Demonstrating an approach for evaluating synthetic geospatial and temporal epidemiologic data utility: Results from analyzing >1.8 million SARS-CoV-2 tests in the United States National COVID Cohort Collaborative (N3C)
OBJECTIVE:To evaluate whether synthetic data derived from a national COVID-19 data set could be used for geospatial and temporal epidemic analyses. MATERIALS AND METHODS/METHODS:Using an original data set (nâ€‰=â€‰1,854,968 SARS-CoV-2 tests) and its synthetic derivative, we compared key indicators of COVID-19 community spread through analysis of aggregate and zip-code level epidemic curves, patient characteristics and outcomes, distribution of tests by zip code, and indicator counts stratified by month and zip code. Similarity between the data was statistically and qualitatively evaluated. RESULTS:In general, synthetic data closely matched original data for epidemic curves, patient characteristics, and outcomes. Synthetic data suppressed labels of zip codes with few total tests (mean=2.9Â±2.4; max=16 tests; 66% reduction of unique zip codes). Epidemic curves and monthly indicator counts were similar between synthetic and original data in a random sample of the most tested (top 1%; nâ€‰=â€‰171) and for all unsuppressed zip codes (nâ€‰=â€‰5,819), respectively. In small sample sizes, synthetic data utility was notably decreased. DISCUSSION/CONCLUSIONS:Analyses on the population-level and of densely-tested zip codes (which contained most of the data) were similar between original and synthetically-derived data sets. Analyses of sparsely-tested populations were less similar and had more data suppression. CONCLUSION/CONCLUSIONS:In general, synthetic data were successfully used to analyze geospatial and temporal trends. Analyses using small sample sizes or populations were limited, in part due to purposeful data label suppression - an attribute disclosure countermeasure. Users should consider data fitness for use in these cases.
Efficacy and tolerability of fesoterodine versus tolterodine in older and younger subjects with overactive bladder: a post hoc, pooled analysis from two placebo-controlled trials
AIMS: To assess the efficacy and tolerability of fesoterodine 8 mg versus tolterodine extended release (ER) 4 mg in subjects with overactive bladder (OAB) stratified by age (<65, 65-74, and >/=75 years). METHODS: This was a post hoc analysis of data from two double-blind trials. Subjects reporting >/=1 urgency urinary incontinence (UUI) episode and >/=8 micturitions/24 hr at baseline were randomized to fesoterodine (4 mg for 1 week, 8 mg for 11 weeks), tolterodine ER 4 mg, or placebo. Subjects completed 3-day bladder diaries, Urgency Perception Scale (UPS), Patient Perception of Bladder Condition (PPBC), and OAB questionnaire (OAB-q) at baseline and week 12. The primary endpoint in both studies was change from baseline to week 12 in UUI episodes. RESULTS: Among subjects <65 years (n = 2,670), improvements in UUI episodes, micturitions, urgency episodes, severe urgency episodes, frequency-urgency sum, UPS, PPBC, and all OAB-q scales and domains were significantly greater with fesoterodine versus tolterodine ER, and diary-dry rates were significantly higher. Among subjects 65-74 years (n = 990), improvements in mean voided volume per void, PPBC, and OAB-q Symptom Bother and Coping were significantly greater with fesoterodine versus tolterodine ER. Among subjects aged >/=75 years (n = 448), improvements in urgency episodes, severe urgency episodes, frequency-urgency sum, UPS, and OAB-q Symptom Bother were significantly greater with fesoterodine versus tolterodine ER. Both active treatments produced significant improvements in most outcomes versus placebo across age groups. Adverse event rates were similar among age groups. CONCLUSIONS: Fesoterodine 8 mg consistently improved several OAB-related variables versus tolterodine ER 4 mg in subjects aged <65, 65-74, and >/=75 years, with some differences reaching statistical significance, and was generally well tolerated.
