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

Focal Epilepsy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03457961
• Other study ID #: 2016-HL-001
• Status: Recruiting
• Start date: July 23, 2016
• Est. completion date: July 1, 2021

Study information

• Verified date: August 2020
• Source: Chinese University of Hong Kong
• Contact: Sau Man Celia Tse
• Phone: 85257431802
• Email: saumanceliatse[@]cuhk.edu.hk
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: July 1, 2021
• Est. primary completion date: July 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Epilepsies, Partial
• Epilepsy
• Epilepsy, Generalized
• Focal Epilepsy
• Generalized Epilepsy
• Partial Seizures, Simple
• Seizures

Intervention

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.

Locations

Country	Name	City	State
Hong Kong	Prince of Wales Hospital	Hong Kong

Sponsors (1)

Lead Sponsor	Collaborator
Chinese University of Hong Kong

Country where clinical trial is conducted

Hong Kong, 

References & Publications (3)

Juhl S, Rubboli G. Perampanel as add-on treatment in refractory focal epilepsy. The Dianalund experience. Acta Neurol Scand. 2016 Nov;134(5):374-377. doi: 10.1111/ane.12558. Epub 2016 Jan 13. — View Citation

Steinhoff BJ, Bacher M, Bast T, Kornmeier R, Kurth C, Scholly J, Staack AM, Wisniewski I. First clinical experiences with perampanel--the Kork experience in 74 patients. Epilepsia. 2014 Jan;55 Suppl 1:16-8. doi: 10.1111/epi.12492. — View Citation

Trinka E, Steinhoff BJ, Nikanorova M, Brodie MJ. Perampanel for focal epilepsy: insights from early clinical experience. Acta Neurol Scand. 2016 Mar;133(3):160-72. doi: 10.1111/ane.12529. Epub 2015 Oct 28. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Efficacy end-points	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
Primary	Seizure freedom rate in study population	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	Psychiatric and behavioral adverse events	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