The primary objective of this study is to compare the effect of TRT and placebo on the incidence of MACE in middle-aged and older hypogonadal men at risk for CV disease. The secondary CV safety endpoint is to compare the effect of TRT and placebo on an expanded list of CV outcomes including MACE plus coronary revascularization procedures/cardiac percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) surgery.
An additional secondary safety objective is to determine the effect of TRT on the incidence of high-grade prostate cancer in this population. Finally, this study will evaluate a number of secondary and tertiary efficacy endpoints defined in the sub-studies.
Men whose age is between 45 and 80 years, inclusive, at the time of Screening. Meet the study definition of clinical hypogonadism as evidenced by:
a) Two serum testosterone levels < 300 ng/dL confirmed by blood samples drawn at least 48 hours apart. These samples should be obtained between 5 AM and
11 AM local time. Subjects meeting either of the below criteria may be considered further for inclusion:
· SV1 value < 300 ng/dL; and Screening Visit 2 (SV2) value < 300 ng/dL OR
· SV1 value < 300 ng/dL; and SV2 value between 300 ng/dL and 333 ng/dL; and with a Screening Visit 3 (SV3) value < 300 ng/dL
AND
b) Presence of at least one sign or symptom that may be related to low testosterone values and is/are consistent with hypogonadism such as the following:
· Decreased sexual desire or libido
· Decreased spontaneous erections (e.g., morning erections)
· Decreased energy or fatigue/feeling tired
· Low mood or depressed mood
· Loss of body (axillary and pubic) hair or reduced shaving
· Hot flashes
3. Have pre-existing CV disease as evidenced by at least one disease in Table 1 OR at least three CV Risk Factors from Table 2.
Table 1. Pre-Existing CV Disease
Coronary Artery Disease
· Acute MI > 4 months before randomization
· Evidence of coronary artery disease (at least a 50% lesion in two of the
major coronary artery distributions including their branches) as documented by angiogram (see Appendix Q for further details)
· Coronary revascularization (coronary artery bypass grafting [CABG]) or percutaneous coronary intervention (PCI) > 4 months before randomization
Cerebrovascular Disease
· Prior ischemic stroke > 4 months before randomization
· Prior catheter-based or surgical revascularization of the carotid or middle cerebral arteries > 4 months before randomization
· Extracranial carotid artery stenosis > 50%, excluding intracranial vessels
Peripheral Arterial Disease
· Symptomatic peripheral arterial disease (i.e., lower extremity arterial disease documented by ankle/brachial index < 0.9 with claudication or resting limb ischemia obtained in the prior 12 months)
· Peripheral arterial revascularization or amputation due to arterial obstructive disease > 4 months before randomization
· Peripheral arterial stenosis > 50%
· History of abdominal aortic aneurysm not due to connective tissue disorders
Table 2.Risk Factor
Hypertension- Medical history of hypertension and currently on medication or repeated systolic blood pressure (SBP) > 140 or diastolic blood pressure (DBP) > 90 mmHg
Dyslipidemia- Medical history of dyslipidemia and currently on medication or confirmed low-density lipoprotein corrected (LDL-C) > 160 mg/dL or high-density lipoprotein cholesterol (HDL-C) < 40 mg/dL
Current Smoker - Current daily cigarette smoker (e-cigarette smoking alone does not satisfy this criterion)
Stage 3 Chronic Kidney Disease (CKD) as defined by eGFR ranges- Estimated Glomerular Filtration Rate (eGFR) > 30 and < 60 mL/min by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation
Diabetes- History of diabetes and currently on diabetes medication or confirmed hemoglobin A1c (HbA1c) ≥ 6.5% or confirmed fasting glucose of
≥ 126 mg/dL
Elevated hsCRP- High-sensitivity C-reactive protein (hsCRP) during Screening ≥ 2.0 mg/L
Documented Historical Agatston Coronary Calcium Score ≥ 75th percentile for age and race- The Agatston coronary calcium score should not be obtained for the purposes of Screening (a link will be provided for calculation of the 75th percentile calcium score)
≥ 65 Years of Age
4. Naïve to testosterone replacement, clomiphene, compounded or over-the-counter (OTC) androgenic steroid derivatives and dehydroepiandrosterone (DHEA), including investigational products that may affect the reproductive hormonal system within the past 6 months.
5. Willingness and the ability to apply topical testosterone gel as instructed by the study staff and comply with the requirements of this study protocol.
6. Intact skin surfaces on the upper arms and shoulders where the topical testosterone will be applied.