Cardiovascular Diseases, Hypogonadism
Conditions
Keywords
hypogonadism, cardiovascular (CV) disease, AndroGel, testosterone replacement therapy (TRT)
Brief summary
This is a double-blinded and placebo-controlled study of topical testosterone replacement therapy (TRT) in symptomatic hypogonadal men with pre-existing cardiovascular disease (CVD) or increased risk for CVD.
Interventions
DRUGAndroGel®
testosterone administered topically
DRUGPlacebo
placebo administered topically
Sponsors
Endo Pharmaceuticals
Acerus Pharmaceuticals Corporation
Allergan Sales, LLC
Upsher-Smith Laboratories
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
45 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Men between 45 and 80 years age * Participants with low serum testosterone concentrations (\< 300 ng/dL) who exhibit at least one sign or symptom of hypogonadism and have evidence of cardiovascular (CV) disease or are at an increased risk for CV disease.
Exclusion criteria
* Participants with congenital or acquired hypogonadism for whom long-term therapy with placebo would not be medically appropriate * Participants with prostate specific antigen (PSA) \> 3.0 ng/mL (or 1.5 if on 5-alpha reductase inhibitors) * Participants who have been treated with testosterone in the past 6 months and for whom testosterone therapy is contraindicated * Confirmed testosterone \< 100 ng/dL * Body Mass Index (BMI) \> 50 * Hemoglobin A1c (HbA1C) \> 11% * Hematocrit (Hct) \> 50% * Estimated Glomerular Filtration Rate (eGFR) \< 30 ml/min * History of deep vein thrombosis or pulmonary embolism or prostate cancer or heart failure (Class III and IV).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time From Randomization to the First Component Event of Major Adverse Cardiac Event (MACE): Number and Percentage of Participants With an Event | Randomization to event or last known date if no event (up to approximately 52 months) | MACE is a composite endpoint including non-fatal myocardial infraction (MI), non-fatal stroke and cardiovascular (CV) death as adjudicated by Clinical Events Committee (CEC). |
| Time From Randomization to the First Component Event of MACE | Randomization to event or last known date if no event (up to approximately 52 months) | MACE is a composite endpoint including non-fatal MI, non-fatal stroke and CV death as adjudicated by CEC. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time From Randomization to the First Component Event of CV Safety Endpoint: Number and Percentage of Participants With an Event | Randomization to event or last known date if no event (up to approximately 52 months). | The CV safety endpoint is a composite endpoint including non-fatal MI, non-fatal stroke, CV death, and coronary revascularization procedures/cardiac percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG) as adjudicated by CEC. |
| Time From Randomization to the First Component Event of CV Safety Endpoint | Randomization to event or last known date if no event (up to approximately 52 months). | The CV safety endpoint is a composite endpoint including non-fatal MI, non-fatal stroke, CV death, and coronary revascularization procedures/cardiac PCI, or CABG as adjudicated by CEC. |
| Incidence of High-Grade Prostate Cancer | Randomization to event or last known date if no event (up to approximately 52 months). | Presented as the number and percentage of participants with any high grade prostate cancer, defined as Gleason grade of 4 + 3 or higher, as adjudicated by Prostate Safety Events Committee (PAC). This grade is based on how abnormal prostate cells appear. Grade 1: cells look almost like normal prostate cells; Grade 5; cells look very different from normal prostate cells. Since most prostate cancers contain cells of different grades, the 2 most common grades are used. Gleason score is determined by adding the 2 most common grades. Higher numbers indicate a faster growing cancer that is more likely to spread. Currently the lowest score assigned to a tumor is grade 3. Grades below 3 show normal to near normal cells. Most cancers have a Gleason score (the sum of the 2 most common grades) of 6 (Gleason scores of 3+3) or 7 (Gleason scores of 3+4 or 4+3). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number and Percentage of Participants With Pre-Diabetes at Baseline Who Progressed to Diabetes at Months 6, 12, 24, 36 and 48 | Baseline, Months 6, 12, 24, 36 and 48 | Number and percentage of participants in each arm who had prediabetes at baseline progressing to diabetes, defined as hemoglobin A1C (HbA1C) equal to or higher than 6.5%, initiation of diabetes medication, or two consecutive fasting glucose levels \>125 mg/dL, assessed at all available time points after baseline. |
| Tertiary Endpoint: Incidence Rate of All Cause Mortality | Randomization to event or last known date if no date (up to approximately 52 months). | Presented as the number and percentage of participants who died, regardless of cause. |
| Tertiary Endpoint: Incidence Rate of Heart Failure | Randomization to event or last known date if no date (up to approximately 52 months). | Presented as the number and percentage of participants with heart failure events (requiring hospitalization and/or urgent visit), as adjudicated by CEC. |
