Evaluating Differential Impact of Digital Therapy for Male LUTS: Insights from the BEST Trial Subgroup Analysis

Evaluating Differential Impact of Digital Therapy for Male LUTS: Insights from the BEST Trial Subgroup Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Evaluating Differential Impact of Digital Therapy for Male LUTS: Insights from the BEST Trial Subgroup Analysis Laura Elisa Wiemer, Christian Gratzke, Kurt Miller, Erik Krieger, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7074786/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Nov, 2025 Read the published version in World Journal of Urology → Version 1 posted 11 You are reading this latest preprint version Abstract Purpose: Men with lower urinary tract symptoms (LUTS) represent a heterogeneous patient population. The BEST trial investigated the effectiveness of a digital health application for male LUTS. This pre-specified subgroup analysis evaluated treatment effects based on key clinical characteristics and additionally reports micturition diary outcomes and adherence data. Methods: In this randomized controlled trial, 237 patients were assigned to either the intervention group (IG, n=112), receiving app-based therapy (Kranus Lutera) alongside standard care, or the control group (CG, n=125), receiving standard care alone. Primary endpoints included 12-week changes in the International Prostate Symptom Score (IPSS) and both subscales of the Overactive Bladder Questionnaire Short Form (OAB-q SF). Subgroup analyses were stratified by diagnosis (OAB, BPH, OAB+BPH), baseline symptom severity, age (≤60, >60 years), and concurrent pharmacological treatment. Additional outcomes included changes in daytime/nighttime voiding frequency and urgency episodes. German Clinical Trials Registry number: DRKS00030935. Results: Subgroup analyses showed consistent improvements after 12 weeks in favour of the IG across diagnoses (between-group differences IPSS -6.4 to -7.4), with the largest improvement in severe LUTS (-10.7; 95% CI -12.7;-8.6, p<0.0001). Patients benefited regardless of age or medication use. These findings were further supported by improvements in OAB scores. Micturition diaries showed reduced daytime (-1.33), nighttime (-0.18), and urgency episodes (-1.59). In the IG, 84% of participants used the app several times per week. Conclusion: The digital therapeutic achieved clinically meaningful symptom and quality-of-life improvements across all subgroups. Additional reductions in voiding frequency and high adherence support its broad applicability in clinical practice. Digital therapy male LUTS BPH OAB subgroups Figures Figure 1 Background Certified digital health applications in Germany are regulated as low-risk medical devices (MDR class I to IIb) and have been implemented across various medical disciplines (e.g., psychology/psychiatry, neurology, oncology, cardiology, endocrinology, gastroenterology, orthopaedics, gynaecology, and urology) for nearly four years. These applications are designed to detect or alleviate diseases, support diagnostic processes, or accompany therapeutic interventions. Lower urinary tract symptoms (LUTS) are highly prevalent among men and can significantly impact quality of life. In the overall cohort of the Bladder Emptying DiSorder Therapy (BEST) study, the digital health application Kranus Lutera demonstrated significant clinical benefits. Specifically, participants experienced improvements in voiding symptoms as measured by the International Prostate Symptom Score (IPSS; between-group difference: -7.0 points; 95% CI: -8.1 to -5.9; p < 0.0001), a reduction in symptom burden according to part 1 of the Overactive Bladder questionnaire short form (OAB-q SF; between-group difference: -18.6 points; 95% CI: -22.2 to -15.0; p < 0.0001), and an increase in health-related quality of life (HRQOL) as measured by part 2 of the OAB-q SF (between-group difference: +17.2 points; 95% CI: 14.18 to 20.16; p < 0.0001). To further assess the robustness of this treatment and identify potential effect modifiers, we now present data from the pre-specified subgroup analyses examining whether treatment effects differ by diagnosis, baseline symptom severity, age, or concomitant medication use, but also analyses of the micturition diaries used within the app. These analyses aim to determine whether specific patient characteristics are associated with differential treatment benefit, thereby supporting a more personalized approach to digital therapy in male LUTS management. Material and Methods The BEST study was a two-arm, randomized, controlled, bicentric, single-blind study assessing Kranus Lutera as treatment for male LUTS. The present report focuses on pre-specified subgroup analyses and additional micturition diary data, all defined in the statistical analysis plan prior to unblinding. Participants in the intervention group (IG) received standard care plus access to the digital therapy Kranus Lutera, while the control group (CG) received standard care alone and was given access to the therapy after 12 weeks. No sham application was used. The primary endpoint was the change from baseline in IPSS score. Secondary endpoints included changes from baseline in OAB-q SF parts 1 (LUTS) and 2 (quality of life). Micturition diary data were collected in a 3-day in-app diary to assess changes in daytime and nighttime voiding frequency and episodes of urgency. Adherence was monitored by patient self-report. All statistical analyses were conducted using SAS® software (Version 9.4). Statistical significance was set at 0.05 (two-sided). The primary efficacy analyses were conducted within the intention-to-treat (ITT) population. Confirmatory endpoints were tested sequentially according to a predefined order and family-wise significance level (α = 0.05) as previously described. All other endpoints were considered exploratory and are presented without adjustment for multiple comparisons. Group differences in mean changes were assessed using ANCOVA, with treatment group as a factor and baseline values as the only covariate. Least squares means (LS means) were calculated for between-group comparisons. Missing data were handled using a conservative Jump-to-Reference (J2R) imputation strategy, referencing the control group. Data on bladder metrics were collected via the app's optional diary feature and analyzed within the per-protocol (PP) population, without imputation of missing values. Results All diagnostic subgroups (Table 1 ) showed significant improvements, with the greatest benefits observed in patients with urge-related symptoms (LS mean difference: -7.3 points [OAB] vs. -6.4 points [BPH] vs. -7.4 points [OAB + BPH]). Correspondingly, significant improvements were also observed in OAB-q-SF scores (-20.2 [OAB] vs. -15.5 [BPH] vs. -22.1 [OAB + BPH]) and HRQOL scores (17.2 [OAB] vs. 14.8 [BPH] vs. 20.6 [OAB + BPH]). In terms of baseline symptom severity (Table 1 ), patients with severe LUTS (IPSS ≥ 20 points) experienced the most pronounced improvements (LS mean difference: -10.7 points vs. -4.6 points [IPSS 8–19] vs. -10.1 points [IPSS 0–7]). OAB-q-SF scores similarly improved with increasing severity (-25.4 [severe] vs. -14.9 [moderate] vs. -17.5 [mild]), with corresponding HRQOL gains (25.5 [severe] vs. 12.8 [moderate] vs. 7.8 [mild], though the latter was not statistically significant [p = 0.2148]). Across age groups (Table 1 ), older patients benefited to a comparable extent (LS mean difference: -7.6 points [≤ 60 years] vs. -6.3 points [> 60 years]), with associated improvements in OAB-q-SF (-18.0 vs. -19.6) and HRQOL (18.1 vs. 16.1). The maximum age observed among participants was 88 years. In the intervention group, 13% of individuals were aged over 70 years. Patients receiving concurrent pharmacological treatment for OAB/BPH (Table 1 ) also showed significant