Effect of Testosterone in Men With Erectile Dysfunction (TED)

Androgen Modulation of Response to Selective Phosphodiesterase Inhibitors in Erectile Dysfunction

The purpose of this placebo-controlled study is to determine if testosterone replacement therapy, administered by transdermal gel, can improve the response to sildenafil (Viagra R) treatment in men who have erectile dysfunction (ED) and low testosterone levels.

Study Overview

• Status: Completed
• Conditions: Diabetes; Erectile Dysfunction; Testosterone Deficiency
• Intervention / Treatment: Drug: Sildenafil citrate (open label); Drug: Testosterone gel; Other: Placebo gel

Detailed Description

This is a double-blind, placebo-controlled, parallel-group, randomized clinical trial in men, 40-70 years of age, who present with mild to moderate erectile dysfunction and have androgen deficiency defined as serum total testosterone level below 300 ng/dL, measured by liquid chromatography tandem mass spectrometry, LC-MS/MS (15) and/or free testosterone level (measured by equilibrium dialysis) below 50 pg/ml. Sexual function assessments will include validated erectile function questionnaires (IIEF), sexual activity diaries, sexual desire, partner interaction and intimacy, affects balance scale, mood, ED-related quality of life, and penile rigidity in response to a visual erotic stimulus. The initial assessment will be made prior to treatment with sildenafil citrate, i.e., in subjects who are naïve to or withdrawn from PDE5 inhibitors and/or testosterone. Participants will then be allotted three sildenafil citrate tablets per week (12 pills per month), but will not use more than one tablet within any 24-hour period. During the Sildenafil-Dose Optimization period, subjects naïve to sildenafil citrate will start with a 50 mg dose. Those who have used sildenafil citrate in the past will take the same dose that was found to be efficacious for them. After three weeks, the dose of sildenafil citrate will be increased to 100-mg in non-responders. For those who cannot tolerate the 50-mg dose, a dose of 25 mg will be given. After three weeks on the optimized dose of sildenafil citrate, subjects will undergo a second evaluation of sexual function. They will then be randomly assigned to receive this optimized dose of sildenafil citrate with either placebo gel (15 g per day) or active testosterone gel (10 g active gel + 5 g placebo gel per day). The daily dose of active testosterone gel was selected to increase average serum into the upper-half of the normal range for healthy, young men (e.g., 500-1000 ng/dL). In order to assure that serum testosterone levels are in the target range (500-1000 ng/dL), testosterone dose will be adjusted by an unblinded individual two to three weeks after initiation of testosterone/placebo treatment, based on the measurement of serum testosterone levels. If the average testosterone level is less than 500 ng/dL, the daily dose will be increased to 15g of active gel. If the average testosterone is greater than 1,000 ng/dL, the daily dose will be decreased to 5 g of active gel (and 10 g of placebo gel). This dose adjustment will take effect at week 4 (day 28) of treatment. Subjects will be treated for an additional 12-weeks with sildenafil citrate and the optimized dose of testosterone gel or placebo gel. Sexual function will be evaluated at the end of this treatment period.

• Study Type: Interventional
• Enrollment (Actual): 140
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Men, 40-70 years of age, in a stable relationship, with mild to moderate erectile dysfunction for at least 6 months; defined as an IIEF-EF domain score between 11 and 25 (mild to moderate ED)
• Neutral or extremely dissatisfied with one's sex life
• Presence of androgen deficiency defined as serum total testosterone level less than 300 ng/dL (measured by LC-MS/MS) and/or free testosterone level (measured by equilibrium dialysis) less than 50 pg/ml.
• Able to understand the nature of the study and provide written, informed consent

Exclusion Criteria:

