Supplement. Updated Literature Search for Pharmacologic Treatments for Urgency UI

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1 Supplement. Updated Literature Search for Pharmacologic Treatments for Urgency UI Authors: Tatyana A. Shamliyan, MD, MS Senior Director, Evidence-Based Medicine Quality Assurance Elsevier 1600 JFK Blvd, 20th floor Philadelphia, PA Timothy J. Wilt, MD, MPH, MACP Professor of Medicine and Core Investigator Minneapolis VA Center for Chronic Disease Outcomes Research University of Minnesota School of Medicine VA Medical Center (111-0) Minneapolis, MN 55417

2 Supplement: Updated Literature Search for Pharmacologic Treatments for Urgency UI We updated the searches on December 10, 2013 and added 201 references to the library after removing duplicates. The library with 5185 references has 5386 references now. We excluded 129 references at the screening and 41 references at full text review. We found 31 eligible publications. We did not grade the evidence from two high-risk of bias randomized trials. 1,2 Updated references Comparison Analyzed s Fesoterodine vs. placebo Darifenacin vs. placebo Solifenacin- dose response vs. placebo Solabegron vs. placebo OnabotulinumtoxinA vs. anticholinergic drugs Solifenacin versus percutaneous tibial nerve stimulation Tolterodine vs. rehabilitation therapy Intravaginal estriol combined with pelvic floor muscle training vs. intravaginal estriol alone Solifenacin vs. darifenacin Fesoterodine vs. tolterodine Tolterodine vs. trospium Trospium vs. oxybutynin Oxybutynin vs. tolterodine Internet-based treatment program vs. behavioral recommendations sent by mail Group pelvic floor muscle training vs. Individual pelvic floor muscle training Pelvic floor muscle training vs. vaginal cones 45 23,24 Multidimensional exercise treatment vs. education Percutaneous tibial nerve stimulation ( no control) 50 26,27 Surgery vs. supervised physiotherapist pelvic floor muscle training ; Protocol29

3 Clinical Effectiveness of Fesoterodine 2 new references Key message: Moderate (low-quality in the report) evidence showed that fesoterodine (antimuscarinic) improved continence more than placebo (RR, 1.5 [CI, 1.1 to 1.9]), where 8 women needed to be treated with fesoterodine to improve continence in 1 woman (CI, 6 to 11). 4 High-quality evidence showed that fesoterodine treatment resulted in higher rates of adverse effects compared to placebo (RR, 1.4 [CI, 1.2 to 1.6]; NNT, 7 [CI, 5 to 9]). 4 Evidence Table 1. Clinical trials of fesoterodine vs. placebo for women with predominant urgency urinary incontinence Trial Sand, Pooled analysis of noncontrolled open-label extensions of 12-week, randomized, double-blind, placebo-controlled studies 32,34 Post-hic subgroup analysis by patient age Risk of bias High % females: 79.2 Active vs. control treatment Fesoterodine 8 mg/day vs. No control Inclusion and exclusion criteria Inclusion criteria Men and women with OAB and >3 UI episodes/day who participated in double-blind studies and opted to continue long-term, open-label treatment with fesoterodine. Exclusion criteria Pregnancy; lower urinary tract pathology that could, in the investigator s opinion, be responsible for urgency or incontinence (e.g., genuine stress incontinence, bladder stones, interstitial cystitis, urothelial tumors), pelvic prolapse of grade III or higher, clinically relevant bladder outlet obstruction, polyuria (>3 l per 24 h), symptomatic or recurrent urinary tract infections, or postvoid residual (PVR) urine volume >100 ml; treatments with antimuscarinic agents within 2 weeks from study enrollment, clinically relevant cardiac arrhythmia and/or unstable angina or a QTcB interval >500. Baseline subject characteristics Mean age 58.4 Baseline severity 79.2% had urinary incontinence with mean 2.1UI episodes/day % with mixed UI Prior treatments 79.2% Concurrent treatments Not Results Most patients regardless of age good or excellent treatment tolerance: Age <45 years- rate >90%; years- rate >93%; years rate >85%; >75 years- rate>86%. Dry mouth was in age <45 years in 31%; years in 30%; years in 32%; >75 years in 26%.

4 Huang, NCT RCT Risk of bias Low % females:100 Fesoterodine 4 mg; At 2-week telephone call and 4-week followup visit, women were offered the option of increasing their dose to fesoterodine 8 mg or an identical placebo daily vs. Placebo Inclusion criteria Ambulatory women >18 years old with self isolated urgency incontinence or mixed incontinence that was associated predominantly with urgency. Exclusion criteria Urinary-tract infection or hematuria, antiincontinence surgery in the past 5 years, lower urinary tract or rectal fistula, interstitial cystitis, symptomatic pelvic organ prolapse, urogenital cancer or radiation, congenital abnormality that leads to incontinence, or major neurologic disorder Mean age Baseline severity Total incontinence episodes per day % with mixed UI Not Prior treatments Not Concurrent treatments Current systemic hormone therapy % Women on fesoterodine therapy 0.9 fewer urgency and 1.0 fewer total incontinence episodes/day, compared with placebo (P <.001). This difference is not clinically important Evidence Table 2. Risk of bias in clinical trials of fesoterodine vs. placebo for women with predominant urgency urinary incontinence Trial Masking Subject flow Intention-to-treat Adequacy of allocation concealment and randomization Sand, Treatment status Open label Outcomes assessment Not Huang, Treatment status Double-blind Outcomes assessment Not Screened 3349 Eligible Not Enrolled 2996 Randomized 1971 Analyzed 1939 Screened 2900 Eligible Not Enrolled Not Randomized 645 Analyzed 604 No: subjects who agreed to participate in the extension of RCT were included in analyses No: Multiple imputation of missing data was conducted Non randomized study Allocation concealment Unclear Randomization Adequate Risk of bias High Low

5 GRADE table: Fesoterodine Comparison: Fesoterodine vs. placebo Outcomes Number of studies Patients Rate, % active/ control Relative risk (95% CI) Continence 2 2,465 61/ (1.1; 1.5) Updated 3 3,110 55/ (1.1;1.9) Absolute risk difference (95% CI) 0.13 (0.06; 0.20) 0.13 (0.09;0.17) Number needed to treat (95% CI) 8 (5;17) 8 (6;11) Attributable events (95% CI) 130 (58; 202) 132 (90;174) Effect in relative/ absolute scale Evidence Low Moderate Adverse effects 4 4,145 51/ (1.2;1.6) Updated 5 4,790 52/ (1.2;1.6) 0.16 (0.11; 0.20) 0.15 (0.11;0.19) 6 (5;9) 7 (5;9) 156 (112; 200) 149 (112;185) High High Clinical Effectiveness of Darifenacin 1 new reference Key message: Moderate strength of evidence from 3RCTs (N=722) suggested that darifenacin, 15mg/day, increased the rates of adverse effects (in 169 per 1000 treated, 95%CI 97; 240) and the rates of dry mouth or constipation leading to treatment discontinuation (in 18 per 1000 treated, 95%CI 2; 35). 5 Darifenacin 7.5 mg or 15 mg significantly improved all OAB symptoms including UI starting at days 6 8 versus placebo. 5 Evidence Table 1. Randomized clinical trials of darifenacin vs. placebo for women with predominant urgency urinary incontinence Trial Khullar, duplicated publication of Chapple, Pooled analysis of patient level data from three RCTs to Active vs. control treatment Darifenacin 7.5 mg or 15 mg/day vs. Placebo Inclusion and exclusion criteria Inclusion criteria Men and women aged>=18 years with OAB and 5 50 episodes of incontinence per week during the run-in period. Exclusion criteria Initiation of a Baseline subject characteristics Mean age 57 Baseline severity All patients had 5 50 episodes of incontinence per week; at baseline median incontinence Results Both darifenacin doses significantly improved all OAB symptoms including UI starting at days 6 8

