Clinical trial NCT00799617: The Testosterone Trials in Older Men
Official title: Randomized, Placebo-controlled, Double-blind Study of Seven Coordinated Testosterone Treatment Trials in Older Men
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Andropause
Keywords: Testosterone
Mobility disability
Decreased libido
Age associated memory impairment
Low vitality
Anemia
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
name: National Institute of Neurological Disorders and Stroke (NINDS)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: National Heart, Lung, and Blood Institute (NHLBI)
name: Abbott
First posted: 2008-12-01
Enrollment: 790
Sex: MALE
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The Testosterone Trials are a multi-center set of trials involving 12 clinical sites geographically distributed across the United States.

The primary specific aims are to test the hypotheses that testosterone treatment of elderly men whose serum testosterone concentrations are unequivocally low - and who have symptoms and objectively measured abnormalities in at least one of five areas that could be due to low testosterone (physical or sexual function, vitality, cognition, and anemia) - will result in more favorable changes in those abnormalities than placebo treatment.

Two additional trials have been incorporated into the T Trial. Only men enrolled in the T Trial are eligible to participate in these trials.

* The Cardiovascular Trial will examine if testosterone treatment results in more favorable changes in cardiovascular risk factors, compared to placebo.
* The Bone Trial will test the hypothesis that testosterone treatment will increase volumetric trabecular bone mineral density (vBMD) of the lumbar spine as measured by quantitative computed tomography (QCT), compared with placebo treatment.

A Pharmacokinetic (PK) Study is also being conducted within the context of the interventional T Trial. It will examine the variability of the serum testosterone (T) concentration after application of testosterone gel or placebo, four months after the start of treatment.

Detailed description: As men get older, they experience many conditions, often together, that eventually result in the inability to perform many activities of daily living, an increased propensity to fall, and decreased independence. These conditions include mobility disability and low vitality. Elderly men also experience increased anemia, metabolic syndrome, decreased sexual function and memory impairment. These conditions likely have multiple causes, but one cause that could contribute to all of them is a low serum testosterone concentration. When young hypogonadal men are treated with testosterone, they experience improvements in sexual function, muscle mass and strength, bone mineral density, sense of well being, and anemia. However, the benefits of testosterone therapy in older men with age-related decline in testosterone concentration are not known and are the subject of this investigation.

Participants will be treated with testosterone or placebo gel for 1 year. The dose will be adjusted in a blinded fashion to achieve a target T level range. Participants will be followed for one additional year following the treatment phase to assess adverse events.

* Men participating in the Cardiovascular Trial will be assessed for changes in atherosclerotic plaque burden from 0 to 12 months.
* Men participating in the Bone Trial will be assessed by QCT of the spine and hip, DXA of the spine and hip and clinical fractures at 0 and 12 months.
* Men participating in the PK Study will attend 3 additional study visits for blood draws at the time of the 4-month assessment.

Eligibility criteria: Inclusion Criteria:

* Men greater than or equal to 65 years old
* Total serum testosterone concentration \< 275 and \< 300 ng/dL at 7 -10 AM at each of two screening visits

Exclusion Criteria:

* Diagnosed prostate cancer, prostatic intraepithelial neoplasia (PIN), prostate nodule or, by the Prostate Cancer Risk Calculator, a \>35% risk of having overall prostate cancer or \>7% risk of having high grade prostate cancer
* Severe lower urinary tract symptoms (score of \> 19) by the International Prostate Symptom Score questionnaire
* Hemoglobin \<10 g/dL or \>16.0 g/dL
* Sleep apnea, diagnosed but untreated
* Alcohol or substance abuse within the past year (based on self report)
* Angina not controlled by treatment
* NYHA class III or IV congestive heart failure
* Myocardial infarction within the previous 3 months before entry
* Stroke within the previous 3 months before entry
* Severe pulmonary disease that precludes physical function tests
* Serum creatinine \>2.2 mg/dL; ALT 3x upper limit of normal; hemoglobin A1c \>8.5%, TSH \> 7.5mIU/L
* Diagnosis or treatment for cancer within the past 3 years, with the exception of nonmelanotic skin cancer
* Body mass index (BMI) \>37 kg/m2
* Mini Mental State Exam (MMSE) Score \<24
* Major psychiatric disorders, including major depression (PHQ-9 score \> 14), mania, hypomania, psychosis, schizophrenia or schizoaffective disorders, that are untreated, unstable, have resulted in hospitalization or medication change within the previous three months, or would result in inability to complete the trial efficacy instruments. Subjects whose disorders have been stable while being treated for more than three months are eligible.
* Use of the following medications within the previous three months:

  * drugs that affect serum testosterone concentration
  * rhGH or megestrol acetate
  * introduction of anti-depressant medication
  * daily use of prednisone for more than two weeks
* Opiate use within the past three months
* Skin conditions at the testosterone gel application site, such as ulcer, erosion, lichenification, inflammation, or crust, or generalized skin conditions such as psoriasis or eczema that might affect testosterone absorption or tolerability of the testosterone gel
* Known skin intolerance to alcohol or allergy to any of the ingredients of testosterone gel

Participants in the T Trial may also enroll in the Cardiovascular and Bone Trials if it is determined that they are eligible based on the specific exclusion criteria.

