The Testosterone Trials in Older Men

Study Overview
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Brief Summary
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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
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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.

Official Title
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Randomized, Placebo-controlled, Double-blind Study of Seven Coordinated Testosterone Treatment Trials in Older Men

Conditions
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Andropause

Intervention / Treatment
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* Drug: AndroGel® (testosterone gel)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: AndroGel® (testosterone gel)<br>The initial dose of AndroGel will be 5.0 g (containing 50 mg of testosterone) once a day. Participants will apply AndroGel once daily to the shoulders, abdomen or upper arms. The serum testosterone concentration will be measured monthly for the first three months, then at months 6, 9 and 12. If the testosterone concentration is not between 500 and 800 ng/dL at any time point, the dose will be either increased by increments of 1.25-2.5 g/day, up to a maximum of 15 g/day or decreased by increments of 1.25-3.75 ng/day. Participants will be taught how to apply the gel and they will be provided with written instructions and precautions. This information will be reviewed at each contact and visit. | Drug: AndroGel® (testosterone gel)<br>* Testosterone levels will be measured at regular intervals in order to achieve a testosterone level in the desired range.<br>* Other names: Testosterone gel;|
| Placebo Comparator: Placebo gel<br>Placebo gel is identical to the testosterone gel and is supplied in an identical pump bottle container. It is applied to the shoulders, abdomen or upper arms once a day. Participants will be taught how to apply the gel and they will be provided with written instructions and precautions. This information will be reviewed at each contact and visit. | Drug: Placebo<br>* Testosterone levels will be measured at regular intervals.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sexual Function Trial - Change in Psychosexual Daily Questionnaire Question 4 (PDQ-Q4) From Baseline to Month 12 | Baseline score and change in responses to Question 4 of the Psychosexual Daily Questionnaire (PDQ-Q4) from baseline to Month 12. Question 4 asks 12 questions about sexual activity. Scores on the PDQ-Q4 range from 0 to 12, with higher scores indicating more activity. The change is measured form the baseline value to Month 12. | 1 year (change from baseline to month 3, 6, 9 and 12) | 
| Physical Function Trial - The 6-Minute Walk Test - no./Total no. (%) | The number and percentage of men who increased the distance walked in the 6-Minute Walk Test by at least 50 meters. | 1 year (Number of participants who increased walk distance > or = 50 meters, change from baseline to month 3, 6, 9 and 12) | 
| Vitality Trial - Increase in Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Score Greater Than or Equal to 4 - no./Total no. (%) | The number of participants whose score on the FACIT-Fatigue scale increased by at least 4 points. Scores on the FACIT- Fatigue scale range from 0 to 52, with higher scores indicating less fatigue. | 1 year (Number of participants who increased FACIT-Fatigue score > or = to 4, change from baseline to month 3, 6, 9 and 12) | 
| Cardiovascular Trial - Assess Impact of Testosterone Treatment in Older Men on Noncalcified Plaque Volume | Non-calcified coronary artery plaque volume, mm3, as determined by coronary computed tomographic angiography (CTA), mean difference in change from baseline to month 12 | 1 year (change in plaque volume measurement from baseline to month 12) | 
| Bone Trial - Volumetric Bone Mineral Density (BMD) of Spine Trabecular Bone by Quantitative Computed Tomography (QCT) in Older Men With Low Testosterone | Volumetric Bone Mineral Density (BMD) of spine trabecular bone as measured by QCT, mg/cm3, the calculated change in measurement from baseline to Month 12 | 1 year (QCT measurement of BMD change between baseline and month 12) | 
