Trial Outcomes & Findings for Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes (NCT NCT02513940)

Last Updated: 2019-08-28

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

14 participants

Primary outcome timeframe

Following 7 days of testosterone, progesterone or placebo

Results posted on

2019-08-28

Participant Flow

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.

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

Participant milestones

Participant milestones
Measure	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 Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval	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. Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval	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 Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval	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. Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval	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. Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval	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. Ibutilide: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval
Overall Study STARTED	2	3	2	2	2	3
Overall Study COMPLETED	2	3	2	2	2	3
Overall Study NOT COMPLETED	0	0	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Study Participants n=14 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.
Age, Categorical <=18 years	0 Participants n=93 Participants
Age, Categorical Between 18 and 65 years	1 Participants n=93 Participants
Age, Categorical >=65 years	13 Participants n=93 Participants
Age, Continuous	73 Years STANDARD_DEVIATION 6 • n=93 Participants
Sex: Female, Male Female	0 Participants n=93 Participants
Sex: Female, Male Male	14 Participants n=93 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=93 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	14 Participants n=93 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants
Race (NIH/OMB) Black or African American	1 Participants n=93 Participants
Race (NIH/OMB) White	13 Participants n=93 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants
Region of Enrollment United States	14 participants n=93 Participants
Weight	90 kg STANDARD_DEVIATION 16 • n=93 Participants

PRIMARY outcome

Timeframe: Following 7 days of testosterone, progesterone or placebo

Outcome measures

Outcome measures
Measure	Testosterone n=14 Participants 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 n=14 Participants 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	Placebo n=14 Participants 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
Baseline (Pre-ibutilide) Individualized Rate-corrected QT Interval (QTF)	393 ms Standard Deviation 19	399 ms Standard Deviation 16	399 ms Standard Deviation 13

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Testosterone n=14 Participants 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 n=14 Participants 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	Placebo n=14 Participants 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
Maximum QTF Following Ibutilide 0.003 mg/kg	416 ms Standard Deviation 19	425 ms Standard Deviation 22	426 ms Standard Deviation 18

PRIMARY outcome

Timeframe: Within 8 hours of ibutilide administration

Outcome measures

Outcome measures
Measure	Testosterone n=14 Participants 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 n=14 Participants 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	Placebo n=14 Participants 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
Maximum Percent Change From Pretreatment Value in QTF Following Ibutilide 0.003 mg/kg	5.6 Percent change Standard Deviation 1.8	5.9 Percent change Standard Deviation 2.3	6.1 Percent change Standard Deviation 1.9

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Testosterone n=14 Participants 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 n=14 Participants 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	Placebo n=14 Participants 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
Area Under the QTF Versus Time Curve for 0-1 Hour Following Ibutilide 0.003 mg/kg	471 ms·hr Standard Deviation 24	480 ms·hr Standard Deviation 24	483 ms·hr Standard Deviation 18

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Testosterone n=14 Participants 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 n=14 Participants 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	Placebo n=14 Participants 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
Number of Participants With Adverse Effects Associated With Testosterone, Progesterone and Placebo Fatigue	0 Participants	1 Participants	0 Participants
Number of Participants With Adverse Effects Associated With Testosterone, Progesterone and Placebo Rash on gel application site	0 Participants	0 Participants	1 Participants

Adverse Events

Testosterone

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Progesterone

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Testosterone n=14 participants at risk 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 n=14 participants at risk 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	Placebo n=14 participants at risk 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
General disorders Fatigue	0.00% 0/14 • 8 days per study phase	7.1% 1/14 • 8 days per study phase	0.00% 0/14 • 8 days per study phase
Skin and subcutaneous tissue disorders Rash on gel application site	0.00% 0/14 • 8 days per study phase	0.00% 0/14 • 8 days per study phase	7.1% 1/14 • 8 days per study phase

Additional Information

Dr. James E Tisdale

Indiana University

Phone: 317-880-5418

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place