Francesco Montorsi1, Gerald Brock2, Jens-Uwe Stolzenburg3, John Mulhall4, Ignacio Moncada5, Hitendra R H Patel6, Daniel Chevallier7, Kazimierz Krajka8, Carsten Henneges9, Ruth Dickson10, Hartwig Büttner11. 1. Vita Salute San Raffaele University, Milan, Italy. 2. University of Western Ontario, London, Ontario, Canada. 3. Universitätsklinikum Leipzig, Leipzig, Germany. 4. Memorial Sloan-Kettering Cancer Centre, New York, NY, USA. 5. Hospital La Zarzuela, Madrid, Spain. 6. University Hospital North Norway, Tromso, Norway. 7. Hôpital Universitaire Archet 2, Nice, France. 8. Uniwersyteckie Centrum Kliniczne, Gdansk, Poland. 9. Lilly Deutschland GmbH, Bad Homburg, Germany. 10. Eli Lilly Canada Inc., Toronto, Ontario, Canada. 11. Lilly Deutschland GmbH, Bad Homburg, Germany. Electronic address: buettnerh@lilly.com.
Abstract
BACKGROUND: The potential rehabilitative and protective effect of phosphodiesterase type 5 inhibitors (PDE5-Is) on penile function after nerve-sparing radical prostatectomy (NSRP) remains unclear. OBJECTIVE: The primary objective was to compare the efficacy of tadalafil 5mg once daily and tadalafil 20mg on demand versus placebo taken over 9 mo in improving unassisted erectile function (EF) following NSRP, as measured by the proportion of patients achieving an International Index of Erectile Function-Erectile Function domain (IIEF-EF) score ≥ 22 after 6-wk drug-free washout (DFW). Secondary measures included IIEF-EF, Sexual Encounter Profile question 3 (SEP-3), and penile length. DESIGN, SETTING, AND PARTICIPANTS: Randomised, double-blind, double-dummy, placebo-controlled trial in men ≤ 68 yr of age with adenocarcinoma of the prostate (Gleason ≤ 7) and normal preoperative EF who underwent NSRP at 50 centres from nine European countries and Canada. INTERVENTIONS: 1:1:1 randomisation to 9 mo of treatment with tadalafil 5mg once daily, tadalafil 20mg on demand, or placebo followed by a 6-wk DFW and 3-mo open-label tadalafil once daily (all patients). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Logistic regression, mixed-effects model for repeated measures, and analysis of covariance, adjusting for treatment, age, and country, were applied to IIEF-EF scores ≥ 22, SEP-3, and penile length. RESULTS AND LIMITATIONS: Four hundred twenty-three patients were randomised to tadalafil once daily (n=139), on demand (n=143), and placebo (n=141). The mean age was 57.9 yr of age (standard deviation: 5.58 yr); 20.9%, 16.9%, and 19.1% of patients in the tadalafil once daily, on demand, and placebo groups, respectively, achieved IIEF EF scores ≥ 22 after DFW; odds ratios for tadalafil once daily and on demand versus placebo were 1.1 (95% confidence interval [CI], 0.6-2.1; p=0.675) and 0.9 (95% CI, 0.5-1.7; p=0.704). At the end of double-blind treatment (EDT), least squares (LS) mean IIEF-EF score improvement significantly exceeded the minimally clinically important difference (MCID: ΔIIEF-EF ≥ 4) in both tadalafil groups; for SEP-3 (MCID ≥ 23%), this was the case for tadalafil once daily only. Treatment effects versus placebo were significant for tadalafil once daily only (IIEF-EF: p=0.016; SEP-3: p=0.019). In all groups, IIEF-EF and SEP-3 decreased during DFW but continued to improve during open-label treatment. At month 9 (EDT), penile length loss was significantly reduced versus placebo in the tadalafil once daily group only (LS mean difference 4.1mm; 95% CI, 0.4-7.8; p=0.032). CONCLUSIONS:Tadalafil once daily was most effective on drug-assisted EF in men with erectile dysfunction following NSRP, and data suggest a potential role for tadalafil once daily provided early after surgery in contributing to the recovery of EF after prostatectomy and possibly protecting from penile structural changes. Unassisted EF was not improved after cessation of active therapy for 9 mo. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01026818.
RCT Entities:
BACKGROUND: The potential rehabilitative and protective effect of phosphodiesterase type 5 inhibitors (PDE5-Is) on penile function after nerve-sparing radical prostatectomy (NSRP) remains unclear. OBJECTIVE: The primary objective was to compare the efficacy of tadalafil 5mg once daily and tadalafil 20mg on demand versus placebo taken over 9 mo in improving unassisted erectile function (EF) following NSRP, as measured by the proportion of patients achieving an International Index of Erectile Function-Erectile Function domain (IIEF-EF) score ≥ 22 after 6-wk drug-free washout (DFW). Secondary measures included IIEF-EF, Sexual Encounter Profile question 3 (SEP-3), and penile length. DESIGN, SETTING, AND PARTICIPANTS: Randomised, double-blind, double-dummy, placebo-controlled trial in men ≤ 68 yr of age with adenocarcinoma of the prostate (Gleason ≤ 7) and normal preoperative EF who underwent NSRP at 50 centres from nine European countries and Canada. INTERVENTIONS: 1:1:1 randomisation to 9 mo of treatment with tadalafil 5mg once daily, tadalafil 20mg on demand, or placebo followed by a 6-wk DFW and 3-mo open-label tadalafil once daily (all patients). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Logistic regression, mixed-effects model for repeated measures, and analysis of covariance, adjusting for treatment, age, and country, were applied to IIEF-EF scores ≥ 22, SEP-3, and penile length. RESULTS AND LIMITATIONS: Four hundred twenty-three patients were randomised to tadalafil once daily (n=139), on demand (n=143), and placebo (n=141). The mean age was 57.9 yr of age (standard deviation: 5.58 yr); 20.9%, 16.9%, and 19.1% of patients in the tadalafil once daily, on demand, and placebo groups, respectively, achieved IIEF EF scores ≥ 22 after DFW; odds ratios for tadalafil once daily and on demand versus placebo were 1.1 (95% confidence interval [CI], 0.6-2.1; p=0.675) and 0.9 (95% CI, 0.5-1.7; p=0.704). At the end of double-blind treatment (EDT), least squares (LS) mean IIEF-EF score improvement significantly exceeded the minimally clinically important difference (MCID: ΔIIEF-EF ≥ 4) in both tadalafil groups; for SEP-3 (MCID ≥ 23%), this was the case for tadalafil once daily only. Treatment effects versus placebo were significant for tadalafil once daily only (IIEF-EF: p=0.016; SEP-3: p=0.019). In all groups, IIEF-EF and SEP-3 decreased during DFW but continued to improve during open-label treatment. At month 9 (EDT), penile length loss was significantly reduced versus placebo in the tadalafil once daily group only (LS mean difference 4.1mm; 95% CI, 0.4-7.8; p=0.032). CONCLUSIONS:Tadalafil once daily was most effective on drug-assisted EF in men with erectile dysfunction following NSRP, and data suggest a potential role for tadalafil once daily provided early after surgery in contributing to the recovery of EF after prostatectomy and possibly protecting from penile structural changes. Unassisted EF was not improved after cessation of active therapy for 9 mo. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01026818.
Authors: Johanna L Hannan; Maarten Albersen; Bernard L Stopak; Xiaopu Liu; Arthur L Burnett; Ahmet Hoke; Trinity J Bivalacqua Journal: J Neurosci Res Date: 2015-01-19 Impact factor: 4.164