Effects of tadalafil once daily or on demand versus placebo on time to recovery of erectile function in patients after bilateral nerve-sparing radical prostatectomy.

Moncada I ，de Bethencourt FR ，Lledó-García E ，Romero-Otero J ，Turbi C ，Büttner H ，Henneges C ，Martinez Salamanca JI ... -  《-》

Effects of Tadalafil Once-Daily or On-Demand vs Placebo on Return to Baseline Erectile Function After Bilateral Nerve-Sparing Radical Prostatectomy--Results from a Randomized Controlled Trial (REACTT).

The multicenter, randomized, double-blind, double-dummy, placebo-controlled REACTT trial suggested that treatment with tadalafil once daily (OaD) started early after bilateral nerve-sparing radical prostatectomy (nsRP) for prostate cancer may contribute to erectile function (EF)-recovery, which was predefined as achieving an International Index of Erectile Function (IIEF)-EF score ≥22. Here, we report descriptive post-hoc analyses, using the more strict definition for EF-recovery of returning back to the pre-surgery IIEF-EF-level ("back-to-baseline analysis"). REACTT included 422 men <68 years with adenocarcinoma of the prostate and preoperative IIEF-EF ≥22 who underwent nsRP at 50 centers from 9 European countries and Canada. Patients were randomized post-nsRP 1:1:1 to 9-month double-blind treatment (DBT) with tadalafil 5 mg OaD (n = 139), tadalafil 20 mg on-demand (pro-re-nata, PRN; n = 142), or placebo (n = 141), followed by 6-week drug-free washout (DFW) and 3-month open-label tadalafil OaD treatment (OLT). Proportion of patients returning to their preoperative IIEF-EF category (22-25 or ≥26) at the end of DBT, DFW, and OLT. Overall, 92.4% of patients had pre-surgery (baseline) IIEF-EF scores ≥26 (tadalafil OaD 94.2%, PRN 91.6%, placebo 91.5%), 7.4% had IIEF-EF 22-25. At the end of DBT, 22.3% of patients on tadalafil OaD had achieved "back-to-baseline" IIEF-EF, compared with 11.3% on tadalafil PRN and 7.8% on placebo. Of all 58 patients "back-to-baseline" at the end of DBT, only 1 PRN-group patient had started from a baseline IIEF-EF <26. The treatment-group difference at the end of DBT was not maintained after DFW. After 3 months of OLT with tadalafil OaD, the proportion of patients with "back-to-baseline" IIEF-EF had almost doubled in all 3 groups. Changing the definition for EF-recovery from IIEF-EF ≥22 to the more strict definition of "returning back-to-baseline IIEF-EF" had no major impact. Tadalafil OaD started early after nsRP improved drug-assisted EF, but had no effect on unassisted EF following treatment cessation after 9 months.

Mulhall JP ，Brock G ，Oelke M ，Fode M ，Probst KA ，Henneges C ，d'Anzeo G ，Rossi A ，Büttner H ... -  《-》

Effects of tadalafil treatment on erectile function recovery following bilateral nerve-sparing radical prostatectomy: a randomised placebo-controlled study (REACTT).

The potential rehabilitative and protective effect of phosphodiesterase type 5 inhibitors (PDE5-Is) on penile function after nerve-sparing radical prostatectomy (NSRP) remains unclear. 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. 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. 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). 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. 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). 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. ClinicalTrials.gov identifier NCT01026818.

Montorsi F ，Brock G ，Stolzenburg JU ，Mulhall J ，Moncada I ，Patel HR ，Chevallier D ，Krajka K ，Henneges C ，Dickson R ，Büttner H ... -  《-》

Exploratory Decision-Tree Modeling of Data from the Randomized REACTT Trial of Tadalafil Versus Placebo to Predict Recovery of Erectile Function After Bilateral Nerve-Sparing Radical Prostatectomy.

