Long QT Syndrome
Conditions
Keywords
Torsades de pointes, Testosterone, Progesterone, Clinical trial, Risk reduction, Electrocardiography
Brief summary
Torsades de pointes (TdP) is a potentially fatal ventricular arrhythmia associated with corrected QT (QTc) interval prolongation. More than 50 commonly used drugs available on the US market may cause QTc interval prolongation and TdP. While TdP occurs more commonly in women, 33-45% of all cases of TdP have occurred in men. Older age is a risk factor for drug-induced TdP in men, possibly due to declining serum testosterone concentrations. Available evidence shows an inverse relationship between QTc intervals and serum testosterone concentrations. In addition, experimental data, including those from the investigators' laboratory, suggest that both exogenous testosterone or progesterone administration may be protective against prolongation of ventricular repolarization and TdP. Specific Aim: Establish the influence of transdermal testosterone administration and oral progesterone administration as preventive methods by which to diminish the degree of drug-induced QT interval prolongation in men 65 years of age or older. Hypothesis: Transdermal testosterone administration and oral progesterone administration both effectively attenuate drug-induced QT interval response in older men. To test this hypothesis, transdermal testosterone, oral progesterone or placebo will be administered in a 3-way crossover study to men 65 years of age or older. QTc interval response to low-dose ibutilide will be assessed. The primary endpoints will be Fridericia-corrected QT interval (QTF) response to ibutilide, in the presence and absence of testosterone, and in the presence or absence of progesterone: 1) Effect on pre-ibutilide QTF, 2) Effect on maximum post-ibutilide QTF, 3) Effect on % change in post-ibutilide QTF, and 2) Area under the QTF interval-time curves.
Interventions
DRUGTestosterone
Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days
DRUGProgesterone
Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days
DRUGPlacebo
Subjects will receive placebo transdermal gel and placebo (lactose) capsules
DRUGIbutilide
Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval
Sponsors
American Heart Association
Purdue University
Indiana University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
65 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Men ≥ 65 years of age
Exclusion criteria
* Prostate cancer; history of prostate cancer; * History of breast cancer; benign prostatic hypertrophy; * Weight \< 60 kg * Weight \> 135 kg * Serum k+ \< 3.6 mEq/L; * Serum mg2+ \< 1.8 mg/dL; * Hemoglobin \< 9.0 mg/dL; * Hematocrit \< 26%; * Hepatic transaminases \> 3x upper limit of normal; * Baseline Bazett's-corrected QT interval \> 450 ms * Heart failure due to reduced ejection fraction (left ventricular ejection fraction \< 40%) * Family or personal history of long-QT syndrome, arrhythmias or sudden cardiac death; * Concomitant use of any QT interval-prolonging drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline (Pre-ibutilide) Individualized Rate-corrected QT Interval (QTF) | Following 7 days of testosterone, progesterone or placebo | QT interval is an electrocardiogram (ECG) measure of ventricular repolarization. Prolonged QT interval is a marker of increased risk of the ventricular arrhythmia known as torsades de pointes, which can cause sudden cardiac death. QT intervals were measured from ECG lead II by one investigator (E.T.M.) who was blinded to the subjects' assigned treatment phases. QT intervals were measured using computerized high-resolution electronic calipers (EP Calipers 1.6). QT and RR intervals at each time point were averaged over 3 consecutive complexes. The end of the T-wave was determined via the tangent method. Only clearly discernable QT intervals were measured. QT intervals vary with heart rate, and therefore must be corrected for heart rate. QT intervals were corrected using the Fridericia (QTF) method. The baseline QTF assesses the influence of testosterone and progesterone on naturally-occurring (before ibutilide administration) QTF |
| Maximum QTF Following Ibutilide 0.003 mg/kg | Within 8 hours following ibutilide administration | QT interval is an ECG measure of ventricular repolarization. Prolonged QT interval is a marker of increased risk of the ventricular arrhythmia known as torsades de pointes, which can cause sudden cardiac death. Three 12-lead ECGs were obtained \ 1 minute apart immediately at the end of the ibutilide infusion and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours post-infusion. QT intervals were measured from ECG lead II by one investigator (E.T.M.) who was blinded to the subjects' assigned treatment phases. QT intervals were measured using computerized high-resolution electronic calipers. QT and RR intervals at each time point were averaged over 3 consecutive complexes. The end of the T-wave was determined via the tangent method. QT intervals vary with heart rate, and therefore must be corrected for heart rate. QT intervals were corrected using the Fridericia (QTF) method. Maximum QTF is the longest QTF measured following ibutilide at any time point. |