The effect of elective sham dose escalation on the placebo response during an antimuscarinic trial for overactive bladder symptoms
PURPOSE: We analyzed the effects of baseline symptom severity and placebo response magnitude on the decision to dose escalate in a 12-week, randomized, double-blind, flexible dose antimuscarinic trial of subjects with overactive bladder symptoms. MATERIALS AND METHODS: Data from the placebo arm of the trial were used for this post hoc analysis. Subjects could elect dose escalation at week 2. Those in the placebo arm received sham escalation. RESULTS: Most placebo treated subjects who continued to week 2 elected dose escalation (75% or 325 of 435). Overactive bladder symptoms at baseline were similar between placebo escalators and nonescalators. Nonescalators showed a significantly larger placebo response than escalators, as measured by improvements in bladder diary end points and patient reported outcomes, and by the incidence rate of adverse events before and after sham escalation. CONCLUSIONS: These findings suggest that the decision to dose escalate among placebo treated subjects is independent of baseline symptom severity but may be influenced by the placebo response magnitude for efficacy assessment and adverse events. Placebo nonescalators showed a rapid, large placebo response while placebo escalators showed a smaller placebo response even after sham escalation. These observations may have important implications for the design and interpretation of flexible dose trials using a placebo control.
Effects of voluntary dose escalation in a placebo-controlled, flexible-dose trial of fesoterodine in subjects with overactive bladder
AIMS: To characterize the response to fesoterodine treatment for overactive bladder (OAB) in subjects who did or did not choose to dose escalate in a flexible-dose study. METHODS: Subjects were randomized to fesoterodine 4 mg or placebo. At week 2, subjects could remain on 4 mg (non-escalators) or choose to increase to 8 mg (escalators) for the remaining 10 weeks (sham escalation for placebo). Subjects completed 3-day bladder diaries at baseline, week 2 and week 12 noting micturitions, urgency episodes, and urgency urinary incontinence (UUI) episodes. RESULTS: Sixty-three per cent of 438 subjects randomized to fesoterodine and 73% of 445 randomized to placebo dose escalated. At baseline, fesoterodine escalators had significantly more micturitions and urgency episodes than fesoterodine non-escalators (P < 0.001); at week 2, before dose escalation, diary-dry rate and improvement in micturitions and urgency episodes were significantly greater among fesoterodine non-escalators versus escalators (P < 0.001); and by week 12, after dose escalation, diary-dry rate and improvements in micturitions and UUI episodes were similar between fesoterodine non-escalators and escalators (P > 0.05). The placebo escalator group did not demonstrate a similar response over placebo non-escalators following the dose escalation decision point. CONCLUSION: A rapid and robust response to fesoterodine 4 mg was demonstrated in non-escalators. Subjects who chose to dose escalate to fesoterodine 8 mg at week 2 showed significant improvement by week 12 versus baseline and week 2 (prior to escalation), as well as versus placebo. Dose escalation to 8 mg fesoterodine provided subjects with efficacy and tolerability similar to those who were satisfied with the 4-mg dose
Early onset of fesoterodine efficacy in subjects with overactive bladder
OBJECTIVE: To assess the onset of efficacy of fesoterodine 4 mg once daily on overactive bladder (OAB) symptoms after 1 week of treatment. PATIENTS AND METHODS: This was a prespecified analysis of data collected during the first week of a 12-week, open-label, single-arm, flexible-dose study of fesoterodine. Eligible subjects were adult men and women (aged >/= 18 years) who reported urinary frequency (eight or more micturitions per 24 h) and urgency (three or more episodes per 24 h) in 5-day bladder diaries at baseline, and dissatisfaction with previous tolterodine or tolterodine extended-release treatment received within 2 years of screening. All subjects received fesoterodine 4 mg once daily during the first 4 weeks of treatment (with an optional dose increase to fesoterodine 8 mg after week 4). Early onset of efficacy of fesoterodine 4 mg was assessed based on changes from baseline to week 1 in variables recorded in 5-day bladder diaries, including total micturitions, urgency episodes, urgency urinary incontinence (UUI) episodes and nocturnal micturitions. Urgency and