| Tertiary Endpoint: Incidence Rate of Venous Thromboembolic Events | Randomization to event or last known date if no date (up to approximately 52 months). | Presented as the number and percentage of participants with venous thromboembolic events, as adjudicated by CEC. Events include deep vein thrombosis, pulmonary embolism, venous thromboembolism (excluding superficial thrombophlebitis). |
| Tertiary Endpoint: Incidence Rate of Peripheral Arterial Revascularization | Randomization to event or last known date if no event (up to approximately 52 months). | Presented as the number and percentage of participants with peripheral arterial revascularization, as adjudicated by CEC. |
| Change in Psychosexual Daily Questionnaire Question 4 (PDQ-Q4) From Baseline to Months 6, 12 and 24 | From Baseline to Months 6, 12, and 24 | PDQ-Q4 asks 12 yes/no questions about sexual activity. Scores on the PDQ-Q4 range from 0 to 12, with higher scores indicating more activity. |
| Tertiary Endpoint: Incidence Rate of Prostate Cancer | Randomization to event or last known date if no event (up to approximately 52 months). | Presented as the number and percentage of participants who with prostate cancer, as adjudicated by Prostate Safety Events Committee (PAC). |
| Tertiary Endpoint: Incidence Rate of Acute Urinary Retention | Randomization to event or last known date if no event (up to approximately 52 months). | Presented as the number and percentage of participants with acute urinary retention, as adjudicated by PAC. |
| Tertiary Endpoint: Incidence Rate of Pharmacologic Treatment for Lower Urinary Tract Symptoms | Randomization to event or last known date if no event (up to approximately 52 months). | Presented as the number and percentage of participants who started pharmacologic treatment for lower urinary tract symptoms. |
| Tertiary Endpoint: Incidence Rate of Invasive Prostate Surgical Procedures for Benign Prostatic Hyperplasia | Randomization to event or last known date if no event (up to approximately 52 months). | Presented as the number and percentage of participants who underwent invasive prostate surgical procedures for benign prostate hyperplasia, as adjudicated by Prostate Safety Events Committee (PAC). Invasive prostate surgical procedures include prostatectomy, transurethral prostate resection, brachytherapy or other prostate surgical procedure. |
| Tertiary Endpoint: Incidence Rate of Prostate Biopsy | Randomization to event or last known date if no event (up to approximately 52 months). | Presented as the number and percentage of participants who underwent prostate biopsy. |
| Number and Percentage of Participants Whose Persistent Depressive Disorder (PDD) Remits During Intervention Per Remission Definition | Months 6, 12, 24 | The remission of low-grade, late-onset PDD was defined as: a) Patient Health Questionnaire (PHQ-9) score less than 4 and Geriatric Depression Scale-15 (GDS-15) score \<5, and b) answer no to the question Give your best guess: Over the past 6 months, have you been feeling sad or depressed more days than not, even if you felt okay sometimes? The PHQ-9 is a 9-item depression scale. Total scores can range from 0 to 27, with higher scores indicating a worse outcome. A total score of 0-4 indicates minimal depression severity. The GDS-15 is a series of 15 yes/no questions asking how the participant felt in the past week. A score greater that 5 indicates depression; a higher score indicates a worse outcome. |
| Time From Randomization to First Clinical Fracture: Number and Percentage of Participants With an Event | Randomization to event or last known date if no event (up to approximately 52 months). | Clinical fracture is defined as a clinical spine or non-spine fracture, documented by imaging or surgery, and confirmed by the Fracture Adjudication Committee (FAC). Fractures of the sternum, fingers, toes, facial bones and skull were excluded. |
| Time From Randomization to First Clinical Fracture | Randomization to event or maximum follow-up (up to approximately 52 months). | Clinical fracture is defined as a clinical spine or non-spine fracture, documented by imaging or surgery, and confirmed by the FAC. Fractures of the sternum, fingers, toes, facial bones and skull were excluded. |
| Number and Percentage of Anemic Participants Whose Baseline Anemia Was Corrected During the Intervention Period | Baseline, Months 6, 12, 24, 36 and 48 | The correction of anemia was defined as an increase in hemoglobin level \>12.7 g/dL during the intervention period (at Months 6, 12, 24, 36 and 48) for participants in TRAVERSE main study with anemia at baseline. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
Participants were recruited in the study across 316 sites in the US and Puerto Rico.
Pre-assignment details
Of the 5246 participants randomized in the study, 42 participant identification numbers (IDs; AndroGel: 22 IDs; Placebo: 20 IDs) were randomized to 20 unique participants and these 42 duplicate/triplicate IDs were excluded from the Full Analysis Set. Additionally, a total of 6 randomized participants (AndroGel: 5 participants; Placebo: 1 participant) did not receive treatment and were excluded from the from the Safety Analysis Set, which resulted in 5198 participants in the Safety Analysis Set.
