Percutaneous Tibial Nerve Stimulation for the Long-Term Treatment of Overactive Bladder: 3-Year Results of the STEP Study

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1 Percutaneous Tibial Nerve Stimulation for the Long-Term Treatment of Overactive Bladder: 3-Year Results of the STEP Study Kenneth M. Peters,*, Donna J. Carrico, Leslie S. Wooldridge, Christopher J. Miller and Scott A. MacDiarmid From the Beaumont Health System, Royal Oak (KMP, DJC), and Mercy Health Partners, Muskegon (LSW), Michigan, NAMSA Integra Division, Golden Valley, Minnesota (CJM), and Alliance Urology Specialists, Greensboro, North Carolina (SAM) Abbreviations and Acronyms GRA global response assessment HRQoL health related quality of life OAB overactive bladder OAB-q OAB-questionnaire PTNS percutaneous tibial nerve stimulation SNS sacral nerve stimulation SUFU Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction Accepted for publication November 29, Study received institutional review board approval. * Correspondence: Department of Urology, Beaumont Royal Oak, 3535 W. 13 Mile Rd., Suite 438, Royal Oak, Michigan (telephone: ; FAX: ; kmpeters@beaumont.edu). Financial interest and/or other relationship with Uroplasty, Medtronic, EMKinetics and TARIS. Financial interest and/or other relationship with Uroplasty. Financial interest and/or other relationship with Astellas, EMKinetics and Uroplasty. Financial interest and/or other relationship with Astellas, Pfizer, Allergan and Uroplasty. Purpose: We report the long-term efficacy and safety of percutaneous tibial nerve stimulation with the Urgent PC Neuromodulation System for overactive bladder after 3 years of therapy. Materials and Methods: Fifty participants in the randomized, double-blind SUmiT (Sham Effectiveness in Treatment of Overactive Bladder Symptoms) Trial who met the primary effectiveness end point after 12 weekly percutaneous tibial nerve stimulation treatments were enrolled in this prospective study to assess long-term outcomes with percutaneous tibial nerve stimulation. STEP (Sustained Therapeutic Effects of Percutaneous Tibial Nerve Stimulation) Study patients were prescribed a fixed schedule 14-week tapering protocol followed by a personal treatment plan aimed at sustaining overactive bladder symptom improvement. Overactive bladder and quality of life questionnaires were completed every 3 months and 3-day voiding diaries were completed every 6 months. Results: A total of 29 patients completed the 36-month protocol and received a median of 1.1 treatments per month after a 14-week treatment tapering protocol. A Bayesian model estimated that 77% (95% CI 64 90) of patients maintained moderate or marked improvement in overactive bladder symptoms at 3 years. Compared to baseline, median voids per day decreased from 12.0 (IQR ) to 8.7 (IQR ), nighttime voids per night decreased from 2.7 (IQR ) to 1.7 (IQR ) and urge incontinence episodes per day decreased from 3.3 (IQR ) to 0.3 (IQR ) (all p ). All quality of life parameters remained markedly improved from baseline through 3 years (all p ). One patient experienced 2 mild treatment related adverse events of bleeding at the needle site during followup. Conclusions: Most STEP participants with an initial positive response to 12 weekly percutaneous tibial nerve stimulation treatments safely sustained overactive bladder symptom improvement to 3 years with an average of 1 treatment per month. Key Words: urinary bladder; urinary bladder, overactive; electric stimulation therapy; tibial nerve; urinary incontinence, urge OVERACTIVE bladder is a chronic condition that significantly impairs the quality of life of those affected, with considerable social and financial costs. 1,2 An estimated 455 million people worldwide (10.7%) experienced at least 1 OAB symptom in 2008, with the prevalence expected to increase to 500 mil /13/ /0 THE JOURNAL OF UROLOGY Vol. 189, , June by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. Printed in U.S.A.

