Zonisamide add-on for drug-resistant partial epilepsy

  • Conclusions changed
  • Review
  • Intervention

Authors


Abstract

Background

The majority of people with epilepsy have a good prognosis and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop refractory epilepsy, especially those with partial seizures. In this review we summarise the current evidence regarding zonisamide, when used as an add-on treatment for drug-resistant partial epilepsy.

Objectives

To evaluate the efficacy and tolerability of zonisamide when used as an add-on treatment for people with drug-resistant partial epilepsy.

Search methods

We searched the Cochrane Epilepsy Group Specialized Register (12 February 2013), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2013, Issue 1) (January 2013), MEDLINE (Ovid, 1946 to 12 February 2013), SCOPUS (13 February 2013), ClinicalTrials.gov (12 February 2013) and the WHO International Clinical Trials Registry Platform ICTRP (13 February 2013). In addition, we contacted Eisai Limited (makers and licensees of zonisamide) and experts in the field to seek any ongoing/unpublished studies.

Selection criteria

Randomised, placebo-controlled, add-on trials of zonisamide in people with drug-resistant partial epilepsy.

Data collection and analysis

Two review authors independently selected trials for inclusion and extracted data. Outcomes were: (1) 50% or greater reduction in total seizure frequency; (2) treatment withdrawal; (3) adverse effects. Primary analyses were intention-to-treat. We estimated summary risk ratios (RRs) for each outcome. All studies were assessed for risk of bias using the Cochrane risk of bias tool and the quality of evidence was assessed using the GRADE approach and presented in a summary of findings table.

Main results

Five trials (949 participants) were included. The overall RR with 95% confidence interval (CI) for 50% reduction in seizure frequency compared to placebo for 300 to 500 mg/day of zonisamide was 2.00 (95% CI 1.58 to 2.54). The RR for 50% reduction in seizure frequency compared to placebo for any dose of zonisamide (100 to 500 mg per day) was 1.92 (95% CI 1.52 to 2.42). The number needed to treat (NNT) was 6 for this outcome. Two trials provide evidence of a dose response relationship for this outcome. The RR for treatment withdrawal for 300 to 500 mg/day of zonisamide compared to placebo was 1.64 (95% CI 1.20 to 2.25) and for 100 to 500 mg per day was 1.47 (95% CI 1.07 to 2.01). NNT for this outcome was 21. The CIs of the following adverse effects indicate that they are significantly associated with zonisamide: ataxia 3.77 (99% CI 1.28 to 11.11); somnolence 1.83 (99% CI 1.08 to 3.11); agitation 2.35 (99% CI 1.05 to 5.27) and anorexia 2.71 (99% CI 1.29 to 5.69). Across the 5 studies, risk of bias domains were rated as low is bias or unclear. None of the evidence for outcomes was downgraded for quality.

Authors' conclusions

Zonisamide has efficacy as an add-on treatment in people with drug-resistant partial epilepsy. In this review minimum effective and maximum tolerated doses cannot be identified. The trials reviewed were of a maximum stable-dose phase of 18 weeks in duration and results cannot be used to confirm longer periods of effectiveness in seizure control. The results cannot be extrapolated to monotherapy or to people with other seizure types or epilepsy syndromes.

Résumé scientifique

Zonisamide en traitement d'appoint dans l'épilepsie partielle résistante aux médicaments

Contexte

La majorité des personnes atteintes d'épilepsie ont un bon pronostic et leurs crises peuvent être bien contrôlées avec l'utilisation d'un agent antiépileptique unique, mais jusqu'à 30% développent une épilepsie réfractaire, en particulier celles souffrant de crises partielles. Dans cette revue, nous avons résumé les preuves actuelles concernant le zonisamide, lorsqu'il est utilisé en tant que traitement d'appoint dans l'épilepsie partielle résistante aux médicaments.

