Memantine for Epileptic Encephalopathy

Randomized Double-blind Placebo-controlled Trial of Memantine Hydrochloride for the Treatment of Childhood-onset Epileptic Encephalopathies

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.

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.

Blue colour capsules, for oral administration, containing 5 mg of active memantine or matching placebo for oral administration. Dose regimen: Memantine Hydrochloride Week #1: 5 mg id (am), 1 caps Week #2: 5 mg bid (am and pm), 2 caps Weeks #3-6: 5 mg am & 2x 5 mg pm, 3 caps Washout (Weeks #7-8) Placebo Week #9: id (am), 1 caps Week #10: bid (am and pm), 2 caps Weeks #11-14: 1 caps am & 2 caps pm, 3 caps

Placebo Week #1: id (am), 1 caps Week #2: bid (am and pm), 2 caps Weeks #3-6: 1 caps am & 2 caps pm, 3 caps Washout (Weeks #7-8) Memantine Hydrochloride Week #9: 5 mg id (am), 1 caps Week #10: 5 mg bid (am and pm), 2 caps Weeks #11-14: 5 mg am & 2x 5 mg pm, 3 caps

Week #1: 5 mg id (am), 1 caps Week #2: 5 mg bid (am and pm), 2 caps Weeks #3-6: 5 mg am & 2x 5 mg pm, 3 caps Weeks #7-8: Washout Placebo Week #9: id (am), 1 caps Week #10: bid (am and pm), 2 caps Weeks #11-14: 1 caps am & 2 caps pm, 3 caps OR Placebo Week #1: id (am), 1 caps Week #2: bid (am and pm), 2 caps Weeks #3-6: 1 caps am & 2 caps pm, 3 caps Weeks #7-8: Washout Memantine Week #9: 5 mg id (am), 1 caps Week #10: 5 mg bid (am and pm), 2 caps Weeks #11-14: 5 mg am & 2x 5 mg pm, 3 caps

"Responder" defined as having ≥ 2 of (1) EEG improvement, (2) decreased seizure frequency, (3) cognitive improvement, (4) caregiver impression of improvement, (5) Serum Inflammatory Markers Change. These outcomes are individually defined in detail in the secondary outcomes below. Description of the primary variable(s) The primary efficacy endpoint is the composite cluster of the first occurrence, over the duration of study (randomization to study end date inclusive), of the EE improvement.

"Responder" defined as having ≥ 2 of (1) EEG improvement, (2) decreased seizure frequency, (3) cognitive improvement, (4) caregiver impression of improvement, (5) Serum Inflammatory Markers Change. These outcomes are individually defined in detail in the secondary outcomes below. Description of the primary variable(s) The primary efficacy endpoint is the composite cluster of the first occurrence, over the duration of study (randomization to study end date inclusive), of the EE improvement.

EEG improvement EEG Change: EEG is not a quantitative measure, and there are many possible different patterns that may be seen in epileptic encephalopathy. In general, improvement usually involves (a) background activity changing to more closely resemble the expected background activity for the patient's age, and/or (b) decrease in frequency of epileptiform activity. The electroencephalographer will compare EEGs to the baseline study, and will score as (1) Interval worsening, (2) No significant change, or (3) Interval improvement. We will be assessing all the frequencies usually assessed on a routine EEG (delta, theta, alpha and beta). The frequency range assessed will be 1-70 Hz.

EEG Change: EEG is not a quantitative measure, and there are many possible different patterns that may be seen in epileptic encephalopathy. In general, improvement usually involves (a) background activity changing to more closely resemble the expected background activity for the patient's age, and/or (b) decrease in frequency of epileptiform activity. The electroencephalographer will compare EEGs to the baseline study, and will score as (1) Interval worsening, (2) No significant change, or (3) Interval improvement. EEG improvement We will be assessing all the frequencies usually assessed on a routine EEG (delta, theta, alpha and beta). The frequency range assessed will be 1-70 Hz.

Reduction in seizure frequency Seizure Frequency Change: Participants will keep seizure diaries throughout the study. If the frequency of seizures decreases by > 50% from the baseline frequency, they will be classified as having a significant reduction in seizure frequency.

Reduction in seizure frequency Seizure Frequency Change: Participants will keep seizure diaries throughout the study. If the frequency of seizures decreases by > 50% from the baseline frequency, they will be classified as having a significant reduction in seizure frequency.

Definite improvement in cognitive functioning by neuropsychological testing Cognitive Cognitive Function Change: Participants will see a neuropsychologist at baseline and at the conclusion of each treatment period. The precise testing used will be to the discretion of the neuropsychologist, based on the participant's cognitive capabilities. The neuropsychologist will compare to the baseline assessment and determine if there has been a significant change, based on her experience using these testing protocols in the given age range. The neuropsychologist will score as (1) Interval worsening, (2) No significant change, or (3) Interval improvement.

Definite improvement in cognitive functioning by neuropsychological testing Cognitive Cognitive Function Change: Participants will see a neuropsychologist at baseline and at the conclusion of each treatment period. The precise testing used will be to the discretion of the neuropsychologist, based on the participant's cognitive capabilities. The neuropsychologist will compare to the baseline assessment and determine if there has been a significant change, based on her experience using these testing protocols in the given age range. The neuropsychologist will score as (1) Interval worsening, (2) No significant change, or (3) Interval improvement.

Subjective perception of improvement by parents Caregiver Impression of Change: At the conclusion of each treatment period, caregivers will be asked the following question: "Compared to before the study, do you feel the overall functioning of your child (including seizure control, development and quality of life) is (1) Improved, (2) No Change, or (3) Worsened.

Subjective perception of improvement by parents Caregiver Impression of Change: At the conclusion of each treatment period, caregivers will be asked the following question: "Compared to before the study, do you feel the overall functioning of your child (including seizure control, development and quality of life) is (1) Improved, (2) No Change, or (3) Worsened.

Changes in serum inflammation Serum inflammatory markers: C Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR) and interleukin-6 (IL-6). CRP and ESR are commonly-used clinical measures of inflammation, and IL-6 was found to be elevated in some epileptic encephalopathies in one study (van den Munckhof et al., 2016). Levels will be compared following each treatment period, to the baseline value.

Changes in serum inflammation Serum inflammatory markers: C Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR) and interleukin-6 (IL-6). CRP and ESR are commonly-used clinical measures of inflammation, and IL-6 was found to be elevated in some epileptic encephalopathies in one study (van den Munckhof et al., 2016). Levels will be compared following each treatment period, to the baseline value.

Participants will be asked at all visits to report any possible adverse events, including those requiring emergent treatment. Adverse events will be classified as "clinically significant" or "not clinically significant" with respect to the likelihood that they are related to use of the investigational drug. The frequency of adverse events will be determined during the period receiving memantine and the period receiving placebo.

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

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.

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.