The Cardiac Benefit of Testosterone Replacement in Men With Low Testosterone Levels With Coronary Artery Disease After Successful Intervention of the Blockage or Narrowed Heart Artery

The Cardiac Benefit of Androgen Replacement in Hypogonadal Males With Coronary Artery Disease Following Successful Percutaneous Coronary Intervention (PCI).

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00413244

Enrollment

Registered

2006-12-19

Start date

2007-01-31

Completion date

2014-11-30

Last updated

2017-01-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Coronary Artery Disease

Keywords

Hypogonadal, coronary artery disease, percutaneous coronary intervention (PCI)

Brief summary

The purpose of the study is to find out if giving the study drug, Androgel (testosterone) as a testosterone replacement help bring the testosterone to an acceptable level and to find out if it will help improve heart condition in males with coronary artery disease (CAD) following successful percutaneous coronary intervention.

Detailed description

Males with coronary heart disease have lower serum levels of bioavailable testosterone than men of a similar age with normal coronary angiograms (English, European Heart Journal, 2000). Low plasma testosterone has been associated with known risk factors for CHD, including age, obesity, hyperinsulinemia, diabetes, and adverse lipid profile. Testosterone has also been shown in numerous studies to be a vasodilator. Recently, testosterone replacement compared with placebo, in hypogonadal men was shown to improve time to ischemic threshold, assessed by treadmill exercise testing at 4 and 12 weeks (Malkin, Heart, 2000). Prior studies had also shown a beneficial effect on exercise-induced ischemia in men with CAD, but not exclusively hypogonadal men (Jaffe,Br Heart J 1977; Rosano, Circulation, 1999; English, Circulation, 2000). In addition, this proposed study would be the first study to assess if the anti-anginal effects persists long term. This is a randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of testosterone supplementation in hypogonadal men with coronary artery disease following successful revascularization with percutaneous coronary intervention (PCI). Only those men who had successful coronary artery revascularization, and on stable cardiac medical regimen for the prior 4 weeks will be included. Eligible patients will then be randomized on a 2:1 basis with 50 subjects receiving 5 grams of AndroGel and 25 subjects receiving placebo gel. The men in this study who demonstrate hypogonadism represent a novel population to demonstrate the safety and efficacy of testosterone supplementation to improve cardiac function and outcomes. We hypothesize that treatment of hypogonadism in men with CAD, following successful PCI, will significantly improve cardiac ischemic threshold as assessed by cardiac stress testing. Furthermore, additional cardiac endpoints such as angina status, endothelial function and inflammatory serum markers will also demonstrate significant benefit in the testosterone treated group.

Interventions

DRUGAndroGel 5 Grams

Placebo (randomization will occur on a 2:1 drug to placebo). A total of 50 subjects will be randomized to receive Androgel 5 grams and 25 subjects will be randomized to receive placebo. Androgel treatment/Placebo (after the treatment arm is assigned, subjects will be instructed to begin the study drug at 1 week post entry into the study and will continue to take the study drug for a total of 6 months. The study drug has to be applied to the skin once daily for 6 months.

DRUGPlacebo

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

MALE

Age

40 Years to 75 Years

Healthy volunteers

Inclusion criteria

* Adult male patients with coronary artery disease (CAD) (one to three vessel diseased). * Stable cardiac status at least 3 months after percutaneous coronary intervention (PCI). * No change in cardiac medications for 4 weeks prior to enrollment. * Testosterone \< 300 ng/dl or free testosterone \< 5.0 ng/dl or bioavailable testosterone \< 150 ng/dl. * Sex Hormone Binding Globulin (SHBG) \< 7nmol/liter and Free Testosterone \< 50pg/dl * Prostate Specific Antigen (PSA) \< 2.5 ng/mL or 2.6-3.7ng/mL with a negative prostate biopsy within the last 6 months and pathology report available for investigator's review. * Subgroup of diabetics with well to moderately controlled diabetes (defined by a HgbA1c of \< 9mg/dL.

