Testosterone Replacement in Older Men and Atherosclerosis Progression

NCT00287586 | Completed Phase 4 Results DMC FDA Drug

• 1 other identifier: H-24192
• Study Type: interventional
• Target: 308
• Locations: 1 country
• Sites: 3

Brief Summary

As men grow older, their testosterone levels decrease with age. One-third of men, 70 years of age or older, have low testosterone levels. It is known that short-term testosterone replacement is safe, and can increase muscle strength and physical function, but the risks of long-term testosterone replacement in older men with low testosterone levels are incompletely understood. Atherosclerosis is characterized by thickening of the artery walls, and the narrowing of the blood vessels as cholesterol is deposited in the lining of the arteries. It is the major cause of cardiovascular disease including ischemic heart disease (heart attacks) and stroke. Although, historically, there has been a widespread perception that higher levels of testosterone might increase the risk of atherosclerosis, the evidence from research does not support this. In observational studies, higher testosterone levels have been correlated with more favorable cardiovascular risk factors, and supplementation with testosterone to bring older men into the normal range for healthy younger men appears to improve several cardiovascular risk factors, and may slow the progression of atherosclerosis. The primary purpose of this study is to look at the effects of testosterone replacement on the progression of atherosclerosis in older men. This study is also being done to find out whether replacement with testosterone in older men with low testosterone levels improves their health-related quality of life.

Conditions

Hypogonadism; Atherosclerosis

Keywords

Testosterone Replacement; Heart Disease; Vascular Disease; Risk Factors for Cardiovascular Disease; Cholesterol; Obesity; Blood pressure; Quality of Life

Outcome Measures

Primary Outcomes (2)

• Change From Baseline in Common Carotid Artery Intima-Media Thickness (IMT)

  B-mode carotid artery images for IMT were acquired from the far wall of the distal centimeter of the right carotid artery with high-resolution ultrasound equipment. IMT is used as a predictor of the incidence of cardiovascular events. An increase in the IMT thickness is associated with a higher incidence of cardiovascular events. Less thickening is best. Change is expressed in millimeters (mm).

  Baseline and Month 36

• Change From Baseline in Coronary Artery Calcium Score

  A multiple detector computed tomography (MDCT) scan was performed. Proximal coronary arteries were visualized, and at least 30 consecutive images were obtained at 3-mm intervals. Coronary calcium was defined as a plaque of at least 3 contiguous pixels (area, 1.02 mm\^2) with a density of more than 130 Hounsfield units.The lesion score was calculated by multiplying lesion area by a density factor derived from Hounsfield units. The Agatston method was used to determine the total calcium score by summing the lesion scores from the left main, left anterior descending, circumflex, and right coronary arteries. The Agatston score is the measure of calcification in arteries expressed on continuous scale with "0" value (better) indicating no calcification and score above 400 (worse) indicating high calcification. There is no upper limit for this measure. A positive change from baseline indicates a worsening.

  Baseline and Month 36

Secondary Outcomes (14)

• Change From Baseline in Lipid Profiles

  Baseline and Month 36

• Changes in Biomarkers of Inflammation

  Three years

• Changes in Blood Pressure

  Three years

• Change From Baseline in Complex Figure (Immediate) and Complex Figure (Delayed)

  Baseline and Month 36

• Change From Baseline in Paragraph Recall Test (Delayed)

  Baseline and Month 36

Study Arms (2)

Testosterone

ACTIVE COMPARATOR

Participants received 7.5 g of 1% testosterone gel to achieve a nominal delivery of 75 mg testosterone daily for 3 years. Dose adjustments were made by an unblinded observer. (Serum testosterone level measured on treatment day 15 was measured in a sample sent separately to the laboratory such that the results were reported directly to unblinded physician, who then communicated the decision about dose adjustment (or not) directly to the research pharmacist through e-mail.)

Drug: Testosterone Gel (Androgel)

Placebo

PLACEBO COMPARATOR

Participants received placebo-matching testosterone gel daily for 3 years.

Drug: Placebo

Interventions

Testosterone Gel (Androgel) DRUG

7.5 g of 1% testosterone gel to achieve a nominal delivery of 75 mg testosterone daily for 3 years

Testosterone

Placebo DRUG

Placebo-matching testosterone gel daily for 3 years

Placebo

Eligibility Criteria

• Age: 60 Years+
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 60 years or greater
• Hypogonadism, Testosterone 100-400 ng/dl or Free Testosterone \< 50 pg/ml
• Generally good health
• At least 8 years of primary school education
• Able to pass screening test for dementia
• Able to give informed consent

You may not qualify if:

