Condition category
Digestive System
Date applied
13/01/2020
Date assigned
13/02/2020
Last edited
13/02/2020
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
Ulcerative colitis (UC) is a long-term condition where the colon and rectum become inflamed. The colon is the large intestine (bowel) and the rectum is the end of the bowel where stools are stored. Small ulcers can develop on the colon's lining, and can bleed and produce pus. About 1 in 5 people with UC report ongoing diarrhoea, even when there is no sign of bowel inflammation. This also causes discomfort and distress, reducing peoples’ quality of life, and impacting on their psychological health and mood.
This is a similar situation to people living with irritable bowel syndrome (IBS), who often experience troublesome diarrhoea. In IBS, a low diet low in poorly absorbed sugars (FODMAPs) improves diarrhoea, because some FODMAPs increase small intestinal water content. Drugs like ondansetron (an antisickness drug), amitriptyline (an antidepressant drug), or loperamide (an antidiarrhoeal drug) can also be effective in IBS with diarrhoea. This is because they change bowel activity, and can relieve tummy pain. These treatments may therefore help people with stable UC.

Who can participate?
People aged over 18 years with stable UC who have diarrhoea.

What does the study involve?
All participants will be provided with standard first-line dietary advice. People will also be given one of the following: a low FODMAP diet; ondansetron; amitriptyline; loperamide; or no additional treatment.
A computer will randomly decide who gets which one. People will be asked to follow the diet or take the tablets for 6 months, in addition to their doctor’s usual treatment for UC. People will be aware of which treatment they get.
People will be followed up at 8 weeks and 6 months. Side effects and adherence to each treatment will be recorded as well as how many flare-ups people experience, whether usual treatment for UC has been changed, and whether surgery has been required.

What are the possible benefits and risks of participating?
Benefits- improvement in symptoms and quality of life for patients with stable UC and ongoing diarrhoea, fewer secondary care hospital visits, should help clinicians, patients and health service planners to make better-informed decisions regarding the management of diarrhoea in patients with stable UC in secondary care.
Risks- side effects associated with the drugs (although thought to be at a reduced rate due to the lower dose used).

Where is the study run from?
Leeds Institute of Medical Research at St James’s Univerity Hospital and 26 UK hospitals.

When is the study starting and how long is it expected to run for?
March 2020 to April 2023

Who is funding the study?
National Institute for Health Research (NIHR), UK

Who is the main contact?
Amy West (public)
modulate@leeds.ac.uk
Prof. Alexander Ford (scientific)
a.c.ford@leeds.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Prof Alexander Ford

ORCID ID

http://orcid.org/0000-0001-6371-4359

Contact details

Leeds Institute of Medical Research at St James’s
Room 7.09 Worsley Building
Leeds
LS2 9JT
United Kingdom
+44 (0)113 343 4802
a.c.ford@leeds.ac.uk

Additional identifiers

EudraCT number

2019-003220-21

ClinicalTrials.gov number

Nil known

Protocol/serial number

CPMS 43987, IRAS 266428

Study information

Scientific title

Management of diarrhoea in ulcerative colitis: multi-arm multi-stage trial of low FODMAP diet, amitriptyline, ondansetron, or loperamide: MODULATE

Acronym

MODULATE

Study hypothesis

The use of at least one of a low FODMAP diet, amitriptyline, ondansetron, or loperamide in this group of people with UC will lead to improvements in both symptoms and quality of life, and less utilisation of secondary care health services by people with UC.

Ethics approval

Approval pending, Yorkshire and Humber- Leeds West REC (NHSBT Newcastle Blood Donor Centre, Holland Drive, Newcastle upon Tyne, NE2 4NQ, UK; +44 (0)207 104 8018; nrescommittee.yorkandhumber-leedswest@nhs.net), ref: 20/YH/0007

Study design

Interventional randomized controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Home

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Ulcerative colitis

Intervention

The MODULATE study incorporates 5 arms, 4 interventional and 1 control. At least 2/4 interventional arms will be dropped when transitioning from a phase 2 trial to a phase 3 trial.
- The control arm consists of standard first-line dietary advice given to all patients with Irritable Bowel Syndrome (IBS).
- The first interventional arm is Amitriptyline, a tricyclic antidepressant, which at low doses is thought to slow colonic transit.
- The second interventional arm is Loperamide, an antidiarrhoeal drug also thought to slow colonic transit.
- The third interventional arm is Ondansetron, an anti-emetic thought to slow colonic transit.
- The fourth interventional arm is the Low FODMAP diet; a diet low in fermentable oligo-, di-, and mono-saccharides and polyols (FODMAPs) thought to reduce bloating and painful gas within the small intestine.

