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

NCT02513940 | Completed Phase 4 Results DMC

• 1 other identifier: 1507526854
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

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.

Conditions

Long QT Syndrome

Keywords

Torsades de pointes; Testosterone; Progesterone; Clinical trial; Risk reduction; Electrocardiography

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (2)

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

  1 hour following ibutilide administration

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

  During 7 day administration periods

Study Arms (6)

Testosterone - progesterone - placebo

EXPERIMENTAL

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; Drug: Progesterone; Drug: Placebo; Drug: Ibutilide

Testosterone - placebo - progesterone

EXPERIMENTAL

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; Drug: Progesterone; Drug: Placebo; Drug: Ibutilide

Progesterone - testosterone - placebo

EXPERIMENTAL

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; Drug: Progesterone; Drug: Placebo; Drug: Ibutilide

Progesterone - placebo - testosterone

EXPERIMENTAL

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; Drug: Progesterone; Drug: Placebo; Drug: Ibutilide

Placebo - testosterone - progesterone

EXPERIMENTAL

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; Drug: Progesterone; Drug: Placebo; Drug: Ibutilide

Placebo - progesterone - testosterone

EXPERIMENTAL

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; Drug: Progesterone; Drug: Placebo; Drug: Ibutilide

Interventions

Testosterone DRUG

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

Also known as: Androgel

Placebo - progesterone - testosterone; Placebo - testosterone - progesterone; Progesterone - placebo - testosterone; Progesterone - testosterone - placebo; Testosterone - placebo - progesterone; Testosterone - progesterone - placebo

Progesterone DRUG

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

Also known as: Generic

Placebo - progesterone - testosterone; Placebo - testosterone - progesterone; Progesterone - placebo - testosterone; Progesterone - testosterone - placebo; Testosterone - placebo - progesterone; Testosterone - progesterone - placebo

Placebo DRUG

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

Also known as: Lactose

Placebo - progesterone - testosterone; Placebo - testosterone - progesterone; Progesterone - placebo - testosterone; Progesterone - testosterone - placebo; Testosterone - placebo - progesterone; Testosterone - progesterone - placebo

Ibutilide DRUG

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

Also known as: Corvert

Placebo - progesterone - testosterone; Placebo - testosterone - progesterone; Progesterone - placebo - testosterone; Progesterone - testosterone - placebo; Testosterone - placebo - progesterone; Testosterone - progesterone - placebo

Eligibility Criteria

• Age: 65 Years+
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Older Adult (65+)

You may qualify if:

• Men ≥ 65 years of age

You may not qualify if:

• 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.

Sponsors & Collaborators

• Indiana University: lead
• American Heart Association: collaborator
• Purdue University: collaborator

Study Sites (1)

Indiana University

Indianapolis, Indiana, 46202, United States

Location

Related Publications (2)

• 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.

  PMID: 31545681 BACKGROUND

• 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.

  PMID: 33020898 DERIVED

MeSH Terms

Conditions

Long QT Syndrome; Torsades de Pointes; Risk Reduction Behavior

Interventions

Testosterone; Progesterone; Drugs, Generic; Lactose; ibutilide

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Cardiac Conduction System Disease; Heart Defects, Congenital; Cardiovascular Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Tachycardia, Ventricular; Tachycardia; Behavior

Intervention Hierarchy (Ancestors)

Androstenols; Androstenes; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Testosterone Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pregnenediones; Pregnenes; Pregnanes; Corpus Luteum Hormones; Progesterone Congeners; Pharmaceutical Preparations; Disaccharides; Oligosaccharides; Polysaccharides; Carbohydrates; Sugars

Results Point of Contact

• Title: Dr. James E Tisdale
• Organization: Indiana University

jtisdale@iu.edu

317-880-5418

Study Officials

• James E Tisdale, PharmD

  Purdue University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Adjunct Professor

Study Record Dates

• First Submitted: July 29, 2015
• First Posted: August 3, 2015
• Study Start: May 1, 2016
• Primary Completion: October 19, 2017
• Study Completion: October 19, 2017
• Last Updated: August 28, 2019
• Results First Posted: March 6, 2019

Record last verified: 2019-08

Locations

US (1)