symptom improvement (LS mean difference: -5.5 points [with medication] vs. -7.3 points [without medication]). The OAB-q-SF and HRQOL outcomes supported these findings (-16.6 and 14.6 [with medication] vs. -19.0 and 18.1 [without medication]). Among those using medication, approximately 40% received alpha-blockers, 30% antimuscarinics, and the remainder were treated with beta-3 mimetics, PDE-5 inhibitors, 5-alpha-reductase inhibitors, or phytotherapy. Thus, a significant treatment effect was also evident among those already receiving medication. Patients with higher BMI (> 25 kg/m²) showed comparable improvements compared to those with lower BMI (IPSS − 7.2 vs -6.5, OAB-q-SF: -18.2 vs -18.5, HRQOL: 17.1 vs 17.5). No substantial differences were found between study centers in subgroup analysis (IPSS − 7.6 vs -6.6, OAB-q SF Part 1 -17.3 vs -18.7, OAB-q SF Part 2 -11.2 vs -11.2). In summary, the intervention demonstrated robust and statistically significant efficacy across all subgroups. The greatest effects were observed in patients with more severe symptoms and those with urge incontinence components. Symptom improvement was independent of age and concurrent medication. Furthermore, at the 12-week follow-up, effects were observed regarding the secondary endpoints: daytime voiding frequency decreased by 1.3, nighttime frequency by 0.2, and episodes of urgency by 1.6. Furthermore, high treatment adherence was observed in the intervention group, with 83.96% of participants reporting app use several times per week. Table 1 Changes of the IPSS, OAB-q-SF, and HRQOL scores for relevant LUTS subgroups – ITT Subgroup Sample size IPSS OAB-q-SF HRQOL LS Mean Difference 95% CI p Value LS Mean Difference 95% CI p Value LS Mean Difference 95% CI p Value IG CG OAB (N32.8) 32 42 -7.3 -9.2;-5.5 < 0.0001 -20.2 -26.5;-13.9 < 0.0001 17.2 14.3; 20.3 < 0.0001 BPH (N40) 54 56 -6.4 -8.0;-4.7 < 0.0001 -15.5 -20.9;-10.2 < 0.0001 14.8 10.5; 19.2 < 0.0001 OAB + BPH (N32.8 + N40) 26 27 -7.4 -9.8;-5,1 < 0.0001 -22.1 -30.3;-14.0 < 0.0001 20.6 14.3; 26.8 < 0.0001 Mild Symptoms (0–7 IPSS points) 6 4 -10.1 -13.4;-6.8 0.0002 -17.5 -29.1;-6.0 0.0088 7.8 -5.7; 21.2 0.2148 Moderate Symptoms (8–19 IPSS points) 68 71 -4.6 -5.8;-3.4 < 0.0001 -14.9 -19.8;-10.0 < 0.0001 12.8 9.1; 16.5 < 0.0001 Severe Symptoms (20–35 IPSS points) 38 50 -10.7 -12.7;-8.6 < 0.0001 -25.4 -31.2;-19.7 < 0.0001 25.5 20.5; 30.6 < 0.0001 Age ≤ 60 years 56 71 -7.6 -8.9;-6.3 < 0.0001 -18.0 -22.6;-13.4 < 0.0001 18.1 14.1; 22.3 60 years 56 54 -6.3 -8.1;-4.5 < 0.0001 -19.6 -25.4;-13.8 < 0.0001 13.4 7.7; 16.1 < 0.0001 With medication for OAB/BPH 31 38 -5.5 -7.4;-3.6 < 0.0001 -16.6 -23.7,-9.4 < 0.0001 14.6 8.8; 20.3 < 0.0001 Without medication for OAB/BPH 81 87 -7.3 -8.6;-5.9 < 0.0001 -19.0 -23.3;-14.8 < 0.0001 18.1 14.6; 21.5 < 0.0001 BMI ≤ 25 kg/m 2 42 52 -6.5 -8.1;-4.8 < 0.0001 -18.5 -23.6,-13.5 < 0.0001 17.5 13.4; 21.7 25 kg/m 2 70 73 -7.2 -8.7;-5.8 < 0.0001 -18.2 -23.3,-13.2 < 0.0001 17.1 12.9; 21.2 < 0.0001 Discussion Consistent effects across subgroups This analysis of pre-specified subgroups from the BEST trial demonstrates that the digital therapy for men with LUTS resulted in consistent and clinically meaningful improvements in lower urinary tract symptoms and health-related quality of life across subgroups. Treatment effects were evident regardless of diagnostic category (BPH, OAB or both), symptom severity, study center, age, BMI or concomitant medication use. These findings underscore the broad applicability of this multimodal digital approach in men with LUTS. Improvements in micturition patterns and adherence In addition to improvements in IPSS and OAB-q SF scores, the digital intervention led to favourable changes in objective voiding behaviour, as demonstrated by micturition diary data: at the 12-week follow-up, daytime voiding frequency decreased by nearly one episode per day, nighttime frequency by 0.11, and episodes of urgency by more than one per day. These improvements complement the questionnaire-based outcomes and provide further evidence that patients achieved meaningful behavioural change in daily life. High treatment adherence was also observed, with 83.96% of participants in the intervention group reporting app use several times per week. This high engagement level suggests that the programme was acceptable, feasible, and well integrated into patients’ daily routines — an important consideration for real-world effectiveness. Greater improvements in severe cases The largest absolute improvements were observed in patients with severe baseline symptoms (IPSS ≥ 20), which is consistent with the general observation that individuals with greater symptom burden often achieve more substantial absolute gains following behavioral or pharmacological interventions. This reinforces the relevance of digital behavioural therapy even in patients with advanced symptomatology, a population often considered more likely to require invasive or pharmacological treatments. A limitation to consider is that, participants experiencing greater symptom burden and may have been more intrinsically motivated to engage in behavioral change. It should be noted that the mild symptom group had few participants, limiting interpretation. Patients with severe symptoms also demonstrated the greatest improvement in quality of life, as measured by OAB-q SF Part 2 (25.5%). This aligns with findings from other studies, which report that patients with higher baseline severity show greater improvements in IPSS. Most studies exclude patients with mild symptoms or include them only in small numbers. In a large study with 1218 men, those with baseline IPSS > 20 showed an average IPSS reduction of 6 points with a reported mild improvement. This suggests that the minimal important difference (MID) is dependent on baseline symptom severity. Higher MID is expected with higher baseline score. Effectiveness in older adults Of particular note is the comparable efficacy observed in patients aged over 60 years. Digital health applications are often assumed to have limited utility in older adults due to concerns about digital literacy. However, our findings suggest that, when designed with user-friendliness and patient education in mind, such interventions can be well-received and clinically effective even in older adults. In the app group, 13% of participants were aged over 70 years, with the oldest reaching 88 years. This further supports the age-independent feasibility of digital therapy in Urology. A potential source of selection bias must be acknowledged, as access to the application required ownership of a smartphone or tablet. Individuals unfamiliar with such technology were thus inherently excluded from participation. Adjunctive or standalone option The benefit observed in patients receiving concurrent LUTS-specific medication (alpha-blockers, antimuscarinics, or beta-3 agonists) suggests that this digital intervention may serve as a valuable adjunctive tool, potentially enhancing or complementing pharmacological effects. Conversely, patients not on pharmacotherapy also experienced significant improvements, indicating the utility of the digital approach as a standalone option. This may be especially relevant for patients with contraindications to medication, concerns about adverse effects, or a preference for non-pharmacologic management strategies. Patient engagement and design With only seven dropouts during the study period (six in the intervention group, one in the control group), the results are robust. Importantly, patients had to complete all primary endpoint questions to finish the survey. The low drop-out rate likely also reflects the high symptom burden and motivation of participants in addressing a sensitive issue but also highlights the importance of patient-centric digital therapy design. Several strengths of this study