Description of the condition
Epilepsy is one of the most common neurological disorders, with an incidence of 55 cases per 100,000 population in the United States and in Europe every year and a prevalence of five to 10 cases per 1000 population (Hesdorffer 2011). It is estimated to affect nearly 70 million people worldwide, and its prevalence in developing areas is reported to be twice that in developed regions (Ngugi 2011). More than half of patients with newly diagnosed epilepsy achieve seizure control without major adverse effects; however, approximately 30% of patients do not respond to one or more licenced agents, and they are considered drug resistant (Schuele 2008). In contrast to patients with well-controlled seizures, complications and comorbidities, such as cognitive impairment and psychosocial and psychiatric disorders, are common in those with drug-resistant epilepsy (Schmidt 2002). Thus, safer and more effective drugs are needed for these patients.
Description of the intervention
Perampanel, an orally active, non-competitive amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, was recently approved in the United States and the European Union as adjunctive treatment for partial epilepsy in patients 12 years of age and older. When orally administered, perampanel is well absorbed through the gastrointestinal tract and reaches a peak plasma concentration after 15 minutes to two hours of administration. Its plasma elimination half-life is approximately 105 hours, allowing once-daily dosing. About 70% of the orally active perampanel is excreted into faeces in the unchanged form, whereas 30% is excreted through the urine (Franco 2013; Owen 2013; Plosker 2012; Rektor 2013; Shvarts 2013). Perampanel is well tolerated across a range of doses from 4 to 12 mg daily. The most frequent adverse effects of treatment include dizziness, somnolence, fatigue and headache (Krauss 2012).
How the intervention might work
AMPA receptors, the main mediators of glutamate, mediate fast postsynaptic excitatory neurotransmission in the central nervous system are critical for the generation and spread of epileptic seizures (Rogawski 2011; Rogawski 2013). Perampanel is a highly selective, non-competitive AMPA receptor antagonist that may exert its antiepileptic effect through selective inhibition of AMPA receptors (Ceolin 2012; Hanada 2011), but it has no significant affinity for kainate and N-methyl-d-aspartate (NMDA) receptors, which are thought to minimise the unexpected effects (Ceolin 2012; Rogawski 2011).
Why it is important to do this review
The novel antiepileptic agent perampanel has demonstrated broad-spectrum antiepileptic effects in animal models of epilepsy (Ceolin 2012; Hanada 2011). In addition, very recent randomised controlled trials (RCTs) have shown that adjunctive treatment with perampanel has possible effects in reducing seizure frequency and has an acceptable safety profile in patients with drug-resistant partial epilepsy. These RCTs have not as yet been systematically reviewed (French 2012; French 2013; Krauss 2012a). This review will therefore focus on the use of perampanel as an add-on therapy for drug-resistant partial epilepsy, summarising evidence about efficacy and safety from the identified RCTs.
To investigate the efficacy and safety of perampanel as an add-on therapy for drug-resistant partial epilepsy.
Criteria for considering studies for this review
Types of studies
Studies will be included if they meet all of the following criteria.
- Randomised controlled trials (RCTs) with an adequate method of concealment of randomisation.
- Double-blind trials in which both participants and treating personnel or outcome assessors were blinded to treatment.
- Placebo-controlled trials.
- Parallel-group or cross-over trials. For cross-over trials, we will include only first treatment period results.
- Trials in which treatment duration of at least eight weeks and baseline seizure data were recorded.
Types of participants
Patients of any age with partial epilepsy (defined as seizures that affect only part of the brain at onset, including simple partial, complex partial or secondary generalised tonic-clonic seizures) who have failed to respond to one or more antiepileptic drugs, or with refractory partial epilepsy according to the definition recently released by the International League Against Epilepsy, are eligible (Kwan 2010).
Types of interventions
- The intervention treatment group will receive perampanel, in addition to one or more existing antiepileptic drugs, from the time of randomisation.
- The control group will be given matched placebo, in addition to one or more existing antiepileptic drugs, from the time of randomisation.
Types of outcome measures
50% or greater reduction in seizure frequency
The proportion of participants with a 50% or greater reduction in seizure frequency from prerandomisation baseline to treatment period. We chose this outcome because it is often reported in this type of study and can be calculated for studies that did not report it, provided that baseline seizure data were recorded.
The proportion of participants with seizure freedom during the whole treatment period.
We will use as a measure of global effectiveness the proportion of participants who withdrew for any reason during the course of the treatment period. Treatment may be withdrawn because of adverse effects, lack of efficacy or a combination of both. Adverse effects are usually the main reason for treatment withdrawal in trials of short duration; we will also assess the proportion of participants who had treatment withdrawn because of adverse effects.
- The proportion of participants experiencing any common adverse effects in relation to perampanel, including dizziness, somnolence, fatigue, ataxia and headache or other clinically important adverse effects reported in the included trials.
- The proportion of participants who experience at least one adverse effect.
Search methods for identification of studies
We will search the following databases.
- Cochrane Epilepsy Group Specialised Register.
- Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library.
- MEDLINE (Ovid).
- WHO International Clinical Trials Registry Platform (ICTRP).
The proposed search strategy for MEDLINE is set out in Appendix 1. This strategy will be modified for use with the other databases.
Searching other resources
We will review the reference lists of retrieved studies to search for additional reports of relevant studies. We will contact pharmaceutical manufacturers and original investigators of relevant trials to identify additional published or unpublished data. We will also search the abstracts from recent years of the International Epilepsy Congress.
