The effect of Lamotrigine on cognitive deficits associated with Neurofibromatosis type 1: a phase II randomized controlled multi-centre trial (NF1-EXCEL)

Neurofibromatosis type I (NF1; incidence 1:3000) is one of the most common
monogenetic causes of cognitive disability. It is an autosomal dominant
disorder, caused by mutations in the NF1 gene, and characterized by a wide
variability of cutaneous manifestations, neurofibromas, and cognitive, social,
motor and emotional problems. Despite the frequency of the disorder and the
impact on daily life, there is currently no evidence-based treatment targeting
the cognitive problems in NF1. The ENCORE-laboratory at Erasmus MC has recently
shown that the cognitive deficits in Nf1 mice are caused by attenuated function
of HCN-channels. In mice, Lamotrigine (LTG), an HCN-channel agonist, rescues
the neuronal plasticity and learning deficits. Lamotrigine is approved to treat
epilepsy and bipolar disorder, and is frequently used in children with NF1 to
treat epilepsy. We hypothesize that Lamotrigine will decrease the
over-inhibition in adolescents with NF1 and improve their cognitive
functioning.

The objective of this proposal is to determine the effect of Lamotrigine on
cognitive functioning and neurophysiology in adolescents with NF1.

Phase II randomized double-blind placebo-controlled parallel group multi-centre
trial

Lamotrigine or placebo tablets: target dose of 2 x 100 mg/d.

Burden: Participants are required to take Lamotrigine or placebo tablets twice
daily for 28 weeks. The total study duration from first inclusion visit till
last outcome measurement will be 53 weeks. They have to keep a patient diary.
Neuropsychological tests are assessed at baseline and after 6 months.
Non-invasive neurophysiology measures are assessed at T=0 and T=10. The
participants will visit the outpatient clinic four times: at T= -1 weeks, T=0
weeks, T=10 weeks and T=26 weeks. The visits at T=-1 weeks and T=26 weeks can
also take place at the patient's home. The nature of the visit at T=18 weeks is
always a home visit. During this visit compliance and adverse events will be
monitored. Between the visits, parents and participants will be contacted by
telephone at time points 4, 8, 14, 22 and 52. After T=26, there is a build-off
phase of 2 weeks, after which there is an extra telephone contact at T=28. At
T=52 weeks, participants receive a questionnaire to monitor off-phase attention
problems. Finger prick for obtaining blood will be done at T=-1 week to assess
renal function, liver values and complete blood count. Venipuncture will be
done at T=10 to monitor blood lamotrigine levels, liver values and complete
blood count. Additionally, at T=18 and T=26 weeks a finger prick for obtaining
blood for lamotrigine plasma levels will be done. Total time investment by the
participants for visits and testing will be +/- 13 hours.

Risks: Side-effects that are associated with Lamotrigine are known and
manageable. (see SPC). Special attention is directed to the occurrence of skin
rash, which will result in immediate withdrawal of study medication. There are
no specific risks associated with outcome assessments. TMS, performed by
trained personnel, is a non-invasive and safe method of measuring cortical
inhibition and plasticity.

Benefit: If Lamotrigine has a positive effect on the cognition of adolescents
with NF1, participants will have a direct benefit of participating in this
trial. In addition, we would establish high-grade evidence for treatment of
cognitive deficits in a vulnerable paediatric population.

Group relatedness: There are several reasons why we perform this study in
children/adolescents instead of adults. These reasons are similar to trials
previously performed in this population (MEC-2005-281 and MEC-2009-086).
We expect the children*s/adolescent*s brain to have the highest ability to
change (most *plastic*). Issues related to cognitive and behavioural deficits
are most prominent in children/adolescents.
* The potential benefit of this study would directly apply to the study
population.
* NF1-children/adolescents have a very characteristic profile of problems with
school performance, behaviour and cognition. In contrast, at adult age, these
problems have accumulated to a mild, broad range of cognitive deficits that are
harder to quantify (probably because of adapting alternative problem-solving
strategies).
* From a practical point of view, we can only use some of the outcome measures
(e.g. some of the attention tasks, parent-rated questionnaires) by testing
children/adolescents.
* Again from a practical point of view, there are no specific outpatient
clinics for adult NF1 patients and the patients that are available often suffer
from complex somatic complications of NF1, reducing the generalizability of the
results of this trial. In contrast, the outpatient clinics of the Sophia*s
Children*s Hospital, UZ Leuven and KBO Kinderklinikum are representative of
children with NF1 because the clinics are easily accessible and children remain
in yearly follow-up after diagnosis.