Prevention of COVID-19 Following a Single Intramuscular Administration of Adintrevimab: Results From a Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Trial (EVADE).

Background: The prevention of coronavirus disease 2019 (COVID-19) in vulnerable populations is a global health priority. EVADE was a phase 2/3 multicenter, double-blind, randomized, placebo-controlled trial of adintrevimab, an extended-half-life monoclonal antibody, for postexposure (PEP) and pre-exposure prophylaxis (PrEP) of symptomatic COVID-19. Methods: Eligible participants (vaccine-naive, aged ≥12 years) were randomized 1:1 to receive a single 300-mg intramuscular injection of adintrevimab or placebo. Primary efficacy end points were reverse transcription polymerase chain reaction (RT-PCR)-confirmed symptomatic COVID-19 through day 28 in the PEP cohort (RT-PCR-negative at baseline) and through month 3 in the PrEP cohort (RT-PCR-negative and seronegative at baseline) among participants randomized before emergence of the severe acute respiratory syndrome coronavirus 2 Omicron variant (November 30, 2021). Safety was assessed through 6 months. Results: Between April 27, 2021, and January 11, 2022, 2582 participants were randomized. In the primary efficacy analysis, RT-PCR-confirmed symptomatic COVID-19 occurred in 3/175 (1.7%) vs 12/176 (6.8%) adintrevimab- and placebo-treated PEP participants, respectively (74.9% relative risk reduction [RRR]; standardized risk difference, -5.0%; 95% CI, -8.87% to -1.08%; P = .0123) and in 12/752 (1.6%) vs 40/728 (5.5%) adintrevimab- and placebo-treated PrEP participants, respectively (71.0% RRR; standardized risk difference, -3.9%; 95% CI, -5.75% to -2.01%; P < .0001). In a prespecified exploratory analysis of 428 PrEP participants randomized after the emergence of Omicron, adintrevimab reduced RT-PCR-confirmed symptomatic COVID-19 by 40.6% (standardized risk difference -8.4%; 95% CI, -15.35% to -1.46%; nominal P = .0177) vs placebo. Adintrevimab was well tolerated, with no serious drug-related adverse events reported. Conclusions: A single intramuscular injection of adintrevimab provided prophylactic efficacy against COVID-19 due to susceptible variants without safety concerns. Clinical trial registration. NCT04859517.

Efficacy and Safety of Adintrevimab (ADG20) for the Treatment of High-Risk Ambulatory Patients With Mild or Moderate Coronavirus Disease 2019: Results From a Phase 2/3, Randomized, Placebo-Controlled Trial (STAMP) Conducted During Delta Predominance and Early Emergence of Omicron.

Background: Safe and effective treatments are needed to prevent severe outcomes in individuals with coronavirus disease 2019 (COVID-19). We report results from STAMP, a phase 2/3, multicenter, double-blind, randomized, placebo-controlled trial of adintrevimab, an extended half-life monoclonal antibody, for treatment of high-risk ambulatory patients with mild to moderate COVID-19. Methods: Nonhospitalized, unvaccinated participants aged ≥12 years with mild to moderate COVID-19 and ≥1 risk factor for disease progression were randomized to receive a single intramuscular injection of 300 mg adintrevimab or placebo. Enrollment was paused due to the global emergence of the Omicron BA.1/BA1.1 variants, against which adintrevimab showed reduced activity in vitro. The primary efficacy endpoint was COVID-19-related hospitalization or all-cause death through day 29 in participants with COVID-19 due to laboratory-confirmed or suspected non-Omicron severe acute respiratory syndrome coronavirus 2 variants. Results: Between 8 August 2021 and 11 January 2022, 399 participants were randomized to receive adintrevimab (n = 198) or placebo (n = 201), including 336 with COVID-19 due to non-Omicron variants. COVID-19-related hospitalization or all-cause death through day 29 occurred in 8 of 169 (4.7%) participants in the adintrevimab group and 23 of 167 (13.8%) participants in the placebo group, a 66% relative risk reduction in favor of adintrevimab (standardized risk difference, -8.7% [95% confidence interval, -14.71% to -2.67%]; P = .0047). Incidence of treatment-emergent adverse events (TEAEs) was similar between treatment groups (33.9% for adintrevimab and 39.5% for placebo). No adintrevimab-related serious TEAEs were reported. Conclusions: Treatment with a single intramuscular injection of adintrevimab provided protection against severe outcomes in high-risk ambulatory participants with COVID-19 due to susceptible variants, without safety concerns. Clinical Trial Registration. NCT04805671.

Randomized Phase III Study of Ganetespib, a Heat Shock Protein 90 Inhibitor, With Docetaxel Versus Docetaxel in Advanced Non-Small-Cell Lung Cancer (GALAXY-2).

PURPOSE: Ganetespib, a highly potent heat shock protein 90 inhibitor, blocks multiple oncogenic pathways, resulting in antitumor activity. We evaluated the combination of ganetespib and docetaxel for second-line therapy of patients with advanced adenocarcinoma of the lung. PATIENTS AND METHODS: In this international phase III trial, patients with stage IIIB or IV adenocarcinoma diagnosed > 6 months before study entry and 1 prior systemic therapy were randomly assigned (1:1) to ganetespib 150 mg/m2 on days 1 and 15 with docetaxel 75 mg/m2 on day 1 of a 21-day cycle or to docetaxel alone. The primary end point was overall survival (OS). RESULTS: Of 677 enrolled patients, 335 were randomly assigned to ganetespib and docetaxel and 337 were assigned to docetaxel. The trial was stopped early as a result of futility at a planned interim analysis. The median OS time was 10.9 months (95% CI, 9.0 to 12.3 months) in the ganetespib and docetaxel arm compared with 10.5 months (95% CI, 8.6 to 12.2 months) in docetaxel arm (hazard ratio [HR], 1.11; 95% CI, 0.899 to 1.372; P = .329). Median progression-free survival was 4.2 months in the ganetespib and docetaxel arm and 4.3 months in the docetaxel arm (HR, 1.16; 95% CI, 0.96 to 1.403; P = .119). The addition of ganetespib did not improve outcomes compared with docetaxel alone for any secondary end point, including survival in the elevated lactate dehydrogenase or EGFR and ALK wild-type populations. The most common grade 3 or 4 adverse event in both arms was neutropenia (30.9% with ganetespib and docetaxel v 25% with docetaxel). CONCLUSION: The addition of ganetespib to docetaxel did not result in improved survival for salvage therapy of patients with advanced-stage lung adenocarcinoma.

Does mean platelet volume influence the attack or attack-free period in the patients with Familial Mediterranean fever?

Familial Mediterranean fever (FMF) is an autosomal recessive hereditary disease which is characterized by recurrent attacks of fever and peritonitis, pleuritis, arthritis, or erysipelas-like skin disease. Mean platelet volume (MPV) is a sign of platelet activation. There are limited studies in the literature about MPV levels in FMF patients. We aimed to investigate MPV levels during the attack period (group 1) and attack-free periods (group 2) in FMF patients, and to compare them with healthy controls (group 3). The study consisted of the data of: 60 group 1 patients, 120 group 2 patients, and 75 group 3 patients. Erythrocyte sedimentation rate, C-reactive protein, white blood cell count, platelet count, and MPV levels were retrospectively recorded from patient files. Statistical analyses showed that MPV was significantly lower in FMF patients both in group 1 and group 2 than in group 3 (p = 0.004, p = 0.002, respectively); however, there was no difference among group 1 and group 2 in patients with FMF (p = 0.279). The mean platelet count of group 1 was higher than that of group 3 (p = 0.010). In conclusion, this study results suggested that MPV level did not increase on the contrary, it decreased in patients with FMF both in group 1 and/or group 2 when compared to group 3. It was concluded that the lower MPV level was an expected result of secondary thrombocytosis in FMF patients.

Reductions in stress urinary incontinence episodes: what is clinically important for women?

AIM: To expand our understanding of the clinical importance to patients with stress urinary incontinence (SUI) of reductions in incontinence episode frequency (IEF) that fall short of a complete cure. METHODS: We used an integrated database that included data from 1,913 women with SUI who were enrolled in four randomized, placebo-controlled pharmaceutical clinical trials and examined the relationship between various levels of reduction in IEF and minimally clinical important difference (MCID) levels established for the validated Incontinence Quality of Life (I-QOL) questionnaire. The first decile of IEF reduction to exceed the within-group MCID was considered to be the point at which the reduction in IEF first became clinically important. The between-group MCID was then used to determine when further reductions in incontinence represented clinically relevant incremental improvements for patients. RESULTS: Improvements in condition-specific quality of life were not clinically important until the fifth decile of IEF reduction, representing a reduction in IEF >40% to 70% to 90% to

Duloxetine compared with placebo for the treatment of women with mixed urinary incontinence.

