Prolonged QT Interval in EKG and Sudden Death
Conditions
Keywords
Torsades de pointes, Progesterone, Clinical trial, Risk reduction, Electrocardiography
Brief summary
Female sex is an independent risk factor for the potentially fatal drug-induced arrhythmia (irregular heartbeat) known as torsades de pointes (TdP), which is associated with prolongation of the corrected QT (QTc) interval on the electrocardiogram (ECG). Mechanisms for this increased risk in women are not well-understood. QTc interval duration has been shown to fluctuate throughout the phases of the menstrual cycle. Evidence indicates that the QTc interval response to drugs that may cause TdP is greater during the menses and ovulation phases of the menstrual cycle, during which serum progesterone concentrations are lowest, and lesser during the luteal phase, during which serum progesterone concentrations are highest. Additional evidence from our laboratory suggests that progesterone may be protective against TdP. Specific Aim 1: Establish the influence of oral progesterone administration as a preventive method by which to diminish the degree of drug-induced QT interval prolongation in women. Working hypothesis: Oral progesterone administration effectively attenuates enhanced drug-induced QT interval response in women. To test this hypothesis, progesterone or placebo will be administered in a crossover fashion to women during the menses phase of the menstrual cycle. QTc interval response to low-dose ibutilide, a drug known to lengthen the QT interval, will be assessed. The primary endpoint will be individually-corrected QT interval (QTcI) response to ibutilide, in the presence and absence of progesterone, which will be assessed by: 1) Effect on maximum change in QTcI, and 2) Area under the QTcI interval-time curves (AUEC). At the conclusion of this study, we will have established that oral progesterone administration is a safe and effective method of attenuating drug-induced QT interval prolongation.
Interventions
DRUGProgesterone
Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days
DRUGPlacebo
Subjects will receive oral placebo two capsules once daily every evening for 7 days
DRUGIbutilide
Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval
Sponsors
American Heart Association
Indiana University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
21 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* Female * Age 21-40 years * Premenopausal
Exclusion criteria
Serum potassium ,\< 3.6 meq/l * Serum magnesium \< 1.8 mg/dl * Serum hemoglobin \< 9.0 mg/dl * Serum hematocrit \< 26% * Hypertension * Coronary artery disease * Heart failure * Liver disease * Kidney disease * Serum creatinine \> 1.5 mg/dl * Taking hormone contraceptives * Baseline Bazett's correct QTc interval \> 450 ms * Family history of long-QT syndrome, arrhythmias, sudden cardiac death * Concomitant use of any QT prolonging drug * Pregnancy * weight \< 45 kg * Unwillingness to use non-hormonal forms of birth control during the study period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline (Pre-Ibutilide) QTcI Intervals | After 7 days of progesterone or placebo, prior to receiving IV ibutilide | — |
| Area Under the QTcI - Time Curve (AUEC) | From beginning of 10-minute ibutilide infusion to 1 hour following ibutilide infusion | — |
| Maximum % Change From Baseline in QTcI Intervals Following Ibutilide Administration | After 7 days of progesterone or placebo | — |
| Maximum Individual-corrected QT Interval (QTcI) | 0, 15 & 30 minutes, and 1, 2, 4, 6, 8, and 12 hours post-ibutilide administration | QT intervals will be corrected as follows: Prior to randomization, subjects will come to the Indiana Clinical Research Center for a 12-hour stay, during which three ECGs, one minute apart, will be obtained at the following times: 0, 15 & 30 minutes, and 1, 2, 4, 6, 8, and 12 hours. Subjects will be discharged, and then return then next morning for the 24 hour ECG. QT and RR intervals will be used to determine each subject's individual rate-corrected QT interval (QTcI) using the parabolic model QT = β•RRα, where RR is the interval between adjacent QRS complexes, and α and β are subject-specific correction factors. |
