The Efficacy and Safety of OnabotulinumtoxinA or Solifenacin Compared with Placebo in Solifenacin Naïve Patients with Refractory Overactive Bladder: Results from a Multicenter, Randomized, Double-Blind Phase 3b Trial.

PURPOSE: In this double-blind, randomized study we compared the efficacy and safety of onabotulinumtoxinA or solifenacin vs placebo in patients with overactive bladder who had urinary incontinence and an inadequate response to or were intolerant of an anticholinergic. Post hoc analysis was done to compare the effects of onabotulinumtoxinA vs solifenacin. MATERIALS AND METHODS: Solifenacin naïve patients were randomized to onabotulinumtoxinA 100 U, solifenacin 5 mg, (which could escalate to 10 mg at week 6 according to predefined criteria) or placebo. Patients could request treatment 2 (open label onabotulinumtoxinA) after fulfilling prespecified criteria. End points included a change from baseline in the number of urinary incontinence episodes per day and the proportion of patients with a 100% reduction (dry) in the number of incontinence episodes per day as co-primaries, other urinary symptoms and quality of life, all at week 12, and adverse events. RESULTS: The change from baseline in incontinence episodes per day was significantly greater with onabotulinumtoxinA or solifenacin vs placebo (-3.19 or -2.56, respectively, vs -1.33, both p <0.001). The incontinence reduction was significantly greater for onabotulinumtoxinA vs solifenacin (p = 0.022). At week 12, 33.8% (vs placebo p <0.001), 24.5% (vs placebo p = 0.028) and 11.7% of patients receiving onabotulinumtoxinA, solifenacin and placebo, respectively, were dry. After treatment 2, which was open label onabotulinumtoxinA, 43.2%, 37.6% and 41.9% of patients in the onabotulinumtoxinA, solifenacin and placebo groups, respectively, were dry. Significant improvements in other urinary symptoms and quality of life were observed for both active treatments. Urinary tract infection in 25.5% of cases and urinary retention in 6.9% were more common with onabotulinumtoxinA. CONCLUSIONS: The efficacy of onabotulinumtoxinA and solifenacin was significantly higher than that of placebo. However, onabotulinumtoxinA showed significantly greater decreases in urinary incontinence than solifenacin with a third of patients achieving a 100% incontinence reduction. No unexpected safety signals were observed.

Positive outcomes with first onabotulinumtoxinA treatment persist in the long term with repeat treatments in patients with neurogenic detrusor overactivity.

OBJECTIVE: To examine whether response to first treatment with onabotulinumtoxinA is predictive of long-term treatment outcome in patients with neurogenic detrusor overactivity (NDO). PATIENTS AND METHODS: Patients with NDO who were enrolled in a 3-year extension study (after a 52-week phase III study) received onabotulinumtoxinA 'as needed', based on fulfilment of prespecified retreatment criteria. This post hoc analysis included patients who received only the 200-U dose during the phase III and extension studies. Data on mean percent reduction from baseline in urinary incontinence (UI) episodes at week 6 after the first treatment were analysed, and the patients were stratified into three response groups: <50% (group 1; n = 33), 50-74% (group 2; n = 23), and 75-100% (group 3; n = 139). The following were assessed: change from baseline in mean percent UI reduction; proportions of patients who achieved ≥50% and 100% UI reduction after each subsequent treatment, and patients who achieved ≥50% UI reduction after all subsequent treatments; change from baseline in Incontinence Quality of Life (I-QOL) total summary score; and the proportion of patients who achieved or exceeded the minimally important difference (MID; +11 points) in I-QOL score. Adverse events (AEs) were also assessed. RESULTS: The majority of the patients (83.1%; 162/195) experienced a ≥50% UI reduction after onabotulinumtoxinA treatment 1. Baseline characteristics were largely similar across the groups. After treatment 1, the mean percent reduction in UI remained consistent in subsequent treatments 2-6 for patients in response group 2 (range: 64.5-83.5%) and group 3 (range: 79.4-88.0%), but increased for those in the low response group (range: 36.3-60.3%). After treatment 1, the proportion of patients who achieved ≥50% reduction in UI episodes was consistent with subsequent treatments 2-6 in group 2 (range: 75.0-100%) and group 3 (range: 87.3-97.1%), but increased in the low response group (range: 48.3-72.7%). Even among those who achieved a low response after treatment 1, 37.9% of patients achieved ≥50% UI reduction in all subsequent treatments. Improvements in I-QOL scores in groups 2 and 3 were consistently 2-3 times the MID. In the low response group, at least 50% of the patients achieved or exceeded the MID with treatments 2-6. AEs were similar across all response groups and consistent across repeated treatments. CONCLUSION: Patients with NDO with a ≥50% UI reduction after their first onabotulinumtoxinA treatment continued to experience consistent improvements in UI and quality of life with subsequent treatments over the duration of 4 years. A <50% UI reduction after first treatment did not necessarily predict low response with subsequent treatments. Thus, these results underscore the importance of attempting at least a second treatment with onabotulinumtoxinA before deeming patients unsuitable for onabotulinumtoxinA therapy.