Primary outcomes:
measure: Sexual Function Trial - Change in Psychosexual Daily Questionnaire Question 4 (PDQ-Q4) From Baseline to Month 12
timeFrame: 1 year (change from baseline to month 3, 6, 9 and 12)
measure: Physical Function Trial - The 6-Minute Walk Test - no./Total no. (%)
timeFrame: 1 year (Number of participants who increased walk distance > or = 50 meters, change from baseline to month 3, 6, 9 and 12)
measure: Vitality Trial - Increase in Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Score Greater Than or Equal to 4 - no./Total no. (%)
timeFrame: 1 year (Number of participants who increased FACIT-Fatigue score > or = to 4, change from baseline to month 3, 6, 9 and 12)
measure: Cardiovascular Trial - Assess Impact of Testosterone Treatment in Older Men on Noncalcified Plaque Volume
timeFrame: 1 year (change in plaque volume measurement from baseline to month 12)
measure: Bone Trial - Volumetric Bone Mineral Density (BMD) of Spine Trabecular Bone by Quantitative Computed Tomography (QCT) in Older Men With Low Testosterone
timeFrame: 1 year (QCT measurement of BMD change between baseline and month 12)
measure: Cognitive Function Trial - Delayed Paragraph Recall Wechsler Memory Scale Revised Logical Memory II (WMS-R LMII)
timeFrame: 1 year (change from baseline to month 6 and month 12)
measure: Anemia Trial - Effect of Testosterone on Hemoglobin Levels - Unexplained Anemia
timeFrame: 1 year (change in hemoglobin g/dL from baseline to month 3, 6, 9 and 12)
Secondary outcomes:
measure: Sexual Function Trial - Sexual Desire Domain
timeFrame: 1 year (change from baseline to month 3, 6, 9 and 12)
measure: Sexual Function Trial - Erectile Function
timeFrame: 1 year (change from baseline to month 3, 6, 9 and 12)
measure: Physical Function Trial - 6 Minute Walk Test - Total Walking Distance in Meters
timeFrame: 1 year (change from baseline to month 3, 6, 9 and 12)
measure: Physical Function Trial - The Physical Function Domain (PF-10) of the SF-36 - no./Total no. (%)
timeFrame: 1 year (change from baseline to month 3, 6, 9 and 12)
measure: Physical Function Trial - PF 10 Overall Score
timeFrame: 1 year (change from baseline to month 3, 6, 9 and 12)
measure: Vitality Trial - FACIT Fatigue Overall Score
timeFrame: 1 year (change from baseline to month 3, 6, 9 and 12)
measure: Vitality Trial - SF-36 Score
timeFrame: 1 year (change from baseline to month 3, 6, 9 and 12)
measure: Vitality Trial - Change in the Positive Affect Score of the Positive and Negative Affect Scales (PANAS) From Baseline to Month 12.
timeFrame: 1 year (change from baseline to month 3, 6, 9 and 12)
measure: Vitality Trial - Change in the Total Negative Affect Score of the Positive and Negative Affect Scales (PANAS) From Baseline to Month 12
timeFrame: 1 year (change from baseline to month 3, 6, 9 and 12)
measure: Vitality Trial - Patient Health Questionnaire 9 (PHQ-9) Change in Overall Score
timeFrame: 1 year (change from baseline to month 3, 6, 9 and 12)
measure: Cardiovascular Trial - Total Plaque Volume Change From Baseline
timeFrame: 1 year (change from baseline to month 12)
measure: Cardiovascular Trial - Coronary Artery Calcium Score, Agatston Units Change From Baseline
timeFrame: 1 year (change from baseline to month 12)
measure: Bone Trial - Volumetric Bone Mineral Density (BMD) of Spine Peripheral Bone by Quantitative Computed Tomography (QCT)
timeFrame: 1 year (baseline to month 12)
measure: Bone Trial - Volumetric Bone Mineral Density (BMD) of Spine Whole Bone by Quantitative Computed Tomography (QCT)
timeFrame: 1 year (baseline to month 12)
measure: Bone Trial - Volumetric Bone Mineral Density (BMD) of Hip Trabecular Bone by Quantitative Computed Tomography (QCT)
timeFrame: 1 year (baseline to month 12)
measure: Bone Trial - Volumetric Bone Mineral Density (BMD) of Hip Peripheral Bone by Quantitative Computed Tomography (QCT)
timeFrame: 1 year (baseline to month 12)
measure: Bone Trial - Volumetric Bone Mineral Density (BMD) of Hip Whole Bone by Quantitative Computed Tomography (QCT)
timeFrame: 1 year (baseline to month 12)
measure: Bone Trial - Bone Strength of Spine Whole Bone by Finite Element Analysis, N
timeFrame: 1 year (baseline to month 12)
measure: Bone Trial - Bone Strength of Spine Trabecular Bone by Finite Element Analysis, N
timeFrame: 1 year (baseline to month 12)
measure: Bone Trial - Bone Strength of Spine Peripheral Bone by Finite Element Analysis, N