For all patients randomised to an interventional arm, they will receive treatment for 6 months. All patients in the study will be asked to complete a set of questionnaires at baseline, 8 weeks and 6 months, and will visit their secondary care site at baseline and 6 months for additional investigations (following previous eligibility assessments). All participants randomised to an IMP arm will receive additional phone calls within the 6 months to collect toxicity data and for advice on dose titration. Follow-up will be completed at 6 months for all participants.

Randomisation will be performed by the University of Leeds CTRU (Clinical Trials Research Unit)’s 24-hour registration and randomisation system. Randomisation will be via minimisation at the level of the individual, stratified according to centre, degree of discomfort from diarrhoea, the extent of UC and Hospital Anxiety and Depression Scale (HADS)-Depression score.

Intervention type

Other

Phase

Drug names

Primary outcome measure

Phase 2. Improvement in diarrhoea measured using the GSRS-IBS questionnaire at 8 weeks post-randomisation: improvement defined as those reporting minor discomfort from diarrhoea or less (scoring ≤2 on the diarrhoea subscale)
Phase 3. Disease-specific quality of life measured using the Inflammatory Bowel Disease Questionnaire overall score at 6 months post-randomisation (measuring bowel symptoms, systemic symptoms, emotional, and social factors)

Secondary outcome measures

Phase 2 and 3. Measured at both 8 weeks and 6 months:
1. Improvement in diarrhoea measured using the GSRS-IBS
2. Blood for CRP, stool for FC at 6 months only, reviewing case notes for escalation of medical therapy for UC
3. Anxiety and depression will be measured by the HADS

Overall trial start date

01/04/2018

Overall trial end date

01/04/2023

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. A histological diagnosis of UC in secondary care, including left-sided colitis or extensive colitis
2. Age > = 18 years
3. At least moderate discomfort from diarrhoea according to the GSRS-IBS [26] (equating to a score of > = 4 on the diarrhoea subscale of the GSRS-IBS)
4. On stable doses of UC-related medication for > = 2 months at time of initial screening telephone call
5. Ongoing diarrhoea for 3 months prior to initial screening telephone call
6. A CRP < = 5mg/L (measured as per local practise) within 4 weeks prior to randomisation
7. FC < 250mcg/g [29] within 4 weeks prior to randomisation
8. Mayo score of < = 1 at flexible sigmoidoscopy within the past 3 months prior to initial screening telephone call
9. No evidence of active suicidal ideation at time of initial screening telephone call and prior to randomisation, as determined by the three clinical screening questions:
9.1. Whether the patient has experienced any thoughts of harming themselves, or ending their life in the last 7-10 days?
9.2. Whether the patient currently has any thoughts of harming themselves or ending their life?
9.3. Whether the patient has any active plans or ideas about harming themselves, or taking their life, in the near future?
10. No recent history of self-reported self-harm (an episode of self-harm within the last 12 months)
11. Willing to be considered for all treatment arms of the trial, and to remain in the treatment arm to which they are assigned
12. If female must be:
12.1. Post-menopausal (no menses for 12 months without an alternative medical cause), or;
12.2. Surgically sterile (hysterectomy, bilateral salpingectomy or bilateral oophorectomy), or;
12.3. Using highly effective contraception (and must agree to continue for 7 days after the last dose of the investigational medicinal product [IMP])
13. Able to complete questionnaires and trial assessments
14. Able to provide written informed consent

