Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Testosterone - progesterone - placebo Subjects received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days. After a washout of at least 13 days, they then received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days. After a washout period of at least 13 days, they then received transdermal placebo gel once daily every morning for 7 days and oral placebo once daily every morning x 7 days |
Drug: Testosterone
Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days
Other Names:
Drug: Progesterone
Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days
Other Names:
Drug: Placebo
Subjects will receive placebo transdermal gel and placebo (lactose) capsules
Other Names:
Drug: Ibutilide
Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval
Other Names:
|
| Experimental: Testosterone - placebo - progesterone Subjects received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days. After a washout of at least 13 days, they then received transdermal placebo gel once daily every morning for 7 days and oral placebo ( 2 capsules) once daily every morning x 7 days. After a washout period of at least 13 days, they then received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days. |
Drug: Testosterone
Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days
Other Names:
Drug: Progesterone
Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days
Other Names:
Drug: Placebo
Subjects will receive placebo transdermal gel and placebo (lactose) capsules
Other Names:
Drug: Ibutilide
Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval
Other Names:
|
| Experimental: Progesterone - testosterone - placebo Subjects received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days. After a washout period of at least 13 days, they then received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days. After a washout period of at least 13 days, they then received transdermal placebo gel once daily every morning for 7 days and oral placebo (2 capsules) once daily every morning x 7 days |
Drug: Testosterone
Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days
Other Names:
Drug: Progesterone
Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days
Other Names:
Drug: Placebo
Subjects will receive placebo transdermal gel and placebo (lactose) capsules
Other Names:
Drug: Ibutilide
Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval
Other Names:
|
| Experimental: Progesterone - placebo - testosterone Subjects received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days. After a washout period of at least 13 days, they then received transdermal placebo gel once daily every morning for 7 days and oral placebo (2 capsules) once daily every morning x 7 days. After a washout period of at least 13 days, they then received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days. |
Drug: Testosterone
Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days
Other Names:
Drug: Progesterone
Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days
Other Names:
Drug: Placebo
Subjects will receive placebo transdermal gel and placebo (lactose) capsules
Other Names:
Drug: Ibutilide
Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval
Other Names:
|
| Experimental: Placebo - testosterone - progesterone Subjects received transdermal placebo gel once daily every morning for 7 days and oral placebo once daily every morning x 7 days. After a washout period of at least 13 days, they then received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days. After a washout period of at least 13 days, they then received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days. |
Drug: Testosterone
Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days
Other Names:
Drug: Progesterone
Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days
Other Names:
Drug: Placebo
Subjects will receive placebo transdermal gel and placebo (lactose) capsules
Other Names:
Drug: Ibutilide
Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval
Other Names:
|
| Experimental: Placebo - progesterone - testosterone Subjects received transdermal placebo gel once daily every morning for 7 days and oral placebo once daily every morning x 7 days. After a washout period of at least 13 days, they then received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days. After a washout period of at least 13 days, they then received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days. |
Drug: Testosterone
Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days
Other Names:
Drug: Progesterone
Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days
Other Names:
Drug: Placebo
Subjects will receive placebo transdermal gel and placebo (lactose) capsules
Other Names:
Drug: Ibutilide
Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Indiana University | Indianapolis | Indiana | United States | 46202 |
Sponsors and Collaborators
- Indiana University
- American Heart Association
- Purdue University
Investigators
- Principal Investigator: James E Tisdale, PharmD, Purdue University
Study Documents (Full-Text)
More Information
Publications
- 1507526854
Study Results
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 Detail | 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 |
| Arm/Group Title | Testosterone - Progesterone - Placebo | Testosterone - Placebo - Progesterone | Progesterone - Testosterone - Placebo | Progesterone - Placebo - Testosterone | Placebo - Testosterone - Progesterone | Placebo - Progesterone - Testosterone |