timeFrame: 1 year (baseline to month 12)
measure: Bone Trial - Bone Strength of Hip Whole Bone by Finite Element Analysis, N
timeFrame: 1 year (baseline to month 12)
measure: Bone Trial - Bone Strength of Hip Trabecular Bone by Finite Element Analysis, N
timeFrame: 1 year (baseline to month 12)
measure: Bone Trial - Bone Strength of Hip Peripheral Bone by Finite Element Analysis, N
timeFrame: 1 year (baseline to month 12)
measure: Bone Trial - Area Bone Mineral Density (BMD) of Lumbar Spine by Dual-energy X-ray Absorptiometry (DXA)
timeFrame: 1 year (baseline to month 12)
measure: Bone Trial - Area Bone Mineral Density (BMD) of Total Hip by Dual-energy X-ray Absorptiometry (DXA)
timeFrame: 1 year (baseline to month 12)
measure: Bone Trial - Area Bone Mineral Density (BMD) of Femoral Neck by Dual-energy X-ray Absorptiometry (DXA)
timeFrame: 1 year (baseline to month 12)
measure: Cognitive Function Trial - Visual Memory - Benton Visual Retention Test (BVRT)
timeFrame: 1 year (baseline to month 6 and month 12)
measure: Cognitive Function Trial - Spatial Ability Card Rotation Test (CRT)
timeFrame: 1 year (baseline to month 6 to month 12)
measure: Cognitive Function Trial - Executive Function - Trail Making Test B - A
timeFrame: 1 year (baseline to month 6 to month 12)
measure: Anemia Trial - Effect of Testosterone on Hemoglobin Levels - Unexplained Anemia - Hemoglobin (Continuous)
timeFrame: 1 year (baseline to month 12)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: La Jolla
country: United States
facility: University of California San Diego
state: California
city: Torrance
country: United States
facility: Center for Men's Health LA BioMed at Harbor-UCLA Medical Center
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Boston
country: United States
facility: Boston University
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Bronx
country: United States
facility: Albert Einstein College of Medicine
state: New York
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Seattle
country: United States
facility: VA Puget Sound Health Care System
state: Washington
Study officials:
affiliation: University of Pennsylvania
name: Peter J Snyder, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Stephens-Shields AJ, Snyder PJ, Ellenberg SS, Taylor L, Bhasin S. Relation of Testosterone, Dihydrotestosterone, and Estradiol With Changes in Outcomes Measures in the Testosterone Trials. J Clin Endocrinol Metab. 2022 Apr 19;107(5):1257-1269. doi: 10.1210/clinem/dgac028.
citation: Artz AS, Stephens-Shields AJ, Bhasin S, Ellenberg SS, Cohen HJ, Snyder PJ. Markers of Iron Flux during Testosterone-Mediated Erythropoiesis in Older Men with Unexplained or Iron-Deficiency Anemia. J Clin Endocrinol Metab. 2020 Nov 1;105(11):3396-403. doi: 10.1210/clinem/dgaa521.
citation: Shaikh K, Ellenberg SS, Nakanishi R, Snyder PJ, Lee J, Wenger NK, Lewis CE, Swerdloff RS, Preston P, Hamal S, Stephens-Sheilds A, Bhasin S, Cherukuri L, Cauley JA, Crandall JP, Cunningham GR, Ensrud KE, Matsumoto AM, Molich ME, Alla VM, Birudaraju D, Nezarat N, Rai K, Almeida S, Roy SK, Sheikh M, Trad G, Budoff MJ. Biomarkers and Noncalcified Coronary Artery Plaque Progression in Older Men Treated With Testosterone. J Clin Endocrinol Metab. 2020 Jul 1;105(7):2142-9. doi: 10.1210/clinem/dgz242.
citation: Bhasin S, Ellenberg SS, Storer TW, Basaria S, Pahor M, Stephens-Shields AJ, Cauley JA, Ensrud KE, Farrar JT, Cella D, Matsumoto AM, Cunningham GR, Swerdloff RS, Wang C, Lewis CE, Molitch ME, Barrett-Connor E, Crandall JP, Hou X, Preston P, Cifelli D, Snyder PJ, Gill TM. Effect of testosterone replacement on measures of mobility in older men with mobility limitation and low testosterone concentrations: secondary analyses of the Testosterone Trials. Lancet Diabetes Endocrinol. 2018 Nov;6(11):879-890. doi: 10.1016/S2213-8587(18)30171-2.
citation: Mohler ER 3rd, Ellenberg SS, Lewis CE, Wenger NK, Budoff MJ, Lewis MR, Barrett-Connor E, Swerdloff RS, Stephens-Shields A, Bhasin S, Cauley JA, Crandall JP, Cunningham GR, Ensrud KE, Gill TM, Matsumoto AM, Molitch ME, Pahor M, Preston PE, Hou X, Cifelli D, Snyder PJ. The Effect of Testosterone on Cardiovascular Biomarkers in the Testosterone Trials. J Clin Endocrinol Metab. 2018 Feb 1;103(2):681-688. doi: 10.1210/jc.2017-02243.
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