Urogynecology Office. Can You Hold? An Update on the Treatment of OAB. Can You Hold? Urogynecology Office

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1 Urogynecology Office Urogynecology Office Can You Hold? An Update on the Treatment of OAB Can You Hold? Karen Noblett, MD Professor and Chair Department of OB/GYN University of California, Riverside

2 Disclosures Speakers Bureau for Astellas Research support and advisory board Medtronic Research support and advisory board Allergan

3 Objectives Review the epidemiology of OAB Briefly review the evaluation and diagnosis of OAB Describe the management strategies for OAB Review the major updates in the management of OAB Myrbetriq Botox Sacral neuromodulation Percutaneous tibial nerve stimulation

4 What Is Overactive Bladder? 2002 ICS Terminology Urgency, with or without urge incontinence, usually with frequency and nocturia, in the absence of pathologic or metabolic factors that would explain these symptoms Urgency A sudden, compelling desire to pass urine, which is difficult to defer Urinary frequency Urinary urgency Nocturia Urge incontinence Abrams P et al. Neurourol Urodyn. 2002;21:

5 Respondents (%) Prevalence of OAB Symptoms in US Adults 40 Years (EpiLUTS) Adults who had experienced urgency or urge incontinence in the last 4 weeks and defined occurrence as at least sometimes Men Women Coyne KS, et al. Urology. 2011;77: Age (years)

6 Overactive Bladder: Patient Concerns I drink less before I go on a trip I missed the best part of the show I need to have a bathroom nearby because I worry that I won t make it Abrams P, et al. Am J Manag Care. 2000;6(suppl 11):S580-S590.

7 Overactive Bladder: Medical Consequences More Urinary Tract Infections* More Physician Visits/Year OAB Sufferers Twice as Likely to Fall* OAB Patients Were Less Likely to Report Excellent or Very Good Health All comparisons with age- and gender-matched controls. *P< Brown JS, et al. Am J Manag Care. 2000;6:S574-S579. Wagner T, et al. Am J Manag Care. 2002;8:S598-S607.

8 AUA Guidelines for the Diagnosis of Overactive Bladder Most cases of overactive bladder can be diagnosed based on: Patient history, symptom assessment Physical examination Urinalysis Initiation of noninvasive treatment does not require an extensive further workup Gormley EA et al, J Urol Dec;188(6 Suppl):

9 AUA Treatment Guidelines First-line therapies Behavioral therapies (e.g., bladder training, bladder control strategies, pelvic floor muscle training, fluid management) Second-line therapies Anti-muscarinics including darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine or trospium Transdermal formulations Third-line therapies Sacral neuromodulation (SNS) -recommended Peripheral Tibial Nerve Stimulation (PTNS) - recommended Intradetrusor onabotulinumtoxin A - standard Gormley EA et al, J Urol Dec;188(6 Suppl):

10 AUA Treatment Guidelines First-line therapies Behavioral therapies (e.g., bladder training, bladder control strategies, pelvic floor muscle training, fluid management) Second-line therapies Anti-muscarinics including darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine or trospium Transdermal formulations now over the counter New class of medication β-3 agonists Third-line therapies Sacral neuromodulation (SNS) -recommended Peripheral Tibial Nerve Stimulation (PTNS) recommended Intradetrusor onabotulinumtoxin A - standard Gormley EA et al, J Urol Dec;188(6 Suppl):

11 Pharmacotherapy for OAB Goals of treatment Decrease detrusor activity during filling phase but not during voiding Have bladder selectivity without undesirable side effects Approved options Antimuscarinic agents blocks detrusor contractions 3 adrenoceptor agonist promotes bladder relaxation

12 Innervation and Neurophysiologic Control of Bladder Function β-3 receptors M = muscarinic N = nicotinic α = α 1 and α 2 -adrenergic β = β 3 -adrenergic Detrusor muscle (M 2 80%; M 3 20%; β) Mucosa and submucosa (M 2, M 3 ) Bladder neck (α) Pelvic floor (N) Urethra (α)

13 Antimuscarinics (Anticholinergics) Multiple options and formulations Most widely used treatment for OAB Efficacy demonstrated in randomized controlled trials Selection for a particular patient depends on prior treatment history, comorbidities, other current medications, dosing/formulation, potential side effects Limiting factor Adverse events Over 50% of patients discontinue therapy as a consequence of side effects or lack of efficacy