6 analyze the time between starting the drug and improvement in UI. Risk of bias Low % females: % bladder training; pregnancy and lactation; clinically significant stress incontinence (i.e.>= 1 episode of stress incontinence per week), clinically significant pelvic prolapse; indwelling catheter or intermittent self- catheterization; urogenital surgery in the previous 6 months; history of alcohol/drug abuse. episodes/week was % with mixed UI Not Prior treatments not but all had 2 weeks washout period Concurrent treatments Not versus placebo. Evidence Table 2. Risk of bias in randomized clinical trials of darifenacin vs. placebo for women with predominant urgency urinary incontinence Trial Masking Subject flow Intention-to-treat Adequacy of allocation concealment and randomization Khullar, duplicated publication of Chapple, Treatment status Double-blind Outcomes assessment Not Screened Not Eligible Not Enrolled Not Randomized 1059 Analyzed 1053 Yes: all participants who received at least one dose of randomized study medication and had efficacy assessed both at baseline (where applicable) and afterward Allocation concealment Unclear Randomization Adequate Risk of bias Low GRADE table: Darifenacin Outcome: Harms Comparison: darifenacin vs. placebo Darifenacin dose Outcome (as defined in the study) 7.5 mg Discontinuation due to adverse effect 15 mg Discontinuation due to adverse effect Rate active[control] Absolute risk difference Number needed to treat Rate% 1.5[2.6] ARD -0.01(-0.03;0.01) Rate% 5.1[2.6] ARD 0.03(0.00;0.05) 7.5 mg Adverse effects Rate% 54.0[48.7] ARD 0.05(-0.02;0.13) 15 mg Adverse effects Rate% 65.6[48.7] ARD 0.17(0.10;0.24) NNT 6(4;10) Relative measure of association* Evidence Quality RR 0.6(0.2;1.7) 3RCT(725) 5 Moderate No difference RR 2.0(0.9;4.3) 3RCT(722) 5 Moderate No difference RR 1.1(1.0;1.3) 3RCT(725) 5 Moderate No difference RR 1.3(1.2;1.5) 3RCT(722) 5 Moderate Favors placebo

7 7.5 mg Dry mouth or constipation leading to treatment discontinuation 15 mg Dry mouth or constipation leading to treatment discontinuation Rate% 0.6[0.3] ARD 0.00(-0.01;0.01) Rate% 2.1[0.3] ARD 0.02(0.00;0.03) NNT 54(29;452) RR 2.3(0.2;25.3) 3RCT(725) 5 Moderate No difference RR 8.1(1.0;65.8) 3RCT(722) 5 Moderate Favors placebo Bold-significant at 95%CL; ARD- absolute risk difference; NNT- number needed to treat to achieve 1 event; RR- relative risk; * all calculations were conducted among randomized patients (intention to treat) Clinical Effectiveness of Solifenacin 1 new reference Key message. Low strength of evidence from a single RCT (n= 275) suggested the higher dose of solifenacin did not decrease the frequency of UI episodes but increased the risk of adverse effects, severe adverse effects, dry mouth and gastro-intestinal disorders. 6 Evidence Table 1. Randomized clinical trial of solifenacin for women with predominant urgency urinary incontinence Trial Active vs. control treatment Inclusion and exclusion criteria Baseline subject characteristics Results Cardozo, randomized extension of SUNRISE trial, 36 Solifenacin 10 mg vs. solifenacin 5 mg Risk of bias Low % females: Inclusion criteria Men and women with >3 severe urgency episodes with or without incontinence, >8micturitions/24 h who did not respond to 5 mg solifenacin in SUNRISE trial Exclusion criteria not Mean age 58 Baseline severity Patient Perception of Bladder Condition ; Mean UI daily episodes: % with mixed UI % Prior treatments 100% failed 5mg solifenacin treatment; % failed other antimuscarinics Concurrent treatments Not Reductions in the mean number of severe urgency episodes were 0.9 after 10mg vs. 0.4 after 5 mg. No differences in UI frequency

8 Evidence Table 2. Risk of bias in a randomized clinical trial of solifenacin for women with predominant urgency urinary incontinence Trial Masking Subject flow Intention-to-treat Adequacy of allocation concealment and randomization Cardozo, Treatment status Double-blind Outcomes assessment Not Screened Not relevant Eligible Not relevant Enrolled 275 Randomized 275 Analyzed 275 Yes Allocation concealment Unclear Randomization Adequate Risk of bias Low GRADE table: Solifenacin Outcomes: Harms Comparison: Solifenacin 10 vs. 5mg Outcome (as defined in the study) Rate active[control] Absolute risk difference Number needed to treat Discontinued due to TEAEs Rate% 1.4[0.0] ARD 0.01(-0.01;0.04) Serious TEAEs Rate% 0.7[0.0] ARD 0.01(-0.01;0.03) Any TEAE Rate% 22.1[7.4] ARD 0.15(0.07;0.23) NNT 7(4;15) Mild Rate% 11.4[3.7] ARD 0.08(0.02;0.14) NNT 13(7;64) Moderate Rate% 5.7[3.7] ARD 0.02(-0.03;0.07) Severe Rate% 5.0[0.0] ARD 0.05(0.01;0.09) NNT 20(11;86) Any drug-related TEAE Rate% 13.6[3.7] ARD 0.10(0.03;0.16) NNT 10(6;30) Relative measure of association* Evidence Quality RR 4.8(0.2;99.5) 1RCT(275) 6 Low No difference RR 2.9(0.1;70.4) 1RCT(275) 6 Low No difference RR 3.0(1.5;5.9) 1RCT(275) 6 Low Favors lower dose RR 3.1(1.2;8.2) 1RCT(275) 6 Low Favors lower dose RR 1.5(0.5;4.6) 1RCT(275) 6 Low No difference RR 14.5(0.8;250.9) 1RCT(275) 6 Low Favors lower dose RR 3.7(1.4;9.5) 1RCT(275) 6 Low Favors lower dose

9 Gastrointestinal disorders Rate% 8.6[2.2] ARD 0.06(0.01;0.12) NNT 16(9;92) Dry mouth Rate% 5.7[0.7] ARD 0.05(0.01;0.09) NNT 20(11;116) Constipation Rate% 2.1[0.7] ARD 0.01(-0.01;0.04) Nervous system disorders Rate% 2.9[0.7] ARD 0.02(-0.01;0.05) Skin and subcutaneous tissue disorders Rate% 0.0[2.2] ARD -0.02(-0.05;0.01) RR 3.9(1.1;13.4) 1RCT(275) 6 Low Favors lower dose RR 7.7(1.0;60.9) 1RCT(275) 6 Low Favors lower dose RR 2.9(0.3;27.5) 1RCT(275) 6 Low No difference RR 3.9(0.4;34.1) 1RCT(275) 6 Low No difference RR 0.1(0.0;2.6) 1RCT(275) 6 Low No difference Bold-significant at 95%CL; ARD- absolute risk difference; NNT- number needed to treat to achieve 1 event; RR- relative risk; * all calculations were conducted among randomized patients (intention to treat) Clinical effectiveness of B3-adrenoceptor agonists- 6 new references Key messages: resolved urinary incontinence in patients with overactive bladder per 1000 treated, patients had improvement in incontinence (moderate strength of evidence). Higher (300mg/day) but not lower (200mg/day) doses improved treatment satisfaction and quality of life (low strength of evidence). Adverse effects did not differ after the drug vs. placebo except for nasopharyngitis and gastrointestinal disorders that were more frequent with the drug. Solabegron decreased the frequency of urinary incontinence episodes with dose response association (low strength of evidence). Adverse effects did not differ after the drug vs. placebo

