In women with OAB, what is the comparative effectiveness of pharmacological interventions?

Study details Participants Interventions Methods Outcomes and Comments Results

Full citation Sample size Interventions Details Results Limitations

Chapple,C., DuBeau,C., N = 400 Following a 2-week screening Efficacy was based on 3-day Week 4 NICE guidelines manual. Ebinger,U., Rekeda,L., Darifenacin = 266 period, candidates entered a diaries completed prior to Not reported Appendix D: Viegas,A., Darifenacin Placebo = 144 1-week placebo run-in peroid. clinical visit at week, 1, 2 and Methodology checklist: treatment of patients >or= 65 Eligible patients were then 6. A seven-day diary was Week 12 Randomised controlled years with overactive bladder: allocated to Darifenacin 7.5 completed at baseline and 12 Patient satisfaction trials results of a randomized, Characteristics mg qd or placebo. After 2 weeks. with treatment A Selection bias controlled, 12-week trial, weeks dose could be titrated Tolerability and safety were Not reported A1 - Was there Current Medical Research Gender - Female/N (% female) up to Darifenacin 15mg qd or monitored throughout the appropriate and Opinion, 23, 2347-2358, DAR: 206/266 (77.4%) sham titration study. Self-reported rate randomisation - Unclear - 2007 PLA: 100/133 (75.2% Post-void residual volumes of absolute not reported were recorded at week 12 symptom A2 - Was there adequate Ref Id Age (years) - Mean ± SD A standard 12-lead ECG was reduction per day concealment - Yes - DAR: 72 ± 5 conducted on day 1 and Incontinence randomisation numbers 100152 PLA: 73 ± 5 week 12. episodes - served as packaging for Vital signs and laboratory reported as mean interventions Country/ies where the Incontinence episodes/week - variables were assessed at change from A3 - Were groups study was carried out Median (range) screening and study end. baseline comparable at baseline - DAR: 19.8 (4 - 142) DAR: - 2 (no SD) Yes - No apparent United Kingdom, United PLA: 21 (7 - 155.4) N = 166 differences between States, Poland, South Africa, Power calculation PLA: -1.86 (no groups at baseline Hungary, Sweden, Germany Urgency episodes/day - Median SD) N = 133 Level of bias: Low (range) Sample size calculation was Study type DAR: 7.6 (1 - 24.4) based on a previous study Urgency episodes B Performance bias PLA: 7.4 (1.3 - 22.2) and the aim was to include - reported as B1 - Did groups get Randomized controlled trial 399 patients. This number mean change from same level of care - Yes Detrusor overactivity - n/N (%) was expected to achieve baseline B2 - Were participants Aim of the study Not reported 81% power for the primary DAR: -13.3 (no blinded - Yes - Study efficacy variable and a SD) N = 266 was double-blind and "To evaluate the efficacy, probability of 0.59 for PLA: -13.1 (no double-dummy tolerability and safety, and Duration of OAB - Mean ± SD darifenacin superiority over SD) N = 133 B3 - Were clinical staff associated QoL in patients ≥ Not reported placebo usning a 2-sided blinded - Yes 65 years with OAB following Wilcoxon rank sum test with Continence status Level of bias: Low 12 weeks of darifenacin an assumed dropout rate of (zero episodes per treatment" 5% day) C Attrition bias

431

Study details Participants Interventions Methods Outcomes and Comments Results

Inclusion criteria Incontinence C1 - Was follow-up equal episodes for both groups - Yes Study dates 1] OAB symptoms ≥ 6 months Intention to treat analysis DAR: 80/266 C2 - Were groups 2] aged ≥ 65 years (30.7%) comparable for dropout - Not reported 3] capable of independent toileting Last observation carried PLA: 21/134 Yes 4] able to complete the diary forward (LOCF) was used (15.7%) C3 - Were groups Source of funding independently where variables were missing comparable for missing if at least 1 dose of Urgency episodes data - Yes Study was funded by Novartis Darifenacin or placebo was Not reported Level of bias: Low Pharmaceuticals Inc. Exclusion criteria taken. Incontinence- D Detection bias 1] treatment with drugs known to specific quality of D1 - Was follow-up affect urinary bladder function or life appropriate length - Yes the external urethral sphincter Scale used - OAB- D2 - Were outcomes 2] a total daily volume > 3000ml q - mean change defined precisely - Yes 3] mean volume voided per from baseline D3 - Was a valid and micturition of > 300ml DAR: 20.9 (no SD) reliable methods used to 4] clinically significant stress N = 266 assess outcome - Yes urinary incontinence or bladder PLA: 15.3 (no SD) D4 - Were investigators outlet obstruction N = 133 blinded to intervention - 5] post-void residual urinary Yes volume > 100ml Adverse effects D5 - Were investigators 6] women with marked cystocele Any adverse effect blinded to confounding or other clinically significant Stage DAR: 99/266 factors - Unclear 3 or Stage 4 pelvic prolapse (37.2%) Level of bias: Low 7] had received bladder training or PLA: 24/134 received electric stimulation within (19%) 3 months of screening Indirectness 8] serious or intermittent urinary Dry mouth tract infection DAR: 59/266 Does the study match 9] any clinically significant (22.2%) the protocol in terms of: congenital or acquired disorder of PLA: 5/134 (3.8%) 1] Population: Yes the urinary tract 2] Interventions: Yes 10] any urinary bladder Dropouts for any 3] Outcome: Yes dysfunction (other than OAB) reason Indirectness: None 11] a history of chronic pain DAR: 22/266 syndrome of the low urinary tract (8.3%) 12] other significant medical PLA: 17/134 conditions which in the triallists (12.7%)

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Study details Participants Interventions Methods Outcomes and Comments Results

opinion made them an unsuitable candidate for the study Dropouts for adverse effects Other information DAR: 12/266 (4.5%) None PLA: 9/134 (6.7%)

Psychological outcomes Not reported

Clinical measures - Post-void residual volume Mean change from baseline (95% CI) DAR: 11.9 (1.7 to 22.1) ml N = 266 PLA: 17.3 (-18.1 to 52.8) ml N = 133

Full citation Sample size Interventions Details Results Limitations

Chapple,C., Van,Kerrebroeck N = 1135 Patients were randomised to All patients recruited into the Week 4 NICE guidelines manual. P., Tubaro,A., Haag- Tolterodine extended release 4mg one of four treatments once trial entered a two-week No data reported bAppendix D: Molkenteller,C., Forst,H.T., = 290 daily for 12 weeks: placebo 'wash out' phase in Methodology checklist: Massow,U., Wang,J., Fesoterodine 4mg = 272 tolterodine ER 4mg which they received either a Week 12 Randomised controlled Brodsky,M., Clinical efficacy, Fesoterodine 8mg = 288 fesoterodine 4mg capsule (tolterodine placebo) Patient satisfaction trials safety, and tolerability of Placebo = 285 fesoterodine 8mg or a tablet (fesoterodine with treatment once-daily fesoterodine in placebo placebo). reported as subjects with overactive response A Selection bias bladder.[Erratum appears in Characteristics For assessment of efficacy, TOL ER 4mg: A1 - Was there Eur Urol. 2008 patients were required to 72/290 (24.8%) appropriate Jun;53(6):1319], European Gender - Female/N (% female) complete a 3-day micturition FES 4mg: 75/272 randomisation - Yes - Urology, 52, 1204-1212, 2007 TOL ER 4mg = 226/290 (78%) diary noting the time of each (27.6%) computer-generated FES 4mg = 220/272 (81%) micturition and/or urgency FES 8mg: 79/288 schedule A2 - Was there adequate

433

Study details Participants Interventions Methods Outcomes and Comments Results

Ref Id FES 8mg = 235/287 (82%) episode, urine volume (each (27.4%) concealment - Yes - Placebo = 229/283 (81%) micturition), any episodes of Placebo: 53/285 randomisation numbers 100153 incontinence and severity of (18.6%) served as packaging for Age - Mean ± SD urgency (1 = none; 2 = mild interventions Country/ies where the TOL ER 4mg = 57.7 ± 14.6 years or 3 = moderate or 4 Self reported rate A3 - Were groups study was carried out FES 4mg = 57.1 ± 13.2 years = severe) before visit 2 and of absolute comparable at baseline - FES 8mg = 55.6 ± 14.1 years days immediately preceding symptom Yes - No apparent Belgium, Bulgaria, Czech Placebo = 56.0 ± 13.7 years visits 3, 5 & 6. In addition, on reduction per day differences between Republic, Estonia, France, one of the three days the Incontinence groups at baseline Germany, Hungary, Italy, the Incontinence episodes (UUI) / day patients had to record their episodes - Mean Level of bias: Low Netherlands, Poland, - Mean ± SD micturition volume. ± sd (Change Romania, Russia, Spain, TOL ER 4mg: 3.8 ± 3.1 scores) Ukraine, United Kingdom, FES 4mg: 3.8 ± 3.4 Safety assessments were TOL ER 4mg: - South Africa, Australia and FES 8mg: 3.7 ± 3.0 conducted at each clinic visit 1.74 ± 2.39 N = New Zealand Placebo: 3.7 ± 3.1 and after the safety follow- 223 B Performance bias up. FES 4mg: -1.95 ± B1 - Did groups get Study type Urgency episodes / day - Mean ± 2.40 N = 199 same level of care - Yes SD FES 8mg: -2.22 ± B2 - Were participants Randomised controlled trial TOL ER 4mg: 11.0 ± 3.4 Power calculation 2.40 N = 223 blinded - Yes - Study FES 4mg: 11.0 ± 4.2 Placebo: -1.14 ± was double-blind and Aim of the study FES 8mg: 11.5 ± 4.2 Not reported. 2.32 N = 211 double-dummy Placebo: 11.4 ± 4.0 B3 - Were clinical staff "To investigate the efficacy, Urgency episodes blinded - Yes tolerability, and safety of Detrusor overactivity Intention to treat analysis TOL ER 4mg: - Level of bias: Low fesoterodine 4 and 8 mg Not reported 2.03 ± 3.20 N = versus placebo in subjects Not described. Table 3 283 with OAB." Duration of OAB (mean ± SD) refers to LOCF used to FES 4mg: -1.88 ± calculate baseline and TOL ER 4mg =: 8.7 ± 10.1 years 3.26 N = 265 C Attrition bias baseline to end of treatment FES 4mg: 9.0 ± 11.2 years FES 8mg: -2.36 ± C1 - Was follow-up equal Study dates in bladder efficacy variables. FES 8mg: 7.6 ± 8.4 years 3.22 N = 276 for both groups - Yes Placebo: 7.9 ± 9.6 years Placebo: -1.07 ± Not reported C2 - Were groups 3.17 N = 279 comparable for dropout - Yes Source of funding Inclusion criteria Continence status C3 - Were groups Incontinence comparable for missing The study was supported by 1] ≥ 18 years old episodes data - Yes Schwarz Biosciences GmbH 2] ≥ 8 micturitions/24hr and ≥ 6 Not reported Level of bias: Low and Pfizer Inc urgency episodes or ≥ 3 UUI episodes in 24hrs Urgency episodes

434

Study details Participants Interventions Methods Outcomes and Comments Results

3] Indicated OAB caused them at Not reported least moderate problems on a Likert scale Incontinence- D Detection bias 4] Negative pregnancy test specific quality of D1 - Was follow-up life appropriate length - Yes Not reported D2 - Were outcomes Exclusion criteria defined precisely - Yes Adverse effects D3 - Was a valid and 1] lower urinary tract pathology Any adverse event reliable methods used to that could be responsible for TOL ER 4mg: assess outcome - Yes urgency or incontinence (e.g. 144/290 (49.7%) D4 - Were investigators genuine SUI, bladder stones, FES 4mg: 135/272 blinded to intervention - interstitial cystitis, urothelial (49.6%) Yes tumours) FES 8mg: 167/288 D5 - Were investigators 2] pelvic prolapse (grade III or (58.2%) blinded to confounding higher) Placebo: 107/285 factors - Unclear 3] clinically relevant outlet (37.5%) Level of bias: Low obstruction 4] polyuria (> 3l per 24 hr) Dry mouth 5] symptomatic recurrent UTIs TOL ER 4mg: 6] postvoid residual volume (PVR) 49/290 (16.9%) > 100ml FES 4mg: 59/272 Indirectness 7] currently receiving treatment or (21.7%) treated within 2 wks of screening FES 8mg: 97/288 Does the study match visit with antimuscarinic drugs (33.8%) the protocol in terms of: 8] treated in past 4 wks with Placebo: 20/285 1] Population: Yes electrostimulation for bladder (7.0%) 2] Interventions: Yes training 3] Outcome: Yes 9] active UTI Dropouts for any Indirectness: None 10] underlying neurological reason disease causing their OAB TOL ER 4mg: symptoms 37/290 (12.8%) Other information 11] clinically relevant cardiac FES 4mg: 42/272 arrhythymia and/or unstable (15.4%) "After the start of the trial, angina FES 8mg: 37/288 the protocol was 12] QtcB interval > 500ms (12.8%) amended to ensure Placebo: 34/285 enrollment of the planned (11.9%) 80% of subjects with UUI at baseline; the

435

Study details Participants Interventions Methods Outcomes and Comments Results

Dropouts for amendment required ≥ 3 adverse effects UUI episodes per 24 h in TOL ER 4mg: all remaining subjects". 9/290 (3.1%) FES 4mg: 7/272 (2.6%) FES 8mg: 14/288 (4.9%) Placebo: 6/285 (2.1%)

Psychological outcomes Not reported

Clinical measures Post-void residual volume Not reported

Full citation Sample size Interventions Details Results Limitations

Choo,M.S., Lee,J.Z., N = 357 Solifenacin 5mg once-daily All patients received two Week 4 NICE guidelines manual. Lee,J.B., Kim,Y.H., Solifenacin 10mg once-daily weeks of placebo medication Patient satisfaction Appendix D: Jung,H.C., Lee,K.S., Solifenacin 5mg = 120 Tolterodine immediate- twice-daily and after this with treatment Methodology checklist: Kim,J.C., Seo,J.T., Solifenacin 10mg = 119 release 4 mg patients were randomised to Not reported Randomised controlled Paick,J.S., Kim,H.J., Na,Y.G., Tolterodine IR = 118 All medications taken for 12 take solifenacin 5mg, 10mg trials Lee,J.G., Efficacy and safety weeks. or tolterodine 4mg. Three Self reported rate of solifenacin succinate in days before the second visit of absolute Korean patients with Characteristics (4 weeks into the study), symptom overactive bladder: a patients recorded episodes reduction per day randomised, prospective, Baseline characteristics: of urgency and urgency Incontinence A Selection bias double-blind, multicentre Gender - Female/N (% female) incontinence, times of episodes - Mean ± A1 - Was there study, International Journal of SOL 5mg: 90/107 (84.11%) voiding and volumes voided sd (endpoint appropriate Clinical Practice, 62, 1675- SOL 10mg:83/111 (74.77%) per void in a bladder diary. scores) randomisation - Unclear - 1683, 2008 TOL 4mg: 88/111 (79.28%) Patients visited the TOL IR 4mg: 0.90 Not reported investigational sites at the ± 1.16 N = 100 A2 - Was there adequate

436

Study details Participants Interventions Methods Outcomes and Comments Results

Ref Id Age - mean and SD following intervals: SOL 5mg: 0.97 ± concealment - Unclear - SOL 5mg: 53.07 ± 10.52 years - Screening (visit 1) 1.49 N = 98 Not reported 100168 SOL 10mg: 52.65 ± 12.7 years - 2-week placebo run-in SOL 10mg: 0.76 ± A3 - Were groups TOL 4mg: 53.05 ± 12.19 years period (visit 2) 1.10 N = 98 comparable at baseline - Country/ies where the - Week 4 (visit 3) Yes - No apparent study was carried out Incontinence episodes - mean and - Week 8 (visit 4) Urgency episodes differences between SD - Week 12 (visit 5 = endpoint) TOL IR 4mg: 2.32 groups at baseline Korea SOL 5mg: 1.92 ± 2.19 ± 2.86 N = 92 Level of bias: Unclear SOL 10mg: 2.59 ± 2.91 The following data were SOL 5mg: 2.32 ± Study type TOL 4mg: 1.74 ± 1.55 collected at each visit: 3.00 N = 83 Mean daily micturition SOL 10mg: 2.09 ± Randomised Controlled Trial Incontinence episodes - mean and frequency; 2.49 N = 88 SD Mean micturition vol per B Performance bias Aim of the study SOL 5mg: 4.29 ± 3.45 voiding; Continence status B1 - Did groups get SOL 10mg: 3.81 ± 3.04 Mean daily urgency Incontinence same level of care - Yes To compare the efficacy and TOL 4mg: 3.89 ± 3.12 incontinence freq; episodes B2 - Were participants tolerability of solifenacin 5 Mean daily no. of urgency Not reported blinded - Yes - Study and 10 mg once daily and Detrusor overactivity episodes; was double-blind tolterodine 2mg twice daily in Not reported Mean no. of nocturia Urgency episodes B3 - Were clinical staff patients with symptoms of episodes Not reported blinded - Unclear - Not OAB. Duration of OAB reported Not reported Adverse events elicited by Incontinence- Level of bias: Low general questioning by the specific quality of Study dates investigator or volunteered life Inclusion criteria by the patient. Not reported Not reported Weeks 4, 8 and 12 safety C Attrition bias 1] an average frequency of ≥ 8 assessments were made and Adverse effects C1 - Was follow-up equal Source of funding voids per 24 hr these inc. vital signs, Not applicable for both groups - Yes 2] at least 3 episodes of urgency physical exam and C2 - Were groups Research grant received from OR 3 episodes of urgency electrocardiograms and AE Psychological comparable for dropout - Astellas Pharma, Inc. Toyko, incontinence in the 3-day voiding recordings. outcomes No - more dropouts abd Japan. diary period Not reported protocol violation in SOL

Baseline and 12 weeks: PVR 5mg group

volume was assessed by Clinical measures C3 - Were groups

bladder scanning. Post-void residual comparable for missing volume data - LOCF used Exclusion criteria Quality of life was assessed Not reported Level of bias: Low at baseline and endpoint 1] clinicallly significant bladder using the King's Health Week 12

437

Study details Participants Interventions Methods Outcomes and Comments Results

outlet obstruction Questionnaire. Patient satisfaction 2] PVR volume of > 200ml; with treatment 3] incontinence for which stress Not reported D Detection bias was determined to be the Power calculation D1 - Was follow-up predominant factor; Self reported rate appropriate length - Yes 4] presence of a neurological Not reported. of absolute D2 - Were outcomes cause for detrusor muscle symptom defined precisely - Yes overactivity; reduction per day D3 - Was a valid and Intention to treat analysis 5] evidence of urinary tract Incontinence reliable method used to infection or bladder stones, episodes - Mean ± assess outcome - Yes "For subject withdrawal, data previous pelvic irridation, or sd (endpoint D4 - Were investigators available at the point of previous or current malignant scores) blinded to intervention - withdrawal were analysed. disease in the pelvic organs; TOL IR 4mg: 0.67 Unclear Missing data were accepted 6] any medical condition ± 1.16 N = 100 D5 - Were investigators as such. Nonetheless, data contraindicating the use of SOL 5mg: 0.78 ± blinded to confounding analysis with the last antimuscarinic medication; 1.76 N = 98 factors - Unclear observation carried forward 7] non-pharmacological treatment SOL 10mg: 0.72 ± Level of bias: Low for OAB including (LOCF) method were 1.51 N = 98 electrostimulation therapy or performed and presented for bladder training during the 2 efficacy analysis". Urgency episodes weeks before or during the study; TOL IR 4mg: 1.68 8] use of any drugs with ± 2.88 N = 100 Indirectness cholinergic or anticholinergic side SOL 5mg: 1.77 ± effects and participation in a 2.74 N = 98 Does the study match clinical trial within 30 days before SOL 10mg: 1.42 ± the protocol in terms of; study entry; 2.21 N = 98 1] Population: Yes 9] women of childbearing potential 2] Intervention: Yes who were pregnancy or nursing, Continence status 3] Outcomes: Yes intending to become pregnant Incontinence Indirectness: None during the study, or who were not episodes using reliable contraceptive Not reported methods were ineligible. Other information Urgency episodes Not reported Patients were regarded compliant if they had Incontinence- taken at least 70% of the specific quality of required study life medication. Not reported

438

Study details Participants Interventions Methods Outcomes and Comments Results

Data from SOL 5mg Adverse effects group used in meta- Any adverse effect analysis based on BNF Not reported starting dose

Dry mouth TOL IR 4mg: 22/118 (18.6%) SOL 5mg: 9/120 (7.5%) SOL 10mg: 23/119 (19.3%)

Dropout for any reason TOL IR 4mg: 18/118 (15.3%) SOL 5mg: 22/120 (18.3%) SOL 10mg: 21/119 (17.6%)

Dropout for adverse event TOL IR 4mg: 2/118 (1.7%) SOL 5mg: 5/120 (4.2%) SOL 10mg: 7/119 (5.9%)

Psychological outcomes Not reported

Clinical measures Post-void residual volume TOL IR 4mg: 4.8 ±

439

Study details Participants Interventions Methods Outcomes and Comments Results

31.5 N = 108 SOL 5mg: 8.4 ± 40.78 N = 110 SOL 10mg: 4.6 ± 50.5 N = 111

Full citation Sample size Interventions Details Results Limitations

Dmochowski,R.R., N = 564 Subjects were allocated to 3-day bladder diary was Week 4 NICE guidelines manual. Sand,P.K., Zinner,N.R., Trospium externder release (TRO receive Trospium extended completed for visits at 1, 4 Patient Appendix D: Staskin,D.R., Trospium 60 ER) = 280 release (60 mg) oral capsules and 12 weeks. Urgency satisfactiopn with Methodology checklist: mg once daily (QD) for Placebo (PLA) = 284 or matching placebo once severity was measured ising treatment Randomised controlled overactive bladder syndrome: daily for 12 weeks the Indevus Urgency Severity Not reported trials results from a placebo- Scale. The OAB Symptom controlled interventional Characteristics Composite Score was used Self-reported rate A Selection bias study, Urology, 71, 449-454, to assess the overall of absolute A1 - Was there 2008 Gender - Female/N (% female) complex of OAB symptoms. symptoms appropriate TRO ER: 230/280 (82.1%) Complaints and adverse reduction/day - randomisation - Yes - Ref Id PLA: 249/284 (87.7%) effects were assessed at 1, 4 Mean ± SD Randomizatyion was and 12 weeks. Incontinence stratified by number of 100195 Age (years) - Mean ± SD* episodes - change voids/day TRO ER: 61.2 ± 11.7 from baseline A2 - Was there adequate Country/ies where the PLA: 58.4 ± 11.8 Power calculation reported concealment - unclear - study was carried out TRO ER: -2.3 ± not reported Number of incontinence Not reported 3.3 N = 267 A3 - Were groups United states episodes/week Mean ± SD* PLA: -1.5 ± 3.3 N comparable at baseline - TRO ER: 4.0 ± 2.2 = 276 Yes - No apparent Study type PLA: 4.0 ± 3.4 Intention to treat analysis differences between Urgency episodes groups at baseline Randomized controlled trial Urgency episodes Last observation carried Not reported Level of bias: Low Not reported forward (LOCF) was used to Aim of the study account for any missing data Continence status B Performance bias Detrusor overactivity (Zero episodes per B1 - Did groups get "To evaluate the effects of Not reported day) same level of care - Yes Trospium 60mg (QD) Incontinence B2 - Were participants compared with placebo on Duration of OAB - Mean ± SD episodes blinded - Yes - Study urinary frequency, UUI, and Not reported TRO ER: 78/280 was double-blind other symptoms related to

440

Study details Participants Interventions Methods Outcomes and Comments Results

OAB over a 12-week (27.8%) B3 - Were clinical staff treatment period" PLA: 48/284 blinded - Yes Inclusion criteria (16.9%) Level of bias: Low

Study dates 1] aged ≥ 18 years Urgency episodes C Attrition bias 2] OAB ≥ 6 months Not reported C1 - Was follow-up equal September 2005 to June 3] symptoms of urinary frequency for both groups - Yes 2006 (a mean of 10 or more toilet voids Incontinence- C2 - Were groups per day) specific quality of comparable for dropout - Source of funding 4] urgency (1 or more episodes of life Yes severe urgency related to toilet Not reported C3 - Were groups Study supported by Esprit voids) comparable for missing Phama and Indevas 5] UUI (a mean of 1 or more UUI Adverse effects data - Yes Pharmaceuticals INc episodes per day) Not reported at 4 Level of bias: Low weeks D Detection bias Exclusion criteria Psychological D1 - Was follow-up outcomes appropriate length - Yes 1] total voided volume ≥ Not reported D2 - Were outcomes 3000ml/day or a mean volume defined precisely - Yes volume voided/void ≥ 250ml Clinical measures D3 - Was a valid and 2] predominant stress, insensate Not reported reliable methods used to or overflow incontinence assess outcome - Yes 3] history of neurogenic bladder Week 12 D4 - Were investigators 4] history of indwelling or Patient blinded to intervention - intermittent catheterization satisfactiopn with Yes 5] history of significant renal treatment D5 - Were investigators disease (serum creatinine ≥ Not reported blinded to confounding 1.5mg/dl) factors - Unclear 6] uninvestigated hematuria Self-reported rate Level of bias: Low 7] urinary tract infection during of absolute screening symptoms 8] history of > 3 urinary tract reduction/day - Indirectness infections in previous 12 months Mean ± SD 9] other baldder pathogies, UUI episodes - Does the study match including clinically significant change from the protocol in terms of: urinary retention (postvoid residual baseline reported 1] Population: Yes volume > 100ml), cancer, institial TRO ER: -2.4 ± 2] Interventions: Yes cystitis 3.3 N = 267 3] Outcome: Yes

441

Study details Participants Interventions Methods Outcomes and Comments Results

10] a prostate specific antigen PLA: -1.6 ± 3.3 N Indirectness: None level ≥ 4 ng/ml, prostate cancer or = 276 chronic prostatitis Urgency episodes Other information Not reported SD for continuous data Continence status calculated by NCC-WCH (Zero episodes per from SEM reported day) Data for 'Dropout for any Incontinence reason" taken from episodes pooled analysis in TRO ER: 95/280 "Dmochowski et al., (33.9%) 2010" PLA: 58/284 (20.4%)

Urgency epsiodes Not reported

Incontinence- specific quality of life OAB-SCS used TRO ER: - 9.9. (No SD) N = 267 PLA: -6.5 (No SD) N = 276

Adverse effects Any adverse effect TRO ER: 154/280 (55.0%) PLA: 130/284 (45.8%)

Dry mouth TRO ER: 36/280 (12.9%) PLA: 13/284

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Study details Participants Interventions Methods Outcomes and Comments Results

(4.6%)

Dropout for any reason TRO ER: 37/280 (13.2%) PLA: 36/284 (12.3%)

Dropouts for adverse effects TRO ER: 18/280 (6.4%) PLA: 8/284 (2.8%)

Psychological outcomes Not reported

Clinical measures Not reported

Full citation Sample size Interventions Details Results Limitations

Dmochowski,R.R., N = 896 Women were allocated to Subjects completed a 3-day Week 4 results NICE guidelines manual. Peters,K.M., Morrow,J.D., Fesoterodine (FES) = 448 FES 4mg or matching bladder diary before the Not reported Appendix D: Guan,Z., Gong,J., Sun,F., Placebo (PLA) = 448 placebo to be taken once baseline visit and at each Methodology checklist: Siami,P., Staskin,D.R., daily with 4 hours of bedtime. subsequent visit. Subjects Week 12 results Randomised controlled Randomized, double-blind, After 2 weeks, women could, recorded all micturitions, Patient satisfaction trials placebo-controlled trial of Characteristics after a consultaion regarding including incontinence with treatment flexible-dose fesoterodine in efficacy and adverse effects, episodes. The Urinary FES: 310/448 A Selection bias subjects with overactive Gender - Female/N (% female) increase dose to FES 8mg Sensations Scale, Patient (69.2%) A1 - Was there bladder.[Erratum appears in FES: 368//446 (82.1%) once daily or sham dose Perception of Bladder PLA: 257/448 appropriate Urology. 2010 PLA: 364/448 (82.1%) escalation for the remaining Condition and Urgency (57.4%) randomisation - Yes - Jun;75(6):1519], Urology, 75, 10 weeks. No dose Perception Scale were also computer generated 62-68, 2010 Age (years) - Mean ± SD adjustment were permitted completed at baseline and all Self-reported rate A2 - Was there adequate FES: 60.1 ± 12.9 after week 2. visits and the Overactive of absolute concealment - Unclear -

443

Study details Participants Interventions Methods Outcomes and Comments Results

Ref Id PLA: 59.7 ± 13.7 Bladder Questionnaire symptom not reported reduction per day A3 - Were groups 100197 Incontinence episodes/week - (LS mean change comparable at baseline - Mean ± SD Power calculation from baseline, no Yes - No apparent Country/ies where the Urge incontinence data used SD reported) differences between study was carried out FES: 2.2 ± 2.7 Using published studies it Incontinence groups at baseline PLA: 2.0 ± 1.9 was calculated that 350 episodes Level of bias: Low United States subjects per arm would FES: -1.5 (No SD) Urgency episodes/day - Mean ± provide ≥ 85% ppower to N = 267 B Performance bias Study type SD detect a difference in 24-hour PLA: -1.2 (No SD) B1 - Did groups get FES: 9.2 ± 4.3 micturitions using a 2-sided t N = 251 same level of care - Yes Randomized controlled trial PLA: 9.2 ± 3.8 test with a 0.05 significance B2 - Were participants level. Urgency episodes blinded - Yes - Study Aim of the study Detrusor overactivity - n/N (%) FES: -4 (No SD) N was double-blind and Not reported = 434 double-dummy The study assessed the Intention to treat analysis PLA: -3 (No SD) N B3 - Were clinical staff efficacy, safety and Duration of OAB - Mean ± SD = 428 blinded - Yes tolerability of a flexible-dose Not reported Not reported Level of bias: Low regimen of fesoterdine in Continence status subjects with OAB. (zero episodes per C Attrition bias Inclusion criteria day) C1 - Was follow-up equal Incontinence for both groups - Yes Study dates 1] OAB symptoms ≥ 3 months episodes - C2 - Were groups before screening incontinent at comparable for dropout - August 2007 to April 2008 2] recorded mean of ≥ 8 baseline only Yes micturitions per 24 hours and ≥ 3 FES: 162/257 C3 - Were groups Source of funding urgency episodes per 24 in a 3- (63%) comparable for missing day bladder diary PLA: 133/260 data - Yes Study was funded by Pfizer 3] rated their bladder problem (51%) Level of bias: Low Inc condition as baseline as causing at least soome moderate problems Urgency episodes D Detection bias using Patient Perception of Not reported D1 - Was follow-up Bladder Condition appropriate length - Yes Incontinence- D2 - Were outcomes specific quality of defined precisely - Yes Exclusion criteria life D3 - Was a valid and Not reported reliable methods used to 1] history of acute urinary retention assess outcome - Yes requiring catheterisation Adverse effects D4 - Were investigators

444

Study details Participants Interventions Methods Outcomes and Comments Results

2] severe voiding difficulties Any adverse effect blinded to intervention - 3] urinary inconntinence symptoms Not reported Yes attributed to stress urinary D5 - Were investigators incontinence Dry mouth blinded to confounding 4] significant pelvic organ prolapse FES: 113/448 factors - Unclear or lower urinary tract surgery in (25.2%) Level of bias: Low preceding 6 months PLA: 34/448 5] clinically significant hepatic or (7.6%) rebnal disease Indirectness 6] neurologic disease that Dropouts for any significantly affects bladder reason Does the study match function FES: 66/448 the protocol in terms of: 7] treatment with an antimuscarinic (14.7.%) 1] Population: Yes OAB medication or potent PLA: 63/448 2] Interventions: Yes CYP3A4 inhibitor within 2 weeks of (14.1%) 3] Outcome: Yes screening Indirectness: None 8] any contraindications to Dropouts for fesoterodine adverse effects 9] mean with intermittent or FES: 34/448 Other information unstable use of alpha blockers or (7.6%) 4-alpha-reductase inhibitors or PLA: 21/448 Only continence status who started such treatment within (4.7%) and discontinuation for 4 weeks of screening any reason data used in Psychological the network meta- outcomes analysis Not reported

Clinical measures Not reported

Full citation Sample size Interventions Details Results Limitations

Herschorn,S., Swift,S., N = 1712 Fesoterodine (4mg for 1 week Patients were randomised in Week 4 NICE guidelines manual. Guan,Z., Carlsson,M., then 8mg for 11 weeks) the ratio in a 2:2:1 to Patient satisfaction Appendix D: Morrow,J.D., Brodsky,M., Fesoterodine (FES): 679 Tolterodine ER 4mg fesoterodine (4mg for 1 week with treatment Methodology checklist: Gong,J., Comparison of Tolterodine (TOL ER): 684 Placebo then 8mg for 11 weeks), Improved on Randomised controlled fesoterodine and tolterodine Placebo (PLA): 334 tolterodine ER or placebo. Patients

