Eslicarbazepine acetate add‐on for drug‐resistant partial epilepsy
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To evaluate the efficacy and tolerability of ESL when used as an add‐on treatment for people with drug‐resistant partial epilepsy.
Background
Description of the condition
Epilepsy is a common neurological condition. The incidence of epilepsy is estimated to be about 50 per 100,000 in a year (range 40 to 70) in the developed world, and it seems higher in less developed countries. Prevalence is around 5 to 10 per 1000 in most settings (Sander 2003).
The majority of people with epilepsy have a good prognosis but up to 30% of patients continue to have seizures despite several regimens of antiepileptic drugs (AEDs) (Walker 1997).
People with refractory epilepsy often experience psychosocial, psychiatric and medical comorbidities, which are due to recurrent seizures, long‐term drug effects and employment restrictions (Schuele 2008). The new drug eslicarbazepine acetate may help to alleviate some of these problems by reducing seizure frequency.
Description of the intervention
Over the past two decades, a large number of AEDs have been licensed in the world. Eslicarbazepine acetate (ESL) is a novel, once daily antiepileptic drug under development for the adjunctive treatment of drug‐resistant epilepsy. It shares a similar structure with carbamazepine and oxcarbazepine but does not inhibit most cytochrome P450 enzymes (CYP450) and has a low potential for drug interaction (Almeida 2007). Eslicarbazepine is the main active component of ESL and its pharmacokinetics are not affected by age, gender, food or moderate hepatic impairment, but clearance of ESL is dependent on renal function (McCormack 2009; Mestre 2009).
How the intervention might work
Eslicarbazepine acetate is a drug whose main mechanism of action is thought to work by blocking voltage‐gated sodium channels (VGSCs) (Almeida 2007).
Why it is important to do this review
ESL was launched onto the UK market in 2009 as an adjunctive therapy in adults with partial‐onset seizures, with or without secondary generalisation. In this review, we will assess the efficacy and tolerability of ESL when used as an add‐on treatment in patients with drug‐resistant partial epilepsy.
Objectives
To evaluate the efficacy and tolerability of ESL when used as an add‐on treatment for people with drug‐resistant partial epilepsy.
Methods
Criteria for considering studies for this review
Types of studies
(1) Randomized controlled trials (RCTs) in which an adequate method of concealment of randomization is used (e.g. sequential allocation of sealed packages of medication, sealed opaque envelopes, telephone randomization).
(2) Double blind trials in which both participant and clinician treating or assessing the outcome are blinded to the treatment allocated.
(3) Placebo controlled.
(4) Parallel group or cross‐over studies. For cross‐over studies, we plan to use the first treatment period as a parallel trial.
Types of participants
People of any age with drug‐resistant partial epilepsy (that is experiencing simple partial, complex partial or secondary generalized tonic‐clonic seizures).
In this review, drug resistance is defined as continued seizures despite treatment with one or more antiepileptic agents.
Types of interventions
(1) The active treatment group received ESL in addition to an existing antiepileptic drug regimen at the time of randomization.
(2) The control group received a matched placebo in addition to an existing antiepileptic drug regimen at the time of randomization.
Types of outcome measures
Primary outcomes
A 50% or greater reduction in seizure frequency
The proportion of people with a 50% or greater reduction in seizure frequency within the treatment period compared to the pre‐randomization, baseline period is the primary outcome. It is chosen because it is a commonly reported outcome and can be calculated for studies that did not report this outcome provided that baseline seizure data were recorded.
Secondary outcomes
Freedom from seizures
The proportion of patients with complete cessation of seizures from randomization to the trial conclusion.
Treatment withdrawal
The proportion of participants withdrawn from treatment, for any reason, during the course of the treatment period will be used as a measure of global effectiveness. Treatment is likely to be withdrawn due to adverse effects, lack of efficacy, or a combination of both, and this is an outcome to which the individual makes a direct contribution. In trials of short duration, it is likely that adverse effects will be the most common reason for withdrawal. We will also assess the proportion of people having treatment withdrawn because of adverse effects.
Adverse effects
(a) The proportion of participants experiencing any of the following five adverse effects, which we consider to be common and important adverse effects of antiepileptic drugs:
(i) ataxia;
(ii) dizziness;
(iii) fatigue;
(iv) nausea;
(v) somnolence.
(b) The proportion of participants experiencing rash and the five most common adverse effects different from (a) above.
Drug interactions
Any drug interactions reported in included studies.
Search methods for identification of studies
Electronic searches
We will search the following electronic databases for RCTs and impose no language restrictions.
(a) The Cochrane Epilepsy Group Specialized Register.
(b) MEDLINE (PubMed): the proposed strategy is outlined in Appendix 1.
