The Testosterone Trials in Older Men

NCT00799617 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: U01AG030644R01AG037679
• Study Type: interventional
• Target: 790
• Locations: 1 country
• Sites: 12

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.

Conditions

Andropause

Keywords

Testosterone; Mobility disability; Decreased libido; Age associated memory impairment; Low vitality; Anemia

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (30)

• Sexual Function Trial - Sexual Desire Domain

  1 year (change from baseline to month 3, 6, 9 and 12)

• Sexual Function Trial - Erectile 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

  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. (%)

  1 year (change from baseline to month 3, 6, 9 and 12)

• Physical Function Trial - PF 10 Overall Score

  1 year (change from baseline to month 3, 6, 9 and 12)

Study Arms (2)

AndroGel® (testosterone gel)

ACTIVE COMPARATOR

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)

Placebo gel

PLACEBO COMPARATOR

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

Interventions

AndroGel® (testosterone gel) DRUG

Testosterone levels will be measured at regular intervals in order to achieve a testosterone level in the desired range.

Also known as: Testosterone gel

AndroGel® (testosterone gel)

Placebo DRUG

Testosterone levels will be measured at regular intervals.

Placebo gel

Eligibility Criteria

• Age: 65 Years+
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Pennsylvania: lead
• National Institute on Aging (NIA): collaborator
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Abbott: collaborator

Study Sites (12)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

University of California San Diego

La Jolla, California, 92093, United States

Location

Center for Men's Health LA BioMed at Harbor-UCLA Medical Center

Torrance, California, 90501, United States

Location

Yale University

New Haven, Connecticut, 06520, United States

Location

University of Florida

Gainesville, Florida, 32611, United States

Location

Northwestern University

Chicago, Illinois, 60208, United States

Location

Boston University

Boston, Massachusetts, 02215, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Albert Einstein College of Medicine

The Bronx, New York, 10461, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15261, United States

Location

Baylor College of Medicine

Houston, Texas, 76798, United States

Location

VA Puget Sound Health Care System

Seattle, Washington, 98108, United States

Location

Related Publications (15)

• Lee H, Hwang EC, Oh CK, Lee S, Yu HS, Lim JS, Kim HW, Walsh T, Kim MH, Jung JH, Dahm P. Testosterone replacement in men with sexual dysfunction. Cochrane Database Syst Rev. 2024 Jan 15;1(1):CD013071. doi: 10.1002/14651858.CD013071.pub2.

  PMID: 38224135 DERIVED

• 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.

  PMID: 35041751 DERIVED

• 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.

  PMID: 32785689 DERIVED

• 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.

  PMID: 31784747 DERIVED

• 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.

  PMID: 30366567 DERIVED

• 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.

  PMID: 29253154 DERIVED

• Resnick SM, Matsumoto AM, Stephens-Shields AJ, Ellenberg SS, Gill TM, Shumaker SA, Pleasants DD, Barrett-Connor E, Bhasin S, Cauley JA, Cella D, Crandall JP, Cunningham GR, Ensrud KE, Farrar JT, Lewis CE, Molitch ME, Pahor M, Swerdloff RS, Cifelli D, Anton S, Basaria S, Diem SJ, Wang C, Hou X, Snyder PJ. Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment. JAMA. 2017 Feb 21;317(7):717-727. doi: 10.1001/jama.2016.21044.

  PMID: 28241356 DERIVED

• Budoff MJ, Ellenberg SS, Lewis CE, Mohler ER 3rd, Wenger NK, Bhasin S, Barrett-Connor E, Swerdloff RS, Stephens-Shields A, Cauley JA, Crandall JP, Cunningham GR, Ensrud KE, Gill TM, Matsumoto AM, Molitch ME, Nakanishi R, Nezarat N, Matsumoto S, Hou X, Basaria S, Diem SJ, Wang C, Cifelli D, Snyder PJ. Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone. JAMA. 2017 Feb 21;317(7):708-716. doi: 10.1001/jama.2016.21043.

  PMID: 28241355 DERIVED

• Roy CN, Snyder PJ, Stephens-Shields AJ, Artz AS, Bhasin S, Cohen HJ, Farrar JT, Gill TM, Zeldow B, Cella D, Barrett-Connor E, Cauley JA, Crandall JP, Cunningham GR, Ensrud KE, Lewis CE, Matsumoto AM, Molitch ME, Pahor M, Swerdloff RS, Cifelli D, Hou X, Resnick SM, Walston JD, Anton S, Basaria S, Diem SJ, Wang C, Schrier SL, Ellenberg SS. Association of Testosterone Levels With Anemia in Older Men: A Controlled Clinical Trial. JAMA Intern Med. 2017 Apr 1;177(4):480-490. doi: 10.1001/jamainternmed.2016.9540.

