Effects of Tadalafil or Tamsulosin on Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia and on Erectile Dysfunction: Results from an International, Double-Blind, Placebo-Controlled Trial
Matthias Oelke 1; Francois Giuliano 2; Vincenzo Mirone 3, Lei Xu 4, David Cox 4; Lars Viktrup 4
1 Department of Urology, Hannover Medical School, Hannover, Germany; 2 Neuro-Urology-Andrology, Raymond Poincaré Hospital, Versailles Saint Quentin University, Garches, France;
3 Department of Obstetrical-Gynaecological Science and Reproductive Medicine, University of Naples Federico II, Naples, Italy; 4 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States
BACKGROUND STATISTICAL ANALYSES Figure 3: Placebo-adjusted Change in Primary and Key Secondary Measures at Endpoint Table 3: Q
• The primary endpoint comparison was between tadalafil and placebo, tamsulosin was included as an active control. The study
IPSS Total B Tadalafil 5 mg Tamsulosin 0.4 mg
was not powered for direct comparison between active treatments.
• The prevalence of signs and symptoms of benign prostatic hyperplasia (LUTS/BPH) increases with age. Epidemiological links
, and PVR were evaluated as change from baseline (randomization) to W eek 12/last-
between LUTS/BPH and erectile dysfunction (ED) are well established 1, 2
observation-carried-forward (LOCF) endpoint. Analyses for 1 or 4 weeks did not use LOCF imputation. Continuous efficacy
• Tadalafil is a long-acting phosphodiesterase type-5 inhibitor widely approved for on-demand or once daily treatment of ED, and
measures were assessed using analysis of covariance. For CGI-I and PGI-I , the 7 response-category questionnaire was
was recently approved in the USA for the treatment for LUTS/BPH with or without ED
administered, however data collapsed to 3 categories for presentation.
• Improvements in LUTS/BPH with tadalafil 5 mg once daily have been demonstrated in several randomized, placebo-controlled
• A fixed-sequence testing procedure was used to control Type I error in analyses of primary and key secondary outcomes for
tadalafil (but not tamsulosin), using the following pre-specified order: total IPSS at endpoint; total IPSS after 4 weeks; BII at
endpoint; mIPSS after 1 week; and BII after 4 weeks. Statistical significance was interpreted only if results of preceding analysis
• Given that the α–blocker tamsulosin is often used as first-line treatment for LUTS/BPH, assessing the efficacy of monotherapy
were significant at the 0.05 level. However, the results of all primary and key secondary analyses achieved statistical
with either tadalafil or tamsulosin in the same trial is of particular interest.
significance under this procedure; therefore results were presented independent of this sequence.
Abbreviations: N = number of subjects in the analysis population; n = number of subjects evaluable; Q
Data labels show value for LS mean difference from placebo (95% confidence interval) and p-value versus placebo.
rate; PVR = post-void residual urine volume. Data are mean ± standard deviation. 1
Changes from baseline compared using a ranked analysis of variance
• For the IPSS voiding sub-score, changes from baseline to endpoint versus placebo were statistically significant for tadalafil
• (p=0.001) and for tamsulosin (p=0.026). Changes were not significant versus placebo for the IPSS voiding sub-score for either
Table 4: Adverse Events
• To assess the efficacy of monotherapy with tadalafil 5 mg once-daily versus placebo on LUTS/BPH at week 12
• tadalafil or tamsulosin (each p=0.055), nor were they significant for the IPSS nocturia sub-score for tadalafil (p=0.08) or for
Figure 2: Patient Disposition
• tamsulosin (p=0.118). (IPSS QoL shown in Table 2)
Tadalafil 5 mg Tamsulosin 0.4 mg Secondary Objectives: Screened,
• To assess the efficacy of monotherapy with tamsulosin 0.4 mg once-daily versus placebo on LUTS/BPH as an active control
Figure 4: Change in Efficacy Measures over Time
• To assess the effect of tadalafil 5 mg or tamsulosin 0.4 mg once-daily versus placebo on LUTS/BPH bother, quality of life, and
Randomized, IPSS Total
• To assess the effect of tadalafil 5 mg or tamsulosin 0.4 mg once-daily versus placebo on ED
Tadalafil 5 mg Tamsulosin 0.4 mg*
• To assess the effects of tadalafil 5 mg or tamsulosin 0.4 mg once-daily versus placebo on maximum urinary flow rate (Q
• To assess the safety of tadalafil 5 mg once daily or tamsulosin 0.4 mg once daily. Discontinued, n (%) Discontinued, n (%) Discontinued, n (%) Adverse event, Adverse Event, Adverse event, Entry criteria not met, Entry Criteria not Met, Entry criteria not met,
Subjects discontinuing due to an AE, n (%)
STUDY DESIGN Lost to follow-up, Lost to follow-up, Lost to follow-up,
N = number of subjects in the analysis population; n = number of subjects with an event; TEAE = treatment emergent adverse event;
• Phase III, randomized, double-blind, parallel-design, placebo- and active-controlled trial conducted at 44 centers in Australia,
AE = adverse event; SAE = serious adverse event. Perceived lack of efficacy, Perceived lack of efficacy, Perceived lack of efficacy,
• Austria, Belgium, France, Germany, Greece, Italy, Mexico, the Netherlands, and Poland.
• Single-blind placebo lead-in period, double-blind treatment period. Protocol violation, Protocol Violation, Protocol violation, Sponsor decision, Sponsor Decision, Sponsor Decision, Figure 1: Study Design Schematic
Error bars represent standard error. *p < 0.05 compared with placebo.