severe urgency episodes were defined as those rated >/= 3 and >/= 4, respectively, on the five-point Urinary Sensation Scale (USS) (1 = no urgency, 5 = UUI); frequency-urgency sum (a combined measure of micturition frequency and urgency) was defined as the sum of all USS ratings. RESULTS: All bladder diary variables, including total and nocturnal micturitions, UUI episodes, urgency episodes, severe urgency episodes and frequency-urgency sum per 24 h, were significantly improved (all P < 0.0001) after 1 week of treatment with fesoterodine 4 mg compared to baseline. The diary-dry rate at week 1 (i.e. subjects with at least one UUI episode at baseline who subsequently reported no UUI episodes on week 1 diary) was 38%. CONCLUSION: In this open-label study of subjects with OAB who had been previously treated and dissatisfied with tolterodine, fesoterodine 4 mg showed a rapid onset of efficacy at 1 week
Patient-optimized doses of fesoterodine improve bladder symptoms in an open-label, flexible-dose study
OBJECTIVE: To assess changes in overactive bladder (OAB) symptoms and patient-reported outcomes in a post hoc analysis in which subjects from a 12-week, open-label, flexible-dose fesoterodine study were stratified according to whether they opted for dose escalation. PATIENTS AND METHODS: Subjects with OAB (eight or more micturitions and three or more urgency episodes per 24 h) who reported dissatisfaction with tolterodine within 2 years of screening received fesoterodine 4 mg once daily for 4 weeks, with an optional dose increase to 8 mg after week 4 based on discussion of efficacy and tolerability between the subject and investigator. Subjects completed 5-day diaries, the Patient Perception of Bladder Condition (PPBC) and Urgency Perception Scale (UPS) at baseline and weeks 4 and 12, and the Overactive Bladder Questionnaire (OAB-q) at baseline and week 12. Subjects rated treatment satisfaction at week 12. RESULTS: Dose escalation to 8 mg at week 4 was chosen by 255 (50%) of 513 subjects. At baseline, subjects who opted for dose escalation at week 4 (escalators) had significantly higher means for all diary variables except urgency urinary incontinence (UUI) episodes, significantly greater OAB-q Symptom Bother scores and significantly lower OAB-q health-related quality of life (HRQL) scores (all P < 0.05) compared to subjects who did not opt for dose escalation (non-escalators). There was no significant difference in the percentage of escalators (51%) and non-escalators (48%) who reported at least one UUI episode on baseline diary. At week 4 (before the decision to escalate was made), all outcomes were significantly improved vs baseline among both groups (all P < 0.0001), although non-escalators had significantly greater improvements in all diary variables and in PPBC and UPS scores than escalators (all P < 0.05), and the 5-day diary-dry rate (i.e. the percentage of subjects with at least one UUI episode on baseline diary and no UUI episodes on week 4 diary) was significantly higher (P = 0.0016) among non-escalators (62%) than among escalators (42%). At week 12, all outcomes were again significantly improved vs baseline among both groups (all P < 0.0001). There were no significant differences between non-escalators and escalators in week 12 improvements for most diary variables, UPS scores, OAB-q Symptom Bother scores, the diary-dry rate (68% vs 60%) or the percentage of subjects who reported treatment satisfaction (82% vs 78%). However, escalators still had significantly greater improvements from baseline in urgency episodes, PPBC scores and OAB-q total HRQL and Coping domains (P < 0.05). Adverse event rates were similar between non-escalators and escalators. Dry mouth was the most frequently reported adverse event; most cases were mild. CONCLUSION: Flexible-dose fesoterodine significantly improved OAB symptoms and patient-reported outcomes in subjects who chose to remain on the initial 4-mg dose, as well as in the 50% of subjects who escalated to the 8-mg dose after 4 weeks. Non-escalators had significantly fewer OAB symptoms at baseline and significantly greater improvements than escalators before dose escalation. Escalators showed increased symptom relief after dose escalation; improvements in most outcomes were similar among non-escalators and escalators by week 12. Flexible-dose fesoterodine was well tolerated, with similar adverse-event profiles observed in the escalator and non-escalator groups. These results may help clinicians to identify patients more likely to require fesoterodine 8 mg to achieve maximum relief of OAB symptoms and thus facilitate dose escalation in these patients