14 Distribution of Muscarinic Receptors Muscarinic receptors are also located in the CNS.

15 Medication Adherence (%) OAB Treatment Adherence Relative to Other Chronic Therapies Statins Bisphosphonates Oral Antidiabetics N = 94,700 N = 10,268 N = 22, ARBs 35 OAB Medications N = 29,876 N = 7,722 Yeaw J, et al. J Manag Care Pharm. 2009;15: ARBs: angiotensin II receptor blockers

16 Mirabegron (Myrbetriq ) Selective -3 adrenergic agonist Stimulation of the -3 adrenoreceptor subtype results in direct relaxation of detrusor muscle First new class of oral therapy for OAB in over 30 years Extended release tablets, 25, 50 mg daily FDA approval June 2012 Bhide A, et al. Int Urogynecol J. 2012;23:

17 Reduction from Baseline at Week 12 Reduction from Baseline at Week 12 Mirabegron Phase 3 Results 2 North American Trial (N = 1328) 2 European-Australian Trial (N = 1978) * 1.5 * * 1.5 * Incontinence Episodes/24 hrs Micturitions/24 hrs 0 Incontinence Episodes/24 hrs Micturitions/24 hrs Placebo Mirabegron 50 mg Tolterodine 4 mg *P < 0.05 vs placebo Khullar V, et al. Neurourol Urodynam. 2011;30(6) Nitti V, et al. Neurourol Urodynam. 2011;30(6)

18 Study Mirabegron Safety and Tolerability European-Australian Phase 3 Trial North American Phase 3 Trial Placebo (%) Mirabegron 50 mg (%) Tolterodine ER 4mg (%) Overall adverse events Hypertension Headache Nasopharyngitis Urinary tract infection Overall adverse events Hypertension Headache Nasopharyngitis Urinary tract infection Khullar V, et al. Neurourol Urodynam. 2011;30(6):abstract 328. Nitti V, et al. Neurourol Urodynam. 2011;30(6):abstract 92.

19 AUA Treatment Guidelines First-line therapies Behavioral therapies (e.g., bladder training, bladder control strategies, pelvic floor muscle training, fluid management) Second-line therapies Anti-muscarinics including darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine or trospium Transdermal formulations now over the counter New class of medication β-3 agonists Third-line therapies Sacral neuromodulation (SNS) -recommended Peripheral Tibial Nerve Stimulation (PTNS) recommended Intradetrusor onabotulinumtoxin A - standard Gormley EA et al, J Urol Dec;188(6 Suppl):

20 Prevalence funnel - OAB 36.2M 1 8.5M 2 Population with OAB Actively seeking healthcare 4.6M 3 3.2M 4 Patients who cannot tolerate Rx Patients actively seeking further treatment What % of patients should go to 3 rd line? 3.2 / 8.5 = 37% 1. Stewart WF, et al. World J Urol 2003: 20: Garnett S, et alj Urol. 2003: Haab F, et al,. Int J Clin Prac. 2005: 59(8): % patients have access (insurance) Zimen Market Research 2005.

21 Which Alternative Treatment Do I Choose?

22 Sacral Neuromodulation Therapy Sacral nerve stimulation is an effective treatment for voiding dysfunction patients who have not been helped or could not tolerate more conventional treatments, including pharmacotherapy.

23 What is Sacral Neuromodulation Therapy? Implantable, programmable neurostimulation system Similar to a pacemaker Involves placing an electrode wire adjacent to a sacral nerve root Typically placed at the S3 level Attached to a programmable stimulator Two-stage therapy Test stimulation phase Implantation phase

24 Indications for Sacral Neuromodulation Therapy Urge Incontinence Urgency/frequency Non-obstructive Retention Fecal Incontinence Failure of other therapies

25 InSite Study The purposes of this study are two fold: 1. To provide evidence from a randomized controlled trial that InterStim Therapy provides better relief of symptoms of OAB than standard medical treatments in current use. 2. To fulfill the requirements of the FDA-mandated postapproval study of the safety of the tined lead using a minimally invasive approach ClinicalTrials.gov. Available at:

26 InSite Study 5-year prospective multi-center post-approval trial 38 centers Initial six month Phase 1 - Patients randomized to SNM or SMT in 1:1 ratio Enrollment from N=147 (SNM=70; SMT=77) Quality of Life was measured using the validated disease-specific International Consultation on Incontinence Modular Questionnaire Overactive Bladder Quality of Life (ICIQ-OABqol) instrument. No difference between SNM and SMT at baseline. Siegel S, Noblett K, Mangel J, et al. [published on line ahead of print Jan ]. Neurourol Urodyn 2014.

