Effectiveness of methylphenidate in children and adults with Smith Magenis syndrome and attention-deficit/hyperactivity disorder: An N-of-1 series

Smith Magenis syndrome (SMs) is a rare genetic disorder characterised by
complex pervasive and progressive behavioural and sleep disturbances with an
estimated prevalence of 1:25.000 births. SMs is caused by a deletion on
chromosome 17 (17p11.2) or linked to mutation in the RAI-1 gene that is
encompassed by the common 17p11.2 microdeletion. Manifestations are distinctive
physical features, developmental delay, cognitive impairment, and behavioural
abnormalities including inappropriate or self-injurious, aggressive or
stereotypic behaviour, and attention problems, hyperactivity, and impulsivity.
Furthermore, infants experience feeding difficulties, failure to thrive,
hypotonia, hyporeflexia, and sleep disturbances caused by an altered circadian
rhythm. Treatment of SMs is complex due to the heterogeneity of symptoms.
Currently, little research has been performed to inform effective treatments
for manifestations of SMs.
Traditionally , treatment has focused on psycho-education and
professional guidance for reducing symptoms and improving quality of life of
both the person with SMs and its family. A retrospective study demonstrated
that the vast majority of adults and children used at least one psychotropic
medication, including stimulants, antidepressants, antipsychotics, sleep aids,
mood stabilizers, alfa2 agonists, and benzodiazepines. No prospective studies
on efficacy of psychotropic drugs have been performed. Considering the sleep
disturbances, it is recommended in the 2008 NVAVG guideline to consider
melatonin for circadian rhythm disturbances combined with metoprolol to reduce
the inappropriate daytime melatonin secretion. Next to these sleep
disturbances, an effective treatment should be examined for the remaining
behavioural problems including symptoms of attention deficit (hyperactivity)
disorder (AD(H)D). Patients with conduct problems, impulsivity and
hyperactivity might benefit from treatment with a stimulant drug such as
methylphenidate. As far as our knowledge goes, no studies have been performed
to investigate the effectiveness of stimulants in SMs.
The randomized controlled trial (RCT) has conventionally been
considered as the evidence for the effectiveness of an intervention. However,
an RCT at population level is not feasible when it comes to rare disorders due
to multi- and comorbidities. Reliable conclusions about the effectiveness of
the intervention cannot be drawn due to matching issues. The n-of-1 trial is an
alternative that has been considered as the most ideal study design to
demonstrate causality of a symptomatic intervention in relatively stable
disorders or with clear prediction of the progression at an individual level
and with reversible outcome measures. The n-of-1 trial is a multiple cross-over
placebo-controlled randomized study within an individual patient. N-of-1 trials
are suitable in examining the efficacy of interventions in diverse and
relatively small populations. Combining the results of several n-of-1 trials
yields information at a population level. N-of-1 trials enable within-subject
comparisons, also applicable to similar conditions as the cross-over
efficients, provide flexibility in the performance at an individual level, and
therewith, demonstrate the relative efficacy at an individual level. Thus,
n-of-1 trials regard the variability in treatment responses between
individuals.
By using an n-of-1 series in patients with SMs, we will examine the efficacy of
an intervention with methylphenidate on behaviour and relevant outcome
measures. N-of-1 trials with methylphenidate for ADHD symptoms in SMs are
suitable due to 1) ADHD has a chronic and stable clinical course; 2)
methylphenidate has a rapid onset and termination of actions; and 3) caregivers
seek for evidence for the use of stimulants because of biases and doubts. In
this way, structured and evidence-based decisions can be made for an individual
patient.

The primary objective is to determine the efficacy of methylphenidate on ADHD
symptoms in Smith Magenis syndrome.
The secondary objectives include the efficacy of methylphenidate on emotion
dysregulation and specific goals that are important to the patient and its
environment. Those personalized goals will be determined together with the
participants using Goal Attainment Scaling and personal questionnaires,
specifically paying attention to
A. Reduction of distraction, conduct problems, and impulsivity and
hyperactivity;
B. Reduction of emotion dysregulation;
C. Minimization of burden for parents.

The n-of-1 series will consist of a double-blind randomized placebo-controlled
multiple crossover trials within six individuals. The n-of-1 trial will consist
of several cycles with each cycle containing a randomized order of one period
of active treatment and one period of placebo treatment. One period lasts for
seven days with a wash-out period of seven days with placebo after each period.
The trial will start with a baseline measurement without any intervention
followed by the consecutive periods of placebo or active intervention with
methylphenidate. The total duration of a trial will be 12 to 13 weeks with a
follow-up measurement three months after termination of the N-of-1 trial.

Prior to the start of the trial during a clinical visit, the clinician will
determine the dose of methylphenidate that is appropriate for the participant
based on body weight and taking into account possible side effects.
Methylphenidate or the placebo will be administered twice a day at 8.00 am and
1.00 pm. In case of a child, the medication will be administered by the parents
and caregivers.

Questionnaires will be filled out daily and participants will be contacted at
the end of each period in order to assess personal goals, possible side effects
and the expectation of the treatment.

No additional burden is expected as the design including blinded cross-over
periods and the use of placebo for treating ADHD with methylphenidate is
already Good Clinical Practice. However, the wash-out periods extend the time
without active treatment. Furthermore, participants are required to fill in
some questionnaires daily. On the other hand, every participant is exposed to
the active treatment condition and an individual treatment decision will be
retrieved in terms of evidence-based medicine. Therefore, we expect the
benefits substantially outweighing the burden to be able to evaluate the
effects.