Off-label use of Risperidone in Children and Adolescents (ORCA): a double-blind placebo-controlled discontinuation trial

Over the past decades, risperidone has been increasingly prescribed to children
and adolescents on an off-label basis, while long-term effects have been
insufficiently investigated and discontinuation of long term use need not lead
to behavior deterioration and might have several health benefits. In our study
we will investigate whether or not continued long-term use of risperidone is
still effective beyond one year of treatment and what the effects of
discontinuation are on behaviour and health.

Primary Objective:
To investigate the behavioral effects of controlled discontinuation as well as
the feasibility of discontinuing currently ongoing treatment with risperidone
in children and adolescents with behavioral problems who have used risperidone
for at least one year.

Secondary objectives:
(1) to investigate the effects of discontinuation of risperidone on a number of
secondary outcome variables (problem behavior and comorbidity, clinical
improvement, general functioning and quality of life of the child, parental and
family functioning, and neuropsychological functioning) and tolerability
ratings (side effects and withdrawal effects, physical measures, and blood
values).
(2) to identify moderators and predictors of treatment discontinuation and
long-term outcome six months later. This includes treatment duration and
compliance, child factors (age, sex, presence of comorbid psychiatric problems,
temperamental traits, biologic factors) as well as parent factors
(socio-economic status, parental and family factors).

A double-blinded randomized placebo-controlled multicenter discontinuation
trial. The centers together will recruit 120 children or adolescents.

The participating subjects will be randomized (ratio 1:1) to either continued
use of risperidone or to placebo during sixteen weeks. Subjects will first be
switched to study medication in their regular dose for two weeks. Withdrawal
will subsequently be gradually over a period of six weeks, followed by eight
weeks of complete placebo. There will be four visits: pre-baseline, at
baseline, eight weeks and fourteen week after. After six months there will be
a follow up by phone. In subjects who have stopped their discontinuation
schedule based on behavioral worsening, the measurements of the 14th week
follow-up will be scheduled as soon as possible after stopping taking the study
medication. If this occurs before the eight-week visit, these measurements will
be cancelled.

All participating children/adolescents will use risperidone at study entry, so
we do not expect any unknown risks regarding the use of risperidone. With
regard to the discontinuation of risperidone we expect some deterioration of
behavioral symptoms. Subjects can stop with participating in the trial at any
point of time and start their regular medication if the symptoms are too much
of a burden. We accept a modest worsening of behavior, but the PI can decide
further participation in the study is no longer safe based on clinical
judgement.
The study includes physical examination and blood draws as well as questions
and questionnaires. All study procedures are designed to minimize burden of the
subjects. Invasive examinations have been reduced to a minimum to minimize
burden (e.g. frequency of blood-drawing). Study staff is experienced in child
and adolescent psychiatry and pediatrics. We will act towards study
participants in such a way as to minimize pain, distress and fear, while at the
same time have taken measures and approaches to maximize scientific benefit
(e.g. collecting several blood samples for chemistry etc. by one puncture of
the vein). Local anesthetics (e.g. cream) can be provided for minimizing pain
by blood drawing. No examination will be conducted against the will of the
subject or the caregiver. Any clinically relevant presentations will be managed
in a clinically appropriate way by each study site.