445

Study details Participants Interventions Methods Outcomes and Comments Results extended release for the Perception of trials treatment of overactive All patients took their Bladder Condition bladder: a head-to-head Characteristics medication once a day in the TOL ER: 370/684 placebo-controlled trial, BJU morning. Treatment was (54.1%) International, 105, 58-66, Gender - Female/N (% female) double-blind with all patients FES: 420/679 2010 TOL ER = 564/684 (82.5%) receiving one tablet (61.9%) A Selection bias FES = 558/679 (82.2%) (fesoterodine 4 mg or 8 mg PLA: 152/334 A1 - Was there Ref Id PLA = 269/334 (80.5%) or matching placebo) or a (45.5%) appropriate capsule for those taking randomisation - Yes - 100249 Age - Mean ± SD tolterodine 4mg or matching Self reported rate block randomisation TOL ER = 58.5 ± 13.2 years placebo. of absolute using a centralised Country/ies where the FES = 57.8 ± 12.8 years symptom system study was carried out PLA = 58.4 ± 13.7 years reduction per day A2 - Was there adequate At baseline and 12 weeks, Episodes of concealment - Yes - USA Incontinence episodes (UUI) / day patients completed 3-day incontinence / day randomisation schedule - Mean ± SD bladder diaries recording UUI - Mean ± sd generated and stored off Study type TOL ER: 11.7 ± 3.1 episodes per 24 (change scores) site FES: 11.7 ± 3.4 hours (primary endpoint), TOL ER: -1.40 ± A3 - Were groups Randomised controlled trial PLA: 11.9 ± 3.5 mean volume voided, 1.50 N = 626 comparable at baseline - noctural voids, urgency FES: -1.52 ± 1.49 Yes - No apparent Aim of the study Urgency episodes / day - Mean ± episodes, severe urgency N = 618 differences between SD episodes and frequency- PLA: -1.06 ± 1.75 groups at baseline "The primary objective of the TOL ER: 9.3 ± 3.9 urgency sum per 24 hours. N = 307 Level of bias: Low present study was to assess FES: 9.3 ± 3.7 They also completed the whether the efficacy of PLA: 9.4 ± 4.2 Perception of Bladder Episodes of fesoterodine 8 mg is superior Condition (PPBC) and the urgency / day - to that of tolterodine ER 4 mg Detrusor overactivity Urgency Perception Scales Mean ± sd B Performance bias and placebo in improving Not reported (UPS) and the Overactive (change scores) B1 - Did groups get symptoms of OAB and Bladder Questionnaire (OAB- TOL ER: -2.4 ± 5.0 same level of care - Yes patient-reported outcomes." Duration of OAB (mean ± SD) q) at both time points. N = 631 B2 - Were participants TOL ER: 6.9 years FES: -2.6 ± 5.00 N blinded - Yes - Study FES: 7.1 years = 627 was double-blind and Study dates PLA: 7.3 years Power calculation PLA: -1.2 ± 3.5 N double-dummy

= 311 B3 - Were clinical staff Not reported A sample size of 606 patients blinded - Unclear - not Inclusion criteria per active treatment group Continence status reported Source of funding was required to detect a Incontinence Level of bias: Low 1] aged ≥ 18 years difference between episodes "The study was sponsored by 2] symptoms of OAB (self- fesoterodine and tolterodine TOL ER: 290/684

446

Study details Participants Interventions Methods Outcomes and Comments Results

Pfizer Inc." assessed) for ≥ 3 months before ER in the change in UUI (42.4%) screening episodes from baseline to FES: 306/679 3] mean of one or more UUI week 12 using a two-sided t- (45.1%) C Attrition bias episodes/24hr test at the 5% significance PLA: 97/334 C1 - Was follow-up equal 4] ≥8 voids/24h reported in 3-day level with 90% power. Based (29.0%) for both groups - Yes bladder diaries completed at on the previously observed C2 - Were groups baseline mean (SD) treatment Urgency episodes comparable for dropout - differences of 1.07 (2.85) Not reported Yes between fesoterodine 8 mg C3 - Were groups Exclusion criteria and placebo groups in an Incontinence- comparable for missing earlier study. specific quality of data - Yes 1] clinically significant hepatic or life Level of bias: Low renal disease 303 patients were required in Not reported 2] lower genitourinary pathology or the placebo group for ≥ 88% having undergone surgery that power for each comparison. Adverse effects of could cause voiding dysfunction; Thus, 1515 patients were treatment 3] neurological conditions, e.g. required. Assuming that Any adverse effect D Detection bias stroke, MS, spinal cord injury, or approximately 90% of the Not reported D1 - Was follow-up Parkinson's disease: randomized patients would appropriate length - Yes 4] previous history of acute urinary contribute to the full analysis Dry mouth D2 - Were outcomes retention requiring catherterization set, it was planned to Not reported defined precisely - Yes 5] predominately SUI symptoms randomize 1675 patients D3 - Was a valid and (in the opinion of the investigator) Dropout for any reliable methods used to 6] treatment with antimuscarinic reason assess outcome - Yes medication within 2 weeks before Intention to treat analysis Not reported D4 - Were investigators screening: blinded to intervention - 7] use of any electrostimulation, "Missing postbaseline data Dropout for Yes bladder training or pelvic floor were imputed based on the adverse event D5 - Were investigators exercises within 4 weeks of last-observation-carried Not reported blinded to confounding screening; forward principle using data factors - Unclear 8] female pts of childbearing age, from interim visits; baseline Psychological Level of bias: Low heterosexually active and not data were not carried outcomes using contraception forward". Not reported 9] pregnant, nursing or with a positive pregnancy test. Clinical measures Indirectness - Post-void residual volume Does the study match Not reported the protocol in terms of:

447

Study details Participants Interventions Methods Outcomes and Comments Results

12 weeks results 1] Population: Yes Patient satisfaction 2] Interventions: Yes with treatment - 3] Outcome: Yes Improved on Indirectness: None Patients Perception of Bladder Condition Other information TOL ER: 399/684 (58.3%) Additional data on FES: 452/679 baseline levels and (66.6%) results taken from PLA: 169/334 NCT00444925 (50.6%) (www.clinicaltrials.gov)

Self reported rate of absolute symptom reduction per day Episodes of incontinence / day - Mean ± sd (change scores) TOL ER: -1.61 ± 1.50 n = 626 FES: -1.72 ± 1.72 n = 619 PLA: -1.46 ± 1.75 n = 307

Episodes of urgency / day - Mean ± sd (change scores) TOL ER: -3.5 ± 5.0 n = 631 FES: -3.5 ± 5.00 n = 628 PLA: -2.00 ± 5.30 n = 311

448

Study details Participants Interventions Methods Outcomes and Comments Results

Continence status Incontinence episodes TOL ER: 358/684 (52.3%) FES: 396/679 (58.3%) PLA: 138/334 (41.3%)

Urgency episodes Not reported

Incontinence- specific quality of life (endpoint week 12) Scale used - OAB- q: Total HRQOL TOL ER: 16.3 ± 24.2 n = 588 FES: 19.3 ± 23.9 n = 572 PLA: 12.0 ± 21.3 n = 289

Adverse effects of treatment Any adverse effect TOL ER: 232/684 (33.9%) FES: 305/679 (44.9%) PLA: 84/334 (25.1%)

Dry mouth TOL ER: 112/684

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Study details Participants Interventions Methods Outcomes and Comments Results

(18.6%) FES: 189/679 (27.8%) PLA: 20/334 (6.0%)

Dropout for any reason TOL ER: 56/684 (8.2%) FES: 81/679 (11.9%) PLA: 30/334 (9.0%)

Dropout for adverse event TOL ER: 28/684 (4.1%) FES: 44/679 (6.5%) PLA: 6/334 (2.08%)

Psychological outcomes Not reported

Clinical measures - Post-void residual volume Not reported

Full citation Sample size Interventions Details Results Limitations

Hill,S., Khullar,V., N = 439 DAR 7.5, DAR 15, DAR 30 After a screening visit (history Week 4 NICE guidelines manual. Wyndaele,J.J., Lheritier,K., and PLA was given as once and urinalysis) eligible Not reported Appendix D:

450

Study details Participants Interventions Methods Outcomes and Comments Results

Darifenacin Study Group., Darifenacin 7.5mg (DAR 7.5) = daily controlled realease patients entered a 2-week Methodology checklist: Dose response with 108 tablets or matching placebo placebo washout phase (if Week 12 Randomised controlled darifenacin, a novel once- Darifenacin 15mg (DAR 15) = 107 required) before screening Patient satisfaction trials daily M3 selective receptor Darifenacin 30mg (DAR 30) = 115 assessments. Patients then with treatment A Selection bias antagonist for the treatment Placebo (PLA) = 109 entered a 2-week run-in Not reported A1 - Was there of overactive bladder: results phase with daily appropriate of a fixed dose study, assessments using an Self-reported rate randomisation - Yes - International Urogynecology Characteristics electronic urinary dairy. of absolute blocks of eight used Journal, 17, 239-247, 2006 Patients still eligible were symptom A2 - Was there adequate Gender - Female/N (% female) randomized to 12 weeks of reduction per concealment - Unclear - Ref Id DAR 7.5: 94/108 (87.0%) active treatment or placebo. week Not reported DAR 15: 92/107 (86.0%) A double dummy technique Incontinence A3 - Were groups 100250 DAR 30: 99/115 (86.1%) was used to maintain episodes (Median comparable at baseline - PLA: 90/109 (82.6%) blinding. No dose change from Yes - No apparent Country/ies where the adjustments were allowed baseline) differences between study was carried out Age (years) - Mean (range) and compliance was DAR 7.5: -8.1 N = groups at baseline DAR 7.5: 56.1 (23 - 88) measured by a pill count. 107 Level of bias: Low UK DAR 15: 55.1 (24 - 82) DAR 15: -10.4 N = DAR 30: 54.0 (23 - 79) 106 B Performance bias Study type PLA: 53.7 (21 - 85) Power calculation DAR 30: -11.4 N = B1 - Did groups get 114 same level of care - Yes Randomized controlled trial Incontinence episodes/week - Sample size calculation was PLA: -5.9 N = 108 B2 - Were participants Median (95% CI) based on previous blinded - Yes - Study Aim of the study DAR 7.5: 13.7 (11.8 to 17.8) darifenacin studies. Urgency episodes was double-blind and DAR 15: 17.3 (13.5 to 21.5) Assuming a difference vs. (Median change double-dummy To evaluate 'the efficacy, DAR 30: 19.1 (15.8 to 22.8) placebo of 5 incontinence from baseline) B3 - Were clinical staff tolerability, and safety of PLA: 16.1 (14.0 to 19.4) episodes per week and using DAR: -1.8 N = 107 blinded - Yes varying doses of darifennacin a two-sided 5% significance DAR 15: -2.3 N = Level of bias: Low in patients with OAB' Urgency episodes/day - Median level with 90% power to the 106 (range) the null hypothesis of no DAR 30: -3.0 N = C Attrition bias DAR 7.5: 8.5 (7.0 to 8.7) difference it was estimated 114 C1 - Was follow-up equal Study dates DAR 15: 8.6 (7.8 to 9.4) that 85 patients would be PLA: -1.2 N = 108 for both groups - Yes DAR 30: 8.4 (7.8 to 8.8) needed. Assuming a 20% C2 - Were groups Not reported PLA: 8.1 (7.4 to 8.7) withdrawal rate 424 patients Continence status comparable for dropout - (106 per group) would be (zero episodes per Yes Source of funding Detrusor overactivity - n/N (%) required. day) - n/N (%) C3 - Were groups Not reported Incontinence comparable for missing Study was funded by Pfizer episodes - data - Yes Inc. Duration of OAB - Mean ± SD Reported as 7- Level of bias: Low

451

Study details Participants Interventions Methods Outcomes and Comments Results

Not reported Intention to treat analysis consecutive dry days D Detection bias Not reported DAR 7.5: Not D1 - Was follow-up Inclusion criteria reported appropriate length - Yes DAR 15: 26/107 D2 - Were outcomes 1] aged ≥ 18 (24/3%) defined precisely - Yes 2] urge incontinence (at least 10 DAR 30: 29/115 D3 - Was a valid and episodes over 14 days) (25.2%) reliable methods used to 3] high micturition frequency PLA: 17/109 assess outcome - Yes (mean of at least 8 voids per day) (15.6%) D4 - Were investigators 4] urinary urgency (a strong desire blinded to intervention - to void on average at least once a Urgency episodes Yes day) Not reported D5 - Were investigators 5] OAB symptoms ≥ 6 months blinded to confounding Incontinence- factors - Unclear specific quality of Level of bias: Low Exclusion criteria life Not reported 1] clinically significant stress Indirectness incontinence (judged by Adverse effects - investigator) n/N (%) Does the study reflect 2] bladder outlet obstruction Any adverse effect the review protocol in 3] postvoid residual urinary volume DAR 7.5: 62/108 terms of: > 200ml (57.4%) Population: Yes 4] local pathology that could cause DAR 15: 73/107 Intervention: Yes urinary symptoms (e.g. interstitial (68.2%) Outcome: Yes cyctitis, bladder stones, severe DAR 15: 92/115 Indirectness: None constipation (≤ bowel movements (82.0%) per week) PLA: 54/110 5] history of intermittent urinary (49.5%) Other information tract infections 6] urogenital surgery in previous 6 Dry mouth Data from Darifenacin months DAR 7.5: 7.5 mg group used in 7] cystoscopy in previous 30 days 25/108 (23.1%) review 8] patients with an indwelling DAR 15: 43 /107 catheter or using intermittent self- (40.2%) catheterization DAR 30: 68/115 9] clinically significnt systemic (59.1%) disease PLA: 6/109 (5.5%)

452

Study details Participants Interventions Methods Outcomes and Comments Results

10] pregnant or lactating women 11] patients who inteneted to start Dropouts for any bladder training reason 12] any contraindication to DAR 7.5: 9/108 antimuscarinic therapy (8.3%) DAR 15: 14/107 (13.1%) DAR 30: 19/115 (16.5%) PLA: 8/109 (7.3%)

Dropouts for adverse effects DAR 7.5: 2/108 (1.9%) DAR 15: 6/107 (5.6%) DAR 30: 13/115 (11.3%) PLA: 3/109 (2.8%)

Psychological outcomes Not reported

Clinical measures Not reported

Full citation Sample size Interventions Details Results Limitations

Ho,C.H., Chang,T.C., N = 75 Patients received either 5 mg Patients completed a voiding Week 4 NICE guidelines manual. Lin,H.H., Liu,S.P., solifenacin once daily or 4 mg diary three days before clinic Not reported Appendix D: Huang,K.H., Yu,H.J., Solifenacine 5mg = 39 tolterodine once daily for 12 visits at 4, 8 and 12 weeks, Methodology checklist: Solifenacin and tolterodine Tolterodine ER 4mg = 36 weeks. and completed the Patient Week 12 Randomised controlled are equally effective in the Perception of Bladder Patient satisfaction trials treatment of overactive Patients were asked to Condition (PPBC) and a with treatment bladder symptoms, Journal of complete a 3-day voiding Visual Analogue Scale (VAS) Scale:Patient

453

Study details Participants Interventions Methods Outcomes and Comments Results the Formosan Medical Characteristics diary scales for dry mouths. Any Perception of Association, 109, 702-708, other adverse events were Bladder Condition 2010 Baseline characteristics Dry mouth was assessed recorded by researchers at (PPBC) A Selection bias using a Viaual Analogue these time points. SOL: 32/39 A1 - Was there Ref Id Gender - Female/N (% female) Scale (82.1%) appropriate SOL:26/39 (66.7%) PVR assessed by TOL ER: 28/36 randomisation - Unclear - 100252 TOL ER:24/36 (66.7%) ultrasonography at the visit in (77.8%) randomisation method week 12. not repored Country/ies where the Age - Mean ± SD Self-reported rate A2 - Was there adequate study was carried out SOL: 58.9 ± 15.1 years of absolute concealment - Unclear - TOL ER: 55.3 ± 15.7 years Response to treatment was symptom not reported Taiwan assessed by patients and reduction per day A3 - Were groups Incontinence episodes/day - Mean investigators using a 3-point Incontinence comparable at baseline - Study type ± SD scale (not, a little and much episodes Yes - No apparent SOL: 3.21 ± 3.05 improved). SOL: -2.79 ± 2.82 differences between Randomised controlled trial TOL ER: 6.19 ± 5.83 N = 34 groups at baseline TOL ER: -4.67 ± Level of bias: Low Aim of the study Urgency episodes/day - Mean ± Power calculation 9.29 N = 32 SD

"To compare the efficacy and SOL: 4.57 ± 5.83 Not reported. Urgency episodes safety of 5mg solifenacin TOL ER: 3.68 ± 4.45 SOL: -1.70 ± 3.07 once daily and 4mg N = 34 B Performance bias tolterodine once daily" Detrusor overactivity - n/N (%) Intention to treat analysis TOL ER:-1.15 ± B1 - Did groups get Not reported 2.68 N = 32 same level of care - Yes None - All efficacy analyses B2 - Were participants Study dates were based on 'per protocol Duration of OAB - Mean ± SD Continence status blinded - No - study was set' SOL:4.2 ± 6.2 years (zero episodes per open-label Feb 2007 - May 2008 TOL ER:4.4 ± 4.9 years day) B3 - Were clinical staff blinded - No - study was Source of funding Incontinence episodes open-label Inclusion criteria Level of bias: High Not reported. Not reported 1] aged ≥ 18 years old

2] offered informed consent Urgency episodes 3] willing and able to complete the Not reported micturition diary daily C Attrition bias 4] have OAB symptoms (inc. urine Incontinence- C1 - Was follow-up equal freq, urgency or urge incontinence) specific quality of for both groups - Yes ≥ 3 months life C2 - Were groups

454

Study details Participants Interventions Methods Outcomes and Comments Results

5] Must have experienced Not measured comparable for dropout - frequency, defined as ≥ 8 Yes micturitions/24 hrs Adverse effects C3 - Were groups Any adverse effect comparable for missing SOL: 15/39 data - Yes Exclusion criteria (38.5%) Level of bias: Low TOL ER: 9/36 1] pregnant or lactating patients or (25.0%) those intending to become pregnant Dry mouth D Detection bias 2] clinical significant bladder SOL: 7/39 (17.9%) D1 - Was follow-up outflow obstruction (females with TOL ER: 3/36 appropriate length - Yes bladder outlet obstruction or (8.3%) D2 - Were outcomes benign prostatic hyperplasia in defined precisely - Yes males) Dropouts for any D3 - Was a valid and 3] significant post-void residual reason reliable methods used to volume (PVR) SOL: 5/39 (12.8%) assess outcome - Yes 4] stress incontinence TOL ER: 4/36 D4 - Were investigators 5] evidence of symptomatic UTI, (11.1%) blinded to intervention - chronic inflammation, bladder No - study was open- stones, previous pelvic radiation Dropouts for label therapy, precious or current adverse effects D5 - Were investigators malignant disease of the pelvic SOL: 1/39 (2.6%) blinded to confounding organs TOL ER: 1/36 factors - No - study was 6] patients with a medical condition (2.8%) open-label that contraindicated the use of Level of bias: Low antimuscarinic drugs Psychological 7] uncontrolled narrow angle outcomes glaucoma, urinary or gastic Not reported retention, or any additional medication condition that, in the Clinical measures Indirectness opinion of the investigator, - Post-void contraindicated the use of residual volume Does the study match antimuscarinics. SOL: 0.60 ± 44.6 the protocol in terms of: mL N = 34 1] Population: Yes TOL ER: 3.51 ± 2] Interventions: Yes 2.26 mL N = 32 3] Outcome: Yes Indirectness: None

455

Study details Participants Interventions Methods Outcomes and Comments Results

Other information

Unclear on dropout numbers

Full citation Sample size Interventions Details Results Limitations

Junemann,K.P., N = 988 Propiverine hydrochloride Following a run-in period of Week 4 NICE guidelines manual. Hessdorfer,E., Unamba- immediate release 15mg seven days, patients Patient satisfaction Appendix D: Oparah,I., Berse,M., Propiverine IR = 395 twice daily received propiverine with treatment Methodology checklist: Brunjes,R., Madersbacher,H., Propiverine ER = 391 hydrochloride IR 15mg twice PRO IR: 249/395 Randomised controlled Gramatte,T., Propiverine Placebo = 202 Propiverine a day, propiverine (63.0%) trials hydrochloride immediate and hydrochloride extended hydrochloride ER 30mg once PRO ER: 245/391 extended release: release 30mg once daily a day or a placebo for 32 (62.7%) comparison of efficacy and Characteristics days. Investigators undertook PLA: 87/202 tolerability in patients with Placebo regular assessments of (43.1%) overactive bladder, Urologia Gender - Female/N (% female) efficacy and tolerability. A Selection bias Internationalis, 77, 334-339, PRO IR: 353/395 (89.4%) Self-reported rate A1 - Was there 2006 PRO ER: 348/391 (89.0%) of absolute risk appropriate PLA: 13/202 (90.6) Power calculation reduction per day randomisation - Ref Id Incontinence A2 - Was there adequate Not reported. episodes - Mean ± concealment - 100270 Age - Mean ± SD SD (endpoint A3 - Were groups PRO IR: 56.3 (no SD given) scores) comparable at baseline - Country/ies where the PRO ER: 55.3 Intention to treat analysis PRO IR: 1.08 ± Level of bias: study was carried out PLA: 57.2 2.10 N = 360 Reference made to the PRO ER: 0.91 ± Bulgaria, Czech Republic, intention to treat population 1.70 N = 363 Germany, UK, Spain, Incontinence episodes/ day - Mean but no details offered on how PLA: 1.72 ± Ukraine, Romanian, Austria ± SD missing data was treated. 2.78 N = 187 B Performance bias and France. PRO IR: 3.29 ± 2.65 B1 - Did groups get PRO ER: 3.38 ± 2.75 Urgency episodes same level of care - Study type PLA: 3.50 ± 3.63 - Mean ± SD B2 - Were participants PRO IR: 4.10 ± blinded - Randomised controlled trial Urgency episodes/ day - Mean ± 3.67 N = 360 B3 - Were clinical staff blinded -

456

Study details Participants Interventions Methods Outcomes and Comments Results

Aim of the study SD PRO ER: 3.79 ± Level of bias: PRO IR: 6.13 ± 3.83 3.29 N = 363 To compare the efficacy and PRO ER: 6.37 ± 4.13 PLA: 4.44 ± tolerability of propiverine PLA: 6.05 ± 4.08 4.06 N = 187 hydrochloride immediate release (IR), propiverine Detrusor overactivity - n/N (%) Continence status C Attrition bias hydrochloride extended Not reported (zero episodes per C1 - Was follow-up equal release (ER) and placebo for day) n/N (%) for both groups - the treatment of overactive Incontinence C2 - Were groups bladder Duration of OAB - Mean ± SD episodes comparable for dropout - Not reported PRO IR: 184/395 C3 - Were groups (46.6%) comparable for missing Study dates PRO ER: 199/391 data - Inclusion criteria (50.1%) Level of bias: December 2001 to August PLA: 76/202 2003 1] ≥18 years old (35.1%) 2] able to provide voluntarily Source of funding signed informed consent Urgency episodes D Detection bias 3] at least 2 incontinence episodes Not reported D1 - Was follow-up Apogepha Arzneimittel GmbH within 3 days appropriate length - 4] at least 10 micturitions within 24 Incontinence- D2 - Were outcomes hours specific quality of defined precisely -

life D3 - Was a valid and Scale: Kings's reliable methods used to Exclusion criteria Health assess outcome - Questionnaire D4 - Were investigators 1] stress incontinence (total score) blinded to intervention - 2] intermittent catheterization PRO IR: 40.38 ± D5 - Were investigators 3] neurogenic detrusor under- and 21.70 N = 360 blinded to confounding overactivity PRO ER: 40.58 ± factors - 4] postvoid residual urine ≥100ml 21.86 N = 363 Level of bias: 5] acute UTI PLA: 44.23 ± 6] electrostimulation therapy, 21.28 N = 187 bladder training if performed within 4 weeks before the run-period for Adverse event n/N the study (%) Indirectness 7] anomalies of the lower GU tract Any adverse effect (e.g. ectopic ureters, fistulas etc) PRO IR: 152/395 Does the study match 8] pre-existing medical (38.5%) the protocol in terms of:

457

Study details Participants Interventions Methods Outcomes and Comments Results

contraindications for PRO ER: 134/391 1] Population: Yes anticholinergics (e.g. obstruction of (34.3%) 2] Intervention: Yes the bowel) PLA: 41/202 3] Outcomes: Yes 9] cardiac insufficiency (20.3%) Indirectness: None 10] multiple sclerosis 11] evidence of severe renal, Dry mouth hepatic or metabolic disorders PRO IR: 90/395 Other information 12] history of drug or alcohol (22.8%) abuse PRO ER: 85/391 Data from the PRO IR 13] concomitant medications (21.7%) group not used in review known to have a potential to PLA: 13/202 or network meta- interfere with the study medication (6.4%) analysis as dose used 14] pregnant or breast feeding (15mg twice daily) was women Dropouts for any less than the 15] women of childbearing reason recommended starting potential not using a reliable form PRO IR: 26/395 doses of 15mg three of contraception. (6.6%) times daily PRO ER: 23/391 (5.9%) PLA:11/202 (5.4%)

Dropouts for adverse event PRO IR: 15/395 (3.8%) PRO ER: 11/391 (2.8%) PLA: 1/202 (0.5%)

Psychological outcomes Not reported

Clinical measures Post-void residual volume Not reported

458

Study details Participants Interventions Methods Outcomes and Comments Results

Week 12 Not applicable

Full citation Sample size Interventions Details Results Limitations

Karram,M.M., Toglia,M.R., N = 739 SOL or PLA given as Participants completed 3-day Week 4 results NICE guidelines Serels,S.R., Andoh,M., Solifenacin (SOL) = 372 5mg/day for 4 weeks, then bladder diaries before each Not reported manual.Appendix D: Fakhoury,A., Forero- Placebo (PLA) = 367 the dose could be maintained study visit (weeks 0, 4, 8, 12) Methodology checklist: Schwanhaeuser,S., or increased to 10mg/day. At to record each urinary event Week 12 results Randomised controlled Treatment with solifenacin 8 weeks dose could be including micturitions, Patient satisfaction trials increases warning time and Characteristics maintained or increased from inocntinence episodes and with treatment improves symptoms of 5mg/day to 10mg/day or urgency episodes. Reported as A Selection bias overactive bladder: results Gender - Female/N (% female)* decreased from 10mg/day to improved on A1 - Was there from VENUS, a randomized, SOL: 317/372 (85%) 5mg/day PPBC appropriate double-blind, placebo- PLA: 305/367 (83%) Power calculation SOL: 207/372 randomisation - Unclear - controlled trial, Urology, 73, (55.6%) not reported 14-18, 2009 Triallists determined that 289 PLA: 145/367 A2 - Was there adequate Age (years) - Mean ± SD* patients per treatment arm (39.5%) concealment - Unclear - Ref Id SOL: 57 ± 14 would provide 90% power at not reported PLA: 57 ± 15 α - 0.05 to detect a group Self-reported rate A3 - Were groups 100280 difference of 1 urgency of absolute comparable at baseline - Incontinence episodes/day - Mean episode/day with a standard symptom Yes - No apparent Country/ies where the ± SD deviation of 3.7. Using a 20% reduction per day differences between study was carried out SOL: 2.82 ± 2.71 dropout rate, 720 would be Incontinence groups at baseline PLA: 2.56 ± 2.72 required* episodes - mean ± Level of bias: Low United States SD change from Urgency episodes/day - Mean ± *data from secondary baseline B Performance bias Study type SD publication (Toglia et al., SOL: -2.10 ± 2.39 B1 - Did groups get SOL: 6.15 ± 3.93 2009) n = 229 same level of care - Yes Randomized controlled trial PLA: 6.03 ± 3.90 PLA: -1.24 ± 2.30 B2 - Were participants n = 224 blinded - Yes - Study Aim of the study Detrusor overactivity - n/N (%) Intention to treat analysis was double-blind Not reported Urgency episodes B3 - Were clinical staff Not reported Last observation carried - mean ± SD blinded - Yes forward (LOCF) was used change from Level of bias: Low Duration of OAB - Mean ± SD baseline Study dates Not reported SOL: -3.91 ± 3.54 C Attrition bias

459

Study details Participants Interventions Methods Outcomes and Comments Results

Not reported n = 348 C1 - Was follow-up equal *data from secondary publication PLA: -2.73 ± 3.84 for both groups - Yes Source of funding (Toglia et al., 2009) n = 336 C2 - Were groups comparable for dropout - Astellas Pharma US, Inc and Continence status Yes GlaxoSmithKline Inclusion criteria (zero episodes per C3 - Were groups day) comparable for missing 1] aged 18 or over Incontinence data - Yes 2] OAB defined as at leats 1 episodes Level of bias: Low urgency episode/day, with or reported as no without urge incontinence, usually episodes at D Detection bias accompanied by frequency (at leat endpoint (week 12 D1 - Was follow-up 8 micturitions/day), nocturia or or last appropriate length - Yes both for at least 3 months observation) D2 - Were outcomes SOL: 133/229 defined precisely - Yes (58.1%) D3 - Was a valid and Exclusion criteria PLA: 93/224 reliable methods used to (41.5%) assess outcome - Yes 1] stress incontinence or mixed D4 - Were investigators incontinence with predominant Urgency episodes blinded to intervention - stress Not reported Unclear 2] urinary tract infection D5 - Were investigators 3] chronic inflammation (e.g. Incontinence- blinded to confounding institial cystitis) specific quality of factors - Unclear 4] bladder stones life Level of bias: Low 5] clinically significant bladder Not reported outflow obstruction 6] other conditions (including Adverse effects Indirectness hypersensitivity to anticholinergic Any adverse effect drugs) that might prevent safe SOL: 160/372 Does the study match completion of the study (43.0%) the review protocol in PLA: 88/367 terms of (24.0%) Population: Yes Intervention: Yes Dry mouth Outcome: Yes SOL: 94/372 Indirectness: None (25.3%) PLA: 33/367 (9.0%)

460

Study details Participants Interventions Methods Outcomes and Comments Results

Other information Dropouts for any reason Data on continence SOL: 58/372 status and dropouts for (15.6%) any reason used in PLA: 64/367 network meta-analysis (17.4%) Data on dropouts taken Dropouts for from secondary adverse effects publication "Toglia et al., SOL: 25/372 2009" (6.7%) PLA: 16/367 (4.4%)

Psychological outcomes Not reported

Clinical measures - Post-void residual volume Not reported

Full citation Sample size Interventions Details Results Limitations

Malone-Lee,J.G., Al- N = 307 Participants received eith Subjects completed a diary Week 4 NICE guidelines manual. Buheissi,S., Does TOL ER 4mg qd or placebo card for the 7 days before the Not reported Appendix D: urodynamic verification of Tolterodine extended release (TOL for 12 weeks first (baseline) study visit. Methodology checklist: overactive bladder determine ER) 4mg QD = 165 They were assessed for Week 12 Randomised controlled treatment success? Results Placebo (PLA) = 142 eligibility and after Patient satisfaction trials from a randomized placebo- urodynamic study returned with treatment controlled study, BJU for two further visits at 4 and Not reported A Selection bias International, 103, 931-937, Characteristics 12 weeks, and completed A1 - Was there 2009 diary cards for the 7 days Self-reported rate appropriate Gender - Female/N (% female) before each study visit. of absolute randomisation - Yes - Not reported by group but overall symptom independent stratified

461

Study details Participants Interventions Methods Outcomes and Comments Results

Ref Id 228/307 (74.3%) were female The information to be reduction per day randomization recorded on the diary card Incontinence A2 - Was there adequate 100338 Age (years) - Mean ± SD included the time of each episodes concealment - Yes - Not reported by group but overall bladder void and whether the Not reported randomisation numbers Country/ies where the age = 56.4 ± 14.1 void was voluntary or served as packaging for study was carried out involuntary, the number of Urgency episodes interventions Incontinence episodes/week incontinence pads used, and Not reported A3 - Were groups UK Not reported the number of laundry loads. comparable at baseline - Subjects were also asked to Continence status Yes - No apparent Study type Urgency episodes/week record the volume at each (zero episodes per differences between Not reported void for 3 of the 7 days. day) groups at baseline Randomized controlled trial reported as no UI Level of bias: Low Detrusor overactivity - n/N (%) episodes (of those Aim of the study TOL ER: 81/165 (49.1%) Power calculation incontinent at B Performance bias PLA: 73/142 (51.4%) baseline) B1 - Did groups get To determine whether The study was designed with TOL ER: 41/96 same level of care - Yes patients with OAB manifest Duration of OAB 90% power to detect any (42.7%) B2 - Were participants different treatment Not reported difference in treatment by PLA: 26/73 blinded - Yes - Study responses, dependent on outcome interaction (35.6%) was double-blind and whether a urodynamics study assuming that the interaction double-dummy had demonstrated detrusor Inclusion criteria effect was 30 ml (standard Incontinence- B3 - Were clinical staff overactivity deviation [SD], 40 ml) at a specific quality of blinded - Yes 1] aged ≥ 18 years 5% level of significance (two- life Level of bias: Low 2] urinary frequency (defined as an tailed test). With an expected Not reported Study dates average of ≥ 8 voids/24 h, discontinuation rate of 20%, C Attrition bias measured over a 7-day period) it was calculated that 450 Adverse effects C1 - Was follow-up equal Not reported and urgency (with or without UUI) subjects would have to be Any adverse effect for both groups - Yes 3] symptoms of OAB for ≥ 6 recruited to the study. TOL ER: 88/165 C2 - Were groups Source of funding months with no significant stress (53%) comparable for dropout - UI PLA: 67/142 Yes Sponsored by Pharmacia 4] Female subjects were required Intention to treat analysis (47%) C3 - Were groups (now Pfizer) to use a medically accepted form comparable for missing of contraception for the duration of Last observation carried Dry mouth data - Yes the study. forward (LOCF) was used. Not reported Level of bias: Low

Dropouts for any D Detection bias Exclusion criteria reason D1 - Was follow-up DAR: 21/165 appropriate length - Yes 1] significant hepatic or renal (12.7%) D2 - Were outcomes

462

Study details Participants Interventions Methods Outcomes and Comments Results

disease PLA: 19/142 defined precisely - Yes 2] symptomatic UTI (13.4%) D3 - Was a valid and 3] diagnosed interstitial cystitis reliable methods used to 4] un-investigated haematuria Dropouts for assess outcome - Yes 5] clinically significant bladder adverse effects D4 - Were investigators outlet obstruction DAR: 7/165 (4.2%) blinded to intervention - 6] receiving anticholinergic drugs PLA: 2/142 (1.4%) Yes or other treatments for OAB in the D5 - Were investigators 14 days before randomization Psychological blinded to confounding 7] known hypersensitivity to outcomes factors - Unclear tolterodine-ER or any of its Not reported Level of bias: Low excipients 8] receiving oral cytochrome P450 Clinical outcomes 3A4 inhibitors (e.g. macrolide Not reported Indirectness antibiotics) 9] had received electrostimulation Does the study match or bladder retraining in the 3 the protocol in terms of: months before randomization. 1] Population: Yes 2] Interventions: Yes 3] Outcome: Yes Indirectness: None

