A Two Arm Randomized Clinical Trial comparing the effects of an Elimination Diet and a Healthy Diet in Children with ADHD (TRACE Study). Effects on the Brain * an exploratory investigation

Rationale: Food seems to trigger Attention-Deficit Hyperactivity Disorder
(ADHD) symptoms in some children and an individually constructed elimination
diet (ED) might be an effective treatment for ADHD. It is unknown what the
effects of ED are after 12 months and how the effects of ED compare to those of
a healthy diet and * in a small comparator arm, care as usual (CAU). This is
studied in our ongoing TRACE study (CMO 2014-1349, NL50015.091.14). However,
it is still unclear 1) whether food or diet interventions also affect the
fronto-striatal and fronto-amygdalar brain systems that are involved in
cognitive and emotional control processing deficits whereof are associated with
ADHD, and 2) whether effects on these brain systems mediate effects on
behaviour.

Objective: The present protocol is nested in the TRACE study (CMO 2014-1349,
NL50015.091.14 and in the linked TRACE-BIOME study, CMO 2015-1806,
NL53630.091.15), and explores whether an ED, compared to healthy diet, affects
the fronto-striatal and fronto-amygdalar brain systems, and whether effects on
the brain mediate effects on behaviour

Study design: TRACE uses a patient-preference design where parents/children can
choose between diet and care-as-usual (CAU). If they opt for diet they will be
randomized to either ED or healthy diet. The proposed TRACE-MRI study will add
high quality 3 Tesla MRI assessments (structural MRI, diffusion MRI, functional
activations using a stop-signal task and emotional faces (amygdala) task,
resting state MRI) at baseline (T0) and endpoint (T1, after 5 weeks of
treatment) in the ED and health control diet conditions. The MRI acquisition
will as much as possible be combined with the assessments for TRACE, so
avoiding extra visits.

Intervention of the TRACE study: The ED trajectory consists of a 5-week
elimination phase, in which children consume a standardized restricted diet,
and a 9-12 months reintroduction phase to find those products triggering ADHD
symptoms. Non-responders to ED and children who drop out during the
reintroduction phase will be switched to CAU.
Standard intervention to be compared to:
- Healthy diet comparable to a normal dietary pattern prescribed in a strict
and structured way, requiring the family, as in ED, to adapt the rules and
structure of the family.
- CAU consisting of medication and / or psychosocial interventions.

The TRACE-MRI study will not add any further interventions.

Nature and extent of the burden and risks associated with participation,
benefit and group relatedness: In the TRACE study, burden for the RED
participants are mainly related to the reintroduction phase of the diet, which
can take up to 1.5 years, in which ADHD symptoms may re-occur after the
reintroduction of a food. Furthermore, all participants and parents are asked
to undergo recurrent non-invasive assessments: For children (IQ [once],
behavior observation, and cognitive test) the time duration per assessment
varies between 1.5 and 2.5 hours (three assessments in total in 1.5 years). For
parents (parent-child observation, questionnaires) the time duration of the
begin/end point assessment (T0, T1, T4) is around 60 to 90 minutes and at other
time points (T2, T3) around 15 minutes. Finally, all participants will undergo
venapuncture (15 ml) at the main assessments to examine potential
insufficiencies in nutrients levels, i.e., at at the start of the study (T0),
after 5 weeks (T1) and at the end of the study (T4).

The risk of the proposed MRI assessments can be considered as negligible, and
the burden for the participants can be considered as acceptable. We have
extensive experience in MRI scanning children and adolescents with various
psychiatric disorders from age 6 onward, such as in autism (CMO 2013-455,
NL45500.091.13), ADHD (CMO 2008-163, NL23894.091.08), and conduct
disorders/aggressive behaviour (CCMO 15.0071, NL49997.091.14). We have
personnel that has been trained to MRI scan children, is experienced in
practising children in the mock scanner, and sensitive to sign of resistance of
participants. For TRACE-MRI, the benefits for the participants include good
monitoring of treatment effectiveness and the possibility to be treated with an
elimination diet free of charge, which is currently not yet covered by health
insurance. There will be no direct benefits for the participants in this
TRACE-MRI study. By participation, parents and child will help our
understanding of the biological mechanisms involved in the ED*s treatment
response, which may significantly improve future care for patients with ADHD.
Parents receive ¤30 per assessment for compensation of travel expenses and time
investment; children receive a small gift (worth ¤3,-).