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1 Author's Accepted Manuscript Convective Radiofrequency Water Vapor Thermal Therapy with Rezūm System: Durable Two-Year Results of Randomized Controlled and Prospective Crossover Studies for Treatment of Lower Urinary Tract Symptoms due to Benign Prostatic Hyperplasia Claus G. Roehrborn, Steven N. Gange, Marc C. Gittelman, Kenneth A. Goldberg, Kalpesh Patel, Neal D. Shore, Richard M. Levin, Michael Rousseau, J. Randolf Beahrs, Jed Kaminetsky, Barrett E. Cowan, Christopher H. Cantrill, Lance A. Mynderse, James C. Ulchaker, Thayne R. Larson, Christopher M. Dixon, Kevin T. McVary PII: S (16) DOI: /j.juro Reference: JURO To appear in: The Journal of Urology Please cite this article as: Roehrborn CG, Gange SN, Gittelman MC, Goldberg KA, Patel K, Shore ND, Levin RM, Rousseau M, Beahrs JR, Kaminetsky J, Cowan BE, Cantrill CH, Mynderse LA, Ulchaker JC, Larson TR, Dixon CM, McVary KT, Convective Radiofrequency Water Vapor Thermal Therapy with Rezūm System: Durable Two-Year Results of Randomized Controlled and Prospective Crossover Studies for Treatment of Lower Urinary Tract Symptoms due to Benign Prostatic Hyperplasia, The Journal of Urology (2017), doi: /j.juro DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain. Embargo Policy All article content is under embargo until uncorrected proof of the article becomes available online.

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3 Convective Radiofrequency Water Vapor Thermal Therapy with Rezūm System: Durable Two- Year Results of Randomized Controlled and Prospective Crossover Studies for Treatment of Lower Urinary Tract Symptoms due to Benign Prostatic Hyperplasia Claus G. Roehrborn, Steven N. Gange, Marc C. Gittelman, Kenneth A. Goldberg, Kalpesh Patel, Neal D. Shore, Richard M. Levin, Michael Rousseau, J. Randolf Beahrs, Jed Kaminetsky, Barrett E. Cowan, Christopher H. Cantrill, Lance A. Mynderse, James C. Ulchaker, Thayne R. Larson, Christopher M. Dixon, Kevin T. McVary Study Sponsor: NxThera Inc., Maple Grove, MN Brief Title: Convective Radiofrequency Thermal Therapy for BPH Key Words: prostate, prostatic hyperplasia, lower urinary tract symptoms, thermal therapy, minimally invasive procedure, crossover study Corresponding Author Claus G. Roehrborn, MD Professor and Chair Department of Urology UT Southwestern Medical Center 5323 Harry Hines Blvd, J8 142 Dallas, TX Office (214) Office FAX (214)

4 ABSTRACT Purpose: To report two-year outcomes of a multi-center randomized controlled trial plus oneyear results of a crossover trial after treatment with convective radiofrequency water vapor thermal energy for lower urinary tract symptoms due to benign prostatic hyperplasia. Materials and Methods: 197 men at least 50 years old with International Prostate Symptom Scores 13 or greater, maximum flow rate of 15 ml per second or less and prostate size 30 to 80 cc were randomized 2:1 between thermal therapy with the Rezūm System and control. Rigid cystoscopy with simulated active treatment sounds served as the control procedure. After unblinding at 3 months, control subjects could re-qualify for crossover study. Convectively delivered radiofrequency thermal energy was delivered into obstructive prostate tissue, including the median lobe as needed. The primary efficacy endpoint was change in severity of symptom scores. Results: Convective radiofrequency thermal therapy improved urinary symptoms significantly over controls at 3 months and provided a sustained 51% reduction from baseline at 24 months (p<0.0001). This produced a 5- and 8-point or greater score decrease in 84% and 74% of subjects at 24 months, respectively. Crossover subjects symptoms, flow rate and quality of life measures were markedly improved after thermal therapy compared to their prior control procedure (p = to <0.0001). No de novo erectile dysfunction was reported. 2

5 Conclusions: Convective radiofrequency water vapor thermal therapy is a minimally invasive office or outpatient procedure providing early effective symptom relief that remains durable for 2 years and is applicable to the median lobe. 3

6 Introduction Many men begin medical therapy for bothersome LUTS associated with BPH but have inadequate improvement in their symptoms and quality of life or experience undesirable sideeffects that lead to discontinuation. Increasingly, men do not wish to commit to lifetime pharmaceutical treatments. Pharmaceutical agents are costly, particularly for long periods of time and, in some older patients, compliance with medications is problematic. Lack of drug compliance may be attributable to a combination of drug side effects and improvements lower than perceived expectations. 1,2 Minimally invasive treatments for BPH associated LUTS allow the urologist to tailor therapy in a continuum of medical management to more invasive surgical procedures approaches. Convective water vapor energy is a minimally invasive RF thermal therapy for BPH; RF current generates wet thermal energy in the form of water vapor. This therapy is performed in the office or out-patient surgical center with minimal anesthesia and can be used to treat the median lobe. The Rezūm System (NxThera Inc., Maple Grove, MN, USA) convectively delivers sterile RF water vapor thermal therapy in a transurethral procedure that provides targeted ablation confined to the transition and central zones. The principles of convective RF thermal therapy and characteristic ablation of prostatic adenomas, demonstrated by histologic, MRI and clinical studies, have been reported in previous publications. 3-6 The convective RF thermal therapy provides rapid and significant improvements in LUTS, preserves erectile and ejaculatory function, and enhances quality of life in these patients. 7,8 We herein report the two-year outcomes of the multicenter, randomized controlled blinded trial (RCT). The prospective design of this study also included a crossover of subjects who underwent the control (sham) procedure 4

