Post-market Study of AMPA Receptor Antagonists for Epilepsy Patients in Hong Kong

August 25, 2020 updated by: Dr. Howan Leung, Chinese University of Hong Kong

Background:

Epilepsy is a chronic neurological disease which affects approximately 70,000 patients in Hong Kong and 50 billion people worldwide. Among these patients one-third remained unresponsive to antiepileptic agents. Continual drug manipulation is an essential therapeutic option for these patients with refractory epilepsy. In particular, rational polytherapy has become the mainstay of treatment for the sub-group of patients who have failed two or more antiepileptic drugs (AEDs).

A substantial amount of research has shown that N-methyl-D-aspartate receptors (NMDA) may play a key role in the pathophysiology of several neurological diseases, including epilepsy. Animal models of epilepsy and clinical studies demonstrate that NMDA receptors activity and expression can be altered in association with epilepsy and particularly in some specific seizure types. NMDA receptor antagonists have been shown to have antiepileptic effects in both clinical and preclinical studies. There is some evidence that conventional antiepileptic drugs may also affect NMDA receptor function.

Aims:

To investigate the medium to long-term effects of AMPA/NMDA receptor antagonist in an Asian cohort as there is a relative lack of clinical data in this population To explore the efficacy of AMPA/NMDA receptor antagonist in patients with partial onsets seizures that may secondarily generalize and the specific side effects of AMPA/NMDA receptor antagonist in relation to behavioral problems.

Methods:

A semi-prospective design is adopted to recruit patients who are indicated and started on AMPA/NMDA receptor antagonist aged 12 or above in Hong Kong. This study will collect information about demographic details, medical history and seizure information. Assessment of seizure frequency is based on seizure diary and interviews with family members. Physical examination, electrocardiogram and other medical information relevant to the follow-up of the patient will be collected.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Epilepsy is a chronic neurological disease which affects approximately 70,000 patients in Hong Kong and 50 billion people worldwide. Among these patients, one-third remained unresponsive to antiepileptic agents. Continual drug manipulation is an essential therapeutic option for these patients with refractory epilepsy. In particular, rational polytherapy has become the mainstay of treatment for the sub-group of patients who have failed two or more antiepileptic drugs (AEDs).

Using AEDs with different mechanisms of action is a strategy adopted by many doctors around the world. In this regard, perampanel (PER) is an agent which is first in its class, with specific antagonistic action on ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) glutamate receptor of post-synaptic neurons. The pharmacokinetics of PER suggested that it has a half-life of approximately 105 hours and the steady-state concentrations that can be reached in 14 days. PER is approximately 95% bound to plasma proteins. This metabolism is mediated by CYP 3A4 or CYP 3A5. The usual dosage of PER is between 2mg and 12 mg. PER can be administered once daily.

A total of five clinical studies demonstrated the efficacy of PER among patients with refractory epilepsy. These were all double-blind studies and all of them evaluated the 50% responder rate as a seizure outcome. The corresponding risk ratio for 50% responder rates for 4mg, 8mg and 12mg were 1.54, 1.8 and 1.72. The most common treatment-emergent adverse effects were dizziness, drowsiness, headache, fatigue, nasopharyngitis. The pooled results suggested that a higher dose was more efficacious if the side effects could be tolerated. There was an on-going study on the use of PER among patients with secondarily generalized seizures. Perampanel has been approved in many countries such as USA, EU, Australia, Canada, Switzerland, Singapore, and Malaysia, as an adjunctive therapy for refractory partial seizures with or without secondary generalisation among patients above 12 years of age.

A substantial amount of research has shown that N-methyl-D-aspartate receptors (NMDA) may play a key role in the pathophysiology of several neurological diseases, including epilepsy. Animal models of epilepsy and clinical studies demonstrate that NMDA receptors activity and expression can be altered in association with epilepsy and particularly in some specific seizure types. NMDA receptor antagonists have been shown to have antiepileptic effects in both clinical and preclinical studies. There is some evidence that conventional antiepileptic drugs may also affect NMDA receptor function.

