Zonisamide monotherapy for epilepsy
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective is to assess the efficacy and tolerability of zonisamide monotherapy for partial onset seizures and generalized onset tonic‐clonic seizures in children and adults.
Background
Epilepsy is a common neurological condition, with an estimated incidence of 50 per 100,000 and prevalence of 5 to 10 per 1000 in the developed world (Sander 1996). Between two and three per cent of the population will be given a diagnosis of epilepsy at some time in their lives, the majority of whom will go into remission. However, up to 30% will fail to respond to monotherapy (Cockerell 1995; Hauser 1993), often requiring the use of newer antiepileptic drugs (AEDs). Given that standard AEDs (e.g. carbamazepine, phenytoin, valproate) do not control all patients' seizures, and cause a number of side effects, over the past 15 to 20 years, there has been renewed interest in the development of new AEDs. Zonisamide is a new generation antiepileptic drug, exhibiting broad spectrum antiepileptic activity.(Leppik 2004) This newer antiepileptic drug originally developed and marketed in Japan, has multiple mechanisms of action including blockage of sodium channels, T‐type Calcium channels, increasing GABA release from hippocampus and scavenging hydroxyl and nitric oxide radicals (Sackellares 2004). It has been approved both as an add‐on and as monotherapy in Japan (Masuda 1998) for the control of partial or generalized seizures in adults and in children (Yagi 2004). The data from non systematic reviews support the suggestion that zonisamide monotherapy is effective for variety of seizures including partial seizures, in adults and children (Brodie 2004; Fukushima 2004; Seki 2004; Yagi 2004; Yamauchi 2004).
In this review we will investigate the efficacy and tolerability of zonisamide monotherapy for partial onset seizures and generalized onset tonic‐clonic seizures in children and adults. This review is part of a series of reviews investigating the new AEDs as monotherapy.
Objectives
The objective is to assess the efficacy and tolerability of zonisamide monotherapy for partial onset seizures and generalized onset tonic‐clonic seizures in children and adults.
Methods
Criteria for considering studies for this review
Types of studies
(1) Randomized parallel group monotherapy trials which include zonisamide versus placebo or zonisamide versus standard antiepileptic drug treatment.
(2) The studies may be double blind, single blinded or unblinded.
(3) The studies should have either adequate or quasi methods (e.g. by date of birth) of randomization.
(4) The studies which are not fulfilling the inclusion criteria and those studies which are inadequately randomized are excluded.
Types of participants
(1) Children or adults with partial onset seizures (simple partial, complex partial, or secondarily generalized tonic‐clonic seizures) or generalized onset tonic‐clonic seizures (with or without other generalized seizure types).
(2) People treated with monotherapy.
Types of interventions
Zonisamide monotherapy versus placebo or standard antiepileptic drug treatment
Types of outcome measures
(1) Time to withdrawal of allocated treatment (retention time) was chosen as the primary outcome. Participants achieved this outcome if allocated treatment was withdrawn for poor seizure control, adverse effects, non‐compliance or if additional add‐on treatment was initiated (i.e. allocated treatment had failed). This is a combined outcome reflecting both efficacy and tolerability and is an outcome to which the individual makes a contribution. It is the primary outcome measure recommended by the Commission on Antiepileptic Drugs of the International League Against Epilepsy (Commission 1998).
(2) Time to achieve 12‐month or 24 month remission (seizure‐free period).
(3) Time to achieve six‐month remission.
(4) Time to first seizure post randomization.
(5) Proportion of participants remaining seizure free for six months, one year and two years.
(6) Validated quality of life measures like overall quality of life or any of the sub domains.
(7) Adverse effects
(a) The proportion of participants experiencing any of the following five adverse effects, that we considered 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 the ten most common adverse effects if different from (a) above.
Search methods for identification of studies
(1) We will search the Epilepsy Group Specialized Register. This register contains reports of trials identified from regular searches of the Cochrane Central Register of Controlled Trials (CENTRAL) and of MEDLINE. Relevant reports are also identified by handsearching selected journals and conference proceedings. A more detailed description of this activity is given in the Specialized Register section of the Cochrane Epilepsy Group module.
(2) We will review the reference lists of retrieved studies to search for additional reports of relevant studies.
(3) We will contact the manufacturers and original investigators of relevant trials to identify any additional published or unpublished data.
(4) We will attempt to get the English translation of non English language studies and include those studies.
Data collection and analysis
Trial identification and data collection
Two review authors will independently assess trials for inclusion based on a pre determined strategy. Results will be compared and any disagreements will be resolved by discussion.
The effectiveness and efficacy outcomes chosen for this review are time to event outcomes and require analysis using survival methods. The most effective way to assess time to event outcomes in a meta‐analysis is to use original datasets also known as individual patient data (IPD). In the first instance we plan to use aggregate data. If our results suggest that an IPD approach is worth‐while this will be undertaken and reported in an update of this review.
We plan to obtain the following information for each trial meeting our inclusion criteria. If the information is not available in the published manuscript we will contact the original investigators for further data.
Methodological/trial design
(1) Method of randomization.
(2) Method of concealment of randomization.
(3) Stratification factors.
(4) Methods of blinding.
(5) Description of withdrawals and dropouts.
6)Duration of baseline period.
(7) Duration of treatment period.
(8) Dose(s) of zonisamide tested.
Patient factors
(1) Seizure type(s).
(2) Age.
(3) Sex.
(4) Presence of neurological deficit/signs at baseline.
(5) Number of seizures or Seizure frequency prior to randomization.
(6) Duration of Epilepsy.
(7) Electroencephalography (EEG) results at baseline.
(8) Etiology of epilepsy and imaging data.
Treatment data
Medication dose per treatment group.
Outcomes
Outcomes data as listed earlier.
Time to event effectiveness and efficacy measures will be estimated from:
(1) hazard ratio estimates (with confidence intervals);
(2) proportion of people achieving each outcome at certain time points at six, 12 and 24 months (with confidence intervals).
Quality assessment
Both authors will independently assess the study quality.
We will use the Jadad validated quality scale (Jadad 1996) to rate the quality of the studies including the following items.
(a) Was the study described as randomized? Yes = one point. No = zero points.
(b) Was the study described as double blind? Yes = one point. No = zero points.
(c) Was there a description of withdrawals and dropouts? Yes = one point. No = zero points.
(d) Was the blinding appropriate? Yes = one point. No = deduct one point.
(e) Was the randomization appropriate? Yes = one point. No = deduct one point.
Each study will be given a total score between zero and five points, with the higher scores corresponding to higher quality studies (Jadad 1996). The Jadad score for each study will be reported.
Data analysis
(1) Initially, we have planned a review using aggregate data. If after undertaking this review it seems appropriate, a further review using individual patient data will be attempted.
(2) We will compare outcomes across trials and treatment regimens to assess clinical heterogeneity and compare patient populations. We will check for statistical heterogeneity using the I2 as well as the chi‐square test for heterogeneity. Provided no significant clinical or statistical heterogeneity is detected, we will synthesize data using a fixed‐effect model. We will also synthesize the data using a random‐effects model and compare the results with those of fixed‐effect model .For binary outcomes we shall use relative risk (RR) and 95% confidence intervals (CIs). For continuous data, we shall use weighted mean difference (WMD) with 95% confidence intervals (CI).
(3) If sufficient trials are found and appropriate data are made available, we plan to summarize data for time to event outcomes in a meta‐analysis using a number at risk approach (Parmar 1998; Williamson 2002).
(4) Our primary analysis will be an intention‐to‐treat analysis of patients according to the treatment allocation regardless of the final treatments.
(5) If possible we will undertake a subgroup analysis according to seizure type (partial onset versus generalized onset) and age groups (children less than 17 years versus adult).
(6) We plan to do a sensitivity analysis to test the robustness of the meta‐analysis.
(7) We plan to examine the dose response relationships using logistic regression, in the framework of generalized linear models (McCullagh 1989)
(8) We will describe data on neurological examinations, computerized tomography (CT) scans, magnetic resonance imaging (MRI) scans, EEG results and adverse effects.