AIMS: Evaluate duloxetine in the treatment of women with mixed urinary incontinence (MUI). MATERIALS AND METHODS: 588 women, 19-85 years old with >or=4 incontinence episodes/week were randomly assigned to duloxetine 80 mg/day (N = 300) or placebo (N = 288). Patients were classified into three symptom subgroups: stress or urge predominant MUI (SPMUI or UPMUI) or balanced MUI (BMUI) based on their responses to the validated Stress/Urge Incontinence Questionnaire. Half the population was randomly assigned to have urodynamics; SPMUI, UPMUI, and BMUI condition diagnoses were based on signs, symptoms, and urodynamic observations. The primary outcome measure was the change in incontinence episode frequency (IEF). Secondary outcome measures included the Incontinence Quality of Life (I-QOL) scores, the ICI Quality of Life (ICIQ-SF) score, and the Patient Global Impression of Improvement (PGI-I) rating. RESULTS: At baseline, women with SPMUI averaged 15.9 IEF/week (61% stress), those with UPMUI averaged 13.2 (70% urge), and those with BMUI averaged 16.5 (52% urge). Overall IEF decreases were significantly greater with duloxetine than placebo (median percent reduction 60% vs. 47%, P < 0.001); both UUI and SUI episodes were significantly decreased with duloxetine (median SUI IEF reduction 59% vs. 43%, P = 0.001; UUI IEF reduction 58% vs. 40%, P < 0.001). Duloxetine IEF decreases were significantly greater for patients with SPMUI conditions and symptoms and for those with UPMUI conditions but not symptoms. Significant benefits were also demonstrated with duloxetine for improvements in I-QOL total score (11.5 points vs. 8.1 points, P = 0.002), all three I-QOL subscale scores, and for the ICIQ-SF score (-2.6 vs. -1.7, P = 0.002) as well as for PGI-I ratings (much/very much better 44.2% vs. 27.3%, P = 0.001). CONCLUSION: Duloxetine demonstrated significant efficacy in this population of women with MUI.

Duloxetine compared with placebo for treating women with symptoms of overactive bladder.

OBJECTIVE: To evaluate duloxetine (a serotonin-noradrenaline reuptake inhibitor) in women with symptoms of overactive bladder (OAB), as it has been shown to increase the bladder capacity in an animal model. PATIENTS AND METHODS: In all, 306 women (aged 21-84 years) were recruited and randomly assigned to placebo (153) or duloxetine (80-mg/day for 4 weeks increased to 120-mg/day for 8 weeks; 153). Symptoms of OAB were defined as bothersome urinary urgency and/or urge urinary incontinence (UI) for > or =3 months. Participants were also required to have a mean daytime voiding interval (VI) of < or=2 h and urodynamic observations of either detrusor overactivity (DOA) or urgency which limited bladder capacity to <400 mL, both with no stress UI (SUI). The primary efficacy analysis compared the treatment effects on mean change from baseline to endpoint in the mean number of voiding episodes (VE)/24 h. The secondary efficacy analyses compared the treatment effects on the number of UI episodes (IE)/24 h, in the Incontinence Quality of Life questionnaire (I-QOL) score, and on the mean daytime VI. Safety was assessed with vital signs, adverse event reporting, routine laboratory testing, electrocardiogram, and the measurement of postvoid residual urine volumes (PVR). RESULTS: Patients randomized to duloxetine had significant improvements over those randomized to placebo for decreases in VE and IE, for increases in the daytime VI, and for improvements in I-QOL scores at both doses of duloxetine. Urodynamic studies showed no significant increases in maximum cystometric capacity or in the volume threshold for DOA. The most common treatment-emergent adverse events with duloxetine (nausea, 31%; dry mouth, 16%; dizziness, 14%; constipation, 14%; insomnia, 13%; and fatigue, 11%) were the same as those reported by women with SUI and were significantly more common with duloxetine than placebo. Laboratory assessments, vital signs and electrocardiograms were stable relative to baseline, with no relevant differences detected between groups. There was a significant difference in the change in PVR with duloxetine (<5 mL mean increase) but no patient reported hesitancy or retention. CONCLUSION: In this trial, duloxetine was better than placebo for treating women with 'wet' and 'dry' symptoms of OAB associated with DOA or a bladder capacity of <400 mL.

Comparison of physician and patient assessments of incontinence severity and improvement.

