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Completed

NCT Number: NCT02513940

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

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.

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Key information

Conditions

Long QT Syndrome Arrhythmias, Cardiac Behavior Cardiac Conduction System Disease Cardiovascular Abnormalities Cardiovascular Diseases Congenital Abnormalities Congenital, Hereditary, and Neonatal Diseases and Abnormalities Heart Defects, Congenital Heart Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms Risk Reduction Behavior Tachycardia Tachycardia, Ventricular Torsades de Pointes

Age range

65 year and older

Sex eligibility

Male

Study type

Interventional

Phase

Phase 4

Primary location

Indiana University

Indianapolis, Indiana, 46202, United States

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Testosterone

Drug

Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days

Other names: Androgel

Progesterone

Drug

Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days

Other names: Generic

Placebo

Drug

Subjects will receive placebo transdermal gel and placebo (lactose) capsules

Other names: Lactose

Ibutilide

Drug

Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval

Other names: Corvert

Primary outcomes

  1. Baseline (Pre-ibutilide) Individualized Rate-corrected QT Interval (QTF)

    Time frame: 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

  2. Maximum QTF Following Ibutilide 0.003 mg/kg

    Time frame: 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.

  3. Maximum Percent Change From Pretreatment Value in QTF Following Ibutilide 0.003 mg/kg

    Time frame: 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 outcomes

  1. Area Under the QTF Versus Time Curve for 0-1 Hour Following Ibutilide 0.003 mg/kg

    Time frame: 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.

  2. Number of Participants With Adverse Effects Associated With Testosterone, Progesterone and Placebo

    Time frame: 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

Sponsors and collaborators

Lead sponsor

Indiana University

Other

Collaborators

  • American Heart Association
  • Purdue University

Registry information

Important dates

Study start
2016
Primary completion
2017
Study completion
2017
First posted
Aug 3, 2015
Registry last updated
Aug 28, 2019

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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