Participants by arm
| Arm | Count |
|---|---|
| AndroGel 1.62% Participants received topical testosterone starting with a 40.5 mg dose (2 pump actuations) of the study drug OD. Participants may have received a dose in the range of 20.25 mg (1 actuation) to 101.25 mg (5 actuations) in 20.25 mg increments during the course of the study if titrations were necessary. | 2,596 |
| Placebo Participants received matching placebo OD. | 2,602 |
| Total | 5,198 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 138 | 130 |
| Overall Study | COVID-19 Logistical Restriction | 7 | 3 |
| Overall Study | Lack of Efficacy | 11 | 23 |
| Overall Study | Lost to Follow-up | 446 | 458 |
| Overall Study | Not Treated | 5 | 1 |
| Overall Study | Other, Not Specified | 84 | 53 |
| Overall Study | Reason Missing | 2 | 3 |
| Overall Study | Serum Testosterone Level >750 ng/dL | 5 | 0 |
| Overall Study | Withdrawal by Subject | 309 | 351 |
Baseline characteristics
| Characteristic | Placebo | Total | AndroGel 1.62% |
|---|---|---|---|
| Age, Continuous | 63.3 years STANDARD_DEVIATION 7.85 | 63.3 years STANDARD_DEVIATION 7.89 | 63.3 years STANDARD_DEVIATION 7.93 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 439 Participants | 848 Participants | 409 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2161 Participants | 4347 Participants | 2186 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 14 Participants | 30 Participants | 16 Participants |
| Race (NIH/OMB) Asian | 47 Participants | 87 Participants | 40 Participants |
| Race (NIH/OMB) Black or African American | 432 Participants | 877 Participants | 445 Participants |
| Race (NIH/OMB) More than one race | 18 Participants | 33 Participants | 15 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 7 Participants | 21 Participants | 14 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 2083 Participants | 4149 Participants | 2066 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 2602 Participants | 5198 Participants | 2596 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2,601 | 0 / 2,603 | 144 / 2,601 | 148 / 2,603 |
| other Total, other adverse events | 0 / 0 | 0 / 0 | 160 / 2,601 | 170 / 2,603 |
| serious Total, serious adverse events | 19 / 2,601 | 10 / 2,603 | 585 / 2,601 | 562 / 2,603 |
Outcome results
Primary
Time From Randomization to the First Component Event of MACE
MACE is a composite endpoint including non-fatal MI, non-fatal stroke and CV death as adjudicated by CEC.
Time frame: Randomization to event or last known date if no event (up to approximately 52 months)
Population: TRAVERSE Main Study Safety Set: all randomized participants who received at least one dose of study drug and have no duplicate/triplicate participant IDs.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AndroGel 1.62% | Time From Randomization to the First Component Event of MACE | NA months |
| Placebo | Time From Randomization to the First Component Event of MACE | NA months |
Comparison: The hazard ratio (HR) and 2-sided 95% confidence interval (CI) were calculated using a Cox proportional-hazards regression model, with adjustment for pre-existing cardiovascular disease (CVD) status. In this analysis, the time to event for a participant is defined as the time from randomization to the first component event of MACE. If a subject does not experience a MACE during the study, the time is right-censored at the time of participant's last available follow-up observation.95% CI: [0.78, 1.17]
Primary
Time From Randomization to the First Component Event of Major Adverse Cardiac Event (MACE): Number and Percentage of Participants With an Event
MACE is a composite endpoint including non-fatal myocardial infraction (MI), non-fatal stroke and cardiovascular (CV) death as adjudicated by Clinical Events Committee (CEC).
Time frame: Randomization to event or last known date if no event (up to approximately 52 months)
Population: TRAVERSE Main Study Safety Set: all randomized participants who received at least one dose of study drug and have no duplicate/triplicate participant IDs.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AndroGel 1.62% | Time From Randomization to the First Component Event of Major Adverse Cardiac Event (MACE): Number and Percentage of Participants With an Event | 182 Participants |
| Placebo | Time From Randomization to the First Component Event of Major Adverse Cardiac Event (MACE): Number and Percentage of Participants With an Event | 190 Participants |
Secondary
Incidence of High-Grade Prostate Cancer
Presented as the number and percentage of participants with any high grade prostate cancer, defined as Gleason grade of 4 + 3 or higher, as adjudicated by Prostate Safety Events Committee (PAC). This grade is based on how abnormal prostate cells appear. Grade 1: cells look almost like normal prostate cells; Grade 5; cells look very different from normal prostate cells. Since most prostate cancers contain cells of different grades, the 2 most common grades are used. Gleason score is determined by adding the 2 most common grades. Higher numbers indicate a faster growing cancer that is more likely to spread. Currently the lowest score assigned to a tumor is grade 3. Grades below 3 show normal to near normal cells. Most cancers have a Gleason score (the sum of the 2 most common grades) of 6 (Gleason scores of 3+3) or 7 (Gleason scores of 3+4 or 4+3).
Time frame: Randomization to event or last known date if no event (up to approximately 52 months).
Population: TRAVERSE Main Study Safety Set: all randomized participants who received at least one dose of study drug and have no duplicate/triplicate participant IDs.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AndroGel 1.62% | Incidence of High-Grade Prostate Cancer | 5 Participants |
| Placebo | Incidence of High-Grade Prostate Cancer | 3 Participants |
Comparison: The high grade prostate cancer endpoint was analyzed using a discrete time proportional hazard regression model with event time intervals based on scheduled visits, and adjusting for pre-existing CVD status. The HR of AndroGel to Placebo and its 2-sided 95% CI were provided.95% CI: [0.39, 6.77]
Secondary
Time From Randomization to the First Component Event of CV Safety Endpoint
The CV safety endpoint is a composite endpoint including non-fatal MI, non-fatal stroke, CV death, and coronary revascularization procedures/cardiac PCI, or CABG as adjudicated by CEC.
Time frame: Randomization to event or last known date if no event (up to approximately 52 months).
Population: TRAVERSE Main Study Safety Set: all randomized participants who received at least one dose of study drug and have no duplicate/triplicate participant IDs.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AndroGel 1.62% | Time From Randomization to the First Component Event of CV Safety Endpoint | NA months |
| Placebo | Time From Randomization to the First Component Event of CV Safety Endpoint | NA months |
Comparison: The HR and 2-sided 95% CI were calculated using a Cox proportional-hazards regression model, with adjustment for pre-existing CVD status. In this analysis, the time to event for a participant is defined as the time from randomization to the first component event of CV safety endpoint. If a participant does not experience a CV safety endpoint during the study, the time is right-censored at the time of participant's last available follow-up observation.95% CI: [0.86, 1.21]
Secondary
Time From Randomization to the First Component Event of CV Safety Endpoint: Number and Percentage of Participants With an Event
The CV safety endpoint is a composite endpoint including non-fatal MI, non-fatal stroke, CV death, and coronary revascularization procedures/cardiac percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG) as adjudicated by CEC.
Time frame: Randomization to event or last known date if no event (up to approximately 52 months).
Population: TRAVERSE Main Study Safety Set: all randomized participants who received at least one dose of study drug and have no duplicate/triplicate participant IDs.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AndroGel 1.62% | Time From Randomization to the First Component Event of CV Safety Endpoint: Number and Percentage of Participants With an Event | 269 Participants |
| Placebo | Time From Randomization to the First Component Event of CV Safety Endpoint: Number and Percentage of Participants With an Event | 264 Participants |
Other Pre-specified
Change in Psychosexual Daily Questionnaire Question 4 (PDQ-Q4) From Baseline to Months 6, 12 and 24
PDQ-Q4 asks 12 yes/no questions about sexual activity. Scores on the PDQ-Q4 range from 0 to 12, with higher scores indicating more activity.
Time frame: From Baseline to Months 6, 12, and 24
Population: TRAVERSE Sexual Function Sub-Study: participants in the TRAVERSE main study full analysis set (i.e., randomized, no duplicate/triplicate participant IDs) who were eligible for the sexual function sub-study.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| AndroGel 1.62% | Change in Psychosexual Daily Questionnaire Question 4 (PDQ-Q4) From Baseline to Months 6, 12 and 24 | Change at Month 24 | 0.94 score on a scale |
| AndroGel 1.62% | Change in Psychosexual Daily Questionnaire Question 4 (PDQ-Q4) From Baseline to Months 6, 12 and 24 | Change at Month 6 | 1.03 score on a scale |
| AndroGel 1.62% | Change in Psychosexual Daily Questionnaire Question 4 (PDQ-Q4) From Baseline to Months 6, 12 and 24 | Change at Month 12 | 0.97 score on a scale |
| Placebo | Change in Psychosexual Daily Questionnaire Question 4 (PDQ-Q4) From Baseline to Months 6, 12 and 24 | Change at Month 12 | 0.50 score on a scale |
| Placebo | Change in Psychosexual Daily Questionnaire Question 4 (PDQ-Q4) From Baseline to Months 6, 12 and 24 | Change at Month 6 | 0.54 score on a scale |
| Placebo | Change in Psychosexual Daily Questionnaire Question 4 (PDQ-Q4) From Baseline to Months 6, 12 and 24 | Change at Month 24 | 0.46 score on a scale |
Comparison: A linear mixed regression model was used to analyze the change in PDQ-Q4 from baseline to months 6, 12, and 24, with the dependent variable being the change in PDQ-Q4 score. The model included fixed effects for treatment, visit, and the interaction between treatment and visit, while adjusting for baseline PDQ-Q4 score and pre-existing CVD status. An unstructured covariance matrix was used to account for correlations among repeated measures within-subject.p-value: 0.011linear mixed regression model
