Sulthiame add‐on therapy for epilepsy
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To compare the efficacy and side‐effect profile of sulthiame as an add‐on therapy when compared to placebo or another AED.
Background
Description of the condition
Epilepsy is a common neurological condition which is characterised by recurrent seizures. It has an estimated worldwide prevalence of between eight and 10 per 1,000 of the general population (WHO 2001). The majority of patients will respond well to conventional antiepileptic drugs (AEDs) (Epilepsia 1997), although around 30% will not achieve remission (Sander 1993; Schmidt 1995; Brodie 1996) despite trying numerous antiepileptic drugs, often in combination. In an attempt to improve outcomes for these drug refractory patients, a number of newer potential antiepileptic drugs have been assessed over the past 20 to 30 years.
Sulthiame is used widely as an AED in some European countries and Israel (Gross‐Selbeck 2001; Koepp 2002; Engler 2003; Ben‐Zeev 2004; Chahem 2007).
When used as monotherapy, sulthiame has been reported to reduce the occurrence of seizures and reduce electroencephalograpic (EEG) discharges in patients with benign epilepsy of childhood with centrotemporal spikes (Rating 2000; Bast 2003; Ben‐Zeev 2004; Wirrell 2008), benign partial epilepsy of childhood (Engler 2003; Ben‐Zeev 2004), symptomatic, localisation‐related epilepsy, juvenile myoclonic epilepsy (Ben‐Zeev 2004) and adults with refractory epilepsy and learning disability (Koepp 2002).
In addition, sulthiame as an add‐on therapy has been reported to reduce seizure activity in patients with refractory epilepsy (Livingston 1967; Chahem 2007; Miyajima 2009).
Reported adverse effects of sulthiame include deterioration of reading ability, memory, attention skills and mathematic ability (Wirrell 2008), mixed respiratory and metabolic acidosis (Weissbach 2010) and crystalluria (Go 2006).
Description of the intervention
Sulthiame is usually taken in tablet form, with doses taken two to three times per day.
How the intervention might work
Sulthiame is a sulphonamide which may exert its antiepileptic activity by producing a modest intracellular acidosis in central neurons via its action as a carbonic anhydrase inhibitor, thereby reducing the frequency of action potentials and epileptiform bursts (Leniger 2002).
Why it is important to do this review
A summary of the best available evidence about the efficacy and tolerability of sulthiame for patients with refractory epilepsy is required to inform the use of this drug and to inform decisions about the further assessment of this drug.
Objectives
To compare the efficacy and side‐effect profile of sulthiame as an add‐on therapy when compared to placebo or another AED.
Methods
Criteria for considering studies for this review
Types of studies
(1) Randomised controlled trials (RCTs).
(2) Double, single or unblinded trials.
(3) Placebo controlled trials.
(4) Parallel group or crossover studies.
Types of participants
(1) Patients with refractory epilepsy (defined as epilepsy in which seizure control is not adequately managed with one or more antiepileptic drugs).
(2) Patients of any age.
(3) Patients with epilepsy of any aetiology.
Types of interventions
(1) For the active treatment group, sulthiame as an adjunct to the participant's AED regimen.
(2) For the control group, placebo or another AED added to the participant's AED regimen.
Types of outcome measures
Primary outcomes
(1) A reduction in seizure frequency of 50% or greater. We have selected this outcome as it is commonly reported in studies assessing the efficacy of AEDs.
Secondary outcomes
(1) Complete cessation of seizures during follow‐ up.
(2) Mean in seizure frequency.
(3) Time to treatment withdrawal; reflective of both intolerable adverse effects and lack of efficacy.
(4) Any reported adverse drug effects such as, but not limited to, deterioration in cognitive ability, crystalluria or respiratory and metabolic acidosis.
(5) Overall improvement or deterioration in quality of life.
Search methods for identification of studies
Electronic searches
We will search the following databases:
(a) The Cochrane Epilepsy Group Specialised Register, using the search term "sulthiame OR Ospolot";
(b) The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) using the search strategy outlined in Appendix 1;
(c) MEDLINE (Ovid) using the search strategy outlined in Appendix 2;
(d) The International Clinical Trial Registry Platform (http://apps.who.int/trialsearch), using the search term "sulthiame OR Ospolot".
We will not impose any language restrictions.
Searching other resources
We will check the reference lists of retrieved reports to check for additional reports of relevant studies. We will also contact the manufacturers of sulthiame, and colleagues in the field for information about ongoing or unpublished studies.
Data collection and analysis
Selection of studies
Two review authors (PMM and GP) will assess studies for inclusion independently. We will resolve disagreements by discussion.
Data extraction and management
We plan to extract data from the trials and assess the design of the trials and demographic makeup of the participants in addition to the outcomes listed in the Types of outcome measures section. Two review authors (PMM and GP) will assess studies independently and disagreements will be resolved by discussion.
Trial design
(1) Method of randomisation
(2) Method of concealment
(3) Duration of baseline period
(4) Duration of treatment period
(5) Duration of "wash‐out" period for crossover studies
(6) Dose of sulthiame
(7) Description of adverse effects
(8) Description of withdrawals and drop‐outs
Demographic information
(1) Number of patients in treatment group
(2) Number of patients in control group
(3) Age
(4) Sex
(5) Type of seizure and epilepsy
(6) Mean baseline seizure frequency
(7) Which AED(/s) participants are already established on
Assessment of risk of bias in included studies
Two review authors (PMM and GP) will assess the quality of each study's methodology independently using the factors outlined in the Data extraction and management section. We will resolve disagreements by discussion.
Measures of treatment effect
For binary data, we plan to express relative treatment effects as risk ratios (RR) with 95% confidence intervals (CI) and for continuous data, mean difference (MD) with 95% CI. A P value of less than 0.05 will qualify statistical significance.
Dealing with missing data
We plan to implement an intention‐to‐treat analysis, assuming treatment withdrawal to be due to either lack of efficacy or intolerable adverse effects. We plan to calculate any missing statistics from the raw data where possible.
Assessment of heterogeneity
We will assess methodological heterogeneity by comparing each trial for aspects outlined in the trial design section of Data extraction and management. We will assess clinical heterogeneity by comparing each trial for aspects outlined in the demographic information section of Data extraction and management. We will assess statistical heterogeneity using the I squared test.
Assessment of reporting biases
We will report bias according to Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Sterne 2008). If we identify sufficient RCTs, we will devise a funnel plot to help identify publication bias and investigate any visual asymmetry by exploratory analysis. We will attempt to obtain source data for any studies included in the analysis in order to assess any non‐reported outcomes.
Data synthesis
We plan to analyse data in a meta‐analysis using a random‐effects model within Review Manager 5 (RevMan 2011), provided this is clinically appropriate, and we find no evidence of substantial heterogeneity. We will use a fixed‐ effects model to perform meta‐analysis if we do find evidence of substantial heterogeneity.
Subgroup analysis and investigation of heterogeneity
We plan to assess separately the effects of sulthiame in patients with focal epilepsy and patients with generalised epilepsy.
Sensitivity analysis
To assess the influence on results of studies of poor methodological quality we will undertake analyses with and without these studies.
