Ondansetron for Low Anterior Resection Syndrome after rectal cancer treatment
| ISRCTN | ISRCTN48772765 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN48772765 |
| EudraCT/CTIS number | 2020-004560-25 |
| IRAS number | 264493 |
| Secondary identifying numbers | CPMS 44460, IRAS 264493 |
- Submission date
- 25/02/2021
- Registration date
- 10/06/2021
- Last edited
- 14/05/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Digestive System
Plain English Summary
Background and study aims
Rectal cancer is one of the most common cancers in the UK, and although chemo-radiotherapy and surgery are effective treatments, up to half of all patients report severe distressing problems after their treatment has finished. These include diarrhoea and problems with bowel control, ranging from needing to rush to the toilet (urgency), to complete bowel incontinence. This range of symptoms is known as “Low Anterior Resection Syndrome” (LARS) and can significantly affect quality of life. 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 in Irritable Bowel Syndrome (IBS). In IBS it has been shown that a cheap, widely available drug, called ondansetron. Ondansetron is normally used to treat nausea and vomiting and is effective and safe in treating diarrhoea and urgency.
The aim of this study is to find out if ondansetron helps resolve LARS symptoms.
Who can participate?
Adult patients with LARS symptoms in from hospitals in England, at least 1 year after completion of all treatments for their rectal cancer
What does the study involve?
To find out whether they are suitable to take part in the study, participants will first need to record details of symptoms and any medication taken for 2 weeks in a screening diary. Information in the screening diary will be reviewed by the research team who will confirm to the participant if they are eligible to take part.
Eligible participants will be allocated to one of two groups, with an equal chance of being in either group (like tossing a coin), so that half of the participants will receive ondansetron capsules and the other half will receive a placebo (this will look exactly the same as ondansetron but with no active ingredient). Neither the researchers nor the participants will know which capsules they are getting.
Participants will take ondansetron or placebo orally for 6 weeks, and complete a daily diary to record details on urgency, frequency, and consistency of their bowel movements, and any medications they have taken. Participants will also complete questionnaires about their bowel symptoms and quality of life, at the beginning and end of the trial.
What are the possible benefits and risks of participating?
Taking part in the study may not directly benefit participants, but information from the study will help to improve the treatment of people that suffer from the symptoms of LARS in the future.
Ondansetron has been widely used for over 25 years to treat nausea. As with all medications, there is a small risk of side effects. At the doses used in the study, the main side effect is expected to be constipation. Other common side effects include feeling hot and/or headaches. Uncommon side effects include arrhythmias (irregular heartbeat), chest pain, hiccups, low blood pressure, movement disorders, oculogyric crisis (upward rolling of the eyes), and seizure. Rare side effects include dizziness, QT interval prolongation (a problem with the heart’s electrical activity), and vision disorders.
Where is the study run from?
Nottingham University Hospitals NHS Trust (UK). Participants will be recruited from at least 6 secondary care centres in the UK.
When is the study starting and how long is it expected to run for?
From July 2021 to January 2026
Who is funding the study?
The National Institute for Health Research (UK)
Who is the main contact?
researchsponsor@nuh.nhs.uk
Contact information
Public
Nottingham University Hospitals NHS Trust
Queen’s Medical Centre
Nottingham Health Science Partners
C Floor, South Block
Derby Road
Nottingham
NG7 2UH
United Kingdom
| Phone | +44 (0)115 823 1589 |
|---|---|
| researchsponsor@nuh.nhs.uk |
Scientific
Nottingham Digestive Diseases BRC
University of Nottingham
Queen's Medical Centre
Nottingham
NG7 2UH
United Kingdom
| Phone | +44 (0)115 9249924 |
|---|---|
| maura.corsetti@nottingham.ac.uk |
Study information
| Study design | Multicentre blinded randomized placebo-controlled parallel-group trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | Ondansetron for low Anterior Resection Syndrome (OARS) after rectal cancer treatment: a multicentre randomised blinded placebo-controlled parallel-group trial investigating the efficacy of ondansetron on symptoms |
| Study acronym | OARS |
| Study hypothesis | The aim of this trial is to determine if ondansetron is tolerable and effective in reducing symptoms and improving quality of life in patients with low anterior resection syndrome (LARS). |
| Ethics approval(s) | Approved 27/01/2021, North East - Newcastle & North Tyneside 2 Research Ethics Committee (NHS BT Blood Donor Centre, Holland Drive, Newcastle upon Tyne, Tyne and Wear, NE2 4NQ; +44 (0)207 1048091; newcastlenorthtyneside2.rec@hra.nhs.uk), ref: 21/NE/0015 |