Exclusion criteria

* Hematocrit greater than 50%. * Severe hypertension (exhibit systolic blood pressure \>180mmHg and diastolic blood pressure \>110 mmHg at baseline visit or a have a history of malignant hypertension. * Significant cardiac arrhythmia (supraventricular tachycardia \[SVT\] or ventricular tachycardia with heart rate exceeding 110 beats per minute at Visit 1). * ECG abnormalities precluding ST segment analysis on treadmill, or inability to walk on treadmill. * Poorly controlled, symptomatic, active medical problems (HIV, hepatitis, cancer, benign prostatic hypertrophy, alcohol or drug abuse, major depressive disorder). * Neurological or psychiatric disorder that would compromise the patient's ability to give informed consent or adhere to the requirements of the protocol. * History of prostate cancer * History of hypersensitivity to transdermal testosterone gel. * International Prostate Symptom Score (IPSS) \>19 at Visit 1.

Design outcomes

Primary

Measure	Time frame	Description
Cardiac Stress Test: Time to ST Depression	at 6 months	Treadmill exercise testing performed according to the Bruce protocol (MAX-1 Marquette advanced exercise system, software version 002E). The system analyzed the signal averaged ECG and produces a graphical display of the level of the ST segment 80 ms after the J point against time. Time to 1 mm ST depression was measured from computer derived analysis, effectively eliminating observer bias.
Cardiac Stress Testing: Exercise Capacity	At 1 month, 3 months, and 6 months	Exercise capacity was measured using exercise time.

Secondary

Measure	Time frame	Description
International Prostate Symptom Score (IPSS)	6 months	IPSS has 7 questions related to symptoms, each item scored 1-5. Total score can range from 0 to 35 (asymptomatic to very symptomatic). The 8th question refers to the patient's perceived quality of life ranged from 0 to 6 (delighted to terrible.) Data not collected.
Metabolic Equivalents of Task (METS)	6 months	The Metabolic Equivalent of Task (MET), or simply metabolic equivalent, is a physiological measure expressing the energy cost of physical activities and is defined as the ratio of metabolic rate (and therefore the rate of energy consumption) during a specific physical activity to a reference metabolic rate, set by convention to 3.5 ml O2·kg-1·min-1 or equivalently
Aging Male Symptoms (AMS)	At baseline, 1 month, 3 months, and 6 months	The scale assesses symptoms of aging and their impact on HRQoL in males, and increases with increasing severity (1 to 5) of subjectively perceived complaints in 17 items. Scale ranges from 17-85 (no symptoms to extremely severe symptoms.)
International Index of Erectile Function (IIEF)	At baseline, 1 month, 3 months, and 6 months	Questions 1-5 15 of the IIEF relates to erectile function scale 0 - 30 (severe erectile dysfunction to no erectile dysfunction).
Seattle Angina Questionnaire (SAQ)	up to 6 months	A cardiac disease-related quality-of-life measure. The SAQ is a self-report instrument with 19 items that, yields five subscale scores: physical limitation, angina stability, angina frequency, treatment satisfaction, and disease perception. The possible range of scores for each of the five subscales is 0 to 100, with higher scores indicating better quality of life. A change of 10 points in any of the subscales is considered to be clinically important. Data not collected.
IIEF -III: Sexual Desire	At baseline, 1 month, 3 months, and 6 months	Questions 11-12 of the IIEF relates to sexual desire scale 0-10 (from very low to very high)
IIEF-IV: Intercourse Satisfaction	At baseline, 1 month, 3 months, and 6 months	Questions 6,7, 8 of the IIEF relates to intercourse satisfaction scale 0 - 15 (from very dissatisfied to very satisfied)
IIEF-V: Over-all Satisfaction	At baseline, 1 month, 3 months, and 6 months	Questions 13,14 of the IIEF relates to specifically to overall satisfaction scale from 0 - 10 (very dissatisfied to very satisfied)
IIEF-II Orgasmic Function	At baseline, 1 month, 3 months, and 6 months	Questions 9-10 of the IIEF relates to orgasmic function scale 0 - 10 (from no impairment to severe impairment)
Reactive Hyperemia Index	6 months	The Reactive Hyperemia Index measures the endothelial function and predicts future coronary events. In general RHI values below 2 are categorized as endothelial dysfunction and have a greater plaque burden, whereas higher RHI values are considered normal or improved endothelial function. PAT is the technique to non-invasively assess endothelial function. It comprises finger probes to evaluate digital volume changes.

