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

Study Overview
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Brief Summary
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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.

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

Conditions
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Long QT Syndrome

Intervention / Treatment
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* Drug: Testosterone
* Drug: Progesterone
* Drug: Placebo
* Drug: Ibutilide


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Testosterone - progesterone - placebo<br>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<br>* Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days<br>* Other names: Androgel;Drug: Progesterone<br>* Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days<br>* Other names: Generic;Drug: Placebo<br>* Subjects will receive placebo transdermal gel and placebo (lactose) capsules<br>* Other names: Lactose;Drug: Ibutilide<br>* Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval<br>* Other names: Corvert;|
| Experimental: Testosterone - placebo - progesterone<br>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<br>* Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days<br>* Other names: Androgel;Drug: Progesterone<br>* Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days<br>* Other names: Generic;Drug: Placebo<br>* Subjects will receive placebo transdermal gel and placebo (lactose) capsules<br>* Other names: Lactose;Drug: Ibutilide<br>* Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval<br>* Other names: Corvert;|
| Experimental: Progesterone - testosterone - placebo<br>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<br>* Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days<br>* Other names: Androgel;Drug: Progesterone<br>* Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days<br>* Other names: Generic;Drug: Placebo<br>* Subjects will receive placebo transdermal gel and placebo (lactose) capsules<br>* Other names: Lactose;Drug: Ibutilide<br>* Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval<br>* Other names: Corvert;|
| Experimental: Progesterone - placebo - testosterone<br>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<br>* Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days<br>* Other names: Androgel;Drug: Progesterone<br>* Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days<br>* Other names: Generic;Drug: Placebo<br>* Subjects will receive placebo transdermal gel and placebo (lactose) capsules<br>* Other names: Lactose;Drug: Ibutilide<br>* Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval<br>* Other names: Corvert;|
| Experimental: Placebo - testosterone - progesterone<br>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<br>* Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days<br>* Other names: Androgel;Drug: Progesterone<br>* Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days<br>* Other names: Generic;Drug: Placebo<br>* Subjects will receive placebo transdermal gel and placebo (lactose) capsules<br>* Other names: Lactose;Drug: Ibutilide<br>* Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval<br>* Other names: Corvert;|
| Experimental: Placebo - progesterone - testosterone<br>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<br>* Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days<br>* Other names: Androgel;Drug: Progesterone<br>* Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days<br>* Other names: Generic;Drug: Placebo<br>* Subjects will receive placebo transdermal gel and placebo (lactose) capsules<br>* Other names: Lactose;Drug: Ibutilide<br>* Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval<br>* Other names: Corvert;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Following 7 days of testosterone, progesterone or placebo | 
| 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. | Within 8 hours following ibutilide administration | 
| 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. | Within 8 hours of ibutilide administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 1 hour following ibutilide administration | 
| 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 | During 7 day administration periods | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Torsades de pointes, Testosterone, Progesterone, Clinical trial, Risk reduction, Electrocardiography