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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Coronary Artery Disease

Intervention / Treatment
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* Drug: AndroGel 5 Grams
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Androgel treatment<br>Androgel 5 grams Androgel treatment - 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. | Drug: AndroGel 5 Grams<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Placebo - 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. | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | at 6 months | 
| Cardiac Stress Testing: Exercise Capacity | Exercise capacity was measured using exercise time. | At 1 month, 3 months, and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Seattle Angina Questionnaire (SAQ) | 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. | up to 6 months | 
| Reactive Hyperemia Index | 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. | 6 months | 
| International Prostate Symptom Score (IPSS) | 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. | 6 months | 
| Metabolic Equivalents of Task (METS) | 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 | 6 months | 
| 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.) | At baseline, 1 month, 3 months, and 6 months | 
| International Index of Erectile Function (IIEF) | Questions 1-5 15 of the IIEF relates to erectile function scale 0 - 30 (severe erectile dysfunction to no erectile dysfunction). | At baseline, 1 month, 3 months, and 6 months | 
| IIEF-II Orgasmic Function | Questions 9-10 of the IIEF relates to orgasmic function scale 0 - 10 (from no impairment to severe impairment) | At baseline, 1 month, 3 months, and 6 months | 
| IIEF -III: Sexual Desire | Questions 11-12 of the IIEF relates to sexual desire scale 0-10 (from very low to very high) | At baseline, 1 month, 3 months, and 6 months | 
| IIEF-IV: Intercourse Satisfaction | Questions 6,7, 8 of the IIEF relates to intercourse satisfaction scale 0 - 15 (from very dissatisfied to very satisfied) | At baseline, 1 month, 3 months, and 6 months | 
| IIEF-V: Over-all Satisfaction | Questions 13,14 of the IIEF relates to specifically to overall satisfaction scale from 0 - 10 (very dissatisfied to very satisfied) | At baseline, 1 month, 3 months, and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypogonadal, coronary artery disease, percutaneous coronary intervention (PCI)