New enhancements of the scrotal one-incision technique for placement of artificial urinary sphincter allow proximal cuff placement.

INTRODUCTION: Urinary incontinence impairs sexual functioning and sexual satisfaction. Traditional artificial urinary sphincter (AUS) implantation requires perineal incision for cuff placement and a second inguinal incision for reservoir and pump placement. We believed AUS could be placed easier and quicker through one scrotal incision. Aim. In an effort to effect more proximal placement of the cuff while keeping the advantages of the one scrotal incision technique, we report enhancements to the original surgical technique. METHODS: Thirty patients have been operated upon using the enhanced technique. A modification of the SKW retractor system (AMS) facilitates deep bulbar exposure. Twenty patients were first time implantations and 10 were revisions with five of the revisions having had the original AUS placed by traditional two-incision technique. Two of the first time AUS patients received an inflatable penile prosthesis through the same incision. MAIN OUTCOME MEASURES: We evaluated site of cuff placement, sizes of cuffs used, postoperative continence status. RESULTS: All of the virgin AUS required dissection of the bulbocavernosus muscle prior to cuff placement. In scrotally placed revisions, replacement cuffs were situated considerably proximal (4.5-7.5 cm) to the original cuff site. The perineal placed revisions were accomplished through a scrotal incision with replacement of two cuffs in the same site and the three other patients immediately distal. No intraoperative complications were seen. One patient developed scrotal hematoma requiring drainage. Only 15 patients are available for follow-up and all are socially continent (one pad or less). CONCLUSIONS: Transscrotal approach is used safely and efficiently for penile implants and AUS implantation. The new enhancements to the one-scrotal incision technique allow more proximal cuff placement as evidenced by the bulbocavernosus muscle dissection and use of larger cuffs. Continence rate is similar to rates achieved with perineal placement of cuff found in the literature.

Absorbable Hydrogel Spacer Use in Prostate Radiotherapy: A Comprehensive Review of Phase 3 Clinical Trial Published Data.

OBJECTIVE: To provide an update on SpaceOAR System, a Food and Drug Administration-approved hydrogel indicated to create distance between the prostate and the rectum which has been studied in phase 2 and 3 clinical trials. Here, we review and summarize these clinical results including the safety of prostate-rectum spacer application technique, the implant quality and resulting rectal dose reduction, acute and long-term rectal, urinary, and sexual toxicity, as well as patient-reported outcomes. MATERIALS AND METHODS: A prospective, randomized patient-blinded clinical study was performed comparing image-guided intensity modulated prostate radiotherapy (79.2 Gy in 44 fractions) in men with or without prostate-rectum hydrogel spacer. Patients were followed up for 3 years, allowing assessment of long-term safety and efficacy. RESULTS: Spacer application was well tolerated with a 99% technical success rate. The mean additional space created between the prostate and the rectum was just over 1 cm, which allowed significant rectum and penile bulb radiation dose reduction, resulting in less acute pain, lower rates of late rectal toxicity, and improved bowel and urinary quality of life (QOL) scores from 6 months onward. Improvements in sexual QOL were also observed at 37 months in baseline-potent men, with 37.5% of control and 66.7% of spacer men capable of "erections sufficient for intercourse." CONCLUSION: Prostate-rectum hydrogel spacer application is a relatively safe technical procedure that is well tolerated and has a high technical success rate. Spacer application significantly reduces rectal radiation dose and results in long-term reductions in rectal toxicity, as well as improvements in bowel, urinary, and sexual QOL.

A Framework of Care in Multiple Sclerosis, Part 2: Symptomatic Care and Beyond.