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 491; UK Sample Size: 491

Participant exclusion criteria

1. Inflammatory bowel disease unclassifiable or Crohn’s disease
2. Ulcerative proctitis
3. Previous or planned gastrointestinal IBD-related resectional surgery or previous cholecystectomy
4. Having received steroids for UC within the last 2 months prior to the initial screening telephone call
5. Coeliac disease (as confirmed via anti-tissue transglutaminase (tTG) antibodies)
6. A previous diagnosis of colorectal dysplasia or cancer, or no up to date surveillance colonoscopy, as per current British Society of Gastroenterology guidelines
7. Known allergy to TCAs, ondansetron, or loperamide.
8. Current use of a TCA at time of initial screening telephone call.
9. Previous failed treatment with regular use of amitriptyline, ondansetron, or loperamide for diarrhoea.
10. Currently on, or have previously tried and failed, a low FODMAP diet under dietitian guidance.3
11. Contraindications4 to the current use of TCAs including patients with any of the following:
11.1. Taking monoamine oxidase inhibitors, or receiving them within the last 2 weeks;
11.2. Already currently prescribed a TCA for the treatment of depression
11.3 Previous myocardial infarction;
11.4. Recorded arrhythmias, particularly heart block of any degree, or prolonged Q-T interval on electrocardiogram;
11.5. Mania;
11.6. Severe liver disease;
11.7. Porphyria;
11.8. Congestive heart failure;
11.9. Coronary artery insufficiency;
11.10 Receiving concomitant drugs that prolong the QT interval (e.g. amiodarone, terfenadine, or sotalol)
12. Contraindications to the current use of ondansetron, including:
12.1. Concomitant use of apomorphine;
12.2. Concomitant use of other drugs that prolong the QT interval.
13. Contraindications to the current use of loperamide, including:
13.1. Acute UC;
13.2. Acute dysentery, which is characterised by blood in stools and high fever;
13.3. Bacterial enterocolitis caused by invasive organisms;
13.4. Pseudomembranous colitis associated with the use of broad-spectrum antibiotics
14. Pregnancy, planned pregnancy within 3 months of study completion, or breastfeeding

Recruitment start date

01/03/2020

Recruitment end date

01/04/2022

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Royal Devon and Exeter Hospital
Royal Devon and Exeter NHS Hospital Foundation Trust Barrack Road
Exeter
EX2 5DW
United Kingdom

Trial participating centre

Royal Wolverhampton Hospitals NHS Trust
Wednesfield Road
Wolverhampton
WV10 0QP
United Kingdom

Trial participating centre

Royal Liverpool Hospital
Royal Liverpool & Broadgreen University Hospitals NHS Trust Prescot Street
Liverpool
L7 8XP
United Kingdom

Trial participating centre

St George's University NHS Foundation Trust
Blackshaw Road
London
SW1 0QT
United Kingdom

Trial participating centre

Torbay Hospital
Torbay and South Devon NHS Foundation Trust Lowes Bridge
Torquay
TQ2 7AA
United Kingdom

Trial participating centre

Cheltenham General Hospital
Gloucestershire Hospitals NHS Foundation Trust Sandford Road
Cheltenham
GL53 7DR
United Kingdom

Trial participating centre

Salford Royal Hospital
Salford Royal NHS Foundation Trust Stott Lane
Salford
M6 8HD
United Kingdom

Trial participating centre

Croydon University Hospital
Croydon Health Services NHS Trust 530 London Road Thronton Heath
Croydon
CR7 7YE
United Kingdom

Trial participating centre

Epsom and St Helier NHS Trust
Dorking Road
Epsom
KT18 7EG
United Kingdom

Trial participating centre

St James's University Hospital (lead centre)
Leeds Teaching Hospitals Trust Beckett Street
Leeds
LS9 7TF
United Kingdom

Sponsor information

Organisation

University of Leeds

Sponsor details

Woodhouse Lane
Leeds
LS2 9JT
United Kingdom
-
a@b.c

Sponsor type

University/education

Website

http://www.leeds.ac.uk/

Funders

Funder type

Government

Funder name

NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC); Grant Codes: 17/33/03

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

National Institute for Health Research (NIHR) (UK)

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

With regards to updating the general public with our trial progress and results we will publicise our trial via Crohn’s and Colitis UK, by offering to contribute to their newsletter and website and we plan to make plain English summaries and podcasts available online for relevant patient groups, as well as trial participants. For other outlets, we will discuss our emerging findings with the NIHR Dissemination Centre to work out key messages for specific public, professional and policy audiences.

Results will be presented at national and international gastroenterology and dietetic meetings. As well as being published in the publically available HTA journal, we expect that the findings will be published as an article, or articles, in high-impact, high-quality multi-disciplinary journals (e.g New England Journal of Medicine, Lancet, or British Medical Journal). We have included estimates for open-access article processing charges within the direct costs of our application.

Intention to publish date

01/04/2024

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

13/01/2020: Trial’s existence confirmed by National Institute for Health Research (NIHR)