  PMID: 28241237 DERIVED

• Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, Ellenberg SS, Cauley JA, Ensrud KE, Lewis CE, Barrett-Connor E, Schwartz AV, Lee DC, Bhasin S, Cunningham GR, Gill TM, Matsumoto AM, Swerdloff RS, Basaria S, Diem SJ, Wang C, Hou X, Cifelli D, Dougar D, Zeldow B, Bauer DC, Keaveny TM. Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial. JAMA Intern Med. 2017 Apr 1;177(4):471-479. doi: 10.1001/jamainternmed.2016.9539.

  PMID: 28241231 DERIVED

• Cunningham GR, Stephens-Shields AJ, Rosen RC, Wang C, Bhasin S, Matsumoto AM, Parsons JK, Gill TM, Molitch ME, Farrar JT, Cella D, Barrett-Connor E, Cauley JA, Cifelli D, Crandall JP, Ensrud KE, Gallagher L, Zeldow B, Lewis CE, Pahor M, Swerdloff RS, Hou X, Anton S, Basaria S, Diem SJ, Tabatabaie V, Ellenberg SS, Snyder PJ. Testosterone Treatment and Sexual Function in Older Men With Low Testosterone Levels. J Clin Endocrinol Metab. 2016 Aug;101(8):3096-104. doi: 10.1210/jc.2016-1645. Epub 2016 Jun 29.

  PMID: 27355400 DERIVED

• Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, Gill TM, Barrett-Connor E, Swerdloff RS, Wang C, Ensrud KE, Lewis CE, Farrar JT, Cella D, Rosen RC, Pahor M, Crandall JP, Molitch ME, Cifelli D, Dougar D, Fluharty L, Resnick SM, Storer TW, Anton S, Basaria S, Diem SJ, Hou X, Mohler ER 3rd, Parsons JK, Wenger NK, Zeldow B, Landis JR, Ellenberg SS; Testosterone Trials Investigators. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016 Feb 18;374(7):611-24. doi: 10.1056/NEJMoa1506119.

  PMID: 26886521 DERIVED

• Abd Alamir M, Ellenberg SS, Swerdloff RS, Wenger NK, Mohler ER 3rd, Lewis CE, Barrett-Conner E, Nakanishi R, Darabian S, Alani A, Matsumoto S, Nezarat N, Snyder PJ, Budoff MJ. The Cardiovascular Trial of the Testosterone Trials: rationale, design, and baseline data of a clinical trial using computed tomographic imaging to assess the progression of coronary atherosclerosis. Coron Artery Dis. 2016 Mar;27(2):95-103. doi: 10.1097/MCA.0000000000000321.

  PMID: 26554661 DERIVED

• Cunningham GR, Stephens-Shields AJ, Rosen RC, Wang C, Ellenberg SS, Matsumoto AM, Bhasin S, Molitch ME, Farrar JT, Cella D, Barrett-Connor E, Cauley JA, Cifelli D, Crandall JP, Ensrud KE, Fluharty L, Gill TM, Lewis CE, Pahor M, Resnick SM, Storer TW, Swerdloff RS, Anton S, Basaria S, Diem S, Tabatabaie V, Hou X, Snyder PJ. Association of sex hormones with sexual function, vitality, and physical function of symptomatic older men with low testosterone levels at baseline in the testosterone trials. J Clin Endocrinol Metab. 2015 Mar;100(3):1146-55. doi: 10.1210/jc.2014-3818. Epub 2014 Dec 30.

  PMID: 25548978 DERIVED

• Meng J, Mostaghel EA, Vakar-Lopez F, Montgomery B, True L, Nelson PS. Testosterone regulates tight junction proteins and influences prostatic autoimmune responses. Horm Cancer. 2011 Jun;2(3):145-56. doi: 10.1007/s12672-010-0063-1.

  PMID: 21761342 DERIVED

Related Links

• Find out more information about The Testosterone Trial and the list of participating clinical sites.

MeSH Terms

Conditions

Anemia

Interventions

Testosterone

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Androstenols; Androstenes; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Testosterone Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: Peter J. Snyder, MD
• Organization: University of Pennsylvania, Perelman School of Medicine

pjsnyder@upenn.edu

215-898-0208

Study Officials

• Peter J Snyder, MD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 26, 2008
• First Posted: December 1, 2008
• Study Start: November 1, 2009
• Primary Completion: July 1, 2014
• Study Completion: December 1, 2018
• Last Updated: February 21, 2019
• Results First Posted: August 28, 2017

Record last verified: 2019-02

Locations

US (12)