madman
Super Moderator
ABSTRACT
Background: Testosterone exerts some effects on the cardiovascular system that could be considered beneficial; some other effects may potentially increase the risk of cardiovascular (CV) events. Neither the long-term efficacy nor safety of testosterone treatment has been studied in an adequately powered randomized trial.
Study Design: The Testosterone Replacement Therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study is a randomized, double-blind, placebo-controlled, parallel-group, non-inferiority, multicenter study. Eligible participants are men, 45 to 80 years, with serum testosterone concentration <300 ng/dL and hypogonadal symptoms, who have evidence of pre-existing CV disease or increased risk of CV disease. Approximately 6,000 subjects will be randomized to either 1.62% transdermal testosterone gel or a matching placebo gel daily for an anticipated duration of up to 5 years. The primary outcome is CV safety defined by the major adverse CV event (MACE) composite of nonfatal myocardial infarction, nonfatal stroke, or death due to CV causes. The trial will continue until at least 256 adjudicated MACE endpoints have occurred to assess whether the 95% (2- sided) upper confidence limit for a hazard ratio of 1.5 can be ruled out. Secondary endpoints include prostate safety defined as the incidence of adjudicated high-grade prostate cancer and efficacy in domains of sexual function, bone fractures, depression, anemia, and diabetes. As of July 1, 2021, 5,076 subjects had been randomized.
Conclusions: The TRAVERSE study will determine the CV safety and long-term efficacy of testosterone treatment in middle-aged and older men with hypogonadism with or at increased risk of CV disease.
INTRODUCTION
Testosterone replacement therapy (TRT) is approved for the treatment of hypogonadism associated with known diseases of the testis, pituitary, and the hypothalamus, but it is not approved by the United States Food and Drug Administration (FDA) for the treatment of age-associated decline in testosterone levels (1). Prior to the development of radioimmunoassays for the measurement of circulating testosterone levels, men diagnosed with severe hypogonadism typically suffered from clinically apparent testosterone deficiency, in whom the diagnosis relied upon the loss of secondary sex characteristics, gynecomastia, and small testes. In young men with severe hypogonadism, testosterone treatment-induced visible changes in secondary sex characteristics and body habitus and restored sexual function with low frequency of adverse events. However, 80% of testosterone prescriptions have historically been written for men 45 - 74 years (1-2), who often report symptoms that are also common with aging; testosterone levels in these middle-aged and older men are typically either in the low-normal range or only mildly reduced, and these men have few overt physical signs of testosterone deficiency. Neither the long-term efficacy nor the long-term safety of testosterone treatment in middle-aged and older men with age-related decline in testosterone levels has been demonstrated in adequately powered randomized trials (3).
Between the years 2000 and 2013, the prescription sales of testosterone products underwent explosive growth (4-5), driven by several historical factors, including direct-to-consumer advertising of testosterone products; the availability of easy-to-use transdermal testosterone products; and the development of men's health clinics that catered almost exclusively to men's sexual and genitourinary problems (6). In 2013, in response to a petition by a citizen's interest group and conflicting reports of cardiovascular (CV) events from small clinical trials, retrospective analyses of medical records data, and pharmacovigilance studies of testosterone-treated men, the FDA conducted an extensive review of the available information (7). FDA concluded that “the studies...have significant limitations that weaken their evidentiary value for confirming a causal relationship between testosterone and adverse cardiovascular outcomes”. An independent review conducted by the European Medicines Agency also found no consistent evidence of an increased risk of coronary heart disease associated with testosterone treatment of men with hypogonadism. Given the broad and growing use of TRT among middle-aged and older men with or at risk for CV disease, the FDA issued updated testosterone labeling inclusive of a limitation of use in men with “age-related hypogonadism”, along with a guidance “… requiring manufacturers of approved testosterone products to conduct a well-designed clinical trial to more clearly address the question of whether an increased risk of heart attack or stroke exists among users of these products.” The Testosterone Replacement Therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study was designed in response to this FDA guidance to determine the effects of testosterone treatment on the incidence of major adverse CV events in middle-aged and older men with hypogonadism with or at high risk of CV disease.