|---|---|---|---|---|---|---|
| Arm/Group Description | Subjects received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days. After a washout of at least 13 days, they then received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days. After a washout period of at least 13 days, they then received transdermal placebo gel once daily every morning for 7 days and oral placebo once daily every morning x 7 days Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval | Subjects received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days. After a washout of at least 13 days, they then received transdermal placebo gel once daily every morning for 7 days and oral placebo ( 2 capsules) once daily every morning x 7 days. After a washout period of at least 13 days, they then received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days. Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval | Subjects received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days. After a washout period of at least 13 days, they then received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days. After a washout period of at least 13 days, they then received transdermal placebo gel once daily every morning for 7 days and oral placebo (2 capsules) once daily every morning x 7 days Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval | Subjects received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days. After a washout period of at least 13 days, they then received transdermal placebo gel once daily every morning for 7 days and oral placebo (2 capsules) once daily every morning x 7 days. After a washout period of at least 13 days, they then received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days. Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval | Subjects received transdermal placebo gel once daily every morning for 7 days and oral placebo once daily every morning x 7 days. After a washout period of at least 13 days, they then received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days. After a washout period of at least 13 days, they then received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days. Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval | Subjects received transdermal placebo gel once daily every morning for 7 days and oral placebo once daily every morning x 7 days. After a washout period of at least 13 days, they then received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days. After a washout period of at least 13 days, they then received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days. Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval |
| Period Title: Overall Study | ||||||
| STARTED | 2 | 3 | 2 | 2 | 2 | 3 |
| COMPLETED | 2 | 3 | 2 | 2 | 2 | 3 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | All Study Participants |
|---|---|
| Arm/Group Description | 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. |
| Overall Participants | 14 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
1
7.1%
|
| >=65 years |
13
92.9%
|
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
73
(6)
|
| Age (Years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [Years] |
73
(6)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
0
0%
|
| Male |
14
100%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
0
0%
|
| Not Hispanic or Latino |
14
100%
|
| Unknown or Not Reported |
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
1
7.1%
|
| White |
13
92.9%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
0
0%
|
| Region of Enrollment (participants) [Number] | |
| United States |
14
100%
|
| Weight (kg) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [kg] |
90
(16)
|
Outcome Measures
| Title | Baseline (Pre-ibutilide) Individualized Rate-corrected QT Interval (QTF) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Testosterone | Progesterone | Placebo |
|---|---|---|---|
| Arm/Group Description | Testosterone gel 1% 100 mg daily x 7 days Testosterone: Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval | Progesterone 400 mg orally daily x 7 days Progesterone: Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval | Dual matching placebo capsules and placebo topical gel every day x 7 days Placebo Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval |
| Measure Participants | 14 | 14 | 14 |
| Mean (Standard Deviation) [ms] |
393
(19)
|
399
(16)
|
399
(13)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Testosterone, Progesterone, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.09 |
| Comments | ||
| Method | Mixed Models Analysis | |
| Comments | ||
| Title | Maximum QTF Following Ibutilide 0.003 mg/kg |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Testosterone | Progesterone | Placebo |
|---|---|---|---|
| Arm/Group Description | Testosterone gel 1% 100 mg daily x 7 days Testosterone: Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval | Progesterone 400 mg orally daily x 7 days Progesterone: Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval | Dual matching placebo capsules and placebo topical gel every day x 7 days Placebo Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval |
| Measure Participants | 14 | 14 | 14 |
| Mean (Standard Deviation) [ms] |
416
(19)
|
425
(22)
|
426