2 PERCUTANEOUS TIBIAL NERVE STIMULATION FOR OVERACTIVE BLADDER SYNDROME 2195 lion in 2013 and 546 million in Approximately 34 million Americans have OAB, 4,5 with associated costs exceeding $9 billion per year including direct care, health related consequences and lost productivity. 6 This financial cost is accompanied by concomitant morbidity with a higher risk of falls and fractures as well as social costs of quality of life, self-esteem and health perception. 7,8 The first lines of treatment are typically behavioral interventions followed by antimuscarinic or anticholinergic drugs. These drugs effectively reduce OAB symptoms. However, side effects such as dry mouth, blurred vision, constipation, erythema, fatigue and urinary retention are significant in many patients. 9,10 Several studies have shown that more than 70% of patients discontinue these drugs within 1 year due to intolerability or ineffectiveness Neuromodulation using PTNS or implantable SNS is a clinically effective treatment alternative to drug therapies. SNS has been shown to be effective in treating OAB, 14 but its use may be limited due to its high cost, surgical implantation and potential for surgical revision. Therefore, SNS is not suitable for all patients as there are many who wish to avoid the surgical burden and the potential for serious adverse events. PTNS using the Urgent PC Neuromodulation System is an easily administered office procedure that delivers retrograde neuromodulation through the tibial nerve to the sacral nerve plexus via a percutaneous 34-gauge needle electrode. PTNS therapy is initiated with 12 weekly 30-minute treatments, and responders to treatment are advised to continue therapy to sustain their OAB symptom improvement with approximately 1 treatment per month. The efficacy of PTNS in treating OAB symptoms has been demonstrated in 3 randomized controlled trials, durability studies of 1 to 2 years in duration, meta-analyses 21,22 and more than 30 peer reviewed articles. The STEP Study was designed to assess the durability of PTNS effectiveness and safety in improving OAB symptoms in the long term, and to determine the interval of treatments needed to maintain a positive clinical response. MATERIALS AND METHODS The STEP Study was an institutional review board approved extension of the 12-week double-blind randomized SUmiT Trial illustrating the superiority of PTNS over a validated sham treatment for OAB. The design, methods and results of SUmiT have been described in detail in an earlier report. 16 PTNS therapy was delivered through the temporary insertion of a 34 gauge needle electrode at a 60-degree angle cephalad to the medial malleolus and slightly posterior to the tibia. The needle electrode was then connected to the handheld Urgent PC stimulator. A current level of 0.5 to 9.0 ma at 20 Hz was then selected based on the participant s motor and/or sensory responses. Patients who met the primary end point of reporting bladder symptoms as moderately or markedly improved on the 7-point GRA after 12 weekly treatments were eligible for enrollment in the STEP Study. Positive responders were chosen as the study population for this investigation to assess the long-term safety and durability of PTNS therapy. Participants in the sham arm or nonresponders to PTNS in the SUmiT Trial were not followed past the completion of the trial as it would have been unethical to continue administering an inferior sham treatment or providing active PTNS to someone not responding to therapy. After the conclusion of the 12 weekly PTNS treatments in the SUmiT Trial, STEP participants continued to receive PTNS therapy under a fixed schedule 14-week prescribed tapering protocol consisting of 2 PTNS treatments at 14-day intervals, followed by 2 treatments at 21-day intervals, followed by 1 additional treatment after 28 days. This gradual tapering protocol over 3 months allowed patients and clinicians to assess OAB symptom