Countries

United States

Participant flow

Recruitment details

Subjects recruited for the study were male patients with stable cardiac status at least 3 months after Percutaneous Coronary Intervention (PCI) at the Cardiac Catheterization Lab of Mount Sinai Hospital from July 2007 to August 2013.

Participants by arm

Arm	Count
Androgel Androgel 5 grams	31
Placebo Matching Placebo	20
Total	51

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Withdrawal by Subject	10	1

Baseline characteristics

Characteristic	Androgel	Placebo	Total
Age, Continuous	58.3 years STANDARD_DEVIATION 8.2	58.9 years STANDARD_DEVIATION 7.3	58.5 years STANDARD_DEVIATION 7.81
Aging male syndrome questionnaire	36.48 units on a scale STANDARD_DEVIATION 11.36	35.85 units on a scale STANDARD_DEVIATION 10.24	36.24 units on a scale STANDARD_DEVIATION 10.83
Body Mass Index	30.8 kg/m^2 STANDARD_DEVIATION 5.8	28.0 kg/m^2 STANDARD_DEVIATION 4.3	29.7 kg/m^2 STANDARD_DEVIATION 5.4
Diabetes No	15 participants	14 participants	29 participants
Diabetes Yes	16 participants	6 participants	22 participants
Diastolic Blood Pressure	76.32 mmHg STANDARD_DEVIATION 9.03	75.10 mmHg STANDARD_DEVIATION 11.65	75.84 mmHg STANDARD_DEVIATION 10.04
Exercise Time	507.29 seconds STANDARD_DEVIATION 153.48	530.00 seconds STANDARD_DEVIATION 120.08	516.20 seconds STANDARD_DEVIATION 104.49
Gender Female	0 Participants	0 Participants	0 Participants
Gender Male	31 Participants	20 Participants	51 Participants
Hematocrit	40.69 percent of cells STANDARD_DEVIATION 3	40.93 percent of cells STANDARD_DEVIATION 3.18	40.78 percent of cells STANDARD_DEVIATION 3.04
Hypertension No	1 participants	4 participants	5 participants
Hypertension Yes	30 participants	16 participants	46 participants
International Prostate Symptom Score (IPSS)	5.68 units on a scale STANDARD_DEVIATION 4.77	4.55 units on a scale STANDARD_DEVIATION 4.7	5.24 units on a scale STANDARD_DEVIATION 4.73
LDL	86.48 mg/dL STANDARD_DEVIATION 40.52	80.90 mg/dL STANDARD_DEVIATION 26.77	84.29 mg/dL STANDARD_DEVIATION 35.57
Metabolic equivalent of task (METs)	10.03 MET units STANDARD_DEVIATION 2.58	10.05 MET units STANDARD_DEVIATION 1.99	10.04 MET units STANDARD_DEVIATION 2.34
Reactive hyperemia index (RHI)	1.97 ml STANDARD_DEVIATION 0.72	1.85 ml STANDARD_DEVIATION 0.54	1.92 ml STANDARD_DEVIATION 0.66
Red Blood Cell Count	4.58 cells x10^6/uL STANDARD_DEVIATION 0.44	4.67 cells x10^6/uL STANDARD_DEVIATION 0.42	4.62 cells x10^6/uL STANDARD_DEVIATION 0.43
Systolic Blood Pressure	123.81 mmHg STANDARD_DEVIATION 13.81	128.05 mmHg STANDARD_DEVIATION 20.84	125.47 mmHg STANDARD_DEVIATION 16.85
Total Cholesterol	157.29 mg/dL STANDARD_DEVIATION 47.1	144.45 mg/dL STANDARD_DEVIATION 28.85	152.25 mg/dL STANDARD_DEVIATION 41.08
Total Testosterone	246.7 ng/dL STANDARD_DEVIATION 63.5	263.7 ng/dL STANDARD_DEVIATION 71.9	253.36 ng/dL STANDARD_DEVIATION 66.8
Triglycerides	142.23 mg/dL STANDARD_DEVIATION 100.95	109.90 mg/dL STANDARD_DEVIATION 50.86	129.55 mg/dL STANDARD_DEVIATION 85.74
Waist Circumference	42.66 inches STANDARD_DEVIATION 5.21	41.31 inches STANDARD_DEVIATION 4.65	42.13 inches STANDARD_DEVIATION 4.99
Weight	205.73 lbs STANDARD_DEVIATION 39.22	194.50 lbs STANDARD_DEVIATION 36.62	201.32 lbs STANDARD_DEVIATION 38.25
White Blood Cell Count	6.25 cells x10^3/uL STANDARD_DEVIATION 1.78	6.49 cells x10^3/uL STANDARD_DEVIATION 1.63	6.34 cells x10^3/uL STANDARD_DEVIATION 1.71