Secondary
| Measure | Time frame |
|---|---|
| Incidence of Progesterone-associated Adverse Effects Compared to Placebo | During 7 days of treatment with oral progesterone or placebo |
Other
| Measure | Time frame |
|---|---|
| Adverse Effects Associated With Ibutilide in the Progesterone and Placebo Phases | Within 8 hours following ibutilide administration |
| Ratio of Serum Progesterone:Estradiol Concentrations During the Progesterone and Placebo Phases | After 7 days of progesterone or placebo |
| Serum Progesterone Concentrations During Progesterone and Placebo Phases | After 7 days of progesterone or placebo |
| Serum Estradiol Concentrations During the Progesterone and Placebo Phases | Following 7 days of progesterone or placebo |
| Maximum (Peak) Serum Ibutilide Concentrations During Progesterone and Placebo Phases | Within 1 hour following ibutilide administration (0, 15 & 30 minutes and 1 hours.) |
Countries
United States
Participant flow
Recruitment details
Subjects recruited from a) INResearch database, maintained by Indiana Clinical Translational Research Institute (CTSI), and b) Hard copy and electronic advertisements on the IUPUI and Purdue University campuses Participants were recruited between October 2012 and February 2014
Pre-assignment details
n=333 subjects assessed for eligibility; n=27 consented, n=306 excluded (n=108 did not meet inclusion criteria, n=198 declined to participate); of n=27 consented, n=19 enrolled, n=8 excluded because they met one or more exclusion criteria
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population n=15 subjects who completed the study | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Intervention 1 | Lost to Follow-up | 2 | 0 |
| Intervention 1 | Nonadherent to study medications | 1 | 0 |
| Intervention 2 | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants |
| Age, Continuous | 29 years STANDARD_DEVIATION 5 |
| Region of Enrollment United States | 15 participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 16 | 2 / 17 |
| serious Total, serious adverse events | 1 / 16 | 0 / 17 |
Outcome results
Primary
Area Under the QTcI - Time Curve (AUEC)
Time frame: From beginning of 10-minute ibutilide infusion to 1 hour following ibutilide infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Progesterone | Area Under the QTcI - Time Curve (AUEC) | 497 ms*hr | Standard Deviation 13 |
| Placebo | Area Under the QTcI - Time Curve (AUEC) | 510 ms*hr | Standard Deviation 16 |
p-value: 0.002t-test, 2 sided
Primary
Baseline (Pre-Ibutilide) QTcI Intervals
Time frame: After 7 days of progesterone or placebo, prior to receiving IV ibutilide
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Progesterone | Baseline (Pre-Ibutilide) QTcI Intervals | 412 ms | Standard Deviation 15 |
| Placebo | Baseline (Pre-Ibutilide) QTcI Intervals | 419 ms | Standard Deviation 14 |
p-value: 0.04t-test, 2 sided
Primary
Maximum % Change From Baseline in QTcI Intervals Following Ibutilide Administration
Time frame: After 7 days of progesterone or placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Progesterone | Maximum % Change From Baseline in QTcI Intervals Following Ibutilide Administration | 7.5 percentage change from baseline value | Standard Deviation 2.4 |
| Placebo | Maximum % Change From Baseline in QTcI Intervals Following Ibutilide Administration | 9.3 percentage change from baseline value | Standard Deviation 3.4 |
p-value: 0.02t-test, 2 sided
Primary
Maximum Individual-corrected QT Interval (QTcI)
QT intervals will be corrected as follows: Prior to randomization, subjects will come to the Indiana Clinical Research Center for a 12-hour stay, during which three ECGs, one minute apart, will be obtained at the following times: 0, 15 & 30 minutes, and 1, 2, 4, 6, 8, and 12 hours. Subjects will be discharged, and then return then next morning for the 24 hour ECG. QT and RR intervals will be used to determine each subject's individual rate-corrected QT interval (QTcI) using the parabolic model QT = β•RRα, where RR is the interval between adjacent QRS complexes, and α and β are subject-specific correction factors.
