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Memantine for Epileptic Encephalopathy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03779672
Recruitment Status : Recruiting
First Posted : December 19, 2018
Last Update Posted : March 12, 2019
Sponsor:
Information provided by (Responsible Party):
Kenneth Myers, MD, McGill University Health Centre/Research Institute of the McGill University Health Centre

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.

Condition or disease Intervention/treatment Phase
Epileptic Encephalopathy, Childhood-Onset Drug: Memantine Hydrochloride 10 mg Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Monocentric, Off-Label Use, Randomized, crossover, Double-blinded Placebo vs Memantine.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blinded Placebo vs Memantine
Primary Purpose: Treatment
Official Title: Randomized Double-blind Placebo-controlled Trial of Memantine Hydrochloride for the Treatment of Childhood-onset Epileptic Encephalopathies
Actual Study Start Date : February 7, 2019
Estimated Primary Completion Date : February 28, 2020
Estimated Study Completion Date : May 30, 2020


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 Name: 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 Name: PrSANDOZ MEMANTINE FCT10 mg Drug Identification Number (DIN) 02375532




Primary Outcome Measures :
  1. Rate of Responder versus Non-Responder Status with Memantine [ Time Frame: Week 6 or 14 ]

    "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.


  2. Rate of Responder versus Non-Responder Status with Placebo [ Time Frame: Week 6 or 14 ]

    "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.



Secondary Outcome Measures :
  1. EEG Change with Memantine [ Time Frame: Week 6 or 14 ]

    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.


  2. EEG Change with Placebo [ Time Frame: Week 6 or 14 ]

    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.


  3. Seizure Frequency Change with Memantine [ Time Frame: Week 6 or 14 ]
    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.

  4. Seizure Frequency Change with Placebo [ Time Frame: Week 6 or 14 ]
    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.

  5. Cognitive Function Change with Memantine [ Time Frame: Week 6 or 14 ]
    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.

  6. Cognitive Function Change with Placebo [ Time Frame: Week 6 or 14 ]
    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.

  7. Caregiver Impression of Change with Memantine [ Time Frame: Week 6 or 14 ]
    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.

  8. Caregiver Impression of Change with Placebo [ Time Frame: Week 6 or 14 ]
    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.

  9. Serum Inflammatory Markers Change with Memantine [ Time Frame: Week 6 or 14 ]
    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.

  10. Serum Inflammatory Markers Change with Placebo [ Time Frame: Week 6 or 14 ]
    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.


Other Outcome Measures:
  1. Adverse events [ Time Frame: Week 16 ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03779672


Contacts
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Contact: MYERS KENNETH, MD (514) 412-4446 kenneth.myers@mcgill.ca

Locations
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Canada, Quebec
Children Hospital - MUHC Recruiting
Montréal, Quebec, Canada, H4A 3J1
Contact: Saoussen Berrahmoune, PhD    514-934-1934 ext 76204    saoussen.berrahmoune@rimuhc.ca   
Principal Investigator: Kenneth Myers, MD, PHD, FRCPC         
Sponsors and Collaborators
Kenneth Myers, MD

Publications:
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Responsible Party: Kenneth Myers, MD, Assistant Professor (Clinical), Neurologist Pediatrician, McGill University Health Centre/Research Institute of the McGill University Health Centre
ClinicalTrials.gov Identifier: NCT03779672    
Other Study ID Numbers: 22838
First Posted: December 19, 2018    Key Record Dates
Last Update Posted: March 12, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Kenneth Myers, MD, McGill University Health Centre/Research Institute of the McGill University Health Centre:
Memantine
N-methyl-D-aspartate receptor
Serum inflammatory
Seizure
Additional relevant MeSH terms:
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Brain Diseases
Epilepsy
Central Nervous System Diseases
Nervous System Diseases
Memantine
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents