By Chris Berrie
STOCKHOLM, Sweden -- March 23, 2009 -- Testosterone gel therapy significantly improves the response to tadalafil in nonresponding patients with erectile dysfunction (ED) -- but only if they have total testosterone levels of less than 3 ng/mL or bioavailable testosterone levels of less than 0.6 ng/mL, stated researchers presenting here at the 24th Annual European Association of Urology (EAU) Congress.
Principal investigator Jacques Buvat, MD, CETPARP, Lille, France, described the results of a multicentre, randomised, double-blind, placebo-controlled study here on March 19 on behalf of the investigators for the Testosterone With PDE5 Inhibitors in ED Patient Non-Responders to PDE5 Inhibitors [Tadalafil] Alone (TADTEST) trial.
One of the reasons proposed for the failure of phosphodiesterase type 5 (PDE5) inhibitors in the treatment of ED, Dr. Buvat indicated, has been a neglected testosterone deficiency. The aim of this study was to determine whether the action of PDE5 inhibitors in men with ED is androgen-dependent.
Subjects in this trial ranged in age from 45 to 80 years and had ED of greater than 3 months duration; all were nonresponders to PDE5 inhibitors. Total testosterone level for all subjects was under 4 ng/mL, and bioavailable testosterone level was under 1 ng/mL. Subjects were excluded if they had received prior androgen therapy within 6 months or whether they had standard contraindications to PDE5 inhibitors or testosterone therapy.
The primary efficacy endpoint was the mean change from baseline in Erectile Function Domain (EFD) score of the International Index of Erectile Function (IIEF). Various secondary efficacy endpoints were based on EFD scores and other IIEF domain scores.
Enrolment (week 0) was into a 4-week run-in phase on tadalafil 10 mg orally per day, where, Dr. Buvat said, "If not improved after 4 weeks, these patients were randomised."
Patients were randomised at week 4 to continued tadalafil 10 mg orally per day, plus 5 g of a gel either containing placebo (n = 86; mean age 59.9 years) or containing 50 mg testosterone (n = 87; mean age 58.3 years). From week 8 or 12, titration to 10 g gel (100 mg testosterone) was allowed if there was insufficient improvement according to the patient.
The mean enrolment baseline clinical characteristics across the treatment groups were similar: ED duration, 5.9 versus 5.1 years; inability to penetrate, 81% for both; total testosterone, 3.36 ng/mL versus 3.37 ng/mL; bioavailable testosterone, 0.77 mg/mL versus 0.73 mg/mL.
From this baseline, in the testosterone group, the total and bioavailable testosterone increased significantly over placebo from 4 weeks of testosterone treatment (to 5.58, 1.30 ng/mL; P < .001), a level maintained to the end of the study (week 16, 5.58, 1.35 ng/mL; P < .001); no significant changes were seen for patients on placebo.
The EFD increased from randomisation in both patient groups without significant difference, indicating the need for 8 to 12 weeks of tadalafil treatment for maximum benefits. Similarly, no significant benefits were seen for testosterone gel over placebo across the range of secondary endpoints.
As Dr. Buvat indicated, however, assessment of efficacy effects according to baseline testosterone levels demonstrated a threshold below which the combination of tadalafil and testosterone provided significant benefit: total testosterone, 3 ng/mL; bioavailable testosterone, 0.6 ng/mL.
In these patients, there was a continuous beneficial trend for the primary efficacy endpoint from 4 weeks of testosterone to the end of the study, with significance reached over placebo at 8 weeks of testosterone (EFD score, 6.18 vs 2.33; P = .027). Some significant benefits for the secondary endpoints were also seen for testosterone gel use by 8 weeks of treatment.
In summary, Dr. Buvat said, "First, tadalafil 10 mg once a day is able to salvage by itself about 40% to 50% of those patients nonresponding to PDE5 inhibitors on demand, and secondly, with this treatment, if you want to add testosterone, it is useful only if the testosterone level is less than 3 ng/mL."
As an overall consideration, he added, "Lastly, the lower the baseline testosterone, the lower the improvement over time by tadalafil alone in the placebo group, supporting the androgen dependence of PDE5 inhibitors in man, which has until now only been unquestionably demonstrated in animals."
Funding for this study was provided by Bayer Schering Pharma. Tadalafil tablets were supplied by Lilly Research Laboratories.
[Presentation title: What Is the Threshold Level of the PDE5 Inhibitors' Testosterone Dependence in Men? A Double-Blind, Placebo-Controlled Trial of Testosterone Gel Addition in Men With ED Non Responding to Tadalafil 10 mg Once a Day Alone. Abstract 376]
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