merit emphasis. The subgroup analyses were pre-specified in the study protocol and conducted within the context of a randomized controlled trial, enhancing internal validity. The use of validated and disease-specific outcome measures (IPSS and OAB-q SF) ensures clinical relevance. Limitations Although pre-specified, the subgroup analyses were not powered for interaction testing, and therefore formal statistical comparisons between subgroups should be interpreted cautiously. Furthermore, the 12-week follow-up period does not permit conclusions about long-term adherence, sustainability of symptom improvement, or prevention of disease progression. However, the longer-term follow-up assessment is ongoing. Treatment adherence in the intervention group was high, with 83.96% of participants reporting app use multiple times per week. Whether patients continue to apply what they have learned beyond this period cannot be definitively assessed at this time. Many studies on self-management programs for LUTS assess endpoints at longer follow-up periods (6 or 12 months), often reporting further symptom improvement over time. Furthermore, the control group did not employ a sham application, which presents a potential bias, as the use of a generic health app could itself yield beneficial effects. Regarding severity subgroups, due to the smaller sample size in the subgroup with mild symptoms, confidence intervals were comparatively wide, limiting precision. Nevertheless, the confidence intervals for both mild and severe symptom subgroups did not overlap, suggesting a meaningful difference in treatment response. Patients with severe symptoms, as classified by the IPSS, demonstrated the greatest improvement in symptom burden and the most pronounced gains in HRQOL. Regarding data on micturition frequency and urgency episodes, these were only documented if participants chose to use the app's diary. Consequently, it is unclear whether the lack of data is due to an absence of symptoms or due to no entries. A digital therapy for LUTS can reduce symptom burden and improve quality of life. However, it cannot influence progressive prostate enlargement or associated obstructive symptoms. Similarly, underlying neurogenic causes of LUTS will not be addressed, and patients with significant psychological distress are unlikely to benefit solely from a digital therapy. Selecting suitable patients requires close collaboration with treating physicians as well as therapists. In real-world clinical practice, where pharmacological treatments are often quickly initiated or patients are simply observed (watchful waiting), a digital therapy, including monitoring, lifestyle counseling, pelvic floor training, nutrition, mental health, and education on the underlying condition, can help bridge a care gap for a broad spectrum of patients with LUTS. From a clinical perspective, the consistent efficacy across diagnostic and demographic subgroups positions this digital intervention as a versatile tool within the therapeutic algorithm for male LUTS. Given the multifactorial and heterogeneous nature of LUTS, individualized and multimodal treatment strategies are increasingly advocated. The present findings support the integration of digital behavioural therapy into routine care pathways, either as first-line therapy or in combination with other modalities. Conclusions Overall, the findings indicate that the intervention is effective regardless of age, diagnosis (OAB vs. BPH), symptom severity, or medication status. Particularly noteworthy is the substantial gain in quality of life (OAB-q SF part 2), underscoring the clinical relevance of the intervention. These results highlight the value of digital health applications as an effective, conservative, and flexible treatment option for men with LUTS. Declarations Consent to participate Informed consent was obtained from all individual participants included in the study. Ethics approval All procedures performed in this study involving human participants were conducted in accordance with the ethical standards of the institutional and national research committees and with the 1964 Helsinki Declaration and its later amendments. The study was reviewed and approved by the Ethics Committee of the Medical Faculty of Martin Luther University Halle-Wittenberg (Approval No.: 2022-139) and the Ethics Committee of Albert Ludwig University Freiburg (Application No.: EK-Freiburg: 23-1219-S1-AV). It was registered in the German Clinical Trials Register under DRKS00030935. Funding This RCT was supported by Kranus Health GmbH, while the secondary analysis presented here received no funding. All authors had full access to all the data and had final responsibility for the decision to submit for publication. Competing interests Laura Wiemer, C. Patrick Papp, Erik Krieger and Kurt Miller are presently (partly) employed by Kranus Health GmbH. Sandra Schönburg and Christian Gratzke were prinicipial investigators of the BEST (Bladder Emptying DiSorder Therapy)-trial. Authors’ contribution statements L.W. and S.S. wrote the main manuscript text and were responsible for the concept of the manuscript, C.P. , C.G., K.M. and E.K. reviewed and edited the manuscript, C.P. prepared tables , formal analyses has been performed by external statisticians (CRMB statistics), data curation has been performed by an external CRO (CW-research), data interpretation has been performed by all authors, patient inclusion / screening process of original study has been performed S.S and C.G. , all authors had access to all the data. References Schönburg, S., et al., [Digital health applications in urology]. Urologie, 2024. 63 (9): p. 850-859. Gravas S., et al., EAU Guidelines on Management of Non-Neurogenic Male LUTS Including Benign Prostatic Obstruction. 2022: European Association of Urology; Arnhem, The Netherland: 2022. Sandhu, J.S., et al., Management of Lower Urinary Tract Symptoms Attributed to Benign Prostatic Hyperplasia (BPH): AUA Guideline Amendment 2023. J Urol, 2024. 211 (1): p. 11-19. Gratzke, C., et al., A Randomized Trial of an App-Based Therapeutic for Lower Urinary Tract Symptoms. NEJM Evidence, 2025. 4 (4): p. EVIDoa2400290. Barry, M.J., 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 (5): p. 1770-4. Blanker, M.H., et al., Determining the minimal important differences in the International Prostate Symptom Score and Overactive Bladder Questionnaire: results from an observational cohort study in Dutch primary care. BMJ Open, 2019. 9 (12): p. e032795. Albarqouni, L., et al., Self-Management for Men With Lower Urinary Tract Symptoms: A Systematic Review and Meta-Analysis. Ann Fam Med, 2021. 19 (2): p. 157-167. Chapple, C.R., et al., Lower urinary tract symptoms revisited: a broader clinical perspective. Eur Urol, 2008. 