Data collection and analysis
Selection of studies
Two review authors (Huang J, Xiao Y) will independently read the titles and abstracts of all studies identified by the search strategy. Once we have retrieved all potential relevant papers, each review author will independently evaluate the full text of each paper for inclusion. We will resolve any disagreements by discussion, or with a third author (Wang J) acting as an arbitrator if necessary.
Data extraction and management
Two review authors (HJ and XY) will independently extract the following data, using a data extraction form.
- Participants: seizure types, total and number in each group, age, gender, seizure frequency at the time of randomisation, exclusion criteria.
- Methods: study design, randomisation method, allocation concealment method, blinding methods.
- Interventions: details of perampanel treatment, such as administration method, dosage and duration, number of background drugs.
- Outcomes: the proportion of participants with a 50% or greater reduction in seizure frequency, the proportion of participants with seizure freedom during the whole treatment period, the proportion of participants who withdrew during the course of the treatment period for any reason, the proportion of participants experiencing dizziness, somnolence, fatigue and headache or other clinically important adverse effects reported in the included trials.
- Other: country and setting, publication year, sources of funding, intention-to-treat (ITT) analysis.
Any disagreements will be resolved by discussion between the two review authors.
Assessment of risk of bias in included studies
Two review authors (HJ and XY) will independently assess the risk of bias of included trials using the risk of bias tool recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The risk of bias tool consists of six specific parameters: (1) sequence generation, (2) allocation concealment, (3) blinding, (4) incomplete outcome data, (5) selective outcome reporting and (6) other bias. For each entry, the judgement ('low risk' of bias, 'high risk' of bias or 'unclear risk' of bias) is followed by a description of the design, conduct or observations that underlie the judgement (Higgins 2011). We will also assess the potential impact of outcome reporting bias by placing an ORBIT table into the review (Kirkham 2010).
Any disagreements will be evaluated by discussion between the two review authors, or with a third review author (WJ) acting as an arbitrator if necessary.
Measures of treatment effect
Data will be managed according to the intention-to-treat principle. For dichotomous outcomes (50% or greater reduction in seizure frequency, seizure freedom, treatment withdrawal), we will use risk ratios (RRs) with 95%confidence intervals (CIs) to analyse the outcomes. For individual adverse effects, 99% CIs are quoted to make allowance for multiple testing. For the primary analysis, participants not completing follow-up or with inadequate seizure data were assumed to be non-responders.
Unit of analysis issues
We will deal with any unit of analysis issues according to guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). For cross-over studies, only the first period data will be included for analyses.
Dealing with missing data
If data are insufficient or missing, we will attempt to obtain additional information from the authors of included studies through personal communication. If we do not receive a response, we will analyse the available data according to the intention-to-treat principle.
Assessment of heterogeneity
Clinical and methodological heterogeneity of included trials will be evaluated by comparing the characteristics of participants (age, seizure frequency, epilepsy duration and geographical origin of included participants), interventions (administration dose and duration, cointerventions) and study design (randomisation, allocation concealment and blinding methods) between studies. Statistical heterogeneity will be evaluated among the included studies using a Chi² test with significance set at 0.1 and the I² statistic. A P value greater than 0.1 indicates no significant statistical heterogeneity. If a P value from the Chi
- 0% to 40%: might not be important.
- 30% to 60%: may represent moderate heterogeneity*.
- 50% to 90%: may represent substantial heterogeneity*.
- 75% to 100%: represents considerable heterogeneity*.
*The importance of the observed value of the I² statistic depends on (1) the magnitude and direction of effects and (2) the strength of the evidence for heterogeneity (e.g. P value from the Chi² test or a confidence interval for the I² statistic).
Assessment of reporting biases
If more than 10 studies are identified, we will investigate potential biases of publications using funnel plots and visual inspection for asymmetry to assess reporting bias according to the approach outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Review Manager 5.2 (RevMan 2012) will be used to synthesise the available data. Whether a fixed-effect or a random-effects model is used depends mainly on the results of the Chi² test and the I² statistic for heterogeneity (Higgins 2011). If a P value is greater than 0.1, indicating no significant statistical heterogeneity, we will use a fixed-effect model. If a P value is less than 0.1 and the I² statistic indicates no important or moderate heterogeneity, we will use a fixed-effect model. If a P value is less than 0.1 and the I² statistic indicates substantial heterogeneity, we will first explore factors contributing to heterogeneity to determine whether a subgroup analysis is needed. If the substantial heterogeneity cannot readily be explained, we will adopt a random-effects model.
Subgroup analysis and investigation of heterogeneity
If sufficient trials are identified, we will perform subgroup analyses according to the different ages of participants (children younger than 17 years vs adults) and the different doses of perampanel.
We will perform sensitivity analyses if missing data for the primary outcome are available from the study authors.
We would like to thank the contact editor and the Cochrane Epilepsy Review Group for their help in developing this review. We would also like to thank the peer reviewers for their suggestions and comments.
Appendix 1. MEDLINE search strategy
This strategy is based on the Cochrane Highly Sensitive Search Strategy for identifying randomised trials (Lefebvre 2011).
1. randomized controlled trial.pt.
2. controlled clinical trial.pt.
5. clinical trials as topic.sh.
8. 1 or 2 or 3 or 4 or 5 or 6 or 7
9. exp animals/ not humans.sh.
10. 8 not 9
11. exp Epilepsy/
12. exp Seizures/
13. (epilep$ or seizure$ or convuls$).tw.
14. 11 or 12 or 13
15. (perampanel or fycompa).tw.
16. 10 and 14 and 15
Contributions of authors
All authors listed contributed to this protocol. Dr Jianyi Huang and Dr Yousheng Xiao contributed equally to this protocol.
Declarations of interest