Ondansetron for Low Anterior Resection Syndrome after rectal cancer treatment

INTERVENTION: Eligible patients will be randomised (at a ratio of 1:1) to receive either ondansetron or matching placebo; the dose of ondansetron will be between 4‐24 mg daily for 6 weeks. Dose titration will be undertaken in the first two weeks of the study to optimise the dose and avoid constipation. Treatment will be assigned using a secure, online computerised programme created and maintained by the Nottingham Clinical Trials Unit. Treatment will be assigned using a minimisation algorithm balancing on the following factors: recruiting site; LARS score at baseline (minor 21‐29, major =30); and loperamide use over the 14 day baseline period (0 days, 1‐6 days, =7 days). The treatment period is 6 weeks and participants will be asked to complete a daily diary (online or paper option will be offered) which will collect important outcome data including stool frequency, consistency and urgency, and the number of study medication capsules taken. Participants will begin their study treatment by taking a single capsule of study medication per day. Participants will be required to adjust the number of capsules of study medication they are taking every day from day 3 onwards, until they find the daily dose that best controls their symptoms. Participants will be given clear instructions on the process of titrating the dose of their study medication to control their symptoms and will be provided with contact information for their local site research team in case they have any questions or experience any problems. In addition, the research nurse or doctor will telephone the participant after 1 week and again after 2 weeks of taking the study medication to ensure that they are titrating the dose correctly and answer any questions/offer advice to CONDITION: Low anterior resection syndrome following rectal cancer treatment ; Digestive System ; Postprocedural complications and disorders of the digestive system PRIMARY OUTCOME: The proportion of days with no or mild urgency over the last 14 days of the planned 6 week treatment period measured using participant report in a daily diary between baseline and 6 weeks. Participants will record whether or not they had a bowel movement with urgency that day (yes or no), and those who responded yes will score their most urgent bowel movement that day as one of the following: mild (time able to delay bowel movement =10 mins), moderate (time able to delay bowel movement =5 to <10 mins), severe (time able to delay bowel movement =1 to <5 mins), or very severe (time able to delay bowel movement <1 min). SECONDARY OUTCOME: ; 1. Bowel dysfunction following a low anterior resection measured using the Low Anterior Resection Syndrome (LARS) questionnaire at 6 weeks; 2. Bowel dysfunction score measured using the Memorial Sloan‐Kettering Cancer Center (MSKCC) questionnaire at 6 weeks; 3. Quality of life measured using the European Organization for Research and Treatment of Cancer QLQ‐C30 (EORTC QLQ‐C30) questionnaire and the EuroQol 5‐dimension 5‐level (EQ‐5D‐5L) questionnaire at 6 weeks; 4. Psychological status measured using the Hospital Anxiety and Depression Scale (HADS) at 6 weeks; 5. Anxiety measured using the anxiety subscale of the HADS at 6 weeks; 6. Depression measured using the depression subscale of the HADS at 6 weeks; 7. Percentage of participants with =30% improvement from baseline in the percentage of days with urgency for =50% of the days of the planned 6 week treatment period (“Urgency responders”) measured using participant report of urgency in a daily diary between baseline and 6 weeks. Participants will record whether or not they had a bowel movement with urgency that day (yes or no), and those who responded yes will score their most urgent bowel movement that day as one of the following: mild (time able to delay bowel movement =10 mins), moderate (time able to delay bowel movement =5 to <10 mins), severe (time able to delay bowel movement =1 to <5 mins), or very severe (time able to delay bowel movement <1 min).; 8. Percentage of participants with =50% improvement from baseline in the percentage of days with any stool consistency of 6 or 7 on the Bristol Stool Form Scale (BSFS) for more than 50% of the days of the planned 6 week treatment period (“Stool consistency responders”) measured using participant report using the BSFS in a daily diary between baseline and 6 weeks.; 9. Number of stools per day over the last 14 days of the planned 6 week treatment period measured using participant report of stool frequency in a daily diary between baseline and 6 weeks; 10. Number of episodes of urgency per day over the last 14 days of the planned 6 week treatment period measured using participant report of urgency in a daily diary between baseline and 6 weeks; 11. Proportion of participants taking study medication as required at the end of each week of the planned 6 week treatment period measured using participant report of the number of study medication capsules taken in a daily diary between baseline and 6 weeks and telephone conversation at 1 and 2 weeks; 12. Proportion of days when study medication is taken during the planned 6 week treatment period measured using participant report of the number of study medication capsules taken in a daily diary between baseline and 6 weeks; 13. The number of capsules of study medication taken daily during the planned 6 week treatment period measured using participant report of the number of study medication capsules taken in a daily diary between baseline and 6 weeks; 14. Proportion of days when loperamide is taken during the planned 6 week treatment period measured using participant report of loperamide taken in a daily diary between baseline and 6 weeks; 15. The dose of loperamide taken daily during the planned 6 week treatment period measured using participant report of loperamide taken in a daily diary between baseline and 6 weeks; 16. Proportion of participants who report at the end of the 6 week treatment period that their LARS symptoms have improved from the start of the trial measured using the Low Anterior Resection Syndrome (LARS) questionnaire at baseline and 6 weeks; 17. Frequency and severity of constipation experienced during the 6 week treatment period measured using participant report of constipation in a daily diary between baseline and 6 weeks; 18. Frequency and type of new symptoms/health problems experienced during the 6 week treatment period measured using participant records at 6 weeks; 19. Frequency of worsening of existing symptoms/health problems experienced during the 6 week treatment period measured using participant records at 6 weeks; 20. Serious adverse events (including unplanned hospital admissions) during the 6 week treatment period measured using participant records at 6 weeks; INCLUSION CRITERIA: 1. Aged =18 years 2. Previously undergone standard total mesorectal excision (TME) resection with, or without, neoadjuvant chemoradiotherapy (CRT) for pT0‐4, N0‐2, M0 rectal cancer 3. =1 year after the end of any chemoradiotherapy and surgical treatment (ileostomy closure or primary resection if a stoma was not performed) 4. No evidence of rectal cancer recurrence 5. LARS questionnaire symptom score of =21 (minor or major LARS) 6. LARS symptoms to include both of the following: 6.1. Presence of =4 bowel movements per day on average during the 14 days prior to the baseline visit 6.2. Moderate, severe or very severe faecal urgency (unable to delay bowel movements by 10 min or more) on =4 days during the 14 days prior to the baseline visit 7. LARS symptoms not adequately controlled by current treatme