Subject decision, Subject Decision, Subject decision, Screening/
• In comparison to placebo, tadalafil 5 mg and tamsulosin 0.4 mg each resulted in statistically
Table 2: IPSS QoL, TSS-BPH, and CGI-I and PGI-I Placebo lead-in
significant and clinically meaningful7 improvements in the primary efficacy measure of change
Double-blind Treatment Period Tadalafil 5 mg Tamsulosin 0.4 mg Completed 12 wks, n=148 Completed 12 wks, n=156 Completed 12 wks, n=150
in total IPSS at endpoint. Total IPSS also improved significantly versus placebo for both
tadalafil and tamsulosin at 1 and 4 weeks.
Tamsulosin 0.4 mg QD
* One subject randomized to tamsulosin did not take at least one dose of study drug and was excluded from the efficacy analyses.
• Tadalafil and tamsulosin also each improved BII compared with placebo at 4 and 12 weeks.
Table 1: Baseline Characteristics of All Randomized Patients
• Tadalafil 5 mg and tamsulosin 0.4 mg each improved Q
Placebo QD Tadalafil 5 mg Tamsulosin 0.4 mg Characteristic
• Tadalafil, but not tamsulosin, showed significant improvements versus placebo on the IPSS
Tadalafil 5 mg QD
QoL, TSS-BPH, and PGI-I and CGI-I instruments. Age, mean years (range) Race, n (%)
• Tadalafil significantly improved the IIEF-EF domain score at endpoint compared with placebo,
• The incidence of TEAEs was numerically higher in both the tadalafil (23.4%) and tamsulosin
Randomization/ Region, n (%)
(23.8%) groups compared with placebo (20.3%). Baseline INCLUSION CRITERIA
• Men ≥45 years of age with diagnosis of LUTS/BPH for >6 months
BMI, mean kg/m2 (range)
≥4 to ≤15 ml/s at the beginning of placebo lead-in period
CONCLUSIONS Prior therapy (last 12 months ), n (%)
Abbreviations: N = number of subjects in the analysis population; n = number of subjects evaluable; IPSS = International Prostate Symptom
• No use of finasteride for ≥3 months, dutasteride for ≥6 months, or any BPH therapy (including herbal preparations), overactive
Score; QoL = quality of life; TSS-BPH = Treatment Satisfaction Scale-BPH; CGI-I = Clinician Global Impression of Improvement; PGI-I =
bladder therapy, or ED therapy for ≥4 weeks prior to Visit 2
Patient Global Impression of Improvement. 1 van Elteren test for differences in medians (for differences versus placebo). 2 Cochran-Mantel-
Both tadalafil and tamsulosin significantly improved LUTS/BPH as measured by IPSS as EXCLUSION CRITERIA early as 1 week, and both improved Q at endpoint. Only tadalafil significantly improved
• The IIEF-EF domain was assessed in the 309 men in the efficacy population who reported ED at baseline and intended to be
BPH-LUTS severity, n (%)
• sexually-active during the study. secondary LUTS/BPH measures of QoL, global improvement, and treatment satisfaction,
• Prostate specific antigen >10 ng/ml, or 4 -10 ng/ml if prostate malignancy had not been ruled out
and only tadalafil improved ED.
• Post-void residual (PVR) volume was ≥300 ml
Figure 5: IIEF-EF Domain Change from Baseline
• Due to inclusion of a tamsulosin dosing arm, men were excluded for planned cataract surgery, history of symptomatic orthostatic
hypotension, recurrent dizziness, vertigo, loss of consciousness, or syncope
category, n (%)** Acknowledgements: EFFICACY AND SAFETY MEASURES
Thomas Melby (PharmaNet/I3, Indianapolis, IN) assisted in the preparation of this poster. The authors would like to
• The primary efficacy measure was total IPSS, while BPH Impact Index (BII) was a key secondary efficacy measure. A W eek-1
acknowledge all investigators and their staff, as well as the participants for their contributions to this study.
IPSS (mIPSS) used questions beginning with “Since your last visit. The IPSS-Quality-of-Life index (QoL) , BPH-Treatment
PSA, ng/ml (mean ± SD)
Satisfaction Scale (TSS-BPH), Patient and Clinician Global Impression of Improvement scales (PGI-I and CGI-I), and International
Index of Erectile Function – Erectile Function domain (IIEF-EF) were also assessed as secondary measures.
References: IPSS total (mean ± SD)**
Rosen et al. Eur Urol. 2003;44:637-649.
• Uroflowmetry was performed using standard calibrated devices at screening, baseline, and endpoint visits. Traces were centrally
IPSS QoL (mean
Andersson et al. Neurourol Urodyn. 2011;30:292-301.
read for the baseline and endpoint visits. Valid Q
measurements required pre-void total bladder volume (assessed by
BII (mean ± SD)
Roehrborn et al. J Urol 2008;180:1128-1234.
ultrasound) of ≥150 to ≤550 ml and voided volume (V
Egerdie et al. J Sex Med 2012 Jan;9(1):271-81. IIEF-EF domain (mean ± SD)
• Safety assessments included treatment-emergent adverse events (TEAEs), serious AEs (SAEs), and PVR.
Porst et al. Eur Urol 2011;60:1105-13.
* Some subjects enrolled in Mexico self-reported their race as American Indian/Alaska Native.
• Safety and uroflowmetry were assessed in all randomized patients. Efficacy was assessed in all randomized patients who
** Values were obtained at randomization/baseline (Visit 3) following the placebo lead-in period; subjects with improvements in IPSS or Q
Broderick et al. Urology 2010;75:1452-1458.
during placebo lead-in were not excluded.
Data labels show LS mean difference from placebo (95% confidence interval) and p-value versus placebo.
AUA Annual Meeting, Atlanta, GA, May 19-23, 2012 Sponsored by Eli Lilly and Company
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