Efficacy of fesoterodine over 24 hours in subjects with overactive bladder
OBJECTIVE: Fesoterodine is an antimuscarinic agent indicated for the treatment of overactive bladder (OAB) symptoms. The objective of this study was to evaluate the efficacy of fesoterodine versus placebo over selected intervals during a 24-hour period in subjects with OAB. RESEARCH DESIGN AND METHODS: In a post hoc analysis, data were analyzed from two randomized, double-blind, placebo-controlled 12-week phase III trials in which subjects with a history of OAB symptoms for >or=6 months were treated with morning doses of fesoterodine 4 mg, fesoterodine 8 mg, or placebo. CLINICAL TRIAL REGISTRATION: These trials are registered at ClinicalTrials.gov (NCT00220363 and NCT00138723). MAIN OUTCOME MEASURES: Changes were evaluated in number of micturitions, urgency episodes, urgency urinary incontinence (UUI) episodes, and mean voided volume (MVV) divided into three 8-hour intervals: 08:00-15:59 (daytime), 16:00-23:59 (evening), and 00:00-07:59 (nighttime). Comparisons with placebo were made using analysis of covariance (for least squares mean changes) and Wilcoxon rank sum test (for median percent changes); differences were considered significant at p < 0.05. RESULTS: Data from 1674 subjects, 80% of whom were women, were included in the analysis. At the end of treatment, the least squares mean change from baseline for all efficacy endpoints was significantly greater with fesoterodine 4 mg and fesoterodine 8 mg compared with placebo during each 8-hour time interval (all p < 0.05). Median percent change in number of micturitions, urgency episodes, and UUI episodes also was significantly greater with both fesoterodine doses compared with placebo during all time intervals (all p < 0.05). CONCLUSIONS: Fesoterodine 4 mg and 8 mg given once daily demonstrated efficacy over placebo for OAB symptoms during all three 8-hour intervals of a 24-hour period, thus providing clinical support for once-daily dosing. Limitations include that this was a post hoc analysis
Randomized, double-blind, placebo-controlled trial of flexible-dose fesoterodine in subjects with overactive bladder
OBJECTIVES: To evaluate the efficacy and tolerability of flexible-dose fesoterodine vs placebo in subjects with overactive bladder (OAB). METHODS: In a 12-week double-blind trial, subjects were randomized to fesoterodine 4 mg or placebo once daily, taken within 4 hours of bedtime. At week 2, subjects could increase the fesoterodine dose to 8 mg (sham escalation for placebo). Subjects completed 3-day bladder diaries, Patient Perception of Bladder Condition, and Urgency Perception Scale at baseline and weeks 2, 6, and 12 as well as OAB Questionnaire at baseline and week 12. RESULTS: Of 883 subjects, 63% and 73% of the fesoterodine (n = 438) and placebo (n = 445) groups, respectively, opted for dose escalation. Week 12 improvements from baseline in total micturitions, urgency episodes, urgency urinary incontinence episodes, frequency-urgency sum, and all OAB Questionnaire scales and domains, but not nocturnal micturitions or nocturnal urgency episodes, were significantly greater with fesoterodine than placebo (all P <.05). Treatment differences in micturitions and frequency-urgency sum were significant by week 2 and in urgency urinary incontinence and urgency episodes by week 6. Significantly greater percentages of subjects taking fesoterodine had improved Patient Perception of Bladder Condition and Urgency Perception Scale scores at weeks 2, 6, and 12 (P <.05). Dry mouth (fesoterodine, 26%; placebo, 8%) and constipation (fesoterodine, 11%; placebo, 6%) were the most common adverse events. In both groups, 87% of the subjects completed the trial; 8% and 5% of the fesoterodine and placebo groups, respectively, discontinued because of an adverse event. CONCLUSIONS: Flexible-dose fesoterodine was efficacious and generally well tolerated for treatment of OAB symptoms
Comparison of fesoterodine and tolterodine extended release for the treatment of overactive bladder: a head-to-head placebo-controlled trial