10 Evidence table 1. Randomized control clinical trials of B3-adrenoceptor agonists for overactive bladder Trial Active vs. control treatment Inclusion and exclusion criteria Baseline subject characteristics Chapple, NCT , Phase 2, proof-of-concept Randomized trial Risk of bias Medium % females: 85 b3-adrenoceptor agonist 100 or 150 mg twice-daily vs. Placebo Nitti, Individual patient data meta-analysis of 3 Randomized trials NCT /NCT / NCT Publications of the primary RCTs 9-12 Risk of bias Medium % females: 85% in the FAS-incontinence (FAS-I) set (patients who incontinence episodes at baseline). b3-adrenoceptor agonist mg twice-daily vs. Placebo Inclusion criteria: Men and women >18 years of age with symptoms of OAB (urinary frequency and urgency with or without urgency incontinence) for >3 months; a frequency of micturition on average >8 times/24 hr.; and >3 episodes of urgency (grade 3 or 4), with or without incontinence, during the 3-day micturition diary period. Exclusion criteria: Outflow obstruction; significant post-void residual (PVR) volume (>200 ml); predominantly stress UI, self-catheterization; neurological causes for abnormal detrusor activity; diabetic neuropathy; symptomatic bladder disorders, bladder stones, previous pelvic radiation therapy or previous or current malignant disease of the pelvic organs; contraindications for anticholinergics; nondrug treatment including electro stimulation therapy; use of other urinary incontinence medications; clinically significant cardiovascular or cerebrovascular disease; any other condition making the patient unsuitable for the study (as deemed by the investigator). Inclusion criteria: Male and female patients aged > 18 years with OAB symptoms for >3 months were enrolled Exclusion criteria: Stress incontinence or mixed incontinence with stress predominance at screening or had an average total daily urine volume > 3000 ml. Age Baseline severity % had incontinence % with mixed UI % Prior treatments Effective drug therapy % Concurrent treatments Not Mean age Baseline severity: Mean number of incontinence episodes/24 h- 1.8 % with mixed UI Prior drug treatment % Concurrent treatments Not Ohlstein, b3-adrenoceptor Agonist Solabegron Inclusion criteria: Women (18 80 yrs. of Mean age

11 Randomized trial Risk of bias Low % females:100% vs. Placebo age) with OAB, symptoms of urgency, urge incontinence, and frequency Exclusion criteria: Bladder-related pain, volume voided of < 250 ml per micturition, total urine volume of 3000 ml/24 h; stress urinary incontinence (SUI) or mixed stress/urge incontinence with SUI as the predominant factor, grade III/IV pelvic organ prolapse with or without cystocele, history of interstitial cystitis or bladder-related pain, urinary tract infections or bladder stones, urogenital neoplasms or malignancies, or neuropathology likely to affect the lower urinary tract Baseline severity: Baseline incontinence >3 episodes per day 56-62% % with mixed UI not Prior drug treatment 35-41% Concurrent treatments not Evidence Table 2. Risk of bias in randomized control clinical trials of B3-adrenoceptor agonists for overactive bladder Drug Chapple, Nitti, Masking Subject flow Intention-to-treat Adequacy of allocation concealment and randomization Treatment status Double blind Screened Not No Allocation concealment Adequate Outcomes assessment Not Eligible Not Randomization Adequate Enrolled 314 Randomized 262 Treatment status Double blind Outcomes assessment Not Analyzed 255 Screened Not Eligible Not Enrolled Not Randomized 3542/2317 in FAS I population Analyzed 2317 women in FAS I population No Allocation concealment Adequate Randomization Adequate Risk of bias Medium Medium Ohlstein, Solabegron Treatment status Double blind Outcomes assessment Not Screened 300 Eligible Not Enrolled Not Randomized 258 Analyzed 258 Yes Allocation concealment Unclear Randomization Adequate Low

12 GRADE Tables: Outcome: Continence Comparison: vs. placebo Comparison Outcome Rate active[control] Absolute risk difference Number needed to treat 50 mg twice/day No incontinence episodes No incontinence episodes Rate% 44.1[37.8] ARD 0.06(0.02;0.11) NNT 16(9;59) Rate% 46.4[37.8] ARD 0.09(0.03;0.14) NNT 12(7;29) Relative measure of association* RR 1.2(1.0;1.3) OR adjusted for gender and study 1.3(1.1;1.6) RR 1.2(1.1;1.4) OR adjusted for gender and study 1.6(1.3;2.0) Evidence Quality 3RCT(1760) 8 Moderate Favors drug, no doseresponse effect 3RCT(1425) 8 Moderate Bold-significant at 95%CL; ARD- absolute risk difference; NNT- number needed to treat to achieve 1 event; RR- relative risk; * all calculations were conducted among randomized patients (intention to treat); OR- odds ratios Outcome: Improvement in urinary incontinence Comparison: vs. placebo Comparison Outcome Rate active[control] Absolute risk difference Number needed to treat 50 mg twice/day > 50% reduction from baseline in incontinence episodes/24 h > 50% reduction from baseline in incontinence episodes/24 h Responders for reduction in urgency incontinence Rate% 69.5[59.6] ARD 0.10(0.05;0.14) NNT 10(7;18) Rate% 70.5[59.6] ARD 0.11(0.06;0.16) NNT 9(6;17) Rate% 64.9[34.1] ARD 0.30(0.13;0.46) NNT 3(2;7) Relative measure of association* RR 1.2(1.1;1.3) OR adjusted for gender and study 1.5(1.3;1.9) RR 1.2(1.1;1.3) OR adjusted for gender and study Evidence Quality 3RCT(1760) 8 Moderate 3RCT(1425) 8 Moderate Favors drug, no dose response effect 1.6(1.3;2.1) RR 1.9(1.3;2.7) Low Lower but not high dose favors drug Responders for Rate% 46.3[34.1] RR 1.3(0.9;2.0) Low

13 150 mg twice/day reduction in urgency incontinence ARD 0.11(- 0.05;0.28) Bold-significant at 95%CL; ARD- absolute risk difference; NNT- number needed to treat to achieve 1 event; RR- relative risk; * all calculations were conducted among randomized patients (intention to treat) Outcome: Quality of life Comparison: vs. placebo Comparison Outcome Rate active[control] Absolute risk difference Number needed to treat 150 mg twice/day Responders in quality of life (improvement of at least one category for patients perception of their bladder condition compared to baseline) Responders in quality of life (improvement of at least one category for patients perception of their bladder condition compared to baseline) Responders in quality of life (improvement of at least two categories for patients perception of their bladder condition compared to Rate% 55.0[53.0] ARD 0.02(-0.15;0.19) Rate% 68.0[53.0] ARD 0.15(-0.02;0.31) Rate% 28.0[17.0] ARD 0.11(-0.03;0.25) Relative measure of association* Evidence Quality RR 1.0(0.8;1.4) Low No better than placebo RR 1.3(1.0;1.7) Low RR 1.7(0.9;3.2) Low Higher but not lower dose favors drug