Comparison: Month 6 (results were derived from a linear mixed regression model that had a dependent variable of the change in PDQ-Q4 from baseline to months 6, 12, and 24. The model included fixed effects for treatment, visit, and the interaction between treatment and visit, while adjusting for baseline PDQ-Q4 score and pre-existing CV disease status. Additionally, an unstructured covariance matrix was used to account for correlations among repeated measures within participants).95% CI: [0.19, 0.79]
Comparison: Month 12 (results were derived from a linear mixed regression model that had a dependent variable of the change in PDQ-Q4 from baseline to months 6, 12, and 24. The model included fixed effects for treatment, visit, and the interaction between treatment and visit, while adjusting for baseline PDQ-Q4 score and pre-existing CV disease status. Additionally, an unstructured covariance matrix was used to account for correlations among repeated measures within participants).95% CI: [0.11, 0.83]
Comparison: Month 24 (results were derived from a linear mixed regression model that had a dependent variable of the change in PDQ-Q4 from baseline to months 6, 12, and 24. The model included fixed effects for treatment, visit, and the interaction between treatment and visit, while adjusting for baseline PDQ-Q4 score and pre-existing CV disease status. Additionally, an unstructured covariance matrix was used to account for correlations among repeated measures within participants).95% CI: [-0.01, 0.96]
Other Pre-specified
Number and Percentage of Anemic Participants Whose Baseline Anemia Was Corrected During the Intervention Period
The correction of anemia was defined as an increase in hemoglobin level \>12.7 g/dL during the intervention period (at Months 6, 12, 24, 36 and 48) for participants in TRAVERSE main study with anemia at baseline.
Time frame: Baseline, Months 6, 12, 24, 36 and 48
Population: All randomized participants in TRAVERSE main study who had anemia at baseline; participants with an assessment at given time point.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AndroGel 1.62% | Number and Percentage of Anemic Participants Whose Baseline Anemia Was Corrected During the Intervention Period | Month 12 | 152 Participants |
| AndroGel 1.62% | Number and Percentage of Anemic Participants Whose Baseline Anemia Was Corrected During the Intervention Period | Month 36 | 94 Participants |
| AndroGel 1.62% | Number and Percentage of Anemic Participants Whose Baseline Anemia Was Corrected During the Intervention Period | Month 24 | 124 Participants |
| AndroGel 1.62% | Number and Percentage of Anemic Participants Whose Baseline Anemia Was Corrected During the Intervention Period | Month 48 | 41 Participants |
| AndroGel 1.62% | Number and Percentage of Anemic Participants Whose Baseline Anemia Was Corrected During the Intervention Period | Month 6 | 143 Participants |
| Placebo | Number and Percentage of Anemic Participants Whose Baseline Anemia Was Corrected During the Intervention Period | Month 48 | 38 Participants |
| Placebo | Number and Percentage of Anemic Participants Whose Baseline Anemia Was Corrected During the Intervention Period | Month 6 | 103 Participants |
| Placebo | Number and Percentage of Anemic Participants Whose Baseline Anemia Was Corrected During the Intervention Period | Month 12 | 122 Participants |
| Placebo | Number and Percentage of Anemic Participants Whose Baseline Anemia Was Corrected During the Intervention Period | Month 24 | 95 Participants |
| Placebo | Number and Percentage of Anemic Participants Whose Baseline Anemia Was Corrected During the Intervention Period | Month 36 | 76 Participants |
Comparison: Repeated measures log-binomial regression with effects for treatment, visit, treatment-by-visit interaction, and adjusted for pre-existing CVD, and an unstructured covariance matrix to account for correlations among repeated measures within-subject.p-value: 0.002omnibus likelihood-ratio chi-square test
Other Pre-specified
Number and Percentage of Participants Whose Persistent Depressive Disorder (PDD) Remits During Intervention Per Remission Definition
The remission of low-grade, late-onset PDD was defined as: a) Patient Health Questionnaire (PHQ-9) score less than 4 and Geriatric Depression Scale-15 (GDS-15) score \<5, and b) answer no to the question Give your best guess: Over the past 6 months, have you been feeling sad or depressed more days than not, even if you felt okay sometimes? The PHQ-9 is a 9-item depression scale. Total scores can range from 0 to 27, with higher scores indicating a worse outcome. A total score of 0-4 indicates minimal depression severity. The GDS-15 is a series of 15 yes/no questions asking how the participant felt in the past week. A score greater that 5 indicates depression; a higher score indicates a worse outcome.