Other information

Data on continence status and discontinuation for any reason only used in network meta-analysis

Full citation Sample size Interventions Details Results Limitations

Minassian,V.A., Ross,S., N = 72 Oxybutynin XL 5mg once- Interventions were given for Week 4 NICE guidelines manual. Sumabat,O., Lovatsis,D., daily 12 weeks No data reported Appendix D: Pascali,D., Al-Badr,A., Oxybutynin XL = 39 A medical history was taken Methodology checklist: Alarab,M., Drutz,H.P., Oxybutynin IR = 33 Oxybutynin IR 2.5 mg three from all patients. Week 12 Randomised controlled

463

Study details Participants Interventions Methods Outcomes and Comments Results

Randomized trial of times a day Patient satisfaction trials oxybutynin extended versus A focused physical and with treatment immediate release for women Characteristics pelvic examination was Not reported aged 65 and older with performed that included overactive bladder: lessons Gender - Female/N (% female) testing the patient lying and Self reported rate learned from conducting a OXY XL: 39/39 (100%) standing for stress of absolute A Selection bias trial, Journal of Obstetrics OXY IR: 33/33 (100%) incontinence and staging of symptom A1 - Was there and Gynaecology Canada: concurrent pelvic organ reduction per day appropriate JOGC, 29, 726-732, 2007 prolapse. Uroflowmetry and Episodes of randomisation - Yes - Age - Mean ± SD measurement of post-void incontinence / day central telephone Ref Id OXY XL:75 ± 6 years residual bladder volume by - Mean ± SD randomisation service OXY IR:73 ± 5 years ultrasound were performed. Not reported A2 - Was there adequate 100357 Patients witha urinary tract concealment - Yes - Incontinence episodes/ day Mean infection were treated with a Episodes of central randomisation to Country/ies where the ± SD one-week course of urgency reduce bias by conealing study was carried out Not reported antibiotics prior to enrolment Not reported allocation in the study. A3 - Were groups Canada Urgency episodes/ day Mean ± SD Continence status comparable at baseline - Not reported Patients were randomised to Incontinence Yes - No apparent Study type either oxybutynin XL 5 mg episodes differences between Detrusor overactivity -n/N (%) once-daily or oxybutynin IR Not reported groups at baseline Randomised controlled trial Not reported 2.5 mg three times a day for Level of bias: Low 12 weeks. Urgency episodes Aim of the study Duration of OAB - Mean ± SD Not reported Not reported Drug dosage was increased, "To investigate whether the in non-responders, after four Incontinence- once daily administration of B Performance bias weeks of treatment to 10mg specific quality of B1 - Did groups get oxybutynin XL is more Inclusion criteria in the oxybutynin XL group life effective than the three times same level of care - Yes and 5mg three times a day in Scale used - U- B2 - Were participants per day administration of 1] female the oxybutynin IR group for UDI - Mean ± SD - blinded - Unclear - Not oxybutynin IR in reducing 2] over 65 years old the remainder of the trial. Endpoint week 12 reported symptoms of OAB, including 3] symptoms of OAB including OXY XL: 2.1 ± 1.0 B3 - Were clinical staff urgency, frequency, and urgency, frequency and nocturia n = 37 blinded - Unclear - Not nocturia with or without urge (as defined by the International Power calculation OXY IR: 1.7 ± 1.0 reported incontinence, in a community- Continence Society) n = 28 Level of bias: Unclear dwelling female population 4] experiencing mixed symptoms A sample of 120 subjects (60 over the age of 65." of OAB and stress urinary per group) was needed for Adverse effects incontinence, with the former being 80% power to detect a Any adverse effect the main presenting symptom difference fo 1.5 in the OXY XL: 19/39

464

Study details Participants Interventions Methods Outcomes and Comments Results

Study dates 5] able to give written informed number of micturitions per 24 (48.7%) consent hours at a two-tailed alpha OXY IR: 16/33 C Attrition bias February 2003 to December level of 5%, a sample of 120 (48.5%) C1 - Was follow-up equal 2005 subjects (60 per group) was for both groups - Yes Exclusion criteria needed. Allowing for a drop- Dry mouth C2 - Were groups Source of funding out rate of 10%, the OXY XL: 14/39 comparable for dropout - 1] bedridden estimated sample required (35.9%) Yes Study was supported by a 2] permanent indwelling catheter was 132 (66 per group) OXY IR: 16/33 C3 - Were groups grant from Janssen-Ortho 3] MMSE score < 24 (48.5%) comparable for missing Inc. 4] incontinence due to causes data - Yes

other than predominant urge Intention to treat analysis Dropouts for any Level of bias: Low incontinence reason 5] evidence of glaucoma, gastric Analysis of data was OXY XL: 13/39 retention or bowel obstruction conducted by "intent to treat" (33.3%) 6] history of allergy to oxybutynin OXY IR: 16/33 or anticholinergic drugs (48.5%) D Detection bias 7] taking antidepressants or D1 - Was follow-up anticholinesterase inhibitors Dropouts for appropriate length - Yes 8] post-void residual bladder vol. of adverse effects: D2 - Were outcomes more than 100mL OXY XL: 12/39 defined precisely - Yes 9] history of neurologic disorder, (30.8%) D3 - Was a valid and e.g. multiple sclerosis, spinal cord OXY IR: 13/33 reliable methods used to injury or demyelinating disorder. (39.4%) assess outcome - Yes D4 - Were investigators Psychological blinded to intervention - outcomes Unclear Not reported D5 - Were investigators blinded to confounding Clinical measures factors - Unclear Post-void residual Level of bias: Low volume Not reported

Indirectness

Does the study match the protocol in terms of: 1] Population: Yes

465

Study details Participants Interventions Methods Outcomes and Comments Results

2] Intervention: Yes 3: Outcomes: Yes Indirectness: None

Other information

Study stopped recuitment early due to difficulty in recruitment

Full citation Sample size Interventions Details Results Limitations

Nitti,V.W., Dmochowski,R., N = 836 Participants were randomised Participants completed a 3- Week 4 NICE guidelines manual. Sand,P.K., Forst,H.T., Haag- to either fesoterdine 4mg, day bladder diary before Not reported Appendix D: Molkenteller,C., Massow,U., Fesoterodine 4mg (FES 4) = 283 fesoterodine 8mg or matching ransomisation, and 2, 8 and Methodology checklist: Wang,J., Brodsky,M., Fesoterodine 8mg (FES 8) = 279 placebo 12 weeks after starting Week 12 Randomised controlled Bavendam,T., Efficacy, safety Placebo (PLA) = 274 treatment Patient satisfaction trials and tolerability of with treatment fesoterodine for overactive Voided volumes were defined as A Selection bias bladder syndrome, Journal of Characteristics recorded on 1 on the 3 days improved from 4 A1 - Was there Urology, 178, 2488-2494, point treatment appropriate 2007 Gender - Female, n/N (%) Treatment response was benefit scale randomisation - Yes - FES 4: 213/282(76%) assessed using a self- FES 4: 171/283 computer generated Ref Id FES 8: 218/279 (78%) administered treatment (60%) A2 - Was there adequate PLA: 200/271 (74%) benefit scale FES 8: 198/279 concealment - Unclear - 100367 (71%) not reported Age (years). Mean (range) PLA: 120/274 A3 - Were groups Country/ies where the FES 4: 59 (21 - 85) Power calculation (44%) comparable at baseline - study was carried out FES 8: 59 (23 - 91) Yes - No apparent PLA: 59 (24 - 88) Not reported Self reported rate differences between United States of absolute groups at baseline Incontinence episodes / day - symptom Level of bias: Low Study type Mean ± SD Intention to treat analysis reduction per day Not reported reported as Mean B Performance bias Randomised controlled trial Not reported ± SD change from B1 - Did groups get Urgency episodes / day Mean ± baseline same level of care - Yes

466

Study details Participants Interventions Methods Outcomes and Comments Results

Aim of the study SD Incontinence B2 - Were participants Not reported episodes blinded - Yes - Study To evaluate the efficacy, FES 4: -1.65 ± was double-blindB3 - safety and tolerability of 4mg Detrusor overactivity 2.42 N = 228 Were clinical staff and 8mg fesoterodine for Not reported FES 8: -2.28 ± blinded - Yes OAB 2.36 N = 218 Level of bias: Low OAB duration (years) Mean ± SD PLA: -0.96 ± 2.43 FES 4: 9.1 ± 10.3 N = 205 C Attrition bias Study dates FES 8: 10.1 ± 11.5 C1 - Was follow-up equal PLA: 9.8 ± 10.3 Urgency episodes for both groups - Yes October 20 2003 to February FES 4: -1.91 ± C2 - Were groups 10 2005 3.27 N = 267 comparable for dropout - Inclusion criteria FES 8: -2.3 ± 3.27 Yes Source of funding N = 267 C3 - Were groups 1] aged > 18 with OAB symptoms PLA: -0.79 ± 2.86 comparable for missing Supported by Schwarz for at least 6 months N = 205 data - Yes BioSciences GmbH abd 2] at least 8 micturitions per day, at Level of bias: Low Pfizer, Inc. least 6 urinary urgency episodes Continence status per day or 3 UUI epsiodes per day Incontinence D Detection bias episodes D1 - Was follow-up Not reported appropriate length - Yes Exclusion criteria D2 - Were outcomes Urgency episodes defined precisely - Yes 1] lower urinary tract pathology Not reported D3 - Was a valid and that could cause urgency or reliable methods used to incontinence Incontinence- assess outcome - Yes 2] pelvic organ prolapse grade III specific quality of D4 - Were investigators or greater life blinded to intervention - 3] clinically relevant bladder outlet Not reported Yes obstruction D5 - Were investigators 4] PVR volume greater than 100ml Adverse effects blinded to confounding 5] polyuria Any adverse effect factors - Unclear 6] symptomatic or recurrent urinary FES 4: 171/283 Level of bias: Low tract infections (60%) 7] current treatment with FES 8: 193/279 antimuscarinic drugs (69%)) Indirectness 8] a neurogenic cause for OAB PLA: 149/274 9] clinically relevant arrhythmia, (55%) Does the study match unstable angina or a corrected QT the review protocol in

467

Study details Participants Interventions Methods Outcomes and Comments Results

interval (Bazett's formula) of Dry mouth terms of greater than 500 milliseconds FES 4: 45/283 Population: Yes 10] current treatment or within 4 (16%) Intervention: Yes weekks with electrostimulation or FES 8: 99/279 Outcomes: Yes baldder training (36%) Indirectness: None PLA: 19/274 (7%)

Dropout for any Other information reason FES 4: 60/283 N/A (21%) FES 8: 57/279 (20%) PLA: 42/274 (15%)

Dropout for adverse event FES 4: 17/283 (6%) FES 8: 25/279 (9%) PLA: 11/274 (4%)

Psychological outcomes Not reported

Clinical outcomes Not reported

Full citation Sample size Interventions Details Results Limitations

Rackley,R., Weiss,J.P., N = 850 After a 2-week placebo run-in 7-day bladder diaries were Week 4 NICE guidelines manual. Rovner,E.S., Wang,J.T., period, eligible patients were completed for studies visists Not reported Appendix D: Guan,Z., Study Group., Tolterodine extended release (TOL given TOL 2R (4mg qd) or at baseline and weeks 4 and Methodology checklist: Nighttime dosing with ER) = 429 PLA to be taken 4 hours or 12 Week 12 Randomised controlled

468

Study details Participants Interventions Methods Outcomes and Comments Results tolterodine reduces Placebo (PLA) = 421 less before bedtime. Patient satisfaction trials overactive bladder-related with treatment nocturnal micturitions in Power calculation TOL ER: 231/429 A Selection bias patients with overactive Characteristics (54%) A1 - Was there bladder and nocturia, To detect a difference of 7% PLA: 183/421 appropriate Urology, 67, 731-736, 2006 Gender - Female/N (% female) nighttime micturitions (43%) randomisation - Unclear - TOL ER: 223/429 (52%) compared with placebo, 722 not reported Ref Id PLA: 211/421 (50%) patients (361 per grou) would Self-reported rate A2 - Was there adequate be needed to reject the null of absolute concealment - Unclear - 100392 hypothesis at a significance symptom not reported Age (years) - Mean ± SD level of 5% with a power of reduction per day A3 - Were groups Country/ies where the TOL ER: 59 ± 14 80%. Incontinence comparable at baseline - study was carried out PLA: 58 ± 14 episodes Yes - No apparent Not reported differences between United States Urge incontinence episodes/week Intention to treat analysis groups at baseline - Mean ± SD Urgency episodes Level of bias: Low Study type TOL ER: 5.04 ± 11.27 Last observation carried Not reportyed PLA: 4.13 ± 11.06 forward (LOCF) was used. B Performance bias Randomized controlled trial Continence status B1 - Did groups get Urgency episodes/day (zero episodes per same level of care - Yes Aim of the study Not report day) B2 - Were participants Incontinence blinded - Yes - Study To eveluate the efficacy and Detrusor overactivity episodes was double-blind tolerability of nighttime Not reported Not reported B3 - Were clinical staff tolterodine extended release blinded - Yes dosing on urgency and Urgency episodes Level of bias: Low urgency-related micturition in Duration of OAB Not reported patients with OAB and Not reported C Attrition bias nocturia Incontinence- C1 - Was follow-up equal specific quality of for both groups - Yes Inclusion criteria life C2 - Were groups Study dates Not reported comparable for dropout - 1] aged 18 or over Yes Not reported 2] OAB symptoms (8 or more Adverse effects C3 - Were groups micturitions/day and urgency with Any adverse effect comparable for missing Source of funding or without UUI) TOL ER: 47/429 data - Yes 3] nocturia (mean of 2.5 or more (11%) Level of bias: Low Not reported episodes per night) PLA: 25/421 (6%) 4] mean voided volume of D Detection bias

469

Study details Participants Interventions Methods Outcomes and Comments Results

200ml/micturition or less Dry mouth D1 - Was follow-up 5] mean nighttime voided volume TOL ER: 39/429 appropriate length - Yes of less that 40% of total voided (9%) D2 - Were outcomes volume PLA: 8/421 (2%) defined precisely - Yes D3 - Was a valid and Dropouts for any reliable methods used to Exclusion criteria reason assess outcome - Yes TOL ER: 56/429 D4 - Were investigators 1] significant stress urinary (13.1%) blinded to intervention - incontinence PLA: 63/421 Unclear 2] postvoid residual volume (15.0%) D5 - Were investigators greater than 200ml blinded to confounding 3] maximum flow rate of less tha Dropouts for factors - Unclear 20ml/s adverse effects Level of bias: Low 4] 24 hour urine volume greater TOL ER: 4/429 than 3000ml (0.9%) PLA: 17/421 Indirectness (4.0%) Does the study match Psychological the review protocol in outcomes terms of: Not reported Population: Yes Intervention: Yes Clinical measures Outcome: Yes Not reported Indirectness: None

Other information

Data on Dropouts for any reason used in network meta-analysis

Full citation Sample size Interventions Details Results Limitations

Rogers,R., Bachmann,G., N = 413 TOL ER (4mg) or PLA was 5-day bladder diaries were Week 4 NICE guidelines manual. Jumadilova,Z., Sun,F., Tolterodine extended release (TOL given once daily within 4 completed at baseline and at No data reported Appendix D:

470

Study details Participants Interventions Methods Outcomes and Comments Results

Morrow,J.D., Guan,Z., ER) = 202 hours of bedtime for 12 week 12 to record time of Methodology checklist: Bavendam,T., Efficacy of Placebo (PLA) = 211 weeks each micturition and Week 12 Randomised controlled tolterodine on overactive incontinence pad usage. Patient satisfaction trials bladder symptoms and with treatment* sexual and emotional quality Characteristics TOL ER: 139/202 A Selection bias of life in sexually active Power calculation (68.8%) A1 - Was there women, International Gender - Female/N (% female) PLA: 110/211 appropriate Urogynecology Journal, 19, TOL ER: 202/202 (100%) The sample size was (52.1%) randomisation - Unclear - 1551-1557, 2008 PLA: 211/211 (100%) determined based on a not reported projected treatment Self reported rate A2 - Was there adequate Ref Id difference of 1.02 in the of absolute concealment - Unclear Age (years) - Mean ± SD number of UUI episodes. symptom A3 - Were groups 100403 TOL ER: 49 ± 12 Using a two-tailed alpha level reduction per day comparable at baseline - PLA: 47 ± 12 of 0.05 and 80% power to Incontinence Yes - No apparent Country/ies where the detect this difference 174 episodes / day - differences between study was carried out Incontinence episodes/day - Mean subjects were required for LS Mean ± SD groups at baseline ± SD each treatment group. Change from Level of bias: Low United States TOL ER: 2.5 ± 2.1 Assuming a 15% dropuout baseline PLA: 2.2 ± 1.8 rate 400 subjects were to be TOL ER: -1.8 ± B Performance bias Study type randomized. 1.37 N = 189 B1 - Did groups get Urgency episodes/day PLA: -1.4 ± 1.35 N same level of care - Yes Randomized controlled trial Not reported = 182 B2 - Were participants Intention to treat analysis blinded - Yes - Study Aim of the study Detrusor overactivity - n/N (%) Urgency episodes was double-blind Not reported Last observation carried Not reported B3 - Were clinical staff To evaluate the efficacy of forward (LOCF) was used. blinded - Yes tolterodine ER in treating Duration of OAB - Mean ± SD Continence status Level of bias: Low OAB symptoms in sexually- TOL ER: 6 ± 8 Incontinence active women with OAB and PLA: 5 ± 6.5 episodes C Attrition bias UUI TOL ER: 93/202 C1 - Was follow-up equal (46.0%) for both groups - Yes Inclusion criteria PLA: 70/211 C2 - Were groups Study dates (33.2%) comparable for dropout - 1] female outpatients aged 18 or Yes Not reported more Urgency episodes C3 - Were groups 2] mean of 8 or more Not reported comparable for missing Source of funding micturitions/day data - Yes 3] 0.6 or more UUI episodes/day Incontinence- Level of bias: Low Study was funded by Pfizer. 4] 3 or more OAB micturitions specific quality of

471

Study details Participants Interventions Methods Outcomes and Comments Results

Inc (associated with moderate or life D Detection bias severe urgency or UUI)/day IIQ scale used - D1 - Was follow-up 5] reporte at leazst some moderate mean change from appropriate length - Yes problems on Patient Perception of baseline D2 - Were outcomes Bladder Condition Questionnaire TOL ER: -71.6 ± defined precisely - Yes 6] in a stable, sexually active 78.3 N = 182 D3 - Was a valid and relationship with a male partner for PLA: -59.2 ± 77.0 reliable methods used to 6 or more months N = 189 assess outcome - Yes 7] OAB symptoms for 3 or more D4 - Were investigators months Adverse effects blinded to intervention - Any adverse event Unclear TOL ER: 114/202 D5 - Were investigators Exclusion criteria (56.7%) blinded to confounding PLA: 111/211 factors - Unclear 1] stage 3 or greater pelvic organ (52.9%) Level of bias: Low prolapse 2] history of lower urinary tract Dry mouth surgery TOL ER: 26/202 Indirectness 3] lifelong sexual dysfucntion (12.9%) unrelated to lifelong UUI PLA: 19/211 Does the study match 4] predominant stress urinary (9.0%) the review protocol in incontinence terms of: Dropouts for any Population: Yes reason Intervention: Yes TOL ER: 38/202 Outcomes: Yes (18.9%) Indirectness: None PLA: 43/211 (20.4%) Other information Dropouts for adverse effects Data on Continence TOL ER: 9/202 status and Dropouts for (4.5%) any reason used in PLA: 6/211 (2.9%) network meta-analysis

Psychological Satisfaction data taken outcomes from secondary Not reported publication "Rogers et al., 2009"

472

Study details Participants Interventions Methods Outcomes and Comments Results

Clinical measures Not reported SD for IIQ change from baseline scores calculated from the reported SEM

Full citation Sample size Interventions Details Results Limitations

Rudy,D., Cline,K., Harris,R., N = 658 Patients who met the Patient urinary diaries were Week 4 NICE guidelines manual. Goldberg,K., Dmochowski,R., inclusion criteria at baseline completed for 7 days prior to Patient satisfaction Appendix D: Multicenter phase III trial Trospium (TRO) = 329 were randomised to either each study visit at 1 wee, 4 with treatment Methodology checklist: studying trospium chloride in Placebo (PLA) = 329 Trospium chloride 20mg twice weeks and 12 weeks. Not reported Randomised controlled patients with overactive daily or placebo for 12 weeks. trials bladder, Urology, 67, 275- Primary outcomes was Self-reported rate 280, 2006 Characteristics number of toilet voids in 24 of absolute A Selection bias hours symptom A1 - Was there Ref Id Gender - Female/N (% female) reduction per day appropriate TRO: 267/329 (81.2%) Incontinence randomisation - Unclear - 100414 PLA: 269/329 (81.8%) Power calculation episodes not reported TRO: -1.71 (No A2 - Was there adequate Country/ies where the Age (years) - Mean ± SE Sample size was determined SD) N = 323 concealment - Unclear - study was carried out DAR: 61.1 ± 0.69 on the basis for two efficacy PLA: -1.14 (No not reported PLA: 61.0 ± 0.70 outcomes; change in number SD) N = 325 A3 - Were groups United States of voids per day and in urge comparable at baseline - Incontinence episodes/week - urinary incontinence per day, Urgency episodes Yes - No apparent Study type Median assuming 90% power and Not reported differences between TRO: 2.86 (No range reported) 80% power respectively. groups at baseline Randomise controlled trial PLA: 2.86 (No range reported) Patients lost to follow-up Continence status Level of bias: Low during the study were not (zero episodes per Aim of the study Urgency episodes/day replaced. day) B Performance bias Not reported Incontinence B1 - Did groups get To examine the effect of episodes same level of care - Yes trospium chloride 20mg twice Detrusor overactivity - n/N (%) Intention to treat analysis Not reported B2 - Were participants daily as treatment for urinary Not reported blinded - Yes - Study frequency and other related Last observation carried Urgency episodes was double-blind symptoms in patients with Duration of OAB - Mean ± SD forward (LOCF) used Not reported B3 - Were clinical staff OAB. Not reported blinded - Yes

473

Study details Participants Interventions Methods Outcomes and Comments Results

Incontinence- Level of bias: Low specific quality of Study dates Inclusion criteria life C Attrition bias Not reported C1 - Was follow-up equal Not reported 1] 18 years or older for both groups - Yes 2] OAB symptoms for at least 6 Adverse effects C2 - Were groups Source of funding months Any adverse effect comparable for dropout - 3] minimal urinary frequency of 10 Not reported Yes Funded by Indevus or more toilet voids per day C3 - Were groups Pharmaceuticals, Inc 4] symptoms or urgency (at least 1 Dry mouth comparable for missing 'mild', 'moderate' or 'severe' Not reported data - Yes severity rating on patient diary) Level of bias: Low 5] at least 7 urge urinary Dropouts for any incontinence episodes per week reason D Detection bias Not reported D1 - Was follow-up appropriate length - Yes Exclusion criteria Dropouts for D2 - Were outcomes adverse effects defined precisely - Yes 1] predominantly stress, insensate Not reported D3 - Was a valid and or overflow in nature reliable methods used to 2] neurogenic bladder disorders Psychological assess outcome - Yes 3] significant renal disease outcomes D4 - Were investigators 4] uninvestigated hematuria Not reported blinded to intervention - 5] urinary tract infection at washout Yes or more tha twice during the first Clinical measures D5 - Were investigators year - Post-void blinded to confounding 6] significant bladder outlet residual volume factors - Unclear obstruction (postvoid residual Not reported Level of bias: Low volume > 100ml) in clinical opinion of trial investiagtor Week 12 7] concurrent use of any Patient satisfaction Indirectness anticholinergic or other drug with treatment for OAB with 21 days of strat of Not reported Does the study match study the protocol in terms of: 8] bladder surgery with 6 months Self-reported rate 1] Population: Yes 9] cancer or institial cystitis of absolute 2] Interventions: Yes 10] men with a prostate antigen symptom 3] Outcome: Yes level of 10ng/ml or great11] reduction per day Indirectness: None diuretic use Incontinence

474

Study details Participants Interventions Methods Outcomes and Comments Results

11] estrogen therapy episodes - Median 12] non-medical bladder therpay change from as part of a long-standing baseline Other information treatment program TRO: -1.86 (No 13] pregnancy SD) N = 323 All data used in review 14] other contraindiction to PLA: -1.29 (No antimuscarinic therapy SD) N = 325

Urgency episodes Not reported

Continence status (zero episodes per day) Not reported

Incontinence- specific quality of life Not reported

Adverse effects Any adverse effect TRO: 196/329 (59.6%) PLA: 153/329 (46.5)

Dry mouth TRO: 65/329 (19.8%) PLA: 17/329 (5.2%)

Dropouts for any reason TRO: 42/329 (8.3%) PLA: 32/329

475

Study details Participants Interventions Methods Outcomes and Comments Results

(12.7%)

Dropouts for adverse effects TRO: 25/329 (4.5%) PLA: 16/329 (6.7%)

Psychological outcomes Not reported

Clinical measures - Post-void residual volume Not reported

Full citation Sample size Interventions Details Results Limitations

Staskin,D., Sand,P., N = 601 TRO ER (60mg) or matching Patricipants underwent a 7- Week 4 NICE guidelines manual. Zinner,N., Dmochowski,R., PLA was given once daily for day washout period before Patient satisfaction Appendix D: Trospium Study Group., Trospium extended release (TRO 12 weeks completing a written bladder with treatment Methodology checklist: Once daily trospium chloride ER) = 298 diary for 3 days. Eligible Not reported Randomised controlled is effective and well tolerated Placebo (PLA) = 303 patients were the trials for the treatment of randomized by stratification Self-reported rate overactive bladder: results by average baseline daily of absolute A Selection bias from a multicenter phase III Characteristics urinary frequency. 3 day symptoms A1 - Was there trial, Journal of Urology, 178, bladder diaries were reduction/day - appropriate 978-983, 2007 Gender - Female/N (% female) completed before each study Mean ± SD randomisation - Unclear - TRO ER: 254/296 (85.2%) visit at weeks 1, 4 and 12. UUI episodes - not reported Ref Id PLA: 256/303 (84.5%) Diaries and drug change from A2 - Was there adequate accountabiility were reviewed baseline reported concealment - Unclear - 100455 Age (years) - Mean ± SE at each visit and adverse TRO ER: -2.36 ± not reported TRO ER: 59.6 ± 0.77 effects were logged and 2.22 N = 292 A3 - Were groups Country/ies where the PLA: 59.3 ± 0.70 assessed. PLA: -1.75 ± 2.25 comparable at baseline - N = 300 Yes - No apparent

476

Study details Participants Interventions Methods Outcomes and Comments Results study was carried out Number of incontinence differences between episodes/day Urgency episodes groups at baseline United States Not reported Power calculation Not reported Level of bias: Low

Study type Urgency episodes A sample size of 300 in each Continence status B Performance bias Not reported arm was required to provide (Zero episodes per B1 - Did groups get Randomized controlled trial sufficient statistical power day) same level of care - Yes Detrusor overactivity based on the co-primary Incontinence B2 - Were participants Aim of the study Not reported efficacy outcomes with the episodes blinded - Yes - Study primary timepoint for analysis Not reported was double-blind To evaluate the effects of Duration of OAB at week 12. B3 - Were clinical staff trospium chloride (6omg qd) Not reported Urgency episodes blinded - Yes capsules compared with Not reported Level of bias: Low placebo in subjects iwth OAB Intention to treat analysis with predominant UUI Inclusion criteria Incontinence- C Attrition bias Last observation carried specific quality of C1 - Was follow-up equal 1] mean and women 18 years and forward (LOCF) was used life - Mean ± SD for both groups - Yes Study dates older with symptoms of OAV for 6 consisting of data recorded Scale used = C2 - Were groups months or greater or carried forwrad at each OAB-SCS - comparable for dropout - August 2005 to May 2006 2] symptoms of urgency (at least 1 visit. change from Yes 'severe' urgency severity rating per baseline C3 - Were groups Source of funding 3 days as measured using Indevus TRO ER: -9.67 ± comparable for missing Urgency Severity Scale) 9.57 N = 292 data - Yes Supported by Esprit Pharma 3] minimum urgency frequency of PLA: -6.13 ± 11.10 Level of bias: Low and Indevus Pharaceuticals 30 or greater toliet voids per 3 N = 300 days with an average of 1 or D Detection bias greater UUI episode/day Adverse effects D1 - Was follow-up 4] average total volume voided Not reported appropriate length - Yes 3000ml or less per day and 250ml D2 - Were outcomes or less per void Psychological defined precisely - Yes outcomes D3 - Was a valid and Not reported reliable methods used to Exclusion criteria assess outcome - Yes Clinical measures D4 - Were investigators 1] stress, insensate or overflow Not reported blinded to intervention - incontinence Unclear 2] neurogenic bladder disorder Week 12 D5 - Were investigators 3] significant renal disease Patient satisfaction blinded to confounding 4] uninvestiagted hematuria with treatment factors - Unclear

477

Study details Participants Interventions Methods Outcomes and Comments Results

5] urinary tract infection at Not reported Level of bias: Low washout, or greater urinary tract infections requiring treatment Self-reported rate during the previous year of absolute Indirectness 6] significant bladder outlet symptoms obstruction (defined as postvoid reduction/day - Does the study match residual urine volume greater than Mean ± SD the protocol in terms of: 100ml) or an indwelling catheter UUI episodes - 1] Population: Yes 7] active inflammatory bowel change from 2] Interventions: Yes disease baseline reported 3] Outcome: Yes 8] diagnosis of interstitial cystitis or TRO ER: -2.48 ± Indirectness: None bladder cancer with the past 6 2.9 N = 292 months PLA: -1.93 ± 2.8 N 9] males with prostate specific = 300 Other information antigen 4ng/ml or greater, prostate cancer or chronic prostatis Urgency episodes Data on continence 10] subjects undergoing/likely to Not reported status and dropouts for undergo bladder retraining or a any reason only used in bladder drill program Continence status network meta-analysis 11] diuretic estrogen use outside (Zero episodes per of a long-term stable program day) Incontinenec episodes TRO ER: 54/298 (18.1%) PLA: 31/303 (10.3%)

Urgency episodes Not reported

Incontinence- specific quality of life Scale used = OAB-SCS - change from baseline TRO ER: -11.2 ±

478

Study details Participants Interventions Methods Outcomes and Comments Results

9.4 N = 292 PLA: -7.8 ± 11.6 N = 300

Adverse effects Any adverse effect TRO ER: 80/298 (26.8%) PLA: 53/303 (17.5%)

Dry mouth TRO ER: 28/298 (8.7%) PLA: 9/303 (3.0%)

Dropout for any reason TRO ER: 35/298 (11.7%) PLA: 30/303 (9.9%)

Dropouts for adverse effects TRO ER: 12/298 (4.0%) PLA: 11/303 (3.6%)

Psychological outcomes Not reported

Clinical measures Not reported

479

Study details Participants Interventions Methods Outcomes and Comments Results

Full citation Sample size Interventions Details Results Limitations

Staskin,D.R., N = 789 OXY TG (10% weight per Patients were instruced to Week 4 NICE guidelines manual. Dmochowski,R.R., Oxybutynin topical gel (OXY TG) = weight ethanol-based maintain a consistent level of Not reported Appendix D: Sand,P.K., MacDiarmid,S.A., 389 oxybutynin formulation) and fluid intake and Methodology checklist: Caramelli,K.E., Thomas,H., Placebo (PLA) = 400 matching PLA gel was initiate/maintain behavioral Week 12 Randomised controlled Hoel,G., Efficacy and safety applied (1gm) daily to rotating management for Patient satisfaction trials of oxybutynin chloride topical sites on the abdomen, upper incontinence during the with treatment gel for overactive bladder: a Characteristics arm pr shoulder and thigh screening period. Not reported A Selection bias randomized, double-blind, A1 - Was there placebo controlled, Gender - Female, n/N (%) A 2 week period between Self reported rate appropriate multicenter study, Journal of OXY TG: 352/389 (90.5%) visits 1 and 2 provided a of absolute randomisation - Unclear - Urology, 181, 1764-1772, PLA: 352/400 (88.0%) washout for patients on symptom Not reported 2009 antimuscarinics for OAB. At reduction per day A2 - Was there adequate Age (Years) - Mean ± SD visit 2 patients received Incontinence concealment - Unclear Ref Id OXY TG: 59.5 ± 12.5 training to distinguish episodes - change A3 - Were groups PLA: 59.3 ± 12.2 between urge and stress UI from baseline - comparable at baseline - 100463 epsiodes and to properly Mean ± SD Yes - No apparent complete the baldder diary OXY TG 3.9mg: - differences between Country/ies where the Urge Incontinence episodes / day - 3.0 ± 2.7 N = 389 groups at baseline study was carried out Mean ± SD PLA: -2.5 ± 3.1 N Level of bias: Some OXY TG: 5.4 ± 3.3 Power calculation = 400 United States PLA: 5.4 ± 3.3 B Performance bias A sample size of 700 equally Urgency episodes B1 - Did groups get Study type Urgency episodes / day Mean ± divided between groups ould Not reported same level of care - Yes SD be needed to provide 85% B2 - Were participants Randomized controlled trial Not reported power to detect a real Continence status blinded - Yes - Study difference with the two-tailed (zero episodes per was double-blind Aim of the study Detrusor overactivity t test and an α of 0.05. day) B3 - Were clinical staff Not reported Incontinence blinded - Yes To evaluate the efficacy and episodes Level of bias: Low safety of Oxybutynin topical OAB duration (Months) - Mean ± Intention to treat analysis OXY TG: 108/389 gel in adults with overactive SD (27.8%) C Attrition bias bladder OXY TG: 106.6 ± 121.6 MITT population included all PLA: 69/400 C1 - Was follow-up equal PLA: 97.4 ± 96.8 randomized patients who (17.3%) for both groups - Yes received 1 or more doses of C2 - Were groups Study dates study drug and provided data Urgency episodes comparable for dropout - Inclusion criteria for the baseline efficacy Not reported Yes assessent. C3 - Were groups