14 baseline) 150 mg twice/day Responders in quality of life (improvement of at least two categories for patients perception of their bladder condition compared to baseline) Rate% 33.0[17.0] ARD 0.16(0.01;0.30) NNT 6(3;87) RR 1.9(1.0;3.7) Low Bold-significant at 95%CL; ARD- absolute risk difference; NNT- number needed to treat to achieve 1 event; RR- relative risk; * all calculations were conducted among randomized patients (intention to treat) Outcome: Treatment satisfaction Comparison: vs. placebo Comparison Outcome Rate active[control] Absolute risk difference Number needed to treat 150 mg twice/day Patients assessment of treatment as beneficial Patients assessment of treatment as beneficial Rate% 60.0[50.0] ARD 0.10(- 0.07;0.27) Rate% 71.0[50.0] ARD 0.21(0.04;0.37) NNT 5(3;23) Relative measure of association* RR 1.2(0.9;1.6) Low RR 1.4(1.1;1.9) Low Evidence Quality Higher but not lower dose favors drug Bold-significant at 95%CL; ARD- absolute risk difference; NNT- number needed to treat to achieve 1 event; RR- relative risk; * all calculations were conducted among randomized patients (intention to treat) Outcome: Reduction in the frequency of urinary incontinence Comparison: vs. placebo Comparison Outcome Effect size Relative measure of association* Evidence Quality Incontinence Mean Difference RR NR Low episodes/24 hr. from baseline vs. placebo -1.2(-1.9;-0.4) Lower but not higher dose favors drug

15 150 mg twice/day 150 mg twice/day 50 mg twice/day Incontinence episodes/24 hr. Urgency UI episodes Urgency UI episodes Change from baseline in the mean number of incontinence episodes/24 h (FAS-I) Change from baseline in the mean number of incontinence episodes/24 h (FAS-I) Mean Difference from baseline vs. placebo -0.6(-1.3;0.2) Mean Difference from baseline vs. placebo -1.0(-1.7;-0.2) Mean Difference from baseline vs. placebo -0.4(-1.1;0.4) Mean Adjusted for gender and study difference from baseline vs. placebo -0.4(-0.5;-0.2) Mean Adjusted for gender and study difference from baseline vs. placebo -0.4(-0.6;-0.2) Bold-significant at 95%CL; RR- relative risk; NR- not Outcome: Adverse effects Comparison: vs. placebo RR NR Low RR NR Low RR NR Low RR NR 3RCT(1760) 8 Low RR NR 3RCT(1425) 8 Low Lower but not higher dose favors drug Favors drug with no dose response association Comparison Outcome Rate active[control] Absolute risk difference Number needed to treat 150 mg twice/day Discontinuation due to adverse events Discontinuation due to adverse events Rate% 4.6[1.5] ARD 0.03(- 0.03;0.09) Rate% 7.7[1.5] ARD 0.06(- 0.01;0.13) Relative measure of association* RR 3.0(0.3;28.5) Low RR 5.1(0.6;42.3) Low TEAE leading to Rate% 3.7[3.3] RR 1.1(0.7;1.7) 3RCT(2309) 8 Low Evidence Quality No difference with placebo

16 discontinuation ARD 0.00(- 0.01;0.02) 150 mg twice/day All adverse effect Rate% 18.5[24.2] ARD -0.06(- 0.20;0.08) All adverse effect Rate% 24.6[24.2] ARD 0.00(- 0.14;0.15) Any TEAE Rate% 43.3[47.7] ARD -0.04(- 0.09;0.00) NNT -23(-365;-12) Drug-related SAE Rate% 0.3[0.4] ARD 0.00(- 0.01;0.00) Drug-related TEAE Rate% 18.5[16.8] ARD 0.02(- 0.01;0.05) Drug-related TEAE leading to discontinuation Rate% 2.7[2.0] ARD 0.01(- 0.01;0.02) SAE Rate% 2.8[2.1] ARD 0.01(- 0.01;0.02) RR 0.8(0.4;1.5) Low RR 1.0(0.6;1.9) Low RR 0.9(0.8;1.0) 3RCT(2309) 8 Moderate RR 0.7(0.2;3.0) 3RCTs(2s309) 8 Low RR 1.1(0.9;1.3) 3RCTs(2309) 8 Low RR 1.4(0.8;2.4) 3RCTs(2309) 8 Low RR 1.3(0.8;2.2) 3RCTs(2309) 8 Low Bold-significant at 95%CL; ARD- absolute risk difference; NNT- number needed to treat to achieve 1 event; RR- relative risk; * all calculations were conducted among randomized patients (intention to treat) Evidence Table 3. Adverse effects after mirabegron vs. placebo Comparison Outcome Rate active[control] Absolute risk difference Number needed to treat Cardiac disorders Rate% 0.0[4.5] ARD -0.05(-0.10;0.01) Relative measure of association* RR 0.1(0.0;2.8)

17 150 mg twice/day 50 mg twice/day 150 mg twice/day 150 mg twice/day 50 mg twice/day 150 mg twice/day 150 mg twice/day 150 mg twice/day Cardiac disorders Rate% 4.6[4.5] ARD 0.00(-0.07;0.07) Constipation Rate% 1.6[1.4] ARD 0.00(-0.01;0.01) Constipation Rate% 1.6[1.4] ARD 0.00(-0.01;0.01) Diarrhea Rate% 1.5[0.0] ARD 0.02(-0.03;0.06) Diarrhea Rate% 0.0[0.0] ARD 0.00(-0.03;0.03) Dizziness Rate% 1.5[0.0] ARD 0.02(-0.03;0.06) Dizziness Rate% 4.6[0.0] ARD 0.05(-0.01;0.10) Dry mouth Rate% 1.7[2.1] ARD 0.00(-0.01;0.01) Dry mouth Rate% 2.5[2.1] ARD 0.00(-0.01;0.02) Dry mouth Rate% 0.0[1.5] ARD -0.02(-0.06;0.03) Dry mouth Rate% 6.2[1.5] ARD 0.05(-0.02;0.11) Ear and labyrinth disorders Rate% 0.0[3.0] ARD -0.03(-0.08;0.02) Ear and labyrinth disorders Rate% 1.5[3.0] ARD -0.01(-0.07;0.04) Exanthema Rate% 3.1[0.0] ARD 0.03(-0.02;0.08) Exanthema Rate% 0.0[0.0] ARD 0.00(-0.03;0.03) RR 1.0(0.2;4.8) RR 1.1(0.6;2.0) 3RCTs(2755) 8 RR 1.1(0.6;2.2) 3RCTs(2309) 8 RR 3.0(0.1;73.4) RR 0.0(0.0;0.0) RR 3.0(0.1;73.4) RR 7.1(0.4;134.9) RR 0.8(0.5;1.4) 3RCTs(2755) 8 RR 1.2(0.7;2.0) 3RCTs(2309) 8 RR 0.3(0.0;8.2) RR 4.1(0.5;35.4) RR 0.2(0.0;4.1) RR 0.5(0.0;5.5) RR 5.1(0.2;103.7) RR 0.0(0.0;0.0)

