Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia

doi:10.1016/S0090-4295(02)01905-2

Urology

Volume 60, Issue 3, September 2002, Pages 434-441

The results have been presented in part at the 2002 European Association of Urology Annual Meeting, Birmingham, United Kingdom and the 2002 American Urological Association Meeting, Orlando, Florida.

https://doi.org/10.1016/S0090-4295(02)01905-2 Get rights and content

Abstract

Objectives. To study the efficacy and safety of dutasteride, a dual inhibitor of the 5-alpha-reductase isoenzymes types I and II.

Methods. A total of 4325 men (2951 completed) with clinical benign prostatic hyperplasia, moderate to severe symptoms (American Urological Association-Symptom Index score of 12 points or greater), a peak flow rate of 15 mL/s or less, a prostate volume of 30 cm³ or greater (as measured by transrectal ultrasonography), and a serum prostate-specific antigen level of 1.5 to 10.0 ng/mL (inclusive) were enrolled into three identical clinical trials and randomized to 0.5 mg dutasteride daily or placebo. After a 1-month, single-blind, placebo lead-in, patients were followed up for 24 months in a double-blind trial with multiple interval assessments.

Results. At 24 months, serum dihydrotestosterone was reduced from baseline by a mean of 90.2% (median −93.7%; P <0.001), and the total prostate and transition zone volumes were reduced by a mean of 25.7% and 20.4%, respectively (P <0.001). The symptom score was improved by as early as 3 months, with pooled significance from 6 months onward (P <0.001) and a reduction of 4.5 points (21.4%) at 24 months (P <0.001). The maximal flow rate improved significantly from 1 month (P <0.01), with an increase of 2.2 mL/s reported at 24 months (P <0.001). Hence, the risk reduction of acute urinary retention was 57% and the risk reduction of benign prostatic hyperplasia-related surgical intervention was 48% compared with placebo. The drug was well tolerated.

Conclusions. Dutasteride is a potent inhibitor of dihydrotestosterone production that is safe and effective in terms of the reduction of prostate volume and symptoms, flow rate improvement, and the reduction of the risk of acute urinary retention and surgery during a 24-month study period.

Section snippets

Material and methods

Dutasteride, 0.5 mg/day, has been found to be safe and effective, reducing circulating DHT levels by 85% at 1 week and by 90% at 2 weeks.12 Consequently, this dose of dutasteride was chosen for three parallel, randomized, placebo-controlled studies of 24 months’ duration (ARIA 3001 [United States only], ARIA 3002 [United States only], ARIA 3003 [19 countries]) covering 400 sites in total that had identical inclusion and exclusion criteria to allow for a preplanned pooling of the data.

The

Patient demographics

A total of 4325 patients were randomized, of which 2951 men (68%) completed the 24-month studies; the reasons for discontinuation are shown in Figure 1. The reasons for discontinuation were only significantly different statistically between the dutasteride and placebo-treated groups for a lack of efficacy (P <0.001). Pooled baseline data for the two treatment arms are displayed in Table I.

Efficacy

Serum DHT changed by a mean of +9.6% versus −90.2% (median of +5.4% versus −93.7%) at 24 months in the

Comment

Previous experience with 5ARIs have demonstrated that they are most effective in the appropriate patient population.19, 21, 22 Hence, the Phase III studies enrolled only men with a TPV of 30 cm³ or greater by TRUS and a serum total PSA level of 1.5 ng/mL or greater (ie, patients likely to have LUTS as a result of BPH and those at increased risk of disease progression).1 To assess the effect of missing data (discontinuations) in these studies, both last observation carried forward analyses and

Conclusions

The results of this study confirm the hypothesis that the almost complete reduction in DHT levels, through inhibition of the 5-alpha-reductase isoenzymes, can prevent the progression of BPH. Thus, dutasteride represents an additional therapeutic option for clinicians and is particularly suited for men with LUTS due to BPH and enlarged prostates (30 cm³ or greater).

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^☆: The ARIA/B 3001-3003 trials were sponsored and supported by GlaxoSmithKline, the manufacturer of dutasteride.

¹: C. G. Roehrborn and G. Andriole are investigators and consultants for GlaxoSmithKline. K. Hoefner and J. C. Nickel are investigators for GlaxoSmithKline. P. Boyle is a consultant for GlaxoSmithKline.

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Adult urologyEfficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia☆

Abstract

Section snippets

Material and methods

Patient demographics

Efficacy

Comment

Conclusions

Urology

J Urol

Urology

J Urol

Urology

Urology

Urology

Urology

Urology

Eur Urol

Urology

Urology

Urology

The progression of benign prostatic hyperplasiaexamining the evidence and determining the risk

Eur Urol

A meta-analysis on the efficacy and tolerability of alpha1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction

Eur Urol

Adult urology
Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia☆