Compare the subjective and objective assessment of stress urinary incontinence (SUI) severity and improvement with treatment using patient- and clinician-rated global impression of severity (PGI-S, CGI-S) and improvement (PGI-I, CGI-I) scales. Five hundred fifty-three women with mild SUI were recruited via media advertising into a placebo-controlled duloxetine trial. PGI-S and CGI-S (normal, mild, moderate, severe) were administered at baseline and PGI-I and CGI-I (seven responses from "very much worse" to "very much better") during treatment. Incontinence episode frequency (IEF) was determined from diaries. Agreements between clinician and patient ratings were assessed using Kappa and degree of association with Spearman's correlation. There was only a slight agreement regarding severity, with 53% of ratings being different (Kappa = 0.14; 95%CI = 0.08, 0.20). When ratings differed, clinicians rated severity worse in 72% of cases than did patients. Agreement regarding improvement was moderate, with 42% of ratings being different (Kappa = 0.45; 95%CI = 0.39, 0.50). When ratings differed, clinicians rated improvement greater than did patients in 54% of cases. Patients' assessments of severity correlated better with IEF (0.33) than did the clinicians' (0.15). The correlations of PGI-I and CGI-I with IEF changes were similar (0.46 and 0.44). In this study, the subjective (patient) and objective (clinician) assessments of SUI improvement with treatment appear to be more closely aligned than are the assessments of initial SUI severity.

A retrospective pooled analysis of duloxetine safety in 23,983 subjects.

OBJECTIVE: The safety and tolerability of duloxetine for major depressive disorder (MDD), generalized anxiety disorder (GAD), diabetic peripheral neuropathic pain (DPNP), fibromyalgia, and lower urinary tract disorders (LUTD) (including female stress urinary incontinence [SUI] and other LUTDs) has been established in individual clinical studies. The objective of this manuscript is to characterize the overall safety profile of duloxetine, regardless of indication, based on data from the duloxetine exposures integrated safety database. RESEARCH DESIGN AND METHODS: The duloxetine exposures integrated safety database was examined using pooled data from 23,983 patients randomized to receive duloxetine in 64 studies for MDD, GAD, DPNP, fibromyalgia, or LUTDs. Evaluated aspects of drug safety included treatment-emergent adverse events (TEAEs), adverse events leading to discontinuation, serious adverse events (SAEs), clinical laboratory tests, vital signs, and electrocardiograms. RESULTS: Common TEAEs included nausea, headache, dry mouth, insomnia, constipation, dizziness, fatigue, somnolence, diarrhea, and hyperhidrosis. Most TEAEs emerged early; the majority were mild to moderate in severity, and did not worsen. Overall, discontinuation rates due to AEs were 20.0%. SAEs occurred at a rate of 3.5% and no single event was predominant. Mean pulse increased by < 2 beats per minute. Mean increases in systolic and diastolic blood pressure were < 1 mmHg. Mean alanine transaminase and aspartate transaminase values increased by < 2 U/L. CONCLUSIONS: The safety profile for the molecule from the overall duloxetine exposures integrated safety database suggests that benign and common pharmacologic side effects occur with duloxetine treatment. Because these pooled analyses do not allow for statistical comparison to placebo or active comparator, and include data from five different studied indications, these data do not suggest causality for AEs, nor are they necessarily generalizable to each disease stated studied.

Duloxetine treatment of stress urinary incontinence in women: effects of demographics, obesity, chronic lung disease, hypoestrogenism, diabetes mellitus, and depression on efficacy.

OBJECTIVE: To identify poor responders, we evaluated the impact of demographic characteristics and comorbidities on efficacy using an integrated database including data from four large randomized controlled trials. Duloxetine has been shown to be effective in women with stress urinary incontinence (SUI). STUDY DESIGN: A total of 1913 women 22-83 years of age with predominant SUI (diagnosed using a validated clinical algorithm) were randomly assigned to receive placebo (n = 955) or duloxetine (n = 958) for 12 weeks. Efficacy outcome variables included a weekly incontinence episodes frequency (IEF) from patient-completed diaries, the Incontinence Quality-of-Life (I-QOL) questionnaire score, and a Patient Global Impression of Improvement rating. Subgroups selected a priori included: ethnicity, age, body mass index (BMI), chronic lung disease, hypoestrogenism, diabetes mellitus, and depression. For safety comparisons, adverse events were compared across age and ethnicity subgroups. RESULTS: Reduction in IEF was minimal and not significantly different between duloxetine and placebo in women with chronic lung disease. The decrease in IEF for women > or =65 years of age was slightly diminished for duloxetine and placebo groups, but the treatment differences were maintained. There was a significantly different I-QOL improvement by BMI subgroup, with greater increases in scores associated with a higher BMI (>28 kg/m2). There were no other notable subgroup impacts on efficacy. CONCLUSIONS: With the possible exception of chronic lung disease, no characteristic was identified that predicted a lack of treatment response with duloxetine in the treatment of women with SUI. Elderly patients may experience lower response rates to duloxetine presumably due to age related changes in the lower urinary tract.

Effect of dose escalation on the tolerability and efficacy of duloxetine in the treatment of women with stress urinary incontinence.

To assess the impact of duloxetine dose escalation on tolerability and efficacy, 516 women with stress urinary incontinence were randomized to receive placebo or duloxetine in one of three regimens: 40 mg BID for 8 weeks, 40 mg QD for 2 weeks escalating to 40 mg BID for 6 weeks or 20 mg BID for 2 weeks escalating to 40 mg BID for 6 weeks. A non-inferiority analysis confirmed that the 20 mg BID starting dose was significantly better than the other two duloxetine regimens for nausea reduction (16.5% vs 25.2% and 29.4%). There were also significant differences in the discontinuation rates (7.5% vs 11.8% and 16.2%). The efficacy after 4 weeks was significantly better with duloxetine than with placebo. Starting duloxetine at 20 mg BID for 2 weeks before increasing to 40 mg BID significantly improved tolerability but did not impact duloxetine efficacy after all the subjects had been on 40 mg BID for at least 2 weeks.

Minimal clinically important differences in Incontinence Quality-of-Life scores in stress urinary incontinence.

OBJECTIVES: To determine the clinically relevant reference points for the Incontinence Quality of Life (I-QOL) questionnaire scores in women with stress urinary incontinence and compare them with the treatment effects observed with duloxetine and placebo. METHODS: Using data from 1133 women with predominant stress urinary incontinence in two randomized, placebo-controlled duloxetine studies, the within-treatment and between-treatment minimal clinically important differences (MCIDs) were obtained by anchoring the I-QOL scores to the validated Patient Global Impression of Improvement scale (PGI-I). The within-treatment MCID (mean I-QOL for women rating their condition "a little better" with treatment) and between-treatment MCID (difference in scores between the group ratings of "no change" and "a little better") were derived. The treatment effects were compared with these MCIDs. Real-time urinary diaries were completed, along with the I-QOL and PGI-I. RESULTS: The within-treatment and between-treatment MCID for the I-QOL total score was 6.3 and 2.5, respectively. The total and subscale scores had almost identical MCIDs. Duloxetine 80 mg significantly improved the I-QOL total and subscale scores. Treatment differences in the I-QOL scores exceeded the between-treatment MCID and the duloxetine I-QOL treatment effect exceeded the within-treatment MCID. The number of patients needed to treat to gain an additional I-QOL responder was 6.8. CONCLUSIONS: Improvements in I-QOL scores should be greater than the within-treatment MCID, and differences between two treatments should be greater than the between-treatment MCIDs, for statistically significant differences to be considered clinically meaningful. We propose 2.5 points as a reasonable guide for the I-QOL between-treatment MCID and 6.3 points for the within-treatment MCID.

Duloxetine for the treatment of stress urinary incontinence in women: an integrated analysis of safety.

OBJECTIVE: The objective was to characterize the safety of duloxetine for treatment of stress urinary incontinence (SUI) in women, using an integrated database generated from four published placebo-controlled clinical trials. METHODS: The database included 1913 women randomized to duloxetine (N=958) or placebo (N=955), examining adverse events (AEs), serious adverse events (SAEs), vital signs, electrocardiograms, and laboratory analytes. AEs occurring initially or worsening during the double-blind treatment period were considered treatment-emergent (TEAE). Differences between duloxetine-treated and placebo-treated groups were compared statistically. RESULTS: Common TEAEs included: nausea (23.2%), dry mouth (13.4%), fatigue (12.7%), insomnia (12.6%), constipation (11.0%), headache (9.7%), dizziness (9.5%), somnolence (6.8%), and diarrhea (5.1%). Most TEAEs that emerged early were mild to moderate, rarely worsened, and resolved quickly. Overall AE discontinuation rates were 20.5% for duloxetine and 3.9% for placebo (P<.001). Most discontinuations (83%) occurred within the first month of treatment. SAEs were uncommon and did not differ between treatments. Statistically significant, but clinically unimportant mean increases in heart rate (2.4 bpm) and systolic and diastolic blood pressure (

Safety and adverse event profile of duloxetine.

