Condition category
Digestive System
Date applied
14/11/2017
Date assigned
15/11/2017
Last edited
17/10/2018
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Irritable Bowel Syndrome (IBS) is a common condition with symptoms causing around 1 in 10 people to seek help from their GP at some point in their lives. It is a combination of abdominal discomfort or pain and altered bowel habits. Depending on the stool consistency, IBS can be classified as IBS with diarrhoea (IBS-D), IBS with constipation (IBS-C), or mixed IBS (IBS-M). IBS is often a chronic condition that can significantly impair quality of life and cause absence from work and school. The emergence of new drugs for IBS has been slow and there is a need for new treatment alternatives, including drug-free treatments, which are easy to use and can safely be used in different types of patients, including in children and pregnant women. Currently available drug-free treatments include Enterosgel®, which is an intestinal adsorbent that has been approved for use in patients with IBS-D and is available over-the-counter in the UK. It is an orally consumed gel-like product classified as a medical device, which has been shown to adsorb harmful substances like bacterial toxins in the gut. There have been studies suggesting that Enterosgel® and other intestinal adsorbents can improve diarrhoea, bloating and abdominal pain in patients with IBS-D. However, larger studies are needed to further investigate the potential benefits of Enterosgel® in the treatment of IBS-D. This study aims to recruit 430 participants with IBS-D. The goal is to investigate whether Enterosgel® can improve IBS-D symptoms, including diarrhoea and abdominal pain. In addition, the study aims to investigate the impact of this treatment on the quality of life, work productivity and activity and general health. The safety and tolerability of Enterosgel® in this condition will also be evaluated.

Who can participate?
Adults aged 18-75 who have been diagnosed with IBS-D and have diarrhoea symptoms

What does the study involve?
The study involves in total four visits and one follow-up call over 26 weeks. At each visit and at given time points between the visits, the participants complete questionnaires asking about their IBS symptoms, quality of life, work productivity and activity and general health. In addition, the participants are asked to complete a study diary throughout the study to record their symptoms and treatment use. The diary is available as an electronic and paper diary. The diary should be completed daily for the first 18 weeks. At the first visit (week 0), potential participants are provided with the study diary to record their diarrhoea and abdominal symptoms for 2 weeks. Those who had sufficientsymptoms over this period are eligible to take part in the study and are randomly allocated to one of two treatment groups at the second visit (week 2). The first group receive dummy treatment and the second group receive Enterosgel® for 8 weeks. Neither the participants nor the research team know which treatment the participant receives. After 8 weeks, the participants attend the third visit (week 10) and all participants are given Enterosgel® for the next 8 weeks. This time, the participants are informed about the treatment they receive. After 8 weeks of treatment with Enterosgel®, the participants attend the fourth study visit (week 18) and return to standard-of-care. A final follow-up call takes place 8 weeks later (week 26).

What are the possible benefits and risks of participating?
To allow all patients to try Enterosgel®, this study includes an 8-week period where all participants receive it. Some participants may find that Enterosgel® helps with their IBS symptoms while others might not experience any benefit. The aim of this study is to evaluate what proportion of participants can benefit from this treatment, and what the benefits are. In the future, this information can be helpful to the patients and healthcare professionals when they are considering different treatment alternatives. Enterosgel® has been available in some countries for 30 years and is commonly used as a treatment for gastrointestinal conditions, including acute diarrhoea and IBS-D. According to the manufacturer, possible known side effects are nausea and constipation. Enterosgel® is completely excreted from the gut and does not get absorbed into the blood circulation.

Where is the study run from?
This study will be conducted at about 30 medical practices, secondary care centres and private clinics in the UK. In addition to the participating research sites, the study is advertised through local pharmacies and through an IBS research register called ContactME-IBS (https://www.contactme-ibs.co.uk)

When is the study starting and how long is it expected to run for?
March 2017 to July 2020

Who is funding the study?
Bioline Products s.r.o

Who is the main contact?
Dr Carol Howell

Trial website

Contact information

Type

Scientific

Primary contact

Dr Carol Howell

ORCID ID

Contact details

Enteromed Ltd
85 Great Portland Street
London
W1W 7LT
United Kingdom

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

ENT04UK

Study information

Scientific title

Randomised, double-blind, placebo controlled multi-centre study to assess the efficacy, tolerability and safety of Enterosgel® in the treatment of Irritable Bowel Syndrome with Diarrhoea (IBS-D) in adults (RELIEVE IBS-D)

Acronym

RELIEVE IBS-D

Study hypothesis

The hypothesis is that Enterosgel® is superior compared with placebo in terms of patient reported outcomes for stool consistency and abdominal pain, in patients with IBS-D.