54 (3): p. 563-9. Additional Declarations Competing interest reported. Funding: No funding was received to assist with the preparation of this manuscript, however the original study (BEST trial), which is the source of the data used for this manuscript, has been funded by Kranus Health GmbH, Munich, Germany. Conflicts of interest/Competing interests Laura Wiemer, C. Patrick Papp, Erik Krieger and Kurt Miller are presently (partly) employed by Kranus Health GmbH. Sandra Schönburg and Christian Gratzke were prinicipial investigators of the BEST (Bladder Emptying DiSorder Therapy)-trial. Non- financial disclosures: Sandra Schönburg is the deputy coordinator of the German S2e guideline ‘Diagnosis and Treatment of Benign Prostatic Syndrome (BPS)’ and the deputy chair of the Working Group on Benign Prostatic Syndrome of the German Society of Urology (DGU). Christian Gratzke is a member of the Working Group on Benign Prostatic Syndrome of the German Society of Urology (DGU) and contributes to the EAU Guidelines on Non-Neurogenic Male LUTS. Cite Share Download PDF Status: Published Journal Publication published 01 Nov, 2025 Read the published version in World Journal of Urology → Version 1 posted Editorial decision: Revision requested 05 Aug, 2025 Reviews received at journal 02 Aug, 2025 Reviews received at journal 01 Aug, 2025 Reviews received at journal 25 Jul, 2025 Reviewers agreed at journal 19 Jul, 2025 Reviewers agreed at journal 17 Jul, 2025 Reviewers agreed at journal 16 Jul, 2025 Reviewers invited by journal 16 Jul, 2025 Editor assigned by journal 12 Jul, 2025 Submission checks completed at journal 12 Jul, 2025 First submitted to journal 08 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7074786","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":487101827,"identity":"e92489ff-f760-47e6-9d14-e0519282d624","order_by":0,"name":"Laura Elisa Wiemer","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAElEQVRIiWNgGAWjYBACPijNAyY/MBxgYGAGsdhwa4FJgbUwzgBrYSZOCxgw84C0MBDSwn7G7MMPhsMy/GKHj322qbkjb97Of/ABQ5kNbi08OcYzexgO80jOTkuenXPsmeGcw8zMBgzn0vA4LMcY6JHbPAa3c4yZcxsOM85gZmaTYGw7jFsL/xtjxj9ALfa38z8zWzYctgdqYf/B2PYftxYJoOFgW6RzmJkZGw4ngmxhYGw7gEfLs2JmGYP/PBK304wZe44dTgZqMZZIOJeMUws/f/JmxjcVafb8s5MfM/yoOWw7g//gww8fyuxwaoEAA3SBBAIaRsEoGAWjYBTgBwBDsEcS7PwhPQAAAABJRU5ErkJggg==","orcid":"","institution":"Charité- Universitätsmedizin Berlin","correspondingAuthor":true,"prefix":"","firstName":"Laura","middleName":"Elisa","lastName":"Wiemer","suffix":""},{"id":487101828,"identity":"950f6fe6-d654-4301-a7d4-470675430e1e","order_by":1,"name":"Christian Gratzke","email":"","orcid":"","institution":"University of Freiburg","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"","lastName":"Gratzke","suffix":""},{"id":487101829,"identity":"17ba88f6-6ac8-420c-8dfa-2a80eb22acff","order_by":2,"name":"Kurt Miller","email":"","orcid":"","institution":"Charité- Universitätsmedizin Berlin","correspondingAuthor":false,"prefix":"","firstName":"Kurt","middleName":"","lastName":"Miller","suffix":""},{"id":487101830,"identity":"a47f4620-b155-4cfe-acf4-0c64bc036808","order_by":3,"name":"Erik Krieger","email":"","orcid":"","institution":"Kranus Health GmbH","correspondingAuthor":false,"prefix":"","firstName":"Erik","middleName":"","lastName":"Krieger","suffix":""},{"id":487101831,"identity":"c21f7e5e-b96e-44c4-a83f-a8d4d2961bf7","order_by":4,"name":"C. Patrick Papp","email":"","orcid":"","institution":"Kranus Health GmbH","correspondingAuthor":false,"prefix":"","firstName":"C.","middleName":"Patrick","lastName":"Papp","suffix":""},{"id":487101832,"identity":"2bb1a21e-f9a7-4c62-acd2-d9f0f7adc71b","order_by":5,"name":"Sandra Schönburg","email":"","orcid":"","institution":"BG Klinikum Bergmannstrost","correspondingAuthor":false,"prefix":"","firstName":"Sandra","middleName":"","lastName":"Schönburg","suffix":""}],"badges":[],"createdAt":"2025-07-08 12:23:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7074786/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7074786/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00345-025-06016-2","type":"published","date":"2025-11-01T15:57:13+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":87364505,"identity":"c968d4b3-002f-4416-b6e2-f491b71cccfc","added_by":"auto","created_at":"2025-07-23 06:15:28","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":181788,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest Plot of LS Mean Differences by Subgroup and Outcome\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7074786/v1/e7de3d3faecf7ddc6155d405.png"},{"id":95039903,"identity":"c4f1369a-1ecb-46d3-b9d3-bdb26b5bd807","added_by":"auto","created_at":"2025-11-03 16:05:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1124539,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7074786/v1/bce21d97-7aef-4157-a5c9-e9f3df4af32f.pdf"}],"financialInterests":"Competing interest reported. Funding: \nNo funding was received to assist with the preparation of this manuscript, however the original study (BEST trial), which is the source of the data used for this manuscript, has been funded by Kranus Health GmbH, Munich, Germany. \n\nConflicts of interest/Competing interests\n\nLaura Wiemer, C. Patrick Papp, Erik Krieger and Kurt Miller are presently (partly) employed by Kranus Health GmbH. \n\nSandra Schönburg and Christian Gratzke were prinicipial investigators of the BEST (Bladder Emptying DiSorder Therapy)-trial. \n\nNon- financial disclosures:\nSandra Schönburg is the deputy coordinator of the German S2e guideline ‘Diagnosis and Treatment of Benign Prostatic Syndrome (BPS)’ and the deputy chair of the Working Group on Benign Prostatic Syndrome of the German Society of Urology (DGU).\nChristian Gratzke is a member of the Working Group on Benign Prostatic Syndrome of the German Society of Urology (DGU) and contributes to the EAU Guidelines on Non-Neurogenic Male LUTS.","formattedTitle":"Evaluating Differential Impact of Digital Therapy for Male LUTS: Insights from the BEST Trial Subgroup Analysis","fulltext":[{"header":"Background","content":"\u003cp\u003eCertified digital health applications in Germany are regulated as low-risk medical devices (MDR class I to IIb) and have been implemented across various medical disciplines (e.g., psychology/psychiatry, neurology, oncology, cardiology, endocrinology, gastroenterology, orthopaedics, gynaecology, and urology) for nearly four years. These applications are designed to detect or alleviate diseases, support diagnostic processes, or accompany therapeutic interventions. Lower urinary tract symptoms (LUTS) are highly prevalent among men and can significantly impact quality of life. In the overall cohort of the Bladder Emptying DiSorder Therapy (BEST) study, the digital health application Kranus Lutera demonstrated significant clinical benefits. Specifically, participants experienced improvements in voiding symptoms as measured by the International Prostate Symptom Score (IPSS; between-group difference: -7.0 points; 95% CI: -8.1 to -5.9; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), a reduction in symptom burden according to part 1 of the Overactive Bladder questionnaire short form (OAB-q SF; between-group difference: -18.6 points; 95% CI: -22.2 to -15.0; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), and an increase in health-related quality of life (HRQOL) as measured by part 2 of the OAB-q SF (between-group difference: +17.2 points; 95% CI: 14.18 to 20.16; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e\u003cp\u003eTo further assess the robustness of this treatment and identify potential effect modifiers, we now present data from the pre-specified subgroup analyses examining whether treatment effects differ by diagnosis, baseline symptom severity, age, or concomitant medication use, but also analyses of the micturition diaries used within the app. These analyses aim to determine whether specific patient characteristics are associated with differential treatment benefit, thereby supporting a more personalized approach to digital therapy in male LUTS management.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cp\u003eThe BEST study was a two-arm, randomized, controlled, bicentric, single-blind study assessing Kranus Lutera as treatment for male LUTS. The present report focuses on pre-specified subgroup analyses and additional micturition diary data, all defined in the statistical analysis plan prior to unblinding.\u003c/p\u003e\u003cp\u003eParticipants in the intervention group (IG) received standard care plus access to the digital therapy Kranus Lutera, while the control group (CG) received standard care alone and was given access to the therapy after 12 weeks. No sham application was used.\u003c/p\u003e\u003cp\u003eThe primary endpoint was the change from baseline in IPSS score. Secondary endpoints included changes from baseline in OAB-q SF parts 1 (LUTS) and 2 (quality of life).