(18)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Testosterone, Progesterone, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.001 |
| Comments | Pairwise comparisons: Testosterone vs placebo: p=0.008 Progesterone vs placebo: p=0.73 Testosterone vs progesterone: p=0.0008 | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Title | Maximum Percent Change From Pretreatment Value in QTF Following Ibutilide 0.003 mg/kg |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Testosterone | Progesterone | Placebo |
|---|---|---|---|
| Arm/Group Description | Testosterone gel 1% 100 mg daily x 7 days Oral placebo capsules once daily for 7 days Testosterone: Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval | Progesterone 400 mg orally daily x 7 days Transdermal placebo gel once daily for 7 days Progesterone: Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval | Dual matching placebo capsules and placebo topical gel every day x 7 days Placebo Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval |
| Measure Participants | 14 | 14 | 14 |
| Mean (Standard Deviation) [Percent change] |
5.6
(1.8)
|
5.9
(2.3)
|
6.1
(1.9)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Testosterone, Progesterone, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.60 |
| Comments | ||
| Method | Mixed Models Analysis | |
| Comments | Repeated measures ANOVA | |
| Title | Area Under the QTF Versus Time Curve for 0-1 Hour Following Ibutilide 0.003 mg/kg |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Testosterone | Progesterone | Placebo |
|---|---|---|---|
| Arm/Group Description | Testosterone gel 1% 100 mg daily x 7 days Oral placebo capsules once daily for 7 days Testosterone: Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval | Progesterone 400 mg orally daily x 7 days Transdermal placebo gel once daily for 7 days Progesterone: Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval | Dual matching placebo capsules and placebo topical gel every day x 7 days Placebo Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval |
| Measure Participants | 14 | 14 | 14 |
| Mean (Standard Deviation) [ms·hr] |
471
(24)
|
480
(24)
|
483
(18)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Testosterone, Progesterone, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0003 |
| Comments | Pairwise comparisons: Testosterone vs placebo: p = 0.0001 Progesterone vs placebo: p = 0.25 Testosterone vs progesterone: p = 0.002 | |
| Method | Mixed Models Analysis | |
| Comments | Repeated measures ANOVA | |
| Title | Number of Participants With Adverse Effects Associated With Testosterone, Progesterone and Placebo |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Testosterone | Progesterone | Placebo |
|---|---|---|---|
| Arm/Group Description | Testosterone gel 1% 100 mg daily x 7 days Oral placebo capsules once daily for 7 days Testosterone: Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval | Progesterone 400 mg orally daily x 7 days Transdermal placebo gel once daily for 7 days Progesterone: Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval | Dual matching placebo capsules and placebo topical gel every day x 7 days Placebo Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval |
| Measure Participants | 14 | 14 | 14 |
| Fatigue |
0
0%
|
1
NaN
|
0
NaN
|
| Rash on gel application site |
0
0%
|
0
NaN
|
1
NaN
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Testosterone, Progesterone, Placebo |
|---|---|---|
| Comments | Fatigue | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | >0.99 |
| Comments | ||
| Method | Fisher Exact | |
| Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Testosterone, Progesterone, Placebo |
|---|---|---|
| Comments | Rash at gel application site | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | >0.99 |
| Comments | ||
| Method | Fisher Exact | |
| Comments | ||
Adverse Events
| Time Frame | 8 days per study phase | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | Testosterone | Progesterone | Placebo | |||
| Arm/Group Description | Testosterone gel 1% 100 mg daily x 7 days Oral placebo capsules once daily for 7 days Testosterone: Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval | Progesterone 400 mg orally daily x 7 days Transdermal placebo gel once daily for 7 days Progesterone: Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval | Dual matching placebo capsules and placebo topical gel every day x 7 days Placebo Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval | |||
All Cause Mortality |
||||||
| Testosterone | Progesterone | Placebo | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/14 (0%) | 0/14 (0%) | 0/14 (0%) | |||
Serious Adverse Events |
||||||
| Testosterone | Progesterone | Placebo | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/14 (0%) | 0/14 (0%) | 0/14 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Testosterone | Progesterone | Placebo | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/14 (0%) | 1/14 (7.1%) | 1/14 (7.1%) | |||
| General disorders | ||||||
| Fatigue | 0/14 (0%) | 1/14 (7.1%) | 0/14 (0%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Rash on gel application site | 0/14 (0%) | 0/14 (0%) | 1/14 (7.1%) | |||
Limitations/Caveats
More Information
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 | Dr. James E Tisdale |
|---|---|
| Organization | Indiana University |
| Phone | 317-880-5418 |
| jtisdale@iu.edu |
- 1507526854