(c) The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library): the proposed strategy is outlined in Appendix 2.
Searching other resources
We will review the reference lists of retrieved studies to search for additional reports of relevant studies. We will also contact the manufacturers of ESL and experts in the field for information about any unpublished or ongoing studies.
Data collection and analysis
Two review authors (CXC and YH) will independently assess trials for inclusion. We will compare results and resolve any disagreements by discussion. If a disagreement is not resolved, a third review author will be asked to arbitrate. We plan to obtain the following information for each trial meeting our inclusion criteria.
Selection of studies
The process for selecting studies for inclusion in the review will involve merging search results using reference management software and removing duplicates of the same report. We will examine titles and abstracts to remove obviously irrelevant reports. We will retrieve the full texts of these reports and examine studies for compliance with eligibility criteria. The authors will agree on trials for inclusion before proceeding to data collection.
Data extraction and management
The same two review authors will extract the following information from included trials. Disagreements will again be resolved by discussion. If a disagreement is not resolved, a third review author will be asked to arbitrate.
(1) Methodology and trial design:
(a) method of randomization concealment;
(b) method of blinding;
(c) whether any participants had been excluded from reported analyses;
(d) duration of baseline period;
(e) duration of treatment period;
(f) dose(s) of ESL tested.
(2) Participant and demographic information:
(a) total number of participants allocated to each treatment group;
(b) age and sex;
(c) numbers with partial and generalized epilepsy;
(d) seizure types;
(e) number of and background drugs;
(f) seizure frequency during the baseline period.
(3) Outcomes
We will record the number of participants experiencing each outcome (see Types of outcome measures) per randomized group.
(4) Where necessary, original authors will be asked to confirm the following information:
(a) method of randomization;
(b) total number of patients randomized to each group;
(c) number of individuals in each group achieving a 50% or greater reduction in seizures;
(d) number of individuals having treatment withdrawn post‐randomization per treatment group;
(e) for those excluded: the reason for exclusion, whether any of those excluded completed the treatment phase, whether any of those excluded had a 50% or greater reduction in seizure frequency during the treatment phase.
Assessment of risk of bias in included studies
The methodological quality of the studies will be evaluated according to the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009). We will exclude studies with a high risk of bias.
Measures of treatment effect
For dichotomous data, the risk ratio (RR) and 95% confidence interval (CI) will be determined.
For continuous data, we will use mean difference (MD) and 95% CI.
Dealing with missing data
We will contact the manufacturers and original investigators of relevant trials to identify any additional published or unpublished data.
Assessment of heterogeneity
We will assess clinical heterogeneity by comparing the distribution of important patient factors between trials (age, seizure type, duration of epilepsy, number of AEDs taken at time of randomization) and trial factors (randomization concealment, blinding, losses to follow up). Statistical heterogeneity will be assessed by using the I2 statistic as well as the Chi2 test for heterogeneity. If heterogeneity exists, potential causes will be explored. If heterogeneity does not exist, data will be synthesised using a fixed‐effect model.
Assessment of reporting biases
The possibility of publication bias will be explored using funnel plots where appropriate, that is if there are sufficient number of trials for the relevant comparisons.
Data synthesis
Data synthesis and analysis will be performed using the Cochrane Review Manager Software, RevMan 5. The preferred estimator is relative risk (RR). For the outcome measures of 50% reduction in seizure frequency and treatment withdrawal, 95% CIs will be quoted. For individual side effects, 99% CIs are to be quoted to make allowance for multiple testing (Bonferroni correction). Analyses will include all patients in the treatment groups to which they were allocated (intention to treat).
For the efficacy outcome (50% or greater reduction in seizure frequency) three analyses will be undertaken.
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Primary (intention‐to‐treat) analysis: patients not completing follow up or with inadequate seizure data will be assumed to be non‐responders.
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Worst case: patients not completing follow up or with inadequate seizure data will be assumed to be non‐responders in the ESL group and responders in the placebo group.
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Best case: patients not completing follow up or with inadequate seizure data will be assumed to be responders in the ESL group and non‐responders in the placebo group.
Dose regression analysis: we also plan to examine dose response relationships using logistic regression in the framework of generalized linear models (McCullagh 1989). Probabilities for the following will be calculated for differing doses: (i) the percentage of patients having a 50% response; and (ii) the difference in the percentage of patients responding to each dose compared to placebo. A binary variable will be defined with value 0 if the response was less than 50% and value 1 otherwise.
Subgroup analysis and investigation of heterogeneity
If possible, we will undertake a subgroup analysis according to different doses of ESL and age (children less than 17 years versus adult).
Sensitivity analysis
We plan to do a sensitivity analysis to test the robustness of the meta‐analysis.