Time frame: Months 6, 12, 24
Population: PDD Sub-Study participants (those included TRAVERSE main study full analysis set participants \[i.e., randomized, no duplicate/triplicate participant IDs\] who met the criteria for low-grade PDD) with an assessment at given time point.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AndroGel 1.62% | Number and Percentage of Participants Whose Persistent Depressive Disorder (PDD) Remits During Intervention Per Remission Definition | Month 6 | 12 Participants |
| AndroGel 1.62% | Number and Percentage of Participants Whose Persistent Depressive Disorder (PDD) Remits During Intervention Per Remission Definition | Month 12 | 7 Participants |
| AndroGel 1.62% | Number and Percentage of Participants Whose Persistent Depressive Disorder (PDD) Remits During Intervention Per Remission Definition | Month 24 | 5 Participants |
| Placebo | Number and Percentage of Participants Whose Persistent Depressive Disorder (PDD) Remits During Intervention Per Remission Definition | Month 6 | 6 Participants |
| Placebo | Number and Percentage of Participants Whose Persistent Depressive Disorder (PDD) Remits During Intervention Per Remission Definition | Month 12 | 5 Participants |
| Placebo | Number and Percentage of Participants Whose Persistent Depressive Disorder (PDD) Remits During Intervention Per Remission Definition | Month 24 | 5 Participants |
Comparison: Month 6 risk ratio of remission of LG-PDD in the AndroGel versus placebo group was estimated by a repeated measures generalized estimating equations (GEE) Poisson regression model with fixed effects for treatment, visit, treatment-visit interaction, pre- existing CVD, and an unstructured working correlation matrix to account for repeated measures at multiple visits.95% CI: [0.96, 3.86]
Comparison: Month 12 risk ratio of remission of LG-PDD in the AndroGel versus placebo group was estimated by a repeated measures generalized estimating equations (GEE) Poisson regression model with fixed effects for treatment, visit, treatment-visit interaction, pre- existing CVD, and an unstructured working correlation matrix to account for repeated measures at multiple visits.95% CI: [0.64, 3.63]
Comparison: Month 24 risk ratio of remission of LG-PDD in the AndroGel versus placebo group was estimated by a repeated measures generalized estimating equations (GEE) Poisson regression model with fixed effects for treatment, visit, treatment-visit interaction, pre- existing CVD, and an unstructured working correlation matrix to account for repeated measures at multiple visits.95% CI: [0.42, 1.94]
Comparison: Risk ratio of remission of LG-PDD in the TRT versus placebo group was estimated by a repeated measures generalized estimating equations (GEE) Poisson regression model with fixed effects for treatment, visit, treatment-visit interaction, pre- existing CVD, and an unstructured working correlation matrix to account for repeated measures at multiple visits.p-value: 0.197GEE Poisson regression model
Other Pre-specified
Number and Percentage of Participants With Pre-Diabetes at Baseline Who Progressed to Diabetes at Months 6, 12, 24, 36 and 48
Number and percentage of participants in each arm who had prediabetes at baseline progressing to diabetes, defined as hemoglobin A1C (HbA1C) equal to or higher than 6.5%, initiation of diabetes medication, or two consecutive fasting glucose levels \>125 mg/dL, assessed at all available time points after baseline.
Time frame: Baseline, Months 6, 12, 24, 36 and 48
Population: All randomized participants in TRAVERSE main study who had prediabetes at baseline; participants with an assessment at given time point.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AndroGel 1.62% | Number and Percentage of Participants With Pre-Diabetes at Baseline Who Progressed to Diabetes at Months 6, 12, 24, 36 and 48 | Month 12 | 45 Participants |
| AndroGel 1.62% | Number and Percentage of Participants With Pre-Diabetes at Baseline Who Progressed to Diabetes at Months 6, 12, 24, 36 and 48 | Month 36 | 46 Participants |
| AndroGel 1.62% | Number and Percentage of Participants With Pre-Diabetes at Baseline Who Progressed to Diabetes at Months 6, 12, 24, 36 and 48 | Month 24 | 50 Participants |
| AndroGel 1.62% | Number and Percentage of Participants With Pre-Diabetes at Baseline Who Progressed to Diabetes at Months 6, 12, 24, 36 and 48 | Month 48 | 22 Participants |
| AndroGel 1.62% | Number and Percentage of Participants With Pre-Diabetes at Baseline Who Progressed to Diabetes at Months 6, 12, 24, 36 and 48 | Month 6 | 4 Participants |
| Placebo | Number and Percentage of Participants With Pre-Diabetes at Baseline Who Progressed to Diabetes at Months 6, 12, 24, 36 and 48 | Month 48 | 19 Participants |
| Placebo | Number and Percentage of Participants With Pre-Diabetes at Baseline Who Progressed to Diabetes at Months 6, 12, 24, 36 and 48 | Month 6 | 8 Participants |
| Placebo | Number and Percentage of Participants With Pre-Diabetes at Baseline Who Progressed to Diabetes at Months 6, 12, 24, 36 and 48 | Month 12 | 57 Participants |
| Placebo | Number and Percentage of Participants With Pre-Diabetes at Baseline Who Progressed to Diabetes at Months 6, 12, 24, 36 and 48 | Month 24 | 67 Participants |
| Placebo | Number and Percentage of Participants With Pre-Diabetes at Baseline Who Progressed to Diabetes at Months 6, 12, 24, 36 and 48 | Month 36 | 52 Participants |
Comparison: The risk ratio of progression to diabetes in the AndroGel versus placebo group was estimated by a repeated measures log-binomial regression with fixed effects for treatment, visit, treatment-visit interaction, and pre-existing CVD, and an unstructured covariance matrix to account for correlations among repeated measures within-subject.p-value: 0.494Repeated measures log-binomial regr.
