Memantine for Epileptic Encephalopathy

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Epileptic Encephalopathy, Childhood-Onset

Intervention / Treatment
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* Drug: Memantine Hydrochloride 10 mg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Monocentric, Off-Label Use, Randomized, crossover, Double-blinded Placebo vs Memantine.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Memantine Hydrochloride 10 mg Placebo<br>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 | Drug: Memantine Hydrochloride 10 mg<br>* 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<br>* Other names: PrSANDOZ MEMANTINE FCT10 mg Drug Identification Number (DIN) 02375532;|
| Placebo Comparator: Placebo Memantine Hydrochloride 10 mg<br>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 | Drug: Memantine Hydrochloride 10 mg<br>* 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<br>* Other names: PrSANDOZ MEMANTINE FCT10 mg Drug Identification Number (DIN) 02375532;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Responder versus Non-Responder Status with Memantine | 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. | Week 6 or 14 | 
| Rate of Responder versus Non-Responder Status with Placebo | 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. | Week 6 or 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EEG Change with Memantine | 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. | Week 6 or 14 | 
| EEG Change with Placebo | 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. | Week 6 or 14 | 
| Seizure Frequency Change with Memantine | 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. | Week 6 or 14 | 
| Seizure Frequency Change with Placebo | 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. | Week 6 or 14 | 
| Cognitive Function Change with Memantine | 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. | Week 6 or 14 | 
| Cognitive Function Change with Placebo | 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. | Week 6 or 14 | 
| Caregiver Impression of Change with Memantine | 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. | Week 6 or 14 | 
| Caregiver Impression of Change with Placebo | 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. | Week 6 or 14 | 
| Serum Inflammatory Markers Change with Memantine | 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. | Week 6 or 14 | 
| Serum Inflammatory Markers Change with Placebo | 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. | Week 6 or 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Memantine, N-methyl-D-aspartate receptor, Serum inflammatory, Seizure