7 in the blinded phase followed by convective RF thermal therapy 3 to 6 months later. This provides a paired self-control comparison of sham versus active procedure. We hypothesized that the effectiveness and low morbidity would be sustained and that the open label RF thermal therapy results after the crossover would be consistent with the blinded phase active therapy and thus exclude a placebo effect. MATERIALS AND METHODS Study protocol Men with moderate to severe symptomatic BPH were treated and followed for 2 years in a prospective, multicenter, double blinded (follow up investigator blinded to treatment allocation) RCT conducted in 15 centers in the United States (Clincaltrials.gov: NCT ). The Appendix provides the major inclusion and exclusion criteria for the trial. A second study included a crossover design trial of convective RF thermal therapy after the control procedure. After unblinding at 3 months, control subjects who elected to proceed were re-qualified for the crossover study. The study protocol was approved by the USA Food and Drug Administration and the Institutional Review Boards of each enrolling center. Assessments After the blinded comparison of the active and sham control groups, the RF thermal therapy subjects were followed for 24 months and assessed for treatment responses using I-PSS, QOL instruments (QOL from I-PSS, BPHII), peak flow rate (Qmax), incontinence (OAB-q SF, ICS male IS-SF), sexual function (IIEF-15, MSHQ-EjD) and adverse events. Crossover study subjects were similarly assessed over 12 months. Any subject receiving the RF thermal therapy (RCT active 5

8 arm or crossover) is included in annual follow-up evaluations for 5 years. Independent data monitoring and clinical events committees reviewed safety and adjudicated adverse events. Randomization Randomization was conducted with electronic programming prior to treatment using permuted blocks of random sizes, stratified by investigational site, in a 2:1 ratio allocation of thermal treatment and control arms respectively. Statistical Methods Descriptive statistics were used to describe the baseline and follow-up values for all study variables and data are presented as the mean (SD), mean % change (95% CI). The change between baseline and 3 months for the control procedure was compared to the change following the RF thermal therapy using the paired Student s t test for which each subject served as his own control. To evaluate longitudinal change from baseline a general estimation equation (GEE) model was fit to each outcome parameter using an exchangeable working correlation structure. The GEE model takes into account the correlation within a subject over time and uses that information to adjust the estimates and confidence intervals. 9 The model was used to calculate P values for each follow-up period compared to baseline. Thermal Treatment and Control Procedures The RF thermal therapy utilizes the Rezūm System containing an RF power supply in a generator, and a single-use transurethral delivery device that incorporates a standard 4 mm, 30 degree endoscopic cystoscopy lens. The procedure has been previously described in detail. 3-5,7 Briefly, water vapor thermal energy is created by applying RF current against an inductive coil 6

9 heater in the handle of the device. This instrument delivers the RF water vapor thermal energy into the prostate through a retractable needle and saline flush irrigation is used to enhance visualization and cool the urethra. The needle tip is positioned and inserted starting approximately 1 cm distal to the bladder neck into the transition and central prostate adenoma. Intravesical prostatic protrusions both of the lateral and median lobes should be injected starting 1 cm from the edge of the protrusion. Median lobe treatment entails angulation of the needle directly into the tissue. Each RF water vapor (0.5 ml) injection is convectively delivered and dispersed circumferentially to create a cm lesion and remains confined within the prostate zones. The needle is retracted after each treatment and repositioned approximately 1 cm distal from the previous site to the end of the prostatic urethra proximal to the verumontanum. Convective RF thermal therapy creates contiguous, overlapping lesions running parallel to the natural slope of the urethra. The total number of treatments in each lobe of the prostate is determined by the length of the prostatic urethra and can be customized to the configuration of the gland including the median lobe. The control procedure involved rigid cystoscopy with simulated sound effects closely replicating those of the active procedure. For blinding purposes, a surgical drape prevented subjects visualization of the device and treating physician. Outcome assessments were performed by an assessor blinded to the procedures. RESULTS Between September 2013 and August 2014 a total of 197 eligible subjects were enrolled and randomized to receive RF thermal therapy (136) or control (61) procedures (fig. 1). Results of the 1 year follow-up have been reported. 7 Fifty-three (86.9%) of the 61 control subjects who 7

