Title: Low anterior resection syndrome (LARS) after rectal cancer treatment: a multicentre randomised blinded placebo-controlled parallel group trial investigating the efficacy of ondansetron on symptoms
Funder: Department of Health and Social Care

Abstract: Background: Recent studies have reported that up to 50% of patients treated for rectal cancer develop the low anterior resection syndrome (LARS), that is characterised by the presence of symptoms, including diarrhoea, urgency and faecal incontinence. Current treatments for LARS have been tested in uncontrolled studies and appear to provide little benefit to the patient, suggesting other treatment strategies are urgently required. We have recently demonstrated that ondansetron is effective in treating symptoms of urgency and diarrhoea of patients with irritable bowel syndrome (IBS), which are similar to LARS. Moreover a recent uncontrolled study has suggested that ramosetron, another 5-HT3 antagonist marketed in Asia but not the UK to treat IBS, is effective in treating these symptoms in LARS. Aim The aim of this project is to carry out a multicentre, blinded, randomised, placebo-controlled, parallel group trial, involving five NHS centres in UK (Nottingham, London, Basingstoke, Salisbury, Shrewsbury), to investigate the efficacy of ondansetron in treating symptoms in patients with LARS. The hypothesis of this trial is that ondansetron could be effective for reducing symptoms and number of days of urgency in patients with LARS. Objectives: The primary outcome will be proportion of days with absent or mild urgency over the last 14 days of the treatment period. Secondary outcomes will be evaluation of bowel dysfunction and quality of life by means of questionnaires validated in LARS (LARS score, Memorial Sloan-Kettering Cancer Center Score (MSKCC), The European Organization for Research and Treatment of Cancer (EORTC QLQ-C30) and by the generic EQ-5D-5L as well as of psychological status by internationally recognised questionnaire (the Hospital Anxiety and Depression Scale, HADS). The safety of ondanseteron will also be examined. Plan The trial will run over 36 months. A total of 134 eligible participants will be randomised to receive ondansetron or placebo for 6 weeks. Five NHS secondary care surgical and gastroenterological clinics, will participate as recruiting centres representing different service size normally involved in treating LARS patients. Participants will be required to visit the clinic only once at consent and randomisation and then complete dialy symptom diary cards for the entire duration of the trial (6 weeks). They will be asked to enter the data into a web-based online form and complete the questionnaires online at week 6. Benefit to patients and the NHS The lack of effective treatmenst for LARS symptmoms, particularly urgency and frequency of bowel movements, have a significant negative impact on LARS patients everyday lives. For example patients have described how symptoms are so severe they are unable to leave the bathroom. Ondansetron is a safe and cheap drug that has been demonstrated to be able to control the symptoms of urgency and diarrhoea in patients with symptoms similar to LARS. The demonstration of the efficacy of this medication for patients with LARS is expected to lead to rapid introduction in clinical practice.

Lay abstract: Rectal cancer is one of the most common cancers in the UK. Although survival rate of rectal cancer patients has improved, up to half of all patients report severe distressing problems after the treatment has finished. This includes diarrhoea and problems with bowel control from urge incontinence (little warning that your bowel is going to empty) to complete bowel incontinence (no warning). This range of symptoms is known as &ldquo;Low Anterior Resection Syndrome&rdquo; (LARS) and can significantly affect the quality of life of individuals. Unfortunately, at the moment, there are no effective treatments for LARS. The symptoms of urgency and diarrhoea reported by LARS patients are similar to those reported by patients with Irritable Bowel Syndrome (IBS). In IBS we have recently shown that a cheap, widely available drug, Ondansetron, normally used to treat nausea and vomiting, is effective and safe in treating diarrhoea and urgency. This discovery has resulted in an immediate change in clinical practice and ondansetron is now used to treat IBS in many countries worldwide. This leads us to believe that ondansetron could be effective in LARS. The aim is to carry out a study to find out if ondansetron helps resolve LARS symptoms more than the placebo. We will enrol 134 patients presenting 1 year from completion of all treatments, with LARS symptoms, from five UK centres with a special interest in LARS (Nottingham, London, Basingstoke, Salisbury, Shrewsbury). Half of the participants will receive the ondansetron and the other half will receive the placebo. The placebo will be a tablet matched to look exactly the same as the ondansetron but will have no active ingredient. The treatment a patient gets will be selected at random through a computer program and neither the researchers nor the patients will know what tablets they are getting. During the study we will ask patients about urgency, frequency of bowel movements, quality of life, study and what other medications they have been taking for their symptoms. We have received feedback on the study design from our PPI co-applicant and a focus group of LARS patients led by this co-applicant. If we can show ondansetron is effective for LARS patients there will be few barriers to widespread adoption with a substantial improvement in patients quality of life as has happened for ondansetron in the treatment of IBS with diarrhoea.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL