Influence of the dietary history in the prevention of coeliac disease : possibilities of induction of tolerance for gluten in genetically predisposed children. The dutch food intervention study

Coeliac disease (CD) is a chronic disorder caused by hypersensitivity to some
of the most common proteins (gluten) in the diet of the European population. CD
affects as much as 1% of the Europeans (2.5 million people) and is the most
common food intolerance in Europe. If recognised, CD patients have only limited
access to safe foods and there is not causal therapy available. The proposed
study is part of the multicenter European project PREVENTCD, founded by the
European Commission FP-6-2005-FOOD-4B; Proposal/Contract no.: 036383. The
general objective of PREVENTCD is to significantly reduce the number of people
suffering from CD in Europe, by developing primary prevention strategies for
CD. This study represents the Dutch contribution to the dietary intervention
study of PREVENTCD.
The hypothesis of the study is that it is possible to induce tolerance for
gluten in genetically predisposed children through the introduction of small
quantities of gluten during the period of breast-feeding.

1. Development of a prevention strategy for CD in children from high risk
families for the disease by induction of oral tolerance to gluten;
2. Identification of the immunological mechanisms involved in initiating the
aberrant response to gluten introduction in the diet of infants genetically
predisposed to CD;
3. Identification of the factors in the early dietary history involved in the
aberrant response to gluten in children;

European, multicenter, double blind, prospective, randomised food intervention
study

The Dutch Coeliac Society (NCV) will invite to participate their members with
CD expecting a newborn (child or sibling) during the next months. Informed
consent to participate will be asked from the families by the local responsible
physician.
Genotyping for the associated genetic factors associated with CD, including the
strong associated HLA-DQ2 and/or DQ8 factors, will be determined in cord blood
after birth.
The children bearing HLA-DQ2 and/or DQ8 will be blindly randomised to either a
group for "tolerance induction for gluten" or to a "control" group. At least 6
months of breast-feeding will be STRONGLY encouraged for all the children.
At the age of 4 months tolerance induction will be attempted by the daily
intake of 1g wheat flour (100 mg gluten) during 8 weeks while continuing
breast-feeding. No gluten will be given in these 8 weeks to control infants,
but 1g. lactose as a placebo intervention. Compliance will be assessed by visit
or interview.
The infants will be strictly followed up. At 7 fixed time points 5ml blood will
be obtained to allow for the screening of CD-specific antibodies, phenotypic
characterization of 20 markers indicating lymphocyte activation and regulatory
T cell induction, and monitoring for the occurrence of gluten-specific T cell
responses typical for CD.
Children with positive antibodies strongly indicating CD or with clinical
suspicion of CD will
be offered a small bowel biopsy for the definitive diagnosis of CD.

Zie protocol pagpage 23 - 30
Possible burden for participants:
- Invited parents/guardians might feel anxiety when reading the letter inviting
them to the study (annex 3), as it describes her/his child as having high risk
for CD.
- Families, in which the child has increased values of the serological marker
(AtTG) suggesting undiagnosed CD (aprox. 10%), are also likely to experience
some anxiety when waiting for further examinations, thus this time period will
be kept as short as possible.
- The small intestinal biopsy necessary for confirming or excluding CD is a
well-established method for diagnosis and complications are extremely rare,
however, during the procedure some discomfort isn*t uncommon. Biopsy will only
be performed when medically indicated and NOT just for purpose of the study.
- A database system is used for the storage of all findings, e.g. results of
blood sample analyses and replies in the questionnaires, which might worry some
families. However, informed consent is required before inclusion of any child
into the study and the database, only a small group of researchers have access
to the database, and if the child and/or parents express a wish to end their
participation their identity code will immediately be erased.
Advantages for participants:
- Detection of CD BEFORE the start of its clinical manifestations, allowing the
prompt institution of a gluten-free diet and preventing the adverse long-term
health implications of active CD.
- In the immunologically identified and diagnosed sub-group of individuals,
the clinical manifestation will be detected at an early stage allowing the
prompt institution of a gluten-free diet
- the children who, thanks to the study, can be classified as early as possible
as not being prone to CD, will be spared the anxiety of vigilance and
expectation toward the development of CD and
- the small group of children with signs of gluten sensitivity, as evidenced by
the presence of CD antibodies in serum, but without evident small intestinal
lesions, will benefit from the planned follow-up by a paediatric
gastroenterologist.