10 met I-PSS and Qmax criteria later elected and requalified for crossover active treatment. Subject demographics are presented in table 1. Over the 2 year follow-up of 135 subjects initially treated with convective RF water vapor thermal therapy, 121 (89.6%) were accounted for at 12 months and 109 (80.7%) were included in the 24 month per protocol analysis. For crossover study subjects, 45 of 53 (84.9%) were accounted for and analyzed at 12 months. A total of 188 convective RF thermal therapy procedures were performed in the randomized and crossover studies. The median lobe was identified in 70/188 (37%) of subjects and treated in 58 (30.8%). For all treated subjects the retreatment rate was 3.7%. Over the 24 months of follow-up, 8 subjects had a secondary treatment, 1 with an open prostatectomy, 3 with a secondary Rezūm procedure and 4 underwent TURP. Six of these 8 interventions were related to removal of the median lobe that was not initially treated. Nine subjects withdrew from the study, unrelated to the occurrence of adverse events. Management of pain and anxiety was based on discretion of the investigators; 130 (69%) subjects received oral sedation only, 19 (10%) had conscious sedation and 39 (21%) a prostate block. The average number of convective RF water vapor treatments was 4.7 ± 1.9 to prostate zones and 1.6 ± 0.7 to the median lobe when present. Some subjects were electively catheterized for an average of 3.6 ± 3.5 days after treatment. 2 year RF thermal therapy outcomes The observed outcomes per protocol (PP) from baseline to 6, 12 and 24 months after thermal therapy indicate clinically significant relief of LUTS with mean I-PSS reductions of 54%, 52% and 51%, respectively, p< (table 2). Based on I-PSS responses in individual subjects with a 8

11 mean I-PSS of 22.0 ± 4.8 at baseline, 87% had at least a 3 point I-PSS improvement, and of those subjects, 84% actually achieved a 5 (moderate) decrease and 74% a 8 point (marked) I-PSS decrease at 3 months after convective thermal therapy. At 24 months these response levels were similarly sustained in 87%, 84% and 74% of subjects with 3, 5 or 8 I-PSS point decreases, respectively. The maximum flow rate and quality of life measures improved by approximately 50% or more and remained significant and durable over 2 years, p< Relief of urinary symptoms and bother were evident with improved scores at 3 months on the ICS Male IS and the OAB-q bother and HRQL and were sustained through 24 months (p<0.0001). Only subjects who were sexually active at baseline (90 of 135) were included in the long term analysis of sexual function. Rezūm convective thermal therapy had no negative effect on erectile function throughout two years of follow up. No significant changes in IIEF-EF (p> ) and ejaculatory function (MSHQ-EjD Function) (p > ) scores occurred relative to baseline (Table 2). Bother associated with ejaculation (MSHQ-EjD Bother) was significantly improved at 12 and 24 months after treatment (p ). No late occurring device or procedure related AEs were reported in the 12 to 24 month follow-up period. Both storage and voiding urinary functions were shown to be significantly improved at one month after convective RF thermal therapy and remained durable throughout assessments over 2 years, p< (fig. 2A). Without exception, the seven individual I-PSS domains reflected the significant relief of symptoms over 2 years, p< (fig. 2B). 9

12 Crossover study outcomes Convective RF water vapor thermal therapy in the crossover study resulted in significantly greater symptom improvements than achieved by the control procedure at 3 months of followup. Mean I-PSS reduction after the crossover was ± 7.1 points compared with -3.9 ± 6.7 points for control at 3 months, p = (table 3). The time to response and magnitude of I-PSS changes in the crossover study at 3 months after crossover, closely replicate those for the active treatment arm at the same time point (fig. 3) and was durable throughout 12 months, mean ± 8.1 decrease (fig. 4A). In a subset of subjects with median lobe treatments the mean I-PSS decrease was even greater, mean ± 6.9, p = The profile of I-PSS improvements for the crossover subjects replicates that of the RCT (fig 5.) Commensurate improvements in QOL measures, the I-PSS-QOL and BPHII were significant after thermal therapy compared with control subjects (p= and p=0.0241, respectively), (table 3). The Qmax significantly improved after thermal therapy with a mean of 16.4 ± 7.1 ml/sec at 3 months, an increase of 6.3 ± 6.8 ml/sec compared with baseline; improved flow rate remained durable at 12 months (fig. 4B, tables 3 and 4). By comparison, during the control/sham period the Qmax change at 3 months versus baseline was minimal at 0.2 ± 3.9 ml/sec. Crossover subjects had relief of the occurrence and bother of LUTS throughout 12 months as reflected in significant improvements on the ICS male, p <0.02 to , and OAB questionnaires, p< (table 4). Two crossover subjects had three serious AEs adjudicated as procedure-related (table 5). One had two events, a bladder neck contracture and bladder calculi reported 6 months post 10