18 150 mg twice/day 150 mg twice/day 150 mg twice/day 150 mg twice/day 50 mg twice/day 150 mg twice/day 50 mg twice/day Eye disorders Rate% 0.0[0.0] ARD 0.00(-0.03;0.03) Eye disorders Rate% 3.1[0.0] ARD 0.03(-0.02;0.08) Fatigue Rate% 0.0[3.0] ARD -0.03(-0.08;0.02) Fatigue Rate% 0.0[3.0] ARD -0.03(-0.08;0.02) Gastrointestinal disorders Rate% 6.2[3.0] ARD 0.03(-0.04;0.10) Gastrointestinal Rate% 13.8[3.0] disorders ARD 0.11(0.01;0.20) General disorders and administration site conditions General disorders and administration site NNT 9(5;69) Rate% 0.0[4.5] ARD -0.05(-0.10;0.01) Rate% 3.1[4.5] ARD -0.01(-0.08;0.05) conditions Headache Rate% 3.4[3.1] ARD 0.00(-0.01;0.02) Headache Rate% 2.5[3.1] ARD -0.01(-0.02;0.01) Headache Rate% 4.6[3.0] ARD 0.02(-0.05;0.08) Headache Rate% 4.6[3.0] ARD 0.02(-0.05;0.08) Hypertension Rate% 7.5[7.6] ARD 0.00(-0.02;0.02) Hypertension Rate% 2.7[2.5] ARD 0.00(-0.01;0.01) RR 0.0(0.0;0.0) RR 5.1(0.2;103.7) RR 0.2(0.0;4.1) RR 0.2(0.0;4.1) RR 2.0(0.4;10.7) RR 4.6(1.0;20.3) RR 0.1(0.0;2.8) RR 0.7(0.1;3.9) RR 1.1(0.7;1.6) 3RCT(2755) 8 RR 0.8(0.5;1.3) 3RCT(2309) 8 RR 1.5(0.3;8.8) RR 1.5(0.3;8.8) RR 1.0(0.8;1.3) 3RCT(2755) 8 RR 1.1(0.6;1.8) 3RCT(2309) 8 Infections and infestations Rate% 1.5[3.0] RR 0.5(0.0;5.5)

19 ARD -0.01(-0.07;0.04) 150 mg twice/day Infections and infestations Rate% 0.0[3.0] ARD -0.03(-0.08;0.02) 150 mg twice/day 150 mg twice/day 50 mg twice/day 150 mg twice/day 150 mg twice/day 150 mg twice/day Investigations Rate% 1.5[3.0] ARD -0.01(-0.07;0.04) Investigations Rate% 3.1[3.0] ARD 0.00(-0.06;0.06) Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders Rate% 1.5[3.0] ARD -0.01(-0.07;0.04) Rate% 0.0[3.0] ARD -0.03(-0.08;0.02) Nasopharyngitis Rate% 3.9[2.5] ARD 0.01(0.00;0.03) NNT 72(37;1406) Nasopharyngitis Rate% 2.7[1.8] ARD 0.01(0.00;0.02) Nausea Rate% 1.5[0.0] ARD 0.02(-0.03;0.06) Nausea Rate% 1.5[0.0] ARD 0.02(-0.03;0.06) Nervous system disorders Rate% 6.2[6.1] ARD 0.00(-0.08;0.08) Nervous system disorders Rate% 7.7[6.1] ARD 0.02(-0.07;0.10) Palpitations Rate% 0.0[1.5] ARD -0.02(-0.06;0.03) Palpitations Rate% 4.6[1.5] ARD 0.03(-0.03;0.09) Skin and subcutaneous tissue disorders Rate% 6.2[0.0] ARD 0.06(0.00;0.13) RR 0.2(0.0;4.1) RR 0.5(0.0;5.5) RR 1.0(0.1;7.0) RR 0.5(0.0;5.5) RR 0.2(0.0;4.1) RR 1.5(1.0;2.4) 3RCTs(2755) 8 RR 1.5(0.9;2.6) 3RCTs(2309) 8 RR 3.0(0.1;73.4) RR 3.0(0.1;73.4) RR 1.0(0.3;3.9) RR 1.3(0.4;4.5) RR 0.3(0.0;8.2) RR 3.0(0.3;28.5) RR 9.1(0.5;166.4)

20 150 mg twice/day 50 mg twice/day 50 mg twice/day 150 mg twice/day 150 mg twice/day 150 mg twice/day Skin and subcutaneous tissue disorders Rate% 3.1[0.0] ARD 0.03(-0.02;0.08) Urinary tract infection Rate% 2.9[1.8] ARD 0.01(0.00;0.02) Urinary tract infection Rate% 1.8[1.8] ARD 0.00(-0.01;0.01) Vascular disorders Rate% 3.1[0.0] ARD 0.03(-0.02;0.08) Vascular disorders Rate% 0.0[0.0] ARD 0.00(-0.03;0.03) Vertigo Rate% 0.0[3.0] ARD -0.03(-0.08;0.02) Vertigo Rate% 1.5[3.0] ARD -0.01(-0.07;0.04) Vomiting Rate% 1.5[0.0] ARD 0.02(-0.03;0.06) Vomiting Rate% 4.6[0.0] ARD 0.05(-0.01;0.10) RR 5.1(0.2;103.7) RR 1.6(1.0;2.6) 3RCTs(2755) 8 RR 1.0(0.6;1.7) 3RCTs(2755) 8 RR 5.1(0.2;103.7) RR 0.0(0.0;0.0) RR 0.2(0.0;4.1) RR 0.5(0.0;5.5) RR 3.0(0.1;73.4) RR 7.1(0.4;134.9) Bold-significant at 95%CL; ARD- absolute risk difference; NNT- number needed to treat to achieve 1 event; RR- relative risk; * all calculations were conducted among randomized patients (intention to treat) GRADE Tables: Solabegron Outcome: Intermediate outcome- reduction in the frequency of urinary incontinence Comparison: Solabegron vs. placebo Comparison Outcome Effect size Relative measure of association* Evidence Quality Solabegron Reduction in SMD -0.8(-1.1;-0.4) RR NR 1RCT(173) 13 Low 50 mg twice/day incontinence Solabegron 125 mg twice/day episodes per 24 h Reduction in incontinence episodes per 24 h SMD -2.3(-2.7;-1.9) RR NR 1RCT(170) 13 Low Bold-significant at 95%CL; SMD- standardized mean difference, RR- relative risk, NR- not Favors drug with dose response association

21 Outcome: Adverse effects Comparison: Solabegron vs. placebo Comparison Outcome Rate active[control] Absolute risk difference Number needed to treat Solabegron 50 mg twice/day Solabegron 125 mg twice/day Subjects with AE Rate% 38.6[41.2] ARD -0.03(- 0.17;0.12) Subjects with AE Rate% 37.6[41.2] ARD -0.04(- 0.18;0.11) Relative measure of association* RR 0.9(0.7;1.4) 1RCT(173) 13 Low RR 0.9(0.6;1.3) 1RCT(170) 13 Low Evidence Quality No different from placebo Bold-significant at 95%CL; ARD- absolute risk difference; NNT- number needed to treat to achieve 1 event; RR- relative risk; * all calculations were conducted among randomized patients (intention to treat) Adverse drug effects did not differ after solabegron vs. placebo, the results from a single randomized trial, Ohlstein, Data available on request Comparative Effectiveness of OnabotulinumtoxinA vs. anticholinergic drugs for women with predominant idiopathic urgency urinary incontinence - 1 new reference Key messages A single randomized controlled clinical trial (n=249) compared onabotulinumtoxina with anticholinergic medications (solifenacin or trospium) in women with predominant idiopathic urgency urinary incontinence. 14 The study demonstrated similar effects with examined treatments on frequency of the daily episodes of urgency urinary incontinence and on quality of life measures. 14 More women had complete resolution of urgency urinary incontinence (121 attributable events per 1000 treated, 95%CI 25;217) and complete resolution of all incontinence (112 attributable events per 1000 treated, 95%CI 21;202) with onabotulinumtoxina injections than with solifenacin or trospium. 14

22 Total and serious adverse effects did not differ between onabotulinumtoxina and anticholinergic drugs. The study did not report adverse effects leading to treatment discontinuation. Women experienced dry mouth more often with anticholinergic medications than with onabotulinumtoxina. The rates of transient urinary retention and urinary tract infections were significantly higher with OnabotulinumtoxinA than with drugs. 14 Women with predominant idiopathic frequent (>3/day) urgency UI without prior surgery for stress UI or pelvic organ prolapse who failed three or more anticholinergic drugs may be treated with onabotulinumtoxina. Women should be informed about efficacy and adverse effects with both treatment options. Treatment choice should be based on tolerability of the prior drug treatments and increased risks of intermittent catheterization and urinary tract infection with onabotulinumtoxina injections. 14 Evidence Table 1. Randomized control clinical trial of OnabotulinumtoxinA vs. solifenacin for women with predominant idiopathic urgency urinary incontinence Trial Active vs. control treatment Inclusion and exclusion criteria Baseline subject characteristics Visco, The Anticholinergic versus Botulinum Toxin Comparison (ABC) trial, NCT ;the Pelvic Floor Disorders Network RCT Risk of bias Low % females:100 Intradetrusor injection of 100 U of onabotulinumtoxina plus daily oral placebo vs. Solifenacin, 5 mg initially, with possible escalation to 10 mg and, if necessary, subsequent switch to trospium XR, 60 mg plus one intradetrusor injection of saline Inclusion criteria Women with idiopathic moderate-to-severe urgency or predominant urgency urinary incontinence who had >5episodes of urgency urinary incontinence per 3-day period Exclusion criteria Residual urine volume of >150 ml after voiding, previous therapy for urgency urinary incontinence with onabotulinumtoxina Mean age Baseline severity Baseline frequency: 5.0±2.7 episodes of urgency urinary incontinence per day % with mixed UI Not Mean mixed incontinence /day Prior treatments 41% anticholinergic therapy naïve Concurrent treatments Not Evidence Table 2. Risk of bias in randomized control clinical trial of OnabotulinumtoxinA vs. Solifenacin for women with predominant idiopathic urgency urinary incontinence Trial Masking Subject flow Intention-to-treat Adequacy of allocation concealment and randomization Visco, The Anticholinergic versus Botulinum Toxin Comparison Treatment status Double blind Outcomes assessment No Screened 472 Eligible Not Enrolled Not Randomized 249 Modified ITT Allocation concealment Unclear Randomization Adequate Risk of bias Low

23 (ABC) trial, NCT ;the Pelvic Floor Disorders Network Analyzed 241 GRADE Table: Continence and improvement in stress urinary incontinence Comparison: Intradetrusor injection of 100 U of onabotulinumtoxina plus oral placebo vs. solifenacin, 5 mg - 10 mg and plus one intradetrusor injection of saline Outcome (as defined in the study) Rate active[control] Absolute risk difference Number needed to treat Continence (UUI) Rate% 24.8[12.7] ARD 0.12(0.02;0.22) NNT 8(5;41) Continence (total) Rate% 21.5[10.3] ARD 0.11(0.02;0.20) NNT 9(5;47) >75% reduction in UUI Rate% 50.4[38.1] ARD 0.12(0.00;0.25) NNT 8(4;5230) Much better (PGI-I), 3 months Much better (PGI-I), 6 months Adequate control of symptoms 1 month without drugs Adequate control of symptoms 12 month Rate% 50.4[46.8] ARD 0.04(-0.09;0.16) Rate% 49.6[53.2] ARD -0.04(-0.16;0.09) Rate% 62.0[50.0] ARD 0.12(0.00;0.24) Rate% 38.0[25.0] ARD 0.13(0.01;0.24) NNT 8(4;75) Relative measure of association* Evidence Quality RR 2.0(1.1;3.4) 1RCT(247) 14 Low Favors onabotulinumtoxina RR 2.1(1.1;3.9) 1RCT(247) 14 Low RR 1.3(1.0;1.8) 1RCT(247) 14 Low Favors onabotulinumtoxina RR 1.1(0.8;1.4) 1RCT(247) 14 Low No difference RR 0.9(0.7;1.2) 1RCT(247) 14 Low RR 1.2(1.0;1.6) 1RCT(247) 14 Low No difference RR 1.5(1.0;2.2) 1RCT(247) 14 Low Favors onabotulinumtoxina without drugs Bold-significant at 95%CL; UUI urgency urinary incontinence; ARD- absolute risk difference; PGI patient global impression; NNT- number needed to treat to achieve 1 event; RR- relative risk; * all calculations were conducted among randomized patients (intention to treat) Outcome: Adverse effects Comparison: Intradetrusor injection of 100 U of onabotulinumtoxina plus oral placebo vs. solifenacin, 5 mg - 10 mg and plus one intradetrusor injection of saline Outcome (as defined in the study) Rate active[control] Absolute risk difference Number needed to treat 1 serious adverse event Rate% 3.3[4.8] ARD -0.01(-0.06;0.03) Relative measure of association* Evidence Quality RR 0.7(0.2;2.4) 1RCT(247) 14 Low No difference

24 Any adverse event Rate% 72.7[69.8] ARD 0.03(-0.08;0.14) Dry mouth Rate% 30.6[46.0] ARD -0.15(-0.27;-0.03) NNT -6(-29;-4) Dry eyes Rate% 24.0[16.7] ARD 0.07(-0.03;0.17) Constipation Rate% 20.7[28.6] ARD -0.08(-0.19;0.03) Intermittent catheterization at 2 weeks Intermittent catheterization At 1 mo Intermittent catheterization At 2 mo Intermittent catheterization At 4 mo Intermittent catheterization At 6 mo Self-catheterization at 2 weeks Rate% 8.3[0.0] ARD 0.08(0.03;0.13) NNT 12(7;32) Rate% 2.5[0.0] ARD 0.02(-0.01;0.06) Rate% 5.0[0.0] ARD 0.05(0.01;0.09) NNT 20(11;121) Rate% 2.5[0.0] ARD 0.02(-0.01;0.06) Rate% 0.8[0.0] ARD 0.01(-0.01;0.03) Rate% 7.4[3.2] ARD 0.04(-0.01;0.10) Self-catheterization At 1 mo Rate% 14.0[0.8] ARD 0.13(0.07;0.20) NNT 8(5;15) Self-catheterization At 2 mo Rate% 11.6[1.6] ARD 0.10(0.04;0.16) NNT 10(6;26) Self-catheterization At 4 mo Rate% 9.1[0.8] ARD 0.08(0.03;0.14) NNT 12(7;34) Self-catheterization At 6mo Rate% 4.1[0.8] ARD 0.03(-0.01;0.07) Urinary tract infection Rate% 33.1[12.7] ARD 0.20(0.10;0.31) RR 1.0(0.9;1.2) 1RCT(247) 14 Low No difference RR 0.7(0.5;0.9) 1RCT(247) 14 Low Favors onabotulinumtoxina RR 1.4(0.9;2.4) 1RCT(247) 14 Low No difference RR 0.7(0.5;1.1) 1RCT(247) 14 Low No difference RR 21.9(1.3;369.0) 1RCT(247) 14 Low Favors onabotulinumtoxina RR 7.3(0.4;139.6) 1RCT(247) 14 Low No difference RR 13.5(0.8;237.7) 1RCT(247) 14 Low Favors anticholinergic drugs RR 7.3(0.4;139.6) 1RCT(247) 14 Low No difference RR 3.1(0.1;75.9) 1RCT(247) 14 Low No difference RR 2.3(0.7;7.4) 1RCT(247) 14 Low No difference RR 17.7(2.4;131.0) 1RCT(247) 14 Low Favors anticholinergic drugs RR 7.3(1.7;31.4) 1RCT(247) 14 Low Favors anticholinergic drugs RR 11.5(1.5;87.4) 1RCT(247) 14 Low Favors anticholinergic drugs RR 5.2(0.6;43.9) 1RCT(247) 14 Low No difference RR 2.6(1.5;4.4) 1RCT(247) 14 Low Favors anticholinergic drugs