480

Study details Participants Interventions Methods Outcomes and Comments Results

June 2006 to May 2007 1] urge or mixed UI with a Incontinence- comparable for missing preponderance of urge UI specific quality of data - Yes Source of funding episodes life Level of bias: Low 2] mean of 8 or more urinary voids Not reported Supported by Watson per day D Detection bias Pharmaceuticals, Inc 3] 4 or more urge UI episodes per Adverse effects D1 - Was follow-up day Dropouts for any appropriate length - Yes 4] mean voided volume of 350ml reason D2 - Were outcomes or less during a 2 day urine OXY TG: 43/389 defined precisely - Yes collection period (11.1%) D3 - Was a valid and 5] PVR of 250ml or less on PLA: 45/400 reliable methods used to ultrasonography or catheterization (11.3%) assess outcome - Yes D4 - Were investigators Dropouts for blinded to intervention - Exclusion criteria adverse effects Unclear OXY TG: 19/389 D5 - Were investigators 1] pregnancy (4.9%) blinded to confounding 2] breast-feeding PLA: 13/400 factors - Unclear 3] inadequate brith-control by (3.3%) Level of bias: Low premenopausal women not using brith control Any adverse 4] Contraindication to oxybutynin effects Indirectness (uncontrolled narrow angle OXY TG: 221/389 glaucoma, gastic obstruction or (56.8%) Does the study match retention, known hypersensitivity PLA: 193/400 teh review protocol in to oxybutynin related compounds (48.3%) terms of: or any component of the gel Population: Yes 5] treatable condition that could Dry mouth Intervention: Yes cause urinary incontinence or OXY TG: 27/389 Outcomes: Yes urgency (acutre urinary tract (6.9%) Indirectness: None infection, prostatitis, hematuria, PLA: 11/400 urinary tract obstruction, urethral (2.8%) diverticulus, bladder tumor, Other information bladder stones, fecal impaction, Psychological conditions that require diyretic use) outcomes Data on continence 6] interstitial cystitis Not reported status and dropouts for 7] urethral syndrome any reason used in 8] painful bladder syndrome Clinical measures network meta-analysis 9] overflow incontinence - Post-void

481

Study details Participants Interventions Methods Outcomes and Comments Results

secondary to outlet obstruction or residual volume underactive detrusor Not reported 10] lower urinary tract surgery in previous 6 months 11] unstable diabetes mellitus 12] anticipated hormonal changes 13] recurrent urinary tract infections (more than 3 in previous year) 14] clinically significant systemic disease 15] abnormal baseline laboratory test result 16] concomitant medications that affect detrusor activity (antimuscarinics or tricyclic antidepressants) 17] prostate cancer or prostate specific antigen plasma concentration greater than 4ng/ml 18] active skin condition affecting treatment sites 19] excessive consumption of caffeinated beverages (more than 5 cups per day) 20] alcohol or drug use in the previous year 21] participation in another clinical trial in the previous 30 days 22] failure to complete baseline 3- day diary

Full citation Sample size Interventions Details Results Limitations

Yamaguchi,O., Marui,E., N = 1593 (9 subjetcs were non- Solifenacin 5mg Patients received placebo Week 4 NICE guidelines Kakizaki,H., Itoh,N., compliant so not included in group Solifenacin 10mg medication once daily during No data reported manual.Appendix D:

482

Study details Participants Interventions Methods Outcomes and Comments Results

Yokota,T., Okada,H., numbers) Propiverine 20mg a 2-week run-in period and Week 12 Methodology checklist: Ishizuka,O., Ozono,S., SOL 5mg = 398 Placebo were then randomised to one Patient satisfaction Randomised controlled Gotoh,M., Sugiyama,T., SOL 10mg = 381 of four treatment arms: with treatment trials Seki,N., Yoshida,M., PRO 20mg = 400 solifenacin 5mg, solifenacin Not reported Japanese Solifenacin Study PLA = 405 10mg, propiverine 20mg or A Selection bias Group., Randomized, double- placebo for 12 weeks after a Self reported rate A1 - Was there blind, placebo- and three-day diary were of absolute appropriate propiverine-controlled trial of Characteristics recorded symptom randomisation - Unclear - the once-daily antimuscarinic Patients were evaluated reduction per day Not reported agent solifenacin in Japanese Gender - Female/N (% female) every four weeks for the Incontinence A2 - Was there adequate patients with overactive SOL 5mg: 318/383 (83%) following variables: mean episodes - Mean ± concealment - Unclear - bladder, BJU International, SOL 10mg: 316/371 (85.7%) number of voids/24h, sd (Change Not reported 100, 579-587, 2007 PRO 20mg: 321/384 (83.6%) urgency incontinence scores) A3 - Were groups PLA: 333/395 (84.3%) episodes/24hr, urgency SOL 5mg: -1.60 ± comparable at baseline - Ref Id episodes, nocturia episodes, 1.81 n = 274 Yes - No apparent Age - Mean ± SD (range) volume voided per void, SOL 10mg: -1.59 differences between 100508 SOL 5mg: 60.4 ± 13.3 years incontinence episodes. ± 2.12 n = 270 groups at baseline SOL 10mg: 59.9 ± 13.0 years Safety assessments were PRO 20mg: -1.25 Level of bias: Unclear Country/ies where the PRO 20mg: 59.6 ± 13.6 years performed at weeks 4,8 and ± 2.79 n = 295 study was carried out PLA: 60.8 ± 12.5 years 12 and included physical PLA: -0.72 ± 1.95 Incontinence episodes/24hr Mean assessments and recording n = 283 B Performance bias Japan ± SD of adverse events. Vital signs Urgency episodes B1 - Did groups get SOL 5mg: 2.35 ± 2.45 and laboratory test SOL 5mg: -2.41 ± same level of care - Yes Study type SOL 10mg: 2.19 ± 2.04 results were assessed at 0, 4 2.88 n = 383 B2 - Were participants PRO 20mg: 2.15 ± 2.3 and 12 weeks. 12-lead ECG SOL 10mg: -2.78 blinded - Yes - Study Randomised controlled trial PLA: 1.99 ± 2.11 carried out during the run- ± 2.82 n = 371 was double-blind and Urgency episodes/24hr Mean ± period and at the end of the PRO 20mg: -2.30 double-dummy Aim of the study SD study. Patient quality of life ± 3.08 n = 384 B3 - Were clinical staff SOL 5mg: 4.40 ± 3.30 assessed at baseline end of PLA: -1.28 ± 2.90 blinded - Unclear - Not "To assess whether SOL 10mg: 4.42 ± 3.30 study. n = 395 reported soifenacin 5mg and 10mg PRO 20mg: 4.07 ± 3.19 Level of bias: Low once daily was comparable PLA: 4.04 ± 3.11 Continence status with placebo and propiverine Power calculation (Zero episodes per 20 mg once daily (the most Detrusor overactivity -n/N (%) day) commonly prescribed dose in Not reported "The required enrolment was Incontinence C Attrition bias Japan), respectively, in a Duration of OAB - Mean ± SD ≥350 patients per arm to episodes C1 - Was follow-up equal large population of Japanese Not reported detect superiority to placebo SOL 5mg: 154/274 for both groups - Yes patients with OAB" at a power of 90%, and the (56.2%) C2 - Were groups non-inferiority of solifenacin SOL 10mg:

483

Study details Participants Interventions Methods Outcomes and Comments Results

Inclusion criteria to propiverine 20 mg at a 161/270 (59.6%) comparable for dropout - power of 80%" PRO 20mg: Yes Study dates 1] adults ≥20 years old 165/295 (55.9%) C3 - Were groups 2] symptoms of OAB reported ≥6 PLA: 105/283 comparable for missing June 2003 to January 2004 months Intention to treat analysis (37.1%) data - Yes 3] mean number of voids ≥8/24hr Urgency episodes Level of bias: Low Source of funding 4] ≥3 episodes of urgency and/or "Efficacy data were SOL 5mg: 126/400 ≥3 episodes of urgency measured at week 12, and (31.5%) Astellas Pharma Inc (formerly incontinence during a 3-day the last-observation-carried- SOL 10mg: Yamanouchi Pharmaceutical voiding diary forward approach was used 138/385 (35.8%) Co, Ltd), Tokyo, Japan. to determine endpoint values PRO 20mg: D Detection bias if week 12 data were not 128/402 (31.8%) D1 - Was follow-up Exclusion criteria available." PLA: 82/406 appropriate length - Yes (20.2%) D2 - Were outcomes 1] significant bladder outlet defined precisely - Yes obstruction (assessment based on Incontinence- D3 - Was a valid and measuring the postvoid urine specific quality of reliable methods used to volume. life assess outcome - Yes 2] Patients with a PVR of ≥100mL Not reported D4 - Were investigators were excluded blinded to intervention - 3] symptoms of bladder outlet Adverse effects Unclear obstruction Any adverse effect D5 - Were investigators 4] urinary retention Not reported blinded to confounding 5] demonstrable stress Dry mouth factors - Unclear incontinence SOL 5mg: 67/400 Level of bias: Low 6] bladder stones (16.8%) 7] UTI SOL 10mg: 8] interstitial cystitis 130/385 (33.8%) 9] previous or current malignant PRO 20mg: Indirectness disease of the pelvic organs 103/402 (25.6%) 10] previous pelvic radiation PLA: 23/406 Does the study match 11] concomitant anticholinergic (5.7%) the protocol in terms of: medications Dropouts for any 1] Population: Yes 12] known of reason 2] Intervention: Yes suspected hypersensitivity to SOL 5mg: 34/400 3] Outcomes: Yes anticholinergic medications or (8.5%) Indirectness: None lactose SOL 10mg: 32/385 (8.3%) PRO 20mg:

484

Study details Participants Interventions Methods Outcomes and Comments Results

36/402 (9.0%) Other information PLA: 34/406 (8.4%) Dropouts for adverse effects SOL 5mg: 20/400 (5.0%) SOL 10mg: 26/385 (6.8%) PRO 20mg: 26/402 (6.5%) PLA: 11/406 (2.7%)

Psychological outcomes Not reported

Clinical measures - Post-void residual volume Not reported

Full citation Sample size Interventions Details Results Limitations

Zat'ura,F., Vsetica,J., N = 135 Participants were randomised Participants completed a Week 4 NICE guidelines manual. Abadias,M., Pavlik,I., in a proportion of 2:2:1 to bladder diary and underwent Not reported Appendix D: Schraml,P., Brod'ak,M., Cizolirtine (CIZ) = 34 cizolirtine 230 mg two times a baseline urodynamic Methodology checklist: Villoria,J., Sust,M., Study Oxybutynin immediate release per day (bid; given as 400 mg evaluation throughout the Week 12 Randomised controlled Group., Cizolirtine citrate is (OXY IR) = 27 bid of citrate salt), placebo last week prior to Patient satisfaction trials safe and effective for treating Placebo (PLA) = 54 three times per day (tid), or randomisation. with treatment urinary incontinence oxybutynin 5 mg tid, Not reported A Selection bias secondary to overactive respectively, took place after A 21-d wash-out period was A1 - Was there bladder: a phase 2 proof-of- Characteristics a 21-d run-in period. All kept by patients entering the Self-reported rate appropriate concept study, European treatments were given for 12 study following treatment of absolute randomisation - Yes - Urology, 57, 145-152, 2010 Gender - Female/N (% female) weeks. with any of the forbidden symptom based on random block CIZ: 50/54 (92.6%) drugs. reduction per day permutations

485

Study details Participants Interventions Methods Outcomes and Comments Results

Ref Id OXY IR: 22/27 (81.5%) Incontinence A2 - Was there adequate PLA: 53/54 (98.1%) After randomisation, visits episodes concealment - Yes - 100512 were done after 2, 4, 8, and CIZ: -1.2 ± 1.4 N = randomisation code kept Age (years) - Mean ± SD 12 wk. Shortly before the last 52 in sealed envelopes Country/ies where the CIZ: 51.9 ± 11.7 visit, the urodynamic OXY IR: -1.4 ± 1.8 A3 - Were groups study was carried out OXY IR: 54.7 ± 13.0 evaluation was repeated. N = 26 comparable at baseline - PLA: 50.2 ± 13.9 PLA: -0.6 ± 1.9 N Yes - No apparent Czech Republic = 54 differences between Incontinence episodes/day - Mean Power calculation groups at baseline Study type ± SD Urgency episodes Level of bias: Low CIZ: 1.6 ± 1.4 Based on previous studies, a CIZ: -5.2 ± 7.7 N = Randomized controlled trial OXY IR: 2.1 ± 2.0 sample size of 46 in each 52 B Performance bias PLA: 2.0 ± 2.0 group would provide an 80% OXY IR: -4.8 ± 4.0 B1 - Did groups get Aim of the study power to detect a between- N = 26 same level of care - Yes Urgency episodes/day - Median group difference in means of PLA: -2.2 ± 4.0 N B2 - Were participants To demonstrate the efficacy (range) 1.6 voidings per 24 h with a = 54 blinded - Yes - Study of cizolirtine by showing its Not reported common standard deviation was double-blind and superiority over placebo (SD) of 2.7 using a student t Continence status double-dummy Detrusor overactivity test at a 5% two-sided (zero episodes per B3 - Were clinical staff Not reported significance level. day) blinded - Yes Study dates Incontinence Level of bias: Low Duration of OAB episodes February 2002 to April 2003 Not reported Intention to treat analysis reported as C Attrition bias 'complete dryness' C1 - Was follow-up equal Source of funding Last observation carried CIZ: 25/54 for both groups - Yes Inclusion criteria forward (LOCF) was used to (46.3%) C2 - Were groups Laboratorios Doctor Esteve impute missing data. OXY IR: 17/27 comparable for dropout - S.A. sponsored the study 1] outpatients aged 18–80 yr with (63.0%) Yes a diagnosis of urinary incontinence PLA: 17/54 C3 - Were groups with urgency (31.5%) comparable for missing 2] idiopathic detrusor overactivity data - Yes confirmed by urodynamic study Urgency episodes Level of bias: Low 3] showing signs of lower urinary Not reported tract dysfunction (i.e. increased D Detection bias 24-h frequency [eight or more Incontinence- D1 - Was follow-up micturitions per 24 h] and/or urge specific quality of appropriate length - Yes incontinence [one incontinent life D2 - Were outcomes episode or more per 24 h] as Not reported defined precisely - Yes assessed by a bladder diary filled D3 - Was a valid and

486

Study details Participants Interventions Methods Outcomes and Comments Results

out throughout the week prior to Adverse effects reliable methods used to randomisation Any adverse effect assess outcome - Yes 4] present with detrusor CIS: 12/54 D4 - Were investigators overactivity (phasic, terminal, or (22.2%) blinded to intervention - both) and/or increased bladder OXY IR: 8/27 Yes sensation during filling cystometry (29.6%) D5 - Were investigators at a physiologic filling rate in the PLA: 5/54 (9.3%) blinded to confounding baseline urodynamic evaluation factors - Unclear performed for the study. Dry mouth Level of bias: Low CIZ: 6/54 (11.1%) OXY IR: 5/27 Exclusion criteria (18.5%) Indirectness PLA: 0/54 (0%) 1] evidence of a prevailing Does the study match obstructive component (maximum Dropouts for any the protocol in terms of: flow rate < 10 ml per second with a reason 1] Population: Yes postvoiding residual volume > 200 CIZ:15/54 (27.8%) 2] Interventions: Yes ml or chronic retention of urine) OXY IR: 3/27 3] Outcome: Yes 2] urodynamic stress incontinence (11.1%) Indirectness: None (involuntary leakage of urine PLA: 3/54 (5.6%) during increased abdominal pressure in the absence of Dropouts for Other information detrusor contraction) adverse effects 3] an average total voided volume CIZ:8/54 (14.8%) Data on continence > 3000 ml per 24 h OXY IR: 2/27 status and 4] obstructive conditions affecting (7.4%) discontinuation for any the urethra PLA: 0/54 (0%) reason for both OXY IR 5] prostatic diseases and PLA groups only 6] malignant hypertension Psychological used in network meta- 7] allergy or hypersensitivity to outcomes analysis study drugs or to structurally Not reported related drugs 8] history of recurrent bacterial Clinical measures cystitis, bladder pain, or urethral - Post-void pain on voiding; urinary tract residual volume infection within 1 wk prior to study Not reported enrolment; or any other clinically relevant disease which, in the opinion of the investigator, could

487

Study details Participants Interventions Methods Outcomes and Comments Results

interfere with the evaluation of the study drug. 9] pregnant or breast-feeding 10] receiving pharmacologic treatment for incontinence, diuretics, long-acting benzodiazepines, central or peripheral a-adrenergic agonists or antagonists, or changing doses (ie, dose adjustments expected during the study) of drugs with anticholinergic side effects 11] had undergone urogenital surgery within the prior 3 mo or who received concomitant conservative treatment for urinary incontinence (eg, vaginal cones, behavioural modification, intermittent urinary catheterisation).

Full citation Sample size Interventions Details Results Limitations

Cartwright,R., Srikrishna,S., N = 96 Oxybutynin transdermal was After recruitment, patients Week 4 NICE guidelines manual. Cardozo,L., Robinson,D., given in a matrix patch entered a 2-week unblinded Patient satisfaction Appendix D: Patient-selected goals in Oxybutynin Trensdermal (OXT TD) (functionally identical to EU placebo period. Those with treatment Methodology checklist: overactive bladder: a placebo = 48 and US licensed Kentera and already taking OAB Not reported Randomised controlled controlled randomized Placebo = 48 Oxytrol) medication stopped the trials double-blind trial of medication and completed all Self reported rate transdermal oxybutynin for Placebo was given in baseline assessments. of absolute A Selection bias the treatment of urgency and Characteristics matching patches Patients then entered the 4- symptom A1 - Was there urge incontinence, BJU week double-blind period and reduction per day appropriate International, 107, 70-76, Gender - Female, n/N (%) Both OXY TD and plaecbi further efficacy assessments Incontinence randomisation - Yes - 2011 OXY TD 3.9mg: 48/48 (100%) patches were stored in were carried out at the end of episodes true number method PLA: 48/48 (100%) identical sealed foil sachets this period. Safety OXY TD 3.9mg: - used that fully mainteined blinding assessments were carried 0.47 ± 0.81 N not A2 - Was there adequate

488

Study details Participants Interventions Methods Outcomes and Comments Results

Ref Id Age (Years) - Mean ± SD for both patients and out throughout the 6-week reported concealment - Yes - OXY TD 3.9mg: 53.1 ± 14.5 clinicians. Patients were study period. PLA: -0.23 ± 0.61 randomisation numbers 129148 PLA: 50.5 ± 13.7 instructed to apply patches N not reported served as packaging for twice weekly. Patches were interventions Country/ies where the applied to dry intact skin over Power calculation Urgency episodes A3 - Were groups study was carried out Urge Incontinence episodes / day - the abdomen, hip or buttock, OXY TD 3.9mg: - comparable at baseline - Mean ± SD immediately after removal A sample size of 74 was 1.23 ± 1.4 N not Yes - No apparent UK OXY TD 3.9mg: 1.0 ± 0.8 from sealed foil patches. estinated to provide an 80% reported differences between PLA: 0.6 ± 0.6 Patients were asked to place power to detect a 30% PLA: -0.21 ± 1.58 groups at baseline Study type patch on a new site each difference between OXY TD N not reported Level of bias: Low Urgency episodes / day Mean ± application. and placebo with alpha set at Randomized controlled trial SD 0.05. Anticipating a 20% loss Continence status B Performance bias OXY TD 3.9mg: 3.9 ± 2.88 to follow-up, triallists planned Not reported B1 - Did groups get Aim of the study PLA: 2.74 ± 1.82 to randomize 96 patients. same level of care - Yes Incontinence- B2 - Were participants To assess patient-reported Detrusor overactivity specific quality of blinded - Yes - Study goal improvement with Not reported Intention to treat analysis life was double-blind 3.9mg/day transdermal Not reported as B3 - Were clinical staff oxybutynin in comparison OAB duration Mean ± SD ITT analysis reported but no means and SD's blinded - Yes with placebo over a 4-week Not reported details given Level of bias: Low period. Adverse effects Dropouts for any C Attrition bias Inclusion criteria reason C1 - Was follow-up equal Study dates OXY TD 3.9mg: for both groups - Yes 1] > 3 months history of OAB 11/48 (22.9%) C2 - Were groups October 2006 to December symptoms PLA: 7/48 (14.6%) comparable for dropout - 2007 2] with or without urgency urinary Dropouts for Yes incontinence adverse effects C3 - Were groups Source of funding OXY TD 3.9mg: comparable for missing 4/48 (8.3%) data - Yes UCB Pharma Exclusion criteria PLA: 2/48 (4.2%) Level of bias: Low

1] history of hypersensitivity to Any adverse D Detection bias oxybutynin effects D1 - Was follow-up 2] previous transdermal skin patch Not reported appropriate length - Yes 3] pregnancy D2 - Were outcomes 4] breast feeding Dry mouth defined precisely - Yes 5] voiding difficulties (flow rate < Not reported D3 - Was a valid and 15 Ml/s) reliable methods used to

489

Study details Participants Interventions Methods Outcomes and Comments Results

6] postvoid residual > 50mLs Psychological assess outcome - Yes 7] current UTI outcomes D4 - Were investigators 8] one of a number of complaints Not reported blinded to intervention - contraindicating anticholinergic Yes treatmnet as detailed in SPC for Clinical measures D5 - Were investigators Kentera incluing narrow angle - Post-void blinded to confounding glaucome and myasthenia gravis residual volume factors - Unclear Not reported Level of bias: Low

Week 12 Not applicable Indirectness

Does the study match the protocol in terms of: 1] Population: Yes 2] Interventions: Yes 3] Outcome: Yes Indirectness: None

Other information

Only data on dropouts for any reason used in network meta-analysis

Full citation Sample size Interventions Details Results Limitations

Kaplan,S.A., Schneider,T., n = 2417 Tolterodine 4mg Extended A two-week single-blind Week 4 NICE guidelines manual. Foote,J.E., Guan,Z., Release placebo run-in period Patient satisfaction Appendix D: Carlsson,M., Gong,J., Tolterodine (TOL ER) 4mg = 973 Fesoterodine 8mg predated the study. with treatment Methodology checklist: Superior efficacy of Fesoterodine (FES) = 960 Placebo (dummy capsule or TOL ER: 588/973 Randomised controlled fesoterodine over tolterodine Placebo = 478 tablet) Subjects were randomly (60.4%) trials extended release with rapid allocated to festoterodine FES: 614/960 onset: a prospective, head-to- 8mg (*week 1 subjects (64.0%) head, placebo-controlled trial, Characteristics received 4mg and from PLA: 235/478 BJU International, 107, 1432- weeks 2-12 8mg), tolterodine (49.2%) Gender - Female, n/N (%)

490

Study details Participants Interventions Methods Outcomes and Comments Results

1440, 2011 TOL ER: 817/973 (84%) 4mg ER or placebo for A Selection bias FES: 816/960 (85%) twelve weeks. All subjects Self reported rate A1 - Was there Ref Id PLA: 410/478 (86%) took one tablet of absolute appropriate (fesoterodine) or capsule symptom randomisation - Yes - 129248 Age. Mean ± SD (tolterodine) daily or reduction per day block randomisation TOL ER: 58.1 ± 13.8 years matching placebo. Incontinence using a centralised Country/ies where the FES: 57.9 ± 13.5 years episodes system study was carried out PLA: 59.5 ± 13.2 years All subjects completed a TOL ER: -1.52 ± A2 - Was there adequate three-day bladder diary at 1.53 N = 932 concealment - Yes - North America, South baseline, weeks 1, 4 and 12. FES: -1.68 ± 1.52 randomisation schedule America, Europe, Asia and Incontinence episodes / day - N = 920 generated and stored off Africa Mean ± SD PLA: -1.31 ± 1.49 site Not reported Subjective improvement N = 456 A3 - Were groups Study type scales, the Patient comparable at baseline - Urgency episodes / day Mean ± Perception of Bladder Urgency episodes Yes - No apparent Randomised controlled trial SD Condition (PPBS) and the TOL ER: -2.5 ± 6.1 differences between Not reported Urgency Perception Scale N = 929 groups at baseline Aim of the study (UPS) was collected at FES: -3.1 ± 6.0 N Level of bias: Low Detrusor overactivity baseline, 1, 4 and 12 weeks. = 915 "To prospectively assess the Not reported PLA: -1.9 ± 4.3 N superiority of the maximum = 453 available dose of OAB duration Mean ± SD Patients completed the fesoterodine (8mg) over the TOL ER: 6.5 ± 7.3 years Overactive Active Bladder Continence status B Performance bias maximum available dose of FES: 6.6 ±7.7 years questionnaire (OAB-q) at Incontinence B1 - Did groups get tolterodine ER (4mg)" PLA: 6.3 ± 7.2 years baseline and the endpoint of episodes same level of care - Yes the study. TOL ER: 432/963 B2 - Were participants (43.4%) blinded - Yes - Study Study dates Inclusion criteria FES: 464/950 was double-blind and Power calculation (48.3%) double-dummy Feb 2008 - Oct 2009 1] Men and women ≥ 18 years old PLA: 177/472 B3 - Were clinical staff 2] self-reported AOB symptoms for 606 subjects per active (37.0%) blinded - Unclear - not Source of funding three or more months treatment group were reported 3] a mean of at least one UUI required for 90% power for Urgency episodes Level of bias: Low "This study was funded and episode and ≥ 8 micturitions/24hr comparisons at the 5% Not reported conducted by Pfizer Inc." noted in a 3-day bladder diary at significance level. 303 baseline. subjects were required in Incontinence- placebo group for 88% power specific quality of C Attrition bias for each comparison. 1515 life C1 - Was follow-up equal subjetcs were required Not reported

491

Study details Participants Interventions Methods Outcomes and Comments Results

Exclusion criteria assuming 90% of subjects for both groups - Yes woulc ontribute to full Adverse effects C2 - Were groups 1] Clinically significant hepatic or analysis set. Not applicable comparable for dropout - renal disease Yes 2] Voiding dysfunction attributable Psychological C3 - Were groups to lower genitourinary pathology or Intention to treat analysis outcomes comparable for missing surgical treatment Not reported data - Yes 3] Neurological conditions (stroke, Last-observation-carried- Level of bias: Low multiple sclerosis, spinal cord forward was used for all Clinical measures injury or Parkinson's disease) missing post-baseline data - Post-void 4] History of acute urinary but baseline data were not residual volume retention requiring catheterization used. Not reported 5] Symptoms of incontinence D Detection bias being predominately stress urinary Week 12 D1 - Was follow-up incontinence in the opinion of the Patient satisfaction appropriate length - Yes investigator with treatment D2 - Were outcomes 6] Antimuscarinic medication TOL ER: 629/973 defined precisely - Yes within two weeks before screening (64.6%) D3 - Was a valid and or electrostimulation, bladder FES: 676/960 reliable methods used to training or pelvic floor exercises (70.4%) assess outcome - Yes within four weeks of screening PLA: 272/478 D4 - Were investigators 7] Pregnant or nursing (56.9%) blinded to intervention - 8] women of childbearing potential Yes who were heterosexually active Self reported rate D5 - Were investigators without using adequate of absolute blinded to confounding contraceptive measures. symptom factors - Unclear reduction per day Level of bias: Low Incontinence episodes of incontinence - Mean ± sd change Indirectness scores TOL ER: -1.74 ± Does the study match 1.82 N = 926 the protocol in terms of: FES: -1.95 ± 1.51 1] Population: Yes N = 908 2] Intervention: Yes PLA: -1.62 ± 1.48 3] Outcomes: Yes N = 448 Indirectness: None

492

Study details Participants Interventions Methods Outcomes and Comments Results

Urgency episodes TOL ER: -3.5 ± 6.1 N = 933 Other information FES: -4.2 ± 6.0 N = 915 Results taken from PLA: -3.2 ± 4.3 N clinicaltrials.gov = 453 (NCT00611026)

Continence status Incontinence episodes TOL ER: 538/963 (56.0%) FES: 574/950 (60.0%) PLA: 241/472 (50.4%)

Urgency episodes Not reported

Incontinence- specific quality of life OAB-q - HRQOL total score - change score TOL ER: 19.5 ± 29.6 N = 875 FES: 22.9 ± 28.9 N = 894 PLA: 17.2 ± 25.0 N = 435

Adverse effects Any adverse effect TOL ER: 267/973 (27.4%) FES: 388/960

493

Study details Participants Interventions Methods Outcomes and Comments Results

(40.4%) PLA: 91/478 (19.0%)

Dry mouth TOL ER: 130/973 (13.4%) FES: 265/960 (27.6%) PLA: 26/478 (5.4%)

Dropout for any reason TOL ER: 88/973 (9.0%) FES: 98/960 (10.2%) PLA: 47/478 (9.8%)

Dropout for adverse event TOL ER: 28/973 (4.7%) FES: 46/960 (2.9%) PLA: 9/478 (1.9%)

Psychological outcomes Not reported

Clinical measures Post-void residual volume Not reported

494

Study details Participants Interventions Methods Outcomes and Comments Results

Full citation Sample size Interventions Details Results Limitations

Vardy,M.D., Mitcheson,H.D., N = 768 5 mg solifenacin or placebo Eligible patients were Week 4 NICE guidelines manual. Samuels,T.A., Wegenke,J.D., once daily randomised to receive 5mg Dropouts for any Appendix D: Forero-Schwanhaeuser,S., SOL = 386 solifenacin or placebo once reason Methodology checklist: Marshall,T.S., He,W., Effects PLA = 382 daily for 4 weeks. At 4 weeks SOL: 15/386 Randomised controlled of solifenacin on overactive patients could maintain 5mg (3.9%) trials bladder symptoms, symptom dose or increase to 10mg for PLA: 22/382 bother and other patient- Characteristics 4 weeks. At week 8 patients (5.8%) A Selection bias reported outcomes: results taking 10mg could maintain A1 - Was there from VIBRANT - a double- Gender - Female/N (% female) or decrease dose to 5mg, Week 12 appropriate blind, placebo-controlled trial, SOL: 306/377 (81%) patients taking 5mg could Patient satisfaction randomisation - Unclear - International Journal of PLA: 314/374 (84%) increase to 10mg. with treatment not reported Clinical Practice, 63, 1702- SOL: 281/386 A2 - Was there adequate 1714, 2009 Age (years) - Mean ± SD At baseline, and weeks 4, 8 (72.8%) concealment - Yes SOL: 59 ± 13 and 12 patients completed PLA: 197/382 A3 - Were groups Ref Id PLA: 60 ± 12 the OAB-q and 3-day bladder (51.6%) comparable at baseline - diaries. At baseline and 12 Yes - but baseline 129390 Incontinence episodes/day - weeks patients completed Self-reported rate characteristics not Mean ± SD the PBBC and additional of absolute reported for full study Country/ies where the SOL: 2.9 ± 2.7 health-related quality of life symptom population - 17 patients study was carried out PLA: 2.8 ± 2.6 and satisfaction with reduction per day with missing treatment questionnaires. At Incontinence postbaseline OAB-q data USA Urgency episodes/day - Mean ± each visit investigators episodes - change were excluded from data SD conducted brief physical from baseline set Study type SOL: 5.7 ± 3.7 examinations and recorded SOL: -1.85 (No Level of bias: unclear PLA: 5.7 ± 3.9 vital signs. Treatment- SD) N not reported randomized controlled trial emergent adverse events PLA: -1.24 (No B Performance bias Detrusor overactivity - n/N (%) were monitored and SD) N not reported B1 - Did groups get Aim of the study Not reported recorded same level of care - Yes Urgency episodes B2 - Were participants To evaluate the efficacy of Duration of OAB - Mean ± SD SOL: -3.05 (No blinded - Yes solifenacin on symptom Not reported Power calculation SD) N not reported B3 - Were clinical staff bother using the Overactive PLA: -1.84 (No blinded - Yes Bladder Questionnaire The primary efficacy variable SD) N not reported Level of bias: Low Inclusion criteria was mean change on the OAB-q Symptom Bother Continence status C Attrition bias Study dates 1] Aged ≥ 18 years scale from baseline to end of (zero episodes per C1 - Was follow-up equal 2] OAB symptoms for ≥ 3 months treatment. Assuming a day) for both groups - Yes

495

Study details Participants Interventions Methods Outcomes and Comments Results

Not reported (≥ 8 micturitions and ≥ 1 urgency standard deviation of 22.0 Incontinence C2 - Were groups episode with or without and that 80% of randomised episodes comparable for dropout - Source of funding incontinence per 24 h) patients would be evaluable, SOL: 119/273 Yes 3] Score ≥ 3 on Patient Percpetion 381 randomised subjects per (43.6%) C3 - Were groups Astellas Pharma US Inc and of Bladder Condition (PBBC) treatment group provided > PLA: 80/272 comparable for missing GlaxoSmithKline questionnaire 99% power to detect a 10- (29.4%) data - Yes point difference in between Level of bias: Low treatment groups using a Urgency episodes Exclusion criteria two-sided test at a Not reported D Detection bias significance level of 0.05. D1 - Was follow-up 1] Significant stress or stress- Incontinence- appropriate length - Yes predominant mixed incontinence specific quality of D2 - Were outcomes 2] ≥ 3 episodes of urinary tract Intention to treat analysis life defined precisely - Yes infection (UTI) within past 3 Scale used - OAB- D3 - Was a valid and months All efficacy analyses were q - mean change reliable methods used to 3] Evidence of UTI at baseline conducted on the full from baseline assess outcome - Yes 4] Evidence of chronic urologic analysis set which consisted SOL: 29.9 (No SD) D4 - Were investigators inflammation/interstitial cystitis of patients who took ≥1 dose N not reported blinded to intervention - 4] Urinary/gastric retention of study drug, had a baseline PLA: 20.4 (No SD) Yes OAB-q assessment and ≥1 N not reported D5 - Were investigators post baseline OAB-q blinded to confounding assessment Adverse effects factors - Unclear Any adverse effect Level of bias: Low SOL: 100/386 (26%) PLA: 50/382 Indirectness (13%) Does the study match Dry mouth the protocol in terms of: SOL: 51/386 1] Population: Yes (13.2%) 2] Interventions: Yes PLA: 9/382 (2.4%) 3] Outcome: Yes Indirectness: None Dropouts for any reason SOL: 35/386 Other information (9.1%) PLA: 48/382 Use of antimuscarinics, (12.6%) antispasmodics, tricyclic

496

Study details Participants Interventions Methods Outcomes and Comments Results

anitdepressants and anti- Dropouts for Parkinson agents was adverse effects prohibited, use of SOL: 12/386 (3%) tetracyclic PLA: 15/382 (4%) antidepressants, antihistamines and Psychological antiemetics was outcomes permitted to continue if Not reported patients had been taking drug on a long-term Clinical measures basis at a stable dose. Not reported Patients taking OAB medications were eligible after discontinuation and completion of a ≥14 day washout period.

