The Calm Bladder Study-A Phase 3 multicenter randomized controlled trial to evaluate acupuncture for the management of urinary symptoms in patients with NMIBC undergoing induction intravesical therapy - ABSTRACT Non–muscle-invasive bladder cancer (NMIBC) affects over 500,000 individuals in the United States each year, with guidelines recommending adjuvant intravesical immunotherapy or chemotherapy to reduce recurrence and progression. However, both NMIBC and its treatments commonly result in debilitating urinary frequency, urgency, bladder pain, fatigue, and reduced health-related quality of life (HRQOL). Despite the prevalence and impact of these toxicities, effective supportive care interventions are lacking. Acupuncture, a safe non- pharmacologic therapy, has demonstrated efficacy in improving irritative voiding symptoms and bladder pain in overactive bladder and bladder pain syndromes. In oncology, acupuncture has shown consistent benefit in reducing pain, nausea, and fatigue, thereby enhancing overall HRQOL. We previously conducted a pilot study demonstrating that weekly in-clinic acupuncture prior to intravesical therapy in patients with high-risk NMIBC is both safe and feasible with high patient satisfaction, and significant improvements in urinary symptoms on exploratory analyses. We now propose the Calm Bladder Trial: a multi-center, phase III randomized controlled trial comparing weekly in-clinic preprocedure true acupuncture, sham acupuncture, and attention waitlist control (AWC) during 6 weeks of induction intravesical therapy. Eligible patients (≥18 years) with intermediate- or high- risk NMIBC undergoing guideline-recommended 6-week intravesical treatment will be enrolled from three high- volume academic centers. The Primary Aim will assess change in urinary symptom burden using the EORTC- QLQ-NMIBC24 subscale from baseline to weeks 3, 6, and 12. Secondary Aims will compare the effectiveness of true acupuncture compared with sham acupuncture and AWC on other patient-reported outcomes including 1) cancer-specific HRQOL and 2) general HRQOL including fatigue, pain, physical, functional, social/family, and emotional well-being at 3-, 6-, and 12-weeks, 4) patient-reported treatment burden, 3) health care and other symptom-management therapy utilization, and 4) treatment delays and early discontinuation of therapy. We will report the safety and tolerability of the intervention using CTCAE v5.0 and PRO-CTCAE. Exploratory Aims will assess predictors of response (e.g., symptom burden, treatment expectancy, baseline global function [CARE- GA]) and biologic correlates, including urine inflammation markers and machine-learning analysis of cystoscopic aimages. This trial will determine whether true acupuncture improves urinary symptoms and treatment tolerability during NMIBC therapy and will provide novel insights into mechanisms and predictors of response to acupuncture in bladder cancer care. Demonstrating clinical benefit will inform integrative oncology practice and survivorship care guidelines and will provide evidence to support reimbursement and policy decisions aimed at expanding access to acupuncture in cancer care. This work directly aligns with NIH priorities to reduce symptom burden, enhance HRQOL, and promote equitable access to effective supportive care interventions.
