MRI and Microbiota Analysis in Constipation (MIMIC)

Validation of Magnetic Resonance Imaging to Characterise Gastrointestinal Physiology, Gut Luminal Content and Its Interaction With Colonic Microbiota in Patients With Chronic Constipation

The purpose of the study is to test how well magnetic resonance imaging (MRI) can measure whole gut transit time in people with constipation, and how readily it can detect a change in transit time induced by taking a dietary supplement with laxative effects.The investigators expect to demonstrate that ispaghula (psyllium) accelerates movement of matter through the intestinal tract.

The investigators will also assess whether a change in gut bacteria and the chemicals that they release can be detected.

Study Overview

• Status: Completed
• Conditions: Constipation
• Intervention / Treatment: Dietary supplement: Maltodextrin; Dietary supplement: Ispaghula

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Nottingham, United Kingdom, NG7 2UH
    • Nottingham University Hospitals NHS Trust
  • Nottingham, United Kingdom, NG7 2UH
    • University of Nottingham

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Meets Rome III Criteria for diagnosis of Functional Constipation5 on questionnaire (NB. Both those who do and do not meet IBS criteria will be eligible)
• At least one bowel motion per week while taking usual laxatives
• Able to give informed consent
• Aged 18 or older

Exclusion Criteria:

• History declared by the candidate of other pre-existing gastrointestinal disorder, including but not limited to:
• Inflammatory Bowel Disease
• Coeliac Disease diagnosed in the last year
• Pancreatitis
• Cancer of the gastrointestinal tract
• Any reported history of gastrointestinal resection (excluding appendicectomy or cholecystectomy)
• Presence of an intestinal stoma
• Pregnancy declared by candidate (no formal testing)
• Contraindications for MRI scanning i.e. metallic implants, pacemakers, history of metallic foreign body in eye(s) and penetrating eye injury
• Reported alcohol intake of >28 units/ week with daily drinking
• Any use of a product containing ispaghula or psyllium in the 4 weeks prior to consent
• Unable to avoid use of dihydrocodeine or morphine during the study
• If taking other regular opiates such as codeine, fentanyl or Oxycodone, participants should be able to maintain a stable dose throughout the study
• Any reported history of hypersensitivity or significant adverse reaction to ispaghula, maltodextrin or bisacodyl
• Unable to stop drugs and other agents used primarily for their laxative effect, during periods of screening, washout, baseline and treatment (maximum 15 days - rescue medication will be provided).
• Antibiotic or prescribed probiotic treatment in the past 4 weeks
• Inability to lie flat or exceed scanner limits of weight <120kg
• Poor understanding of English language
• Participation in any medical trials for the past 3 months
• Any condition where the candidate is likely to require a course of antibiotics in the next 3 months e.g. severe chronic respiratory disease, recurrent urinary tract infection, lower limb ulceration
• Judgement by the PI that the candidate who will be unable to comply with the full study protocol e.g. Diabetes, severe COPD

During the screening 2 weeks off laxatives

• No bowel motions recorded during screening period
• ≥3 complete spontaneous bowel motions (CSBMs - bowel motion with the feeling of complete evacuation, without the use of rescue therapy in the preceding 24 hours) per week

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Maltodextrin; 7 days without use of laxatives other than standardised rescue therapy 7 grams maltodextrin taken 3 times daily, at least 4 hours apart, for up to 7 days	Dietary supplement: Maltodextrin
ACTIVE_COMPARATOR: Ispaghula; 7 days without use of laxatives other than standardised rescue therapy 7 grams ispaghula/ psyllium taken 3 times daily, at least 4 hours apart, for up to 7 days	Dietary supplement: Ispaghula; Other Names: psyllium