Additional data (continence status) from secondary publication: Vardy et al. Female Pelvic Medicine & Reconstructive Surgery 2011; 17(1): 24-29

Full citation Sample size Interventions Details Results Limitations

Yamaguchi,O., Nishizawa,O., N = 951 The study, which consisted of Efficacy variables were Week 4 NICE guidelines manual. Takeda,M., Yoshida,M., a 2-week placebo run-in assessed with 3-day Patient satisfaction Appendix D: Choo,M.S., Gu,LeeJ, Tong- Fesoterodine 4mg QD (FES $) = period followed by a 12-week micturition diaries that with treatment Methodology checklist: Long,LinA, Lin,H.H., 320 double-blind treatment period, subjects completed on 3 Not reported Randomised controlled Andrew,YipW, Isowa,H., Fesoterodine 8mg QD (FEs 8) = required a total of six clinic consecutive days during the trials Hiro,S., Efficacy, safety and 313 visits. In the placebo run-in 7 days prior to each visit. The Self-reported rate tolerability of fesoterodine in Placebo (PLA) = 318 period, subjects received one primary efficacy endpoint of absolute A Selection bias asian patients with overactive tablet of placebo in the was the change from symptom A1 - Was there bladder, LUTS: Lower Urinary morning. Once eligibility was baseline in the mean number reduction per day appropriate

497

Study details Participants Interventions Methods Outcomes and Comments Results

Tract Symptoms, 3, 43-50, Characteristics established, subjects were of UUI episodes per 24 h at Incontinence randomisation - Unclear - 2011 randomized 1:1:1–12 weeks week 12 of treatment. episodes - mean ± not reported Gender - Female/N (% female) of double-blind treatment (QD SD change from A2 - Was there adequate Ref Id FES 4: 251/320 (78.9%) in the morning) with baseline concealment - Unclear - FES 8: 255/313 (81.5%) fesoterodine 4 mg QD, Power calculation FES 4: -1.61 ± not reported 129406 PLA: 251/318 (78.9%) fesoterodine 8 mg QD, or 1.76 N = 314 A3 - Were groups matching placebo. None reported FES 8: -1.50 ± comparable at baseline - Country/ies where the Age (years) - Mean ± SD 1.71 N = 296 Yes - No apparent study was carried out FES 4: 57.2 ± 14.2 PLA:-1.22 ± differences between FES 8: 58.8 ± 13.4 Intention to treat analysis 1.59 N = 301 groups at baseline Japan, Korea, Taiwan, Hong PLA: 56.7 ± 13.5 Level of bias: Unclear Kong None reported Urgency episodes Number of incontinence FES 4: -2.16 ± B Performance bias Study type episodes/week Mean ± SD 2.91 N = 303 B1 - Did groups get FES 4: 2.2 ± 1.8 FES 8: -2.16 ± same level of care - Yes Randomised controlled trial FES 8: 2.3 ± 1.8 3.07 N = 296 B2 - Were participants PLA: 2.2 ± 1.9 PLA: -1.60 ± 2.78 blinded - Yes - Study Aim of the study N = 301 was double-blind Urgency episodes B3 - Were clinical staff To assess the efficacy, safety Not reported Continence status blinded - Yes and tolerability of (zero episodes per Level of bias: Low fesoterodine 4 and 8 mg QD Detrusor overactivity day) compared with placebo at Not reported Incontinence C Attrition bias week 12 of treatment in Asian episodes - C1 - Was follow-up equal subjects with OAB. Duration of OAB - Mean ± SD incontinent at for both groups - Yes Not reported baseline only C2 - Were groups Not reported comparable for dropout - Study dates Yes Inclusion criteria Urgency episodes C3 - Were groups Not reported Not reported comparable for missing 1] ≥ 20 years of age data - Yes Source of funding 2] a medical history of OAB Incontinence- Level of bias: Low symptoms or signs with urinary specific quality of Sponsored by Pfizer Japan urgency and increased urinary life D Detection bias frequency that lasted for ≥6 Not reported D1 - Was follow-up months prior to enrollment and appropriate length - Yes UUI that lasted for ≥ 1 month prior Adverse effects D2 - Were outcomes to enrollment Not reported defined precisely - Yes 3] ≥ 1 UUI episodes and ≥8 D3 - Was a valid and

498

Study details Participants Interventions Methods Outcomes and Comments Results

micturitions per 24 h during a 3- Psychological reliable methods used to day diary period of the placebo outcomes assess outcome - Yes run-in phase Not reported D4 - Were investigators 4] at least moderate problems blinded to intervention - based on the Patient Perception of Clinical measures Yes Bladder Condition (PPBC) Not reported D5 - Were investigators measure blinded to confounding 5] a negative urine pregnancy test Week 12 factors - Unclear for women of child-bearing Patient satisfaction Level of bias: Low potential. with treatment Not reported Indirectness Exclusion criteria Self-reported rate of absolute Does the study match 1] neurological diseases symptom the protocol in terms of: influencing bladder function (e.g. reduction per day 1] Population: Yes stroke, multiple sclerosis, Incontinence 2] Interventions: Yes Parkinson’s disease, spinal cord episodes - mean ± 3] Outcome: Yes injury, spina bifida and autonomic SD change from Indirectness: None neuropathy) baseline 2] lower urinary tract pathologies FES 4: -1.97 ± potentially responsible for urgency 1.84 N = 284 Other information or incontinence (e.g. bladder FES 8: -1.86 ± 2.0 stone, interstitial cystitis and N = 281 Outcome data taken from urothelial tumors) PLA: -1.59 ± 2.87 NCT00561951 3] clinically relevant bladder outlet N = 284 (www.clinicaltrials.gov) obstruction (e.g. benign prostatic Data from FES 4 group hyperplasia) Urgency episodes used in reviews 4] pelvic organ prolapse FES 4: -2.89 ±

5] predominant symptoms of 2.83 N = 284 stress urinary incontinence FES 8: -3.05 ± 6] active urinary tract infection 3.46 N = 281 7] residual urine volume of > 100 PLA: -2.37 ± 2.98 ml N = 284 8] polyuria (> 3000 ml/24 h) 9] treatment with antimuscarinic Continence status drugs during the study (zero episodes per 10] clinically relevant arrhythmia, day) Incontinence

499

Study details Participants Interventions Methods Outcomes and Comments Results

unstable angina, other unstable episodes - cardiovascular conditions, or incontinent at pacemaker baseline only 11] corrected QT interval (Bazett’s Not reported formula or Fridericia formula) of > 500 ms. Urgency episodes Not reported

Incontinence- specific quality of life OAB-q HRQOL used FES 4: 17.84 ± 17.88 N = 283 FES 8: 17.29 ± 19.67 N = 283 PLA: 12.88 ± 18.87 N = 285

Adverse effects Any adverse effect FES 4: 138/320 (43.1%) FES 8: 185/313 (59.1%) PLA: 66/318 (20.8%)

Dry mouth FES 4: 93/320 (9.1%) FEs 8: 158/313 (50.5%) PLA: 31/318 (9.7%)

Dropouts for any reason

500

Study details Participants Interventions Methods Outcomes and Comments Results

FES 4: 34/320 (10.6%) FES 8: 32/313 (10.2%) PLA: 33/318 (10.4%)

Dropouts for adverse effects FES 4: 14/320 (4.4%) FES 8: 14/313 (4.5%) PLA: 11/318 (3.5%)

Psychological outcomes Not reported

Clinical measures FES 4: 17.8 ± 33.4 N not reported FES 8: 18.8 ± 31.3 N not reported PLA: 10.4 ± 23.4 N not reported

Full citation Sample size Interventions Details Results Limitations

Weiss,Jeffrey P., N = 963 4 mg fesoterodine or placebo After 2-week screening, Week 4 results NICE guidelines manual. Jumadilova,Zhanna, Johnson once daily subjects who met inclusion Not reported Appendix D: II,Theodore M., FES = 476 (463 began treatment) criteria began a 2-week Methodology checklist: FitzGerald,Mary P., PLA = 487 (474 began treatment) single-blind placebo run-in Week 12 results Randomised controlled Carlsson,Martin, period. After run-in period, Patient satisfaction trials Martire,Diane L., subjects with ≤35% decrease with treatment Malhotra,Atul, Efficacy and in nocturnal urgency Not reported A Selection bias

501

Study details Participants Interventions Methods Outcomes and Comments Results

Safety of Flexible-Dose Characteristics episodes/24 h from A1 - Was there Fesoterodine in Men and screening to baseline, total Self-reported rate appropriate Women with Overactive Gender - Female/N (% female) urine volume ≤ 3500 ml of absolute randomisation - Yes Bladder Symptoms, Including FES: 313/463 (67.6%) recorded on 1 of 3 baseline symptom A2 - Was there adequate Nocturnal Urinary Urgency, PLA: 312/474 (65.8%) diary days and nocturnal reduction per day concealment - Yes The Journal of Urology, ePub volume voided ≤ 50% of total Incontinence A3 - Were groups ahead of print, -, 2012 Age (years) - Mean ± SD 24-h urine volume voided episodes - mean ± comparable at baseline - FES: 58.0 ± 14.7 recorded on 1 of 3 baseline SD change from Yes - but baseline data Ref Id PLA: 57.5 ± 14.0 diary days were randomized. baseline only reported for those FES: -1.44 ± 2.42 beginning treatment 214959 Incontinence episodes/week - Eligible subjects were N = 463 Level of bias: Low Mean ± SD randomized to fesoterodine PLA: -1.28 ± 2.02 Country/ies where the FES: 2.20 ± 2.55 4mg or matching placebo N = 474 B Performance bias study was carried out PLA: 2.23 ± 2.49 once daily. At week 4, based B1 - Did groups get on efficacy and tolerability, Urgency same level of care - Yes USA Urgency episodes/day - Mean ± the investigator could episodes - mean ± B2 - Were participants SD increase fesoterodine dose SD change from blinded - Yes Study type FES: 9.8 ± 3.62 to 8mg once daily or continue baseline B3 - Were clinical staff PLA: 10.0 ± 4.0 4mg once daily for remaining FES: - blinded - Yes randomized controlled trial 8 weeks of the study. No 3.53 ± 3.98 N = Level of bias: Low Detrusor overactivity - n/N (%) further dose adjustments 463 Aim of the study Not reported were permitted after week 4. PLA: -2.81 ± 3.81 C Attrition bias N = 474 C1 - Was follow-up equal To test the hypothesis that Duration of OAB - Mean (range) Subjects completed a 3-day for both groups - Yes fesoterodine would be FES: 7.5 (0.3 - 49.8) bladder diary at screening Continence status C2 - Were groups superior to placebo in the PLA: 8.0 (0.3 - 56.0) (week -4), beginning placebo (zero episodes per comparable for dropout - treatment of nocturnal run-in (week -2), end of day) Yes urgency in OAB patients with placebo run-in (baseline), Incontinence C3 - Were groups nocturia Inclusion criteria and weeks 4 and 12. OAB-q episodes comparable for missing completed at baseline and Not reported data - Yes 1] Aged ≥ 18 years week 12 Level of bias: Low Study dates 2] Self-reported OAB symptoms urgency episodes including nocturnal urgency for ≥ 3 Not reported D Detection bias August 2009 - September months before screening Power calculation D1 - Was follow-up 2011 3] Mean ≥ 8 micturitions/24 h, ≥ 3 Incontinence- appropriate length - Yes urgency episodes/24 h, and ≥ 2 Estimated sample size was specific quality of D2 - Were outcomes Source of funding but ≤ 8 nocturnal urgency 426 subjects per group to life defined precisely - Yes episodes/24 h on bladder diary at provide approximately 80% OAB-q used* D3 - Was a valid and Sponsored by Pfizer Inc. screening power to detect a clinically FES: 17.42 ± 18.0 reliable methods used to

502

Study details Participants Interventions Methods Outcomes and Comments Results

Medical writing support meaningful difference of ≥ N = 393 assess outcome - Yes funded by Pfizer Inc 0.25 epsidoes/24 H in mean PLA: 14.39 ± 20.4 D4 - Were investigators Exclusion criteria change from baseline to N = 416 blinded to intervention - week 12 in nocturnal urgency Yes 1] Clinically significant hepatic or episodes between Adverse effects D5 - Were investigators renal disease fesoterodine and placebo Any adverse effect blinded to confounding 2] Treatment with potent CYP3A4 using a 2-sided t-test with FES: 188/476 factors - Unclear inhibitors alpha 5%. Allowing for drop- (39%) Level of bias: Low 3] Intermittent or unstable use of out rate of 8%, 928 PLA: 152/487 tricyclic antidepressants, randomized subjects (464 (31%) estrogens, diuretics, alpha- per group) were required. A Indirectness blockers or 5-alpha reductase blinded sample size re- Dry mouth inhibitors estimation conducted when FES: 98/476 Does the study match 4] Pregnancy or nursing 341 subjects completed the (21%) the protocol in terms of: 5] Recent history/known diagnosis study indicated that no PLA: 36/487 (7%) 1] Population: Yes of any sleep disorder increase in sample size was 2] Interventions: Yes 6] Nocturia due to uncontrolled necessary. Dropouts for any 3] Outcome: Yes conditions other than OAB reason Indirectness: None including chronic heart failure, FES: 95/476 diabetes mellitus, diabetes Intention to treat analysis (20%) insipidus or polyuria PLA: 87/487 Other information 7] History of acute urinary Diary and OAB-q analyses (18%) retention requiring catheterization were based on the full 13 particpants in each or severe voiding difficulties analysis set (i.e. all subjects Dropouts for group dropped out of the 8] Use of indwelling catheter or who took ≥ 1 dose of study adverse effects trial before starting intermittent self-catheterization drug and had at least a FES: 25/476 (5%) treatment 9] Predominant stress urinary baseline and a post-baseline PLA: 11/487 (2%) incontinence efficacy assessment) 12 week data on OAB-q 10] Urinary tract infection or Psychological taken from recurrent UTI (≥ 3 times in past outcomes NCT00911937 year) Not reported (www.clinicaltrials.gov) 11] Initiation of electrostimulation, formal bladder training, or pelvic Clinical measures floor exercises within 4 weeks of Post-void residual screening volume - Mean 12] Prior use of study medication change from 13] Treatment with antimuscarinic baseline (95% CI) OAB medication within 2 weeks of Not reported screening

503

Study details Participants Interventions Methods Outcomes and Comments Results

Full citation Sample size Interventions Details Results Limitations

Huang,Alison J., N = 645 12-weeks flexible dose (4- Eligible women were Week 4 results NICE guidelines manual. Hess,Rachel, Arya,Lily A., 8mg) fesoterodine (Toviaz; randomised 1:1 to either Not reported Appendix D: Richter,Holly E., Fesoterodine = 322 Pfizer, Inc, New York, NY, fesoterodine or placebo. Methodology checklist: Subak,Leslee L., Placebo =323 USA) or identical placebo pill Week 12 results Randomised controlled Bradley,Catherine S., daily Women were initially started Patient satisfaction trials Rogers,Rebecca G., on 4mg fesoterodine or an with treatment Myers,Deborah L., Characteristics idential placebo pill daily. At Not reported A Selection bias Johnson,Karen C., 2-week telephone call and 4- A1 - Was there Gregory,W.Thomas, Gender - Female/N (% female) week follow-up visit women Self-reported rate appropriate Kraus,Stephen R., FES: 322/322 (100%) were offered option of of absolute randomisation - yes Schembri,Michael, PLA: 323/323 (100%) increasing their dose to 8mg symptom A2 - Was there adequate Brown,Jeanette S., fesoterodine or an identical reduction per day concealment - Yes - Pharmacologic treatment for Age (years) - Mean ± SD placebo pill daily. At 8-week Incontinence randomisation numbers urgency-predominant urinary FES: 56.2 ± 14.7 telephone call they were episodes - change served as packaging for incontinence in women PLA: 55.9 ± 14.2 invited to readjust their dose from baseline interventions diagnosed using a simplified to a maximum of 8 or (mean ± SD, N) A3 - Were groups algorithm: a randomized trial, Incontinence episodes/day - Mean minimum of 4 mg daily. FES: - 2.9 ± 2.7 N comparable at baseline - American Journal of ± SD = 303 Yes - No apparent Obstetrics and FES: 3.8 ± 2.9 All clinical efficacy outcomes PLA: -2.1 ± 2.9 N differences between GynecologyAm J Obstet PLA: 4.0 ± 3.0 were measured at baseline, = 301 groups at baseline Gynecol, 206, 444-444, 2012 4 and 12 weeks. Self- Level of bias: Low Urgency episodes/day - Mean ± reported urgency episodes Urgency episodes Ref Id SD were documented by 3-day FES: -2.1 ± 3.8 N B Performance bias FES: 7.5 ±4.1 voiding diary. Measurement = 303 B1 - Did groups get 214960 PLA: 7.8 ± 4.5 of PVR volume was PLA: -1.4 ± 3.9 N same level of care - Yes performed by bladder = 301 B2 - Were participants Country/ies where the Detrusor overactivity - n/N (%) ultrasound scanning or blinded - Yes study was carried out Not reported catheterization at 12 weeks Continence status B3 - Were clinical staff or early termination. (zero episodes per blinded - Yes USA Duration of OAB - Mean ± SD day) Level of bias: Low Not reported Incontinence Study type Power calculation epipsodes C Attrition bias FES: 79/322 C1 - Was follow-up equal randomized controlled trial Sample size of 636 (24.5%) for both groups - Yes

504

Study details Participants Interventions Methods Outcomes and Comments Results

Aim of the study Inclusion criteria participants was estimated to PLA: 34/323 C2 - Were groups provide 90% power to detect (10.5%) comparable for dropout - To examine the efficacy and 1] ≥ 18 years old a net reduction in urgency Yes safety of initiating 2] ≥ 7 incontinence episodes per incontinence frequency with Urgency episodes C3 - Were groups pharmacologic therapy for week in past 3 months a 2 sample t test and the Not reported comparable for missing urgency incontinence in 3] Self-diagnosed with urgency- assumption of a 15% drop- data - Yes women predominant incontinence on the 3 out rate. The effect size was Incontinence- Level of bias: Low Incontinence Questionons (3IQ) based on pooled data from 2 specific quality of questionnaire previous trials that reported life D Detection bias Study dates an average effect size of Scale used - D1 - Was follow-up 0.92 episodes per day and a Overactive appropriate length - Yes February 2009 - Januaruy Exclusion criteria standard deviation of 3.2 Bladder D2 - Were outcomes 2010 episodes per day. Questionnaire defined precisely - Yes 1] Anti-incontinence surgery in Change from D3 - Was a valid and Source of funding past 5 years baseline (mean ± reliable methods used to 2] Other pelvic surgery in past 6 Intention to treat analysis SD) assess outcome - Yes Pfizer Inc provided funding months FES: -17.1 ± 17.6 D4 - Were investigators for the study and study 3] > 3 urinary tract infections in Sensitivity analysis was N = 303 blinded to intervention - medication but did not past year performed to address PLA: -12.0 ± 16.6 Yes provide input into design of 4] Lower urinary tract or rectal potential bias - missing N = 301 D5 - Were investigators study, collection, analysis or fistula imputation analyses were blinded to confounding interpretation of data, writing 5] Interstitial cystitis performed on all participants Adverse effects factors - Unclear of report or decision to submit 6] Symptomatic pelvic organ with intent to treat Any adverse effect Level of bias: Low paper for publication prolapse FES: 187/322 7] Urogenital cancer or radiation (58.1%) 8] Congenital abnormality leading PLA: 149/323 Indirectness to incontinence (46.1%) 9] Major neurologic disorder Does the study match 10] Urinary or gastric retention Dry mouth the protocol in terms of: 11] Uncontrolled narrow-angle Not reported 1] Population: Yes glaucoma 2] Interventions: Yes 12] Myasthenia gravis Dropouts for any 3] Outcome: Yes 13] Severe ulcerative colitis reason Indirectness: None 14] Clinically significant hepatic or FES: 29/322 renal disease (9.0%) 15] Toxic megacolon PLA: 30/323 Other information 16] Potent CYP3A4 inhibitor (9.3%) treatment in the last 2 weeks None 17] Pregnancy or nursing Dropouts for

505

Study details Participants Interventions Methods Outcomes and Comments Results

adverse effects FES: 11/322 (3.4%) PLA: 8/323 (2.5%)

Psychological outcomes Not reported

Clinical measures Post-void residual volume at end point (mean ± SD) FES: 39.1 ± 48.0 N = 303 PLA: 31.2 ± 39.0 N = 301

Full citation Sample size Interventions Details Results Limitations

Oreskovic,S., But,I., N = 171 Following a single blind 2- Treatment efficacy was Week 4 NICE guidelines manual. Banovic,M., Goldstajn,M.S., week placebo run in period, evaluated after one and four Patient satisfaction Appendix D: The efficacy and safety of Solifenacin (SOL) = 77 patients were randomized to weeks treatment periods with treatment Methodology checklist: solifenacin in patients with Placebo (PLA) = 80 4 weeks of solifenacin in 5 mg according to subjective Not reported Randomised controlled overactive bladder syndrome, once daily doses or placebo. assesment using data trials Collegium Antropologicum, recorded in patient diaries in Self-reported rate 36, 243-248, 2012 Characteristics the one and four week of absolute A Selection bias periods preceding the symptom A1 - Was there Ref Id Gender - Female/N (% female) scheduled clinical visits. reduction per day appropriate SOl: 77/77 (100%) Incontinence randomisation - Unclear - 215468 PLA: 80/80 (100%) episodes not reported Power calculation SOL: 0.96 ± 0.57 A2 - Was there adequate Country/ies where the Age (years) - Mean ± SD N = 77 concealment - Unclear - study was carried out SOL: 56.77 ± 10.16 Not reported PLA: 2.75 ± 0.43 not reported PLA: 57.03 ± 10.95 N = 80 A3 - Were groups Croatia comparable at baseline - Incontinence episodes/day - Urgency episodes Yes - No apparent

506

Study details Participants Interventions Methods Outcomes and Comments Results

Study type Range Intention to treat analysis SOL: 5.77 ± 1.33 differences between Not reported N = 77 groups at baseline Randomised controlled trial Not reported PLA: 6.54 ± 0.50 Level of bias: Low Urgency episodes/day N = 80 Aim of the study Not reported B Performance bias Continence status B1 - Did groups get To evaluate the efficacy, Detrusor overactivity (zero episodes per same level of care - Yes tolerability and safety of Not reported day) B2 - Were participants solifenacin in patients with Incontinence blinded - Yes - Study overactive bladder syndrome. Duration of OAB episodes was double-blind Not reported Not reported B3 - Were clinical staff blinded - Yes Study dates Urgency episodes Level of bias: Low Inclusion criteria Not reported Not reported C Attrition bias 1] Patients who complained from Incontinence- C1 - Was follow-up equal Source of funding symptoms of OAB for at least 6 specific quality of for both groups - Yes months life C2 - Were groups Not reported 2] urge incontinence (at least but IIQ used comparable for dropout - no more than 50 episodes per SOL: 36.25 ± Unclear week), frequency of micturition (at 10.34 N = 77 C3 - Were groups least eight voids per 24 hours) and PLA: 46.86 ± 6.81 comparable for missing urgency (a strong desire to void at N = 80 data - Yes least once per day) Level of bias: Low Adverse effects Any adverse effect D Detection bias Exclusion criteria Not reported D1 - Was follow-up appropriate length - Yes 1] contraindications for the use of Dry mouth D2 - Were outcomes antimuscarinic drugs (e.g. Not reported defined precisely - Yes uncontrolled narrow-angle D3 - Was a valid and glaucoma, urinary or gastric Dropouts for any reliable methods used to retention) reason assess outcome - Yes 2] clinically significant stress Not reported D4 - Were investigators urinary incontinence (more than blinded to intervention - one episode per week) Dropouts for Unclear 3] clinically significant bladder adverse effects D5 - Were investigators outlet obstruction and /or a post- Not reported blinded to confounding void residual volume more than factors - Unclear

507

Study details Participants Interventions Methods Outcomes and Comments Results

200 ml Psychological Level of bias: Low 4] genitourinary condition that outcomes could cause urinary symptoms Not reported 5] recent urogenital surgery Indirectness 6] hepatic disease. Clinical measures Not reported Does the study match the review protocol in Week 12 terms of: Not reported Population: Yes Intervention: Yes Outcome: Yes Indirectness: None

Other information

Baseline data incomplete (not available for dropouts)

Full citation Sample size Interventions Details Results Limitations

Homma,Y., Paick,J.S., N = 608 Patients randomized in a Eligible patients were Week 4 results NICE guidelines manual. Lee,J.G., Kawabe,K., 2:2:1 ratio to treatment with enrolled into a 1- or 2-week Not reported Appendix D: Japanese and Korean Tolterodine ER (TOL ER) = 240 tolterodine ER 4 mg capsules wash-out/run-in period during Methodology checklist: Tolterodine Study Group, Oxybutynin IR (OXY IR) = 246 once daily (Detrol® which baseline voiding data Week 12 results Randomised controlled Clinical efficacy and Placebo (PLA) = 122 capsule/Detrusitol, Pharmacia (incontinence episodes, Patient satisfaction trials tolerability of extended- Corporation, USA), urinary frequency, volume with treatment release tolterodine and oxybutynin IR 3 mg tablets voided/void, incontinence reported as 'much A Selection bias immediate-release Characteristics three times daily (Pollakisu®, pad usage) were recorded benefit' at endpoint A1 - Was there oxybutynin in Japanese and Aventis Pharma Ltd, Japan) using voiding diaries. TOL ER: 90/240 appropriate Korean patients with an Gender - Female/N (% female) or placebo. Patients were (37.5%) randomisation - Yes overactive bladder: a TOL ER: 162/240 (68%) randomized using the method Voiding diaries were OXY IR: 100/246 A2 - Was there adequate randomized, placebo- OXY IR: 177/246 (73%) of random permuted blocks. completed over 7 (40.7% concealment - Unclear - controlled trial, BJU PLA: 69/122 (69%) Because the two active drugs consecutive days during the PLA: 26/122 Not reported International, 92, 741-747, differed in appearance and run-in period (baseline) and (21.3%) A3 - Were groups Age (years) - Mean ± SD were administered according the final week of treatment. comparable at baseline - TOL ER: 61.2 ± 11.8

508

Study details Participants Interventions Methods Outcomes and Comments Results

2003 OXY IR: 57.9 ± 12.5 to different daily schedules, All incontinence episodes Self-reported rate Yes PLA: 58.4 ± 14.0 blinding was by a variation on and voids during the 7-day of absolute Level of bias: Low Ref Id the double-dummy technique, periods were recorded. symptom Incontinence episodes/week - so that matching placebos for Volume voided/void and pad reduction per day B Performance bias 220246 Mean ± SD both tolterodine ER 4 mg and usage had to be recorded for Incontinence B1 - Did groups get TOL ER: 20.3 ± 20.6 oxybutynin IR 3 mg were at least two complete days. episodes same level of care - Yes Country/ies where the OXY IR: 21.8 ± 19.8 provided. Patients were Not reported B2 - Were participants study was carried out PLA: 19.0 ± 15.5 instructed to take one blinded - Yes - Study tolterodine ER 4 mg or Power calculation Urgency episodes was double-blind and Japan and South Korea Urgency episodes/day placebo capsule in the Not reported double-dummy Not reported morning plus one oxybutynin Based on an assumed sd of B3 - Were clinical staff Study type IR 3 mg or placebo tablet in 58% in a previous study, the Continence status blinded - Yes Detrusor overactivity - n/N (%) the morning, at midday, and aim was to enrol 600 patients (zero episodes per Level of bias: Low Randomised controlled trial Not reported in the evening. (randomized 2:2:1), to detect day) a mean difference in efficacy Incontinence C Attrition bias Aim of the study Duration of OAB - Mean ± SD No dose adjustment was of 20% between tolterodine episodes C1 - Was follow-up equal Not reported permitted during the study ER and placebo (at 80% Not reported for both groups - Yes To compare tolterodine ER power and 5% significance C2 - Were groups and oxybutynin IR with level) and to show that Urgency episodes comparable for dropout - placebo in Japanese and Inclusion criteria tolterodine ER was not Not reported Yes Korean patients with OAB inferior to oxybutynin IR (at C3 - Were groups 1] Men and women aged ≥ 20 80% power and 2.5% Incontinence- comparable for missing years with symptoms of urinary significance level). specific quality of data - Yes Study dates urgency, urinary frequency (≥ 8 life Level of bias: Low voids/24 h), urge incontinence (≥ 5 Not reported Not reported episodes/week) and symptoms of Intention to treat analysis D Detection bias OAB for ≥ 6 months Adverse effects D1 - Was follow-up Source of funding The efficacy was analysed Any adverse effect appropriate length - Yes on an intent-to-treat basis for Not reported D2 - Were outcomes Supported by a grant from Exclusion criteria all randomized patients who defined precisely - Yes Pharmacia Corporation received at least one dose of Dry mouth D3 - Was a valid and 1] demonstrable stress study drug, using the last- TOL ER: 80/240 reliable methods used to incontinence observation-carried-forward (33.5%) assess outcome - Yes 2] total daily urine volume of > 3 L for any missing 12-week OXY IR: 131/246 D4 - Were investigators 3] average volume voided/void of values. ANOVA was used to (53.3%) blinded to intervention - > 200 ml compare treatment groups, PLA: 12/122 Yes 4] significant hepatic or renal with factors for treatment, (9.8%) D5 - Were investigators disease country and treatment– blinded to confounding 5] any contraindication to country interactions Dropouts for any factors - Unclear

509

Study details Participants Interventions Methods Outcomes and Comments Results

anticholinergic treatment, e.g. (removed from the model if P reason Level of bias: Low uncontrolled narrow-angled > 0.2). Two-sided t-tests with TOL ER: 25/240 glaucoma, urinary retention or significance levels of 5% and (10.4%) gastric retention 95% CIs were calculated OXY IR: 57/246 Indirectness 6] symptomatic or recurrent UTI based on the least-squares (23.2%) 7] interstitial cystitis means. If data were not PLA: 20/122 Does the study match 8] haematuria or BOO normally distributed, i.e. (16.4%) the protocol in terms of: 9] an indwelling catheter or skewed, a pre-planned 1] Population: Yes intermittent self-catheterization nonparametric analysis with Dropouts for 2] Interventions: Yes 10] electrostimulation or bladder ANOVA based on the rank- adverse effects 3] Outcome: Yes training within 14 days before transformation of the original TOL ER: 12/240 Indirectness: None randomization or expected to variable was used. (10.4%) commence during the study period OXY IR: 42/246 11] Concomitant treatment with (23.2%) Other information any other anticholinergic drug or PLA: 1/122 an unstable dosage of any drug (16.4%) Data on Oxybutynin IR with anticholinergic side-effects, 3mg not used in reviews any other drug for OAB (except for Psychological or network meta-analysis oestrogen started > 2 months outcomes as it is lower than the before inclusion), potent CYP3A4 Not reported recommnended starting inhibitors, or any investigational dose drug, was not permitted during the Clinical measures study or in the 14 days before - Post-void randomization residual volume 12] Pregnant or nursing women Not reported and women of childbearing potential not using reliable contraception were also excluded

Full citation Sample size Interventions Details Results Limitations

Chapple,C.R., Rechberger,T., N = 1081 Eligible patients after the run- At an initial screening visit Week 4 NICE guidelines manual. Al Shukri,S., Meffan,P., in period were randmised (week 2) the patients Not reported Appendix D: Everaert,K., Huang,M., Solifenacin 5mg (SOL 5) = 279 equally to 12-week double- provided a medical history, Methodology checklist: Ridder,A., Study Group., Solifenacin 10mg (SOL 10) = 269 blind treatment with either and had a physical Week 12 Randomised controlled Randomized, double-blind Tolterodine IR (TOL IR) = 266 tolterodine 2 mg twice daily, examination, postvoid Patient satisfaction trials placebo- and tolterodine- Placebo (PLA) = 267 placebo, or solifenacin 5 or 10 bladder ultrasonography, with treatment