27 Primary Efficacy Objective OAB therapeutic success rate at 6 months is greater for the SNM group than for the SMT group. >50% improvement in average voids/day from baseline or a return to normal voiding frequency (<8 voids/day) for subjects with UF at baseline > 50% improvement in average leaks/day from baseline for subjects with UI at baseline Secondary Objectives Quality of Life measurements Siegel S, Noblett K, Mangel J, et al. [published on line ahead of print Jan ]. Neurourol Urodyn

28 InSite Study Design Enroll Randomized cohort Non-randomized cohort Randomize Randomized comparison SNM SMT Implant Month 6 To 5 years Month 6 Implant, to 5 years Implant, to 5 years

29 Percent of Patients OAB therapeutic success rate: UI - 50% reduction in leaks UF - 50% reduction in voids or return to normal (<8/day) 80 Intent to Treat p < 0.05 As Treated p < SNM SMT N = 70 N = 77 N = 51 N = 73 SNM compared to SMT at 6 months Siegel S, Noblett K, Mangel J, Neurourol Urodyn, Jan 2014

30 Mean Change in QOL QOL Change 6 months from baseline The InterStim System (SNM) vs. Standard Medical Therapy (SMT) p-value for all measures p < QOL Measure SNM Subjects (n) SMT Subjects (n) Concern Coping Sleep Social HRQL total MID (Minimally Important Difference = 10 points 2 ) Siegel S, Noblett K, Mangel J, Neurourol Urodyn, Jan Coyne KS, et al Determining the importance of change in the OAB-q. J Urol 176:627-32

31 Percent Responder Rate 100% 80% 86% PHASE 2 : LONG-TERM OAB THERAPEUTIC SUCCESS 50% or Greater Improvement Completers Analysis 85% 84% 83% 80% 60% 40% 20% 0% n= 229 n= 240 n= 220 n= 203 n= months Modified Completers analysis was 82% at 12 months, 79% at 24 months and 76% at 36 months. Siegel S, Noblett K, Mangel J, et al. Neurourol Urodyn Mar;34(3): Siegel S, Noblett K, Mangel J, et al. Urology (2016), / j.urology

32 PHASE 2 : LONG-TERM QUALITY OF LIFE Subjects Showed Significant Improvements in Health-Related Quality of Life (HRQL) Baseline: Concern Coping Sleep Social HRQL All paired tests comparing follow-up to baseline had a p-value < Error bars are 95% confidence intervals. *Coyne KS, et al Determining the importance of change in the OAB-q. J Urol 176: Siegel S, Noblett K, Mangel J, et al. Urology (2016), / j.urology

33 Anticholinergic Therapy vs. Botox for Urgency Urinary Incontinence (ABC Trial) Visco A, Brubaker L, Richter H, et al. NEJM Nov 2012

34 Study Design Women with 5 UUI Episodes/3-Day Diary Randomization Anticholinergic Meds + Placebo Injection Bladder Diaries (Months 1-6) Botox 100U + Placebo Pills Bladder Diaries (Months 1-6) All Pills Stopped at 6 Months

35 Primary Outcome: Outcomes Change from baseline in the mean number of UUI episodes over the 6-month period (months 1, 2, 3, 4, 5 and 6) Secondary Outcomes: Efficacy outcomes: % with complete resolution of UUI Quality of life (QOL) Duration of response Adverse events

36 Change in UUIE From Baseline Primary Outcome: Reduction in Mean UUI Episodes/Day Over 6 Months Anticholinergics: 3.36 UUI Episodes/Day Botox: 3.29 UUI Episodes/Day Study Month P=0.81 Anticholinergic Onabotulinum Toxin A