OBJECTIVE: To compare the efficacy and tolerability of fesoterodine 8 mg with tolterodine extended-release (ER) 4 mg and placebo in a randomized clinical trial of patients with an overactive bladder (OAB). PATIENTS AND METHODS: In this 12-week double-blind, double-dummy, placebo-controlled, randomized clinical trial, eligible patients reported OAB symptoms for > or = 3 months and recorded > or = 8 voids and > or = 1 urgency urinary incontinence (UUI) episode per 24 h in 3-day bladder diaries at baseline. Patients were randomized in a 2:2:1 ratio to fesoterodine (4 mg for 1 week then 8 mg for 11 weeks); tolterodine ER 4 mg; or placebo (with sham dose escalation for tolterodine ER and placebo). Endpoints were changes from baseline to week 12 in UUI episodes (primary endpoint), total and nocturnal voids, urgency episodes, severe urgency episodes, and frequency-urgency sum per 24 h; mean voided volume per void (MVV); and the OAB questionnaire (OAB-q), Patient Perception of Bladder Condition (PPBC), and Urgency Perception Scale (UPS). Safety and tolerability were assessed and summarized over the 12-week study period. RESULTS: Fesoterodine (636 patients) significantly improved UUI episodes at week 12 (primary endpoint) compared with tolterodine ER (641 patients; P = 0.017) and placebo (313 patients; P < 0.001). Fesoterodine also produced significantly greater improvements than tolterodine ER in MVV (P = 0.005). Fesoterodine significantly improved all diary endpoints compared with placebo (P < 0.001), except for nocturnal voids (P = 0.327). Tolterodine ER significantly improved all diary endpoints vs placebo (P < 0.001), except for nocturnal voids (P = 0.506) and MVV (P = 0.103). Diary dry rates (the proportion of patients reporting no UUI episodes at endpoint among those with one or more UUI episodes at baseline) were significantly higher with fesoterodine (64%) than with tolterodine ER (57%; P = 0.015) and placebo (45%; P < 0.001). Improvements in PPBC, UPS and OAB-q scale and domain scores at week 12 were all significantly better with fesoterodine than placebo (all P < 0.001) and tolterodine ER (all P < 0.05) except for the OAB-q Sleep domain vs tolterodine ER (P = 0.081). Dry mouth and constipation rates were 28% and 5% in the fesoterodine group, 16% and 4% in the tolterodine ER group, and 6% and 3% with placebo, respectively. Discontinuations due to treatment-emergent adverse events were 6%, 4% and 2% in the fesoterodine, tolterodine ER, and placebo groups, respectively. CONCLUSION: In patients with OAB, fesoterodine 8 mg showed superior efficacy over tolterodine ER 4 mg and placebo in reducing UUI episodes (primary endpoint) and in improving most patient-reported outcome measures. Both active treatments were well tolerated
Effects of tolterodine ER on patient-reported outcomes in sexually active women with overactive bladder and urgency urinary incontinence
OBJECTIVE: To assess the effects of tolterodine extended release (ER) on patient-reported outcomes (PROs) in sexually active women with overactive bladder (OAB) and urgency urinary incontinence (UUI). RESEARCH DESIGN AND METHODS: This multicenter, double-blind, placebo controlled trial included 411 women aged > or =18 years reporting OAB symptoms for > or =3 months; > or =8 micturitions per 24 hours (including > or =0.6 UUI episodes and > or =3 OAB micturitions) in 5-day bladder diaries at baseline, and being in a sexually active relationship for > or =6 months. Subjects randomized to placebo or tolterodine ER completed validated OAB- or incontinence-specific questionnaires, including the Patient Perception of Bladder Condition (PPBC), Overactive Bladder Questionnaire (OAB-q), Urgency Perception Scale (UPS), and the Incontinence Impact Questionnaire (IIQ) at baseline and week 12, as well as the Perception of Treatment Benefit and Treatment Satisfaction questions at week 12. This study is registered with ClinicalTrials.Gov (identifier: NCT00143481). RESULTS: The mean age of enrolled women was approximately 48 years. Compared with placebo, the tolterodine ER group reported significant baseline to week 12 improvements in PPBC responses (p = 0.0048); OAB-q Symptom Bother, total Health-Related Quality of Life (HRQL), and HRQL domain scores (all p < 0.05); IIQ Emotional Health domain scores (p < 0.05); proportions of subjects reporting treatment benefit (79 vs. 54%; p < 0.0001) and satisfaction (78 vs. 59%; p < 0.0001). Improvements on the UPS were not significantly different. CONCLUSIONS: Tolterodine ER treatment was associated with improvements in multiple OAB- and incontinence-specific PROs in a sexually active, relatively young, and racially diverse population of women. The findings provide clinicians with new insights into the impact of OAB and its treatment on HRQL in this population, which has been underrepresented in previous OAB studies. Study limitations include a potential underestimation of the impact of OAB symptoms resulting from the exclusion of women who may not be sexually active because of their urinary symptoms