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A Study to Evaluate the Effect of Testosterone Replacement Therapy (TRT) on the Incidence of Major Adverse Cardiovascular Events (MACE) and Efficacy Measures in Hypogonadal Men (TRAVERSE)

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ClinicalTrials.gov Identifier: NCT03518034
Recruitment Status : Completed
First Posted : May 8, 2018
Results First Posted : March 13, 2024
Last Update Posted : March 13, 2024
Sponsor:
Collaborators:
Endo Pharmaceuticals
Acerus Pharmaceuticals Corporation
Allergan Sales, LLC
Upsher-Smith Laboratories LLC
Information provided by (Responsible Party):
AbbVie

Study Description
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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.

Condition or disease Intervention/treatment Phase
Hypogonadism Cardiovascular Diseases Drug: AndroGel® Drug: Placebo Phase 4

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5246 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy ResponSE in Hypogonadal Men (TRAVERSE) Study
Actual Study Start Date : May 3, 2018
Actual Primary Completion Date : January 19, 2023
Actual Study Completion Date : January 19, 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Active Comparator: AndroGel 1.62%
Participants receive topical testosterone starting with a 40.5 mg dose (2 pump actuations) of the study drug once daily (OD). Participants may receive 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 are necessary.
 Drug: AndroGel®
testosterone administered topically
Placebo Comparator: Placebo
Participants receive matching placebo OD.
 Drug: Placebo
placebo administered topically


Outcome Measures
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Primary Outcome Measures :
  1. Time From Randomization to the First Component Event of Major Adverse Cardiac Event (MACE): Number and Percentage of Participants With an Event [ Time Frame: 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).

  2. Time From Randomization to the First Component Event of MACE [ Time Frame: 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 Outcome Measures :
  1. Time From Randomization to the First Component Event of CV Safety Endpoint: Number and Percentage of Participants With an Event [ Time Frame: 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.

  2. Time From Randomization to the First Component Event of CV Safety Endpoint [ Time Frame: 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.

  3. Incidence of High-Grade Prostate Cancer [ Time Frame: 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 Outcome Measures:
  1. Change in Psychosexual Daily Questionnaire Question 4 (PDQ-Q4) From Baseline to Months 6, 12 and 24 [ Time Frame: 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.

  2. Number and Percentage of Participants Whose Persistent Depressive Disorder (PDD) Remits During Intervention Per Remission Definition [ Time Frame: 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.

  3. Time From Randomization to First Clinical Fracture: Number and Percentage of Participants With an Event [ Time Frame: 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.

  4. Time From Randomization to First Clinical Fracture [ Time Frame: 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.

  5. Number and Percentage of Anemic Participants Whose Baseline Anemia Was Corrected During the Intervention Period [ Time Frame: 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.

  6. Number and Percentage of Participants With Pre-Diabetes at Baseline Who Progressed to Diabetes at Months 6, 12, 24, 36 and 48 [ Time Frame: 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.

  7. Tertiary Endpoint: Incidence Rate of All Cause Mortality [ Time Frame: 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.

  8. Tertiary Endpoint: Incidence Rate of Heart Failure [ Time Frame: 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.

  9. Tertiary Endpoint: Incidence Rate of Venous Thromboembolic Events [ Time Frame: 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).

  10. Tertiary Endpoint: Incidence Rate of Peripheral Arterial Revascularization [ Time Frame: 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.

  11. Tertiary Endpoint: Incidence Rate of Prostate Biopsy [ Time Frame: 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.

  12. Tertiary Endpoint: Incidence Rate of Prostate Cancer [ Time Frame: 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).

  13. Tertiary Endpoint: Incidence Rate of Acute Urinary Retention [ Time Frame: 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.

  14. Tertiary Endpoint: Incidence Rate of Pharmacologic Treatment for Lower Urinary Tract Symptoms [ Time Frame: 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.

  15. Tertiary Endpoint: Incidence Rate of Invasive Prostate Surgical Procedures for Benign Prostatic Hyperplasia [ Time Frame: 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.


Eligibility Criteria
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Ages Eligible for Study:   45 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

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).
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03518034


Locations
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Sponsors and Collaborators
AbbVie
Endo Pharmaceuticals
Acerus Pharmaceuticals Corporation
Allergan Sales, LLC
Upsher-Smith Laboratories LLC
Investigators
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Study Director: ABBVIE INC. AbbVie
  Study Documents (Full-Text)

Documents provided by AbbVie:
Study Protocol  [PDF] May 6, 2021
Statistical Analysis Plan  [PDF] January 1, 2023

More Information
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Additional Information:

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Responsible Party: AbbVie
ClinicalTrials.gov Identifier: NCT03518034    
Other Study ID Numbers: M16-100
First Posted: May 8, 2018    Key Record Dates
Results First Posted: March 13, 2024
Last Update Posted: March 13, 2024
Last Verified: February 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by AbbVie:
hypogonadism
cardiovascular (CV) disease
AndroGel
testosterone replacement therapy (TRT)
Additional relevant MeSH terms:
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Cardiovascular Diseases
Hypogonadism
Gonadal Disorders
Endocrine System Diseases
Testosterone
 Androgens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs