Effect of Testosterone in Men With Erectile Dysfunction (TED)

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.

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 The initial assessment will be made prior to treatment with sildenafil citrate, i.e., in subjects who are naïve to or withdrawn from PDE5 inhibitors and/or testosterone.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

• Erectile Dysfunction
• Testosterone Deficiency
• Diabetes

• 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 Name: Viagra (Pfizer Inc.)
• Drug: Testosterone gel 1% (active or placebo)
  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 Name: Testim (Auxilium Pharmaceuticals, Inc.)
• Drug: Topical testosterone gel 1%
  Testosterone Gel: Starting 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. Blinded achieved by combining a total of 3 tubes of active or placebo gel.
  Other Name: Testim 1% (Auxilium Pharmaceuticals, Inc.)

• Experimental: 1
  Active Testosterone Gel
  Interventions:

  • Drug: Sildenafil citrate (open label)
  • Drug: Testosterone gel 1% (active or placebo)
  • Drug: Topical testosterone gel 1%
• Placebo Comparator: 2
  Placebo Gel
  Interventions:

  • Drug: Sildenafil citrate (open label)
  • Drug: Testosterone gel 1% (active or placebo)

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.