants
|
|
QRS duration
|
86.7 ms
STANDARD_DEVIATION 8.5 • n=5 Participants
|
|
J-Tpeakc (heart rate corrected J-Tpeak interval)
|
229.5 ms
STANDARD_DEVIATION 19.0 • n=5 Participants
|
|
Tpeak-Tend interval
|
81.9 ms
STANDARD_DEVIATION 6.4 • n=5 Participants
|
|
QTc (Fridericia's heart rate corrected QT interval)
|
397.8 ms
STANDARD_DEVIATION 14.2 • n=5 Participants
|
PRIMARY outcome
Timeframe: 5 weeksPopulation: All study participants that completed placebo and dofetilide alone as well as dofetilide + mexiletine and/or dofetilide + lidocaine
After 3rd dose of mexiletine or lidocaine (evening dose) on treatment day when combined with dofetilide to evening dose on dofetilide alone day.
Outcome measures
| Measure |
Dofetilide Alone
n=20 Participants
Subjects that completed placebo and dofetilide alone interventions
|
Dofetilide + Mexiletine
n=20 Participants
Subjects that completed placebo and dofetilide + mexiletine interventions
|
Dofetilide + Lidocaine
n=18 Participants
Subjects that completed placebo and dofetilide + lidocaine interventions
|
|---|---|---|---|
|
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
Placebo corrected change from baseline in QTc
|
37.9 ms
Interval 32.6 to 43.1
|
20.4 ms
Interval 15.1 to 25.6
|
18 ms
Interval 12.7 to 23.3
|
|
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
Placebo corrected change from baseline in J-Tpeakc
|
24.0 ms
Interval 19.2 to 28.9
|
0.8 ms
Interval -4.0 to 5.6
|
3.5 ms
Interval -1.4 to 8.4
|
SECONDARY outcome
Timeframe: 5 weeksPopulation: All study participants that completed placebo, moxifloxacin and moxifloxacin + diltiazem
Evening dose (moxifloxacin+diltiazem) versus afternoon dose (diltiazem alone).
Outcome measures
| Measure |
Dofetilide Alone
n=19 Participants
Subjects that completed placebo and dofetilide alone interventions
|
Dofetilide + Mexiletine
n=19 Participants
Subjects that completed placebo and dofetilide + mexiletine interventions
|
Dofetilide + Lidocaine
Subjects that completed placebo and dofetilide + lidocaine interventions
|
|---|---|---|---|
|
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.
|
29.9 ms
Interval 24.6 to 35.2
|
31.3 ms
Interval 26.0 to 36.6
|
—
|
Adverse Events
Dofetilide
Serious events: 0 serious events
Other events: 3 other events
Deaths: 0 deaths
Dofetilide + Lidocaine
Serious events: 0 serious events
Other events: 1 other events
Deaths: 0 deaths
Dofetilide + Mexiletine
Serious events: 0 serious events
Other events: 11 other events
Deaths: 0 deaths
Moxifloxacin + Diltiazem
Serious events: 0 serious events
Other events: 6 other events
Deaths: 0 deaths
Placebo
Serious events: 0 serious events
Other events: 3 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Dofetilide
n=20 participants at risk
Dofetilide alone arm
Dofetilide: • 8 am: Placebo
* 12 pm (noon): 250 µg
* 5:30 pm: 250 µg
|
Dofetilide + Lidocaine
n=19 participants at risk
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 + Mexiletine
n=21 participants at risk
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 + Diltiazem
n=20 participants at risk
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
n=20 participants at risk
Placebo (#2 gelcap and intravenous saline)
Placebo: Placebo (#2 Gelcap or IV saline)
|
|---|---|---|---|---|---|
|
Nervous system disorders
Dizzines
|
5.0%
1/20 • Number of events 1
|
5.3%
1/19 • Number of events 1
|
28.6%
6/21 • Number of events 6
|
10.0%
2/20 • Number of events 2
|
5.0%
1/20 • Number of events 1
|
|
Gastrointestinal disorders
Nausea
|
5.0%
1/20 • Number of events 1
|
0.00%
0/19
|
19.0%
4/21 • Number of events 4
|
15.0%
3/20 • Number of events 3
|
10.0%
2/20 • Number of events 2
|
|
Gastrointestinal disorders
Vomiting
|
5.0%
1/20 • Number of events 1
|
0.00%
0/19
|
4.8%
1/21 • Number of events 1
|
5.0%
1/20 • Number of events 1
|
0.00%
0/20
|
Additional Information
David G Strauss, MD, PhD
U.S. Food and Drug Administration
Phone: 301-796-6323
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place