Time frame: 0, 15 & 30 minutes, and 1, 2, 4, 6, 8, and 12 hours post-ibutilide administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Progesterone | Maximum Individual-corrected QT Interval (QTcI) | 443 ms | Standard Deviation 17 |
| Placebo | Maximum Individual-corrected QT Interval (QTcI) | 458 ms | Standard Deviation 19 |
p-value: 0.003t-test, 2 sided
Secondary
Incidence of Progesterone-associated Adverse Effects Compared to Placebo
Time frame: During 7 days of treatment with oral progesterone or placebo
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Progesterone | Incidence of Progesterone-associated Adverse Effects Compared to Placebo | Headache | 13 percentage of participants |
| Progesterone | Incidence of Progesterone-associated Adverse Effects Compared to Placebo | Fatigue/general malaise | 38 percentage of participants |
| Progesterone | Incidence of Progesterone-associated Adverse Effects Compared to Placebo | Mood changes | 13 percentage of participants |
| Progesterone | Incidence of Progesterone-associated Adverse Effects Compared to Placebo | Breast tenderness | 13 percentage of participants |
| Progesterone | Incidence of Progesterone-associated Adverse Effects Compared to Placebo | Hypotension | 6 percentage of participants |
| Progesterone | Incidence of Progesterone-associated Adverse Effects Compared to Placebo | Vertigo requiring discontinuation | 6 percentage of participants |
| Placebo | Incidence of Progesterone-associated Adverse Effects Compared to Placebo | Hypotension | 0 percentage of participants |
| Placebo | Incidence of Progesterone-associated Adverse Effects Compared to Placebo | Breast tenderness | 0 percentage of participants |
| Placebo | Incidence of Progesterone-associated Adverse Effects Compared to Placebo | Fatigue/general malaise | 6 percentage of participants |
| Placebo | Incidence of Progesterone-associated Adverse Effects Compared to Placebo | Headache | 6 percentage of participants |
| Placebo | Incidence of Progesterone-associated Adverse Effects Compared to Placebo | Vertigo requiring discontinuation | 0 percentage of participants |
| Placebo | Incidence of Progesterone-associated Adverse Effects Compared to Placebo | Mood changes | 0 percentage of participants |
p-value: 0.04Fisher Exact
p-value: 0.6Fisher Exact
p-value: 0.23Fisher Exact
p-value: 0.23Fisher Exact
p-value: 0.48Fisher Exact
p-value: 0.48Fisher Exact
Other Pre-specified
Adverse Effects Associated With Ibutilide in the Progesterone and Placebo Phases
Time frame: Within 8 hours following ibutilide administration
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Progesterone | Adverse Effects Associated With Ibutilide in the Progesterone and Placebo Phases | Bradycardia (HR < 60 bpm) | 20 percentage of participants |
| Progesterone | Adverse Effects Associated With Ibutilide in the Progesterone and Placebo Phases | Burning at infusion site | 7 percentage of participants |
| Progesterone | Adverse Effects Associated With Ibutilide in the Progesterone and Placebo Phases | Transient QTc interval > 500 ms | 0 percentage of participants |
| Placebo | Adverse Effects Associated With Ibutilide in the Progesterone and Placebo Phases | Bradycardia (HR < 60 bpm) | 12 percentage of participants |
| Placebo | Adverse Effects Associated With Ibutilide in the Progesterone and Placebo Phases | Burning at infusion site | 6 percentage of participants |
| Placebo | Adverse Effects Associated With Ibutilide in the Progesterone and Placebo Phases | Transient QTc interval > 500 ms | 6 percentage of participants |
p-value: 0.65Fisher Exact
p-value: >0.99Fisher Exact
p-value: >0.99Fisher Exact
Other Pre-specified
Maximum (Peak) Serum Ibutilide Concentrations During Progesterone and Placebo Phases
Time frame: Within 1 hour following ibutilide administration (0, 15 & 30 minutes and 1 hours.)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Progesterone | Maximum (Peak) Serum Ibutilide Concentrations During Progesterone and Placebo Phases | 1247 pg/mL | Standard Deviation 770 |
| Placebo | Maximum (Peak) Serum Ibutilide Concentrations During Progesterone and Placebo Phases | 1172 pg/mL | Standard Deviation 709 |
p-value: 0.43t-test, 2 sided
Other Pre-specified
Ratio of Serum Progesterone:Estradiol Concentrations During the Progesterone and Placebo Phases
Time frame: After 7 days of progesterone or placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Progesterone | Ratio of Serum Progesterone:Estradiol Concentrations During the Progesterone and Placebo Phases | 205 Ratio | Standard Deviation 40 |
| Placebo | Ratio of Serum Progesterone:Estradiol Concentrations During the Progesterone and Placebo Phases | 18 Ratio | Standard Deviation 16 |
p-value: 0.0001t-test, 2 sided
Other Pre-specified
Serum Estradiol Concentrations During the Progesterone and Placebo Phases
Time frame: Following 7 days of progesterone or placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Progesterone | Serum Estradiol Concentrations During the Progesterone and Placebo Phases | 89.3 pg/mL | Standard Deviation 62.8 |
| Placebo | Serum Estradiol Concentrations During the Progesterone and Placebo Phases | 71.8 pg/mL | Standard Deviation 31.7 |
p-value: 0.36t-test, 2 sided
Other Pre-specified
Serum Progesterone Concentrations During Progesterone and Placebo Phases
Time frame: After 7 days of progesterone or placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Progesterone | Serum Progesterone Concentrations During Progesterone and Placebo Phases | 16.2 ng/mL | Standard Deviation 11 |
| Placebo | Serum Progesterone Concentrations During Progesterone and Placebo Phases | 1.2 ng/mL | Standard Deviation 1 |
p-value: <0.0001t-test, 2 sided