Objectifs

Évaluer l'efficacité et la tolérance du zonisamide lorsqu’il est utilisé comme traitement adjuvant pour les personnes atteintes d'épilepsie partielle réfractaire aux médicaments.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre spécialisé du groupe Cochrane sur l'épilepsie (12 février 2013), le registre Cochrane des essais contrôlés (The Cochrane Library 2013, numéro 1) (de janvier 2013), MEDLINE (Ovid, de 1946 au 12 février 2013), SCOPUS (13 février 2013), ClinicalTrials.gov (12 février 2013) et WHO International Clinical Trials Registry Platform ICTRP (13 février 2013). En outre, nous avons contacté Eisai Limited (titulaire et fabricant du zonisamide) et des experts dans le domaine afin d'obtenir des études en cours/non publiées.

Critères de sélection

Essais randomisés contrôlés par placebo portant sur le zonisamide en traitement d'appoint chez les personnes atteintes d'épilepsie partielle réfractaire aux médicaments.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment sélectionné les essais à inclure et extrait les données. Les critères de jugement étaient : (1) une réduction de 50% ou plus de la fréquence totale des crises; (2) l'arrêt du traitement; (3) les effets indésirables. Les analyses primaires ont été effectuées en intention de traiter. Nous avons estimé les risques relatifs (RR) pour chaque critère de jugement. Toutes les études ont été évaluées pour les risques de biais en utilisant l'outil Cochrane de risque de biais et la qualité des preuves a été évaluée en utilisant l'approche GRADE et présentées dans un résumé des tables de résultats.

Résultats principaux

Cinq essais (949 participants) ont été inclus. Le RR global avec intervalle de confiance à 95% (IC) pour 50% de réduction de la fréquence des crises par rapport à un placebo à 300 à 500 mg/jour de zonisamide était de 2,00 (IC à 95% 1,58 à 2,54). Le RR de 50% de réduction de la fréquence des crises par rapport à un placebo pour n'importe quelle dose de zonisamide (de 100 à 500 mg par jour) était de 1,92 (IC à 95% 1,52 à 2,42). Le nombre de sujets à traiter (NST) était de 6 pour ce critère de jugement. Deux essais fournissaient des preuves d'une relation dose-réponse pour ce critère de jugement. Le RR d'arrêt prématuré du traitement à 300 à 500 mg/jour de zonisamide par rapport au placebo était de 1,64 (IC à 95% 1,20 à 2,25) et pour 100 à 500 mg par jour était de 1,47 (IC à 95% 1,07 à 2,01). Le NST pour ce critère de jugement était de 21. Les intervalles de confiance pour les effets indésirables suivants indiquent qu’ils sont associés significativement au zonisamide : l'ataxie à 3,77 (IC à 99% 1,28 à 11,11); la somnolence 1,83 (IC à 99% 1,08 à 3,11); l'agitation 2,35 (IC à 99% 1,05 à 5,27) et l’anorexie 2,71 (IC à 99% 1,29 à 5,69). Dans les 5 études, les risques de biais ont été considérés comme faibles ou incertains. Aucune des preuves pour les critères de jugement a été revue à la baisse en raison de la qualité.

Conclusions des auteurs

Le zonisamide présente une efficacité en tant que traitement d'appoint chez les personnes atteintes d'épilepsie partielle réfractaires aux médicaments. Dans cette revue les doses minimales et maximales tolérées n’ont pas pu être identifiées. Les essais examinés avaient une phase à dose stable maximum de 18 semaines et les résultats ne peuvent pas être utilisés pour confirmer de plus longues périodes d'efficacité dans le contrôle des convulsions. Les résultats ne peuvent pas être extrapolés à la monothérapie ou aux personnes présentant d'autres types de crises ou de syndromes épileptiques.

Plain language summary

Zonisamide add-on for drug-resistant partial epilepsy

Zonisamide in combination with another antiepileptic drug can reduce seizures, but with some adverse effects.