510

Study details Participants Interventions Methods Outcomes and Comments Results controlled trial of the once- mg once daily. blood and urine laboratory Not reported A Selection bias daily antimuscarinic agent analyses (including urine A1 - Was there solifenacin in patients with Characteristics culture), and an Self-reported rate appropriate symptomatic overactive electrocardiogram (ECG). of absolute randomisation - Unclear - bladder, BJU International, Gender - Female/N (% female) Eligible patients received symptom not reported 93, 303-310, 2004 SOL 5: 194/266 (72.6%) placebo twice daily (morning reduction per day A2 - Was there adequate SOL 10: 188/264 (71.2%) and evening) over a 2-week Incontinence concealment - Unclear - Ref Id TOL IR: 200/250 (80.0%) run-in period; during the 3 episodes - Mean ± not reported PLA: 193/253 (76.3%) days before the next visit SD change from A3 - Were groups 220250 (week 0), patients recorded baseline comparable at baseline - Age (years) - Mean ± SD in a voiding diary episodes of SOL 5: -1.42 ± Yes - No apparent Country/ies where the SOL 5: 58.1 ± 13.4 urgency and incontinence, 1.82 N = 141 differences between study was carried out SOL 10: 57.2 ± 13.4 the times of voiding, volumes SOL 10: -1.45 ± groups at baseline TOL IR: 56.9 ± 1.8 voided/void, pad use, and 2.24 N = 158 Level of bias: Medium UK PLA: 57.8 ± 13.7 episodes of sleep TOL IR: -1.14 ± disturbance 2.15 N = 157 B Performance bias Study type Incontinence episodes/day: Mean PLA: -0.76 ± 2.26 B1 - Did groups get ± SD N = 153 same level of care - Yes Randomised controlled trial SOL 5: 2.54 ± 2.56 Power calculation B2 - Were participants SOL 10: 2.59 ± 2.88 Urgency episodes blinded - Yes - Study Aim of the study TOL IR: 2.2 ± 1.94 Based on a projected SOL 5: -2.85 ± was double-blind PLA: 2.71 ± 2.83 difference of 1.0 in the 3.74 N = 264 B3 - Were clinical staff To assess the efficacy of change from baseline in SOL 10: -3.07 ± blinded - Yes solifenacin 5mg and 10mg Urgency episodes/day: Mean ± SD voiding frequency/24 h for 3.90 N = 261 Level of bias: Low once-daily compared with SOL 5: 5.77 ± 4.89 solifenacin vs placebo, with a TOL IR: -2.05 ± placebo in a large sample of SOL 10: 5.82 ± 4.45 sd = 3, a significance level of 3.58 N = 250 C Attrition bias patients with symptoms of TOL IR: 5.45 ± 3.87 α= 0.05, two-sided, and a PLA: -1.41 ± 3.67 C1 - Was follow-up equal OAB PLA: 5.30 ± 3.92 power of 90%, 190 evaluable N = 248 for both groups - Yes patients per treatment arm C2 - Were groups Detrusor overactivity were required. To obtain a Continence status comparable for dropout - Study dates Not reported total of 760 evaluable (zero episodes per Yes patients, assuming a day) C3 - Were groups Not reported Duration of OAB discontinuation rate of 20% Incontinence comparable for missing Not reported during the run-in and episodes data - Yes Source of funding treatment periods, 1180 Not reported Level of bias: Low patients had to be enrolled. Supported by a grant from Inclusion criteria Urgency episodes D Detection bias Yamanouchi Pharmaceuticals Not reported D1 - Was follow-up Co. Ltd. Tokyo, Japan 1] Men and women aged ≥ 18 appropriate length - Yes

511

Study details Participants Interventions Methods Outcomes and Comments Results

years with symptoms of OAB Intention to treat analysis Incontinence- D2 - Were outcomes (including urgency, urge specific quality of defined precisely - Yes incontinence, or frequency) for ≥ 3 Not reported life D3 - Was a valid and months Not reported reliable methods used to 2] average frequency of ≥ 8 assess outcome - Yes voids/24 h and have experienced Adverse effects D4 - Were investigators at least three episodes of urgency Any adverse effect blinded to intervention - and/or three episodes of Not reported Yes incontinence during the 3-day D5 - Were investigators voiding diary period Dry mouth blinded to confounding SOL 5: 39/279 factors - Unclear (14.0%) Level of bias: Low Exclusion criteria SOL 10: 57/269 (21.2%) 1] clinically significant BOO TOL IR: 49/266 Indirectness 2] postvoid residual volume of (18.4%) > 200 ml PLA: 13/267 Does the study match 3] incontinence for which stress (4.9%) the protocol in terms of: was determined to be the 1] Population: Yes predominant factor Dropouts for any 2] Interventions: Yes 4] presence of a neurological reason 3] Outcome: Yes cause for detrusor muscle SOL 5: 28/279 Indirectness: None overactivity (11.5%) 5] evidence of UTI or bladder SOL 10: 20/269 stones (7.8%) Other information 6] previous pelvic irradiation TOL IR: 29/266 7] previous or current malignant (12.0%) Data from Sol 10mg not disease of the pelvic organs PLA: 32/267 used in review or 8] Any medical condition (12.0%) network meta-analysis as contraindicating the use of this is more than the antimuscarinic medication Dropouts for recommended starting (including narrow-angle glaucoma adverse effects dose and urinary or gastric retention) SOL 5: 9/279 9] nonpharmacological treatment (3.2%) for OAB including SOL 10: 7/269 electrostimulation therapy or start (2.6%) of a bladder training programme TOL IR: 5/266 during the 2 weeks before or (1.9%) during the study PLA: 10/267

512

Study details Participants Interventions Methods Outcomes and Comments Results

10] diabetic neuropathy, (2.7%) 11] use of drugs intended to treat incontinence 12] use of any drugs with Psychological cholinergic or anticholinergic side- outcomes effects Not reported 13] participation in a clinical trial within 30 days before study entry Clinical measures 14] Women of child-bearing - Post-void potential who were pregnant or residual volume nursing, intending to become Not reported pregnant during the study, or who were not using reliable contraceptive methods, were ineligible

Full citation Sample size Interventions Details Results Limitations

Chapple,C.R., Arano,P., N = 225 Eligible patients received During the single-blind Week 4 NICE guidelines manual. Bosch,J.L., De Ridder,D., placebo for 2 weeks as a run placebo run-in period all Patient satisfaction Appendix D: Kramer,A.E., Ridder,A.M., Solifenacin 2.5mg (SOL 2.5) = 41 in and then were randomized patients received two with treatment Methodology checklist: Solifenacin appears effective Solifenacin 5mg (SOL 5) = 37 to oral therapy with placebo capsules in the Not reported Randomised controlled and well tolerated in patients Solifenacin 10mg (SOL 10) = 35 solifenacin once daily (2.5mg, morning and one in the trials with symptomatic idiopathic Solifenacin 20mg (SOL 20) = 37 5mg, 10mg or 20mg), evening. Eligible patients Self-reported rate detrusor overactivity in a Tolterodine IR (TOL IR) = 37 tolterodine IR capsules 2 mg were randomized to receive of absolute A Selection bias placebo- and tolterodine- Placebo (PLA) = 38 twice daily, or placebo for 4 placebo or one of five active symptom A1 - Was there controlled phase 2 dose- weeks. treatments: solifenacin 2.5, 5, reduction per day appropriate finding study.[erratum 10, or 20 mg once daily, or Incontinence randomisation - Unclear - appears in BJU Int. 2004 Characteristics No dosage adjustment was immediate-release episodes - Mean not reported May;93(7):1135], BJU allowed during the study tolterodine 2 mg twice daily. (No SD reported) A2 - Was there adequate International, 93, 71-77, 2004 Solifenacin 2.5mg (SOL 2.5) = 41 SOL 2.5: -0.66 N = concealment - Yes - Solifenacin 5mg (SOL 5) = 37 40 identical packaging used Ref Id Solifenacin 10mg (SOL 10) = 35 Power calculation SOL 5: -0.83 N = A3 - Were groups Solifenacin 20mg (SOL 20) = 37 37 comparable at baseline - 220251 Tolterodine IR (TOL IR) = 37 With 40 patients per SOL 10: -0.79 N = Yes - No apparent Placebo (PLA) = 38 treatment group it was 33 differences between Country/ies where the considered possible to detect SOL 20: -0.58 N = groups at baseline

513

Study details Participants Interventions Methods Outcomes and Comments Results study was carried out Gender a difference of 0.63 sds/24 h 34 Level of bias: Low Not reported for changes between the TOL IR: -0.41 N = UK solifenacin and placebo 37 B Performance bias Age (years) group, with 80% power at a PLA: -0.28 N = 36 B1 - Did groups get Study type Not reported significance level of P < 0.05. same level of care - Yes Considering a sd of 2.9 Urgency episodes B2 - Were participants Randomised controlled trial Incontinence episodes/day - Mean voids/24 h, the detectable - Mean (No SD blinded - Yes - Study SOL 2.5: 1.6 (No SD reported) difference was 1.8 voids/24 h reported) was double-blind Aim of the study SOL 5: 1,5 (No SD reported) (with no adjustment for SOL 2.5: -1.07 N = B3 - Were clinical staff SOL 10: 1.7 (No SD reported) multiple comparisons). 40 blinded - Yes To evaluate the dose- SOL 20: 1.0 (No SD reported) SOL 5: -2.35 N = Level of bias: Low repsonse relationship of TOL IR: 1.5 (No SD reported) 37 solifenacin in patients with PLA: 1.7 (No SD reported) Intention to treat analysis SOL 10: -2.46 N = C Attrition bias OAB. 33 C1 - Was follow-up equal Urgency episodes/day Not reported SOL 20: -2.24 N = for both groups - Yes SOL 2.5: 5.9 (No SD reported) 34 C2 - Were groups Study dates SOL 5: 5.8 (No SD reported) TOL IR: -1.62 N = comparable for dropout - SOL 10: 5.3 (No SD reported) 37 Yes Not reported SOL 20: 5.2 (No SD reported) PLA: -1.03 N = 36 C3 - Were groups TOL IR: 5.7 (No SD reported) comparable for missing Source of funding PLA: 5.2 (No SD reported) Continence status data - Yes (zero episodes per Level of bias: Low Not reported Detrusor overactivity day) SOL 2.5 = 41/41 (100%) Incontinence D Detection bias SOL 5 = 37/37 (100%) episodes D1 - Was follow-up SOL 10 = 35/35 (100%) Not reported appropriate length - Yes SOL 20 = 37/37 (100%) D2 - Were outcomes TOL IR = 37/37 (100%) Urgency episodes defined precisely - Yes PLA = 38/38 (100%) Not reported D3 - Was a valid and reliable methods used to Duration of OAB Incontinence- assess outcome - Yes Not reported specific quality of D4 - Were investigators life blinded to intervention - Contiliffe QoL Unclear Inclusion criteria scale - Mean ± SD D5 - Were investigators endpoint blinded to confounding 1] Men and women aged 18–80 SOL 2.5: 50.3 ± factors - Unclear years were eligible to enter the 18.0 N = 39 Level of bias: Low study if they had idiopathic SOL 5: 48.5 ± 15.3

514

Study details Participants Interventions Methods Outcomes and Comments Results

detrusor overactivity (defined in N = 35 this study as phasic contractions of SOL 10: 44.4 ± ≥ 10 cmH2O, as assessed by filling 15.0 N = 30 Indirectness cystometry) within 6 months of SOL 20: 39.1 ± study initiation 12.8 N = 29 Does the study match TOL IR: 50.8 ± the review protocol in 19.4 N = 32 terms of: Exclusion criteria PLA: 57.9 ± 21.7 Population: Yes N = 33 Intervention: Yes 1] neurogenic detrusor overactivity Outcome: Yes 2] significant outlet obstruction Adverse effects Indirectness: None 3] urinary retention Any adverse effect 4] urodynamic stress incontinence SOL 2.5: 6/41 5] bladder stones (14.6%) 6] Urinary tract infection SOL 5: 12/37 Other information 7] interstitial cystitis (32.4%) 8] previous or current malignant SOL 10: 12/35 Data from SOl 2.5mg, disease of the pelvic organs (34.3%) SOL 10mg and SOL 9] previous pelvic radiation SOL 20: 21/37 20mg not used in review 10] diabetic neuropathy (56.8%) or network meta-analysis 11] concomitant anticholinergic TOL IR: 12/37 not used as these are not medications (32.4%) the recommended 12] had known or suspected PLA: 6/38 (15.8%) starting dose hypersensitivity to anticholinergic medications or lactose. Dry mouth 13] Women could not be pregnant SOL 2.5: 0/41 or breast-feeding and had to use (0%) approved contraception methods SOL 5: 5/37 throughout the study and for 1 (13.5%) month after completion. SOL 10: 5/35 (14.3%) SOL 20: 14/37 (37.8%) TOL IR: 9/37 (24.3%) PLA: 0/38 (0%)

Dropouts for any reason

515

Study details Participants Interventions Methods Outcomes and Comments Results

SOL 2.5: 5/41 (12.2%) SOL 5: 3/37 (8.1%) SOL 10: 7/35 (20.0%) SOL 20: 7/37 (18.9%) TOL IR: 5/37 (13.5%) PLA: 6/38 (15.8%)

Dropouts for adverse effects SOL 2.5: 1/41 (2.4%) SOL 5: 1/37 (2.7%) SOL 10: 3/35 (8.6%) SOL 20: 5/37 (13.5%) TOL IR: 1/37 (2.7%) PLA: 0/38 (0%)

Psychological outcomes Not reported

Clinical measures - Post-void residual volume Not reported

Week 12 Not applicable

516

Study details Participants Interventions Methods Outcomes and Comments Results

Full citation Sample size Interventions Details Results Limitations

Steers,W., Corcos,J., N = 395 Patients with confirmed After a pre-screening visit to Week 4 NICE guidelines manual. Foote,J., Kralidis,G., An eligibility for study inclusion assess eligibility, patients Not reported Appendix D: investigation of dose titration Darifenacin (DAR) = 268 were then randomized (2 : 1) entered a 2-week washout Methodology checklist: with darifenacin, an M3- Placebo (PLA) = 127 to 12 weeks of oral once-daily phase (if required) before Week 12 Randomised controlled selective receptor antagonist, treatment with darifenacin screening assessments, i.e. Patient satisfaction trials BJU International, 95, 580- controlled-release tablets a physical examination, with treatment 586, 2005 Characteristics 7.5 mg (269 patients) or including a 12-lead Not reported A Selection bias matching placebo (129). electrocardiogram recording, A1 - Was there Ref Id Gender - Female/N (% female) measurement of vital signs Self-reported rate appropriate DAR: 227/268 (84.7%) and PVR, and clinical of absolute randomisation - Unclear - 220252 PLA: 106/127 (83.5%) laboratory tests. Patients symptom not reported then entered a 2-week, reduction per day A2 - Was there adequate Country/ies where the Age (years) - Mean single-blind, placebo run-in Incontinence concealment - Unclear - study was carried out DAR: 57.5 (No SD reported) period, during which urinary episodes - Median not reported PLA: 58.5 (No SD reported) symptoms were recorded change from A3 - Were groups United States over the final 7 days using an baseline comparable at baseline - Incontinence episodes/day - electronic daily diary DAR: -3.0 (No Yes - No apparent Study type Median (MiniDoc AB, Stockholm, other data differences between DAR: 2.7 (No SD reported) Sweden). Blinding was reported) groups at baseline Randomised controlled trial PLA: 2.0 (No SD reported) maintained by a double- PLA: -1.86 (No Level of bias: Medium dummy design. Repeat clinic other data Aim of the study Urgency episodes/day - Median visits were after 2, 6 and reported) B Performance bias DAR: 8.3 (No SD reported) 12 weeks of treatment, B1 - Did groups get To determine the efficacy, PLA: 8.0 (No SD reported) patients having completed Urgency episodes same level of care - Yes tolerability and safety of a daily diaries for 7 days before DAR: -2.3 (No B2 - Were participants flexible-dosing strategy with Detrusor overactivity the 2-week and 12-week other data blinded - Yes - Study darifenacin, in which the dose Not reported visits. Patients were reported) was double-blind and could be adjusted from 7.5 to permitted to double their PLA: -0.9 (No double-dummy 15 mg once daily after 2 Duration of OAB dose of study medication other data B3 - Were clinical staff weeks of treatment if Not reported after 2 weeks of treatment if reported) blinded - Yes additional efficacy was additional efficacy was Level of bias: Low required by both the patient required by both the patient Continence status and physician, and if the Inclusion criteria and physician, and if the (zero episodes per C Attrition bias current dose was well current dose was well day) C1 - Was follow-up equal tolerated 1] patients aged ≥ 18 years with tolerated. Thereafter the Incontinence for both groups - Yes symptoms of OAB for at least 6 dose could not be adjusted; episodes C2 - Were groups months compliance with treatment Not reported comparable for dropout -

517

Study details Participants Interventions Methods Outcomes and Comments Results

Study dates 2] capable of independent toileting was evaluated from returned Yes 3] urge incontinence (at least five tablet counts Urgency episodes C3 - Were groups Not reported episodes per week), voiding Not reported comparable for missing frequency (at least eight voids per data - Yes Source of funding day), and urgency (a strong desire Power calculation Incontinence- Level of bias: Low to void at least once per day) specific quality of Study was funded by Pfizer Sample size was determined life D Detection bias using bootstrap simulation Not reported D1 - Was follow-up Exclusion criteria techniques based on efficacy appropriate length - Yes data observed for the primary Adverse effects D2 - Were outcomes 1] Patients with contraindications variable (number of Any adverse effect defined precisely - Yes to anticholinergic therapy (e.g. incontinence episodes per Not reported D3 - Was a valid and uncontrolled narrow-angle week) from a previous reliable methods used to glaucoma, urinary retention or placebo-controlled study of Dry mouth assess outcome - Yes gastric retention) darifenacin. From the results DAR: 10/269 D4 - Were investigators 2] clinically significant stress of the simulation it was (3.7%) blinded to intervention - incontinence calculated that 312 patients PLA: 18/129 Yes 3] BOO and/or a postvoid residual were required (darifenacin (14.2%) D5 - Were investigators urinary volume (PVR) of > 200 ml 208, placebo 104) for a two- blinded to confounding 4] pregnancy and lactation sided Wilcoxon rank-sum test Dropouts for any factors - Unclear 5] genitourinary conditions that to have 90% power to detect reason Level of bias: Low could cause urinary symptoms a between-group difference DAR: 26/269 6] fecal impaction or severe at the 5% significance level. (9.7%) constipation (two or fewer bowel Allowing for a 15% PLA: 12/129 Indirectness movements per week) withdrawal rate, 372 patients (9.3%) 7] urogenital surgery within the were required to be Does the study match previous 6 months randomized (darifenacin 248, Dropouts for the protocol in terms of: 8] bladder biopsy in the previous placebo 124). adverse effects 1] Population: Yes 30 days DAR: 18/269 2] Interventions: Yes 9] patients with an indwelling (6.7%) 3] Outcome: Yes catheter and those using Intention to treat analysis PLA: 4/129 (3.1%) Indirectness: None intermittent self-catheterization 10] presence of clinically Not reported Psychological significant disease outcomes Other information 11] patients who intended to start Not reported a bladder-training programme Of the 268 patients during the study Clinical measures treated with darifenacin, - Post-void 158 (59%) increased the Concomitant treatment with residual volume dose to 15 mg after

518

Study details Participants Interventions Methods Outcomes and Comments Results

anticholinergic or antispasmodic Not reported 2 weeks of treatment, drugs (including drugs with compared with 86 (68%) significant anticholinergic effects, of the 127 who had a e.g. imipramine), opioids and other pseudo-dose increased drugs known to cause significant in the placebo group (no constipation, hormone- significant difference). replacement therapy (unless taken Average dose at for > 2 months), and drugs known endpoint = 11.9 mg to be potent cytochrome P450 3A4 inhibitors (e.g. ketoconazole) was not permitted. Men receiving finasteride for BPH were required to have been on a stable dose for ≥ 6 months before study inclusion. Other medications considered necessary for the patient's welfare were permitted, provided the treatment regimen remained stable during the study.

Full citation Sample size Interventions Details Results Limitations

Abrams,P., Freeman,R., N = 293 Patient were randomised to Efficacy was measure by a 6- Week 4 NICE guidelines manual. Anderstrom,C., tolterodine immediate release point rating scale Not reported Appendix D: Mattiasson,A., Tolterodine, a Tolterodine immediate release (2mg twice daily), oxybutynin documenting problems and Methodology checklist: new antimuscarinic agent: as 2mg (TOL IR) = 118 immediate release (5mg three severity of problems at Week 12 Randomised controlled effective but better tolerated Oxybutynin immediate release time daily) and placebo baseline and at 12 weeks Patient satisfaction trials than oxybutynin in patients 5mg (OXY IR) = 118 with treatment with an overactive bladder, Placebo (PLA) = 57 Adverse effects were noted OXY IR: 58/118 A Selection bias British Journal of and severity recorded (49%) A1 - Was there UrologyBr.J.Urol., 81, 801- TOL IR: 59/118 appropriate 810, 1998 Characteristics (50%) randomisation - Unclear - Power calculation PLA: 27/57 (47%) not reported Ref Id Gender - Female/N (% female) A2 - Was there adequate TOL IR: 91/118 (77.1%) The number of patients Self-reported rate concealment - Yes - 220263 OXY IR: 88/118 (74.6%) required to detect a true of absolute identical packaging used PLA: 43/57 (75.4%) difference between placebo symptom A3 - Were groups

519

Study details Participants Interventions Methods Outcomes and Comments Results

Country/ies where the and active treatment of a reduction per day comparable at baseline - study was carried out Age (years) - Range reduction in 1.5 in the mean Incontinence Yes - No apparent TOL IR: 19 - 80 frequency of micturition / 24 episodes - Mean ± differences between UK, Ireland & Sweden OXY IR: 21 - 80 hours using a significance SD change from groups at baseline PLA: 26 - 78 level of 5% and a power of baseline Level of bias: Low Study type 80% was estimated to be 47 OXY IR: -1.7 ± 3.1 Incontinence episodes/day - in the placebo group and 95 N = 88 B Performance bias Randomised controlled trial Range in each active treatment TOL IR: -1.3 ± 3.2 B1 - Did groups get TOL IR: 0.1 - 24.0 group. N = 92 same level of care - Yes Aim of the study OXY IR: 0.1 - 24.0 PLA: -0.9 ± 1.5 N B2 - Were participants PLA: 0.1 - 23.5 = 57 blinded - Yes - Study To compare the efficacy and Intention to treat analysis was double-blind safety of tolterodine with that Urgency episodes/day Urgency episodes B3 - Were clinical staff of oxybutynin in patients with Not reported Reported but no details Not reported blinded - Yes overactive bladder provided Level of bias: Low Detrusor overactivity Continence status Not reported (zero episodes per C Attrition bias Study dates day) C1 - Was follow-up equal Duration of OAB Incontinence for both groups - Yes July 1995 to July 1996 Not reported episodes C2 - Were groups Not reported comparable for dropout - Source of funding Unclear - no dropouts Inclusion criteria Urgency episodes reported Supported by Pharmacia & Not reported C3 - Were groups Upjohn AB 1] 18 years or older comparable for missing 2] urodynamically proven bladder Incontinence- data - Yes overactivity specific quality of Level of bias: Low 3] increased frequency of life micturition (≥ micturition / 24 Not reported D Detection bias hours) and urge incontinence (≥ 1 D1 - Was follow-up incontinent episode / 24 hours) Adverse effects appropriate length - Yes and/or urgency during a 2 week Any adverse effect D2 - Were outcomes washout period OXY IR: 114/118 defined precisely - Yes (97%) D3 - Was a valid and TOL IR: 105/118 reliable methods used to Exclusion criteria (89%) assess outcome - Yes PLA: 46/57 (81%) D4 - Were investigators Not reported blinded to intervention - Dry mouth Unclear

520

Study details Participants Interventions Methods Outcomes and Comments Results

OXY IR: 102/118 D5 - Were investigators (86%) blinded to confounding TOL IR: 59/118 factors - Unclear (50%) Level of bias: Low PLA: 12/57 (21%)

Dropouts for any Indirectness reason Not reported Does the study match the review protocol in Dropouts for terms of: adverse effects Population: Yes OXY IR: 20/118 Intervention: Yes (17%) Outcome: Yes TOL IR:10/118 Indirectness: None (8%) PLA: 7/57 (12%) Other information Psychological outcomes None Not reported

Clinical measures Not reported

Full citation Sample size Interventions Details Results Limitations

Jacquetin,B., Wyndaele,J., N = 251 Eligible patients were Eligible patients were Week 4 NICE guidelines manual. Tolterodine reduces the randomised to 4-week randomised to tolterodine Patient satisfaction Appendix D: number of urge incontinence Tolterodine immediate release treatment with either placebo 1mg or 2mg twice daily or with treatment Methodology checklist: episodes in patients with an 1mg (TOL IR 1) = 97 or tolterodine 1 or 2mg twice placebo. Dosage reduction Not reported Randomised controlled overactive bladder, European Tolterodine immediate release daily (bd) was not permitted. trials Journal of Obstetrics, 2mg (TOL IR 2) = 103 Self-reported rate Gynecology and Placebo (PLA) = 51 of absolute A Selection bias Reproductive BiologyEur J Power calculation symptoms A1 - Was there Obstet Gynecol Reprod Biol, reduction/day - appropriate A power analysis (χ = 5%, Mean ± SD randomisation - Yes -

521

Study details Participants Interventions Methods Outcomes and Comments Results

98, 97-102, 2001 Characteristics 80% power) indicated that Incontinence computerised 250 patients would be episodes randomisation Ref Id Gender - Female/N (% female) required TOL IR 1: -1.1 ± A2 - Was there adequate TOL IR 1: 74/97 (76.3%) 2.2 N = 78 concealment - Yes - 220282 TOL IR 2: 84/103 (81.6%) TOL IR 2: -1.3 ± randomisation numbers PLA: 41/51 (80.4%) Intention to treat analysis 1.8 N = 79 served as packaging for Country/ies where the PLA: -0.4 ± 1.9 n = interventions study was carried out Age (years) - Range Not reported 39 A3 - Were groups TOL IR 1: 18 - 85 comparable at baseline - Belgium, France TOL IR 2: 21 - 88 Urgency episodes Yes PLA: 19 - 89 Not reported Level of bias: Low Study type Incontinence episodes/week - Continence status B Performance bias Randomised controlled trial Range (Zero episodes per B1 - Did groups get TOL IR 1: 0.1 - 24.0 day) same level of care - Yes Aim of the study TOL IR 2: 0.1 - 24.0 Incontinence B2 - Were participants PLA: 0.1 - 8.4 episodes blinded - Yes - Study To compare the efficacy and Not reported was double-blind and tolerability of tolterodine at Urgency episodes/day double-dummy fixed doses with placebo in Not reported Urgency episodes B3 - Were clinical staff patients with overactive Not reported blinded - Yes bladder Detrusor overactivity Level of bias: Low TOL IR 1: 97/97 (100%) Incontinence- TOL IR 2: 103/103 (100%) specific quality of C Attrition bias Study dates PLA: 51/51 (100%) life C1 - Was follow-up equal Not reported for both groups - Yes Not reported Duration of OAB C2 - Were groups Not reported Adverse effects comparable for dropout - Source of funding Any adverse effect Yes TOL IR 1: 39/97 C3 - Were groups Supported by Pharmacia Inclusion criteria (40%) comparable for missing Corporation TOL IR 2: 55/103 data - Yes 1] 18 years and older (53%) Level of bias: Low 2] urodynamicall proven overactive PLA: 16/51 (31%) bladder D Detection bias 3] symptoms of urgency and/or Dry mouth D1 - Was follow-up urge incontinence (≥ 1 TOL IR 1: 20/97 appropriate length - Yes incontinence episode / 24 hours) (21%) D2 - Were outcomes with increased frequency of TOL IR 2: 35/103 defined precisely - Yes

522

Study details Participants Interventions Methods Outcomes and Comments Results

miturition (≥ 8 micturitions / 24 (34%) D3 - Was a valid and hours) during a 2 week washout PLA: 3/51 (6%) reliable methods used to period assess outcome - Yes Dropout for any D4 - Were investigators reason blinded to intervention - Exclusion criteria Not reported Yes D5 - Were investigators 1] significant stress incontinence Dropouts for blinded to confounding 2] hepatic or renal disease adverse effects factors - Unclear 3] symptomatic or recurrent urinary TOL IR 1: 3/97 Level of bias: Low tract infection (3%) 4] interstitial cystitis TOL IR 2: 2/103 5] haematuria (2%) Indirectness 6] clinical significant voiding PLA: 1/51 (%) difficulty Does the study match 7] patients receiving bladder Psychological the protocol in terms of: training, electrostimulation therapy outcomes 1] Population: Yes or indwelling catheter or Not reported 2] Interventions: Yes intermittent catheterisation 3] Outcome: Yes 8] pregnant or nursing women Clinical measures Indirectness: None 9] women of childbearing age not Not reported using reliable contraception Week 12 Other information Not applicable Data from TOL IR 2 arm used in review

Full citation Sample size Interventions Details Results Limitations

Dorschner,W., N = 98 Following a week placebo Efficacy was measured using Week 4 NICE guidelines manual. Stolzenburg,J.U., run-in, patients were a mictrition diary, uroflow, Patient satisfaction Appendix D: Griebenow,R., Halaska,M., Propiverine (PRO) = 49 randomised to propiverine ultrasound and an urge score with treatment Methodology checklist: Schubert,G., Murtz,G., Placebo (PLA) = 49 (15mg three times a day) or Not reported Randomised controlled Frank,M., Wieners,F., placebo (three times a day) trials Efficacy and cardiac safety of for a 4 week period. Power calculation Self-reported rate propiverine in elderly patients Characteristics of absolute A Selection bias - a double-blind, placebo- Not reported symptom A1 - Was there Gender - Female/N (% female)

523

Study details Participants Interventions Methods Outcomes and Comments Results controlled clinical study, TOL IR: 40/49 (81.6%) reduction per day appropriate European UrologyEur.Urol., PLA: 37/49 (75.5%) Incontinence randomisation - Unclear - 37, 702-708, 2000 Intention to treat analysis episodes - Mean not reported Age (years) - Range (No SD) change A2 - Was there adequate Ref Id PRO: 68.4 ± 6.5 Not reported from baseline concealment - Unclear - PLA: 66.5 ± 6.0 PRO IR: -0.6 (No not reported 220285 SD) N not reported A3 - Were groups Incontinence episodes/day - PLA: -0.1 (No SD) comparable at baseline - Country/ies where the Range N not reported Yes - No apparent study was carried out Not reported differences between Urgency episodes groups at baseline Germany Urgency episodes/day Not reported Level of bias: Medium Not reported Study type Continence status B Performance bias Detrusor overactivity (zero episodes per B1 - Did groups get Randomised controlled trial Not reported day) same level of care - Yes Incontinence B2 - Were participants Aim of the study Duration of OAB episodes - blinded - Yes - Study Not reported reported as was double-blind To confirm the efficacy of symptom free B3 - Were clinical staff propiverine in patients with PRO IR: 18/43 blinded - Yes detrusor instability Inclusion criteria (41.9%) Level of bias: Low PLA: 13/45 1] Aged > 60 years (28.9%) C Attrition bias Study dates 2] frequency more than 7 episodes C1 - Was follow-up equal per day Urgency episodes for both groups - Yes Not reported 3] urinary incontinence more than - reported as C2 - Were groups 0 episodes per day symptom free comparable for dropout - Source of funding 4] micturition volume less than PRO IR = 15/49 Unclear - not reported 300ml/micturition (30.6%) which group the 9 Supported by Apogepha PLA: 5/49 (10.2%) dropouts were in

C3 - Were groups Incontinence- comparable for missing Exclusion criteria specific quality of data - No life Level of bias: Medium 1] acute urinary tract infection Nor reported 2] mechanical or functional bladder D Detection bias emptying disorers Adverse effects D1 - Was follow-up 3] residual volume of more than Any adverse effect appropriate length - Yes

524

Study details Participants Interventions Methods Outcomes and Comments Results

0% of the voided volume Not reported D2 - Were outcomes 4] renal insufficiency defined precisely - Yes 5] concomitant medication Dry mouth D3 - Was a valid and interfering with drug studied Not reported reliable methods used to assess outcome - Yes Dropouts for any D4 - Were investigators reason blinded to intervention - Not reported Yes D5 - Were investigators Dropouts for blinded to confounding adverse effects factors - Unclear Not reported Level of bias: Low

Psychological outcomes Indirectness Not reported Does the study match Clinical measures the protocol in terms of: Post-void residual 1] Population: Yes volume 2] Interventions: Yes PRO IR: 7.2 ± 3] Outcome: Yes 12.4 ml N = 49 Indirectness: None PLA: 5.9 ± 8.0 ml N = 49 Other information Week 12 Not reported A total of 107 were enrolled but 9 were excluded from efficacy analysis but not reported from which group.