changes with treatments at increasingly longer intervals. After completing the tapering protocol of 5 treatments, patients were individually assessed, and personalized treatment plans were collaboratively determined by investigators and patients with the goal of sustaining OAB symptom improvement. The frequency of PTNS treatments was adjusted based on the patient reporting of the absence or return of symptoms, so the interval between treatments could be tailored to sustain therapeutic benefit. STEP participants were not prescribed OAB medications throughout the study. The Appendix lists the inclusion and exclusion criteria for the SUmiT Trial as well as the additional criteria for STEP Study participation. Patients completed the OAB-q short form, 23 SF-36 health survey 24 and GRA before randomization into the SUmiT Trial (baseline), 25 at the completion of the SUmiT Trial (13 weeks) and at 3-month intervals thereafter until the completion of the STEP Study at 36 months. The primary efficacy end point of the study was defined as marked or moderate improvement on the GRA at 36 months. Study specific 3-day voiding diaries were completed at baseline, 13 weeks and 3 months after entry into STEP, and in 6-month intervals thereafter. Voiding diaries assessed the 24-hour frequency of voids, nighttime voids, and episodes of moderate to severe urgency and urge incontinence. Adverse events, concomitant morbidities and medications were recorded at each visit. Investigators classified adverse events as being related, unrelated or of unknown relation to PTNS treatments and their severity. Data were double-entered in the Clindex Clinical Trial and Data Management System (Fortress Medical, Hopkins, Minnesota). All followup parameters were analyzed using a last value carried forward approach under the intent to treat principle (LVCF-ITT) to address missing data. In addition, a Bayesian shared parameter model was used to estimate the proportion of patients who met the primary end point at 36 months under the assump-

3 2196 PERCUTANEOUS TIBIAL NERVE STIMULATION FOR OVERACTIVE BLADDER SYNDROME tion that patients withdrawing from the study were less likely to meet the end point than those who completed the study. This model allows for valid inference on all enrolled patients by jointly modeling success on the primary end point and loss to followup during the study to account for uncertainty in missing responses. All data were analyzed by an independent biostatistician using SAS version 9.2 for frequentist statistics, and BRugs and OpenBUGS version for the Bayesian model. Changes in continuous outcome parameters from baseline were analyzed using a 2-sided paired t test for quality of life data and nonparametric Wilcoxon signed rank tests for voiding diary data due to nonnormality. Values are presented as mean with SD or median with IQR (IQR 25th and 75th percentiles). RESULTS At the end of enrollment into SUmiT, 110 patients had been randomized to PTNS and 103 completed the trial through 13 weeks. Of these 103 patients 60 (58.3%) met the primary efficacy end point and were eligible for enrollment into the STEP Study. Fifty patients consented to participate in this extension study. The median age of these participants was 61 years (IQR 47 73), 78% were female, 72% had been previously treated with OAB medications, 76% were OAB wet (1 or more urge incontinence episodes on baseline voiding diary) and the median history of OAB symptoms was 6 years (IQR 4 11). Twentynine patients (58%) completed the protocol through Figure 1. STEP Study population diagram. Subject continued enrollment, subject withdrawals and evaluable data through 36 months. Note some subjects did not provide questionnaires and/or voiding diaries at certain followup visits. Asterisk indicates 1 patient included in 24-month interim analysis 19 was later discovered to have been lost to followup at 15 months.

4 PERCUTANEOUS TIBIAL NERVE STIMULATION FOR OVERACTIVE BLADDER SYNDROME 2197 Frequency distribution of number of treatments per month by visit interval for subjects completing the 14-week prescribed tapering protocol No./Total No. (%) Less Than 1.0 Treatment/Mo 1.0-Less Than 2.0 Treatments/Mo 2.0-Less Than 3.0 Treatments/Mo 3.0-Less Than 4 Treatments/Mo 4 or More Treatments/Mo 6 9 Mos 18/45 (40.0) 20/45 (44.4) 4/45 (8.9) 2/45 (4.4) 1/45 (2.2) 9 12 Mos 19/44 (43.2) 21/44 (47.7) 3/44 (6.8) 1/44 (2.3) 0/44 (0) Mos 14/41 (34.2) 21/41 (51.2) 5/41 (12.2) 1/41 (2.4) 0/41 (0.0) Mos 13/38 (34.2) 22/38 (57.9) 2/38 (5.3) 1/38 (2.6) 0/38 (0.0) Mos 18/37 (48.7) 15/37 (40.5) 4/37 (10.8) 0/37 (0) 0/37 (0) Mos 14/35 (40.0) 16/35 (45.7) 5/35 (14.3) 0/35 (0) 0/35 (0.0) Mos 18/34 (52.9) 12/34 (35.3) 2/34 (5.9) 1/34 (2.9) 1/34 (2.9) Mos 16/32 (50.0) 12/32 (37.5) 2/32 (6.3) 2/32 (6.3) 0/32 (0.0) Mos 18/32 (56.3) 10/32 (31.3) 2/32 (6.3) 1/32 (3.1) 1/32 (3.1) Mos 13/29 (44.8) 12/29 (41.4) 4/29 (13.8) 0/29 (0.0) 0/29 (0.0) 36 months (43 at 12 months and 34 at 24 months) (fig. 1). Of those who did not complete the study, 5 withdrew for unknown reasons, 3 withdrew for ineffectiveness, 5 were lost to followup, 2 withdrew for unrelated medical reasons (cancer and congestive heart failure complicated by lung disease), 2 patients moved, study close-out forms not returned for 2 patients and 2 had logistical difficulty in attending followup visits. For the patients who did not complete the entire study, the median followup was 15 months from entry into the SUmiT Trial (IQR 7 23). After completing the 14-week prescribed tapering protocol, the remaining study participants (45) received a median of 1.1 treatments per month (IQR ) from 6 to 36 months. The frequency distribution of treatments per month by visit interval for these patients is shown in the table. Among the study completers the median number of treatments per month (from 6 to 36 months) was 1.0 (IQR ), with 41% receiving an average of less than 1 treatment per month, 55% receiving 1.0 to less than 2.0 treatments per month and 4% receiving 2.0 to less than 3.0 treatments per month. Of those patients who completed the 36-month study assessment per protocol, 97% (28 of 29) met the primary efficacy end point of moderate or marked improvement in overall bladder symptoms on the GRA compared to baseline (fig. 2). LVCF-ITT and Bayesian analyses of the GRA, which accounted for early withdrawal, reached the same conclusion of OAB symptom improvement at 36 months, with 76% of patients (38 of 50) meeting the primary efficacy end point using LVCF-ITT and 77% (95% CI 64 90) meeting the primary efficacy end point using the Bayesian model. All voiding diary parameters were significantly improved from baseline at every 6-month followup visit through 3 years (all p , fig. 3). The median number of voids per day decreased from 12.0 (IQR ) at baseline to 8.7 (IQR ) at 36 months. The number of nighttime voids per night decreased from a median of 2.7 (IQR ) to 1.7 (IQR ). The number of moderate or severe urgency episodes per day decreased from a median of 8.5 (IQR 6 11) to 3.5 (IQR 1 6). Among those with urge incontinence at baseline (38), the number of urge incontinence episodes per day decreased from a median of 3.7 (IQR ) to 0.3 (IQR ). OAB-q HRQoL and symptom severity scores remained significantly improved from baseline throughout the study at all followup visits (all p , fig. 4). Two mild treatment related adverse events of bleeding at the needle site were reported in the same participant. One moderate adverse event of restricted vaginal opening with unknown relation to treatment was reported. Nine patients reported 11 mild adverse events with an unknown relation to treatment including vaginal bleeding, mild depression, shoulder pain, diarrhea, leg pain, stomach ache, pelvic pain, urinary tract infection, a pulling Figure 2. GRA results by followup visit assessed using LVCF- ITT, per protocol and Bayesian estimates.