• Contraindication for use of testosterone, e.g., history of prostate or breast cancer
• benign prostatic hyperplasia with AUA/IPSS symptom scores of 21 or greater
• erythrocytosis (hematocrit >50% at baseline)
• untreated, severe sleep apnea
• serum PSA levels >4 ug/L will be excluded unless they have had a urologic evaluation in the past three months to exclude prostate cancer.
• Contraindication for use of sildenafil, e.g., symptomatic coronary artery disease taking long-acting or short-acting nitrate drugs on a regular basis.
• Symptomatic postural hypotension
• Congestive heart failure with class III or IV symptoms
• History of myocardial infarction or stroke within the past six months
• Primary diagnosis of another sexual disorder such as premature ejaculation
• AST, ALT, alkaline phosphatase elevation greater than three times the upper limit of normal, creatinine greater than 2 mg/dL.
• Currently taking testosterone or oral androgen precursors; unless willing to discontinue their use for 4 weeks (oral precursors or transdermal testosterone patch or gel) or 6 weeks (if injectable testosterone) before the initial screen visit.
• Currently taking medications that affect androgen metabolism, action, or clearance (dilantin, phenobarbital, aldactone, flutamide, finasteride).
• Uncontrolled diabetes mellitus or diabetes mellitus, e.g., if their baseline hemoglobin A1C is less than 8.5%.
• Structural abnormalities of the penis, including Peyronie's disease, will be excluded.
• Men who are taking medications for erectile dysfunction, including sildenafil, must stop using these medications for at least 4 weeks before starting Visit 2.
• DSM-IV criteria for an Axis I psychiatric disorder within the past year, including depression; use of psychotropic medication for at least six months, or dementia is also an exclusion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active Testosterone Gel; Active Testosterone Gel and on demand use of sildenafil citrate (3 tablets per week). Starting dose of 50 mg. Titrated to 100 mg or 25 mg depending on efficacy and tolerability. Begins as open label run in period for 3 - 6 weeks, and continues during the placebo-controlled testosterone gel intervention for 16 weeks.	Drug: Sildenafil citrate (open label); On demand use of sildenafil citrate (3 tablets per week). Starting dose of 50 mg. Titrated to 100 mg or 25 mg depending on efficacy and tolerability. Begins as open label run in period for 3 - 6 weeks, and continues during the placebo-controlled testosterone gel intervention for 16 weeks.; Other Names: Viagra (Pfizer Inc.); Drug: Testosterone gel; Testosterone Gel 1%: Starting active dose 10 g/day. Increased to 15 g/day or decreased to 5 g/day in order to attain morning total testosterone level between 500 - 1000 ng/dL. Blinding achieved by combining a total of 3 tubes of active or placebo gel, applied to upper arms and shoulders each day.; Other Names: Testim (Auxilium Pharmaceuticals, Inc.)
Placebo Comparator: Placebo Gel; Placebo Gel and on demand use of sildenafil citrate (3 tablets per week). Starting dose of 50 mg. Titrated to 100 mg or 25 mg depending on efficacy and tolerability. Begins as open label run in period for 3 - 6 weeks, and continues during the placebo-controlled testosterone gel intervention for 16 weeks.	Drug: Sildenafil citrate (open label); On demand use of sildenafil citrate (3 tablets per week). Starting dose of 50 mg. Titrated to 100 mg or 25 mg depending on efficacy and tolerability. Begins as open label run in period for 3 - 6 weeks, and continues during the placebo-controlled testosterone gel intervention for 16 weeks.; Other Names: Viagra (Pfizer Inc.); Other: Placebo gel; 3 tubes of placebo gel equivalent to the amount of the testosterone gel will be applied during the placebo-controlled testosterone gel intervention for 16 weeks..