13 treatment. The second subject had urosepsis after follow-up cystoscopy. Other non-serious, related AEs post-procedure included anticipated events that can occur after rigid cystoscopy. They were typically mild to moderate in severity and transient; the most common occurring events were dysuria (18.9%) and hematuria (11.3%). No de novo erectile dysfunction was reported. DISCUSSION Results from this RCT show sustained improvements in urinary symptoms, flow rate, incontinence and quality of life to 24 months. Significant responses occur as early as two weeks after convective RF water vapor thermal therapy. 7 The profile of I-PSS improvements of the 2- year and crossover studies in conjunction with comparative published data indicate a consistent therapeutic response for relief of LUTS after water vapor thermal therapy. 6, 7 The experiences of 18 different urologists supports the reproducibility of meaningful relief from LUTS utilizing this minimally invasive procedure. At the 2 year follow-up, 74% of subjects had I-PSS improvements 8 points, defined as a marked response The magnitude of the I-PSS decreases far exceeds the 3 point criterion of a meaningful clinical response established by AUA guidelines. 12 Both storage and voiding symptoms were rapidly reduced after the thermal therapy procedure and remained significantly improved over 24 months. Persistent nocturia despite medical intervention is a predominant motivating factor for men seeking treatment for LUTS/BPH as it has an appreciable impact on quality of life In this 2 year study, the storage symptom of nocturia and all other individual IPSS domains remained consistently improved. 11

14 The preservation of sexual function in subjects treated with convective RF thermal therapy as reported by McVary et al. remains substantiated both after the crossover procedure and throughout the 2-year follow-up in the RCT; there were no reports of de novo erectile dysfunction. 8 Ejaculatory function changes were infrequent and possibly secondary to decreased resistance in the bladder neck after treatment of the median lobe. There is considerable evidence of a placebo effect in medical and surgical treatments for LUTS/BPH The importance of a crossover study, in which subjects serve as self-controls, is to negate a possible placebo effect with this therapy. The paired analysis of outcomes after a sham/control procedure followed by the open-label thermal procedure is a strong aspect of this study. I-PSS, Qmax and QOL measures after the crossover active treatments were all significantly different when compared to the control period at 3 months. While questionnaires are subjective and potentially prone to bias of expectation, the assessment of flow rate is objectively quantitative. The negligible change of Qmax of <1 ml/sec at 3 months in the control period contrasts markedly with the 6.3 ml/sec increase in the crossover arm. Furthermore, the profile of I-PSS responses over 12 month after the crossover open-label convective thermal therapy is almost identical to the active arm of the RCT when observed at 12 months, and pilot trial of the Rezūm System. 6 CONCLUSIONS Convective RF water vapor thermal therapy of prostate hyperplasia results in a significant early onset, as well as enduring relief of BPH symptoms with preservation of erectile function in subjects followed for two years. The therapy can be performed in an office or outpatient 12

15 treatment setting with minimal transient perioperative side effects. This minimally invasive procedure warrants consideration as a first-line therapeutic alternative to medical therapy in men seeking treatment for bothersome moderate to severe symptoms of BPH including those with median lobe hyperplasia. References 1. Nichol MB, Knight TK, Wu J et al: Evaluating use patterns of and adherence to medications for benign prostatic hyperplasia. J Urol 2009; 181: Cindolo L, Pirozzi L, Fanizza C et al: Drug adherence and clinical outcomes for patients under pharmacological therapy for lower urinary tract symptoms related to benign prostatic hyperplasia: population-based cohort study. Eur Urol 2015; 68: Dixon CM, Cedano ER, Mynderse LA et al: Transurethral convection water vapor as a treatment for lower urinary tract symptomology due to benign prostatic hyperplasia using the Rezūm system: evaluation of acute ablative capabilities in the human prostate. Res Rep Urol 2015; 7: Dixon CM, Cedano ER, Pacik D et al: Efficacy and safety of Rezūm system water vapor treatment for lower urinary tract symptoms secondary to benign prostatic hyperplasia. Urology 2015; 86:

16 5. Mynderse LA, Hanson D, Robb RA et al: Rezūm system water vapor treatment for lower urinary tract symptoms/benign prostatic hyperplasia: Validation of convective thermal energy transfer and characterization with magnetic resonance imaging and 3-dimensional renderings. Urol 2015; 86: Dixon CM, Cedano ER, Pacik D, et al: Two-year results after convective water vapor energy treatment of symptomatic benign prostatic hyperplasia. Res Rep Urol 2016; 8: McVary KT, Gange SN, Gittelman MC et al: Minimally invasive prostate convective water vapor energy (WAVE) ablation: A multicenter, randomized, controlled study for treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol 2016; 195: McVary KT, Gange SN, Gittelman MC et al: Erectile and ejaculatory function preserved with convective water vapor energy treatment of LUTS secondary to BPH: randomized controlled study. J Sex Med 2016; 13: Cui L, Hung HMJ, Wang S-J: Modification of sample size in group sequential clinical trials. Biometrics 1999; 55:

17 10. Barry MJ, Williford WO, Chang Y et al: Benign prostatic hyperplasia specific health status measures in clinical research: how much change in the American Urological Association symptom index and the benign prostatic hyperplasia impact index is perceptible to patients? J Urol. 1995; 154: Roehrborn CG, Wilson TH, Black LK. Quantifying the contribution of symptom improvement to satisfaction of men with moderate to severe benign prostatic hyperplasia: 4- year data from the CombAT trial. J Urol 2012; 187: American Urological Association Guideline: Management of Benign Prostatic Hyperplasia (BPH). Revised March ( Accessed October 10, Cornu JN, Abrams P, Chapple CR, et al: A contemporary assessment of nocturia: definition, epidemiology, pathophysiology, and management a systematic review and meta-analysis. Eur Urol 2012; 62:

18 14. Miranda Ede P, Gomes CM, Torricelli FC et al: Nocturia is the lower urinary tract symptom with greatest impact on quality of life of men from a community setting. Int Neurourol J 2014; 18: Welliver C, Sulaver R, Whittington A et al: Analyzing why men seek treatment for lower urinary tract symptoms and factors associated with nonimprovement. Urol 2015; 86: Walach H, Sadaghiani C, Dehm C, Bierman D: The therapeutic effect of clinical trials: understanding placebo response rates in clinical trials a secondary analysis. BMC Med Res Methodol 2005; 5: Sorokin I, Schatz A, Welliver C: Placebo medication and sham surgery responses in benign prostatic hyperplasia treatments: Implications for clinical trials. Curr Urol Rep 2015; 16: Welliver C, Kottwitz M, Feustel P, McVary K: Clinically and statistically significant changes seen in sham surgery arms of randomized, controlled benign prostatic hyperplasia surgery trials. J Urol 2015; 194:

19 Tables Table 1 Baseline characteristics of subjects in the RF thermal therapy and control groups of the randomized study and subsequent crossover study Table 2 Changes in outcomes after convective RF thermal therapy from baseline through 24 months Table 3 Comparison of outcome measures at 3 months during the control/sham and crossover periods Table 4 Paired outcome measures in crossover subjects after RF thermal therapy Table 5 Summary of adjudicated adverse events for subjects during the sham/control and crossover periods 17

20 Figure Legends Fig. 1 CONSORT (Consolidated Standards of Reporting Trials) diagram of subject dispositions in convective RF thermal therapy, control and crossover groups Fig. 2 I-PSS changes after convective RF water vapor thermal therapy including storage and voiding category responses (A) and seven individual questions related to storage and voiding symptoms (B). Values shown are the means and the errors bars represent the 95% CI (A). Improvements relative to baseline are significant at all time points, p< Fig. 3 I-PSS changes from baseline to 3 months in subjects who underwent crossover RF thermal therapy. Plotted for comparison are randomized trial blinded phase results for the control/sham and thermal therapy cohorts. 7 Values are the means and errors bars represent the 95% CI. *P < relative to baseline in RF thermal therapy (RCT) and crossover groups. Fig. 4 Changes in IPSS (A) and Qmax (B) from baseline to 3 months in the blinded sham/control period followed by the significant improvements after crossover RF thermal therapy that remain stable to the 12 month evaluation. The decrease in IPSS indicates improvement whereas the increase in Qmax indicates improvement. Values shown are means and error bars represent 95% CI. *P < relative to baseline; obtained from a general estimating equation. 18

21 Fig. 5 I-PSS outcomes in the randomized trial RF thermal therapy subjects throughout 24 months and the crossover RF thermal therapy group to 12 months. Also plotted are results from a single arm pilot trial showing similarity of outcomes. 6 Values are the means and errors bars represent the 95% CI. Improvements relative to baseline are significant at all time points, p

22 Table 1. Baseline characteristics of subjects in the RF thermal therapy and control groups of the randomized study and subsequent crossover study Treatment Group Control Group Crossover Group Mean (SD) Mean (SD) Mean (SD) N = 136 N = 61 N = 53 Age, years 63.0 (7.1) 62.9 (7.0) 63.8 (7.3) Body mass index (kg/m 2 ) 28.7 (4.4) 28.1 (5.0) 27.8 (4.8) Prostate volume (cc) 45.8 (13.0) 44.5 (13.3) 44.7 (12.4) Prostate specific antigen (ng/ml) 2.1 (1.5) 2.0 (1.6) 1.9 (1.4) IPSS 22.0 (4.8) 21.9 (4.7) 20.0 (6.6) Qmax (ml/sec) 9.9 (2.3) 10.4 (2.1) 10.1 (3.7) PVR (ml) 82.0 (51.5) 85.5 (51.6) 93.9 (77.2) IPSS- QoL score 4.4 (1.1) 4.4 (1.1) 3.9 (1.4) BPH II 6.3 (2.8) 6.2 (2.9) 5.5 (3.3) ICS male IS score - SF 4.4 (2.8) 4.6 (2.3) 4.2 (2.9) IIEF-EF score 17.2 (10.3) 16.5 (9.8) 16.7 (10.2)

23 MSQH-EjD: Function 7.8 (4.1) 9.0 (3.8) 9.1 (4.3) MSHQ-EjD: Bother 2.6 (1.7) 2.0 (1.7) 1.9 (1.8) OAB-q SF Bother scale 39.6 (18.0) 39.9 (18.3) 33.0 (20.4) OAB-q SF HRQL 64.5 (20.0) 66.7 (16.9) 72.6 (19.3)

