Clinical trial NCT03779672: Memantine for Epileptic Encephalopathy
Official title: Randomized Double-blind Placebo-controlled Trial of Memantine Hydrochloride for the Treatment of Childhood-onset Epileptic Encephalopathies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Epileptic Encephalopathy, Childhood-Onset
Keywords: Memantine
N-methyl-D-aspartate receptor
Serum inflammatory
Seizure
Lead sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
Sponsor class: OTHER
First posted: 2018-12-19
Enrollment: 30
Sex: ALL
Minimum age (years): 6
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Monocentric, Off-Label Use, Randomized, crossover, Double-blinded Placebo vs Memantine.
Primary purpose: TREATMENT

Brief summary: This study will evaluate the potential benefit of memantine hydrochloride as treatment for children with epileptic encephalopathy using a double-blind placebo-controlled cross-over design.

Detailed description: Memantine, a drug approved for Alzheimer's dementia, exerts its therapeutic effect through its action as a low to moderate affinity non-competitive (open channel) N-methyl-D-aspartate receptor (NMDA-R) antagonist, which binds preferentially to the NMDA receptor-operated cation channels. It blocks the effects of persistently elevated levels of glutamate that may lead to neuronal dysfunction. Memantine may also have anti-inflammatory effects. Memantine has been used off-label in children and adolescents with autism spectrum disorder, to improve the cognitive impairment.

Epileptic encephalopathy, as well as other forms of epilepsy, may occur as a result of multiple etiologies, including genetic and inflammatory pathologies. Ion channels were long considered to be implicated in genetic epilepsy. Indeed one of the many possible causes of epilepsy is NMDA receptor dysfunction.

In the present study, the investigators plan to investigate the potential benefit of memantine as a treatment for epileptic encephalopathy. A double-blind placebo-controlled cross-over design will be used, with participants receiving 6 weeks of memantine and 6 weeks of placebo, with a 2-week washout period in between.

Eligibility criteria: Inclusion Criteria:

* Written informed consent obtained
* Age 6-18 years (Weight ≥ 20 kg)
* Clinical diagnosis of epileptic encephalopathy

  * Subject with epilepsy and developmental impairment;
  * Epileptic activity itself contributes to severe cognitive and behavioural impairments
  * Patients will typically have already have trialed at least two standard therapies
* Females of childbearing age:
* Negative urinary pregnancy test at screening
* Agree to use effective contraception for the duration of the study

Exclusion Criteria:

* Inability of a parent or legal guardian to give informed consent for any reason.
* Known hypersensitivity to memantine hydrochloride
* Taking concomitant Amantadine, Ketamine or Dextromethorphan, Cimetidine, Ranitidine, Procainamide, Quinidine, Quinine, Hydrochlorothiazide, Anticholinergics, L-dopa, Anticoagulant,
* Any degree of renal impairment

Primary outcomes:
measure: Rate of Responder versus Non-Responder Status with Memantine
timeFrame: Week 6 or 14
measure: Rate of Responder versus Non-Responder Status with Placebo
timeFrame: Week 6 or 14
Secondary outcomes:
measure: EEG Change with Memantine
timeFrame: Week 6 or 14
measure: EEG Change with Placebo
timeFrame: Week 6 or 14
measure: Seizure Frequency Change with Memantine
timeFrame: Week 6 or 14
measure: Seizure Frequency Change with Placebo
timeFrame: Week 6 or 14
measure: Cognitive Function Change with Memantine
timeFrame: Week 6 or 14
measure: Cognitive Function Change with Placebo
timeFrame: Week 6 or 14
measure: Caregiver Impression of Change with Memantine
timeFrame: Week 6 or 14
measure: Caregiver Impression of Change with Placebo
timeFrame: Week 6 or 14
measure: Serum Inflammatory Markers Change with Memantine
timeFrame: Week 6 or 14
measure: Serum Inflammatory Markers Change with Placebo
timeFrame: Week 6 or 14
Other outcomes:
measure: Adverse events
timeFrame: Week 16
Locations:
city: Montréal
country: Canada
facility: Children Hospital - MUHC
state: Quebec
Study officials:
References:
citation: van den Munckhof B, de Vries EE, Braun KP, Boss HM, Willemsen MA, van Royen-Kerkhof A, de Jager W, Jansen FE. Serum inflammatory mediators correlate with disease activity in electrical status epilepticus in sleep (ESES) syndrome. Epilepsia. 2016 Feb;57(2):e45-50. doi: 10.1111/epi.13274. Epub 2015 Dec 14.
citation: Schiller K, Berrahmoune S, Dassi C, Corriveau I, Ayash TA, Osterman B, Poulin C, Shevell MI, Simard-Tremblay E, Sebire G, Myers KA. Randomized placebo-controlled crossover trial of memantine in children with epileptic encephalopathy. Brain. 2023 Mar 1;146(3):873-879. doi: 10.1093/brain/awac380.