MAgnetic Resonance Imaging in COeliac Disease
Condition: Celiac Disease; Coeliac Disease; Celiac Sprue; Gluten Enteropathy
MeSH terms: Celiac Disease; Intestinal Diseases
Study type: Observational

Summary: 
      One in 100 people suffers from coeliac disease. It affects the lining of the bowel and causes
      many symptoms such as diarrhoea, wind, stomach pain, constipation and nausea. The only
      treatment so far is a strict glutenfree diet for life which reverses the bowel damage and
      often improves symptoms. Up to 25% of patients however may have persistent symptoms despite
      the gluten free diet but the reasons for this are not clear.

      This research aims to help us understand how the gluten free diet works. Investigators will
      use medical imaging (magnetic resonance imaging or MRI) to measure the volumes of fluid in
      the small bowel, the size of the large bowel and the time it takes for foods to go through
      the entire bowel in patients who have just been diagnosed with coeliac disease by their
      hospital doctor. Investigators will also carry out a breath test and collect a stool sample
      for basic analysis of the stool bacteria.

      Investigators will also collect questionnaires about their feelings and their bowel habits
      and will try to see how the MRI measurements relate to the patients' symptoms. Investigators
      will observe how all these measures change after one year of the gluten free diet that
      doctors will have prescribed as part of the coeliac patients' standard care. As such there is
      no dietary intervention in this study, investigators will simply study changes in the
      patients due to their standard treatment. Investigators will also look at a matched group of
      healthy volunteers to gather a likely reference range of the measurements. This research will
      be carried out in Nottingham with the help of the specialist coeliac clinics and it will last
      3 years. There is a dedicated Coeliac Patient Public Involvement group who have helped plan
      this study.
    

Detailed description: 
      Hypotheses of the study

      Based on the investigators' pilot data and on the literature available, this study aims to
      test the main hypotheses that in adults newly diagnosed with coeliac disease treatment with
      GFD will:

        1. reduce the water content of the fasting small bowel

        2. reduce the volume of the fasting colon

        3. increase whole gut transit time

      Objectives of the study

      The specific objectives of the study are therefore to quantify any change following treatment
      with a gluten-free diet (GFD) in:

        1. the water content of the fasting small bowel

        2. fasting colon volume

        3. whole gut transit time in adults newly diagnosed with coeliac disease using non-invasive
           MRI Co-variates of interest

      During this study investigators will measure a series of exploratory co-variates of interest
      at diagnosis and at 12 months follow-up:

        1. BMI

        2. Gastrointestinal symptoms (Bristol Stool diary for a week, HAD, PHQ-15, IBSS, QOL, GI
           symptoms VAS scales )

        3. Marsh grading of D2 segment duodenal biopsies (defined as routine clinical assessment in
           NUH)

        4. Fasting breath hydrogen

        5. Serology values (tTG, EMA)

        6. Faecal microbiota and short chain fatty acids

      In a subgroup analysis, investigators will describe associations (if any) between the MRI
      outcomes and these co-variates:

        1. before treatment,

        2. after treatment and

        3. differences between the two.

      The latter will represent the most useful analysis. By using the after treatment measure as
      the outcome and the before treatment measure as a covariate this will be mathematically
      equivalent to analysing the change with treatment (adjusted for baseline).

      Parallel Healthy Volunteers group This study will also include a parallel pilot study healthy
      volunteers (HVs) frequency matched for age (in 20 years bands) and gender to provide
      descriptive statistics on a likely reference range for the healthy population to inform the
      design of future studies.

      A pilot study in 36 newly diagnosed coeliac disease patients before and after a gluten-free
      diet.

      University based

      Pilot study on patients:

      There is no data available to estimate the size of the change in water content of the fasting
      small bowel in patients hence this is a pilot study.

      The investigators' own MRI pilot data in n=20 untreated, newly diagnosed coeliac patients
      showed a fasting small bowel water content of (mean ± SD) 202 ± 115 ml volume. We can predict
      that we should be able to detect a change of 40% (or a reduction of 80 ml volume) after
      gluten free diet with a power of 90% and a Type I error probability of 0.05 using n=24
      patients in a paired study design. This is considered a clinically significant change after
      gluten free diet; this change reflects twice the level of normal control values of 65 ± 43 ml
      volume. Investigators plan to recruit n=36 to allow for dropouts and to increase power also
      for secondary outcomes.)

      Pilot study on healthy volunteers (HVs):

      For exploratory purposes and to provide pilot reference data for the design of future
      studies, investigators aim to collect data on 36 HVs 36 patients and 36 healthy volunteers.

      Pilot study in coeliac disease:

      Investigations include:

        1. Magnetic Resonance Imaging - 2 scans 12 months apart

        2. Self-administered symptom questionnaires

        3. Stool sample

        4. Hydrogen breath test The patients will have had a biopsy and serology as part of their
           standard care. The healthy volunteers will undergo only the blood sample as part of
           screening with no biopsy taken.

      Duration of study = 36 months. Duration of study for each participant = around 12 months.
      Follow-up of participants will stop after 12 months if they fail to receive the subsequent
      MRI scan There is no randomisation or blinding as this is a simple pilot study. Primary
      endpoint

        1. Fasting small bowel water content (SBWC) measured in ml approximately 12 months after
           initiation of GFD

           Secondary endpoints

        2. Fasting colon volume measured in ml

        3. Whole gut transit time measured in hours

      Co-variates analysis as indicated above

      The basic characteristics of the study population will be calculated using frequencies and
      proportions.

      Objective 1:

      For this cohort of patients with newly diagnosed coeliac disease, investigators will compare
      the mean difference of their fasting small bowel water content (the primary outcome) before
      and after the initiation of GFD. This will be done using Paired Test at 5% level of
      significance. This assumes normality of the data, should the data have a high level of
      skewness non-parametric methods will be used. In order to assess the potential effect
      modification with age and gender, investigators will stratify the above analysis by those
      variables. For this purpose age will be considered as categorical variable and analysed as 20
      years bands. This analysis will only be conducted for cases with complete follow-up data on
      MRI scan.

      Objectives 2 and 3:

      This analysis will be repeated for the two secondary outcomes, namely the volume of the
      fasting colon and the gastrointestinal transit time.

      Co-variate analyses in the coeliac disease group. The potential association between
      co-variates (gastrointestinal symptoms, Marsh grading etc.) and the three MRI outcomes will
      be assessed using stepwise linear regression analysis. Investigators will also assess the
      magnitude of the effect in term of mean difference along with their respective confidence
      interval. The analysis would be separately conducted for each outcome and co-variates
      recorded during the first and the subsequent MRI scan.

      Should this analysis highlight a few particularly strong associations, investigators will
      attempt to input those to a regression model to predict either baseline values or change with
      GFD.

      Pilot study in HVs The HVs group is included to provide pilot reference data to inform the
      design of future studies. Investigators will compare the small bowel water content among the
      coeliac disease cases to the HVs (controls), and then compare the mean difference pre- and
      post-measurement between cases and controls using linear regression.
    

Intervention name(s): Gluten free diet
Intervention type(s): Other
Intervention description(s): Patients will follow a gluten free diet
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        36 newly diagnosed coeliac disease patients.

        A parallel group of 36 healthy subjects, frequency matched for age (in 20 years bands) and
        gender.
      
Biospecimen description: 
      Stool sample
    
Keywords: MRI; Gluten; Imaging; Enteropathy-Associated T-Cell Lymphoma