\u003c/p\u003e\u003cp\u003eMicturition diary data were collected in a 3-day in-app diary to assess changes in daytime and nighttime voiding frequency and episodes of urgency. Adherence was monitored by patient self-report.\u003c/p\u003e\u003cp\u003eAll statistical analyses were conducted using SAS\u0026reg; software (Version 9.4). Statistical significance was set at 0.05 (two-sided).\u003c/p\u003e\u003cp\u003eThe primary efficacy analyses were conducted within the intention-to-treat (ITT) population. Confirmatory endpoints were tested sequentially according to a predefined order and family-wise significance level (α\u0026thinsp;=\u0026thinsp;0.05) as previously described. All other endpoints were considered exploratory and are presented without adjustment for multiple comparisons.\u003c/p\u003e\u003cp\u003eGroup differences in mean changes were assessed using ANCOVA, with treatment group as a factor and baseline values as the only covariate. Least squares means (LS means) were calculated for between-group comparisons.\u003c/p\u003e\u003cp\u003eMissing data were handled using a conservative Jump-to-Reference (J2R) imputation strategy, referencing the control group. Data on bladder metrics were collected via the app's optional diary feature and analyzed within the per-protocol (PP) population, without imputation of missing values.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAll diagnostic subgroups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) showed significant improvements, with the greatest benefits observed in patients with urge-related symptoms (LS mean difference: -7.3 points [OAB] vs. -6.4 points [BPH] vs. -7.4 points [OAB\u0026thinsp;+\u0026thinsp;BPH]). Correspondingly, significant improvements were also observed in OAB-q-SF scores (-20.2 [OAB] vs. -15.5 [BPH] vs. -22.1 [OAB\u0026thinsp;+\u0026thinsp;BPH]) and HRQOL scores (17.2 [OAB] vs. 14.8 [BPH] vs. 20.6 [OAB\u0026thinsp;+\u0026thinsp;BPH]).\u003c/p\u003e\u003cp\u003eIn terms of baseline symptom severity (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), patients with severe LUTS (IPSS\u0026thinsp;\u0026ge;\u0026thinsp;20 points) experienced the most pronounced improvements (LS mean difference: -10.7 points vs. -4.6 points [IPSS 8\u0026ndash;19] vs. -10.1 points [IPSS 0\u0026ndash;7]). OAB-q-SF scores similarly improved with increasing severity (-25.4 [severe] vs. -14.9 [moderate] vs. -17.5 [mild]), with corresponding HRQOL gains (25.5 [severe] vs. 12.8 [moderate] vs. 7.8 [mild], though the latter was not statistically significant [p\u0026thinsp;=\u0026thinsp;0.2148]).\u003c/p\u003e\u003cp\u003eAcross age groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), older patients benefited to a comparable extent (LS mean difference: -7.6 points [\u0026le;\u0026thinsp;60 years] vs. -6.3 points [\u0026gt;\u0026thinsp;60 years]), with associated improvements in OAB-q-SF (-18.0 vs. -19.6) and HRQOL (18.1 vs. 16.1). The maximum age observed among participants was 88 years. In the intervention group, 13% of individuals were aged over 70 years. Patients receiving concurrent pharmacological treatment for OAB/BPH (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) also showed significant symptom improvement (LS mean difference: -5.5 points [with medication] vs. -7.3 points [without medication]). The OAB-q-SF and HRQOL outcomes supported these findings (-16.6 and 14.6 [with medication] vs. -19.0 and 18.1 [without medication]). Among those using medication, approximately 40% received alpha-blockers, 30% antimuscarinics, and the remainder were treated with beta-3 mimetics, PDE-5 inhibitors, 5-alpha-reductase inhibitors, or phytotherapy. Thus, a significant treatment effect was also evident among those already receiving medication.\u003c/p\u003e\u003cp\u003ePatients with higher BMI (\u0026gt;\u0026thinsp;25 kg/m\u0026sup2;) showed comparable improvements compared to those with lower BMI (IPSS \u0026minus;\u0026thinsp;7.2 vs -6.5, OAB-q-SF: -18.2 vs -18.5, HRQOL: 17.1 vs 17.5).\u003c/p\u003e\u003cp\u003eNo substantial differences were found between study centers in subgroup analysis (IPSS \u0026minus;\u0026thinsp;7.6 vs -6.6, OAB-q SF Part 1 -17.3 vs -18.7, OAB-q SF Part 2 -11.2 vs -11.2).\u003c/p\u003e\u003cp\u003eIn summary, the intervention demonstrated robust and statistically significant efficacy across all subgroups. The greatest effects were observed in patients with more severe symptoms and those with urge incontinence components. Symptom improvement was independent of age and concurrent medication.\u003c/p\u003e\u003cp\u003eFurthermore, at the 12-week follow-up, effects were observed regarding the secondary endpoints: daytime voiding frequency decreased by 1.3, nighttime frequency by 0.2, and episodes of urgency by 1.6. Furthermore, high treatment adherence was observed in the intervention group, with 83.96% of participants reporting app use several times per week.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cem\u003eChanges of the IPSS, OAB-q-SF, and HRQOL scores for relevant LUTS subgroups \u0026ndash; ITT\u003c/em\u003e\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"12\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026minus;\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026minus;\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eSubgroup\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c3\" namest=\"c2\" rowspan=\"2\"\u003e\u003cp\u003eSample size\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003eIPSS\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c9\" namest=\"c7\"\u003e\u003cp\u003eOAB-q-SF\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c12\" namest=\"c10\"\u003e\u003cp\u003eHRQOL\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eLS Mean Difference\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003ep Value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eLS Mean Difference\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003ep Value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eLS Mean Difference\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003ep Value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIG\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOAB\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(N32.8)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e32\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e42\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e-7.3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e-9.2;-5.5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e-20.2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e-26.5;-13.9\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e17.2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e14.3; 20.3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBPH\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(N40)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e54\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e56\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e-6.4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e-8.0;-4.7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e-15.5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e-20.9;-10.2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e14.8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e10.5; 19.2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOAB\u0026thinsp;+\u0026thinsp;BPH\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(N32.8\u0026thinsp;+\u0026thinsp;N40)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e26\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e27\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e-7.4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e-9.8;-5,1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e-22.1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e-30.3;-14.0\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e20.6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e14.3; 