The Consortium of Multiple Sclerosis Centers (CMSC) convened a Framework Taskforce composed of a multidisciplinary group of clinicians and researchers to examine and evaluate the current models of care in multiple sclerosis (MS). The methodology of this project included analysis of a needs assessment survey and an extensive literature review. The outcome of this work is a two-part continuing education series of articles. Part 1, published previously, covered the updated disease phenotypes of MS along with recommendations for the use of disease-modifying therapies. Part 2, presented herein, reviews the variety of symptoms and potential complications of MS. Mobility impairment, spasticity, pain, fatigue, bladder/bowel/sexual dysfunction, cognitive dysfunction, and neuropsychiatric issues are examined, and both pharmacologic and nonpharmacologic interventions are described. Because bladder and bowel symptoms substantially affect health-related quality of life, detailed information about elimination dysfunction is provided. In addition, a detailed discussion about mental health and cognitive dysfunction in people with MS is presented. Part 2 concludes with a focus on the role of rehabilitation in MS. The goal of this work is to facilitate the highest levels of independence or interdependence, function, and quality of life for people with MS.

CME/CNE Article: A Framework of Care in Multiple Sclerosis, Part 1: Updated Disease Classification and Disease-Modifying Therapy Use in Specific Circumstances.

Activity Available Online: To access the article, post-test, and evaluation online, go to http://www.cmscscholar.org. TARGET AUDIENCE: The target audience for this activity is physicians, physician assistants, nursing professionals, and other health-care providers involved in the management of patients with multiple sclerosis (MS). LEARNING OBJECTIVES: Apply new information about MS to a comprehensive individualized treatment plan for patients with MSIntegrate the team approach into long-term planning in order to optimize rehabilitation care of patients with MSAccreditation Statement: This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Consortium of Multiple Sclerosis Centers (CMSC), Nurse Practitioner Alternatives (NPA), and Delaware Media Group. The CMSC is accredited by the ACCME to provide continuing medical education for physicians. The CMSC designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurse Practitioner Alternatives (NPA) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. NPA designates this enduring material for 1.0 Continuing Nursing Education credit. Laurie Scudder, DNP, NP, has served as Nurse Planner for this activity. She has disclosed no relevant financial relationships. Disclosures: Francois Bethoux, MD, Editor in Chief of the International Journal of MS Care (IJMSC), has served as Physician Planner for this activity. He has received royalties from Springer Publishing and has received intellectual property rights from Biogen. Laurie Scudder, DNP, NP, has served as Nurse Planner for this activity. She has disclosed no relevant financial relationships. Scott D. Newsome, DO, MSCS (author), has served on scientific advisory boards for Biogen, Genentech, Novartis, and Genzyme, and has performed contracted research (institution received funds) for Biogen, Genentech, and Novartis. Philip J. Aliotta, MD, MSHA, CHCQM, FACS (author), has served on speakers' bureaus for Astellas Pharma, Actavis, Augmenix, and Allergan and has performed contracted research for Allergan. Jacquelyn Bainbridge, PharmD (author), has disclosed no relevant financial relationships. Susan E. Bennett, PT, DPT, EdD, NCS, MSCS (author), has served on speakers' bureaus for Acorda Therapeutics, Biogen, and Medtronic; has received consulting fees from and performed contracted research for Acorda Therapeutics; and is chair of the Clinical Events Committee at Innovative Technologies. Gary Cutter, PhD (author), has participated on Data and Safety Monitoring Committees for AMO Pharma, Apotek, Gilead Pharmaceuticals, Horizon Pharmaceuticals, Modigenetech/Prolor, Merck, Merck/Pfizer, Opko Biologics, Neuren, Sanofi-Aventis, Reata Pharmaceuticals, Receptos/Celgene, Teva Pharmaceuticals, NHLBI (Protocol Review Committee), and NICHD (OPRU Oversight Committee); has received consulting fees from and/or served on speakers' bureaus and scientific advisory boards for Cerespir, Genzyme, Genentech, Innate Therapeutics, Janssen Pharmaceuticals, Klein-Buendel Incorporated, MedImmune, Medday, Nivalis, Novartis, Opexa Therapeutics, Roche, Savara, Somahlution, Teva