• Testosterone level \< 100 ng/dl (these individuals will be referred for evaluation of severe hypogonadism)
• Use of testosterone or other androgens \[dehydroepiandrosterone (DHEA), Androstenedione\] in last year
• Use of growth hormone in the last year
• Current alcohol of drug dependence \[Alcohol Use Disorders Identification Test (AUDIT) Score \> 8\]
• Diseases known to affect gonadal function
• Medications known to affect gonadal function eg. anticonvulsants, glucocorticoids such as prednisone
• Prostate cancer, breast cancer
• Any cancer that may limit life expectancy to less than 5 years
• Limiting neuromuscular, joint or bone disease
• History of stroke with residual neurologic deficit
• Neurologic condition that would impair cognitive function including:
• epilepsy, multiple sclerosis, human immunodeficiency virus (HIV), Parkinson's disease, stroke
• Psychiatric disorder in the last year meeting Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSMIV) Axis 1 criteria
• Use of psychotropic medicine for at least 6 months
• Dementia as assessed by (Telephone Interview for Cognitive Status modified score less than 31)

Sponsors & Collaborators

• Brigham and Women's Hospital: lead
• Solvay Pharmaceuticals: collaborator

Study Sites (3)

Kronos Longevity Research Institute

Phoenix, Arizona, 85016, United States

Location

Charles R. Drew University of Medicine and Science

Los Angeles, California, 90059, United States

Location

Boston University / Boston Medical Center

Boston, Massachusetts, 02118, United States

Location

Related Publications (6)

• Huang G, Pencina KM, Li Z, Basaria S, Bhasin S, Travison TG, Storer TW, Harman SM, Tsitouras P. Long-Term Testosterone Administration on Insulin Sensitivity in Older Men With Low or Low-Normal Testosterone Levels. J Clin Endocrinol Metab. 2018 Apr 1;103(4):1678-1685. doi: 10.1210/jc.2017-02545.

  PMID: 29373734 DERIVED

• Bhasin S, Travison TG, O'Brien L, MacKrell J, Krishnan V, Ouyang H, Pencina K, Basaria S. Contributors to the substantial variation in on-treatment testosterone levels in men receiving transdermal testosterone gels in randomized trials. Andrology. 2018 Jan;6(1):151-157. doi: 10.1111/andr.12428. Epub 2017 Oct 5.

  PMID: 28981994 DERIVED

• Gagliano-Juca T, Icli TB, Pencina KM, Li Z, Tapper J, Huang G, Travison TG, Tsitouras P, Harman SM, Storer TW, Bhasin S, Basaria S. Effects of Testosterone Replacement on Electrocardiographic Parameters in Men: Findings From Two Randomized Trials. J Clin Endocrinol Metab. 2017 May 1;102(5):1478-1485. doi: 10.1210/jc.2016-3669.

  PMID: 27992261 DERIVED

• Storer TW, Basaria S, Traustadottir T, Harman SM, Pencina K, Li Z, Travison TG, Miciek R, Tsitouras P, Hally K, Huang G, Bhasin S. Effects of Testosterone Supplementation for 3 Years on Muscle Performance and Physical Function in Older Men. J Clin Endocrinol Metab. 2017 Feb 1;102(2):583-593. doi: 10.1210/jc.2016-2771.

  PMID: 27754805 DERIVED

• Huang G, Wharton W, Bhasin S, Harman SM, Pencina KM, Tsitouras P, Li Z, Hally KA, Asthana S, Storer TW, Basaria S. Effects of long-term testosterone administration on cognition in older men with low or low-to-normal testosterone concentrations: a prespecified secondary analysis of data from the randomised, double-blind, placebo-controlled TEAAM trial. Lancet Diabetes Endocrinol. 2016 Aug;4(8):657-665. doi: 10.1016/S2213-8587(16)30102-4. Epub 2016 Jul 1.

  PMID: 27377542 DERIVED

• Basaria S, Harman SM, Travison TG, Hodis H, Tsitouras P, Budoff M, Pencina KM, Vita J, Dzekov C, Mazer NA, Coviello AD, Knapp PE, Hally K, Pinjic E, Yan M, Storer TW, Bhasin S. Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men With Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial. JAMA. 2015 Aug 11;314(6):570-81. doi: 10.1001/jama.2015.8881.

  PMID: 26262795 DERIVED

MeSH Terms

Conditions

Hypogonadism; Atherosclerosis; Heart Diseases; Vascular Diseases; Obesity

Interventions

Testosterone

Condition Hierarchy (Ancestors)

Gonadal Disorders; Endocrine System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Cardiovascular Diseases; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

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: Shalendar Bhasin, MD
• Organization: Brigham and Women's Hospital

Sbhasin@partners.org

Study Officials

• Shalender Bhasin, MD

  Boston University / Boston Medical Center, Boston, MA

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: February 6, 2006
• First Posted: February 7, 2006
• Study Start: September 1, 2004
• Primary Completion: February 7, 2012
• Study Completion: May 12, 2012
• Last Updated: June 29, 2017
• Results First Posted: June 29, 2017

Record last verified: 2017-05

Locations

US (3)