26.8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMild Symptoms\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(0\u0026ndash;7 IPSS\u0026nbsp; points)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e-10.1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e-13.4;-6.8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e0.0002\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e-17.5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e-29.1;-6.0\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e0.0088\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e7.8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e-5.7; 21.2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e0.2148\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eModerate Symptoms\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(8\u0026ndash;19 IPSS points)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e68\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e71\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e-4.6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e-5.8;-3.4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e-14.9\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e-19.8;-10.0\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e12.8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e9.1; 16.5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSevere Symptoms\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(20\u0026ndash;35 IPSS points)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e38\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e50\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e-10.7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e-12.7;-8.6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e-25.4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e-31.2;-19.7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e25.5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e20.5; 30.6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge\u0026thinsp;\u0026le;\u0026thinsp;60 years\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e56\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e71\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e-7.6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e-8.9;-6.3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e-18.0\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e-22.6;-13.4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e18.1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e14.1; 22.3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge\u0026thinsp;\u0026gt;\u0026thinsp;60 years\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e56\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e54\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e-6.3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e-8.1;-4.5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e-19.6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e-25.4;-13.8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e13.4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e7.7; 16.1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eWith medication for OAB/BPH\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e31\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e38\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e-5.5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e-7.4;-3.6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e-16.6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e-23.7,-9.4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e14.6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e8.8; 20.3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eWithout medication for OAB/BPH\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e81\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e87\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e-7.3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e-8.6;-5.9\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e-19.0\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e-23.3;-14.8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e18.1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e14.6; 21.5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBMI\u0026thinsp;\u0026le;\u0026thinsp;25 kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e42\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e52\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e-6.5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e-8.1;-4.8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e-18.5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e-23.6,-13.5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e17.5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e13.4; 21.7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBMI\u0026thinsp;\u0026gt;\u0026thinsp;25 kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" 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colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e17.1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e12.9; 21.2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eConsistent effects across subgroups\u003c/p\u003e\u003cp\u003eThis analysis of pre-specified subgroups from the BEST trial demonstrates that the digital therapy for men with LUTS resulted in consistent and clinically meaningful improvements in lower urinary tract symptoms and health-related quality of life across subgroups. Treatment effects were evident regardless of diagnostic category (BPH, OAB or both), symptom severity, study center, age, BMI or concomitant medication use. These findings underscore the broad applicability of this multimodal digital approach in men with LUTS.\u003c/p\u003e\u003cp\u003eImprovements in micturition patterns and adherence\u003c/p\u003e\u003cp\u003eIn addition to improvements in IPSS and OAB-q SF scores, the digital intervention led to favourable changes in objective voiding behaviour, as demonstrated by micturition diary data: at the 12-week follow-up, daytime voiding frequency decreased by nearly one episode per day, nighttime frequency by 0.11, and episodes of urgency by more than one per day. These improvements complement the questionnaire-based outcomes and provide further evidence that patients achieved meaningful behavioural change in daily life.\u003c/p\u003e\u003cp\u003eHigh treatment adherence was also observed, with 83.96% of participants in the intervention group reporting app use several times per week. This high engagement level suggests that the programme was acceptable, feasible, and well integrated into patients\u0026rsquo; daily routines \u0026mdash; an important consideration for real-world effectiveness.\u003c/p\u003e\u003cp\u003eGreater improvements in severe cases\u003c/p\u003e\u003cp\u003eThe largest absolute improvements were observed in patients with severe baseline symptoms (IPSS\u0026thinsp;\u0026ge;\u0026thinsp;20), which is consistent with the general observation that individuals with greater symptom burden often achieve more substantial absolute gains following behavioral or pharmacological interventions. This reinforces the relevance of digital behavioural therapy even in patients with advanced symptomatology, a population often considered more likely to require invasive or pharmacological treatments. A limitation to consider is that, participants experiencing greater symptom burden and may have been more intrinsically motivated to engage in behavioral change.