Pharmaceuticals, Transparency Life Sciences, and TG Therapeutics; and is President of Pythagoras, Inc., a private consulting company located in Birmingham, AL. Kaylan Fenton, CRNP, APNP, MSCN (author), has disclosed no relevant financial relationships. Fred Lublin, MD (author), has received consulting fees/fees for non-CME/CE activities from Bayer HealthCare Pharmaceuticals, Biogen, EMD Serono, Novartis, Teva Neuroscience, Actelion, Sanofi/Genzyme, Acorda, Questcor/Mallinckrodt, Roche/Genentech, MedImmune, Osmotica, Xenoport, Receptos/Celgene, Forward Pharma, Akros, TG Therapeutics, AbbVie, Toyama, Amgen, Medday, Atara Biotherapeutics, Polypharma, Pfizer, Johnson & Johnson, Revalesio, Coronado Bioscience, and Bristol-Myers Squibb; has served on speakers' bureaus for Genentech/Roche and Genzyme/Sanofi; has performed contracted research for Acorda, Biogen, Novartis, Teva Neuroscience, Genzyme, Xenoport, and Receptos; is the co-chief editor of Multiple Sclerosis and Related Disorders; and has an ownership interest in Cognition Pharmaceuticals. Dorothy Northrop, MSW, ACSW (author), has disclosed no relevant financial relationships. David Rintell, EdD (author), has received consulting fees from Novartis and has served as a patient education speaker for Teva Neuroscience. He started as a salaried employee of Sanofi Genzyme in November 2015. Dr. Rintell's work on this project was completed before he became a salaried employee of Sanofi Genzyme.Bryan D. Walker, MHS, PA-C (author), has served on scientific advisory boards for EMD Serono and Sanofi Genzyme and owns stock in Biogen. Megan Weigel, DNP, ARNP-C, MSCN (author), has received consulting fees from Mallinckrodt, Genzyme, and Genentech, and has served on speakers' bureaus for Bayer Corp, Acorda Therapeutics, Teva Neuroscience, Biogen, Mallinckrodt, Genzyme, Novartis, and Pfizer. Kathleen Zackowski, PhD, OTR, MSCS (author), has performed contracted research for Acorda Therapeutics. David E. Jones, MD (author), has received consulting fees from Biogen and Novartis, and has performed contracted research for Biogen. One anonymous peer reviewer for the IJMSC has performed contracted research (institution received funds) for Novartis, Chugai, and Biogen. Another reviewer has received consulting fees and served on speakers' bureaus for Biogen, Sanofi Genzyme, Genentech, EMD Serono, and Novartis. The third reviewer has disclosed no relevant financial relationships. Lori Saslow, MS (medical writer), has disclosed no relevant financial relationships. The staff at the IJMSC, CMSC, NPA, and Delaware Media Group who are in a position to influence content have disclosed no relevant financial relationships. Note: Disclosures listed for authors are those applicable at the time of their work on this project and within 12 months previously. Financial relationships for some authors may have changed in the interval between the time of their work on this project and publication of the article. Funding/Support: Funding for the Framework of Care consensus conference was provided by the Consortium of Multiple Sclerosis Centers, Mallinckrodt Pharmaceuticals, and Mylan Pharmaceuticals. Method of Participation: Release Date: December 1, 2016 Valid for Credit Through: December 1, 2017 In order to receive CME/CNE credit, participants must: Review the CME/CNE information, including learning objectives and author disclosures.Study the educational content.Complete the post-test and evaluation, which are available at http://www.cmscscholar.org. Statements of Credit are awarded upon successful completion of the post-test with a passing score of >70% and the evaluation. There is no fee to participate in this activity. Disclosure of Unlabeled Use: This CME/CNE activity may contain discussion of published and/or investigational uses of agents that are not approved by the FDA. CMSC, NPA, and Delaware Media Group do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of CMSC, NPA, or Delaware Media Group. Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any medications, diagnostic procedures, or treatments discussed in this publication should not be used by clinicians or other health-care professionals without first evaluating their patients' conditions, considering possible contraindications or risks, reviewing any applicable manufacturer's product information, and comparing any therapeutic approach with the recommendations of other authorities.

Erectile response to vardenafil in men with a history of nonresponse to sildenafil: a time-from-dosing descriptive analysis.

