Nonceliac Gluten Sensitivity Clinical Trial
Official title:
Randomized, Dose-finding, Double-blind, Placebo-controlled, Crossover Gluten Challenge Trial in Subjects With Nonceliac Gluten-sensitivity
An emerging problem in clinical practice is how to manage the growing number of patients who
experience symptoms related to the ingestion of gluten-containing foods gluten and in whom
celiac disease has been ruled out. These patients most frequently report gastrointestinal
symptoms such as diarrhea, abdominal discomfort or pain, bloating, flatulence, but also
extraintestinal symptoms, including headache, lethargy, attention-deficit/hyperactivity
disorder, ataxia, or recurrent oral ulceration. This heterogeneous syndrome, which has been
reported to improve or even disappear after gluten withdrawal and to relapse after gluten
challenge, is called non-celiac gluten sensitivity.1 The concept of nonceliac gluten
sensitivity is not completely new. Besides several sporadic single cases reported, more than
30 years ago an oral, double-blind, placebo-controlled, cross-over gluten challenge trial
showed that six out of eight adult non-celiac patients, who suffered from intestinal symptoms
caused by the ingestion of gluten-containing food, were affected by gluten-sensitive
diarrhea. Over the last few years, an intense debate about the existence and the prevalence
of nonceliac gluten sensitivity has emerged, as shown by the considerable increase in
internet forums of discussion on this topic and in availability of gluten-free food. A
definition of nonceliac gluten sensitivity based on definitive scientific evidence does not
still exist, and the clinical trials conducted so far in order to fill this knowledge gap are
burdened by a number of biases. In a cross-over trial of subjects with suspected NCGS, the
severity of overall (intestinal plus extraintestinal) symptoms increased significantly during
1 week of intake of small amounts of gluten (daily 4.375 grams), compared with placebo. Among
the 59 participants in this trial, the Investigatotors identified only three true
gluten-sensitive patients, defined as having a delta overall score -calculated by subtracting
the weekly overall score under placebo from that under gluten- higher than the mean delta
overall score plus 2 standard deviations. However, these results should be cautiously
interpreted due to the lack of a control group of non-gluten-sensitive subjects.
On this basis, the Investigators will conduct a randomized, dose-finding, double-blind,
placebo-controlled, cross-over gluten challenge trial aimed at comparing the effects of a
daily dose of 8.4 grams of gluten with those of a daily dose of 6.0 or 4.2 grams of gluten on
a cohort of subjects with nonceliac gluten sensitivity versus healthy volunteers.
The Investigators will consecutively enroll adult patients referred to outpatients' Clinics
of 21 Centres because of persistence of relevant intestinal and extraintestinal symptoms
believed by them to be caused by the ingestion of food containing even low doses of gluten.
In their clinical management patients in gluten-containing diet since at least two months
will undergo ad hoc tests including serum determination of IgA anti-tissue transglutaminase
and anti-endomysial antibodies, IgG anti-gliadin antibodies (AGA), total IgA and IgE,
wheat-specific IgE, upper endoscopy with collection of multiple duodenal biopsies, HLA
genotyping, fecal calprotectin and lactose breath test. The Investigators will investigate
serum AGA IgG since they have been detected in some patients with "suspected" nonceliac
gluten sensitivity. Patients with celiac disease, wheat allergy, intolerance to further food
source of fermentable oligo- and disaccharides, monosaccharides and polyols, lactose
intolerance, Helicobacter pylori infection, giardiasis, inflammatory bowel disease,
cirrhosis, excessive alcohol intake, intake of nonsteroidal anti-inflammatory agents, use of
systemic immunosuppressant medication, poorly controlled psychiatric disease, pregnancy and
those unable to give written informed consent will be excluded. The Investigators will also
recruit as control group 420 age- and sex-matched healthy volunteers, undergoing IgG AGA and
all negative for anti-tissue transglutaminase antibodies. Healthy volunteers will not be
affected by any comorbidity and food intolerance.
Each Centre will enroll 20 patients with suspected nonceliac gluten sensitivity and 20
healthy volunteers. Recruitment of patients and, at greater extent, healthy volunteers should
not be an issue as the 21 Centres involved in this trial are well-known for diagnosis and
treatment of gluten-related disorders. The Investigators will consider drop-outs from the
study all the patients who will fail to attend even a single appointment or test in the
trial. Moreover, compliance with the study treatment will be assessed by unused capsule
counts at T2 and T4. Compliance with the gluten-free diet at each time point will be assessed
through a validated questionnaire. To exclude the possibility of patients being able to
discriminate between gluten capsules and placebo capsules, we preliminarily tested capsule
recognition in a group of 20 healthy volunteers. On two different days, healthy volunteers
were asked to take capsules and then clearly state if the capsules contained gluten or not.
Healthy volunteers were not able to differentiate the appearance and taste of gluten capsules
from those of placebo capsules. Assuming a within-patient comparison and a SD of the overall
score of 40, 70 subjects per arm would be needed in order to achieve a power of 80%, at a
2-sided 5% significance level, if the true difference is 15.
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