Full citation Sample size Interventions Details Results Limitations

Haab,F., Stewart,L., N = 561 After a week placebo run-in, Efficacy was evaluated at Week 4 results NICE guidelines manual. Dwyer,P., Darifenacin, an M3 patients were randomised weeks, 6 and 1 using Not reported Appendix D: selective receptor antagonist, Darifenacin 3.75mg (DAR 3,75) = using unequal allocation electronic patient diaries in Methodology checklist:

525

Study details Participants Interventions Methods Outcomes and Comments Results is an effective and well- 53 (1:4:2:3) to darifencain the 1-week period before Week 12 results Randomised controlled tolerated once-daily treatment Darifenacin 7.5mg (DAR 7.5) = 3.75mg, 7.5mg, 15mg or each clinic visit Patient satisfaction trials for overactive bladder., 229 placebo using blocks of 10. with treatment European UrologyEur.Urol., Darifenacin 15mg (DAR 15) = 115 Not reported A Selection bias 45, 420-429, 2004 Placebo (PLA) = 164 Power calculation A1 - Was there Self-reported rate appropriate Ref Id Sample size was determined of absolute randomisation - Yesr - Characteristics by a computer-generated symptom random blocks used 220287 simulation analysis using a reduction per day - A2 - Was there adequate Gender - Female/N (% female) bootstrap re-sampling Median (95% CI) concealment - Yes - Country/ies where the DAR 3.75: 44/53 (83.0%) technique, whereby data are change from randomisation numbers study was carried out DAR 7.5: 194/229 (84/7%) used repeatedly to simulate baseline served as packaging for DAR 15: 100/115 (87.0%) the inference based on the Incontinence interventions France PLA: 138/164 (78.4%) primary coparison of 15mg episodes A3 - Were groups and 7.5mg darifenacin DAR 3.75: -8.6 comparable at baseline - Study type Age (years) - Mean ± SD versus placebo. Based on (No CI) Yes - No apparent DAR 3.75: 56.7 (No SD reported) assumptions and calculation, DAR 7.5: -9.0 (No differences between Randomised controlled trial DAR 7.5: 57.7 (No SD reported) 200 patients were requiredto CI) groups at baseline DAR 15: 56.6 (No SD reported) complete the study in the DAR 15: -10.4 (No Level of bias: Low Aim of the study PLA: 56.5 (No SD reported) 7.5mg group and 150 in the CI) placebo group to detect a PLA: -7.6 (No CI) B Performance bias To evaluate the clinical Incontinence episodes/day - difference at 80% power. B1 - Did groups get efficacy of darifenacin over a Median (95% CI) Urgency episodes same level of care - Yes broad range of OAB DAR 3.75: 9.6 (7.0 to 13.0) DAR 3.75: - B2 - Were participants parameters as well as to DAR 7.5: 9.3 (8.0 to 11.0) Intention to treat analysis 1.8 (No CI) blinded - Yes - Study assess its tolerability and DAR 15: 8.0 (6.0 to 11.0) DAR 7.5: -2.0 (No was double-blind safety profile PLA: 11.0 (9.5 to 14.9) Full analysis set used. CI) B3 - Were clinical staff DAR 15: -2.0 (No blinded - Yes Urgency episodes/day CI) Level of bias: Low Study dates DAR 3.75: 7.5 (No CI reported) PLA: -0.9 (No CI) DAR 7.5: 7.7 (No CI reported) C Attrition bias Not reported DAR 15: 8.0 (No CI reported) Continence status C1 - Was follow-up equal PLA: 8.30 (No CI reported) (zero episodes per for both groups - Yes Source of funding day) C2 - Were groups Detrusor overactivity Not reported comparable for dropout - Study funded by Pfizer Inc Not reported Yes Incontinence- C3 - Were groups Duration of OAB specific quality of comparable for missing Not reported life data - Yes

526

Study details Participants Interventions Methods Outcomes and Comments Results

Not reported Level of bias: Low

Inclusion criteria Adverse effects D Detection bias Any adverse effect D1 - Was follow-up 1] urge incontinence (at least 5 but DAR 3.75: 24/53 appropriate length - Yes no more that 50 per week) (45.3%) D2 - Were outcomes 2] frequency of micturition (a mean DAR 7.5: 120/229 defined precisely - Yes of least 8 voids per 4 hours) (52.4%) D3 - Was a valid and 3] urgency (a strong desire to void DAR 15: 61/115 reliable methods used to at least once a day) (53%) assess outcome - Yes PLA: 66/164 D4 - Were investigators (40.2%) blinded to intervention - Exclusion criteria Yes Dry mouth D5 - Were investigators 1] contraindications ot DAR 3.75: 7/53 blinded to confounding antimuscarinic drugs (13.2%) factors - Unclear 2] clinically significant stress DAR 7.5: 43/229 Level of bias: Low incontinence (18.8%) 3] clinically significant bladder DAR 15: 36/115 outlet obstruction and/or a post- (31.3%) Indirectness void residual volume > 200ml PLA: 14/164 4] geniturinary conditions that (8.5%) Does the study match could cause urinary symptoms the protocol in terms of: 5] recent urogenital surgery or Dropouts for any 1] Population: Yes hepatic disease reason 2] Interventions: Yes DAR 3.75: 4/53 3] Outcome: Yes (7.5%) Indirectness: None DAR 7.5: 10/229 (4.4%) DAR 15: 8/115 Other information (7.8%) PLA: 12/164 (7.3%)

Dropouts for adverse effects DAR 3.75: 0/53 (0%) DAR 7.5: 3/229

527

Study details Participants Interventions Methods Outcomes and Comments Results

(1.3%) DAR 15: 3/115 (2.6%) PLA: 2/164 (1.2%)

Psychological outcomes Not reported

Clinical measures - Post-void residual volume Not reported

Full citation Sample size Interventions Details Results Limitations

Drutz,H.P., Appell,R.A., N = 277 Patients completed a 2 week Patients were seen at study Week 4 NICE guidelines manual. Gleason,D., Klimberg,I., placebo run in before entry, at baseline and after 2, Not reported Appendix D: Radomski,S., Clinical efficacy Tolterodine IR (TOL IR) = 109 randomisation to either 4, 8 and 12 weeks of Methodology checklist: and safety of tolterodine Oxybutynin IR (OXY IR) = 112 tolterodine mg bid, oxybutynin treatment Week 12 Randomised controlled compared to oxybutynin and Placebo (PLA) = 56 5mg tid or placebo Patient satisfaction trials placebo in patients with with treatment overactive bladder, Power calculation Not reported A Selection bias International Urogynecology A1 - Was there Journal, 10, 283-289, 1999 Characteristics Preliminary micturition diary Self-reported rate appropriate data suggested a standard of absolute randomisation - Unclear - Ref Id Gender - Female/N (% female) deviation of three micturitions symptom not reported TOL IR: 88/109 (80.7%) per 24 hours. In order to reduction per day A2 - Was there adequate 220304 OXY IR: 81/112 (72.3%) have an 80% chance of Incontinence concealment - Unclear - PLA: 45/56 (80.4%) detecting a difference of 1.5 episodes - Mean ± Not reported Country/ies where the in reduction of micturition per SD change from A3 - Were groups study was carried out Age (years) - Mean 24 hours (x = 5%) using a baseline comparable at baseline - TOL IR: 63.0 1:2:2 randomisation ratio. It TOL IR: -1.7 ± 2.0 Yes - No apparent United states & Canada OXY IR: 66.3 was necessary to recruit 47 N = 60 differences between PLA: 62.1 into the placebo group and OXY IR: -1.7 ± 1.7 groups at baseline Study type 95 into the tolterodine and N = 39 Level of bias: Medium Incontinence episodes/day - oxybutynin groups. PLA: -1.0 ± 2.2 N

528

Study details Participants Interventions Methods Outcomes and Comments Results

Randomised controlled trial Range = 33 B Performance bias TOL IR: 7.7 - 22.0 B1 - Did groups get Aim of the study OXY IR: 7.1 - 31.4 Intention to treat analysis Urgency episodes same level of care - Yes PLA: 6.6 - 21.9 Not reported B2 - Were participants To compare the efficacy and Not reported blinded - Yes - Study safety of tolterodine 2mg bid, Urgency episodes/day Continence status was double-blind and oxybutynin 5mg tid and Not reported (zero episodes per double-dummy placebo in patients with day) B3 - Were clinical staff detrusor overactivity and Detrusor overactivity Incontinence blinded - Yes symptoms of frequency and Not reported episodes Level of bias: Low either urge incontinence TOL IR: 23/103 and/or urgency Duration of OAB (22.3%) C Attrition bias Not reported OXY IR: 19/90 C1 - Was follow-up equal (21.1%) for both groups - Yes Study dates PLA: Not reported C2 - Were groups Inclusion criteria comparable for dropout - Not reported Urgency episodes Yes 1] aged 18 years or more Not reported C3 - Were groups Source of funding 2] postmenopausla, surgically comparable for missing sterile or using using an adequate Incontinence- data - Yes Funded by Pharmacia & contraceptive method specific quality of Level of bias: Low Upjohn, AB 3] evidence of detrusor instability life or subtracted cystometry Not reported D Detection bias 4] urinary frequency (at leats 8 D1 - Was follow-up times per day) and either urge Adverse effects appropriate length - Yes incontinence or urinary urgency Any adverse effect D2 - Were outcomes TOL IR: 85/109 defined precisely - Yes (78.0%) D3 - Was a valid and Exclusion criteria OXY IR: 101/112 reliable methods used to (90.2%) assess outcome - Yes 1] clinically significant stress PLA: 42/56 D4 - Were investigators incontinence (75.0%) blinded to intervention - 2] hepatic or renal disease Yes 3] recurrent urinary tract infection Dry mouth D5 - Were investigators 4] interstitial cystitis TOL IR: 33/109 blinded to confounding 5] uninvestiagted hematuria or (30.3%) factors - Unclear hematuria secondary to malignant OXY IR: 77/112 Level of bias: Low disease (68.8%) 6] indwelling catheter or PLA: 8/56 (14.3%)

529

Study details Participants Interventions Methods Outcomes and Comments Results

intermittent catheterisation Indirectness 7] treatemnt with an investigational Dropouts for any drug in 2 months prior to study reason Does the study match 8] previous treatment with TOL IR: 12/109 the protocol in terms of: tolterodine (11.0%) 1] Population: Yes 9] electrostimulation therapy, OXY 35/112 2] Interventions: Yes antimuscarininc or bladder training (31.3%) 3] Outcome: Yes with 14 days of entry to study PLA: 8/56 (14.3%) Indirectness: None 10] clinically significant voiding difficulty Dropouts for adverse effects Other information TOL IR: 7/109 (6.4%) OXY IR: 23/112 (20.5%) PLA: 4/56 (7.1%)

Psychological outcomes Not reported

Clinical measures - Post-void residual volume Not reported

Full citation Sample size Interventions Details Results Limitations

Malone-Lee,J.G., Walsh,J.B., N = 177 Patients were randomised in Efficay was assessed by way Week 4 NICE guidelines manual. Maugourd,M.F., Tolterodine: a 3:3:2 ration to tolderodine of a week's micturition diary Patient satisfaction Appendix D: a safe and effective treatment Tolterodine IR 1mg bid (TOL IR 1) IR img, tolterodine IR mg or completed before the week 4 with treatment Methodology checklist: for older patients with = 61 placebo for a 4 week period assessment. Not reported Randomised controlled overactive bladder., Journal Tolterodine IR 2mg bid (TOL IR 2) trials of the American Geriatrics = 73 Self-reported rate SocietyJ.Am.Geriatr.Soc., 49, Placebo (PLA) = 43 Power calculation of absolute A Selection bias 700-705, 2001 symptom A1 - Was there A sample size of 160 patients reduction per day appropriate

530

Study details Participants Interventions Methods Outcomes and Comments Results

Ref Id Characteristics was chosen to have at least Incontinence randomisation - Unclear - 100 older patients on active episodes - Median not reported 220325 Gender - Female/N (% female) treatment. All statistical tests change 95% CI A2 - Was there adequate TOL IR 1: 38/61 (62.3%) were two-sided and had a from baseline concealment - Yes - Country/ies where the TOL IR 2: 45/73 (61.6%) significance level of 0.05 TOL IR 1: -0.3 (- identical packaging used study was carried out PLA: 32/43 (74.4%) 0.8 to -0.1) N not A3 - Were groups reported comparable at baseline - UK Age (years) - Range Intention to treat analysis TOL IR 2: -0.7 (- No - Nean number of TOL IR 1: 65 - 90 1.3 to -0.2) N not incontinence episodes Study type TOL IR 2: 62 - 92 Not reported reported per day in placebo group PLA: 66 - 88 PLA: 0.0 (-0.4 to - was twice the other Randomised controlled trial 0.3) N not reported groups Incontinence episodes/day - Mean Level of bias: Low Aim of the study ± SD Urgency episodes TOL IR 1: 2.3 (No SD reported) Not reported B Performance bias To compare the clinical saftey OXY IR: 2.8 (No SD reported) B1 - Did groups get and efficacy of two doses of PLA: 5.1 (No SD reported) Continence status same level of care - Yes tolterodine versus placebo in (zero episodes per B2 - Were participants older patients with overactive Urgency episodes/day day) blinded - Yes - Study bladder presenting with Not reported Not reported was double-blind urgency, frequency and/or B3 - Were clinical staff urge incontinence Detrusor overactivity Incontinence- blinded - Yes Not reported specific quality of Level of bias: Low life Study dates Duration of OAB Not reported C Attrition bias Not reported C1 - Was follow-up equal Not reported Adverse effects for both groups - Yes Any adverse effect C2 - Were groups Source of funding Inclusion criteria TOL IR 1: 43/61 comparable for dropout - (70.5%) Yes Supported by Pharmacia & 1] aged 65 or older with urgency, TOL IR 2: 53/73 C3 - Were groups Upjohn urinary frequency (8 or more (47.9%) comparable for missing micturitions per day) and/or urge PLA: 27/43 data - Yes incontinence (1 or more (62.8%) Level of bias: Low incontinence episodes per day) 2] mobile and able to attend an Dry mouth D Detection bias outpatient clinic TOL IR 1: 18/61 D1 - Was follow-up (29.5%) appropriate length - Yes TOL IR 2: 35/73 D2 - Were outcomes

531

Study details Participants Interventions Methods Outcomes and Comments Results

Exclusion criteria (47.9%) defined precisely - Yes PLA: 4/43 (9.3%) D3 - Was a valid and 1] significant stress incontinence reliable methods used to 2] urinary outflow obstruction Dropouts for any assess outcome - Yes 3] urinary retention reason D4 - Were investigators 4] symptomatic urinary infection TOL IR 1: 8/61 blinded to intervention - 5] interstitial cystitis (13.1%) Unclear 6] unexplained hematuria TOL IR 2: 9/73 D5 - Were investigators 7] use of urinary catheterisation or (12.3%) blinded to confounding electrostimulation PLA: 4/43 (9.3%) factors - Unclear 8] hepatic and renal disease with Level of bias: Low markers twice the upper limit of Dropouts for normal reference range adverse effects 9] concomitant antimuscarinic TOL IR 1: 4/61 Indirectness medication (6.6%) 10] previous treatment iwth TOL IR 2: 7/73 Does the study match tolterodine (9.6%) the review protocol in 11] exposure to any other PLA: 1/43 (2.3%) terms of: investigational drug in preceding 3 Population: Yes months Psychological Intervention: Yes outcomes Outcome: Yes Not reported Indirectness: None

Clinical measures Not reported Other information

Week 12 Not reported

Full citation Sample size Interventions Details Results Limitations

Dmochowski,R.R., N = 520 Following symptom Evaluations included patient Week 4 NICE guidelines manual. Davila,G.W., Zinner,N.R., stabilization or treatment urinary diaries, incontinence Not reported Appendix D: Gittelman,M.C., Oxybutynin transdermal 1.3mg withdrawal 520 adult patients specific quality of life and Methodology checklist: Saltzstein,D.R., Lyttle,S., (OXY TD 1.3) = 130 were randomized to 12 weeks safety. Week 12 Randomised controlled Sanders,S.W., For The Oxybutynin transdermal 2.8mg of double-blind daily Patient satisfaction trials Transdermal Oxybutynin (OXY TD 2.8) = 133 treatment with 1.3, 2.6 or 3.9 Patients received basic with treatment

532

Study details Participants Interventions Methods Outcomes and Comments Results

Study Group., Efficacy and Oxybutynin transdermal 3.9mg mg. oxybutynin TDS or information on bladder Not reported A Selection bias safety of transdermal (OXY TD 3.9) = 125 placebo administered twice function, bladder control and A1 - Was there oxybutynin in patients with Placebo (PLA) = 13 weekly, followed by a 12- fluid management and were Self reported rate appropriate urge and mixed urinary week open-label, dose instruucted to maintain usual of absolute randomisation - Unclear - incontinence, Journal of titration period to assess fluid intake. symptom not reported UrologyJ.Urol., 168, 580-586, Characteristics efficacy and safety further. reduction per day A2 - Was there adequate 2002 Incontinence concealment - Unclear - Gender - Female/N (% female) Power calculation episodes not reported Ref Id OXY 1.3: 120/130 (92.3%) OXY TD 1.3mg: - A3 - Were groups OXY 2.8: 123/133 (92.5%) Sample size was calculated 2.6 ± 2.8 N = 128 comparable at baseline - 220334 OXY 3.9: 114/125 (91.2%) based on data from a previos OXY TD 2.8mg: - Yes - No apparent PLA: 121/132 (91.7%) study. Assuming a common 2.4 ± 2.6 N = 131 differences between Country/ies where the standard deviation of 17 OXY TD 3.9mg: - groups at baseline study was carried out Age (years) - Mean ± SD episodes per week and 90 3.1 ± 2.5 N = 123 Level of bias: Low OXY 1.3: 61.5 ± 11.3 patients per treatment group, PLA: -2.7 ± 3.0 N United States OXY 2.8: 61.9 ± 13.5 a difference of 10 episodes = 130 B Performance bias OXY 3.9: 59.4 ± 14.5 could be detected with 95% B1 - Did groups get Study type PLA: 62.7 ± 13.1 power. All statistical tests Urgency episodes same level of care - Yes were conducted as 0.05 Not reported B2 - Were participants Randomised controlled trial Incontinence episodes/week blinded - Yes - Study Unclear Continence status was double-blind Aim of the study Intention to treat analysis Incontinence B3 - Were clinical staff Urgency episodes/day epsiodes blinded - Yes To evaluate the efficacy and Not reported Last observation carried OXY TD 1.3mg: Level of bias: Low safety of a transdermal forward (LOCF) used. 12/130 (10.0%) oxybutynin formulation in a Detrusor overactivity OXY TD 2.8mg: C Attrition bias general population of patients Not reported 7/133 (5.2%) C1 - Was follow-up equal with moderate to severe OXY TD 3.9mg: for both groups - Yes overactive bladder. Duration of OAB 16/125 (12.8%) C2 - Were groups OXY 1.3: 9.1 ± 10.3 PLA: 10/132 comparable for dropout - OXY 2.8: 8.9 ± 8.8 (7.6%) Yes Study dates OXY 3.9: 9.9 ± 9.8 C3 - Were groups PLA: 9.1 ± 9.1 Urgency episodes comparable for missing Not reported Not reported data - Yes Level of bias: Low Source of funding Inclusion criteria Incontinence- specific quality of D Detection bias Not reported but all authors 1] 18 years or more with life D1 - Was follow-up have interest in Watson overactive bladder Not reported appropriate length - Yes

533

Study details Participants Interventions Methods Outcomes and Comments Results

Pharmaceuticals 2] 10 or more urinary incontinence D2 - Were outcomes episodes over a 7-day diary with Adverse effects defined precisely - Yes either pure urge or predominant Dropouts for any D3 - Was a valid and urge reason reliable methods used to 3] 56 or more voids per week Not reported assess outcome - Yes 4] average recorded void volume D4 - Were investigators of less than 350ml Dropouts for blinded to intervention - adverse effects Yes Not reported D5 - Were investigators Exclusion criteria blinded to confounding Any adverse factors - Unclear 1] incontinence due to chronic effects Level of bias: Low illness, anatonomical weakness or Not reported concomitant medications 2] lower urinary tract surgery in Dry mouth Indirectness previos 8 months OXY TD 1.3mg: 3] interstitial cystitis 6/120 (5.0%) Does the study match 4] urethral syndrome OXY TD 2.8mg: the protocol in terms of: 5] painful bladder syndrome and 9/133 (6.8%) 1] Population: Yes overflow urinary incontinence OXY TD 3.9mg: 2] Interventions: Yes 6] alcohol/drug abuse in previous 12/125 (9.6%) 3] Outcome: Yes year PLA: 11/132 Indirectness: None 7] known hypersensitivity to (8.3%) oxybutynin 8] active skin disorder Psychological Other information 9] narrow angle glaucoma or or outcomes shallow anterior chamber Not reported 10] prostate specific antigen 11] excessive caffeine Clinical measures consumption - Post-void residual volume Not reported

Full citation Sample size Interventions Details Results Limitations

Cardozo,L., Lisec,M., N = 911 Patients were allocated to Efficacy was assessed by by 4 weeks NICE guidelines manual. Millard,R., van Vierssen,Trip once-daily solifenacin 5mg, 3-day micturition diaries for Not reported Appendix D:

534

Study details Participants Interventions Methods Outcomes and Comments Results

O., Kuzmin,I., Solifenacin 5mg (SOL 5) = 286 solifenacin 10mg, or placebo 3-day before each Methodology checklist: Drogendijk,T.E., Huang,M., Solifenacin 10mg (SOL 10) = 290 for a 1 week period assessment at 4 week 12 weeks results Randomised controlled Ridder,A.M., Randomized, Placebo (PLA) = 281 intervals. Primary outcome Patient satisfaction trials double-blind placebo was change in the number of with treatment controlled trial of the once *4 did not receive any drugs but micturitions per 4 hours Not reported A Selection bias daily antimuscarinic agent no indication on which group they A1 - Was there solifenacin succinate in were randomised to Self reported rate appropriate patients with overactive Power calculation of absolute randomisation - Unclear - bladder, Journal of symptom Not reported UrologyJ.Urol., 172, 1919- Characteristics Based on the projected reduction per day A2 - Was there adequate 1924, 2004 difference from baseline to Episodes of concealment - Unclear - Gender - Female/N (% female) endpoint of 1 micturition incontinence / day Not reported Ref Id SOL 5: 237/286 (82.9%) episode per 24 hours, with a - Mean change A3 - Were groups SOL 10: 238/290 (82.1%) standard deviation of 3, scores (95% CI) comparable at baseline - 220336 PLA: 227/281 (80.8%) significance level of 0.05, - SOL 5mg: -1.63 Yes - No apparent sided and a power of 90%, (No CI reported) differences between Country/ies where the Age (years) - Range 190 evaluable patients per SOL 10mg: -1.57 groups at baseline study was carried out SOL 5: 19 - 85 arm were required. Assuming (No CI reported) Level of bias: Unclear SOL 10: 18 - 83 a dropout rate of 20%, 894 PLA: -1.35 (No CI UK PLA: 18 - 8 patiemnts were required reported) B Performance bias B1 - Did groups get Study type Incontinence episodes/day Episodes of same level of care - Yes Not reported Intention to treat analysis urgency B2 - Were participants Randomised controlled trial SOL 5mg: -2.94 (- blinded - Yes - Study Urgency episodes/day Last observation carried 1.44 to -0.28) N = was double-blind Aim of the study Not reported forward (LOCF) was used 267 B3 - Were clinical staff SOL 10mg: -2.90 blinded - Yes To assess the efficacy of Detrusor overactivity (-1.49 to -0.35) N Level of bias: Low once daily solifenacin in Not reported = 283 patients with OAB PLA: -1.98 (No CI C Attrition bias Duration of OAB reported) C1 - Was follow-up equal Not reported for both groups - Yes Study dates Continence status C2 - Were groups Not reported comparable for dropout - Not reported Inclusion criteria Yes Incontinence- C3 - Were groups Source of funding 1] 18 years of age or older with specific quality of comparable for missing symptoms of OAB life data - LOCF used Not reported 2] average micturition frequency of Not reported Level of bias: Low

535

Study details Participants Interventions Methods Outcomes and Comments Results

at least 8 per day 3] at least 3 episodes of urgency Adverse effects of D Detection bias and/or 3 episodes of urinary treatment D1 - Was follow-up incontinence durnig 3 days Any adverse effect appropriate length - Yes Not reported D2 - Were outcomes defined precisely - Yes Exclusion criteria Dry mouth D3 - Was a valid and SOL 5mg: 23/299 reliable method used to 1] neurogenic bladder (87.7%) assess outcome - Yes 2] stress urinary incontinence SOL 10mg: 71/307 D4 - Were investigators 3] Bladder outlet obstruction (243.1%) blinded to intervention - 4] Post-void residual volume PLA: 7/301 (2.3%) Unclear >200ml D5 - Were investigators 5] urinary tract infection Dropout for any blinded to confounding 6] contrindication to antimuscarinic reason factors - Unclear drugs, SOL 5mg: 22/299 Level of bias: Low (7.4%) SOL 10mg: 24/307 (7.8%) Indirectness PLA: 31/301 (10.3%) Does the study match the protocol in terms of; Dropout for 1] Population: Yes adverse event 2] Intervention: Yes SOL 5mg: 7/299 3] Outcomes: Yes (2.3%) Indirectness: None SOL 10mg: 12/307 (3.9%) PLA: 10/301 Other information (3.3%)

Psychological outcomes Not reported

Clinical measures Post-void residual volume Not reported

536

Study details Participants Interventions Methods Outcomes and Comments Results

Full citation Sample size Interventions Details Results Limitations

Zinner,N., Gittelman,M., N = 523 Patients were randmised on a Patient treated with OAB Week 4 results NICE guidelines manual. Harris,R., Susset,J., 1:1 basis to either trospium drugs at screening Patient satisfaction Appendix D: Kanelos,A., Auerbach,S., Trospium (TRO) = 262 0mg twice daily or matching underwent a 2-week with treatment Methodology checklist: Trospium Study Group., Placebo (PLA) = 261 placebo for 1 weeks washout. At baseline patient Not reported Randomised controlled Trospium chloride improves were given 7-day baseline trials overactive bladder urinary diary that included Self-reported rate symptoms: a multicenter Characteristics measurement of volume of absolute A Selection bias phase III trial, Journal of voided on days 6 and 7. 7- symptoms A1 - Was there UrologyJ.Urol., 171, 2311- Gender - Female/N (% female) day diaries were completed reduction/day - appropriate 2315, 2004 TRO: 203/262 (77.5%) prior to each study visit at Mean ± SD randomisation - Unclear - PLA: 188/261 (71.3%) weeks 1, 4 and 12. UUI episodes - Not reported Ref Id change from A2 - Was there adequate Age (years) - Mean ± SE Primary efficacy outcomes baseline reported concealment - unclear - 220337 TRO: 63 ± 0.8 were change in the average TRO: -2.3 (No not reported PLA: 61.5 ± 0.8 number of voids per 24 hours SD) N = 256 A3 - Were groups Country/ies where the and change in average PLA: -1.8 (No SD) comparable at baseline - study was carried out Incontinence episodes/day - Mean number of urge incontinence N = 256 Yes - No apparent ± SD episodes per 24 hours. differences between United States TRO: 3.9 (No SD reported) Urgency episodes groups at baseline PLA: 4.3 (No SD reported) TRO: -2.1 (No SD) Level of bias: Medium Study type Power calculation N = 256 Urgency episodes/day - Mean ± PLA: -1.0 (No SD) B Performance bias Randomised controlled trial SD Not reported N = 256 B1 - Did groups get TRO: 11.29 (No SD reported) same level of care - Yes Aim of the study PLA: 11.72 (No SD reported) Continence status B2 - Were participants Intention to treat analysis (Zero episodes per blinded - Yes - Study To examine the effect of Detrusor overactivity day) was double-blind trospium chloride at 20mg Not reported Last observation carried Not reported B3 - Were clinical staff twice daily versus placebo in forward (LOCF) was used blinded - Yes patients presenting with Duration of OAB Incontinence- Level of bias: Low overactive bladder associated Not reported specific quality of with urge incontinence life C Attrition bias Not reported C1 - Was follow-up equal for both groups - Yes

537

Study details Participants Interventions Methods Outcomes and Comments Results

Study dates Inclusion criteria Adverse effects C2 - Were groups Not reported at 4 comparable for dropout - Not reported 1] 18 years of age or older weeks Yes 2] OAB symptoms for at least 6 C3 - Were groups Source of funding months Psychological comparable for missing 3] urinary urgency, a minimum outcomes data - Yes Supported by Indevus voiding frequency of 70 or more Not reported Level of bias: Low Corporation voids per week with at least 7 urge incontinence episodes per week Clinical measures D Detection bias Not reported D1 - Was follow-up appropriate length - Yes Exclusion criteria Week 12 results D2 - Were outcomes Patient defined precisely - Yes 1] stress incontinence satisfactiopn with D3 - Was a valid and 2] insensate or overflow in nature treatment reliable methods used to 3] neurogenic bladder disorders Not reported assess outcome - Yes 4] significant renal disease D4 - Were investigators 5] uninvestigated hematuria Self-reported rate blinded to intervention - 6] urinary tract infection at washout of absolute Yes or more than twice in previous symptoms D5 - Were investigators year reduction/day - blinded to confounding 7] significant bladder outlet Mean (No SD factors - Unclear obstruction reported) Level of bias: Low 8] current use of an anticholinergic UUI episodes - drug or drug therapy for OAB in change from previous 21 days baseline reported Indirectness 9] bladder cancer TRO: -2.3 (No SD) 10] interstitial cystitis N = 256 Does the study match PLA: -1.9 (No SD) the protocol in terms of: N = 256 1] Population: Yes 2] Interventions: Yes Urgency episodes 3] Outcome: Yes TRO: -2.3 (No SD) Indirectness: None N = 256 PLA: -1.1 (No SD) N = 256 Other information

Continence status (Zero episodes per

538

Study details Participants Interventions Methods Outcomes and Comments Results

day) TRO: 46/262 (17.6%) PLA: 24/261 (9.2%)

Incontinence- specific quality of life (using Incontinence Impact Questionnaire) TRO: -54.0 ± 85.8 N = 235 PLA: -36.0 ± 86.0 N = 236

Adverse effects Any adverse effect Not reported

Dry mouth TRO: 57/262 (21.8%) PLA: 17/261 (6.5%)

Dropout for any reason TRO: 43/262 (16.4%) PLA: 43/261 (16.4%)

Dropouts for adverse effects TRO: 23/262 (8.8%)

539

Study details Participants Interventions Methods Outcomes and Comments Results

PLA: 15/261(5.7%)

Psychological outcomes Not reported

Clinical measures Not reported

Full citation Sample size Interventions Details Results Limitations

Appell,R.A., Sand,P., N = 378 Patients were randomised to Primary efficacy outcome 4 weeks NICE guidelines manual. Dmochowski,R., 10mg/day of extended was the numbe rof urge Not reported Appendix D: Anderson,R., Zinner,N., Oxybutynin extended release release oxybutynin or incontinence episodes at 1 Methodology checklist: Lama,D., Roach,M., (OXY ER) = 185 4mg/day (mg twice daily) of weeks as determied by a 7- 12 weeks Randomised controlled Miklos,J., Saltzstein,D., Tolterodine immediate release immediate release tolterodine day urinary diary completed Patient satisfaction trials Boone,T., Staskin,D.R., (TOL IR) = 193 at baseline, weeks 2, 4, 8 with treatment Albrecht,D., Overactive and 12 weeks Not reported A Selection bias Bladder: Judging Effective A1 - Was there Control and Treatment Study Characteristics Self-reported rate appropriate Group., Prospective Power calculation of absolute randomisation - Yes - randomized controlled trial of Gender - Female/N (% female) symptom randomisation stratified extended-release oxybutynin TOL IR: 163/193 (84.5%) Not reported reduction per day - for urge incontinence chloride and tolterodine OXY ER: 152/185 (82.2%) Mean ± SD A2 - Was there adequate tartrate in the treatment of endpoint concealment - yes - overactive bladder: results of Age (years) - Range Intention to treat analysis Incontinence identical packaging used the OBJECT Study., Mayo TOL IR: 21 - 85 episodes A3 - Were groups Clinic ProceedingsMayo OXY ER: 26 - 87 Not reported OXY ER: 1.1 ± 1.7 comparable at baseline - Clin.Proc., 76, 358-363, 2001 N = 160 Yes - No apparent Incontinence episodes/week - TOL IR: 1.3 ± 1.9 differences between Ref Id Mean ± SD N = 172 groups at baseline TOL IR: 28.0 ± 18.3 Level of bias: Low 220347 OXY ER: 28.4 ± 17.8 Urgency episodes Not reported B Performance bias Country/ies where the Urgency episodes/day B1 - Did groups get Not reported Continence status same level of care - Yes

540

Study details Participants Interventions Methods Outcomes and Comments Results study was carried out (zero episodes per B2 - Were participants Detrusor overactivity day) blinded - Yes United States Not reported Incontinence B3 - Were clinical staff episodes blinded - yes Study type Duration of OAB Not reported Level of bias: High Not reported Randomised controlled trial Urgency episodes C Attrition bias Not reported C1 - Was follow-up equal Aim of the study Inclusion criteria for both groups - Yes Incontinence- C2 - Were groups To compare the efficacy and 1] OAB with at between 7 and 50 specific quality of comparable for dropout - tolerability of tolterodine and episodes of urge incontinence per life Yes extended release oxybutynin weeks and 10 or more voids per 4 Not measured C3 - Were groups in patients with overactive hours comparable for missing bladder Adverse effects data - Yes Any adverse effect Level of bias: Low Exclusion criteria Not reported Study dates D Detection bias 1] Incontinence related to urinary Dry mouth D1 - Was follow-up Not reported tract infection, prostatitis, OXY ER: 52/185 appropriate length - Yes interstitial cystitis, urinary tract (28.1%) D2 - Were outcomes Source of funding obstruction, urethral diverticulum, TOL IR: 64/193 defined precisely - Yes bladder minor, bladder tumor, (33.2%) D3 - Was a valid and Funded by ALZA Corporation bladder stone or prostate cancer reliable methods used to 2] undergone pelvioc, vaginal, Dropouts for any assess outcome - Yes bladder or prostate surgery in reason D4 - Were investigators previous 6 months or delivered a OXY ER: 25/185 blinded to intervention - bay in previous 6 months (13,5%) Unclear - not reportedl 3] post-void residual volume of TOL IR: 22/193 D5 - Were investigators more than 150ml or at risk of (11.4%) blinded to confounding developing complete urinary factors - Unclear - Not retention Dropouts for reported 4] clinically important medical adverse effects Level of bias: Low problems OXY ER: 14/185 5] hematuria or positive urine (7.6%) culture or narrow angle glaucome, TOL IR: 15/193 Indirectness obstructive uropathy, myasthenia (7.8%) gravis, pelvic organ prolapse to the Does the study match hymenal ring, or gastrointestinal Psychological the protocol in terms of:

541

Study details Participants Interventions Methods Outcomes and Comments Results

conditions. outcomes 1] Population: Yes Not reported 2] Interventions: Yes 3] Outcome: Yes Clinical measures Indirectness: None - Post-void residual volume Not reported Other information

Full citation Sample size Interventions Details Results Limitations

Diokno,A.C., Appell,R.A., N = 790 Patients were allocated on a Efficacy assessments were Week 4 NICE guidelines manual. Sand,P.K., 1:1 basis to take either based on 7-day diaries at the Not reported Appendix D: Dmochowski,R.R., Oxybutynin extended release extended release oxybutynin baseline week abd at weeks Methodology checklist: Gburek,B.M., Klimberg,I.W., (OXY ER) = 291 at 10mg/day or extended 2, 4, 8 and 12 Week 12 Randomised controlled Kell,S.H., OPERA Study Tolterodine extended release (TOL release tolterodine at Patient satisfaction trials Group., Prospective, ER) = 399 4mg/day orally at 8.00am for with treatment randomized, double-blind 12 weeks Power calculation Not reported A Selection bias study of the efficacy and A1 - Was there tolerability of the extended- Characteristics Not reported Self-reported rate appropriate release formulations of of absolute randomisation - Unclear - oxybutynin and tolterodine for Gender - Female/N (% female) symptom not reported overactive bladder: results of TOL ER:399/399 (100%) Intention to treat analysis reduction per day A2 - Was there adequate the OPERA trial., Mayo Clinic OXY ER: 391/391 (100%) Incontinence concealment - Yes - ProceedingsMayo Clin.Proc., Intention to treat analysis episodes overencapsulation used 78, 687-695, 2003 Age (years) - Mean ± SD used but no details reported Not reported A3 - Were groups TOL ER: 60 (No SD reported) comparable at baseline - Ref Id OXY ER: 60 (No SD reported) Urgency episodes Yes - No apparent Not reported differences between 220348 Incontinence episodes/day- Mean groups at baseline ± SD Continence status Level of bias: Low Country/ies where the TOL ER: 36.9 ± 14.1 (zero episodes per study was carried out OXY ER: 37.2 ± 15.2 day) B Performance bias Incontinence B1 - Did groups get United States Urgency episodes/day episodes same level of care - Yes Not reported TOL ER: 60/399 B2 - Were participants Study type (15.0%) blinded - Yes - Study