*TESTOSTERONE TREATMENT AND THE RISK OF CARDIOVASCULAR EVENTS
-Physiologic effects of testosterone on the cardiovascular system.
-Epidemiological studies of the association of endogenous testosterone levels with cardiovascular disease
-Retrospective analyses of testosterone replacement therapy
-Randomized Trials
*Uncertainty About the Effects of Testosterone Therapy on Prostate Health
*Gaps in the Current Understanding of the Efficacy of Testosterone Replacement Therapy
*TRAVERSE STUDY OBJECTIVES AND DESIGN
-Study Population
-Intervention and Management
*Study Outcomes
-Safety Outcomes
-Efficacy Outcomes
A limited number of pre-specified efficacy endpoints are included as secondary outcomes in five efficacy domains (Table 2). The following efficacy endpoints will be evaluated in sub-studies or analyses of subpopulations using validated patient-reported outcome (PRO) questionnaires:
1. Improvement in sexual activity in hypogonadal men with low libido
2. Remission of depression in hypogonadal men with late-onset, low-grade PDD
3. Reduction in the incidence of clinical fractures
4. Correction of anemia in a subset of participants with baseline anemia, and incidence of anemia among randomized subjects who did not have anemia at baseline
5. Reduction in progression from pre-diabetes to diabetes in a subset of participants with prediabetes at baseline, and glycemic remission in a subset of participants with diabetes at baseline
*STATISTICAL ANALYSES
*Determination of Sample Size
*STUDY ORGANIZATION
PERSPECTIVE
TRAVERSE is the largest and longest duration randomized study of TRT ever conducted. With a greater number of MACE endpoints than all other randomized trials to date combined, TRAVERSE will address the uncertainty regarding CV safety of this therapy among middle-aged or older men with or at high risk for CV disease. By virtue of its large sample size and treatment duration, this study will also allow assessment of prostate safety and provide potentially useful information regarding the long-term efficacy of TRT in improving sexual function, depressive symptoms, anemia, progression from prediabetes to diabetes, or glycemic remission in those with diabetes, and risk of bone fractures.
Background: Testosterone exerts some effects on the cardiovascular system that could be considered beneficial; some other effects may potentially increase the risk of cardiovascular (CV) events. Neither the long-term efficacy nor safety of testosterone treatment has been studied in an adequately powered randomized trial.
Study Design: The Testosterone Replacement Therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study is a randomized, double-blind, placebo-controlled, parallel-group, non-inferiority, multicenter study. Eligible participants are men, 45 to 80 years, with serum testosterone concentration <300 ng/dL and hypogonadal symptoms, who have evidence of pre-existing CV disease or increased risk of CV disease. Approximately 6,000 subjects will be randomized to either 1.62% transdermal testosterone gel or a matching placebo gel daily for an anticipated duration of up to 5 years. The primary outcome is CV safety defined by the major adverse CV event (MACE) composite of nonfatal myocardial infarction, nonfatal stroke, or death due to CV causes. The trial will continue until at least 256 adjudicated MACE endpoints have occurred to assess whether the 95% (2- sided) upper confidence limit for a hazard ratio of 1.5 can be ruled out. Secondary endpoints include prostate safety defined as the incidence of adjudicated high-grade prostate cancer and efficacy in domains of sexual function, bone fractures, depression, anemia, and diabetes. As of July 1, 2021, 5,076 subjects had been randomized.
Conclusions: The TRAVERSE study will determine the CV safety and long-term efficacy of testosterone treatment in middle-aged and older men with hypogonadism with or at increased risk of CV disease.