| Cognitive Function Trial - Delayed Paragraph Recall Wechsler Memory Scale Revised Logical Memory II (WMS-R LMII) | Baseline score and change in score of the Wechsler Memory Scale Revised Logical Memory II (WMS-R LMII) test of Delayed Paragraph Recall, at baseline, Month 6 and Month 12. The WMS-R LM II involves a delayed paragraph recall activity scored in two components, each ranging from 0-25. The final score is the sum of each component, therefore falling in the range 0-50. WMS-R LM II scores were treated as continuous with change compared between treatment arms using linear random effects models adjusting for several factors: site, indicator variables of participation in each primary efficacy trial, baseline testosterone concentration (<200), age (≤ 75), use of anti-depressants, use of PDE-inhibitors, baseline WMSR, categorical education, and version of the WMSR. | 1 year (change from baseline to month 6 and month 12) | 
| Anemia Trial - Effect of Testosterone on Hemoglobin Levels - Unexplained Anemia | Proportion of men age 65 years or older with unexplained anemia who increased their hemoglobin level by 1.0 g/dL from baseline. Values are No. (%) for dichotomous outcomes. Dichotomous hemoglobin response is an increase of 1 g/dL or more from baseline. | 1 year (change in hemoglobin g/dL from baseline to month 3, 6, 9 and 12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sexual Function Trial - Sexual Desire Domain | Baseline score and the changes in the score of the sexual-desire domain of the Derogatis Interview for Sexual Functioning in Men-II (DISF-M-II), from baseline to Month 12. Scores on the (DISF-M-II) range from 0 to 33, with higher scores indicating greater sexual desire. | 1 year (change from baseline to month 3, 6, 9 and 12) | 
| Sexual Function Trial - Erectile Function | Baseline score and the change in score on the International Index of Erectile Function (IIEF) from baseline to Month 12. Scores on the IIEF range from 0-30, with higher scores indicating better function. | 1 year (change from baseline to month 3, 6, 9 and 12) | 
| Physical Function Trial - 6 Minute Walk Test - Total Walking Distance in Meters | Baseline score and the change in distance walked in the 6-Minute Walking Test in meters from baseline to Month 12 | 1 year (change from baseline to month 3, 6, 9 and 12) | 
| Physical Function Trial - The Physical Function Domain (PF-10) of the SF-36 - no./Total no. (%) | The number of participants whose score on the physical-function domain (PF-10; range, 0 to 100, with higher scores indicating better function) of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) increased by at least 8 points from baseline to Month 12. | 1 year (change from baseline to month 3, 6, 9 and 12) | 
| Physical Function Trial - PF 10 Overall Score | Baseline score and the change in score on the physical-function scale (PF-10) of the Medical Outcomes Study 36-Item Short Form Health Survey range from 0 to 100, with higher scores indicating better function. Scores were measured as the change from baseline to Month 12. | 1 year (change from baseline to month 3, 6, 9 and 12) | 
| Vitality Trial - FACIT Fatigue Overall Score | Baseline score and change in the FACIT- Fatigue score from baseline to Month 12. Scores on the Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue scale range from 0 to 52, with higher scores indicating less fatigue. | 1 year (change from baseline to month 3, 6, 9 and 12) | 
| Vitality Trial - SF-36 Score | Baseline score and change in the SF-36 Vitality Score from baseline to Month 12 Scores on the vitality scale of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) range from 0 to 100, with higher scores indicating less fatigue. | 1 year (change from baseline to month 3, 6, 9 and 12) | 
| Vitality Trial - Change in the Positive Affect Score of the Positive and Negative Affect Scales (PANAS) From Baseline to Month 12. | Baseline score and change in the total positive affect score of the Positive and Negative Affect Scales (PANAS) from baseline to Month 12. Scores for positive affect and for negative affect on the Positive and Negative Affect Schedule (PANAS) scales range from 5 to 50, with higher scores indicating a greater intensity of the affect. | 1 year (change from baseline to month 3, 6, 9 and 12) | 
