Testosterone products have been approved in the United States (US) for over 50 years for the treatment of testosterone deficient men. These products are currently indicated for the treatment of congenital or acquired primary hypogonadism and hypogonadotropic hypogonadism in men. Hypogonadism is an endocrine disorder characterized by absent or deficient testosterone levels along with signs and symptoms of androgen deficiency, including delayed development or regression of secondary sexual characteristics, impaired sexual function, impaired sense of well-being, depressed mood, decreased muscle strength associated with a loss of muscle mass, and reduced bone mineral density (BMD). Current guidelines for the use of testosterone replacement therapy (TRT) outline the appropriate assessment and monitoring of men who are candidates for testosterone therapy.
Key components of the Endocrine Society Guidelines2 include criteria for selecting candidates with signs and symptoms consistent with hypogonadism and documented evidence of low testosterone levels, for whom TRT may be indicated. The Endocrine Society Guidelines also offer recommendations for confirmatory testing of serum testosterone concentrations, additional evaluation, and TRT. Cardiovascular (CV) Safety of Testosterone In 2010, the Food and Drug Administration (FDA) began an investigation of the CV safety of approved testosterone products after a small, placebo-controlled testosterone trial in elderly men (TOM Trial) was discontinued prematurely due to increased frequency of CV events in the active TRT treatment arm. After reviewing the TOM Trial results and other available published literature, the FDA determined that there was insufficient evidence to conclude that testosterone therapy in older men was associated with an increased risk of adverse CV outcomes.
In late 2013 and early 2014, two publications based on retrospective observational data reported a possible association with the use of TRT and adverse cardiac outcomes in patients treated withRT versus matched control groups. These studies had a number of limitations such that conclusions on causality between TRT and CV outcomes could not be established. Additionally, other epidemiologic studies published prior to and following the above studies observed no increased CV risk, or risk reduction. Rationale for a CV Safety Study of Testosterone in Hypogonadal Men: A 2014 FDA Advisory Committee examined the CV safety of testosterone and recommended that a CV outcome study be conducted. FDA requested that testosterone manufacturers work together to conduct an adequately sized study to rule out increased CV risk in hypogonadal men treated with TRT.
The rationale for such a study includes the conflicting data for a signal of CV risk in men treated with testosterone and the lack of robust, registration-level clinical efficacy data for TRT in men with hypogonadism associated with aging or co-morbidities. The current TRAVERSE study is designed to fulfill the FDA requirement for a CV safety study as the primary research objective with other safety and efficacy endpoints included as secondary objectives. The primary objective of this study is to assess the CV safety of TRT compared to placebo in men with a history of CV disease or with multiple CV risk factors by measuring the treatment effect on adjudicated major adverse cardiovascular events (MACE) including non-fatal myocardial infarction (MI), non-fatal stroke and CV death. Given the unique nature of this study, which will study the effects of testosterone treatment compared to placebo in several thousand men for up to 5 years, the study will also examine as secondary outcomes the impact of therapy on development of high grade prostate cancer and several efficacy outcomes whose rationale is described below. Impact of Testosterone Replacement on the Incidence of High Grade Prostate Cancer Evidence of a relationship between TRT and the incidence of prostate cancer is mixed. In the Baltimore Longitudinal Study of Aging, aggressive prostate cancers were reported to be associated with higher levels of total and free testosterone.
Also, testosterone administration increases prostate specific antigen (PSA) in men and can promote the growth of metastatic prostate cancer.23 On the other hand, most population-based studies have not associated high total or free testosterone levels with increased cancer risk, and an analysis of the placebo arm from the Prostate Cancer Prevention Trial (PCPT) found no significant associations of total or free testosterone and risk of total, low (Gleason < 7) or high-grade (Gleason 7 – 10) prostate cancer. Occult prostate cancer is common in middle-aged and older men, and the prevalence increases with increases in PSA and age. The designers of the current study recognize that testosterone therapy increases PSA in circulation and thus, in the current study more men randomized to testosterone will be referred for prostate evaluation and possible biopsy based on this laboratory finding. Consequently, testosterone-treated men may have an increased risk of detection of subclinical prostate disease that was present prior to treatment. This inherent surveillance bias could result in a greater number of prostate biopsies that are positive for low-grade indolent prostate cancers in men randomized to the testosterone arm than in those randomized to the placebo arm. With this recognition of the inherent detection bias from testosterone treatment leading to the detection of low grade prostate cancers, this study will assess the effect of testosterone and placebo on the development of high grade prostate cancer, defined as Gleason 4 + 3 or greater. Benefits of Testosterone Therapy: While it has been suggested that the benefits of testosterone treatment are clearer in “classical hypogonadism,” data on TRT risks and benefits specifically in men without structural or genetic abnormalities that cause “classical hypogonadism” with very low circulating testosterone have only begun to emerge.
In men with a variety of comorbid conditions that result in testosterone levels below the accepted normal range (e.g., obesity, diabetes or other chronic diseases), TRT has been shown to increase lean body mass and bone mineral density (theoretically reducing the risk of bone fractures), decrease fat mass and improve sexual desire in most studies, while improvements in mood and energy have been inconsistent.32,33-36 Low testosterone levels are implicated as one of the many factors causing anemia, which is more prevalent with advancing age,37 and testosterone is known to increase hemoglobin (Hgb) levels, thereby presenting a potential benefit of TRT in hypogonadal men with anemia.34,38-41 Also, there is evidence to support a hypothesis that TRT may slow the progression to diabetes in hypogonadal men with prediabetes. There are limited data in men with age-associated and/or comorbidityassociated hypogonadism utilizing patient reported outcomes (PRO) tools created following the FDA guidance for PRO development. Given the opportunity that this protocol affords, the TRAVERSE study will analyze the effects of a testosterone gel (AndroGel 1.62%)1 in middle aged and older men with CV risk factors and/or CV disease on a number of efficacy endpoints that have demonstrated some level of responsiveness in previous TRT studies and that otherwise could not be studied in smaller studies of shorter duration. Specifically, the TRAVERSE study will address the effect of TRT on improving the following efficacy variables versus placebo:
● sexual activity and function in subjects with low libido at Baseline.
● remission of persistent depressive disorder (PDD) in subjects with low-gradePDD at Baseline.
● adjudicated clinical bone fractures.
● correction of anemia in subjects with anemia at Baseline.
● progression to diabetes in subjects with pre-diabetes at Baseline.