INTRODUCTION
Testosterone replacement therapy (TRT) is approved for the treatment of hypogonadism associated with known diseases of the testis, pituitary, and the hypothalamus, but it is not approved by the United States Food and Drug Administration (FDA) for the treatment of age-associated decline in testosterone levels (1). Prior to the development of radioimmunoassays for the measurement of circulating testosterone levels, men diagnosed with severe hypogonadism typically suffered from clinically apparent testosterone deficiency, in whom the diagnosis relied upon the loss of secondary sex characteristics, gynecomastia, and small testes. In young men with severe hypogonadism, testosterone treatment-induced visible changes in secondary sex characteristics and body habitus and restored sexual function with low frequency of adverse events. However, 80% of testosterone prescriptions have historically been written for men 45 - 74 years (1-2), who often report symptoms that are also common with aging; testosterone levels in these middle-aged and older men are typically either in the low-normal range or only mildly reduced, and these men have few overt physical signs of testosterone deficiency. Neither the long-term efficacy nor the long-term safety of testosterone treatment in middle-aged and older men with age-related decline in testosterone levels has been demonstrated in adequately powered randomized trials (3).
Between the years 2000 and 2013, the prescription sales of testosterone products underwent explosive growth (4-5), driven by several historical factors, including direct-to-consumer advertising of testosterone products; the availability of easy-to-use transdermal testosterone products; and the development of men's health clinics that catered almost exclusively to men's sexual and genitourinary problems (6). In 2013, in response to a petition by a citizen's interest group and conflicting reports of cardiovascular (CV) events from small clinical trials, retrospective analyses of medical records data, and pharmacovigilance studies of testosterone-treated men, the FDA conducted an extensive review of the available information (7). FDA concluded that “the studies...have significant limitations that weaken their evidentiary value for confirming a causal relationship between testosterone and adverse cardiovascular outcomes”. An independent review conducted by the European Medicines Agency also found no consistent evidence of an increased risk of coronary heart disease associated with testosterone treatment of men with hypogonadism. Given the broad and growing use of TRT among middle-aged and older men with or at risk for CV disease, the FDA issued updated testosterone labeling inclusive of a limitation of use in men with “age-related hypogonadism”, along with a guidance “… requiring manufacturers of approved testosterone products to conduct a well-designed clinical trial to more clearly address the question of whether an increased risk of heart attack or stroke exists among users of these products.” The Testosterone Replacement Therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study was designed in response to this FDA guidance to determine the effects of testosterone treatment on the incidence of major adverse CV events in middle-aged and older men with hypogonadism with or at high risk of CV disease.
*TESTOSTERONE TREATMENT AND THE RISK OF CARDIOVASCULAR EVENTS
-Physiologic effects of testosterone on the cardiovascular system.
-Epidemiological studies of the association of endogenous testosterone levels with cardiovascular disease
-Retrospective analyses of testosterone replacement therapy
-Randomized Trials
*Uncertainty About the Effects of Testosterone Therapy on Prostate Health
*Gaps in the Current Understanding of the Efficacy of Testosterone Replacement Therapy
*TRAVERSE STUDY OBJECTIVES AND DESIGN
-Study Population
-Intervention and Management
*Study Outcomes
-Safety Outcomes
-Efficacy Outcomes
A limited number of pre-specified efficacy endpoints are included as secondary outcomes in five efficacy domains (Table 2). The following efficacy endpoints will be evaluated in sub-studies or analyses of subpopulations using validated patient-reported outcome (PRO) questionnaires:
1. Improvement in sexual activity in hypogonadal men with low libido
2. Remission of depression in hypogonadal men with late-onset, low-grade PDD
3. Reduction in the incidence of clinical fractures
4. Correction of anemia in a subset of participants with baseline anemia, and incidence of anemia among randomized subjects who did not have anemia at baseline
5. Reduction in progression from pre-diabetes to diabetes in a subset of participants with prediabetes at baseline, and glycemic remission in a subset of participants with diabetes at baseline
*STATISTICAL ANALYSES
*Determination of Sample Size
*STUDY ORGANIZATION
PERSPECTIVE
TRAVERSE is the largest and longest duration randomized study of TRT ever conducted. With a greater number of MACE endpoints than all other randomized trials to date combined, TRAVERSE will address the uncertainty regarding CV safety of this therapy among middle-aged or older men with or at high risk for CV disease. By virtue of its large sample size and treatment duration, this study will also allow assessment of prostate safety and provide potentially useful information regarding the long-term efficacy of TRT in improving sexual function, depressive symptoms, anemia, progression from prediabetes to diabetes, or glycemic remission in those with diabetes, and risk of bone fractures.