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Erectile Function Domain Score of the International Index of Erectile Function (IIEF)	IIEF is a validated, 15-item questionnaire that assesses 5 domains of sexual function: erectile function (range 1-30), orgasmic function (range 0-10), sexual desire (range 2-10), intercourse satisfaction (range 0-15), and overall sexual satisfaction (range 2-10). Each question was answered on a 6-point or 5-point scale from 0/1 to 5 (best) with Erectile Function domain range of 1 to 30 with higher scores representing better function.	Week 0, week 8, week 11, week 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Other Domains of International Index of Erectile Function (IIEF)	IIEF is a validated, 15-item questionnaire that assesses 5 domains of sexual function: erectile function (range 1-30), orgasmic function (range 0-10), sexual desire (range 2-10), intercourse satisfaction (range 0-15), and overall sexual satisfaction (range 2-10). Each question was answered on a 6-point or 5-point scale from 0/1 to 5 (best) with a total possible score (sum of 5 domains) range of 5 to 75 with higher scores representing better function.	Week 0, week 8, week 11, week 14
Change From Baseline in Sexual Encounter Profile (SEP)	Sexual Encounter Profile (SEP) diaries were used to assess frequency of sexual activity, sildenafil use, vaginal penetration, completion of intercourse with ejaculation, and overall satisfaction with sexual encounters. Minimum value is 0 with no maximum limit, wherein higher values representing better sexual encounter.	Week 0, week 8, week 14
Change From Baseline in Successful Sexual Intercourse of Sexual Encounter Profile (SEP)	Sexual Encounter Profile (SEP) diaries were used to assess frequency of sexual activity, sildenafil use, vaginal penetration, completion of intercourse with ejaculation, and overall satisfaction with sexual encounters. Higher percentage of Ejaculations or Satisfaction in successful sexual intercourse represents better sexual function.	Week 0, week 8, week 14
Change From Baseline in Men's Sexual Health Questionnaire (MSHQ)	MSHQ, a 25-item questionnaire, assesses sexual function and satisfaction. It consists 5 domains: Erection (3 items, ranging from 0 to 15 (best)), Ejaculation (7 items, ranging from 1 to 35 (best)), Satisfaction (6 items, ranging from 6 to 30 (best)), Sexual desire (4 items, ranging 4-20 (best)), and Sexual activity (3 items, ranging 3-15 (best)). A composite score is the sum of Ejaculation and Satisfaction domains, ranging from 7 to 65 (best), with higher score representing better sexual function and satisfaction.	Week 0, Week 8, Week 14
Change From Baseline in Quality of Life Specific to Male Erection Difficulties (QOL-MED)	The Quality of Life for men with Erection Difficulties (QOL-MED) is a cross-cultural instrument to measure quality of life specific to male erection difficulties. The 18 items for this scale were generated from interviews with men with erection difficulties by TH Wagner in 1996. Higher QOL-MED scores reflect better quality of life. Scores were standardized to range of 0 to 100.	Week 0, Week 8, Week 14
Change From Baseline in Marital Interaction Scale of CAncer Rehabilitation Evaluation System-Short Form (CARES-SF)	CAncer Rehabilitation Evaluation System-short form (CARES-SF) marital interaction scale consists of 6 items (range from 0 (best) to 4) and mean of these 6 questions was used to determine intimacy and partner interaction. Lower CARES-SF scores correspond with improved marital interaction.	Week 0, Week 8, Week 14
Change From Baseline in Psychological General Well-Being Index Score (PGWBI)	Well-being and mood were assessed using the Psychological General Well-Being Index (PGWBI), a 22-item questionnaire that evaluated six dimensions of self-reported wellness: Anxiety (5 questions), Depressed Mood (3 questions), Positive Well-Being (4 questions), Self Control (3 questions), General Health (3 questions), and Vitality (4 questions). Higher scores in each dimension reflect increasing well-being. A global score (ranging from 0 (poor QoL) to 110 (good QoL)) was calculated as the sum of each domain score. The global score and those of its 6 dimensions were normalized to a 100% scale to facilitate comparison.	Week 0, Week 8, Week 14
Change From Baseline in Derogatis Affects Balance Scale (DABS)	The Derogatis Affects Balance Scale (DABS) is a 40-item mood inventory and consists of 4 positive affect dimensions (joy, contentment, vigor, and affection) as well as 4 negative affect dimensions(anxiety, depression, guilt, and hostility). Each domain was calculated as the sum of 5-items and could range from 0 to 20, wherein higher scores indicate greater affectivity.	Week 0, Week 8, Week 14
Change From Baseline in Positive Affects Ratio (PAR) of Derogatis Affects Balance Scale (DABS)	The Derogatis Affects Balance Scale (DABS) is a 40-item mood inventory and consists of 4 positive affect dimensions (joy, contentment, vigor, and affection) as well as 4 negative affect dimensions(anxiety, depression, guilt, and hostility). Positive Affects Ratio (PAR), ranging from 0 to 1, is the proportion of total scores (sum of all 8 domains) that is positive (sum of 4 positive domains). Higher PAR represents better affectivity.	Week 0, Week 8, Week 14