24 Table 2 Changes in outcomes after convective RF thermal therapy from baseline through 24 months Outcome 1 Mo 3 Mos 6 Mos 12 Mos 24 Mos I-PSS: Score decrease = improvement N (paired values) Mean ± SD baseline 21.9 ± ± ± ± ± 4.5 Mean ± SD follow-up 14.4 ± ± ± ± ± 6.2 Change ± SD -7.5 ± ± ± ± ± 7.3 Change (95% CI) -8.9, , , , , -9.8 % Change 95% CI -32 (-38,-25) -50 (-55, -44) -54 (-59, -49) -52 (-58, -47) -51 (-57, -45) p Value (GEE) <.0001 <.0001 <.0001 <.0001 <.0001

25 Qmax: Rate increase = improvement N (paired values) Mean ± SD baseline 9.9 ± ± ± ± ± 2.3 Mean ± SD follow-up 13.1 ± ± ± ± ± 6.4 Change ± SD 3.2 ± ± ± ± ± 6.2 Change (95% CI) 2.3, , , , , 5.4 % Change 95% CI 36 (26, 46) 67 (53, 80) 61 (48, 73) 55 (43, 68) 47 (33, 60) p Value(GEE) < < < < < PVR:

26 Volume decrease = improvement No. (paired values) Mean ± SD baseline 81.5 ± ± ± ± ± 54.0 Mean ± SD follow-up 77.8 ± ± ± ± ± 92.0 Change ± SD -3.6 ± ± ± ± ± 85.3 Change (95% CI) -15.4, , , , , 16.1 % Change 95% CI 163 (-132, 457) 56 (-40, 151) 78 (-48, 204) 51 (-20, 121) 9 (-13, 30) p Value (GEE) QOL (I-PSS question 8): Score decrease = improvement

27 N (paired values) Mean ± SD baseline 4.4 ± ± ± ± ± 1.0 Mean ± SD follow-up 3.3 ± ± ± ± ± 1.4 Change ± SD -1.1 ± ± ± ± ± 1.5 Change 95% CI -1.4, , , , ,-1.9 % Change (95% CI) -22(-29,-16) -46(-52,-40) -51 (-57,-45) -50 (-56,-44) -50 (-56,-43) p Value (GEE) < < < < BPHII: Score decrease = improvement N (paired values) Mean ± SD baseline 6.3 ± ± ± ± 2.8

28 Mean ± SD follow-up 2.9 ± ± ± ± 2.7 Change ± SD -3.4 ± ± ± ± 3.1 Change 95% CI -4.0, , , ,-3.2 % Change (95% CI) -46(-58,-33) -65(-73,-57) -61(-70,-51) -61 (-69,-53) p Value (GEE < < < < OAB-q SF - Bother Scale: Score decrease = improvement N (paired values) Mean ± SD baseline 39.5 ± ± ± ± 17.3 Mean ± SD follow-up 24.9 ± ± ± ± 16.6 Change ± SD ± ± ± ± 14.2

29 Change 95% CI -17.7, , , , % Change (95% CI) -31 (-40, -22) -40 (-54, -26) -45 (-54, -36) -45 (-51, -39) p Value (GEE) < < < < OAB-q-SF, HRQL: Score increase = improvement N (paired values) Mean ± SD baseline 64.5 ± ± ± ± 18.3 Mean ± SD follow-up 82.0 ± ± ± ± 15.1 Change ± SD 17.5 ± ± ± ± 17.1 Change 95% CI 14.3, , , , 22.1 % Change (95% CI) 36 (27, 44) 39 (30, 48) 36 (26, 46) 36 (27, 45)

30 p Value (GEE) < < < < ICS Male IS SF: Score decrease = improvement N (paired values) Mean ± SD baseline 4.4 ± ± ± ± 2.4 Mean ± SD follow-up 3.2 ± ± ± ± 2.6 Change ± SD -1.2 ± ± ± ± 2.6 Change 95% CI -1.7, , , ,-0.7 % Change (95% CI) -16 (-31,-2) -26 (-39,-14) -24 (-37,-11) -19 (-34,-5) p Value < < < <0.0001

31 IIEF-EF: Score increase = improvement N (paired values) Mean ± SD baseline 22.6 ± ± ± ± 7.3 Mean ± SD follow-up 22.7 ± ± ± ± 8.7 Change ± SD 0.1 ± ± ± ± 7.5 Change 95% CI -1.5, , , , 0.6 % Change (95% CI) 7 (-3, 16) 2 (-7, 10) 4 (-7, 14) -1(-11, 10) p Value MSHQ-EjD Function: Score decrease = improvement

32 N (paired values) Mean ± SD baseline 9.3 ± ± ± ± 3.0 Mean ± SD follow-up 9.7 ± ± ± ± 4.4 Change ± SD 0.3 ± ± ± ± 4.2 Change 95% CI -0.5, , , , 0.5 % Change (95% CI) 11 (-2, 24) 6 (-4, 17) 0.4 (-10, 11) 0.3 (-13, 14) p Value MSHQ-EjD Bother: Score decrease = improvement N (paired values) Mean ± SD baseline 2.2 ± ± ± ± 1.6