| Vitality Trial - Change in the Total Negative Affect Score of the Positive and Negative Affect Scales (PANAS) From Baseline to Month 12 | Baseline score and change in the total negative affect score of the Positive and Negative Affect Scales (PANAS) from baseline to Month 12. Scores for positive affect and for negative affect on the Positive and Negative Affect Schedule (PANAS) scales range from 5 to 50, with higher scores indicating a greater intensity of the affect. | 1 year (change from baseline to month 3, 6, 9 and 12) | 
| Vitality Trial - Patient Health Questionnaire 9 (PHQ-9) Change in Overall Score | Baseline score and change in score in the Patient Health Questionnaire 9 (PHQ-9) from baseline to Month 12. Scores on the Patient Health Questionnaire 9 (PHQ-9) depression scale range from 0 to 27, with higher scores indicating greater intensity of depressive symptoms. | 1 year (change from baseline to month 3, 6, 9 and 12) | 
| Cardiovascular Trial - Total Plaque Volume Change From Baseline | Total plaque volume,mm3 measured by coronary computed tomographic angiography | 1 year (change from baseline to month 12) | 
| Cardiovascular Trial - Coronary Artery Calcium Score, Agatston Units Change From Baseline | Coronary artery calcium score in Agatston units (range of 0 to >400 Agatston units), with higher values indicating more severe atherosclerosis). | 1 year (change from baseline to month 12) | 
| Bone Trial - Volumetric Bone Mineral Density (BMD) of Spine Peripheral Bone by Quantitative Computed Tomography (QCT) | Spine peripheral bone as measured by QCT, mg/cm3 (within-arm mean percent change between baseline and month 12 adjusted for balancing factors) | 1 year (baseline to month 12) | 
| Bone Trial - Volumetric Bone Mineral Density (BMD) of Spine Whole Bone by Quantitative Computed Tomography (QCT) | Spine whole bone as measured by QCT, mg/cm3 (within-arm mean percent change between baseline and month 12 adjusted for balancing factors) | 1 year (baseline to month 12) | 
| Bone Trial - Volumetric Bone Mineral Density (BMD) of Hip Trabecular Bone by Quantitative Computed Tomography (QCT) | Hip trabecular bone as measured by QCT, mg/cm3 (within-arm mean percent change between baseline and month 12 adjusted for balancing factors) | 1 year (baseline to month 12) | 
| Bone Trial - Volumetric Bone Mineral Density (BMD) of Hip Peripheral Bone by Quantitative Computed Tomography (QCT) | Hip peripheral bone as measured by QCT, mg/cm3 (within-arm mean percent change between baseline and month 12 adjusted for balancing factors) | 1 year (baseline to month 12) | 
| Bone Trial - Volumetric Bone Mineral Density (BMD) of Hip Whole Bone by Quantitative Computed Tomography (QCT) | Hip whole bone as measured by QCT, mg/cm3 (within-arm mean percent change between baseline and month 12 adjusted for balancing factors) | 1 year (baseline to month 12) | 
| Bone Trial - Bone Strength of Spine Whole Bone by Finite Element Analysis, N | Spine whole bone (within-arm mean percent change between baseline and month 12 adjusted for balancing factors) | 1 year (baseline to month 12) | 
| Bone Trial - Bone Strength of Spine Trabecular Bone by Finite Element Analysis, N | Spine trabecular bone (within-arm mean percent change between baseline and month 12 adjusted for balancing factors) | 1 year (baseline to month 12) | 
| Bone Trial - Bone Strength of Spine Peripheral Bone by Finite Element Analysis, N | Spine peripheral bone (within-arm mean percent change between baseline and month 12 adjusted for balancing factors) | 1 year (baseline to month 12) | 
| Bone Trial - Bone Strength of Hip Whole Bone by Finite Element Analysis, N | Hip whole bone (within-arm mean percent change between baseline and month 12 adjusted for balancing factors) | 1 year (baseline to month 12) | 
| Bone Trial - Bone Strength of Hip Trabecular Bone by Finite Element Analysis, N | Hip trabecular bone (within-arm mean percent change between baseline and month 12 adjusted for balancing factors) | 1 year (baseline to month 12) | 