Other Pre-specified
Tertiary Endpoint: Incidence Rate of Acute Urinary Retention
Presented as the number and percentage of participants with acute urinary retention, as adjudicated by PAC.
Time frame: Randomization to event or last known date if no event (up to approximately 52 months).
Population: TRAVERSE Main Study Safety Set: all randomized participants who received at least one dose of study drug and have no duplicate/triplicate participant IDs.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AndroGel 1.62% | Tertiary Endpoint: Incidence Rate of Acute Urinary Retention | 20 Participants |
| Placebo | Tertiary Endpoint: Incidence Rate of Acute Urinary Retention | 16 Participants |
95% CI: [0.65, 2.41]
Other Pre-specified
Tertiary Endpoint: Incidence Rate of All Cause Mortality
Presented as the number and percentage of participants who died, regardless of cause.
Time frame: Randomization to event or last known date if no date (up to approximately 52 months).
Population: TRAVERSE Main Study Safety Set: all randomized participants who received at least one dose of study drug and have no duplicate/triplicate participant IDs.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AndroGel 1.62% | Tertiary Endpoint: Incidence Rate of All Cause Mortality | 144 Participants |
| Placebo | Tertiary Endpoint: Incidence Rate of All Cause Mortality | 148 Participants |
95% CI: [0.78, 1.23]
Other Pre-specified
Tertiary Endpoint: Incidence Rate of Heart Failure
Presented as the number and percentage of participants with heart failure events (requiring hospitalization and/or urgent visit), as adjudicated by CEC.
Time frame: Randomization to event or last known date if no date (up to approximately 52 months).
Population: TRAVERSE Main Study Safety Set: all randomized participants who received at least one dose of study drug and have no duplicate/triplicate participant IDs.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AndroGel 1.62% | Tertiary Endpoint: Incidence Rate of Heart Failure | 55 Participants |
| Placebo | Tertiary Endpoint: Incidence Rate of Heart Failure | 50 Participants |
95% CI: [0.76, 1.62]
Other Pre-specified
Tertiary Endpoint: Incidence Rate of Invasive Prostate Surgical Procedures for Benign Prostatic Hyperplasia
Presented as the number and percentage of participants who underwent invasive prostate surgical procedures for benign prostate hyperplasia, as adjudicated by Prostate Safety Events Committee (PAC). Invasive prostate surgical procedures include prostatectomy, transurethral prostate resection, brachytherapy or other prostate surgical procedure.
Time frame: Randomization to event or last known date if no event (up to approximately 52 months).
Population: TRAVERSE Main Study Safety Set: all randomized participants who received at least one dose of study drug and have no duplicate/triplicate participant IDs.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AndroGel 1.62% | Tertiary Endpoint: Incidence Rate of Invasive Prostate Surgical Procedures for Benign Prostatic Hyperplasia | 23 Participants |
| Placebo | Tertiary Endpoint: Incidence Rate of Invasive Prostate Surgical Procedures for Benign Prostatic Hyperplasia | 12 Participants |
95% CI: [0.95, 3.84]
Other Pre-specified
Tertiary Endpoint: Incidence Rate of Peripheral Arterial Revascularization
Presented as the number and percentage of participants with peripheral arterial revascularization, as adjudicated by CEC.
Time frame: Randomization to event or last known date if no event (up to approximately 52 months).
Population: TRAVERSE Main Study Safety Set: all randomized participants who received at least one dose of study drug and have no duplicate/triplicate participant IDs.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AndroGel 1.62% | Tertiary Endpoint: Incidence Rate of Peripheral Arterial Revascularization | 30 Participants |
| Placebo | Tertiary Endpoint: Incidence Rate of Peripheral Arterial Revascularization | 33 Participants |
95% CI: [0.56, 1.51]
Other Pre-specified
Tertiary Endpoint: Incidence Rate of Pharmacologic Treatment for Lower Urinary Tract Symptoms
Presented as the number and percentage of participants who started pharmacologic treatment for lower urinary tract symptoms.
