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.

Study Overview

• Status: Completed
• Conditions: Epileptic Encephalopathy, Childhood-Onset
• Intervention / Treatment: Drug: Memantine Hydrochloride 10 mg

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montréal, Quebec, Canada, H4A 3J1
      • Children Hospital - MUHC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Memantine Hydrochloride 10 mg Placebo; 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; 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; Other Names: PrSANDOZ MEMANTINE FCT10 mg Drug Identification Number (DIN) 02375532
Placebo Comparator: Placebo Memantine Hydrochloride 10 mg; 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; 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; Other Names: PrSANDOZ MEMANTINE FCT10 mg Drug Identification Number (DIN) 02375532

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	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.	Week 16

Collaborators and Investigators

• Sponsor: Kenneth Myers, MD

Publications and helpful links

General Publications

• 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. 2022 Oct 18:awac380. doi: 10.1093/brain/awac380. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): February 7, 2019
• Primary Completion (Actual): November 8, 2021
• Study Completion (Actual): February 8, 2022

Study Registration Dates

• First Submitted: December 5, 2018
• First Submitted That Met QC Criteria: December 17, 2018
• First Posted (Actual): December 19, 2018

Study Record Updates

• Last Update Posted (Actual): March 11, 2022
• Last Update Submitted That Met QC Criteria: March 10, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Memantine; Seizure; N-methyl-D-aspartate receptor; Serum inflammatory
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Epilepsy; Brain Diseases; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Dopamine Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Memantine
• Other Study ID Numbers: 22838

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No