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.
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 Treatment may be withdrawn because of adverse effects, lack of efficacy or a combination of both.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treatment withdrawal in trials of short duration; we will also assess the proportion of participants who had treatment withdrawn because of adverse effects.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.
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 Chi2 test is less than 0.1, we will interpret heterogeneity according to percentage ranges of the I² statistic, as follows (Higgins 2011).
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.