Duloxetine is the first relatively balanced serotonin and noradrenaline re-uptake inhibitor to be widely available for three indications including: major depressive disorder, peripheral diabetic neuropathic pain and female stress urinary incontinence, although it is not currently approved for all indications in all countries. Generally, duloxetine is safe and well-tolerated across indications, with few reported serious side effects. Common adverse events are consistent with the pharmacology of the molecule and are mainly referable to the gastrointestinal and the nervous systems. The studied dose range is up to 400 mg/day (administered 200 mg b.i.d) but the maximum dose approved for marketing is 120 mg/day (administered 60 mg b.i.d). Duloxetine is eliminated (half-life = 12.1 hours) primarily in the urine after extensive hepatic metabolism by multiple oxidative pathways, methylation and conjugation. Duloxetine would not be expected to cause clinically significant inhibition of the metabolic clearance of drugs metabolised by P450 (CYP)3A, (CYP)1A2, (CYP)2C9, or (CYP)2C19, but would be expected to cause some inhibition of CYP 2D6. Duloxetine should not be used in combination CYP 1A2 inhibitors or nonselective, irreversible monoamine oxidase inhibitors. The purpose of this review is to provide an overview of some of the most important information related to safety and tolerability of duloxetine.

Validation of a two-item quantitative questionnaire for the triage of women with urinary incontinence.

OBJECTIVE: To evaluate the reproducibility, construct validity, and preferences for the 2-item Stress/Urge Incontinence Questionnaire. METHODS: The questionnaire asks a patient to recall the number of stress urinary incontinence and urge urinary incontinence episodes she experienced during the preceding week. The 4-week prospective study included 3 office visits and enrolled women with stress, urge, or mixed urinary incontinence symptoms. The test-retest reproducibility was assessed after 3 days, and the construct validity of the questionnaire was evaluated against a diary and other measures of incontinence severity and effect. The bother associated with completing (patients) or analyzing (physicians) the diary was assessed. Both groups also reported their time requirements and preferences for the questionnaire or diary. RESULTS: Reproducibility for the classification of symptoms was moderately strong (kappa = .536). Test-retest agreement was good (64-80%) for all but balanced mixed incontinence (38%). Intraclass correlations revealed good reproducibility for the number of stress (.694), urge (.703), and total (.726) incontinence episodes. Significant (P < .01) correlations with other measures of incontinence established construct validity. Patients and physicians reported it took less time to complete the questionnaire than the diary, but the majority said the completion or analysis of the diary was of little or no bother and preferred the diary. CONCLUSION: The Stress/Urge Incontinence Questionnaire is a valid tool that can be used in clinical practice to differentiate between symptoms of stress and urge urinary incontinence to make an initial diagnosis, especially in primary care where incontinence is not a focus of the practice.

A randomized controlled trial of duloxetine alone, pelvic floor muscle training alone, combined treatment and no active treatment in women with stress urinary incontinence.

PURPOSE: We primarily compared the effectiveness of combined pelvic floor muscle training (PFMT) and duloxetine with imitation PFMT and placebo for 12 weeks in women with stress urinary incontinence (SUI). In addition, we compared the effectiveness of combined treatment with single treatments, single treatments with each other and single treatments with no treatment. MATERIALS AND METHODS: This blinded, doubly controlled, randomized trial enrolled 201 women 18 to 75 years old with SUI at 17 incontinence centers in the Netherlands, United Kingdom and United States. Women averaged 2 or more incontinence episodes daily and were randomized to 1 of 4 combinations of 80 mg duloxetine daily, placebo, PFMT and imitation PFMT, including combined treatment (in 52), no active treatment (in 47), PFMT only (in 50) and duloxetine only (in 52). The primary efficacy measure was incontinence episode frequency. Other efficacy variables included the number of continence pads used and the Incontinence Quality of Life questionnaire score. RESULTS: The intent to treat population incontinence episode frequency analysis demonstrated the superiority of duloxetine with or without PFMT compared with no treatment or with PFMT alone. However, pad and Incontinence Quality of Life analyses suggested greater improvement with combined treatment than single treatment. A completer population analysis demonstrated the efficacy of duloxetine with or without PFMT and suggested combined treatment was more effective than either treatment alone. CONCLUSIONS: The data support significant efficacy of combined PFMT and duloxetine in the treatment of women with SUI. We hypothesize that complementary modes of action of duloxetine and PFMT may result in an additive effect of combined treatment.