25 NNT 5(3;10) Residual volume after Rate% 27.3[5.6] voiding >150 ml ARD 0.22(0.13;0.31) NNT 5(3;8) Residual volume after voiding Rate% 14.0[7.1] >150 ml ARD 0.07(-0.01;0.15) Participants with any AE Rate% 72.7[69.8] ARD 0.03(-0.08;0.14) Respiratory muscle weakness and/or paresis Rate% 1.7[0.0] ARD 0.02(-0.01;0.04) Dry eyes Rate% 24.0[16.7] ARD 0.07(-0.03;0.17) Diarrhea Rate% 14.9[11.1] ARD 0.04(-0.05;0.12) Dry mouth Rate% 30.6[46.0] ARD -0.15(-0.27;-0.03) NNT -6(-29;-4) Flank pain Rate% 5.8[2.4] ARD 0.03(-0.02;0.08) Constipation Rate% 20.7[28.6] ARD -0.08(-0.19;0.03) Mental confusion and/or status changes Rash/hives and/or Other type of allergic reaction Rate% 2.5[0.8] ARD 0.02(-0.01;0.05) Rate% 9.9[4.0] ARD 0.06(0.00;0.12) RR 4.9(2.3;10.7) 1RCT(247) 14 Low Favors anticholinergic drugs RR 2.0(0.9;4.2) 1RCT(247) 14 Low No difference RR 1.0(0.9;1.2) 1RCT(247) 14 Low No difference RR 5.2(0.3;107.3) 1RCT(247) 14 Low No difference RR 1.4(0.9;2.4) 1RCT(247) 14 Low No difference RR 1.3(0.7;2.6) 1RCT(247) 14 Low No difference RR 0.7(0.5;0.9) 1RCT(247) 14 Low Favors onabotulinumtoxina RR 2.4(0.6;9.2) 1RCT(247) 14 Low No difference RR 0.7(0.5;1.1) 1RCT(247) 14 Low No difference RR 3.1(0.3;29.6) 1RCT(247) 14 Low No difference RR 2.5(0.9;6.9) 1RCT(247) 14 Low No difference Bold-significant at 95%CL; ARD- absolute risk difference; NNT- number needed to treat to achieve 1 event; RR- relative risk; * all calculations were conducted among randomized patients (intention to treat)

26 Comparative effectiveness of intravaginal estriol combined with pelvic floor muscle training vs. intravaginal estriol alone for postmenopausal women with stress urinary incontinence - 1 new reference Key messages. Intravaginal estriol combined with pelvic floor muscle training was more effective than intravaginal estriol alone for resolving stress urinary incontinence in postmenopausal non-obese women (689 continent women per 1000 treated, 95%CI 592; 787) (low strength of evidence from a single RCT (n=206)). 17 Evidence table 1. Randomized control clinical trial that examined intravaginal estriol combined with pelvic floor muscle training vs. intravaginal estriol alone for postmenopausal women with stress urinary incontinence. 17 Trial Active vs. control treatment Inclusion and exclusion criteria Baseline subject characteristics Capobianco, RCT Risk of bias Medium % females:100 Pelvic floor muscle training and electrical stimulation plus Intravaginal estriol ovules( 1 ovule (1 mg) once daily for 2 weeks and then 2 ovules once weekly for a total of 6 months) vs. Intravaginal estriol ovules alone Inclusion criteria Postmenopausal women with symptoms and signs of urinary stress incontinence, vaginal atrophy, and histories of recurrent urinary tract infections. The patients with previous hysterectomy were eligible for the study is they have stress UI. Mean age Baseline severity Not % with mixed UI Not Exclusion criteria Detrusor over activity, pathologies or anatomical lesions of the urogenital tract such as uterovaginal prolapse, cystocele, and rectocele of grade II or III, the presence of severe systemic disorders, thromboembolic diseases, biliary lithiasis, previous breast or uterine cancer, abnormal uterine bleeding and body mass index (BMI) >25 kg/m2. Prior treatments Not Concurrent treatments Not Evidence table 2. Risk of bias in randomized control clinical trial that examined intravaginal estriol combined with pelvic floor muscle training vs. intravaginal estriol alone for postmenopausal women with stress urinary incontinence. 17 Masking Subject flow Intention-totreat Capobianco, Treatment status Open-label Screened 466 Yes Outcomes assessment Not Eligible Not Enrolled Not Randomized 206 Adequacy of allocation concealment and randomization Allocation concealment Adequate Randomization Adequate Risk of bias Medium

27 Analyzed 206 GRADE Tables: Intravaginal estriol Outcome: Continence Comparison: intravaginal estriol combined with pelvic floor muscle training vs. intravaginal estriol alone Outcome Rate active[control] Absolute risk difference Number needed to treat No complaints of stress UI Rate% 78.6[9.7] ARD 0.69(0.59;0.79) Relative measure of association* Evidence Quality 8.1(4.5;14.7) 1RCT(206) 17 Low Favors combined treatment NNT 1(1;2) Bold-significant at 95%CL; ARD- absolute risk difference; NNT- number needed to treat to achieve 1 event; RR- relative risk; * all calculations were conducted among randomized patients (intention to treat) Outcome: Adverse effects Comparison: intravaginal estriol combined with pelvic floor muscle training vs. intravaginal estriol alone Outcome Treatment discontinuation due to adverse effects Localized adverse reactions, such as vaginal irritation and burning Rate active[control] Absolute risk difference Number needed to treat Rate% 4.9[5.8] ARD -0.01(-0.07;0.05) Rate% 3.9[4.9] ARD -0.01(-0.07;0.05) Relative measure of association* Evidence Quality 0.8(0.3;2.6) 1RCT(206) 17 Low No difference 0.8(0.2;2.9) 1RCT(206) 17 Low No difference Bold-significant at 95%CL; ARD- absolute risk difference; NNT- number needed to treat to achieve 1 event; RR- relative risk; * all calculations were conducted among randomized patients (intention to treat)