Time frame: Randomization to event or last known date if no event (up to approximately 52 months).
Population: TRAVERSE Main Study Safety Set: all randomized participants who received at least one dose of study drug and have no duplicate/triplicate participant IDs.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AndroGel 1.62% | Tertiary Endpoint: Incidence Rate of Pharmacologic Treatment for Lower Urinary Tract Symptoms | 101 Participants |
| Placebo | Tertiary Endpoint: Incidence Rate of Pharmacologic Treatment for Lower Urinary Tract Symptoms | 87 Participants |
95% CI: [0.87, 1.54]
Other Pre-specified
Tertiary Endpoint: Incidence Rate of Prostate Biopsy
Presented as the number and percentage of participants who underwent prostate biopsy.
Time frame: Randomization to event or last known date if no event (up to approximately 52 months).
Population: TRAVERSE Main Study Safety Set: all randomized participants who received at least one dose of study drug and have no duplicate/triplicate participant IDs.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AndroGel 1.62% | Tertiary Endpoint: Incidence Rate of Prostate Biopsy | 16 Participants |
| Placebo | Tertiary Endpoint: Incidence Rate of Prostate Biopsy | 14 Participants |
95% CI: [0.55, 2.31]
Other Pre-specified
Tertiary Endpoint: Incidence Rate of Prostate Cancer
Presented as the number and percentage of participants who with prostate cancer, as adjudicated by Prostate Safety Events Committee (PAC).
Time frame: Randomization to event or last known date if no event (up to approximately 52 months).
Population: TRAVERSE Main Study Safety Set: all randomized participants who received at least one dose of study drug and have no duplicate/triplicate participant IDs.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AndroGel 1.62% | Tertiary Endpoint: Incidence Rate of Prostate Cancer | 12 Participants |
| Placebo | Tertiary Endpoint: Incidence Rate of Prostate Cancer | 11 Participants |
95% CI: [0.47, 2.42]
Other Pre-specified
Tertiary Endpoint: Incidence Rate of Venous Thromboembolic Events
Presented as the number and percentage of participants with venous thromboembolic events, as adjudicated by CEC. Events include deep vein thrombosis, pulmonary embolism, venous thromboembolism (excluding superficial thrombophlebitis).
Time frame: Randomization to event or last known date if no date (up to approximately 52 months).
Population: TRAVERSE Main Study Safety Set: all randomized participants who received at least one dose of study drug and have no duplicate/triplicate participant IDs.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AndroGel 1.62% | Tertiary Endpoint: Incidence Rate of Venous Thromboembolic Events | 44 Participants |
| Placebo | Tertiary Endpoint: Incidence Rate of Venous Thromboembolic Events | 30 Participants |
95% CI: [0.92, 2.32]
Other Pre-specified
Time From Randomization to First Clinical Fracture
Clinical fracture is defined as a clinical spine or non-spine fracture, documented by imaging or surgery, and confirmed by the FAC. Fractures of the sternum, fingers, toes, facial bones and skull were excluded.
Time frame: Randomization to event or maximum follow-up (up to approximately 52 months).
Population: TRAVERSE Main Study Full Analysis Set: all randomized participants without duplicate/triplicate participant IDs.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AndroGel 1.62% | Time From Randomization to First Clinical Fracture | NA months |
| Placebo | Time From Randomization to First Clinical Fracture | NA months |
Comparison: The HR and 2-sided 95% CI were calculated using a Cox proportional-hazards regression model, with adjustment for pre-existing CVD status. In this analysis, the time to event for a subject is defined as the time from randomization to the first occurrence of a clinical fracture. If a subject does not experience a clinic fracture during the study, the follow-up time is right-censored at the time of subject's last available follow-up observation.95% CI: [1.04, 1.97]
Other Pre-specified
Time From Randomization to First Clinical Fracture: Number and Percentage of Participants With an Event
Clinical fracture is defined as a clinical spine or non-spine fracture, documented by imaging or surgery, and confirmed by the Fracture Adjudication Committee (FAC). Fractures of the sternum, fingers, toes, facial bones and skull were excluded.
Time frame: Randomization to event or last known date if no event (up to approximately 52 months).
Population: TRAVERSE Main Study Full Analysis Set: all randomized participants without duplicate/triplicate participant IDs.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AndroGel 1.62% | Time From Randomization to First Clinical Fracture: Number and Percentage of Participants With an Event | 91 Participants |
| Placebo | Time From Randomization to First Clinical Fracture: Number and Percentage of Participants With an Event | 64 Participants |