Drug-induced QT Prolongation, Pharmacokinetics, Pharmacodynamics
Conditions
Brief summary
The primary objective of this research study is to test the hypothesis that late sodium current blocking drugs (mexiletine or lidocaine) can attenuate the effect of hERG potassium channel blocking drugs (dofetilide) on ventricular repolarization (QTc) by shortening early repolarization (J-Tpeakc). The secondary object is to assess the ability of calcium channel block (diltiazem) to reduce the QTc prolongation associated with hERG block (moxifloxacin).
Detailed description
This is a randomized, double-blind, 5-period crossover study in healthy male and female subjects, 18 to 35 years of age, to compare the electrophysiological response of hERG potassium channel blocking drugs with and without the addition of late sodium or calcium channel blocking drugs. The 5 treatment periods are 1) dofetilide alone, 2) mexiletine with and without dofetilide, 3) lidocaine with and without dofetilide, 4) moxifloxacin with and without diltiazem and 5) placebo. During each treatment period, 12 blood samples for pharmacokinetic measurements are obtained with matched 12-lead ECG recordings.
Interventions
DRUGDofetilide
* 8 am: Placebo * 12 pm (noon): 250 µg * 5:30 pm: 250 µg
DRUGMexiletine
* 8 am: weight x 4 mg/kg * 12 pm (noon): Same as at 8 am * 5:30 pm: Same as at 8 am
DRUGLidocaine
* 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
DRUGMoxifloxacin
* 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)
DRUGDiltiazem
• 7:30 pm: 330 µg/h per kg (loading) for 60 minutes and 61 µg/h per kg (maintenance) for 30 minutes
DRUGPlacebo
Placebo (#2 Gelcap or IV saline)
Sponsors
Spaulding Clinical Research LLC
Food and Drug Administration (FDA)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 35 Years
Healthy volunteers
Yes
Inclusion criteria
1. Subject is a healthy man or woman, 18 to 35 years of age, inclusive, who weighs at least 50 kg (110 pounds), no more than 85 kg (197 pounds) and has a body mass index of 18 to 27 kg/m2, inclusive, at Screening. 2. Subject has normal medical history findings, clinical laboratory results, vital sign measurements, 12 lead ECG results, and physical examination findings at Screening or, if abnormal, the abnormality is not considered clinically significant (as determined and documented by the investigator or designee). 3. Male or female subjects must agree to practice 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique) from Screening until 30 days after the last dose of study drug.
Exclusion criteria
* 1\. Subject has a 12 lead safety ECG result at Screening or Check in of Period 1 with evidence of any of the following abnormalities: * QT corrected interval (QTc) using Fridericia correction (QTcF) \>430 milliseconds (ms) * PR interval \>220 ms or \<120 ms * QRS duration \>110 ms * Second- or third-degree atrioventricular block * Complete left or right bundle branch block or incomplete right bundle branch block * Heart rate \<50 or \>90 beats per minute * Pathological Q-waves (defined as Q wave \>40 ms) * Ventricular pre-excitation 2\. Subject has more than 12 ectopic beats during the 3 hour Holter ECG at Screening. 3\. Subject has a history of unexplained syncope, structural heart disease, long QT syndrome, heart failure, myocardial infarction, angina, unexplained cardiac arrhythmia, torsades de pointes, ventricular tachycardia, or placement of a pacemaker or implantable defibrillator. Subjects will also be excluded if there is a family history of long QT syndrome (genetically proven or suggested by sudden death of a close relative due to cardiac causes at a young age) or Brugada syndrome. 4\. Subject has a history or current evidence of any clinically significant (as determined by the investigator) cardiovascular, dermatologic, endocrine, gastrointestinal, hematologic, hepatic, immunologic, metabolic, neurologic, psychiatric, pulmonary, renal, urologic, and/or other major disease or malignancy (excluding nonmelanoma skin cancer). The investigator may allow exceptions to these criteria (e.g., stable mild joint disease \[that will not interfere with or influence the activities required by the protocol, in the opinion of the investigator\], cholecystectomy, childhood asthma) following discussion with the medical monitor. 5\. Subject has a history of thoracic surgery. 6\. Subject has any condition possibly affecting study drug absorption (e.g., gastrectomy, Crohn's disease, irritable bowel syndrome). 7\. Subject has a skin condition likely to compromise ECG electrode placement. 8\. Subject is a female with breast implants. 9\. Subject's laboratory test results at Screening or Check in of Period 1 are outside the reference ranges provided by the clinical laboratory and considered clinically significant (as determined and documented by the investigator or designee). 10\. Subject's laboratory test results at Screening or Check in of Period 1 indicate hypokalemia, hypocalcemia, or hypomagnesemia according to lower limits of the reference ranges provided by the clinical laboratory. 11\. Subject's laboratory test results at Screening or Check in of Period 1 are \>2 × the upper limit of normal (ULN) for alanine aminotransferase or aspartate aminotransferase, \>1.5 × ULN for bilirubin, or \>1.5 × ULN for creatinine. 12\. Subject has a positive test result at Screening for human immunodeficiency virus, hepatitis C antibodies, or hepatitis B surface antigen. 13\. Subject has a mean systolic blood pressure \<90 or \>140 mmHg or a mean diastolic blood pressure \<50 or \>90 mmHg at either Screening or Check in of Period 1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 5 weeks | After 3rd dose of mexiletine or lidocaine (evening dose) on treatment day when combined with dofetilide to evening dose on dofetilide alone day. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 5 weeks | Evening dose (moxifloxacin+diltiazem) versus afternoon dose (diltiazem alone). |
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Participants who were randomized to receive either dofetilide alone, dofetilide + mexiletine, dofetilide + lidocaine, moxifloxacin + diltiazem or placebo. | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 1 | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period 2 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Period 3 | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Period 5 | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 26.1 years STANDARD_DEVIATION 4.9 |
| Diastolic blood pressure | 60.2 mm Hg STANDARD_DEVIATION 3.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Heart rate | 61.3 beats per minute (bpm) STANDARD_DEVIATION 6.7 |
| J-Tpeakc (heart rate corrected J-Tpeak interval) | 229.5 ms STANDARD_DEVIATION 19 |
| PR interval | 160.8 ms STANDARD_DEVIATION 19.1 |
| QRS duration | 86.7 ms STANDARD_DEVIATION 8.5 |
| QTc (Fridericia's heart rate corrected QT interval) | 397.8 ms STANDARD_DEVIATION 14.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment United States | 22 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 13 Participants |
| Systolic blood pressure | 109.5 mm Hg STANDARD_DEVIATION 5.5 |
| Tpeak-Tend interval | 81.9 ms STANDARD_DEVIATION 6.4 |
| Weight | 69.9 kg STANDARD_DEVIATION 9 |
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 | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 20 | 1 / 19 | 11 / 21 | 6 / 20 | 3 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 19 | 0 / 21 | 0 / 20 | 0 / 20 |
Outcome results
Primary
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
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
Population: All study participants that completed placebo and dofetilide alone as well as dofetilide + mexiletine and/or dofetilide + lidocaine
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Dofetilide Alone | 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 |
| Dofetilide Alone | 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 |
| Dofetilide + Mexiletine | 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 | 20.4 ms |
| Dofetilide + Mexiletine | 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 | 0.8 ms |
| Dofetilide + Lidocaine | 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 | 18 ms |
| Dofetilide + Lidocaine | 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 | 3.5 ms |
Comparison: 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.p-value: 0.02595% CI: [-25.2, -14.3]Mixed Models Analysis
Comparison: 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.p-value: 0.02595% CI: [-25.2, -14.1]Mixed Models Analysis
Comparison: 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.p-value: 0.02595% CI: [-28, -18.3]Mixed Models Analysis
Comparison: 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.p-value: 0.02595% CI: [-25.5, -15.5]Mixed Models Analysis
Secondary
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.
Evening dose (moxifloxacin+diltiazem) versus afternoon dose (diltiazem alone).
Time frame: 5 weeks
Population: All study participants that completed placebo, moxifloxacin and moxifloxacin + diltiazem
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dofetilide Alone | 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 |
| Dofetilide + Mexiletine | 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. | 31.3 ms |
p-value: 0.02595% CI: [-1, 6.7]Mixed Models Analysis