28 Comparative effectiveness of solifenacin versus percutaneous tibial nerve stimulation (PTNS) in women with overactive bladder syndrome - 1 new reference Key message. A single high risk of bias cross over randomized trial (n=40) provided insufficient evidence for comparative effectiveness of percutaneous tibial nerve stimulation when compared with solifenacin in older women with overactive bladder. 15 Evidence Table 1. Randomized control clinical trial of solifenacin succinate versus percutaneous tibial nerve stimulation (PTNS) in women with overactive bladder syndrome Trial Vecchioli-Scaldazza, Cross-over RCT Risk of bias High % females:100 Active vs. control treatment Solifenacin 5 mg once a day for 40 days vs. Percutaneous tibial nerve stimulation twice a week for 30 min for a total of 6 weeks Inclusion and exclusion criteria Inclusion criteria Women with overactive bladder syndrome Exclusion criteria Stress incontinence, urinary tract infection, neurological disease, bladder lithiasis, genital prolapse higher than stage II on POP-Q system, uncontrolled narrow angle glaucoma, pelvic tumors, post void residual urine 100 ml, or previously treatment with pelvic surgery, radiation therapy or antimuscarinic agents Baseline subject characteristics Mean age Baseline severity Urgency incontinence /day % with mixed UI Not Prior treatments Not Concurrent treatments Not Evidence Table 2. Risk of bias in randomized control clinical trial of solifenacin succinate versus percutaneous tibial nerve stimulation (PTNS) in women with overactive bladder syndrome Trial Masking Subject flow Intention-totreat Vecchioli-Scaldazza, Cross-over RCT Treatment status Openlabel Outcomes assessment Not Screened Not Eligible Not Enrolled Not Randomized 40 Analyzed 30 No Adequacy of allocation concealment and randomization Allocation concealment Unclear Randomization Adequate Risk of bias High

29 GRADE tables: Solifenacin vs. PTNS Outcome: Quality of life Comparison: solifenacin succinate versus percutaneous tibial nerve stimulation Outcome (as defined in the study) Rate active[control] Absolute risk difference Number needed to treat Overactive Bladder Questionnaire SMD 0.5(0.0;0.9) Short Form (OAB-qSF) PGI-I SMD 0.9(0.4;1.3) Relative measure of association* Evidence Quality s Not 1RCT(40) 15 Insufficient No difference Not 1RCT(40) 15 Insufficient Favors PTNS Bold-significant at 95%CL; ARD- absolute risk difference; NNT- number needed to treat to achieve 1 event; RR- relative risk; * all calculations were conducted among randomized patients (intention to treat) Intermediate outcome: Frequency and perceived severity of urinary incontinence Comparison: solifenacin succinate versus percutaneous tibial nerve stimulation Outcome (as defined in the study) Rate active[control] Absolute risk difference Number needed to treat Urge incontinence SMD 0.6(0.2;1.1) Patient Perception of Intensity of SMD 0.6(0.1;1.0) Relative measure of association* Not Not Evidence Quality s 1RCT(40) 15 Insufficient Favors PTNS 1RCT(40) 15 Insufficient Favors PTNS Urgency Scale (PPIUS) Bold-significant at 95%CL; ARD- absolute risk difference; NNT- number needed to treat to achieve 1 event; RR- relative risk; * all calculations were conducted among randomized patients (intention to treat)

30 Comparative effectiveness of tolterodine vs. rehabilitation or drug therapy for female urgency urinary incontinence - 1 new reference Key message. Women with predominantly urgency UI experienced greater improvement in overall function after pelvic floor muscle training combined with bladder training when compared with tolterodine 4 mg/day (N=164, low strength of evidence from a single RCT). This study adds to the evidence from BE-DRI RCT (included in the report 37,38 ) suggesting that behavioral treatments were more effective than tolterodine for women with predominant UUI. Pooling was not possible because trials different outcomes. Therefore, I did not upgrade the strength of evidence. Evidence Table 1. Randomized control clinical trial of tolterodine vs. rehabilitation therapy for female urgency urinary incontinence Trial Active vs. control treatment Inclusion and exclusion criteria Kafri, Tolterodine SR 4 mg Inclusion criteria Women NCT Va. bladder training, pelvic floor muscle training, or aged who experienced RCT combined treatment groups with four 50-min visits, >3 episodes of UUI that were Risk of bias Medium 1/ 3 weeks, with female physical therapists who not completely explained by % females:100 specialized in pelvic floor rehabilitation SUI symptoms over the previous 4 weeks Exclusion criteria Current urinary tract infection, neurological disease, diagnosed with psychiatric or depressive disorder, previous pelvic floor surgery, and previous pelvic floor physical therapy Baseline subject characteristics Mean age Baseline severity Not % with mixed UI Not Prior treatments Hormone replacement therapy in % Concurrent treatments Not Evidence Table 2. Risk of bias in randomized control clinical trial of tolterodine vs. rehabilitation therapy for female urgency urinary incontinence Trial Masking Subject flow Intentionto-treat Kafri, NCT Treatment status Open-label Outcomes assessment Yes Screened 1046 Eligible 312 Enrolled 184 Randomized 164 Analyzed 164 Yes Adequacy of allocation concealment and randomization Allocation concealment Adequate Randomization Adequate Risk of bias Medium

31 GRADE tables: Tolterodine vs. rehabilitation or drug therapy Outcome: Frequency, severity and quality of life Comparison: tolterodine versus bladder training Outcome (as defined in the study) Effect size Relative measure Evidence Quality s Number needed to treat of association Number of UUI episodes/week SMD 0.3(-0.2;0.7) Not 1RCT(164) 16 Low No difference Incontinence Severity Index SMD -0.1(-0.5;0.4) Not 1RCT(164) 16 Low I-QOL instrument SMD -0.1(-0.5;0.4) Not 1RCT(164) 16 Low Number of UUI-related symptoms SMD 0.0(-0.4;0.4) Not 1RCT(164) 16 Low Bold-significant at 95%CL; UUI urgency urinary incontinence; NNT- number needed to treat to achieve 1 event; SMD- standardized mean difference Outcome: Frequency, severity and quality of life Comparison: tolterodine versus pelvic floor muscle training Outcome (as defined in the study) Effect size Number needed to treat Relative measure of association Evidence Quality Number of UUI episodes/week SMD 0.2(-0.2;0.7) Not 1RCT(164) 16 Low Incontinence Severity Index SMD 0.4(0.0;0.8) Not 1RCT(164) 16 Low I-QOL instrument SMD -0.2(-0.6;0.3) Not 1RCT(164) 16 Low Number of UUI-related symptoms SMD -0.3(-0.7;0.1) Not 1RCT(164) 16 Low NNT- number needed to treat to achieve one event; SMD- standardized mean difference; NNT- number needed to treat to achieve one event s No difference Outcome: Frequency, severity and quality of life Comparison: tolterodine versus pelvic floor muscle training combined with bladder training Outcome (as defined in the study) Effect size Number needed to treat Relative measure of association Number of UUI episodes/week SMD 0.2(-0.2;0.7) Not 1RCT(164) 16 Low Incontinence Severity Index SMD 0.1(-0.4;0.5) Not 1RCT(164) 16 Low I-QOL instrument SMD -0.1(-0.6;0.3) Not 1RCT(164) 16 Low Number of UUI-related symptoms SMD -0.3(-0.7;0.2) Not 1RCT(164) 16 Low Evidence Quality s No difference