\u003c/p\u003e\u003cp\u003eIt should be noted that the mild symptom group had few participants, limiting interpretation. Patients with severe symptoms also demonstrated the greatest improvement in quality of life, as measured by OAB-q SF Part 2 (25.5%). This aligns with findings from other studies, which report that patients with higher baseline severity show greater improvements in IPSS. Most studies exclude patients with mild symptoms or include them only in small numbers. In a large study with 1218 men, those with baseline IPSS\u0026thinsp;\u0026gt;\u0026thinsp;20 showed an average IPSS reduction of 6 points with a reported mild improvement. This suggests that the minimal important difference (MID) is dependent on baseline symptom severity. Higher MID is expected with higher baseline score.\u003c/p\u003e\u003cp\u003eEffectiveness in older adults\u003c/p\u003e\u003cp\u003eOf particular note is the comparable efficacy observed in patients aged over 60 years. Digital health applications are often assumed to have limited utility in older adults due to concerns about digital literacy. However, our findings suggest that, when designed with user-friendliness and patient education in mind, such interventions can be well-received and clinically effective even in older adults. In the app group, 13% of participants were aged over 70 years, with the oldest reaching 88 years. This further supports the age-independent feasibility of digital therapy in Urology. A potential source of selection bias must be acknowledged, as access to the application required ownership of a smartphone or tablet. Individuals unfamiliar with such technology were thus inherently excluded from participation.\u003c/p\u003e\u003cp\u003eAdjunctive or standalone option\u003c/p\u003e\u003cp\u003eThe benefit observed in patients receiving concurrent LUTS-specific medication (alpha-blockers, antimuscarinics, or beta-3 agonists) suggests that this digital intervention may serve as a valuable adjunctive tool, potentially enhancing or complementing pharmacological effects. Conversely, patients not on pharmacotherapy also experienced significant improvements, indicating the utility of the digital approach as a standalone option. This may be especially relevant for patients with contraindications to medication, concerns about adverse effects, or a preference for non-pharmacologic management strategies.\u003c/p\u003e\u003cp\u003ePatient engagement and design\u003c/p\u003e\u003cp\u003eWith only seven dropouts during the study period (six in the intervention group, one in the control group), the results are robust. Importantly, patients had to complete all primary endpoint questions to finish the survey. The low drop-out rate likely also reflects the high symptom burden and motivation of participants in addressing a sensitive issue but also highlights the importance of patient-centric digital therapy design.\u003c/p\u003e\u003cp\u003eSeveral strengths of this study merit emphasis. The subgroup analyses were pre-specified in the study protocol and conducted within the context of a randomized controlled trial, enhancing internal validity. The use of validated and disease-specific outcome measures (IPSS and OAB-q SF) ensures clinical relevance.\u003c/p\u003e\u003cp\u003e\u003cb\u003eLimitations\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAlthough pre-specified, the subgroup analyses were not powered for interaction testing, and therefore formal statistical comparisons between subgroups should be interpreted cautiously. Furthermore, the 12-week follow-up period does not permit conclusions about long-term adherence, sustainability of symptom improvement, or prevention of disease progression. However, the longer-term follow-up assessment is ongoing. Treatment adherence in the intervention group was high, with 83.96% of participants reporting app use multiple times per week. Whether patients continue to apply what they have learned beyond this period cannot be definitively assessed at this time. Many studies on self-management programs for LUTS assess endpoints at longer follow-up periods (6 or 12 months), often reporting further symptom improvement over time. Furthermore, the control group did not employ a sham application, which presents a potential bias, as the use of a generic health app could itself yield beneficial effects. Regarding severity subgroups, due to the smaller sample size in the subgroup with mild symptoms, confidence intervals were comparatively wide, limiting precision. Nevertheless, the confidence intervals for both mild and severe symptom subgroups did not overlap, suggesting a meaningful difference in treatment response. Patients with severe symptoms, as classified by the IPSS, demonstrated the greatest improvement in symptom burden and the most pronounced gains in HRQOL. Regarding data on micturition frequency and urgency episodes, these were only documented if participants chose to use the app's diary. Consequently, it is unclear whether the lack of data is due to an absence of symptoms or due to no entries.\u003c/p\u003e\u003cp\u003eA digital therapy for LUTS can reduce symptom burden and improve quality of life. However, it cannot influence progressive prostate enlargement or associated obstructive symptoms. Similarly, underlying neurogenic causes of LUTS will not be addressed, and patients with significant psychological distress are unlikely to benefit solely from a digital therapy. Selecting suitable patients requires close collaboration with treating physicians as well as therapists.\u003c/p\u003e\u003cp\u003eIn real-world clinical practice, where pharmacological treatments are often quickly initiated or patients are simply observed (watchful waiting), a digital therapy, including monitoring, lifestyle counseling, pelvic floor training, nutrition, mental health, and education on the underlying condition, can help bridge a care gap for a broad spectrum of patients with LUTS. From a clinical perspective, the consistent efficacy across diagnostic and demographic subgroups positions this digital intervention as a versatile tool within the therapeutic algorithm for male LUTS. Given the multifactorial and heterogeneous nature of LUTS, individualized and multimodal treatment strategies are increasingly advocated. The present findings support the integration of digital behavioural therapy into routine care pathways, either as first-line therapy or in combination with other modalities.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOverall, the findings indicate that the intervention is effective regardless of age, diagnosis (OAB vs. BPH), symptom severity, or medication status. Particularly noteworthy is the substantial gain in quality of life (OAB-q SF part 2), underscoring the clinical relevance of the intervention. These results highlight the value of digital health applications as an effective, conservative, and flexible treatment option for men with LUTS.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures performed in this study involving human participants were conducted in accordance with the ethical standards of the institutional and national research committees and with the 1964 Helsinki Declaration and its later amendments. The study was reviewed and approved by the Ethics Committee of the Medical Faculty of Martin Luther University Halle-Wittenberg (Approval No.: 2022-139) and the Ethics Committee of Albert Ludwig University Freiburg (Application No.: EK-Freiburg: 23-1219-S1-AV). It was registered in the German Clinical Trials Register under DRKS00030935.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis RCT was supported by Kranus Health GmbH, while the secondary analysis presented here received no funding. All authors had full access to all the data and had final responsibility for the decision to submit for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLaura Wiemer, C. Patrick Papp, Erik Krieger and Kurt Miller are presently \u0026nbsp;(partly) employed by Kranus Health GmbH.