The need for comparison of oral food challenge outcome: the ALlergy Diagnosed by Open oR DOuble blind food challenge (ALDORADO) trial

It is of major importance to diagnose food allergy accurately. Current
guidelines support the use of oral food challenges to do so. The double-blind
placebo controlled food challenge (DBPCFC) has been regarded as the *gold
standard* for decades. However, DBPCFCs are costly, time- and resource
intensive procedures. Structural implementation of less demanding open food
challenges will only find support if research demonstrates that their outcome
will be comparable to DBPCFC, yet this has been proven difficult to
investigate. This non-inferiority study has been set up to address the research
question to investigate if open food challenges are comparable to DBPCFC.

We aim to compare the outcome of open and double-blind placebo controlled food
challenges in children suspected of having food allergy. Within the first
non-inferiority study, the ALDORADO trial, we hypothesise that the open food
challenge is comparable to the *gold standard* DBPCFC in children suspected of
having food allergy for cashew nut, hazelnut or peanut.

The ALDORADO trial is a single-centre non-inferiority study to compare the
outcome of the DBPCFC and open food challenge in children who are suspected to
be food allergic. Data will be collected prospectively and registered
anonymously in the database. Informed consent will be obtained prior to
inclusion.

Participants will undergo both challenges for the specific potential food
allergen. As patients and/or their parents might be reluctant to perform a
second test if symptoms occurred during the first one, we chose not to perform
the OFCs in random order but always start with the DBPCFC. Furthermore, the
DBPCFC outcome will be kept blinded until the last challenge has been
performed. Parents will be instructed not to introduce the food into their
child*s diet until the last and final test has been performed. We defined
unequivocal criteria to decide whether the OFC can be continued in case of
(severe) symptoms. In case of an anaphylactic reaction, no further challenges
will be planned. The interval between both challenges will be at least one week
and no more than six weeks.

All challenges will be performed according to the European Academy of Allergy
and Clinical Immunology (EAACI) guidelines. Symptoms are registered using the
scoring system as proposed in a recent publication by Grabenhenrich et al.
based on the EAACI guidelines. If mild symptoms (e.g. oral discomfort or
abdominal pain) occur and do not aggravate in the next 30 minutes, patients
will be encouraged to eat or drink the same dose again to determine OFC
outcome. All OFCs will be conducted by specially pediatric trained nurses. At
least the second challenge of each patient will be performed by a different
nurse and if possible there will be a different nurse each day. For this study,
during the open food challenge the recipe for the verum day of DBPCFC will be
used to exclude possible matrix differences. We chose to only use recipes in
which the suspected food will be hidden in gingerbread, because these are
validated in the Netherlands.

Within this study children are exposed to an extra food challenge with
additional risk for the occurrence of severe symptoms. We will include as
little children as possible needed to support our results and use defined
unequivocal criteria to stop if clinically indicated. For this study, the
previously mentioned scoring system by Grabenhenrich et al. will be used.
Safety will be guaranteed to stop the specific OFC if one of the predefined
symptoms occur and/or if clinically indicated. Following international
guidelines anaphylaxis is defined as *a serious allergic reaction that is rapid
in onset and may cause death*. Until now, it appeared difficult to refine this
definition in such a way that it is suitable for a practical approach.
Therefore, we decided to use the EAACI criteria to diagnose anaphylaxis.
Further participation within our study will be ended if these criteria are met.
During a weekly scheduled meeting the included patients will be discussed to
decide whether it is safe to perform the second challenge or if participation
should be ended. Paediatricians, paediatric dieticians and researchers will be
present during this meeting.

During the design of this study, parents were interviewed to find out important
aspects that should be taken into account. We included both parents whose child
had already underwent at least one OFC as well as parents who were advised to
perform their child*s first OFC. Parents were selected irrespectively whether
it was an open food challenge or DBPCFC. We did not include children, because
we aimed to collect information useful for our study design and estimated this
would be too difficult for children to understand. In case parents of teenagers
were interviewed, they were stimulated to discuss the topic with their child
beforehand so their opinion could also be taken into account. All parents were
convinced of the relevance of the study and were well aware of the necessity to
perform an OFC to draw firm conclusion about a suspected food allergy. On the
other hand, they mentioned that they may be more anxious as well as their child
to perform a second OFC in case severe objective symptoms (e.g. dyspnoea) or
discomfort occurs during the first OFC. Therefore, we decided to define clear
stopping criteria.