The objective of this study is to determine whether influencing the protein pathway thought to underlie TSC by Everolimus treatment will improve cognitive abilities in these children.
ID
Source
Brief title
Condition
- Chromosomal abnormalities, gene alterations and gene variants
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To determine the effect of Everolimus on cognitive development (measured by IQ)
in children with TSC.
Secondary outcome
To evaluate the effect on symptoms of autism spectrum disorder, other (neuro)
psychological test parameters, seizure frequency, EEG-abnormalities and
specific symptoms of learning disability. Furthermore, we will observe the
tolerability of Everolimus in children with TSC.
The MRI will show structural abnormalities in the brains of the participants.
We can evaluate the size of these abnormalities before and after Everolimus
treatment, and relate these abnormalities to the cognitive abilities of that
participant. Moreover, we want to investigate whether improvement of the
structural abnormalities in the brain is accompanied by an improvement of the
cognitive abilities of that participant.
Background summary
Tuberous sclerosis complex (TSC) is a genetic disorder with an approximate
birth incidence of 1:6.000-10.000. The brain shows typical cortical and
subcortical malformations, called tubers, giving the disease its name. The
majority of children with TSC show epilepsy (90%), many with mental retardation
(IQ <80), autism, behavioral problems and/or learning disabilities. These
symptoms have a negative impact on quality of life of patients and their
families.
Preclinical studies from our lab and other labs showed that the TSC mouse model
is a good model for the disease. For instance, TSC mutants show epilepsy,
learning deficits, and social behavior deficits. Preclinical studies using
mouse models further revealed that the TSC pathway plays a critical role in the
protein synthesis dependent phase of synaptic plasticity. Loss of TSC gene
function causes increased activity of mTOR, and results in synaptic plasticity
deficits.
Importantly, recent pre-clinical studies also showed that epilepsy, as well as
deficits in plasticity and cognition, can be ameliorated by early treatment
with Everolimus, a specific and potent inhibitor of mTOR. Clinical trials in
adult TSC patients suggest that Everolimus can rescue some of the symptoms of
TSC patients, such as renal tumors (angiomyolipoma) and brain tumors
(subependymal giant cell astrocytoma). Moreover, a case study showed a dramatic
improvement of epilepsy in a child with TSC treated with Everolimus. Together
these findings suggest that early treatment with Everolimus may reduce the
development of the neurological problems associated with TSC.
TSC is a rare disease, but due to its consequences, affects patients and
families severely. It is a unique syndrome with respect that the underlying
deficit in protein function can be partly rescued by a drug that is already
registered for use in humans. This drug is highly specific. In mouse models
administration of this drug improves seizures and learning. This suggests that
there is a good chance that the symptoms of children with TSC will improve with
this medication.
Study objective
The objective of this study is to determine whether influencing the protein
pathway thought to underlie TSC by Everolimus treatment will improve cognitive
abilities in these children.
Study design
After informed consent, participants will be randomized to Everolimus or
placebo treatment for 12 months. This study is doubleblind.
Intervention
Treatment with Everolimus or placebo.
Study burden and risks
TSC patients with a (severe) deficit on cognitive, social and motor level are
often not able to take care of themselves. Most of these patients have to be
looked after day and night, and some of them are institutionalized. For these
patients, further development of their cognitive, social and motor skills would
mean they can communicate (more) with other people, that they understand the
world around them and they might even become able to take care of themselves.
Everolimus has side effects, but the medication these patients take on a daily
basis to control the several features of TSC have similar side effects.
The study burden for participants will be
- taking the medication
- possible side effects. We will try to minimize the side effects by lowering
the dose when side effects occur. All side effects are dose dependent.
Frequently observed side effects include diarrhea, mouth ulcers and skin rash.
Rare side effects are headache, peripheral edema, infectious diseases and
slowed wound healing. Parents will receive detailed information about when to
contact a doctor. The side effects caused by Everolimus are similar to those of
the other medication these patients use. No fatal side effects were reported in
TSc patients.
- Two EEGs (an additional one or two times compared to standard treatment)
- Two neuropsychological examinations
- Eight times a capillary bloodtest (vingerstick) for determining bloodlevels.
In regular care TSC children have bloodtests at least once a year.
- Twice MRI (1 or 2 additional MRIs compared to regular follow-up
- Possible anaesthesia during MRI, with a chance of allergic reaction to the
anaesthetic.
Dr. Molewaterplein 60
Rotterdam 3015 GJ
NL
Dr. Molewaterplein 60
Rotterdam 3015 GJ
NL
Listed location countries
Age
Inclusion criteria
Children with a definite diagnosis of TSC between 4 and 17 years.
Estimated IQ <80 and/or special schooling and/or autism spectrum disorder and/or learning disability requiring remedial teaching.
Written informed consent by parents/care-takers, and the patient if he or she is 12 years or older and cognitively able to consent.
Exclusion criteria
Hepatic dysfunction.
Surgery less than 6 weeks before entering the study.
Infection at time of inclusion.
Allergy for any of the components of the study medication.
Additional diseases or disorders that may influence the endpoints.
Developmental age estimated below 3.5 years.
Intractable epilepsy with more than 1 seizure per week.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-019519-39-NL |
| CCMO | NL38619.078.11 |