Around 70% of epileptic patients can become seizure-free with antiepileptic drug treatment. The remaining 30% of people with epilepsy may be resistant to antiepileptic drugs and still experience seizures. Older drugs do not prevent seizures for everyone and they have adverse effects. New drugs have been developed to try to treat those people who are resistant to the old drugs and to try to limit the adverse effects. These newer drugs are taken as well as the patient's existing medication, as an 'add-on' treatment. Zonisamide is used as an add-on treatment.

A search of databases was carried out on 12/02/2013. Five trials were found which included 949 people with partial epilepsy. These trials were all randomised controlled trials which compared the antiepileptic drug Zonisamide to a placebo drug for a period of 12 weeks. Taking all the evidence of the trials into account, the review found that seizure frequency was significantly reduced for people with drug-resistant partial epilepsy if zonisamide is added to their usual treatment. Patients treated with 300 to 500 mg/day of zonisamide were twice as likely as people given placebo tablets in addition to their usual treatment to experience at least a 50% reduction in the frequency of their seizures. However, adding zonisamide to the usual treatment is associated with an increase in adverse effects such as problems with co-ordination (ataxia), drowsiness (somnolence), agitation and anorexia.

The trials were assessed with regards to bias and quality and overall, the quality of the evidence was rated as high quality. However more research is need which concentrates on examining the dose of zonisamide.

Résumé simplifié

Zonisamide en traitement d'appoint dans l'épilepsie partielle résistante aux médicaments

Le zonisamide en combinaison avec un autre médicament antiépileptique peut réduire les crises mais est associé à certains effets indésirables.

Environ 70% des patients épileptiques peuvent rester sans crise avec le traitement antiépileptique. Les autres 30% des personnes souffrant d'épilepsie peuvent être résistantes aux médicaments antiépileptiques et continuent de présenter des crises. Les médicaments plus anciens ne préviennent pas les crises chez tous les patients et ont des effets indésirables. Les nouveaux médicaments ont été développés pour essayer de traiter les personnes qui sont résistantes aux anciens médicaments et pour tenter de limiter les effets indésirables. Ces nouveaux médicaments sont administrés en supplément des médicaments actuels du patient, en tant que traitement d'appoint. Le zonisamide est utilisé comme traitement adjuvant.

Une recherche dans les bases de données a été effectuée le 12/02/2013. Cinq essais ont été trouvés qui portaient sur 949 patients atteints d'épilepsie partielle. Ces essais étaient tous des essais contrôlés randomisés qui comparaient le médicament antiépileptique zonisamide à un placebo pendant une période de 12 semaines. Prenant toutes les preuves des essais en compte, la revue a constaté que la fréquence des crises a été significativement réduite chez les personnes atteintes d'épilepsie partielle réfractaires aux médicaments si zonisamide est ajoutée à leur traitement habituel. Les patients traités avec de 300 à 500 mg/jour de zonisamide ont été deux fois plus susceptibles que les personnes ayant reçu un comprimé de placebo en plus de leur traitement habituel à éprouver au moins une réduction de 50% de la fréquence de leurs crises. Cependant, l'ajout de zonisamide pour le traitement habituel est associé à une augmentation des effets indésirables tels que des problèmes de coordination (ataxie), une somnolence, de l'agitation et de l'anorexie.

Les essais ont été évalués en termes de biais et de qualité et dans l'ensemble, la qualité des preuves a été considérée comme étant de haute qualité. Toutefois des recherches supplémentaires axées sur l'examen de la dose de zonisamide sont nécessaires.

Notes de traduction

Traduit par: French Cochrane Centre 14th January, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Summary of findings(Explanation)