Ethics approval

North East - Tyne & Wear South Research Ethics Committee, 19/02/2018, REC ref: 18/NE/0023

Study design

Randomised double-blind placebo-controlled multi-centre trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Condition

Irritable Bowel Syndrome with diarrhoea (IBS-D)

Intervention

Using a centralised computer-based randomisation tool, patients will be randomised 1:1 to receive intestinal adsorbent Enterosgel® or placebo. The patients will receive blinded study treatment for 8 weeks according to study-specific dosage instructions, which allow adjusting the dosage based on IBS symptoms. The treatment is provided in 90g tubes, each containing a single treatment dose. The Enterosgel® tubes contain 22.5g Enterosgel® pre-diluted in water. The placebo tubes contain water with chalk added to mimic the appearance and consistency of Enterosgel®. Updated 17/10/2018: The control group will receive identical tubes containing placebo.

Treatments are taken orally up to 6 doses per day, depending on the symptoms.

After 8 weeks of blinded treatment, all patients will receive open-label Enterosgel® treatment for 8 weeks to take if they experience diarrhoea.

Following the open-label treatment period, all patients will return to standard-of-care and will be followed up for 8 weeks.

Intervention type

Device

Phase

Drug names

Primary outcome measure

Percentage of patients defined as responders for abdominal pain and stool consistency based on daily study diary data, during at least 4 weeks in the 8-week blinded treatment period, where:
1. An Abdominal Pain Intensity Weekly Responder is defined as a patient who experiences a decrease in the weekly average abdominal pain score of at least 30 percent compared with baseline. The weekly average abdominal pain score is derived by scoring the worst pain experienced each day and taking the average for one week
AND
2. A Stool Consistency Weekly Responder is defined as a patient who experiences a 50 percent or greater reduction in the number of days per week with at least one stool that has a consistency of Bristol Stool Form Scale (BSFS) Type 6 or 7 compared with baseline

Secondary outcome measures

Double-blind treatment phase and open-label treatment phase:
1. Stool frequency based on daily study diary data; mean over 8 weeks and the last 4 weeks of each treatment period
2. Stool consistency assessed as average number of days/week with Bristol Stool Scale type >5 based on daily study diary data and percentage of responders over 8 weeks and the last 4 weeks of each treatment period
3. Abdominal pain based on daily study diary data; mean on a VAS scale from 0 to 10 over 8 weeks and the last 4 weeks, percentage of responders over 8 weeks and the last 4 weeks of each treatment period
4. Bloating based on weekly study diary data; mean weekly score on a numerical scale from 0 to 6 over 8 weeks and the last 4 weeks of each treatment period
5. Urgency based on weekly study diary data; mean weekly score on a numerical scale from 0 to 6 over 8 weeks and the last 4 weeks of each treatment period
6. Percentage of patients reporting adequate relief of global IBS symptoms based on weekly study diary data weekly from baseline until week 8 of each treatment period
7. Irritable Bowel Syndrome Severity Scoring System (IBS-SSS) score weekly from baseline until week 8 of each treatment period
8. Irritable Bowel Syndrome Quality of Life (IBS-QOL) score every 4 weeks from baseline until week 8 of each treatment period
9. Patient Health Questionnaire-12 Somatic Symptom scale (PHQ-12 SS) score to measure severity of somatic symptoms excluding gastrointestinal symptoms every 4 weeks from baseline until week 8 of each treatment period
10. IBS-related Work Productivity and Activity Impairment (WPAI:IBS) score; weekly from baseline until week 8 of each treatment period
11. Use of rescue medication, i.e. loperamide, based on weekly study diary data; number of days over each 8 weeks of treatment
12. Adverse events over each 8 weeks of treatment

Follow-up:
1. Satisfaction with bowel symptoms based on weekly study diary data; mean weekly score on a numerical scale from 0 to 6, over 8 weeks
2. Satisfaction with abdominal pain based on weekly study diary data; mean weekly score on a numerical scale from 0 to 6, over 8 weeks
3. Loperamide use based on weekly study diary data; mean number of days per week over 8 weeks
4. Irritable Bowel Syndrome Severity Scoring System (IBS-SSS) score at baseline and 8 weeks
5. Patient Health Questionnaire-12 Somatic Symptom scale (PHQ-12 SS) score to measure severity of somatic symptoms excluding gastrointestinal symptoms at baseline and 8 weeks
6. Irritable Bowel Syndrome Quality of Life (IBS-QOL) score at baseline and 8 weeks
7. IBS-related Work Productivity and Activity Impairment (WPAI:IBS) score at baseline and 8 weeks
8. Percentage of patients who maintained treatment benefit over 8 weeks after cessation of treatment based on weekly study diary data over 8 weeks

Updated 17/10/2018:
Follow-up:
In patients who reported adequate relief in the last 4 weeks of open-label period:
1. Maintenance of treatment benefit (percentage of patients who report increased or maintained treatment benefit at 8 weeks)
2. Enterosgel® use (percentage of patients who report having used Enterosgel® during the follow-up period; frequency of use in these patients)
3. Loperamide use (percentage of patients who report having used less loperamide during the follow-up period than before the trial)