Understanding predictors for the recovery of erectile function (EF) after nerve-sparing radical prostatectomy (nsRP) might help clinicians and patients in preoperative counseling and expectation management of EF rehabilitation strategies. To describe the effect of potential predictors on EF recovery after nsRP by post hoc decision-tree modeling of data from A Study of Tadalafil After Radical Prostatectomy (REACTT). Randomized double-blind double-dummy placebo-controlled trial in 423 men aged <68 yr with adenocarcinoma of the prostate (Gleason ≤7, normal preoperative EF) who underwent nsRP at 50 centers from nine European countries and Canada. Postsurgery 1:1:1 randomization to 9-mo double-blind treatment with tadalafil 5mg once a day (OaD), tadalafil 20mg on demand, or placebo, followed by a 6-wk drug-free-washout, and a 3-mo open-label tadalafil OaD treatment. Three decision-tree models, using the International Index of Erectile Function-Erectile Function (IIEF-EF) domain score at the end of double-blind treatment, washout, and open-label treatment as response variable. Each model evaluated the association between potential predictors: presurgery IIEF domain and IIEF single-item scores, surgical approach, nerve-sparing score (NSS), and postsurgery randomized treatment group. The first decision-tree model (n=422, intention-to-treat population) identified high presurgery sexual desire (IIEF item 12: ≥3.5 and <3.5) as the key predictor for IIEF-EF at the end of double-blind treatment (mean IIEF-EF: 14.9 and 11.1), followed by high confidence to get and maintain an erection (IIEF item 15: ≥3.5 and <3.5; IIEF-EF: 15.4 and 7.1). For patients meeting these criteria, additional non-IIEF-related predictors included robot-assisted laparoscopic surgery (yes or no; IIEF-EF: 19.3 and 12.6), quality of nerve sparing (NSS: <2.5 and ≥2.5; IIEF-EF: 14.3 and 10.5), and treatment with tadalafil OaD (yes and no; IIEF-EF: 17.6 and 14.3). Additional analyses after washout and open-label treatment identified high presurgery intercourse satisfaction as the key predictor. Exploratory decision-tree analyses identified high presurgery sexual desire, confidence, and intercourse satisfaction as key predictors for EF recovery. Patients meeting these criteria might benefit the most from conserving surgery and early postsurgery EF rehabilitation. Strategies for improving EF after surgery should be discussed preoperatively with all patients; this information may support expectation management for functional recovery on an individual patient level. Understanding how patient characteristics and different treatment options affect the recovery of erectile function (EF) after radical surgery for prostate cancer might help physicians select the optimal treatment for their patients. This analysis of data from a clinical trial suggested that high presurgery sexual desire, sexual confidence, and intercourse satisfaction are key factors predicting EF recovery. Patients meeting these criteria might benefit the most from conserving surgery (robot-assisted surgery, perfect nerve sparing) and postsurgery medical rehabilitation of EF. ClinicalTrials.gov, NCT01026818.

Montorsi F ，Oelke M ，Henneges C ，Brock G ，Salonia A ，d'Anzeo G ，Rossi A ，Mulhall JP ，Büttner H ... -  《-》

Effect of Tadalafil Once Daily on Penile Length Loss and Morning Erections in Patients After Bilateral Nerve-sparing Radical Prostatectomy: Results From a Randomized Controlled Trial.

To report penile integrity measures, including stretched penile length (SPL), from a randomized, double-blind, double-dummy, placebo-controlled trial evaluating treatment with tadalafil initiated after nerve-sparing radical prostatectomy (nsRP). Patients aged ≤ 68 years were randomized after nsRP 1:1:1 to 9-month double-blind treatment (DBT) with tadalafil 5 mg once daily (OaD), 20-mg tadalafil on-demand ("pro-re-nata"; PRN), or placebo, followed by 6-week drug-free washout and 3-month open-label OaD treatment. Secondary outcome measures included the change in SPL from pre-nsRP to the end of DBT (analysis of covariance adjusting for treatment, country, baseline, age, and nerve-sparing score), responses to Sexual Encounter Profile (SEP) questions 1-3 (mixed models for repeated measures adjusting for treatment, country, visit, visit-treatment-interaction, age), and Standardized Morning Erection Question (Cochran-Mantel-Haenszel test adjusted for age and country). Four hundred twenty-three patients were randomized to tadalafil OaD (N = 139), tadalafil PRN (N = 143), and placebo (N = 141). Greater retainment of SPL was observed with tadalafil OaD vs placebo at the end of DBT (least-square mean [95% confidence interval] difference OaD vs placebo, 4.1 mm [0.4 to 7.8 mm]; P = .032). No significant effects on SPL were found for tadalafil PRN vs placebo, or for the nerve-sparing score. Penile tumescence (SEP1) and ability for vaginal insertion (SEP2) significantly improved vs placebo at the end of double-blind and open-label treatment for patients randomized to tadalafil OaD only. The ability for successful sexual intercourse (SEP3) significantly improved with tadalafil OaD vs placebo only during DBT. The distribution of Standardized Morning Erection Question responses was different at the end of DBT (P = .045); 34.2% of patients on tadalafil OaD, 50.0% on tadalafil PRN, and 56.5% on placebo reported absence of morning erections. These data suggest the early initiation of tadalafil OaD protects from penile length loss and may contribute to protection from structural cavernosal changes after nsRP.

Brock G ，Montorsi F ，Costa P ，Shah N ，Martinez-Jabaloyas JM ，Hammerer P ，Ludovico GM ，Lee JC ，Henneges C ，Hamidi K ，Rossi A ，Mulhall J ，Büttner H ... -  《-》