5 2198 PERCUTANEOUS TIBIAL NERVE STIMULATION FOR OVERACTIVE BLADDER SYNDROME Figure 3. Voiding diary (LVCF-ITT in 50) results by followup visit. BL, baseline. sensation in both feet, bladder pressure and pinched nerve pain. DISCUSSION In this study we report that at least 75% of patients with a positive response to 12 weekly PTNS treatments can expect to sustain symptom improvement through 3 years with an average of about 1 treatment per month. Symptom improvement was well documented by subjective assessment and all objective voiding diary parameters including frequency, nighttime voids, and moderate to severe urgency and urge incontinence. It is well-known that behavioral, medical and SNS therapy for the management of OAB requires continuous treatment to sustain symptom improvement. Examples include caffeine restriction and use of antimuscarinics or anticholinergics as well as SNS therapy, which require continuous use for ongoing efficacy. The original SUmiT Trial provided Level 1 evidence that 12 weeks of PTNS therapy provide patients with OAB clinically and statistically significant symptom improvement compared to validated sham. The purpose of the STEP Study was to determine the interval of treatments that patients deemed necessary to sustain a positive therapeutic response in those demonstrating improvement in symptoms after 12 weekly PTNS treatments. Little was known about the need for long-term treatment in this patient population. Thus, STEP patients completed a fixed schedule 14-week tapering protocol to gather early evidence on the impact of less frequent PTNS treatments on OAB symptoms. The STEP Study was the first trial to prescribe a tapering protocol after the initial 12 weekly treatments. This tapering protocol allowed patients to recognize the return of their OAB symptoms and to schedule their treatments at appropriate intervals during the personalized treatment plan. The unique and real-world aspect of this study was that after PTNS treatments were tapered, additional treatments were only provided when OAB symptoms returned or at an interval known to the patient to sustain OAB symptom control. The STEP Study demonstrated long-term durability of PTNS therapy in the treatment of OAB with no major safety concerns when treatments are continued on an

6 PERCUTANEOUS TIBIAL NERVE STIMULATION FOR OVERACTIVE BLADDER SYNDROME 2199 Figure 4. OAB-q HRQoL and symptom severity scores (LVCF-ITT in 50) by followup visit. Increase in HRQoL and decrease in symptom severity score are positive outcomes of OAB-q. BL, baseline. approximately monthly basis over 3 years. This information is important for clinicians, payers and patients. These favorable long-term results also support PTNS as a viable treatment alternative to drug and surgical therapies, particularly considering the high rate of discontinuation of OAB drug therapies within the first year due to their considerable side effect profile This is further supported by the AUA/SUFU and AHRQ (Agency for Healthcare Research and Quality) guidelines. 26,27 The AUA/SUFU guideline algorithm of care for patients with OAB includes behavioral therapies as first line therapy followed by drugs as second line therapy. For those in whom these more conservative treatment options have failed, the AUA/SUFU and AHRQ guidelines identify neuromodulation, including PTNS and SNS, as third line therapy. 26,27 Patients in the STEP Study had OAB symptoms for a median of 6 years and more than 70% were previously treated with OAB medications with unsatisfactory results. Although not all STEP Study participants reported previous drug therapy, the STEP Study demonstrates that PTNS can be an effective and safe treatment option, and provides important clinical insights into an innovative long-term care option for patients with OAB refractory to first line treatments. In the current health care paradigm, clinical effectiveness is defined by empirical clinical measures as well as by patient centered outcomes, especially those that affect quality of life. Clinical Investigations of Devices Indicated for the Treatment of Urinary Incontinence, a recent Food and Drug Administration guidance document, states that the impact of urinary incontinence on quality of life is a primary motivator for patients to seek treatment. 28 The STEP Study demonstrated that PTNS markedly improves quality of life in patients with OAB symptoms, with significant improvements in all quality of life parameters reported from baseline through 3 years. In addition to the clinical outcomes, cost-effectiveness is also a primary focus when reviewing OAB treatment options. A recent publication by Staskin et al notes that of the third line OAB therapies, PTNS is the least costly and compares favorably with antimuscarinic therapy. 29 Furthermore, Martinson et al reported that the cumulative 3-year costs for patients who remain on one of the following 4 kinds of therapies are approximately $7,565 for PTNS, $11,748 for botulinum toxin A, $16,830 for augmentation cystoplasty and $24,681 for SNS. 30 A limitation of our investigation includes the loss to followup during the course of the study. To address this limitation, the results for success on the primary end point are presented using LVCF-ITT and Bayesian analyses, the latter of which empirically addresses the sensitivity of the results to different assumptions for the missing responses. Both methodologies reached the same conclusion with regard to the success rate at 36 months, with 76% and 77% (95% CI 64 90) of responders sustaining their improvement of OAB symptoms, respectively. Another potential limitation of PTNS therapy is the time and logistical constraints for some patients who may find it difficult to attend treatment sessions. In this study only 2 patients withdrew for that reason. CONCLUSIONS This study demonstrates the long-term efficacy and safety of PTNS in reducing OAB symptoms throughout 3 years of therapy with an average of 1 treatment per month following the initial 12- week treatment protocol. Improvements in objective and subjective outcome measures were all clinically and statistically significant, and remained consistent through followup with no major safety concerns. The STEP Study demonstrates that PTNS is an effective long-term treatment for patients with OAB.