Overall trial start date

01/03/2017

Overall trial end date

31/07/2020

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 17/10/2018:
1. Written informed consent
2. Irritable Bowel Syndrome with diarrhoea (IBS-D) according to Rome IV criteria
3. Aged 18-75
4. Considered suitable to take part in the study by the consenting doctor/nurse
5. Diary completed on at least 11 of 14 days (≥75%) during the screening period

Previous inclusion criteria:
1. Irritable Bowel Syndrome with diarrhoea (IBS-D) according to Rome IV criteria
2. Negative calprotectin test or adequate exclusion of Inflammatory Bowel Disease (IBD)
3. Aged 18+
4. Considered suitable to take part in the study by the consenting physician

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

430

Participant exclusion criteria

Current exclusion criteria as of 17/10/2018:
1. Loose stools (BSFS 6 or 7) on less than 3 days during the 14 days after Screening Visit
2. Average abdominal pain <3 during the 14 days after Screening Visit (scale 0–10: 0 = no pain; 10 = worst possible pain)
3. IBS-SSS≥400
4. Previously diagnosed coeliac disease
5. Previously diagnosed Inflammatory Bowel Disease
6. Previous bowel cancer or bowel resection
7. Other previously known gastrointestinal disorder contributing to the diarrhoea
8. Unexplained weight loss
9. Unexplained rectal bleeding
10. Previous use of Enterosgel®
11. Use of antidepressant agents, unless used at a stable dose for at least 6 weeks
12. Use of any probiotic supplements, other intestinal adsorbents, slow-release medications or strong opioids
13. Participation in any research where treatment is provided, or was provided in the last three months
14. Pregnancy

Previous exclusion criteria:
1. Loose stools (BSFS 6 or 7) on less than 3 days during the last 14 days before Baseline
2. IBS-SSS≥400
3. Organic gastrointestinal disorder
4. Celiac disease (existing diagnosis)
5. Lactose malabsorption (existing diagnosis)
6. Bile acid malabsorption (existing diagnosis)
7. Bowel cancer
8. Previous use of Enterosgel®
9. Pregnancy
10. Diary completed on at least 11 of 14 days (≥75%) during the screening period

Recruitment start date

15/10/2018

Recruitment end date

01/12/2019

Locations

Countries of recruitment

United Kingdom

Trial participating centre

University Hospital of North Durham
DH1 5TW
United Kingdom

Trial participating centre

Newcastle Upon Tyne Hospitals
NE7 7DN
United Kingdom

Trial participating centre

Bodey Medical Centre
M14 6WP
United Kingdom

Trial participating centre

The Village Practice
FY5 2TZ
United Kingdom

Trial participating centre

Blackpool Victoria Hospital
FY3 8NR
United Kingdom

Trial participating centre

Vauxhall Primary Health Care
L5 8XR
United Kingdom

Trial participating centre

Ashgate Medical Practice
S40 4AA
United Kingdom

Trial participating centre

Newton Place Surgery
ME13 8FH
United Kingdom

Trial participating centre

Pound Hill Medical Group
RH10 7DX
United Kingdom

Trial participating centre

West Walk Surgery
BS37 4AX
United Kingdom

Trial participating centre

Pickering Medical Centre
YO18 8BL
United Kingdom

Trial participating centre

Functional Gut Clinic
W1G 6NB
United Kingdom

Trial participating centre

University Hospital Coventry and Warwickshire
CV2 2DX
United Kingdom

Trial participating centre

Warrington Hospital
WA5 1QG
United Kingdom

Sponsor information

Organisation

Enteromed Ltd

Sponsor details

85 Great Portland Street
London
W1W 7LT
United Kingdom

Sponsor type

Industry

Website

http://enteromed.co.uk

Funders

Funder type

Industry

Funder name

Bioline Products s.r.o

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Study results will be submitted for presentation(s) at gastroenterology conference(s) and for publication in international peer-reviewed scientific journal(s). Results will be disseminated to the patients and the public through the study website. Protocol will be made available immediately following publication with no end date.

IPD sharing statement
After publication, individual anonymised participant data that underlie the results reported in the publication will be available to researchers upon request from Dr Carol Howell at Enteromed Ltd. Participants have provided their consent for the sharing of anonymised data for research purposes.

Intention to publish date

31/07/2021

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

17/10/2018: The following changes were made to the trial record: 1. The interventions, secondary outcome measures and inclusion and exclusion criteria were updated. 2. The overall trial end date was changed from 31/12/2019 to 31/07/2020. 3. The recruitment start date was changed from 01/09/2018 to 15/10/2018. 4. The recruitment end date was changed from 01/06/2019 to 01/12/2019. 5. The funder was changed from Enteromed Ltd to Bioline Products s.r.o. 6. The trial participating centres were added. 11/06/2018: The following changes were made to the trial record: 1. The ethics approval details were added. 2. The recruitment start date was changed from 01/03/2018 to 01/09/2018.