| Condition | Low anterior resection syndrome following 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 the participant as required. At the end of the 6 week treatment period participants will be sent study questionnaires to complete and return in the post. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | ondansetron |
| Primary outcome measure | 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 measures | 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 |
| Overall study start date | 01/02/2020 |
| Overall study end date | 01/01/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 134; UK Sample Size: 134 |
| Participant 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 treatment 7. For participants of childbearing potential, or their partners, agreement to use medically accepted contraception (e.g. oral contraceptive and condom, Intra-uterine device (IUD) and condom, or diaphragm with spermicide and condom) for the duration of study treatment and for at least 30 days afterwards for women, and 90 days afterwards for men. 8. Able to read and understand questionnaires in English 9. Written informed consent provided |
| Participant exclusion criteria | 1. Clinical and radiological anastomotic leakage after rectal cancer surgery, defined as a defect of the intestinal wall at the anastomotic site (including suture and staple lines of neorectal reservoirs) leading to a communication between the intra- and extraluminal compartments 2. Gastrectomy 3. Other known organic GI diseases (e.g. Crohn’s disease, ulcerative colitis, coeliac disease) 4. Untreated thyroid dysfunction 5. Taking other medications influencing colonic motility (e.g. opioids, cholinergic agents, prokinetics, metoclopramide, cisapride, etc.) which are likely to be stopped or changed during the course of the trial 6. Lactose intolerance 7. Known QTc interval ≥450 ms for men and ≥470 ms for women 8. Continuous use of ondansetron for >1 month within the past year 9. Contraindications to ondansetron (e.g. concomitant use with apomorphine, hypersensitivity to any component of the preparation, rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption) 10. Currently participating in any interventional phase of another clinical trial 11. Pregnant or breastfeeding |
| Recruitment start date | 01/08/2024 |
| Recruitment end date | 31/03/2025 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
Watford Road
Harrow
HA1 3UJ
United Kingdom
Odstock Road
Salisbury
SP2 8BJ
United Kingdom
Shrewsbury
SY3 8XQ
United Kingdom
Basingstoke
RG24 9NA
United Kingdom
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom
Queens Medical Centre
Derby Road
Nottingham
NG7 2UH
United Kingdom
Sponsor information
Hospital/treatment centre
Research and Innovation
Queen's Medical Centre
C Floor, South block
Nottingham
NG7 2UH
England
United Kingdom
| Phone | +44 (0)115 9709049 |
|---|---|
| researchsponsor@nuh.nhs.uk | |
| Website | http://www.nuh.nhs.uk/ |
"ROR" |
https://ror.org/05y3qh794 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/10/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | The dissemination of the proposed research findings will be via a NIHR report, research papers for publication in peer reviewed journals, presentation at medical conferences and communication to groups involved in guideline development. Results of this trial will be submitted for publication in a peer reviewed journal. |
| IPD sharing plan | The datasets analysed during the current study will be available upon request from the NCTU (ctu@nottingham.ac.uk), a minimum of 6 months after publication of the main results paper. Access to the data will be subject to review of a data sharing and use request by a committee including the CI and sponsor, and will only be granted upon receipt of a data sharing and use agreement. Any data shared will be pseudoanonymised which may impact on the reproducibility of published analyses. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
14/05/2024: The following changes were made to the study record:
1. The recruitment start date was changed from 01/01/2023 to 01/08/2024.
2. The recruitment end date was changed from 31/05/2024 to 31/03/2025.
3. Study contact details updated.
04/08/2022: The following changes have been made:
1. The recruitment end date has been changed from 01/01/2026 to 31/05/2024.
2. The intention to publish date has been changed from 31/01/2024 to 01/10/2026.
19/07/2022: The following changes have been made:
1. The recruitment start date has been changed from 01/07/2022 to 01/01/2023.
2. The recruitment end date has been changed from 31/12/2022 to 01/01/2026.
3. The overall trial end date has been changed from 31/03/2023 to 01/01/2026 and the plain English summary has been updated accordingly.
15/07/2022: The study contact has been updated and the plain English summary has been updated accordingly.
23/02/2022: The recruitment start date has been changed from 01/03/2022 to 01/07/2022.
06/10/2021: The recruitment start date has been changed from 01/10/2021 to 01/03/2022.
08/07/2021: The recruitment start date has been changed from 31/07/2021 to 01/10/2021.
24/02/2021: Trial’s existence confirmed by the National Institute for Health Research (NIHR).