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Total Testosterone	Total testosterone levels were measured between 7:30 and 10:10 a.m. using a liquid chromatography-tandem mass spectrometry assay certified by the Centers for Disease Control and Prevention's Hormone Standardization Program.	Week 0, Week 14
Change From Baseline in Free Testosterone	Free testosterone levels were calculated from total testosterone at screening and equilibrium dialysis at randomization and at trial end.	Week 0, Week 14
Change From Baseline in Sex Hormone Binding Globulin (SHBG)		Week 0, Week 14

Collaborators and Investigators

• Sponsor: Boston University
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Publications and helpful links

General Publications

• Wilson E, Gannon H, Chimhini G, Fitzgerald F, Khan N, Lorencatto F, Kesler E, Nkhoma D, Chiyaka T, Haghparast-Bidgoli H, Lakhanpaul M, Cortina Borja M, Stevenson AG, Crehan C, Sassoon Y, Hull-Bailey T, Curtis K, Chiume M, Chimhuya S, Heys M. Protocol for an intervention development and pilot implementation evaluation study of an e-health solution to improve newborn care quality and survival in two low-resource settings, Malawi and Zimbabwe: Neotree. BMJ Open. 2022 Jul 5;12(7):e056605. doi: 10.1136/bmjopen-2021-056605.
• Spitzer M, Bhasin S, Travison TG, Davda MN, Stroh H, Basaria S. Sildenafil increases serum testosterone levels by a direct action on the testes. Andrology. 2013 Nov;1(6):913-8. doi: 10.1111/j.2047-2927.2013.00131.x. Epub 2013 Sep 18.
• Spitzer M, Basaria S, Travison TG, Davda MN, DeRogatis L, Bhasin S. The effect of testosterone on mood and well-being in men with erectile dysfunction in a randomized, placebo-controlled trial. Andrology. 2013 May;1(3):475-82. doi: 10.1111/j.2047-2927.2013.00075.x. Epub 2013 Mar 15.
• Spitzer M, Basaria S, Travison TG, Davda MN, Paley A, Cohen B, Mazer NA, Knapp PE, Hanka S, Lakshman KM, Ulloor J, Zhang A, Orwoll K, Eder R, Collins L, Mohammed N, Rosen RC, DeRogatis L, Bhasin S. Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial. Ann Intern Med. 2012 Nov 20;157(10):681-91. doi: 10.7326/0003-4819-157-10-201211200-00004.

Study record dates

Study Major Dates

• Study Start: November 1, 2006
• Primary Completion (Actual): May 1, 2010
• Study Completion (Actual): May 1, 2010

Study Registration Dates

• First Submitted: August 7, 2007
• First Submitted That Met QC Criteria: August 7, 2007
• First Posted (Estimate): August 8, 2007

Study Record Updates

• Last Update Posted (Actual): June 29, 2017
• Last Update Submitted That Met QC Criteria: May 28, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: sildenafil; erectile dysfunction; testosterone
• Additional Relevant MeSH Terms: Mental Disorders; Sexual Dysfunctions, Psychological; Sexual Dysfunction, Physiological; Erectile Dysfunction; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Androgens; Sildenafil Citrate; Testosterone
• Other Study ID Numbers: H-25065; R01HD047722-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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.: Yes