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	0 / 31	0 / 20
serious Total, serious adverse events	0 / 31	0 / 20

Outcome results

Primary

Cardiac Stress Testing: Exercise Capacity

Exercise capacity was measured using exercise time.

Time frame: At 1 month, 3 months, and 6 months

Population: Subjects analyzed were only those subjects with ST depression at baseline

Arm	Measure	Group	Value (MEAN)	Dispersion
Androgel	Cardiac Stress Testing: Exercise Capacity	at 3 months	607.6 seconds	Standard Deviation 152
Androgel	Cardiac Stress Testing: Exercise Capacity	at 1 month	589.7 seconds	Standard Deviation 114.6
Androgel	Cardiac Stress Testing: Exercise Capacity	at 6 months	614.0 seconds	Standard Deviation 115.4
Placebo	Cardiac Stress Testing: Exercise Capacity	at 3 months	472.1 seconds	Standard Deviation 98.6
Placebo	Cardiac Stress Testing: Exercise Capacity	at 1 month	452.4 seconds	Standard Deviation 122.7
Placebo	Cardiac Stress Testing: Exercise Capacity	at 6 months	470.0 seconds	Standard Deviation 143.8

Primary

Cardiac Stress Test: Time to ST Depression

Treadmill exercise testing performed according to the Bruce protocol (MAX-1 Marquette advanced exercise system, software version 002E). The system analyzed the signal averaged ECG and produces a graphical display of the level of the ST segment 80 ms after the J point against time. Time to 1 mm ST depression was measured from computer derived analysis, effectively eliminating observer bias.

Time frame: at 6 months

Population: Subjects analyzed were only those subjects with ST depression at baseline

Arm	Measure	Group	Value (MEAN)	Dispersion
Androgel	Cardiac Stress Test: Time to ST Depression	at 1 month	439.1 seconds	Standard Deviation 205.2
Androgel	Cardiac Stress Test: Time to ST Depression	at 3 months	364.0 seconds	Standard Deviation 141.4
Androgel	Cardiac Stress Test: Time to ST Depression	at 6 months	433.0 seconds	Standard Deviation 123.2
Placebo	Cardiac Stress Test: Time to ST Depression	at 1 month	279.5 seconds	Standard Deviation 130
Placebo	Cardiac Stress Test: Time to ST Depression	at 3 months	292.6 seconds	Standard Deviation 63.5
Placebo	Cardiac Stress Test: Time to ST Depression	at 6 months	342.2 seconds	Standard Deviation 62.7

Comparison: Statistician used all the time points post-baseline together (Overall). The result gives the estimates and 95% CI of the treatment effect from longitudinal analyses (generalized estimating equation method) which basically pools data from all visits post-baseline.p-value: 0.03log mean

Secondary

Aging Male Symptoms (AMS)

The scale assesses symptoms of aging and their impact on HRQoL in males, and increases with increasing severity (1 to 5) of subjectively perceived complaints in 17 items. Scale ranges from 17-85 (no symptoms to extremely severe symptoms.)