BACKGROUND: The efficacy and tolerability of vardenafil hydrochloride in men with erectile dysfunction (ED) and a history of nonresponse to sildenafil citrate have previously been reported. OBJECTIVE: The aim of this descriptive analysis was to assess the efficacy and tolerability of vardenafil at various times after dosing in men with ED and a history of nonresponse to sildenafil and who chose to attempt sexual intercourse between 0.25 and 6 hours after dosing with vardenafil. METHODS: This analysis used data from a previously published 12-week, prospective, randomized, double-blind, flexible-dose, placebo-controlled study conducted at 41 hospitals and outpatient clinics across Australia, Europe, Asia, and North America. In that study, men with ED and sildenafil nonresponse, defined using 6 rigorous criteria (including nonresponse to the highest recommended dose, 100 mg/d) were assigned to receive vardenafil 10 mg or placebo QD. At study weeks 4 and 8, patients in both groups were given the option to maintain the 10-mg/d dose, or have the dose titrated to 5 or 20 mg/d. The present analysis used data from patient diaries completed daily, which included information concerning attempts at sexual intercourse, time from dosing to attempt, penetration, and maintenance of erection sufficient for successful intercourse. At week 12, diary data were categorized into time intervals (in hours) after dosing. For each interval, the per-patient success rate was based on the total number of attempts made in that interval. Comparative statistics were not performed on the time-interval analysis. Tolerability was monitored throughout the study. Data concerning the primary end point were reported previously. RESULTS: A total of 463 men were enrolled, of whom 457 were included in the safety analysis (vardenafil, n = 231; placebo, n = 226) and 454 in the intent-to-treat analysis (vardenafil, n = 229; placebo, n = 225; mean age, 60.1 vs 59.0 years; mean body mass index, 28.7 vs 28.0 kg/m2). Six patients were excluded from the safety analysis (2 patients did not use study medication [placebo group], postbaseline safety data unavailable in 4 patients [2 in each study group]). Men receiving vardenafil had numerically greater penetration and completion success rates compared with those receiving placebo at all time intervals. Penetration success rates were numerically higher with vardenafil compared with placebo as early as within 0.25 hour after dosing (62% vs 30%); efficacy continued beyond 6 hours after dosing in 77% and 50% of patients, respectively. Similarly, vardenafil-treated patients had numerically greater completion success rates compared with those receiving placebo at 0.25 hour (53% vs 12%) and beyond 6 hours after dosing (70% vs 24%). The most common drug-related adverse events in the vardenafil and placebo groups were flushing (7% vs 1%), headache (6% vs 2%), and nasal congestion (5% vs <1%). CONCLUSIONS: This descriptive analysis suggests that erection sufficient for penetration and intercourse completion was achieved within 0.25 hour and lasted for >6 hours after dosing with vardenafil 10 mg in these men with mostly moderate to severe ED and a history of nonresponse to sildenafil and who chose to make attempts during those intervals. The drug was generally well tolerated.

OnabotulinumtoxinA is effective in patients with urinary incontinence due to neurogenic detrusor overactivity [corrected] regardless of concomitant anticholinergic use or neurologic etiology.

INTRODUCTION: To evaluate the efficacy and safety of onabotulinumtoxinA for the treatment of neurogenic detrusor overactivity (NDO) in subpopulations of etiology (multiple sclerosis [MS] or spinal cord injury [SCI]) and concomitant anticholinergics (use/non-use). METHODS: Data were pooled from two double-blind, placebo-controlled, pivotal, phase 3 studies including a total of 691 patients with ≥ 14 urinary incontinence (UI) episodes/week due to MS (n = 381) or SCI (n = 310). Patients received intradetrusor injections of onabotulinumtoxinA 200U (n = 227), 300U (n = 223), or placebo (n = 241). Change from baseline at week 6 in UI episodes/week (primary endpoint), urodynamics, quality of life (QOL), and adverse events (AEs) were assessed. RESULTS: Significant and similar reductions in UI episodes were observed regardless of etiology or anticholinergic use: at week 6, mean weekly decreases of -22.6 and -19.6 were seen in MS and SCI patients, respectively, and -20.3 and -22.5 in anticholinergic users and non-users, respectively, treated with onabotulinumtoxinA 200U. The 300U dose did not add to the clinical efficacy in any subpopulation. Similar proportions of patients achieved ≥ 50% or 100% reductions in UI episodes in all subgroups. Improvements in maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and QOL were significant in both etiologies and were independent of anticholinergic use. The most common AEs in all groups were urinary tract infection and urinary retention. CONCLUSION: Regardless of concomitant anticholinergic use or etiology, onabotulinumtoxinA significantly improved UI symptoms, urodynamics, and QOL in patients with UI due to NDO. OnabotulinumtoxinA was well tolerated in all groups.

Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Neurogenic detrusor overactivity (NDO) frequently results in urinary incontinence (UI) which impairs quality of life (QOL) and puts the upper urinary tract at risk. OBJECTIVE: To assess the effects of onabotulinumtoxinA (BOTOX(®), Allergan, Inc.) on UI, urodynamic variables, and QOL in incontinent patients with NDO. DESIGN, SETTING, AND PARTICIPANTS: This multicentre, randomised, double-blind, placebo-controlled study enrolled patients with multiple sclerosis (MS; n=154) or spinal cord injury (SCI; n=121) with UI due to NDO (≥14 UI episodes per week). INTERVENTION: Patients received 30 intradetrusor injections of onabotulinumtoxinA 200 U (n=92), 300 U (n=91), or placebo (n=92), avoiding the trigone. MEASUREMENTS: Primary end point was change from baseline in UI episodes per week (week 6). Secondary end points included urodynamics (maximum cystometric capacity [MCC], maximum detrusor pressure during first involuntary detrusor contraction [P(detmaxIDC)]), and Incontinence Quality of Life (I-QOL) total score. Adverse events (AEs) were assessed. RESULTS AND LIMITATIONS: At baseline, mean UI episodes per week (33.5) were similar across groups. At week 6, onabotulinumtoxinA 200 U and 300 U significantly reduced UI episodes per week (-21.8 and -19.4, respectively) compared with placebo (-13.2; p<0.01); onabotulinumtoxinA benefit was observed by the first posttreatment study visit at week 2. Improvements in MCC, P(detmaxIDC), and I-QOL at week 6 were significantly greater with both onabotulinumtoxinA doses than with placebo (p<0.001). Benefits were observed in both the MS and SCI populations. The median time to patient request for retreatment was the same for both onabotulinumtoxinA doses (42.1 wk) and greater than placebo (13.1 wk; p<0.001). Most frequent AEs were localised urologic events (urinary tract infections and urinary retention, which were dose related in patients not using clean intermittent catheterisation [CIC] at baseline). Significant increases in postvoid residual were observed in patients not using CIC prior to treatment, and 12%, 30%, and 42% of patients in the placebo, 200-U, and 300-U groups, respectively, initiated CIC posttreatment. CONCLUSIONS: OnabotulinumtoxinA significantly reduced UI and improved urodynamics and QOL in MS and SCI patients with NDO. Both doses were well tolerated with no clinically relevant differences in efficacy or duration of effect between the two doses (http://www.clinicaltrials.gov; NCT00461292).

Erectile response with vardenafil in sildenafil nonresponders: a multicentre, double-blind, 12-week, flexible-dose, placebo-controlled erectile dysfunction clinical trial.

OBJECTIVE: To evaluate the efficacy of vardenafil in patients previously unresponsive to sildenafil. PATIENTS AND METHODS: A multicentre, double-blind, 12-week, flexible-dose, placebo-controlled trial was conducted, involving 463 men aged > or = 18 years with moderate-to-severe erectile dysfunction (ED) and who were unresponsive to sildenafil (by history). After a 4-week treatment-free run-in, patients received placebo or vardenafil 10 mg with the option to maintain current dose or to titrate by one dose level (5, 10 or 20 mg) based on efficacy and tolerability at 4 and 8 weeks. Outcome measures were the erectile function (EF) domain score of the International Index of Erectile Function, two Sexual Encounter Profile diary questions (vaginal penetration and maintenance of erection until successful completion of intercourse), and the Global Assessment Question (GAQ). RESULTS: There was significantly better EF with vardenafil than with placebo throughout the study. The least-square mean EF domain scores increased from 9.3 at baseline to 17.6 at the 'last' observation carried forward (LOCF) analysis with vardenafil (P < 0.001). Overall least-square mean per-patient success rates more than doubled for penetration (30.3% to 62.3%) and quadrupled for successful intercourse (10.5% to 46.1%) with vardenafil. Improved erections (positive response to the GAQ) were reported by 61.8% of patients receiving vardenafil and 14.7% of those receiving placebo at LOCF (P < 0.001). Normal EF (domain score > or = 26) was achieved by 30% of patients receiving vardenafil and 6% receiving placebo at LOCF (P < 0.001). Adverse events were infrequent and representative of the phosphodiesterase-5 inhibitor profile. CONCLUSION: Vardenafil is an effective and generally safe treatment for ED, even in men unresponsive to sildenafil (by history).