37 Secondary Efficacy Outcomes Urgency Incontinence Anticholinergics N=127 Botox N=120 P value Complete Resolution (Cure) 13% 27% Quality of Life: OABq-SF Severity Scale OABq-SF QOL Scale PFDI-SF PFIQ-SF

38 Conclusions Anticholinergic therapy and Botox 100 units: Both significantly improve: Urgency urinary incontinence Quality of Life No significant difference between treatment groups Botox compared to anticholinergics: Two-fold likelihood of complete resolution of UUI Higher transient urinary retention and UTI Less dry mouth

39 Posterior Tibial Nerve Stimulation (PTNS) Initially discovered as part of transcutaneous patch tibial nerve stimulation (McGuire et al, J Urol 121:78-9, 1983) Stoller investigated direct stimulation since it is a terminal projection of S3 Technique involves 34 G needle placement in office 3-4 cm above medial malleolus and ground pad on same foot near arch Connect lead to stimulator

40 OrBIT Trial Study Purpose: To compare the effectiveness of PTNS to drug therapy for the treatment in reducing the frequency of voids/day Materials & Methods Randomized, multi-center trial (11 sites in US); 100 patients with urgency-frequency (94 females); 1:1 12 weeks PTNS vs. Tolterodine (4 mg or 2 mg/day) In PTNS arm, subjects received 12 weekly 30-minute treatments. No placebo, not blinded Secondary endpoints included additional voiding diary measures, OAB-q scales and investigator and subject GRA.** GRAs were completed by subjects and investigators after 12 weeks. Clinical success defined as self-reporting improvement or cure on GRA. *OrBIT= The Overactive Bladder Innovative Therapy **GRA = Global Response Assessment: a non-validated, self-assessment patient questionnaire. 1 Peters, K., et al. J Urol 182: ,2009

41 Results: The mean reduction in voids/day from baseline to 12 weeks for PTNS (-2.4) was comparable to the reduction for tolterodine (- 2.5 ) (p=0.44). 79.5% of PTNS patients reported improvement or cure on GRA compared to 54.8% of tolterodine patients (p=0.01); Investigator reported GRA responses were 79.5% and 60.5%, respectively, which did not reach statistical significance (p = 0.05). PTNS (p<0.001) Drug (P<0.001) OrBIT Trial Baseline voids/day 12 week voids/day Change in voids The reduction levels between PTNS and tolterodine are not statistically different (p=0.44) 1 Peters, K., et al. J Urol 182: ,2009

42 OrBIT Trial Conclusions: PTNS shows significant improvements in patient assessment of overactive bladder symptoms and objective effectiveness comparable to that of pharmacotherapy. Study shows similar objective improvements Perception of improvement greater in PTNS arm Reported Adverse Evenys: a) Drug had greater dry mouth/constipation b) PTNS had more pain/bruising at needle site.

43 Randomized Trials: Three independent studies against Drug Therapy Study (n) OrBIT 1 (100) ABC 2 (249) InSite 3 (147) Study Comparison PTNS vs. Tolterodine (4mg/day) Single 100U Botox Injection vs. Anticholinergic Regimen Sacral Neuromodulation Implant vs. SMT No Placebo Not Blinded Double Placebo Double Blinded No Placebo Not Blinded Duration 12 weeks 6 month 6 month Drug naïve Quality of life improvements Yes (?) Similar Improvements (p=ns) Yes (40%) Similar Improvements (p=0.98) No Superior Improvements (p<0.001) Therapy benefit relative to drug Similar Improvements (p=0.44) Similar Improvements (p=0.81) Superior Improvements (p=0.002) This is not intended to infer comparison of therapeutic benefits between PTNS, Botox and Sacral Neuromodulation 1 Peters, K., et al. J Urol 182: , Visco AG, Brubaker L, Richter HE, et al. N Engl J Med 2012;367: Siegel S, Noblett K, Mangel J, et al.. Neurourol Urodyn. Jan 2014

44 Treatment Ladder for OAB Absorbent pads or undergarments Non-reversible Surgery: Bladder denervation; augmentation cystoplasty Intravesical Botox. Sacral Nerve Stimulation, PTNS Medications: Anticholinergics, beta-3 agonists Behavioral techniques, E-stim, Biofeedback, Pelvic Floor Exercise Diet modifications

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