7 2200 PERCUTANEOUS TIBIAL NERVE STIMULATION FOR OVERACTIVE BLADDER SYNDROME APPENDIX Inclusion and exclusion criteria for STEP Study STEP Study Inclusion Criteria Randomized, treated with active PTNS therapy during their participation in the SUmiT Trial Indicated moderately or markedly improved on 13-week GRA questionnaire following initial 12-weekly treatments in the SUmiT Trial Initiated PTNS ongoing therapy within 2 weeks of their last SUmiT Trial PTNS treatment Was capable and willing to follow all study related procedures for an additional 33 months for a total participation of 3 years Women and men age 18 years or older* A score of 4 or more on the OAB-q short form for urgency* Average urinary frequency of 10 or more voids per day* Self-reported OAB symptoms for 3 or more months* Self-reported failure with conservative care* Discontinued all antimuscarinics for 2 or more weeks* Capable of giving informed consent* Ambulatory and able to use the toilet independently and without difficulty* STEP Study Exclusion Criteria Patients who were not able or willing to follow original SUmiT Trial treatment schedule Pregnant or planning to become pregnant during study duration* Neurogenic bladder* Botox use in bladder or pelvic floor muscles within past 1 year* Pacemakers or implantable defibrillators* Current urinary tract infection* Current vaginal infection* Use of InterStim * Use of Bion * Current use of transcutaneous electrical nerve stimulation in pelvic region, back or legs* Previous PTNS treatment* Use of investigational drug/device therapy within past 4 weeks* Participation in any clinical investigation involving gynecologic, urinary or renal function within past 4 weeks* * Original SUmiT Trial enrollment criteria. 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8 PERCUTANEOUS TIBIAL NERVE STIMULATION FOR OVERACTIVE BLADDER SYNDROME Gormley EA, Lightner DJ, Burgio KL et al: Diagnosis and treatment of overactive bladder (nonneurogenic) in adults: AUA/SUFA Guideline. American Urological Association Education and Research Available at content/media/oab_guideline.pdf. Accessed November 13, Agency for Healthcare Research and Quality: Nonsurgical treatments for urinary incontinence in adult women: diagnosis and comparative effectiveness. U.S. Department of Health and Human Services. Available at ahrq.gov/search-for-guides-reviews-and-reports/? pageaction displayproduct&productid Accessed November 13, Food and Drug Administration: Guidance for Industry and Food and Drug Administration Staff: Clinical Investigations of Devices Indicated for the Treatment of Urinary Incontinence. U.S. Department of Health and Human Services Available at DeviceRegulationandGuidance/GuidanceDocuments/ ucm pdf. Accessed November 13, Staskin DR, Peters KM, MacDiarmid S et al: Percutaneous tibial nerve stimulation: a clinically cost effective addition to the overactive bladder algorithm of care. Curr Urol Rep 2012; 13: Martinson M, MacDiarmid S and Black E: Cost of neuromodulation therapies for overactive bladder: percutaneous tibial nerve stimulation versus sacral nerve stimulation. J Urol 2013; 189: 210.