CNS drug effect profiling in adolescents: an educational class experiment using alcohol as a model.

Children and adolescents are increasingly involved in clinical drug trials
because of the intensification of pediatric drug research following the
adoption and implementation of the EU pediatric regulation. Therefore, there is
a need to educate them about the need for and procedures involving clinical
drug trials in children. Ultimately, children and adolescents learn most about
these issues by being involved themselves at several levels/phases of this type
of research, from being participants to being project team members. The
proposed study will therefore be conducted as an educational class experiment
(as part of the Pre University College Program) on the effects of ethanol, an
approach that was successfully followed in a previous educational class
experiment investigating the psychostimulant effects of caffeine (CHDR0918,
data on file). Given the high prevalence of use and alcohol-associated problems
during adolescence, it is important that additional research is done to better
understand the effects of alcohol during this developmental period. Clinical
studies on the acute effects of alcohol have primarily been done in adult
student populations. Animal models have shown clear differences between
adolescents and adults on many aspects of ethanol exposure, including motor and
memory impairments and it is therefore conceivable that effects in adults can
not be merely translated to younger subjects. As a consequence, the effects of
alcohol at certain blood concentrations are well known in adults but not in
children and there are no data on the time course of acute effects of ethanol
in adolescents.

- To educate adolescents about clinical drug studies by involving them as
project team members and participants in a class experiment with negligible
risk and minimal burden;
- To educate adolescents about the effects of a low (*social*) dose of alcohol;
- To investigate the CNS effects of ethanol on neurocognitive and psychomotor
functioning in adolescents;
- To investigate the effects of ethanol on the autonomic nervous system in
adolescents;
- To describe ethanol breath concentrations;
- To describe the PK/PD relationship using the obtained breath concentrations
and the effects that were investigated;
- To evaluate the applicability of the Neurocart test battery in adolescents,
including evaluation how adolescents have experienced trial participation.

Randomized, placebo-controlled, double-blind cross-over study with a wash-out
period of at least 3 days between occasions.

Alcohol challenge will be done with a two oral doses of approx. 10 grams
alcohol each (e.g., two standard glasses of 200 mL containing Malibu mixed with
orange juice); (2) placebo (same total volume orange juice without alcohol but
with coconut milk).

Non-therapeutic research in minors is only permitted if the imposed risks are
negligible, the imposed burden is minimal and if the study objectives cannot be
met by performing the study in legally competent adults (*group relatedness*).
A detailed overview of study related activities will therefore be given in
relation to these aspects.

1 Risks
Alcohol has a few unwanted side effects. However, it is expected that these
will not occur at the low dose that will be administered during this study.
Subjects with previously experienced serious adverse events due to alcohol use
will be excluded. All measurements are without imposing risks on the volunteer.
Therefore, the risk related to participating in this study is considered to be
minimal.

2 Burden
Adolescents participating in this trial will be asked to come to CHDR for two
measurement days each lasting approximately 8 hours. To prevent unnecessary
school absence, these measurement days will be planned on weekend days, during
holiday periods or on days that are considered to be suitable by the parents,
school and the adolescent.
At each measurement day the participants will be requested to complete ten 11
measurement sessions of approximately 20 min. Subjects will be fully occupied
with study-related activities for approximately 2.5 hours after alcohol intake.
Thereafter, time between sessions can be spent with the other volunteers and/or
parents in a room, where entertainment like game consoles, DVD player and
computers with internet access is available. Staff experienced in working with
adolescents will be present to supervise and entertain the volunteers. Food and
beverages will be provided at regular intervals.
The duration of study days is comparable to the duration of a day in school.
Additionally, all measurements are non-invasive. A similar data-intensive study
with caffeine in the same age group was well tolerated and evaluated positively
by all subjects. Therefore, although intensive, this study is considered below
the threshold of minimal burden.
When a volunteer displays resistance against any study related activity, the
*Gedragscode verzet minderjarigen* (Code of conduct in case of resistance in
minors) will be followed.

3 Group relatedness
Results of this study in an adult population can only be partly extrapolated to
adolescents, since results on neurocognitive tasks can be expected to develop
with age, with maturation of cognitive processes continuing well into the
adolescent years, reflected in differences between prepubertal, pubertal and
postpubertal subjects in several neuropsychological task performances. In
addition, developmental changes may influence the pharmacokinetics and/or
pharmacodynamcis of alcohol. It has been demonstrated that ethanol, both acute
and chronic, produces effects that are age dependent in animals. This is
supported by findings in clinical practice, as adolescents appear to have a
higher risk at alcohol intoxication when exposed to large quantities of alcohol
compared to adults. Also, habitual alcohol use, which becomes more prevalent
with age, has an effect on ethanol pharmacokinetics and pharmacodynamics. The
study objectives thus cannot be met by performing the study in legally
competent adults. Moreover, the results are highly relevant for the adolescent
age group, since alcohol use is very common in adolescents, and considered
socially quite acceptable if limited.