Effect of Testosterone in Men With Erectile Dysfunction

Phase 4

Completed

Conditions: Testosterone Deficiency
Erectile Dysfunction
Diabetes

Interventions: Drug: Sildenafil citrate (open label)
Drug: Testosterone gel
Other: Placebo gel

Registration Number: NCT00512707

Lead Sponsor: Boston University

Brief Summary: 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.

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 The initial assessment will be made prior to treatment with sildenafil citrate, i.e., in subjects who are naïve to or withdrawn from PDE5 inhibitors and/or testosterone.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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 140

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Active Testosterone Gel	Sildenafil citrate (open label)	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.
Active Testosterone Gel	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.
Placebo Gel	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.
Placebo Gel	Sildenafil citrate (open label)	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.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Erectile Function Domain Score of the International Index of Erectile Function (IIEF)	Week 0, week 8, week 11, week 14	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.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Quality of Life Specific to Male Erection Difficulties (QOL-MED)	Week 0, Week 8, Week 14	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.
Change From Baseline in Marital Interaction Scale of CAncer Rehabilitation Evaluation System-Short Form (CARES-SF)	Week 0, Week 8, Week 14	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.
Change From Baseline in Positive Affects Ratio (PAR) of Derogatis Affects Balance Scale (DABS)	Week 0, Week 8, Week 14	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.
Change From Baseline in Other Domains of International Index of Erectile Function (IIEF)	Week 0, week 8, week 11, week 14	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.
Change From Baseline in Successful Sexual Intercourse of Sexual Encounter Profile (SEP)	Week 0, week 8, week 14	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.
Change From Baseline in Derogatis Affects Balance Scale (DABS)	Week 0, Week 8, Week 14	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.
Change From Baseline in Sexual Encounter Profile (SEP)	Week 0, week 8, week 14	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.
Change From Baseline in Men's Sexual Health Questionnaire (MSHQ)	Week 0, Week 8, Week 14	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.
Change From Baseline in Psychological General Well-Being Index Score (PGWBI)	Week 0, Week 8, Week 14	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.