| Bone Trial - Bone Strength of Hip Peripheral Bone by Finite Element Analysis, N | Hip peripheral bone (within-arm mean percent change between baseline and month 12 adjusted for balancing factors) | 1 year (baseline to month 12) | 
| Bone Trial - Area Bone Mineral Density (BMD) of Lumbar Spine by Dual-energy X-ray Absorptiometry (DXA) | Lumbar spine as measured by DXA, g/cm2 (within-arm mean percent change between baseline and month 12 adjusted for balancing factors) | 1 year (baseline to month 12) | 
| Bone Trial - Area Bone Mineral Density (BMD) of Total Hip by Dual-energy X-ray Absorptiometry (DXA) | Total hip as measured by DXA, g/cm2 (within-arm mean percent change between baseline and month 12 adjusted for balancing factors) | 1 year (baseline to month 12) | 
| Bone Trial - Area Bone Mineral Density (BMD) of Femoral Neck by Dual-energy X-ray Absorptiometry (DXA) | Femoral neck as measured by DXA, g/cm2 (within-arm mean percent change between baseline and month 12 adjusted for balancing factors) | 1 year (baseline to month 12) | 
| Cognitive Function Trial - Visual Memory - Benton Visual Retention Test (BVRT) | Baseline score and mean change in score in the Visual Memory Using the Benton Visual Retention Test (BVRT) from baseline, Month 6 and Month 12. The BVRT measures short term visual memory and visuo-constructional abilities and was administered and scored according to standard procedures. Each of 10 designs was presented one at a time for 10 seconds, and immediately after the design was withdrawn, the participant was instructed to draw it from memory on a blank sheet of paper. The score was the total number of figures with errors and ranged from 0 to 26. Scores were inverted to 0 to -26 so that higher scores would reflect better performance. Change in BVRT scores from baseline are treated as continuous and compared between AAMI Androgel and placebo subjects using linear random effects models adjusting for balancing factors as described in the primary analysis. | 1 year (baseline to month 6 and month 12) | 
| Cognitive Function Trial - Spatial Ability Card Rotation Test (CRT) | Baseline score and change in score in the Spatial Ability Using the Card Rotation Test at baseline, Month 6 and Month 12. Change in performance on the Card Rotations Test will be analyzed using linear random effects models adjusting for baseline performance, balancing factors, education, and test version. The test consists of a series of 10 primary figures, each of which has 8 corresponding secondary figures. Subjects are asked to determine which of the secondary figures is the same as the corresponding primary figure, and the score is taken as the number of figures answered correctly minus the number of figures answered incorrectly. The maximum score is 80 for subjects who answer all items correctly. | 1 year (baseline to month 6 to month 12) | 
| Cognitive Function Trial - Executive Function - Trail Making Test B - A | Baseline score and change in score in Executive Function as Measured by Trail-Making Test (TMT) B - A, at baseline, Month 6 and Month 12. Change in performance on the Trail Making Test was analyzed using linear random effects models adjusting for baseline performance, balancing factors, education, and test version. Participants are required to connect a set of numbers (Part A) or alternating letters and numbers (Part B) in sequential order. The score for each part is the total time (in seconds) to complete both parts. The outcome analyzed will be the total time for Trails B minus the total time for Trails A to provide a measure of working memory, adjusted for attention and processing speed. Higher scores reflect lower executive function. | 1 year (baseline to month 6 to month 12) | 
| Anemia Trial - Effect of Testosterone on Hemoglobin Levels - Unexplained Anemia - Hemoglobin (Continuous) | Proportion of men age 65 years or older with unexplained anemia who increased their hemoglobin level by 1.0 gm/dL from baseline. Values are means (SDs) for continuous outcomes. | 1 year (baseline to month 12) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Testosterone, Mobility disability, Decreased libido, Age associated memory impairment, Low vitality, Anemia