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSandra Sch\u0026ouml;nburg and Christian Gratzke were prinicipial investigators of the BEST (Bladder Emptying DiSorder Therapy)-trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contribution statements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eL.W. and S.S. wrote the main manuscript text and were responsible for the concept of the manuscript, C.P. , C.G., K.M. and E.K. reviewed and edited the manuscript, C.P. \u0026nbsp; prepared tables , formal analyses has been performed by external statisticians (CRMB statistics), data curation has been performed by an external CRO (CW-research), data interpretation has been performed by all authors, patient inclusion / screening process of original study has been performed S.S and C.G. , all authors had access to all the data.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSch\u0026ouml;nburg, S., et al., \u003cem\u003e[Digital health applications in urology].\u003c/em\u003e Urologie, 2024. \u003cstrong\u003e63\u003c/strong\u003e(9): p. 850-859.\u003c/li\u003e\n\u003cli\u003eGravas S., et al., \u003cem\u003eEAU Guidelines on Management of Non-Neurogenic Male LUTS Including Benign Prostatic Obstruction.\u003c/em\u003e 2022: European Association of Urology; Arnhem, The Netherland: 2022.\u003c/li\u003e\n\u003cli\u003eSandhu, J.S., et al., \u003cem\u003eManagement of Lower Urinary Tract Symptoms Attributed to Benign Prostatic Hyperplasia (BPH): AUA Guideline Amendment 2023.\u003c/em\u003e J Urol, 2024. \u003cstrong\u003e211\u003c/strong\u003e(1): p. 11-19.\u003c/li\u003e\n\u003cli\u003eGratzke, C., et al., \u003cem\u003eA Randomized Trial of an App-Based Therapeutic for Lower Urinary Tract Symptoms.\u003c/em\u003e NEJM Evidence, 2025. \u003cstrong\u003e4\u003c/strong\u003e(4): p. EVIDoa2400290.\u003c/li\u003e\n\u003cli\u003eBarry, M.J., et al., \u003cem\u003eBenign 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?\u003c/em\u003e J Urol, 1995. \u003cstrong\u003e154\u003c/strong\u003e(5): p. 1770-4.\u003c/li\u003e\n\u003cli\u003eBlanker, M.H., et al., \u003cem\u003eDetermining the minimal important differences in the International Prostate Symptom Score and Overactive Bladder Questionnaire: results from an observational cohort study in Dutch primary care.\u003c/em\u003e BMJ Open, 2019. \u003cstrong\u003e9\u003c/strong\u003e(12): p. e032795.\u003c/li\u003e\n\u003cli\u003eAlbarqouni, L., et al., \u003cem\u003eSelf-Management for Men With Lower Urinary Tract Symptoms: A Systematic Review and Meta-Analysis.\u003c/em\u003e Ann Fam Med, 2021. \u003cstrong\u003e19\u003c/strong\u003e(2): p. 157-167.\u003c/li\u003e\n\u003cli\u003eChapple, C.R., et al., \u003cem\u003eLower urinary tract symptoms revisited: a broader clinical perspective.\u003c/em\u003e Eur Urol, 2008. \u003cstrong\u003e54\u003c/strong\u003e(3): p. 563-9.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"world-journal-of-urology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjur","sideBox":"Learn more about [World Journal of Urology](https://link.springer.com/journal/345)","snPcode":"345","submissionUrl":"https://submission.nature.com/new-submission/345/3","title":"World Journal of Urology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Digital therapy, male LUTS, BPH, OAB, subgroups","lastPublishedDoi":"10.21203/rs.3.rs-7074786/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7074786/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMen with lower urinary tract symptoms (LUTS) represent a heterogeneous patient population. The BEST trial investigated the effectiveness of a digital health application for male LUTS. This pre-specified subgroup analysis evaluated treatment effects based on key clinical characteristics and additionally reports micturition diary outcomes and adherence data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this randomized controlled trial, 237 patients were assigned to either the intervention group (IG, n=112), receiving app-based therapy (Kranus Lutera) alongside standard care, or the control group (CG, n=125), receiving standard care alone. Primary endpoints included 12-week changes in the International Prostate Symptom Score (IPSS) and both subscales of the Overactive Bladder Questionnaire Short Form (OAB-q SF). Subgroup analyses were stratified by diagnosis (OAB, BPH, OAB+BPH), baseline symptom severity, age (≤60, \u0026gt;60 years), and concurrent pharmacological treatment. Additional outcomes included changes in daytime/nighttime voiding frequency and urgency episodes. German Clinical Trials Registry number: DRKS00030935.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSubgroup analyses showed consistent improvements after 12 weeks in favour of the IG across diagnoses (between-group differences IPSS -6.4 to -7.4), with the largest improvement in severe LUTS (-10.7; 95% CI -12.7;-8.6, p\u0026lt;0.0001). Patients benefited regardless of age or medication use. These findings were further supported by improvements in OAB scores.\u003c/p\u003e\n\u003cp\u003eMicturition diaries showed reduced daytime (-1.33), nighttime (-0.18), and urgency episodes (-1.59). In the IG, 84% of participants used the app several times per week.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe digital therapeutic achieved clinically meaningful symptom and quality-of-life improvements across all subgroups. Additional reductions in voiding frequency and high adherence support its broad applicability in clinical practice.\u003c/p\u003e","manuscriptTitle":"Evaluating Differential Impact of Digital Therapy for Male LUTS: Insights from the BEST Trial Subgroup Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-23 06:15:23","doi":"10.21203/rs.3.rs-7074786/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-05T10:44:43+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-02T14:34:45+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-01T13:13:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-25T13:13:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"296447982641384037653511476827184926059","date":"2025-07-19T07:36:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"158508813626221368285680153287104230649","date":"2025-07-17T05:18:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"115045585782523992934416982132505385952","date":"2025-07-17T03:26:54+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-16T13:29:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-12T18:17:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-12T12:34:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"World Journal of Urology","date":"2025-07-08T12:10:04+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"world-journal-of-urology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjur","sideBox":"Learn more about [World Journal of Urology](https://link.springer.com/journal/345)","snPcode":"345","submissionUrl":"https://submission.nature.com/new-submission/345/3","title":"World Journal of Urology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"404d88d4-5125-42dd-bdbf-669a2e749dc8","owner":[],"postedDate":"July 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-03T16:00:18+00:00","versionOfRecord":{"articleIdentity":"rs-7074786","link":"https://doi.org/10.1007/s00345-025-06016-2","journal":{"identity":"world-journal-of-urology","isVorOnly":false,"title":"World Journal of Urology"},"publishedOn":"2025-11-01 15:57:13","publishedOnDateReadable":"November 1st, 2025"},"versionCreatedAt":"2025-07-23 06:15:23","video":"","vorDoi":"10.1007/s00345-025-06016-2","vorDoiUrl":"https://doi.org/10.1007/s00345-025-06016-2","workflowStages":[]},"version":"v1","identity":"rs-7074786","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7074786","identity":"rs-7074786","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}