Neurocognitive testing in children with ADHD

Neurocognitive tasks are frequently employed in scientific research. Task
results can be used as correlates of disease state, are often used by
neuropsychologists to elucidate the pathogenesis of neuropsychologic disorders
and can serve as biomarker of drug effects.

Development and use of such biomarkers in pediatric populations lags behind
when compared to the adult population. The need for validated biomarkers in
pediatric drug research is substantial in the light of an expected
intensification of pediatric drug research following the adoption of EU
regulation No. 1901/2006.

The Centre for Human Drug Research (Leiden, the Netherlands) has extensive
experience with a test battery called the Neurocart. The Neurocart consists of
a selected set of neurocognitive tasks, the results of which are used as a
biomarker cq trial endpoint in early phase drug research in adults. It is
reasonable to expect that tasks incorporated in this test battery are also
suited for use in the pediatric population to detect drug effects and/or
discriminate between disease states.

Preliminary results of a pilot study in 15 healthy children aged 8-12 years
show that children are well able to perform the tasks and find these fully
acceptable, and task results are reproducible and related to age.

To investigate whether drug effects can be measured using these neurocognitive
tasks, we propose a study in children with a confirmed diagnosis of Attention
Deficit Hyperactivity Disorder (ADHD) currently treated with methylphenidate
(MPH).

The objectives of this study are to establish whether methylphenidate PD
effects can be measured using neurocognitive tasks, to describe the drug
concentrations of methylphenidate in saliva, to describe the PK/PD relationship
using the obtained saliva samples, to describe cardiovascular effects of
methylphenidate, to evaluate clinical treatment effect during the trial and to
evaluate how children have experienced trial participation.

In an exploratory manner it will be investigated if measurements in this group
differ from a group of normal children performed earlier.

Randomised, placebo-controlled, 2-way cross-over design

Children willing to participate will be randomised to either 1 week placebo
followed by one week MPH or to 1 week MPH followed by one week placebo.

Risks
Participating children will be off-treatment during one of the 2 weeks. Several
guidelines recommend suspending treatment at set intervals in order to evaluate
the effect of treatment. This risk is negligible. Patients with ADHD are known
to have so-called *medication holidays* in weekends and school holidays,
without experiencing adverse effects such as withdrawal symptoms.

Burden
Children participating in this trial will be asked to come to CHDR for a
measurement day twice (one day at the end of each treatment week). To prevent
unnecessary school absence, these measurement days will be planned on weekend
days or on days that are considered to be suitable by the parents, the child
and school.
One measurement day will last for approximately 8 hours. In between measurement
sessions (7 sessions of approx. 20 minutes each - see paragraph *proceedings
and management* for details), children will be able to spend with the other
children and parents in a room, where entertainment like game consoles, dvd
player and computers with internet access are available. Children will be
supplied with a structured programme between tests to minimize ADHD symptoms.
Apart from parents, staff experienced in working with children will be present
to supervise and entertain the children. Food and beverages will be provided.
Children will be on placebo during one of the two trial weeks, and thus not
receive treatment for their ADHD. This may cause children to be more
hyperactive during the placebo week. School teacher will be informed of study
participation to make them aware of this fact. We will evaluate treatment
effect at the end of each week so that we can offer a therapy evaluation as is
recommended in most treatment guidelines.
The duration of study days is comparable to the duration of a day in school.
Additionally, all measurements are non-invasive. This study therefore is below
the threshold of minimal burden.
In case children display resistance against any study related activity, the
*Gedragscode verzet minderjarigen* (Code of conduct in case of resistance in
minors) will be followed.

Group relatedness
Although there is some evidence that ADHD symptoms extend into adulthood, the
disease is considered to have its main incidence in the age group considered
for this study. Additionally, performing this study in an adult population
would yield major difficulties since results on neurocognitive tasks can be
expected to develop with age. This phenomenon was demonstrated for instance in
a developmental study of visuospatial attention. In addition, developmental
changes may influence the pharmacokinetics of methylphenidate. The study
objectives thus cannot be met by performing the study in legally competent
adults.