| Maximum Percent Change From Pretreatment Value in QTF Following Ibutilide 0.003 mg/kg | Within 8 hours of ibutilide administration | QT interval is an ECG measure of ventricular repolarization. Prolonged QT interval is a marker of increased risk of the ventricular arrhythmia known as torsades de pointes, which can cause sudden cardiac death. Three 12-lead ECGs were obtained \ 1 minute apart immediately at the end of the ibutilide infusion and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours post-infusion. QT intervals were measured from ECG lead II by one investigator (E.T.M.) who was blinded to the subjects' assigned treatment phases. QT intervals were measured using computerized high-resolution electronic calipers. QT and RR intervals at each time point were averaged over 3 consecutive complexes. The end of the T-wave was determined via the tangent method. QT intervals were corrected using the Fridericia (QTF) method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the QTF Versus Time Curve for 0-1 Hour Following Ibutilide 0.003 mg/kg | 1 hour following ibutilide administration | Prolonged QT interval is a marker of increased risk of the ventricular arrhythmia known as torsades de pointes, which can cause sudden cardiac death. Three 12-lead ECGs were obtained \ 1 minute apart immediately at the end of the ibutilide infusion and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours post-infusion. QT intervals were measured from ECG lead II by one investigator (E.T.M.) who was blinded to the subjects' assigned treatment phases. QT intervals were measured using computerized high-resolution electronic calipers. QT and RR intervals at each time point were averaged over 3 consecutive complexes. The end of the T-wave was determined via the tangent method. Area under the QTF curve was calculated using the trapezoidal rule and reflects overall QTF interval exposure over time. |
| Number of Participants With Adverse Effects Associated With Testosterone, Progesterone and Placebo | During 7 day administration periods | Adverse effects were assessed by study investigators using telephone calls during the 7-day treatment period in each phase, as well as by asking participants about adverse effects on ibutilide administration days |
Countries
United States
Participant flow
Recruitment details
Recruitment began in July 2015; procedures were completed on last enrolled subject in October 2017. Subjects were recruited from advertisements placed in a seniors magazine, assisted living facilities, and local health fairs.
Pre-assignment details
n=77 subjects initially assessed for eligibility; n=16 declined to participate, n= 49 excluded (met one or more exclusion criteria); n=22 provided written informed consent (these participants were not considered to be enrolled); n= 8 excluded after providing consent because they were found to meet an exclusion criterion
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Men 65 years of age or older were enrolled. Exclusion criteria were: prostate cancer; history of prostate or breast cancer; benign prostatic hyperplasia; weight \< 60 kg or \> 135 kg; serum potassium \< 3.6 mEq/L; serum magnesium \< 1.8 mg/dL; hematocrit \< 26%; hepatic transaminases \> 3x upper limit of normal; baseline Bazett's-corrected QTc interval \> 450 ms; heart failure with reduced ejection fraction (left ventricular ejection fraction \< 40%); family or personal history of long QT syndrome, arrhythmias or sudden cardiac death; permanently paced ventricular rhythm; concomitant use of any QT interval-prolonging drug or strong non-QT interval-prolonging cytochrome P450 3A inhibitors. | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 13 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 73 Years STANDARD_DEVIATION 6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 13 Participants |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 14 Participants |
| Weight | 90 kg STANDARD_DEVIATION 16 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 0 / 14 | 1 / 14 | 1 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 | 0 / 14 |
Outcome results
Primary
Baseline (Pre-ibutilide) Individualized Rate-corrected QT Interval (QTF)
QT interval is an electrocardiogram (ECG) measure of ventricular repolarization. Prolonged QT interval is a marker of increased risk of the ventricular arrhythmia known as torsades de pointes, which can cause sudden cardiac death. QT intervals were measured from ECG lead II by one investigator (E.T.M.) who was blinded to the subjects' assigned treatment phases. QT intervals were measured using computerized high-resolution electronic calipers (EP Calipers 1.6). QT and RR intervals at each time point were averaged over 3 consecutive complexes. The end of the T-wave was determined via the tangent method. Only clearly discernable QT intervals were measured. QT intervals vary with heart rate, and therefore must be corrected for heart rate. QT intervals were corrected using the Fridericia (QTF) method. The baseline QTF assesses the influence of testosterone and progesterone on naturally-occurring (before ibutilide administration) QTF
Time frame: Following 7 days of testosterone, progesterone or placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Testosterone | Baseline (Pre-ibutilide) Individualized Rate-corrected QT Interval (QTF) | 393 ms | Standard Deviation 19 |
| Progesterone | Baseline (Pre-ibutilide) Individualized Rate-corrected QT Interval (QTF) | 399 ms | Standard Deviation 16 |
| Placebo | Baseline (Pre-ibutilide) Individualized Rate-corrected QT Interval (QTF) | 399 ms | Standard Deviation 13 |
p-value: 0.09Mixed Models Analysis
Primary
Maximum Percent Change From Pretreatment Value in QTF Following Ibutilide 0.003 mg/kg
QT interval is an ECG measure of ventricular repolarization. Prolonged QT interval is a marker of increased risk of the ventricular arrhythmia known as torsades de pointes, which can cause sudden cardiac death. Three 12-lead ECGs were obtained \ 1 minute apart immediately at the end of the ibutilide infusion and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours post-infusion. QT intervals were measured from ECG lead II by one investigator (E.T.M.) who was blinded to the subjects' assigned treatment phases. QT intervals were measured using computerized high-resolution electronic calipers. QT and RR intervals at each time point were averaged over 3 consecutive complexes. The end of the T-wave was determined via the tangent method. QT intervals were corrected using the Fridericia (QTF) method.
Time frame: Within 8 hours of ibutilide administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Testosterone | Maximum Percent Change From Pretreatment Value in QTF Following Ibutilide 0.003 mg/kg | 5.6 Percent change | Standard Deviation 1.8 |
| Progesterone | Maximum Percent Change From Pretreatment Value in QTF Following Ibutilide 0.003 mg/kg | 5.9 Percent change | Standard Deviation 2.3 |
| Placebo | Maximum Percent Change From Pretreatment Value in QTF Following Ibutilide 0.003 mg/kg | 6.1 Percent change | Standard Deviation 1.9 |
p-value: 0.6Mixed Models Analysis
Primary
Maximum QTF Following Ibutilide 0.003 mg/kg
QT interval is an ECG measure of ventricular repolarization. Prolonged QT interval is a marker of increased risk of the ventricular arrhythmia known as torsades de pointes, which can cause sudden cardiac death. Three 12-lead ECGs were obtained \ 1 minute apart immediately at the end of the ibutilide infusion and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours post-infusion. QT intervals were measured from ECG lead II by one investigator (E.T.M.) who was blinded to the subjects' assigned treatment phases. QT intervals were measured using computerized high-resolution electronic calipers. QT and RR intervals at each time point were averaged over 3 consecutive complexes. The end of the T-wave was determined via the tangent method. QT intervals vary with heart rate, and therefore must be corrected for heart rate. QT intervals were corrected using the Fridericia (QTF) method. Maximum QTF is the longest QTF measured following ibutilide at any time point.
Time frame: Within 8 hours following ibutilide administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Testosterone | Maximum QTF Following Ibutilide 0.003 mg/kg | 416 ms | Standard Deviation 19 |
| Progesterone | Maximum QTF Following Ibutilide 0.003 mg/kg | 425 ms | Standard Deviation 22 |
| Placebo | Maximum QTF Following Ibutilide 0.003 mg/kg | 426 ms | Standard Deviation 18 |
p-value: 0.001Mixed Models Analysis
Secondary
Area Under the QTF Versus Time Curve for 0-1 Hour Following Ibutilide 0.003 mg/kg
Prolonged QT interval is a marker of increased risk of the ventricular arrhythmia known as torsades de pointes, which can cause sudden cardiac death. Three 12-lead ECGs were obtained \ 1 minute apart immediately at the end of the ibutilide infusion and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours post-infusion. QT intervals were measured from ECG lead II by one investigator (E.T.M.) who was blinded to the subjects' assigned treatment phases. QT intervals were measured using computerized high-resolution electronic calipers. QT and RR intervals at each time point were averaged over 3 consecutive complexes. The end of the T-wave was determined via the tangent method. Area under the QTF curve was calculated using the trapezoidal rule and reflects overall QTF interval exposure over time.
Time frame: 1 hour following ibutilide administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Testosterone | Area Under the QTF Versus Time Curve for 0-1 Hour Following Ibutilide 0.003 mg/kg | 471 ms·hr | Standard Deviation 24 |
| Progesterone | Area Under the QTF Versus Time Curve for 0-1 Hour Following Ibutilide 0.003 mg/kg | 480 ms·hr | Standard Deviation 24 |
| Placebo | Area Under the QTF Versus Time Curve for 0-1 Hour Following Ibutilide 0.003 mg/kg | 483 ms·hr | Standard Deviation 18 |
p-value: 0.0003Mixed Models Analysis
Secondary
Number of Participants With Adverse Effects Associated With Testosterone, Progesterone and Placebo
Adverse effects were assessed by study investigators using telephone calls during the 7-day treatment period in each phase, as well as by asking participants about adverse effects on ibutilide administration days
Time frame: During 7 day administration periods
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Testosterone | Number of Participants With Adverse Effects Associated With Testosterone, Progesterone and Placebo | Fatigue | 0 Participants |
| Testosterone | Number of Participants With Adverse Effects Associated With Testosterone, Progesterone and Placebo | Rash on gel application site | 0 Participants |
| Progesterone | Number of Participants With Adverse Effects Associated With Testosterone, Progesterone and Placebo | Fatigue | 1 Participants |
| Progesterone | Number of Participants With Adverse Effects Associated With Testosterone, Progesterone and Placebo | Rash on gel application site | 0 Participants |
| Placebo | Number of Participants With Adverse Effects Associated With Testosterone, Progesterone and Placebo | Fatigue | 0 Participants |
| Placebo | Number of Participants With Adverse Effects Associated With Testosterone, Progesterone and Placebo | Rash on gel application site | 1 Participants |
Comparison: Fatiguep-value: >0.99Fisher Exact
Comparison: Rash at gel application sitep-value: >0.99Fisher Exact