Study Type

Observational

Enrollment (Anticipated)

80

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Hong Kong
      • Hong Kong, Hong Kong, 0000
        • Recruiting
        • Prince of Wales Hospital
        • Contact:
        • Principal Investigator:
          • Ho Wan Leung

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

12 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Patients (diagnosed epilepsy with simple partial seizure) who have a baseline seizure rate of more than 2 months would be provided perampanel as adjunctive treatment.

Description

Inclusion Criteria:

  1. Subject aged 12 years or above
  2. Subject has a diagnosis of epilepsy with simple partial seizure and/or complex partial seizures
  3. Subjects who have a baseline seizure rate of more than 2 per month in the eight week period preceding the start of AMPA / NMDA receptor antagonist
  4. No seizure free period longer than 21 days during the eight week period before AMPA receptor antagonist was started
  5. Patients who already had neuropsychiatric inventory completed twice during the treatment period spanning at least 16 weeks.

Exclusion Criteria:

  1. Subjects with idiopathic generalised epilepsy (for example, juvenile myoclonic epilepsy and absence epilepsy)
  2. Patients who only suffer from isolated auras
  3. Baseline creatinine clearance of less than 50ml/min
  4. Severe hepatic impairment with ALT three times the upper limits of normal
  5. Significant psychiatric conditions before the start of AMPA / NMDA receptor antagonist
  6. Progressive neurodegenerative conditions
  7. Active history of malignancy
  8. History of severe haematological conditions or serious blood dyscrasias
  9. Corrected QT interval more than 450 milli-second on ECG
  10. Substance abuse
  11. Pregnancy, breastfeeding

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Adjunctive Perampanel
A group of patients who aged 12 years or above and have a diagnosis of epilepsy with simple partial seizure and/or complex partial seizures
Drug: Perampanel
This study collects clinical information during the first 16 weeks after the first dose of AMPA/NMDA receptor antagonist. Subjects or caregivers shall provide seizure diary which documents seizure type and seizure frequency as per usual medical care. The final visit will be based on the week-16 visit.
Other Names:
  • Fycompa

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Efficacy end-points
Time Frame: 16 weeks
The primary efficacy end-points evaluates seizure frequency (per month) in week 0 (baseline) and week 16 (maintenance phase). The investigators will used those seizure frequencies (per month) to calculate the percentage change from baseline to maintenance phase for each subject and categories: no change, between 0 to 50% decrease, 50% to 75% decrease, 75% to 100% decrease.
16 weeks
Seizure freedom rate in study population
Time Frame: 16 weeks
The proportion of subjects achieving seizure freedom during the maintenance period will be documented. The percentage of seizure free days in the maintenance phase will also be collected. The investigators will report the seizure freedom rate for the present study population and the average days of achieving seizure freedom.
16 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Psychiatric and behavioral adverse events
Time Frame: 16 weeks
The investigators would use the Neuropsychiatric Inventory Questionnaire (NPI) with 12 domains to evaluate the neuropsychiatric events in week 0 (baseline) and week 16 (maintenance phase). The investigators will record each symptom severity (rated 1 occasional to 4 very frequent) and frequency (rated 1 mild to 3 severe).
16 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Chinese University of Hong Kong

Investigators

  • Principal Investigator: Ho Wan Leung, Chinese University of Hong Kong

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 23, 2016

Primary Completion (Anticipated)

July 1, 2021

Study Completion (Anticipated)

July 1, 2021

Study Registration Dates

First Submitted

February 25, 2018

First Submitted That Met QC Criteria

March 1, 2018

First Posted (Actual)

March 8, 2018

Study Record Updates

Last Update Posted (Actual)

August 27, 2020

Last Update Submitted That Met QC Criteria

August 25, 2020

Last Verified

August 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2016-HL-001

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

This is a cohort study for perampanel in Hong Kong. There is no plan to make individual participant data to share. The results would be shared in publications. Electronic data will be saved in secured computer of the individual sites with restricted access. The anonymous data will be managed installed for developing future studies.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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