The effect of previous treatment experience and incontinence severity on the placebo response of stress urinary incontinence.

OBJECTIVE: The placebo response associated with stress urinary incontinence (SUI) is sizeable but poorly understood. The aim of this study was to examine the relationship between previous treatment experience and baseline urinary incontinence severity with placebo response. STUDY DESIGN: Nine hundred twenty-one women ages 24 to 83 years received placebo in 4 12-week randomized trials evaluating duloxetine for SUI in 16 countries in Africa, Australia, Europe, and North and South America. Incontinence episode frequency (IEF) was calculated before and after randomization with entries from subject-completed real-time diaries. At baseline, subjects reported on their experience with previous continence surgery and with current pelvic floor muscle training (PFMT) with standardized questions. Analyses included Pearson correlations and the Wilcoxon two-sample test, and were based on intent-to-treat principles. RESULTS: The placebo group averaged 17 IEF per week at baseline. Fifty-five percent of placebo-treated subjects averaged >or=14 IEF/wk, 11.8% had previous continence surgery, and 16.5% currently performed PFMT. The overall median decrease in IEF with placebo was 33%, but ranged from 11% to 57% for individual countries. The placebo response was lower in women with more severe SUI (29.6% vs 36.4%, P=.07), in those who had previous continence surgery (25.0% vs 33.3%, P=.26), and for those using PFMT (23.6% vs 33.3%, P=.02). There was a significant positive correlation (rho=.44; P <.0001) between the placebo response within a country and that country's use rate for PFMT. CONCLUSION: Treatment naivete and less severe incontinence are associated with an increased placebo response in clinical trials for stress urinary incontinence, although this difference was statistically significant only for PFMT.

Validation of a clinical algorithm to diagnose stress urinary incontinence for large studies.

PURPOSE: We assessed the accuracy with which a clinical diagnostic algorithm for stress urinary incontinence (SUI) based on symptoms and signs without including urodynamics predicted the observation of urodynamic SUI and the condition of SUI. Such an algorithm would have applicability to ensure that the majority of women entering large SUI clinical trials would have urodynamic SUI and/or the condition of SUI without performing urodynamic testing in all subjects. MATERIALS AND METHODS: A total of 1455 women with urinary incontinence at least 3 months in duration were enrolled in 3 randomized clinical trials (1 phase 2 and 2 phase 3 trials) of duloxetine vs placebo for the treatment of SUI in Europe and North America. Subjects were identified as having SUI based on a clinical algorithm that required a predominant symptom of SUI with a weekly incontinence episode frequency of 4 or greater (phase 2 study), or 7 or greater (phase 3 studies), absent predominant urge symptoms, normal diurnal and nocturnal frequency, a bladder capacity of 400 ml or greater, and a positive cough stress (sign of SUI) and stress pad test. Multichannel urodynamic studies were performed in a subset of 184 women at 23 study sites. Of these urodynamic tracings 173 (94%) were of adequate quality to make an assessment of the filling phase and assign a diagnosis of urodynamic SUI, detrusor overactivity or a normal filling phase. Two-sided 95% exact CIs for the proportions were calculated. RESULTS: The clinical algorithm had a positive predictive value of 90.2% for urodynamic SUI with or without detrusor overactivity and 76.9% for urodynamic SUI only (pure urodynamic SUI). The positive predictive value for the condition of pure SUI was 85.0%, while for the condition of SUI in pure and mixed forms the positive predictive value was 98.3%. Patient age, previous continence surgery or the severity of incontinence did not influence algorithm accuracy. CONCLUSIONS: The algorithm is suitably feasible and sufficiently predictive to be used in large clinical trials designed to evaluate conservative treatment for women with SUI. It ensures that the overwhelming majority of the study population would have urodynamic SUI and the condition of SUI.

Duloxetine versus placebo in the treatment of European and Canadian women with stress urinary incontinence.

OBJECTIVE: To assess the efficacy and safety of duloxetine in women with stress urinary incontinence. DESIGN: Randomised double-blind, placebo-controlled clinical trial. SETTING: Fort-six centres in seven European countries and Canada. POPULATION: Four hundred and ninety-four women aged 24-83 years identified as having predominant symptoms of stress urinary incontinence using a clinical algorithm that was 100% predictive of urodynamic stress urinary incontinence in a subgroup of 34 women. METHODS: The case definition included a predominant symptom of stress urinary incontinence with a weekly incontinence episode frequency > or =7, the absence of predominant symptoms of urge incontinence, normal diurnal and nocturnal frequencies, a bladder capacity > or =400 mL and both a positive cough stress test and positive stress pad test. Subjects completed two urinary diaries prior to randomisation and three diaries during the active treatment phase of the study, each completed during the week prior to monthly visits. Subjects also completed quality of life questionnaires at each visit. Safety was assessed by the evaluation of treatment-emergent adverse events, discontinuation of treatment because of adverse events, serious adverse events, vital sign measurements, electrocardiograms (ECG) and clinical laboratory tests. INTERVENTION: After a two-week placebo lead-in, women received placebo or duloxetine 40 mg BD for 12 weeks. MAIN OUTCOME MEASURES: The percentage decrease in incontinence episode frequency and the change in the Incontinence Quality of Life (I-QOL) questionnaire total score were prespecified as co-primary outcome variables in the protocol. RESULTS: Incontinence episode frequency decreased significantly with duloxetine compared with placebo (median decrease of 50%vs 29%; P= 0.002) with comparable improvements in the more severely incontinent subgroup (those experiencing at least 14 incontinence episodes per week at baseline; 56%vs 27% decreases; P < 0.001). The primary analysis of I-QOL scores did not reveal a significant difference between treatment groups, due primarily to the carrying forward of low scores from patients who discontinued treatment very early due to duloxetine-associated adverse events. The increase in I-QOL scores was significantly greater for duloxetine than for placebo at each of the three postrandomisation visits after 4, 8, and 12 weeks of treatment. Discontinuation rates for adverse events were higher for duloxetine (22%vs 5%; P < 0.001) with nausea being the most common reason for discontinuation (5.3%). Nausea tended to be mild to moderate, not progressive, and transient. CONCLUSIONS: The findings support duloxetine as a potential treatment for women with stress urinary incontinence.

Duloxetine versus placebo for the treatment of North American women with stress urinary incontinence.

PURPOSE: Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, increases rhabdosphincter contractility via the stimulation of pudendal motor neuron alpha-1 adrenergic and 5-hydroxytryptamine-2 receptors. In this first phase 3 study we assessed the efficacy and safety of duloxetine in women with stress urinary incontinence (SUI). MATERIALS AND METHODS: A total of 683 North American women 22 to 84 years old were enrolled in this double-blind, placebo controlled study. The case definition included a predominant symptom of SUI with a weekly incontinence episode frequency (IEF) of 7 or greater, the absence of predominant symptoms of urge incontinence, normal diurnal and nocturnal frequency, a bladder capacity of 400 ml or greater, and a positive cough stress test and stress pad test. After a 2-week placebo lead-in period subjects were randomly assigned to receive placebo (339) or 80 mg duloxetine daily (344) as 40 mg twice daily for 12 weeks. Primary outcome variables included IEF and an incontinence quality of life questionnaire. Van Elteren's test was used to analyze percent changes in IEF with a stratification variable of weekly baseline IEF (less than 14 and 14 or greater). ANCOVA was used to analyze incontinence quality of life scores. RESULTS: Mean baseline IEF was 18 weekly and 436 subjects (64%) had a baseline IEF of 14 or greater. There was a significant decrease in IEF with duloxetine compared with placebo (50% vs 27%, p <0.001) with comparably significant improvements in quality of life (11.0 vs 6.8, p <0.001). Of subjects on duloxetine 51% had a 50% to 100% decrease in IEF compared with 34% of those on placebo (p <0.001). These improvements with duloxetine were associated with a significant increases in the voiding interval compared with placebo (20 vs 2 minutes, p <0.001) and they were observed across the spectrum of incontinence severity. The discontinuation rate for adverse events was 4% for placebo and 24% for duloxetine (p <0.001) with nausea the most common reason for discontinuation (6.4%). Nausea, which was also the most common side effect, tended to be mild to moderate and transient, usually resolving after 1 week to 1 month. Of the 78 women who experienced treatment emergent nausea while taking duloxetine 58 (74%) completed the trial. CONCLUSIONS: These phase 3 data are consistent with phase 2 data and they provide further evidence for the safety and efficacy of duloxetine as a pharmacological agent for the treatment of women with SUI.