Pathway of Low Anterior Resection Syndrome (LARS) Relief After Surgery (POLARiS) Trial Protocol. A prospective, international, open-label, multi-arm, phase 3 randomised superiority trial within a cohort toexplore the natural history of LARS and compare the trans-anal irrigation and sacral neuromodulation to optimised conservative management for people with major LARS.

IntroductionAs a result of improving survival rates, the adverse consequences of rectal cancer surgery are becoming increasingly recognised. Low Anterior Resection Syndrome (LARS) is one such consequence and describes a constellation of bowel symptoms after rectal cancer surgery which includes urgency, faecal incontinence, stool clustering and incomplete evacuation. LARS has a significant adverse impact on Quality-of-Life (QoL) and symptoms are present in up to 75% of patients in the first year after surgery. Despite this, little is known about the natural history and there is poor evidence to support current treatment options. Methods and AnalysisThe objectives of POLARiS are to explore the natural history of LARS and to evaluate the clinical and cost-effectiveness of trans-anal irrigation (TAI) or sacral neural modulation (SNM) compared to optimised conservative management (OCM) for people with major LARS. POLARiS is a prospective, international, open-label, multi-arm, phase 3 randomised superiority trial within a cohort (TWiCs design), with internal pilot phase, qualitative sub-study, process evaluation, and economic evaluation. Approximately 1500 adult participants from UK hospitals and 500 from Australian hospitals who have undergone a high or low anterior resection for colorectal cancer in the last 10 years will be recruited into the cohort. 600 participants from the UK and 200 participants from Australia, with major LARS symptoms, defined as a LARS score of [≥]30, will be recruited to the randomised controlled trial (RCT) element. Participants entering the RCT will be randomised between OCM, TAI or SNM, all with equal allocation ratios. Cohort and RCT participants will be followed up for a 24-month period, completing a series of questionnaires measuring LARS symptoms and QoL, as well as clinical review for those in the RCT. A process evaluation, qualitative sub-study and economic evaluation will also be conducted. The primary outcome measure of the POLARiS cohort and RCT is the LARS score up to 24 months post registration/randomisation. Analyses of the RCT will be conducted on an intention-to-treat basis. Comparative effectiveness analyses for each endpoint will consist of two pairwise treatment comparisons: TAI vs OCM and SNM vs OCM. Secondary outcomes include health-related QoL, adverse events, treatment compliance and cost effectiveness (up to 24 months post registration/randomisation) Ethics and DisseminationEthical approval has been granted by Wales REC 4 (reference: 23/WA/0171) in the UK and Sydney Local Health District HREC (reference: 2023/ETH00749) in Australia. The results of this trial will be disseminated to participants upon request and published on completion of the trial in a peer-reviewed journal and at international conferences Trial Registration NumberISRCTN12834598 Registered 04/08/2023 ACTRN12623001166662 Registered 10/11/2023 Strengths and LimitationsO_LIThe trial is pragmatically designed to optimise and assess recruitment and retainment. C_LIO_LIThis trial includes an economic evaluation of treatment options specific to both the UK and Australia. C_LIO_LILay representatives with personal experience of bowel cancer and LARS have contributed throughout the trial design and ongoing Trial Management Group meetings. C_LIO_LIThere are recognised potential limitations to the LARS score, including limited sensitivity to detect real time change in response to treatment. Additional outcome measures of Quality of Life and a new LARS Patient Reported Outcome Measure (PROM) are being collected to give a more nuanced picture of treatment response. C_LI