33 Mean ± SD follow-up 1.8 ± ± ± ± 1.7 Change ± SD -0.3 ± ± ± ± 1.7 Change 95% CI -0.7, , , ,-0.1 % Change (95% CI) -14 (-34, 5) -6 (-29, 17) -18 (-41, 4) -25 (-45,-6) p Value

34 Table 3 Comparison of outcome measures at 3 months during the control/sham and crossover period Mean ± SD Mean ± SD Outcome Baseline 3 Mos Measure (No. Response) (No. Response) Control Crossover RF thermal therapy p Value Mean ± SD Change Mean ± SD Mean ± SD Mean ± SD Change Control vs (95% CI) Baseline 3 Mos (No. Response) (No. Response) (95% CI) Treatment I-PSS 21.9 ± 4.9 (50) 18.0 ± 7.6 (50) -3.9 ± 6.7 (-5.8,-2.0) 19.9 ± 6.7 (50) 9.8 ± 6.0 (50) ± 7.1 (-12.1,-8.0) Qmax 10.2 ± 2.2 (49) 10.4 ± 3.8 (49) 0.2 ± 3.9 (-0.9, 1.3) 10.1 ± 3.7 (49) 16.4 ± 7.1 (49) 6.3 ± 6.8 ( 4.3, 8.3) < I-PSS QoL 4.5 ± 1.1 (50) 3.7 ± 1.5 (50) -0.8 ± 1.5 (-1.2,-0.3) 3.9 ± 1.4 (50) 1.9 ± 1.4 (50) -2.0 ± 1.8 (-2.5,-1.5) BPH II 6.2 ± 2.8 (50) 4.9 ± 3.5 (50) -1.3 ± 2.9 (-2.1,-0.5) 5.5 ± 3.2 (50) 2.6 ± 2.6 (50) -2.9 ± 3.3 (-3.9,-2.0) IIEF-EF 16.1 ± 10.0 (47) 17.0 ± 10.5 (47) 0.9 ± 6.1 (-0.9, 2.7) 16.7 ± 10.4 (47) 16.6 ± 11.3 (47) -0.1 ± 8.9 (-2.7, 2.5) MSHQ-EjD 9.1 ± 4.0 (46) 9.4 ± 4.4 (47) 0.6 ± 3.0 (-0.3, 1.4) 9.5 ± 4.2 (46) 8.9 ± 5.2 (47) -0.4 ± 4.0 (-1.6, 0.8) Function MSHQ-EjD Bother 2.0 ± 1.8 (46) 1.7 ± 1.8 (47) -0.3 ± 1.7 (-0.8, 0.2) 1.8 ± 1.8 (46) 1.7 ± 1.7 (47) -0.1 ± 1.9 (-0.6, 0.5) *p-value compares the changes between control and crossover periods with a paired Student s t test.

35 Table 4. Paired outcome measures in crossover subjects after RF thermal therapy Outcome measure 1 Mo 3 Mos 6 Mos 12 Mos I-PSS: Score decrease = improvement N (paired values) Mean ± SD baseline 20.0 ± ± ± ± 6.6 Mean ± SD follow-up 15.3 ± ± ± ± 6.6 Change ± SD -4.7 ± ± ± ± 8.1 Change 95% CI -7.6, , , ,-8.4 % Change (95% CI) 0.7 (-30, 32) -47 (-57,-36) -47 (-57,-37) -51 (-63,-39) P Value (GEE) < < <0.0001

36 Qmax: Rate increase = improvement N (paired values) Mean ± SD baseline 10.3 ± ± ± ± 3.8 Mean ± SD follow-up 13.2 ± ± ± ± 7.9 Change ± SD 2.9 ± ± ± ± 7.9 Change 95% CI 1.1, , , , 8.2 % Change (95% CI) 34 (19, 50) 74 (50, 97) 76 (46, 105) 68 (43, 92) P Value (GEE) < < < PVR: Volume decrease = improvement

37 N (paired values) Mean ± SD baseline 93.1 ± ± ± ± 79.2 Mean ± SD follow-up 81.5 ± ± ± ± 80.5 Change ± SD ± ± ± ± Change 95% CI -35.8, , , , 14.8 % Change (95% CI) 24 (-15, 63) 17 (-22, 56) 25 (-36, 86) 11 (-28, 51) P value (GEE) QOL (I-PSS question 8): Score decrease = improvement N (paired values) Mean ± SD baseline 4.0 ± ± ± ± 1.3

38 Mean ± SD follow-up 3.3 ± ± ± ± 1.2 Change ± SD -0.7 ± ± ± ± 1.6 Change 95% CI -1.3, , , ,-1.6 % Change (95% CI) -7 (-27, 12) -45 (-58,-32) -45 (-57,-32) -52 (-62,-41) P Value (GEE) < < < BPHII: Score decrease = improvement N (paired values) Mean ± SD baseline 5.5 ± ± ± 3.2 Mean ± SD follow-up 2.6 ± ± ± 2.3 Change ± SD -2.9 ± ± ± 3.0