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weighted Average Position Score of transit marker capsules as determined by MRI	After 4 days of study product participants will ingest 5 transit mark capsules, the use of which has been shown to measure whole gut transit in a similar manner to more established techniques. They will continue to take study product before undergoing an MRI scan to assess capsule position	24 hours after ingestion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weighted Average Position Score of 5 transit marker capsules, as determined by MRI	After 4 days of study product participants will ingest 5 transit mark capsules, the use of which has been shown to measure whole gut transit in a similar manner to more established techniques. They will continue to take study product before undergoing an MRI scan to assess capsule position	48 hours after ingestion
Small Bowel Water Content (SBWC) in millilitres(mL) measured by MRI	Area under the curve (mL.min) will be calculated from hourly MRI scans	-60, 0, 60, 120, 180, 240, 300, 360, 420 minutes after test meal
Small Bowel Water Content (SBWC) in millilitres measured by MRI	After 5 days of taking the study product participants will undergo an MRI scan while fasted.	Baseline, 60 minutes before test meal
Ascending Colon Water Content in millilitres measured by MRI	After 5 days taking study product participants will undergo an MRI scan while fasted	Baseline, 60 minutes before test meal
Ascending Colon Water Content in millilitres measured by MRI	Area under the curve (mL.min) will be calculated from hourly MRI scans	-60, 0, 60, 120, 180, 240, 300, 360, 420 minutes after test meal
Change from baseline in Ascending Colon Water Content in millilitre measured by MRI	Difference between measurement Meal -60 (fasting) and Meal +60	test meal -60, test meal +60
Change from before to after challenge meal in Ascending Colon Water Content before in millilitre measured by MRI	Difference between time points Meal2 -20 and Meal 2 +40	test meal +360 minutes, test meal + 420 minutes
Ascending Colon T1	Area under the curve of MRI parameter measured at hourly time points	-60, 0, 60, 120, 180, 240, 300, 360, 420 minutes after test meal
Descending Colon T1	Area under the curve of MRI parameter measured at hourly time points	-60, 0, 60, 120, 180, 240, 300, 360, 420 minutes after test meal
Ascending colon T2	Area under the curve of MRI parameter measured at hourly time points	-60, 0, 60, 120, 180, 240, 300, 360, 420 minutes after test meal
Descending Colon T2	Area under the curve of MRI parameter measured at hourly time points	-60, 0, 60, 120, 180, 240, 300, 360, 420 minutes after test meal

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Colonic volume	Area under the curve (mL.min) will be measured from hourly MRI scans by segmentation into ascending colon (AC), transverse colon (TC) and descending colon (DC)	-60, 0, 60, 120, 180, 240, 300, 360, 420 minutes after test meal
Colonic gas volume	Area under the curve (mL.min), measured on hourly MRI scans by segmentation into AC, TC and DC	-60, 0, 60, 120, 180, 240, 300, 360, 420 minutes after test meal
Gastric volume	Area under the curve (mL.min) measured on hourly MRI scans	-60, 0, 60, 120, 180, 240, 300, 360, 420 minutes after test meal
Abdominal circumference	Measured at the umbilicus in cm, determined by MRI	-60, 0, 60, 120, 180, 240, 300, 360, 420 minutes after test meal
Change from baseline of stool water content percentage by mass	Stool will be sampled during the baseline week and between days 3-7 of the intervention week during each treatment period	after an average 5 days of intervention
Change from baseline in stool frequency	Each treatment period includes 1 day washout, 7 days baseline, up to 7 (minimum 6) days intervention. Total = 15 days. Stool frequency will be sampled on days 2-8 and 9-14, since participants may stop taking intervention before day 15.	during days 9-14 of treatment period
Change from baseline in stool consistency	Each treatment period includes 1 day washout, 7 days baseline, up to 7 (minimum 6) days intervention. Total = 15 days. Stool consistency will be sampled on days 2-8 and 9-14, since participants may stop taking intervention before day 15.	During days 9-14 of treatment period
Change from baseline in faecal microbiota	Will be assessed for relative abundance, richness and diversity	Change from baseline after an average 5 days of intervention
Change from baseline in faecal short-chain fatty acids	Stool samples collected during baseline week and after 3 or more days of intervention in each treatment period.	Change from baseline after an average 5 days of intervention
Symptoms during study day	4 symptoms will be measured on 2 scales: a previously validated questionnaire on an ordinal scale (OS) of 0 (none), 1 (mild/ distinct but negligible), 2 (moderate/ annoying), 3 (severe/ disabling); and a Visual Analogue Scale (VAS) (0-100) Symptoms include abdominal pain, bloating, gas/flatulence, and diarrhoea. Clinically important symptoms will be defined as additive total score of 3 or greater on OS. VAS scores will be analysed alongside MRI data	-60, 0, 60, 120, 180, 240, 300, 360, 420 minutes after test meal

Collaborators and Investigators

• Sponsor: University of Nottingham
• Collaborators: Ironwood Pharmaceuticals, Inc.
• Investigators: Study Chair: Robin Spiller, MSc MD FRCP, University of Nottingham; Principal Investigator: Giles Major, BM BCh MRCP, University of Nottingham; Study Director: Luca Marciani, MSc PhD, University of Nottingham

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (ACTUAL): February 1, 2015
• Study Completion (ACTUAL): June 1, 2016

Study Registration Dates

• First Submitted: March 25, 2014
• First Submitted That Met QC Criteria: May 21, 2014
• First Posted (ESTIMATE): May 22, 2014

Study Record Updates

• Last Update Posted (ESTIMATE): January 5, 2017
• Last Update Submitted That Met QC Criteria: January 4, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: MRI; Constipation; Magnetic Resonance Imaging; microbiota; psyllium; ispaghula
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Constipation; Gastrointestinal Agents; Cathartics; Psyllium
• Other Study ID Numbers: UON14011; 14GA006 (OTHER: Nottingham University Hospitals NHS Trust)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO