Celiac Disease Clinical Trial
Official title:
MRI Assessment in Newly Diagnosed Coeliac Disease and Following Gluten-free Diet Treatment
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.
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.
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