Summary of findings for the main comparison. Zonisamide versus placebo for drug-resistant partial epilepsy
Zonisamide versus placebo for drug-resistant partial epilepsy
Patient or population: patients with drug-resistant partial epilepsy
Settings: hospital out-patient setting
Intervention: zonisamide versus placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Zonisamide versus placebo
50% responder rate - whole treatment period - any dose Study population RR 1.92
(1.52 to 2.42)
949
(5 studies)
⊕⊕⊕⊕
high
3 out of 5 studies found a non-significant effect of zonisamide on responder rate but the combined overall effect was statistically significant
191 per 1000 367 per 1000
(290 to 462)
Moderate
175 per 1000 336 per 1000
(266 to 424)
Withdrawal rates - any dose Study population RR 1.47
(1.07 to 2.01)
949
(5 studies)
⊕⊕⊕⊕
high
No study produced a statistically significant effect of zonisamide on withdrawal rates independently but a statistically significant effect was found overall
113 per 1000 166 per 1000
(121 to 227)
Moderate
95 per 1000 140 per 1000
(102 to 191)
Adverse effects - ataxia Study population 3.77
(1.28 to 11.11)
494
(3 studies)
⊕⊕⊕⊕
high
No study found a statistically significant effect of zonisamide on ataxia independently, but there was a significant effect when study data were combined
26 per 1000 100 per 1000
(34 to 294)
Moderate
24 per 1000 90 per 1000
(31 to 267)
Adverse effects - dizziness Study population 1.46
(0.88 to 2.44)
949
(5 studies)
⊕⊕⊕⊕
high
No study found a statistically significant effect of zonisamide on dizziness independently
88 per 1000 128 per 1000
(77 to 215)
Moderate
118 per 1000 172 per 1000
(104 to 288)
Adverse effects - nausea Study population 1.21
(0.61 to 2.4)
598
(4 studies)
⊕⊕⊕⊕
high
No study found a statistically significant effect of zonisamide on nausea independently
76 per 1000 91 per 1000
(46 to 181)
Moderate
69 per 1000 83 per 1000
(42 to 166)
Adverse effects - fatigue Study population 1.41
(0.76 to 2.62)
598
(4 studies)
⊕⊕⊕⊕
high
No study found a statistically significant effect of zonisamide on fatigue independently
86 per 1000 122 per 1000
(66 to 226)
Moderate
79 per 1000 111 per 1000
(60 to 207)
Adverse effects - somnolence Study population 1.83
(1.08 to 3.11)
949
(5 studies)
⊕⊕⊕⊕
high
4 out of 5 studies found no statistically significant difference in the occurrence of somnolence between the zonisamide group and the control group
75 per 1000 138 per 1000
(81 to 234)
Moderate
118 per 1000 216 per 1000
(127 to 367)
Adverse effects - agitation/irritability Study population 2.35
(1.05 to 5.27)
598
(4 studies)
⊕⊕⊕⊕
high
1 out of 4 studies found a significant effect of zonisamide on agitation/irritability and there was a statistically significant effect overall
43 per 1000 101 per 1000
(45 to 227)
Moderate
44 per 1000 103 per 1000
(46 to 232)
Adverse effects - anorexia Study population 2.71
(1.29 to 5.69)
494
(3 studies)
⊕⊕⊕⊕
high
None of 3 studies found significant effects of zonisamide on anorexia, but overall there was a significant effect when data were combined
62 per 1000 167 per 1000
(80 to 351)
Moderate
81 per 1000 220 per 1000
(104 to 461)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Standard antiepileptic drugs (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, therefore, there has been renewed interest in the development of new AEDs. Several new AEDs are now licensed for use as an 'add-on' treatment in a variety of countries: felbamate; gabapentin; lamotrigine; levetiracetam; oxcarbazepine; pregabalin; tiagabine; topiramate; vigabatrin and zonisamide.

In this review we investigate the efficacy and tolerability of add-on zonisamide in people with drug-resistant partial epilepsy. For the purpose of this review, people with drug-resistant partial epilepsy have been defined as having partial onset seizures (simple partial and/or complex partial and/or secondary generalised tonic-clonic seizures) that have failed to respond to monotherapy with a standard AED. This review is part of a series of reviews investigating the new AEDs.

Description of the condition

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 treatment with combinations of AEDs. These individuals will often experience significant adverse psychological and quality of life outcomes, due to continued and unpredictable seizures, side effects of drugs, and reduced education and employment prospects.

Description of the intervention

In the majority of cases, epilepsy is treated using AEDs. These AEDs have varying mechanisms of action and certain AEDs are more effective at treating specific seizure types. For example, carbamazepine is more effective for focal seizures (Marson 2000) and valproate is more effective for generalised onset seizures (Marson 2007). Conventional first-line drugs include carbamazepine, lamotrigine and sodium valproate, which have a broad therapeutic effect but are associated with a number of adverse effects. In cases where monotherapy fails to induce seizure remission, AED 'add-on therapy' may be used in an attempt to improve seizure control. Zonisamide is one such add-on therapy. Zonisamide is a synthetic 1,2-benzisoxazole-3-methanesulfonamide with anticonvulsant properties (Sackellares 2004). Zonisamide has a long half-life (63 to 69 hours) (Baulac 2007) and the typical maintenance dose in adults over the age of 18 is 300 to 500 mg/day, possibly split in to two doses per day (British National Formulary).

How the intervention might work

Proposed neuropharmacological mechanisms of action for zonisamide include blockade of voltage-sensitive sodium channels, blockade of voltage-dependent T-type calcium channels, blockade of potassium-evoked glutamate response, reduced glutamate-mediated synaptic excitation (Leppik 2004) and increased synaptic concentration of gamma-aminobutyric acid (GABA) (Ueda 2003). It has been proposed that zonisamide might help patients who are resistant to other AEDs because it blocks both voltage-sensitive sodium and T-type calcium channels (Leppik 2004). Although zonisamide does not induce liver enzymes, it is metabolised by cytochrome P450. Therefore concomitant AEDs which are liver enzyme-inducing will enhance zonisamide metabolism and so the zonisamide dosage strategy may need to be adjusted to compensate for the effect of other AEDs (Leppik 2004). By scavenging hydroxyl and nitric oxide free radicals, zonisamide may also be neuroprotective (Mori 1998).

Why it is important to do this review

While the majority of people with epilepsy do respond to AEDs, a treatment solution needs to be found for the 30% who do not. This review update aims to inform clinical practitioners as to the efficacy and tolerability of zonisamide when used as add-on therapy to treat patients with drug-refractory partial epilepsy.

Objectives

To evaluate the efficacy and tolerability of zonisamide 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. Randomised controlled trials, in which an adequate method of concealment of randomisation was used (e.g. allocation of sequentially numbered, sealed packages of medication, sealed opaque envelopes, telephone randomisation).

  2. Double-blind trials, in which both participant and clinician treating or assessing outcome are blinded to treatment allocated.

  3. Placebo-controlled.

  4. Parallel-group or cross-over studies.

  5. Minimum treatment period of eight weeks. This period was selected as it represents the minimum time over which changes in seizure frequency can be determined, given the propensity of seizures to occur in clusters.

  6. Studies using a response conditional design would have been excluded, however none were found. In this type of study, participants are given active treatment during a pre-randomisation baseline period, and only those having a pre-defined response to treatment are allocated to treatment groups. We decided to exclude this type of trial as they are really evaluating the effect of drug withdrawal in a highly selected population of individuals. In addition, there is no drug-free baseline from which a reduction in seizure frequency can be calculated.

  7. Head-to-head drug trials where zonisamide is compared directly to another add-on AED.

Types of participants

Participants of any age with drug-resistant partial epilepsy (i.e. experiencing simple partial, complex partial or secondary generalised tonic-clonic seizures).

Types of interventions

  1. The active treatment group received treatment with zonisamide in addition to conventional AED treatment.

  2. The control group received matched placebo in addition to conventional AED treatment.

Types of outcome measures

Primary outcomes
(1) Efficacy

Proportion of participants with a 50% or greater reduction in seizure frequency in the treatment period compared to the pre-randomisation baseline period. We chose this outcome as it is commonly reported in this type of study, and can be calculated for studies that do not report this outcome provided that baseline seizure data were recorded.