39 Change 95% CI -3.9, , , -2.7 % Change (95% CI) -39 (-68, -11) -57 (-71,- 43) -71 (-82, -59) P Value (GEE) < < < ICS Male IS-SF: Score decrease = improvement N (paired values) Mean ± SD baseline 4.3 ± ± ± 2.5 Mean ± SD follow-up 3.2 ± ± ± 1.8 Change ± SD -1.1 ± ± ± 2.6 Change 95% CI -2.0, , ,-0.5 % Change (95% CI) -19 (-36,-2) -14 (-33, 4) -18 (-47, 12) P Value (GEE)

40 OAB-q SF Symptom Score: Score decrease = improvement N (paired values) Mean ± SD baseline 33.1 ± ± ± 17.9 Mean ± SD follow-up 21.4 ± ± ± 12.4 Change ± SD ± ± ± 16.7 Change 95% CI -17.2, , ,-9.9 % Change (95% CI) -29 (-43,-15) -32(-49,-16) -36 (-56,-17) P Value (GEE) < < < OAB-q SF HRQL:

41 Score increase = improvement N (paired values) Mean ± SD baseline 72.5 ± ± ± 17.6 Mean ± SD follow-up 86.7 ± ± ± 12.6 Change ± SD 14.2 ± ± ± 17.1 Change 95% CI 8.8, , , 19.1 % Change (95% CI) 28 (15, 42) 26 (15, 36) 25 (14, 35) P Value (GEE) < < < IIEF-EF: Score increase = improvement N (paired values)

42 Mean ± SD baseline 23.2 ± ± ± 6.6 Mean ± SD follow-up 21.3 ± ± ± 10.0 Change ± SD -1.9 ± ± ± 8.3 Change 95% CI -5.3, , ,-0.7 % Change (95% CI) -6 (-23, 11) 1 (-16, 19) -17 (-33,-0.5) P Value (GEE) MSHQ EjD Function: Score decrease = improvement N (paired values) Mean ± SD baseline 9.9 ± ± ± 3.6 Mean ± SD follow-up 9.7 ± ± ± 4.6

43 Change ± SD -0.2 ± ± ± 3.7 Change 95% CI -1.7, , , 0.8 % Change (95% CI) 2 (-18, 22) -8 (-26, 10) 11 (-32, 55) P Value (GEE) MSHQ-EjD Bother: Score decrease = improvement N (paired values) Mean ± SD baseline 1.6 ± ± ± 1.7 Mean ± SD follow-up 1.6 ± ± ± 1.9 Change ± SD -0.1 ± ± ± 1.7 Change 95% CI -0.8, , , 1.1

44 % Change (95% CI) -33 (-57, -9) -23 (-47, 0.5) 1 (-47, 49) P Value (GEE)

45 Table 5 Summary of adjudicated adverse events for subjects during the sham/control and crossover periods Adverse Event Control (n=61) 0 3 Mos Crossover (n=53) 0 3 Mos Crossover (n=53) >3 12 Mos No. Events No. Subjects (%) No. Events No. Subjects (%) No. Events No. Subjects (%) Serious AEs 0 0 (0.0%) 0 0 (0.0%) 8 6 (11.3%) Related Serious AEs 0 0 (0.0%) 0 0 (0.0%) 3 2 (3.8%) Bladder neck contracture 0 0 (0.0%) 0 0 (0.0%) 1 1 (1.9%) Bladder stone formation 0 0 (0.0%) 0 0 (0.0%) 1 1 (1.9%) Sepsis 0 0 (0.0%) 0 0 (0.0%) 1 1 (1.9%) Non-Serious AEs (26.4%) (54.7%) (24.5%) Related Non-Serious AEs 11 6 (11.3%) (47.2%) 5 4 (7.5%) Dysuria 1 1 (1.9%) (18.9%) 0 0 (0.0%)

46 Hematuria, Gross 0 0 (0.0%) 6 6 (11.3%) 0 0 (0.0%) Urinary Retention 0 0 (0.0%) 5 3 (5.7%) 0 0 (0.0%) UTI, Suspected 0 0 (0.0%) 4 4 (7.5%) 0 0 (0.0%) Decrease in Ejaculatory 0 0 (0.0%) 3 3 (5.7%) 1 1 (1.9%) Volume Urinary Frequency 0 0 (0.0%) 3 3 (5.7%) 0 0 (0.0%) Hematospermia 0 0 (0.0%) 2 2 (3.8%) 0 0 (0.0%) Terminal Dribbling 2 2 (3.8%) 1 1 (1.9%) 1 1 (1.9%)

47

48

49

50

51

52 Abbreviations and Acronyms AE = adverse event BPH = benign prostatic hyperplasia BPHII = BPH Impact Index ICS male IS- SF = International Continence Society Male Incontinence Scale questionnaire- Short Form IIEF = International Index of Erectile Function I-PSS = International Prostate Symptom Score ITT = intent to treat LUTS = lower urinary tract symptoms MSHQ-EjD =Male Sexual Health Questionnaire for Ejaculatory Dysfunction OAB-q SF = Over Active Bladder Questionnaire Short Form PP = per protocol PVR = post-void residual volume Qmax = peak urinary flow QOL = quality of life RCT = randomized controlled trial

53 RF = radiofrequency TURP = transurethral resection of the prostate UTI = urinary tract infection