Clinical trial NCT02513940: Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
Official title: Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Long QT Syndrome
Keywords: Torsades de pointes
Testosterone
Progesterone
Clinical trial
Risk reduction
Electrocardiography
Lead sponsor: Indiana University
Sponsor class: OTHER
Collaborators: name: American Heart Association
name: Purdue University
First posted: 2015-08-03
Enrollment: 14
Sex: MALE
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: PREVENTION

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.


Eligibility 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.

Primary outcomes:
measure: Baseline (Pre-ibutilide) Individualized Rate-corrected QT Interval (QTF)
timeFrame: Following 7 days of testosterone, progesterone or placebo
measure: Maximum QTF Following Ibutilide 0.003 mg/kg
timeFrame: Within 8 hours following ibutilide administration
measure: Maximum Percent Change From Pretreatment Value in QTF Following Ibutilide 0.003 mg/kg
timeFrame: Within 8 hours of ibutilide administration
Secondary outcomes:
measure: Area Under the QTF Versus Time Curve for 0-1 Hour Following Ibutilide 0.003 mg/kg
timeFrame: 1 hour following ibutilide administration
measure: Number of Participants With Adverse Effects Associated With Testosterone, Progesterone and Placebo
timeFrame: During 7 day administration periods
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
Study officials:
affiliation: Purdue University
name: James E Tisdale, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Muensterman ET, Jaynes HA, Sowinski KM, Overholser BR, Shen C, Kovacs RJ, Tisdale JE. Effect of Transdermal Testosterone and Oral Progesterone on Drug-Induced QT Interval Lengthening in Older Men: A Randomized, Double-Blind, Placebo-Controlled Crossover-Design Study. Circulation. 2019 Sep 24;140(13):1127-1129. doi: 10.1161/CIRCULATIONAHA.119.041395. Epub 2019 Sep 23. No abstract available.
citation: Tomaselli Muensterman E, Jaynes HA, Sowinski KM, Overholser BR, Shen C, Kovacs RJ, Tisdale JE. Transdermal Testosterone Attenuates Drug-Induced Lengthening of Both Early and Late Ventricular Repolarization in Older Men. Clin Pharmacol Ther. 2021 Jun;109(6):1499-1504. doi: 10.1002/cpt.2072. Epub 2020 Nov 15.