Secondary outcomes
(2) Tolerability

The proportion of participants having treatment withdrawn during the course of the treatment period was used as a measure of global tolerability. 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 participants can make a direct contribution. In trials of short duration it is likely that adverse effects will be the most common reason for withdrawal.

(3) Adverse effects
  • The proportion of participants experiencing any of the following five adverse effects, that are found through research to be common and important adverse effects of AEDs:

    • ataxia;

    • dizziness;

    • fatigue;

    • nausea;

    • somnolence.

  • The proportion of participants experiencing the five most common adverse effects if different from (a) above (also seeMethods).

Search methods for identification of studies

Electronic searches

We searched the following databases. There were no language restrictions.

  1. Cochrane Epilepsy Group Specialized Register (12 February 2013), using the search strategy outlined in Appendix 1

  2. The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, January 2013), using the search strategy outlined in Appendix 2.

  3. MEDLINE (Ovid, 1946 to 12 February 2013) using the search strategy outlined in Appendix 3.

  4. SCOPUS (13 February 2013) using the search strategy outlined in Appendix 4

  5. ClinicalTrials.gov (12 February 2013) - searched for "zonisamide and epilepsy".

  6. WHO International Clinical Trials Registry Platform ICTRP (13 February 2013) - searched for "zonisamide and epilepsy".

Searching other resources

In addition, we contacted Eisai Limited (makers and licensees of zonisamide) and experts in the field to seek any ongoing or unpublished studies.

Data collection and analysis

Selection of studies

Two review authors (Katie Carmichael and Jennifer Pulman) independently assessed trials for inclusion. Any disagreement was resolved by mutual discussion.

The same two review authors, together with Shaheen Lakhan, extracted the following information from included trials; we resolved disagreements by majority decision.

Data extraction and management

We extracted the following information for each trial using a data extraction sheet:

Methodological/trial design
  1. Method of randomisation and allocation concealment.

  2. Method of blinding.

  3. Whether any participants had been excluded from reported analyses.

  4. Duration of baseline period.

  5. Duration of treatment period.

  6. Dose(s) of zonisamide tested.

Participant/demographic information
  1. Total number of participants allocated to each treatment group.

  2. Age/sex.

  3. Number with partial/generalised epilepsy.

  4. Seizure types.

  5. Seizure frequency during the baseline period.

  6. Number of background drugs.

Four of the five studies found so far have been sponsored by Eisai (no source of funding was used to assist in the conduct of the Lu 2011 trial). They have supplied copies of internal trial reports which will be used to confirm the following information.

  1. The method of randomisation.

  2. The total number randomised to each group.

  3. The number of people in each group achieving a 50% or greater reduction in seizure frequency per treatment group.

  4. The number of people having treatment withdrawn post-randomisation per treatment group.

  5. For those excluded:

    1. the reason for exclusion;

    2. whether any of those excluded completed the treatment phase;

    3. whether any of those excluded had a 50% or greater reduction in seizure frequency during the treatment phase.

Outcomes

We recorded the number of participants experiencing each outcome (see Types of outcome measures) per randomised group.

Assessment of risk of bias in included studies

Two review authors (Katie Carmichael and Shaheen Lakhan) independently assessed risk of bias for each of the five included trials using the Cochrane 'Risk of bias' tool as found in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreement in the assessment of the level of bias was resolved by a third party. We extracted data from the five included studies relating to sequence generation, concealment of allocation, methods of blinding, incomplete outcome data, selective reporting and other types of bias. We made a judgement of the level of bias involved for each of these categories for all included studies.

Measures of treatment effect

We presented the outcomes 50% of greater reduction in seizure frequency, treatment withdrawal and adverse effects as risk ratios (RR).

Unit of analysis issues

There were no special issues to consider with the design of the included studies. All included studies utilised a parallel design, four with a stable-dose phase of 12 weeks and one with a stable-dose phase of 18 weeks.

Dealing with missing data

We conducted intention-to-treat, best-case and worst-case analyses to account for any missing data.

Assessment of heterogeneity

We assessed clinical heterogeneity by evaluating similarities and differences in the methodologies and outcomes measured in the included studies and by visually inspecting forest plots. We assessed statistical heterogeneity using the Chi2 test and I2 statistic according to section 9.5.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011): 0% to 40% might not be important, 30% to 60% may represent moderate heterogeneity, 50% to 90% may represent substantial heterogeneity, and 75% to 100% indicating considerable heterogeneity. Our intention was to utilise a fixed-effect model if no statistically significant heterogeneity was found between the included studies. If statistical heterogeneity had been present we would have employed a random-effects model.

Assessment of reporting biases

We contacted authors of all included studies and requested trial protocols in order to identify any discrepancies between protocol and trial methodology.

Data synthesis

We utilised a fixed-effect meta-analysis to synthesise the collected data. Planned comparisons included:

  1. 50% or greater reduction in seizure frequency in the intervention group versus the control group;

  2. treatment withdrawal rates in the intervention group versus the control group;

  3. adverse effects in the intervention group versus the control group.

The preferred estimator was the Mantel-Haenszel risk ratio (RR). We used 95% confidence intervals (CIs) for 50% or greater reduction in seizure frequency and treatment withdrawal outcomes. We used a 99% CI for the adverse effects outcome. All analyses included all participants who had been randomised to the group to which they were allocated. For the 50% or greater reduction in seizure frequency outcome, we conducted three analyses:

(1) Primary (intention-to-treat) analysis

Participants not completing follow-up or with inadequate seizure data are assumed to be non-responders.

(2) Worst-case analysis

Participants not completing follow-up or with inadequate seizure data are assumed to be non-responders in the zonisamide group and responders in the placebo group.

(3) Best-case analysis

Participants not completing follow-up or with inadequate seizure data are assumed to be responders in the zonisamide group and non-responders in the placebo group.

Dose regression analysis

We planned to examine dose response relationships using logistic regression, in the framework of generalised linear models (McCullagh 1989). The structure of the data within the trials did not allow this approach (see Results).

Subgroup analysis and investigation of heterogeneity

We conducted subgroup analysis for adverse effect data and produced risk ratios for each different adverse effect. We also conducted subgroup analysis for mg/day dose of zonisamide.

Sensitivity analysis

If trial methodologies were found to be sufficiently distinct, we conducted sensitivity analysis in order to identify which factor(s) were influential in the degree of heterogeneity.

Results

Description of studies

Once any duplicates were removed, the literature search resulted in 292 records being identified from the Cochrane Epilepsy Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, SCOPUS, clinicaltrials.gov and WHO International Clinical Trials Registry Platform ICTRP. We removed 86 duplicated records and screened the remaining 206 records for suitability. We excluded 199 records after initial screening and assessed the full text of the remaining seven articles in order to ascertain eligibility for inclusion based on the extent to which the records met the inclusion criteria. Four records were identified as having met the inclusion criteria for the previous version of this review. One new record met the inclusion criteria and so a total of five records were included in this review update. One of the remaining two records was deemed ineligible and was excluded from this review (see Figure 1). The full report for the other study was unobtainable and was placed in awaiting classification.

Figure 1.

Study flow diagram.

The five included studies (949 participants) were parallel-group (although Faught 2001 added a cross-over phase for all participants in the final five weeks) with a stable-dose phase of 12 or 18 weeks. Two studies (Sackellares 2004; Schmidt 1993) allowed some dose titration according to seizure response and tolerability. In both studies the median daily dose for participants completing the study was 400 mg. A third study (Faught 2001) titrated to 400 mg/day, but participants randomised to zonisamide followed different rates of titration during the first five weeks of the study, which allowed some comparison of placebo, 100 mg/day and 200 mg/day during this period of the study. In the fourth study (Brodie 2005) participants were randomised to placebo, 100 mg, 300 mg or 500 mg of zonisamide in a 2:1:1:2 ratio, allowing further investigation of dose response relationships. In the newly included study (Lu 2011) two different titration strategies were utilised; in the first, a 100 mg/day zonisamide dose was given for the first two weeks after baseline, 200 mg/day for the third week and 300 mg/day from week four onwards. The initial dose in the second strategy was 100 mg/day of zonisamide increasing weekly by increments of 100 mg/day until a target of 400 mg/day was reached in week four and continued onwards for the duration of the trial. See Characteristics of included studies for full details of the included studies.

