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Trial record 20 of 74 for:    "Andersen-Tawil syndrome" OR "Long QT Syndrome"

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

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ClinicalTrials.gov Identifier: NCT02513940
Recruitment Status : Completed
First Posted : August 3, 2015
Results First Posted : March 6, 2019
Last Update Posted : April 9, 2019
Sponsor:
Collaborators:
American Heart Association
Purdue University
Information provided by (Responsible Party):
James E. Tisdale, Indiana University

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Condition Long QT Syndrome
Interventions Drug: Testosterone
Drug: Progesterone
Drug: Placebo
Drug: Ibutilide
Enrollment 14
Recruitment Details

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.

Pre-assignment Details 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
Arm/Group Title Testosterone - Progesterone - Placebo Testosterone - Placebo - Progesterone Progesterone - Testosterone - Placebo Progesterone - Placebo - Testosterone Placebo - Testosterone - Progesterone Placebo - Progesterone - Testosterone
Hide Arm/Group Description

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

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

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

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

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

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

Period Title: Overall Study
Started 2 [1] 3 2 2 2 3
Completed 2 3 2 2 2 3
Not Completed 0 0 0 0 0 0
[1]
This was a crossover study, with a total n=14. All 14 subjects completed each phase of the study
Arm/Group Title All Study Participants
Hide Arm/Group Description 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.
Overall Number of Baseline Participants 14
Hide Baseline Analysis Population Description
Men 65 years of age or older were enrolled
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
<=18 years
0
   0.0%
Between 18 and 65 years
1
   7.1%
>=65 years
13
  92.9%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 14 participants
73  (6)
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 14 participants
73  (6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
Female
0
   0.0%
Male
14
 100.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
Hispanic or Latino
0
   0.0%
Not Hispanic or Latino
14
 100.0%
Unknown or Not Reported
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
American Indian or Alaska Native
0
   0.0%
Asian
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
1
   7.1%
White
13
  92.9%
More than one race
0
   0.0%
Unknown or Not Reported
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 14 participants
14
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 14 participants
90  (16)
1.Primary Outcome
Title Baseline (Pre-ibutilide) Individualized Rate-corrected QT Interval (QTF)
Hide Description 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
Time Frame Following 7 days of testosterone, progesterone or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Testosterone Progesterone Placebo
Hide Arm/Group Description:

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 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

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

Overall Number of Participants Analyzed 14 14 14
Mean (Standard Deviation)
Unit of Measure: ms
393  (19) 399  (16) 399  (13)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Testosterone, Progesterone, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.09
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
2.Primary Outcome
Title Maximum QTF Following Ibutilide 0.003 mg/kg
Hide Description 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.
Time Frame Within 8 hours following ibutilide administration
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Testosterone Progesterone Placebo
Hide Arm/Group Description:

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 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

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

Overall Number of Participants Analyzed 14 14 14
Mean (Standard Deviation)
Unit of Measure: ms
416  (19) 425  (22) 426  (18)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Testosterone, Progesterone, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.02
Comments

Post-hoc Bonferroni correction:

Testosterone vs placebo: p=0.004 Progesterone vs placebo: p >0.99 Testosterone vs progesterone: 0.05

Method ANOVA
Comments Repeated measures ANOVA
3.Primary Outcome
Title Maximum Percent Change From Pretreatment Value in QTF Following Ibutilide 0.003 mg/kg
Hide Description 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.
Time Frame Within 8 hours of ibutilide administration
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Testosterone Progesterone Placebo
Hide Arm/Group Description:

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 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

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

Overall Number of Participants Analyzed 14 14 14
Mean (Standard Deviation)
Unit of Measure: Percent change
5.6  (1.8) 5.9  (2.3) 6.1  (1.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Testosterone, Progesterone, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.70
Comments [Not Specified]
Method ANOVA
Comments Repeated measures ANOVA
4.Secondary Outcome
Title Area Under the QTF Versus Time Curve for 0-1 Hour Following Ibutilide 0.003 mg/kg
Hide Description 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.
Time Frame 1 hour following ibutilide administration
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Testosterone Progesterone Placebo
Hide Arm/Group Description:

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 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

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

Overall Number of Participants Analyzed 14 14 14
Mean (Standard Deviation)
Unit of Measure: ms·hr
471  (24) 480  (24) 483  (18)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Testosterone, Progesterone, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments

Post-hoc Bonferroni correction:

Testosterone vs placebo: p = 0.002 Progesterone vs placebo: p = 0.57 Testosterone vs progesterone: p = 0.05

Method ANOVA
Comments Repeated measures ANOVA
5.Secondary Outcome
Title Number of Participants With Adverse Effects Associated With Testosterone, Progesterone and Placebo
Hide Description 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
Time Frame During 7 day administration periods
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Testosterone Progesterone Placebo
Hide Arm/Group Description:

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 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

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

Overall Number of Participants Analyzed 14 14 14
Measure Type: Count of Participants
Unit of Measure: Participants
Fatigue
0
   0.0%
1
   7.1%
0
   0.0%
Rash on gel application site
0
   0.0%
0
   0.0%
1
   7.1%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Testosterone, Progesterone, Placebo
Comments Fatigue
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.99
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Testosterone, Progesterone, Placebo
Comments Rash at gel application site
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.99
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Time Frame 8 days per study phase
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Testosterone Progesterone Placebo
Hide Arm/Group Description

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 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

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

All-Cause Mortality
Testosterone Progesterone Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/14 (0.00%)   0/14 (0.00%)   0/14 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
Testosterone Progesterone Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/14 (0.00%)   0/14 (0.00%)   0/14 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Testosterone Progesterone Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/14 (0.00%)   1/14 (7.14%)   1/14 (7.14%) 
General disorders       
Fatigue   0/14 (0.00%)  1/14 (7.14%)  0/14 (0.00%) 
Skin and subcutaneous tissue disorders       
Rash on gel application site   0/14 (0.00%)  0/14 (0.00%)  1/14 (7.14%) 
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Dr. James E Tisdale
Organization: Indiana University
Phone: 317-880-5418
Publications:
Muensterman Tomaselli E, Sowinski KM, Jaynes HA, Overholser BR, Kovacs RJ, Tisdale JE. Transdermal testosterone administration attenuates drug-induced QT interval lengthening in older men. Circulation 2018;138:A15197.
Responsible Party: James E. Tisdale, Indiana University
ClinicalTrials.gov Identifier: NCT02513940     History of Changes
Other Study ID Numbers: 1507526854
First Submitted: July 29, 2015
First Posted: August 3, 2015
Results First Submitted: February 14, 2019
Results First Posted: March 6, 2019
Last Update Posted: April 9, 2019