542

Study details Participants Interventions Methods Outcomes and Comments Results

Randomised controlled trial Detrusor overactivity OXY ER: 78/391 was double-blind Not reported (19.9%) B3 - Were clinical staff Aim of the study blinded - Yes Duration of OAB Urgency episodes Level of bias: Low To compare extended Not reported Not reported release fromulation of both C Attrition bias tolterodine and oxybutynin Incontinence- C1 - Was follow-up equal Inclusion criteria specific quality of for both groups - Yes life C2 - Were groups Study dates 1] women with OAB, aged 18 or Not reported comparable for dropout - older Yes November 21, 2000 to 2] document 21 to 60 urge urinary Adverse effects C3 - Were groups October 18, 2001 incontinence episodes per week Any adverse effect comparable for missing 3] an average of 10 or more voids Not reported data - Yes Source of funding per 24 hours Level of bias: Low Dry mouth Supported by ALZA TOL ER: 89/399 D Detection bias Corporation Exclusion criteria (22.3%) D1 - Was follow-up OXY ER: 116/391 appropriate length - Yes 1] treatable urinary conditions that (29.7%) D2 - Were outcomes could cause incontinence defined precisely - Yes 2] 2 post-void residual volumes Dropouts for any D3 - Was a valid and shown by ultrasonography to reason reliable methods used to exceed 150ml TOL ER: 42/399 assess outcome - Yes 3] pronounced risk of developing (10.5%) D4 - Were investigators complete urinary retention OXY ER: 52/391 blinded to intervention - 4] clinically important medical (13.3%) Unclear problems, D5 - Were investigators 5] hematuria Dropouts for blinded to confounding 6] uncontrolled narrow angle adverse effects factors - Unclear glaucome TOL ER: 19/399 Level of bias: Low 7] obstructive uropathy (4.8%) 8] reduced gastrointestinal motility OXY ER: 20/391 9] known hypersensitivity to study (5.1%) Indirectness medications Psychological Does the study match outcomes the review protocol in Not reported terms of: Population: Yes

543

Study details Participants Interventions Methods Outcomes and Comments Results

Clinical measures Intervention: Yes Not reported Outcome: Yes Indirectness: None

Other information

Full citation Sample size Interventions Details Results Limitations

Van Kerrebroeck,P., N = 1529 Eligible patients were At an initial screening visit, a Week 4 NICE guidelines manual. Kreder,K., Jonas,U., subsequently randomized complete medical and drug Not reported Appendix D: Zinner,N., Wein,A., Tolterodine ER (TOL ER) = 507 (1:1:1), using the procedure history was taken, along with Methodology checklist: Tolterodine Study Group., Tolterodine IR (TOL IR) = 514 of random permuted blocks, a full laboratory screen and a Week 12 Randomised controlled Tolterodine once-daily: Placebo (PLA) = 508 to oral therapy with midstream specimen of urine Patient satisfaction trials superior efficacy and tolterodine ER capsules 4 mg for culture/urinalysis. Eligible with treatment* tolerability in the treatment of once daily, tolterodine IR patients were enrolled into a Reported as A Selection bias the overactive bladder, Characteristics tablets 2 mg twice daily, or 1 to 2-week washout/run-in 'improved' A1 - Was there Urology, 57, 414-421, 2001 placebo for 12 weeks. period, during which the TOL ER: 336/507 appropriate Gender - Female/N (% female) number of incontinence (66.3%) randomisation - Yes - Ref Id TOL IR: 406/514 (79.4%) No dosage adjustment was episodes and frequency of TOL IR: 313/514 numbered blocks used TOL ER: 417/507 (82.2%) allowed during the study. micturition were recorded for (60.9%) A2 - Was there adequate 220399 PLA: 410/508 (80.7%) 7 consecutive days using PLA: 218/508 concealment - Yes - micturition diaries. The (46.1%) double-dummy drug Country/ies where the Age (years) - Range volume voided (in milliliters) packaging used study was carried out TOL IR: 22 - 92 for every micturition and the Self-reported rate A3 - Were groups TOL ER: 20 - 89 use of incontinence pads of absolute comparable at baseline - The Netherlands PLA: 22 - 93 were recorded for at least 2 symptom Yes - No apparent complete days. reduction per day differences between Study type Incontinence episodes/day - Mean (Mean ± SD groups at baseline ± SD change from Level of bias: Low Randomised controlled trial TOL IR: 23.2 (No SD reported) Power calculation baseline) TOL ER: 22.1 (No SD reported) Incontinence B Performance bias Aim of the study PLA: 23.3 (No SD reported) Not reported episodes B1 - Did groups get TOL ER: -1.7 ± 2.5 same level of care - Yes To evaluate the efficacy and Urgency episodes/day N = 507 B2 - Were participants tolerability of the new ER Not reported Intention to treat analysis TOL IR: -1.5 ± 2.4 blinded - Yes - Study formulation of tolterodine for

544

Study details Participants Interventions Methods Outcomes and Comments Results once-daily treatment of over- An analysis of efficacy was N = 514 was double-blind and active bladder Detrusor overactivity performed for all randomized PLA: -1.0 ± 2,2 N double-dummy Not reported patients on an intent-to-treat = 507 B3 - Were clinical staff basis using the last blinded - Yes Study dates Duration of OAB observation carried forward Urgency episodes Level of bias: Low Not reported to estimate the values for Not reported Not reported patients that dropped out of C Attrition bias the study early. Continence status C1 - Was follow-up equal Source of funding Inclusion criteria (zero episodes per for both groups - Yes day) C2 - Were groups Sponsored by Pharmacia 1] Male and female patients, 18 Incontinence comparable for dropout - Corporation years of age or older, with urinary episodes Yes frequency (eight or more Not reported C3 - Were groups micturitions every 24 hours), urge comparable for missing incontinence (five or more Urgency episodes data - Yes incontinence episodes Not reported Level of bias: Low per week), and symptoms of an overactive bladder for 6 months or Incontinence- D Detection bias longer were eligible for inclusion. specific quality of D1 - Was follow-up life appropriate length - Yes Not reported D2 - Were outcomes Exclusion criteria defined precisely - Yes Adverse effects D3 - Was a valid and 1] demonstrable stress Any adverse effect reliable methods used to incontinence, Not reported assess outcome - Yes 2] total daily urine volume greater D4 - Were investigators than 3 L Dry mouth blinded to intervention - 3] any contraindications to TOL ER: 118/507 Yes antimuscarinic treatment (23.3%) D5 - Were investigators 4] significant hepatic or renal TOL IR: 156/514 blinded to confounding disease (biochemical markers (30.4%) factors - Unclear twice the upper limit of the normal PLA: 39/508 Level of bias: Low reference range) (7.7%) 5] symptomatic or recurrent urinary tract infections Dropouts for any Indirectness 6] interstitial cystitis reason 7] hematuria or bladder outlet TOL ER: 56/507 Does the study match obstruction~ (11.6%) the protocol in terms of: 8] current electrostimulation or TOL IR: 63/514 1] Population: Yes

545

Study details Participants Interventions Methods Outcomes and Comments Results

bladder training therapy (12.1%) 2] Interventions: Yes 9] indwelling catheter or PLA: 68/508 3] Outcome: Yes intermittent selfcatheterization. (13.0%) Indirectness: None

Pregnant or nursing women and Dropouts for women of childbearing potential adverse effects Other information not using reliable contraceptive TOL ER: 27/507 methods were also excluded from (5.3%) Data on dropouts for any enrollment. TOL IR: 28/514 reason and improvement Other treatments for an overactive (5.4%) taken from this paper bladder such as anticholinergic PLA: 5/508 (1.0%) and "Chancellor et al., drugs or drugs that inhibit 2000" (see excluded cytochrome P450 3A4 isoenzymes Psychological studies table) were not allowed. An exception outcomes was made for those receiving Not reported Data on 'Patient estrogen treatment who had satisfaction with started therapy more than 2 Clinical measures treatment' taken from months before randomization. - Post-void "Zinner et al., 2002" (see Treatment with an investigational residual volume excluded studies table) drug in the 2 months before study Not reported entry was also prohibited by the protocol.

Full citation Sample size Interventions Details Results Limitations

Jonas,U., Hofner,K., N = 242 Following a washout period, Efficacy was assessed at Week 4 NICE guidelines manual. Madersbacher,H., patients were randomised to baseline, at weeks or at Patient satisfaction Appendix D: Holmdahl,T.H., Efficacy and Tolterodine IR 1mg (TOL IR 1) = tolterodine 1mg or mg bid or withdrawal. with treatment Methodology checklist: safety of two doses of 99 placebo Not reported Randomised controlled tolterodine versus placebo in Tolterodine IR 2mg (TOL IR 2) = trials patients with detrusor 99 Power calculation Self-reported rate overactivity and symptoms of Placebo (PLA) = 44 of absolute A Selection bias frequency, urge incontinence, Not reported symptoms A1 - Was there and urgency: urodynamic reduction/day - appropriate evaluation. The International Characteristics Mean ± SD randomisation - Unclear - Study Group.[erratum Intention to treat analysis Not reported not reported appears in World J Urol Gender - Female/N (% female) A2 - Was there adequate

546

Study details Participants Interventions Methods Outcomes and Comments Results

1997;15(3):210], World TOL IR 1: 73/99 (74%) Not reported Urgency episodes concealment - Unclear - Journal of UrologyWorld TOL IR 2: 76/99 (77%) Not reported not reported J.Urol., 15, 144-151, 1997 PLA: 33/44 (75%) A3 - Were groups Continence status comparable at baseline - Ref Id Age (years) - Range (Zero episodes per Yes - No apparent TOL IR 1: 21 - 81 day) differences between 220405 TOL IR 2: 20 - 83 Incontinence groups at baseline PLA: 23 - 9 episodes Level of bias: Low Country/ies where the Not reported study was carried out Incontinence episodes/day - B Performance bias Range Urgency episodes B1 - Did groups get Germany, Austria & Sweden Not reported Not reported same level of care - Yes B2 - Were participants Study type Urgency episodes/day Incontinence- blinded - Yes - Study Not reported specific quality of was double-blind Randomised controlled trial life B3 - Were clinical staff Detrusor overactivity Not reported blinded - Yes Aim of the study TOL IR 1: 99/99 (100%) Level of bias: Low TOL IR 2: 99/99 (100%) Adverse effects To compare the efficacy of PLA: 44/44 (100%) Any adverse effect C Attrition bias tolterodine at 1 or 2 mg bid TOL IR 1: 31/99 C1 - Was follow-up equal versus placebo and evaluate Duration of OAB (31%) for both groups - Yes the safety over 4 weeks of Not reported TOL IR 2: 32/99 C2 - Were groups treatment (32%) comparable for dropout - PLA: 17/44 (39%) Yes Inclusion criteria C3 - Were groups Study dates Dry mouth comparable for missing 1] at least 18 years of age with TOL IR 1: 8/99 data - Yes Not reported detrusor overactivity (8%) Level of bias: Low 2] evidence of frequency (8 or TOL IR 2: 10/99 Source of funding more micturitions per 24 hours) in (10%) D Detection bias combination with either urge PLA: 1/44 (2%) D1 - Was follow-up Not reported incontinence (1 or more appropriate length - Yes incontinence episodes per 4 Dropout for any D2 - Were outcomes hours), urinary urgency or both reason defined precisely - Yes Not reported D3 - Was a valid and reliable methods used to Exclusion criteria Dropouts for assess outcome - Yes adverse effects D4 - Were investigators

547

Study details Participants Interventions Methods Outcomes and Comments Results

1] significant stress incontinence TOL IR 1: 4/99 blinded to intervention - 2] hepatic disease (4%) Unclear 3] renal disease TOL IR 2: 3/99 D5 - Were investigators 4] condition contraindication (3%) blinded to confounding anticholinergic therapy PLA: 3/44 (6%) factors - Unclear 5] recurrent urinary tract infections Level of bias: Low 6] interstitial cystitis Psychological 7] uninvestigated hematuria outcomes 8] clinically significant voiding Not reported Indirectness difficulty with risk of urinary retention Clinical measures Does the study match 9] patients on anticolinergic Not reported the review protocol in treatment, using an indwelling terms of: catheter or electrostimulation or Week 12 Population: Yes bladder training within 14 days of Not applicable Intervention: Yes study Outcome: Yes Indirectness: None

Other information

79 (80%), 83 (84%) and 38 (86) were incontinent in the TOL IR 1, TOL IR 2 and PLA groups respectively

Full citation Sample size Interventions Details Results Limitations

Madersbacher,H., N = 366 15 mg propiverine (sugar- In a double-blind, Week 4 results NICE guidelines manual. Halaska,M., Voigt,R., coated tablets, registered as randomized, prospective Patient satisfaction Appendix D: Alloussi,S., Hofner,K., A Propiverine immediate release Detrunorm® /Mictonorm® , multicentre clinical trial, the with treatment Methodology checklist: placebo-controlled, (PRO IR) = 149 Apogepha Arzneimittel treatment results of PRO IR: 104/149 Randomised controlled multicentre study comparing Oxybutynin immediate release GmbH, Dresden, Germany) propiverine, oxybutynin and (70.5%) trials the tolerability and efficacy of (OXY IR) = 145 were administered three placebo were compared in a OXY IR: 96/145 propiverine and oxybutynin in Placebo (PLA) = 72 times daily three-armed parallel-group (66.2%) A Selection bias patients with urgency and design. After a 1-week PLA: 43/72 A1 - Was there

548

Study details Participants Interventions Methods Outcomes and Comments Results urge incontinence, BJU 5 mg oxybutynin tablets 'washout' period, treatments (59.7%) appropriate International, 84, 646-651, (registered as were administered for 4 randomisation - Unclear - 1999 Characteristics Ditropan® /Dridase® ) twice weeks; 15 mg propiverine Self-reported rate not reported daily (sugar-coated tablets, of absolute A2 - Was there adequate Ref Id Gender - Female/N (% female) registered as symptom concealment - Unclear PRO IR: 117/126 (92.9%) Placebo three times daily Detrunorm® /Mictonorm® , reduction per day A3 - Were groups 220409 OXY IR: 113/118 (93.4%) Apogepha Arzneimittel Incontinence comparable at baseline - PLA: 59/53 (93.7%) GmbH, Dresden, Germany) episodes Yes - No significant Country/ies where the were administered three Not reported difference between study was carried out Age (years) - Mean ± SD times daily (group 1), or 5 mg groups PRO IR: 49.6 ± 13.0 oxybutynin tablets (registered Urgency episodes Level of bias: Medium Germany OXY IR: 50.3 ± 13.5 as Ditropan® /Dridase® ) - Mean change PLA: 47.6 ± 12.0 twice daily (group 2), or from baseline B Performance bias Study type placebo three times daily PRO IR: -3.1 (No B1 - Did groups get Incontinence episodes/day (group 3). To ensure the SD) N not reported same level of care - Yes Randomised controlled trial Not reported double-blind condition, each OXY IR: -3.0 (No B2 - Were participants of the patients received SD) N not reported blinded - Yes - Study Aim of the study Urgency episodes/day - Mean ± additional placebos (the PLA: - 1.2 (No SD) was double-blind and SD double-dummy technique). N not reported double-dummy To assess evidence for the PRO IR: 9.5 (No SD reported) B3 - Were clinical staff equal efficacy of propiverine OXY IR: 1.4 (No SD reported) Continence status blinded - Yes and oxybutynin in patients PLA: 11.3 (No SD reported) Power calculation (zero episodes per Level of bias: Low with urgency and urge day) incontinence Detrusor overactivity Not reported Not reported C Attrition bias Not reported C1 - Was follow-up equal Incontinence- for both groups - Yes Study dates Duration of OAB Intention to treat analysis specific quality of C2 - Were groups Not reported life comparable for dropout - Not reported Not reported Not reported Yes C3 - Were groups Source of funding Inclusion criteria Adverse effects comparable for missing Any adverse effect data - Yes Not reported 1] history of urgency or urge PRO IR: 95/149 Level of bias: Low incontinence (63.8%) 2] a maximum cystometric bladder OXY IR: 105/145 D Detection bias capacity of ≤ 300 ml (71.7%) D1 - Was follow-up 3] age ≥ 18 years PLA: 30/72 appropriate length - Yes 4] body weight ≥ 45 kg (41.7%) D2 - Were outcomes defined precisely - Yes

549

Study details Participants Interventions Methods Outcomes and Comments Results

Dry mouth D3 - Was a valid and Not reported reliable methods used to Exclusion criteria assess outcome - Yes Dropouts for any D4 - Were investigators 1] detrusor hyperreflexia reason blinded to intervention - 2] postoperative (bladder) PRO IR: 19/149 Yes incontinence (12.8%) D5 - Were investigators 3] infravesical obstruction OXY IR: 16/145 blinded to confounding 4] a postvoid residual urine (PVR) (11.0%) factors - Unclear of > 15% of the maximal PLA: 7/72 (9.7%) Level of bias: Low cystometric bladder capacity 5] acute UTIs Dropouts for 6] angina pectoris adverse effects Indirectness 7] glaucoma Not reported 8] megacolon Does the study match 9] clinically relevant cardiac, renal Psychological the protocol in terms of: or hepatic dysfunctions outcomes 1] Population: Yes 10] tachy/dysrhythmias Not reported 2] Interventions: Yes 11] frequency or nocturia due to 3] Outcome: Yes heart or renal insufficiency Clinical measures Indirectness: None 12] overt cerebral sclerosis. - Post-void The following concomitant residual volume medications were considered as Not reported Other information exclusion criteria: other spasmolytics or anticholinergics, Week 12 Baseline data on all β-sympathomimetics, calcium Not applicable patients randomised not antagonists, dopamine agonists, reported prolactin inhibitors, prostaglandin synthesis inhibitors, striated muscle relaxants, or medication for Parkinsonism.

Full citation Sample size Interventions Details Results Limitations

Chapple,C.R., Martinez- N = 1177 Patients were randomised After 4 weeks of treatment, Week 4 results NICE guidelines manual. Garcia,R., Selvaggi,L., (stratified by centre) to patients had the option of Patient satisfaction Appendix D: Toozs-Hobson,P., Solifenacin (5mg or 10mg) (SOL) receive either solifenacin 5 either continuing with their with treatment Methodology checklist:

550

Study details Participants Interventions Methods Outcomes and Comments Results

Warnack,W., Drogendijk,T., = 578 mg OD or tolterodine ER 4 original dose or requesting a Not reported Randomised controlled Wright,D.M., Bolodeoku,J., A Tolterodine extended release (TOL mg OD as double-blind dose increase based on their trials comparison of the efficacy ER) = 599 treatment satisfaction with treatment Self-reported rate and tolerability of solifenacin efficacy and tolerability, and of absolute A Selection bias succinate and extended discussions with the symptom A1 - Was there release tolterodine at treating Characteristics investigator. reduction per day appropriate overactive bladder syndrome: Incontinence randomisation - Yes - Results of the STAR trial, Gender - Female/N (% female) Patients completed the 3-day episodes - remote randmisation European UrologyEur.Urol., SOL: 493/578 (85.3%) micturition diary prior to each Mean (No SD) A2 - Was there adequate 48, 464-470, 2005 TOL ER: 529/599 (88.2%) scheduled visit at weeks 4, 8 change from concealment - Yes - and 12. For each episode of baseline randomisation numbers Ref Id Age (years) - Mean ± SD urinary symptoms, the SOL: -1.3 (No SD) served as packaging for SOL: 56.5 (No SD reported) patient recorded the date and N not reported interventions 220410 TOL ER: 56.4 (No SD reported) time of each episode, TOL ER: -0.9 (No A3 - Were groups whether or not they voided, SD) N not reported comparable at baseline - Country/ies where the Incontinence episodes/day - the presence of urgency Yes - No apparent study was carried out Range and/or incontinence, the Urgency episodes differences between SOL: 2.77 ± 2.65 volume voided (for at least 2 SOL: -1.98 (No groups at baseline UK TOL ER: 2.55 ± 2.37 of the 3 days), whether or not SD) N not reported Level of bias: Low the episode disturbed the TOL ER: -1.67 (No Study type Urgency episodes/day patient's sleep, and the time SD) N not reported B Performance bias SOL: 6.01 ± 4.66 of rising from, and retiring to, B1 - Did groups get Randomised controlled trial TOL ER: 5.84 ± 4.12 bed. Continence status same level of care - Yes (zero episodes per B2 - Were participants Aim of the study Detrusor overactivity day) blinded - Yes - Study Not reported Power calculation Incontinence was double-blind and To compare the efficacy and episodes double-dummy tolerability of solifenacin and Duration of OAB The sample size calculation SOL: 225/593 B3 - Were clinical staff extended release tolterodine Not reported and analytical strategy was (37.9%) blinded - Yes based upon CPMP TOL ER: 204/607 Level of bias: Low guidelines and enabled the (33.6%) Study dates Inclusion criteria primary efficacy analysis to C Attrition bias be performed with a power of Urgency episodes C1 - Was follow-up equal May 2003 to October 2004 1] Men and women aged at least 80% as the between- Not reported for both groups - Yes 18 years who had OAB symptoms treatment non-inferiority C2 - Were groups Source of funding (including urinary frequency, comparison of the change Incontinence- comparable for dropout - urgency or urge incontinence) for 3 from baseline to endpoint in specific quality of Yes Supported by Yamanouchi months or more and being treated the mean number of life C3 - Were groups Pharmaceutical Co. Ltd as outpatients micturitions per 24 hours by Not reported comparable for missing

551

Study details Participants Interventions Methods Outcomes and Comments Results

2] an average of 8 micturitions per using the Per Protocol Set data - Yes 24 hours (PPS) population. Adverse effects Level of bias: Low 3] an average of 1 incontinence Any adverse effect episode per 24 hours Not reported D Detection bias 4] an average of 1 urgency Intention to treat analysis D1 - Was follow-up episode per 24 hours Dry mouth appropriate length - Yes Not reported SOL: 108/593 D2 - Were outcomes (18.2%) defined precisely - Yes Exclusion criteria TOL ER: 91/607 D3 - Was a valid and (14.5%) reliable methods used to 1] stress incontinence or mixed assess outcome - Yes incontinence where stress was Dropouts for any D4 - Were investigators predominant (mixed incontinence reason blinded to intervention - was allowed otherwise) Not reported Yes 2] patients with a neurological D5 - Were investigators cause of abnormal detrusor activity Dropouts for blinded to confounding adverse effects factors - Unclear SOL: 18/593 Level of bias: Low (3.0%) TOL ER: 17/607 (2.8%) Indirectness

Psychological Does the study match outcomes the protocol in terms of: Not reported 1] Population: Yes 2] Interventions: Yes Clinical measures 3] Outcome: Yes Not reported Indirectness: None

Week 12 results Patient satisfaction Other information with treatment Not reported 52% of patients in SOL group requested a dose Self-reported rate increase from 5mg to of absolute 10mg after 4 weeks - symptom average dose at endpoint reduction per day = 7.9mg Incontinence

552

Study details Participants Interventions Methods Outcomes and Comments Results

episodes - Mean (No SD) change from baseline SOL: -1.6 (No SD) N not reported TOL ER: -1.1 (No SD) N not reported

Urgency episodes SOL: -2.85 (No SD) N not reported TOL ER: - 2.42 (No SD) N not reported

Continence status (zero episodes per day) Incontinence episodes SOL: 341/593 (57.5%) TOL ER: 294/607 (48.4%)

Urgency episodes Not reported

Incontinence- specific quality of life Not reported

Adverse effects Any adverse effect Not reported

Dry mouth

553

Study details Participants Interventions Methods Outcomes and Comments Results

SOL: 174/593 (29.3%) TOL ER: 144/607 (23.7%)

Dropouts for any reason SOL: 34/593 (5.7%) TOL ER: 44/607 (7.2%)

Dropouts for adverse effects SOL: 20/593 (3.4%) TOL ER: 18/607 (3.0%)

Psychological outcomes Not reported

Clinical measures Not reported

Full citation Sample size Interventions Details Results Limitations

Millard,R., Tuttle,J., Moore,K., N = 316 Patients were randomised to The primary efficacy Week 4 NICE guidelines manual. Susset,J., Clarke,B., tolterodine immediate release outcomes were the number Not reported Appendix D: Dwyer,P., Davis,B.E., Clinical Tolterodine immediate release 1mg twice daily, tolterodine of voids per 4 hours, mean Methodology checklist: efficacy and safety of 1mg (TOL IR 1) = 123 immediate release mg twice volume per void and the Week 12 Randomised controlled tolterodine compared to Tolterodine immediate release daily or placebo number of incontinence Patient satisfaction trials placebo in detrusor 2mg (TOL IR 2) = 129 episodes per 4 hours with treatment overactivity., Journal of Placebo (PLA) 64 TOL IR 1: 48/123 A Selection bias UrologyJ.Urol., 161, 1551- (37.4%) A1 - Was there TOL IR 2: 67/129 appropriate

554

Study details Participants Interventions Methods Outcomes and Comments Results

1555, 1999 Characteristics Power calculation (51.9%) randomisation - Unclear - PLA: 23/64 not reported Ref Id Gender - Female/N (% female) Sample size was chosed to (35.9%) A2 - Was there adequate TOL IR 1: 96/123 (78%) provide an 80% chance of concealment - Unclear - 220411 TOL IR 2: 99/129 (77%) detecting a 15% decrease in Self-reported rate not reported PLA: 42/64 (66%) the number fo voids daily at of absolute A3 - Were groups Country/ies where the 0.05 significance. symptoms comparable at baseline - study was carried out Age (years) - Range reduction/day - Yes - No apparent TOL IR 1: 24 - 89 Mean ± SD differences between Australia TOL IR 2: 24 - 83 Intention to treat analysis TOL IR 1: -1.7 ± groups at baseline PLA: 25 - 84 2.8 N = 109 Level of bias: Medium Study type Not reported TOL IR 2: -1.7 ± Incontinence episodes/day - Mean 2.5 N = 117 B Performance bias Randomised controlled trial ± SD PLA: -1.3 ± 2.5 N B1 - Did groups get TOL IR 1: 3.9 (No SD reported) = 55 same level of care - Yes Aim of the study TOL IR 2: 3.6 (No SD reported) B2 - Were participants PLA: 3.9 (No SD reported) Urgency episodes blinded - Yes - Study To measure the efficacy of 2 Not reported was double-blind doses of tolterodine versus Urgency episodes/day B3 - Were clinical staff placebo during a 12 week Not reported Continence status blinded - Yes treatment period (Zero episodes per Level of bias: Low Detrusor overactivity day) TOL IR 1: 123/123 (100%) TOL IR 1: 12/108 C Attrition bias Study dates TOL IR 2: 129/129 (100%) (11.1%) C1 - Was follow-up equal PLA: 64/64 (100%) TOL IR 2: 22/116 for both groups - Yes Not reported (18.9%) C2 - Were groups Duration of OAB PLA: 6/55 (10.9%) comparable for dropout - Source of funding Not reported Yes Incontinence- C3 - Were groups Supported by Pharmacia and specific quality of comparable for missing Upjohn AB, Uppsala, Sweden Inclusion criteria life data - Yes Not reported Level of bias: Low 1] Aged 18 or older with OAB 2] detrusor overactivity Adverse effects D Detection bias withaverage urinary frequency of 8 Any adverse effect D1 - Was follow-up or more voids per 24 hours TOL IR 1: 91/123 appropriate length - Yes 3] urge incontinence (an average (74.0%) D2 - Were outcomes of 1 or more incontinence TOL IR 2: 94/129 defined precisely - Yes episodes per 24 hours) and/or (72.9%) D3 - Was a valid and

555

Study details Participants Interventions Methods Outcomes and Comments Results

urinary urgency PLA: 50/64 reliable methods used to (78.1%) assess outcome - Yes D4 - Were investigators Exclusion criteria Dry mouth blinded to intervention - TOL IR 1: 30/123 Yes 1] demonstrable stress (24.4%) D5 - Were investigators incontinence TOL IR 2: 50/129 blinded to confounding 2] clinically significant voiding (38.8%) factors - Unclear difficulty PLA: 8/64 (12.5%) Level of bias: Low 3] proved recurrent urinary tract infections Dropout for any 4] interstitial cystitis reason Indirectness 5] uninvestigated hematuria TOL IR 1: 7/123 6] bladder cancer (5.7%) Does the study match 7] on intermittent catheterisation or TOL IR 2: 15/129 the protocol in terms of: indwelling catheter (11.6%) 1] Population: Yes 8] hepatic or renal disease PLA: 3/64 (4.7%) 2] Interventions: Yes 9] had undergone 3] Outcome: Yes electrostimulation or bladder Dropouts for Indirectness: None training or on antimuscarinic drugs adverse effects within 14 days of study or during TOL IR 1: 2/123 study (1.6%) Other information 10] average total voided volume of TOL IR 2: 8/129 greater than 3000ml per 24 hours (6.2%) PLA: 0/64 (0%)

Psychological outcomes Not reported

Clinical measures Not reported

Full citation Sample size Interventions Details Results Limitations

Thuroff,J.W., Bunke,B., N = 169 After a 1 week run-in period, Efficacy was based on 3-day Week 4 NICE guidelines manual. Ebner,A., Faber,P., patients were given micturition charts, and self- Patient satisfaction Appendix D:

556

Study details Participants Interventions Methods Outcomes and Comments Results de,Geeter P., Hannappel,J., Oxybutynin immediate release Oxybutynin immediate report of urinary symptoms with treatment Methodology checklist: Heidler,H., Madersbacher,H., (OXY IR) = 63 release (5mg three times Not reported Randomised controlled Melchior,H., Schafer,W., Propantheline (PRO) = 54 daily), propantheline (15mg trials Randomized, double-blind, Placebo (PLA) = 52 three times daily) and Power calculation Self-reported rate multicenter trial on treatment placebo. Patients were of absolute A Selection bias of frequency, urgency and instructed to take the tablets Not reported symptom A1 - Was there incontinence related to Characteristics 30m mins before meals reduction per day appropriate detrusor hyperactivity: Incontinence randomisation - Yes - oxybutynin versus Gender - Female/N (% female) Intention to treat analysis episodes computerised propantheline versus OXY IR: 59/63 (93.6%) Not reported randomisation used placebo, Journal of Urology, PRO: 53/54 (98.1%) Not reported A2 - Was there adequate 145, 813-816, 1991 PLA: 50/52 (96.2%) Urgency episodes concealment - Yes - Not reported opaque packaging used Ref Id Age (years) - Range A3 - Were groups OXY IR: 17 - 83 Continence status comparable at baseline - 220412 PRO: 16 - 78 (zero episodes per Yes - No apparent PLA: 20 - 83 day) differences between Country/ies where the Incontinenec groups at baseline study was carried out Incontinence episodes/week episodes Level of bias: Low Not reported Not reported Germany B Performance bias Urgency episodes/day Urgency episodes B1 - Did groups get Study type Not reported Not reported same level of care - Yes B2 - Were participants Randomised controlled trial Detrusor overactivity Incontinence- blinded - Yes - Study Not reported specific quality of was double-blind Aim of the study life B3 - Were clinical staff Duration of OAB Not reported blinded - Yes To determine the clinical Not reported Level of bias: Low efficacy and possible Adverse effects differences of treatment Any adverse effect C Attrition bias results between oxybutynin Inclusion criteria OXY IR: 40/63 C1 - Was follow-up equal and propantheline in patients (63.5%) for both groups - Yes with urinary frequency, 1] 15 years of age and older PRO: 24/54 C2 - Were groups urgency and/or incontinence 2] frequency, urgency and/or (44.4%) comparable for dropout - related to detrusor incontinence related to detrusor PLA: 17/52 Yes hyperactivity hyperactivity (32.7%) C3 - Were groups 3] not be taking drugs affecting comparable for missing lower urinary tract function Dry mouth data - Yes

557

Study details Participants Interventions Methods Outcomes and Comments Results

Study dates OXY IR: 30/63 Level of bias: Low (47.6%) Not reported Exclusion criteria PRO: 17/54 D Detection bias (31.5%) D1 - Was follow-up Source of funding 1] pregnancy PLA: 6/52 (11.5%) appropriate length - Yes 2] congestive heart failure D2 - Were outcomes Not reported 3] severe renal / liver disease Dropouts for any defined precisely - Yes 4] myasthenia gravis reason D3 - Was a valid and Pharmacia Leo Therapuetics, 5] unable to swallow / OXY IR: 8/63 reliable methods used to Helsingborg, Sweden uncooperative patient (6.3%) assess outcome - Yes provided the pharmaceutical 6] hiatal hernic / reflux esophagitis PRO: 6/54 D4 - Were investigators preparations 7] gastrointestinal tract obstruction (11.1%) blinded to intervention - 8] urnary tract obstruction PLA: 5/52 (9.6%) Yes 9] residual urine > 50ml D5 - Were investigators 10] untreated urinary tract infection Dropouts for blinded to confounding 11] hyperreflexia without urge adverse effects factors - Unclear OXY IR: 2/63 Level of bias: Low (3.2%) PRO: 3/54 (5.6%) PLA: 0/52 (0%) Indirectness

Psychological Does the study match outcomes the protocol in terms of: Not reported 1] Population: Yes 2] Interventions: Yes Clinical measures 3] Outcome: Yes - Post-void Indirectness: None residual volume Mean ± SE change at Other information endpoint OXY IR: 27.0 ± None 11.6 N = 59 PRO: - 2.2 ± 2.0 N = 48 PLA: -1.9 ± 1.6 N 46

Week 12

558

Study details Participants Interventions Methods Outcomes and Comments Results

Not applicable

559