One add-on study compared zonisamide with valproate rather than placebo in a head-to-head trial (Anderson 1988) which did meet the inclusion criteria. However, only a single-page summary was available, which gave too little information on methods or outcome data. We are therefore currently unable to include information from this trial in the review (see Characteristics of studies awaiting classification). Shimizu 1988 was excluded as no control group was used (see Characteristics of excluded studies).

Risk of bias in included studies

See Figure 2 for a summary of the risk of bias in the included studies.

Figure 2.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Allocation

In three studies allocation was concealed by dispensing sequentially numbered packages to each participant (Faught 2001; Sackellares 2004; Schmidt 1993), whilst Brodie 2005 used a telephone randomisation service. In two studies (Brodie 2005; Schmidt 1993) patients were assigned to groups in blocks of six and four respectively. Randomisation codes were generated centrally (Faught 2001) or by the study sponsor (Sackellares 2004). Lu 2011 used a process of restricted randomisation as zonisamide and placebo were assigned in a ratio of 1:1.

Patient codes were hidden by use of numbered containers (Lu 2011; Sackellares 2004) or sealed envelopes containing an individual patient code (Faught 2001). However, the appearance of the items used to conceal codes was not explicitly described so it cannot be certain how effective these concealment methods were.

Blinding

We deemed all five of the included studies to be at low risk of performance bias (participants) as placebo and zonisamide tablets were identical in appearance (Brodie 2005; Faught 2001; Lu 2011; Sackellares 2004; Schmidt 1993). Blinding of outcome assessors was not detailed in any of the included studies and we therefore classified this as being at an unclear risk of bias. However, patients self reported seizure frequency and duration and therefore we thought that a lack of detail on the outcome assessors would have a minimal impact overall. One trial report (Schmidt 1993) did not provide any detail with regard to blinding of study personnel or outcome assessors and as such was classified as being at unclear risk of bias overall.

Incomplete outcome data

We classified the trials Brodie 2005 and Lu 2011 as being at a low risk of attrition bias overall as few participants left the study for any reason before completion and these participants were reasonably evenly spread across the different intervention groups. We assessed Faught 2001 to be at an unclear risk of attrition bias due to unclear reporting of missing data and study attrition rates. Sackellares 2004 did not clearly report all data in relation to study attrition and missing data. The attrition rate was not clearly reported in the trial by Schmidt 1993 and as such we classified it as being at an unclear risk of attrition bias.

All of the trials conducted a modified version of an intention-to-treat (ITT) analysis, while one trial also conducted a second, unmodified ITT analysis (Faught 2001). Four trials failed to include all randomised participants in their ITT analysis (Brodie 2005; Lu 2011; Sackellares 2004) and instead omitted participants who had not completed the trial for any reason. In these four trials participants were included in the ITT analysis if they had taken at least one dose of the intervention to which they had been allocated. The fifth trial (Schmidt 1993) also conducted a modified ITT analysis, but instead included participants who had received at least seven days of treatment.

Selective reporting

We contacted all study authors but no included trial protocols were made available. All primary and secondary outcomes outlined in the methods section of each trial were analysed and reported in the results section of each study and we therefore classified them as being at a low risk of reporting bias.

Other potential sources of bias

One potential source of bias would be the unequal duration of stable-dose phase depending on which dosage group a participant had been allocated to. Specifically, in one study (Brodie 2005) participants allocated to the 100 mg/day zonisamide dose were on a stable dose for 23 weeks in total as their titration phase was relatively brief in comparison to those participants in the 300 mg/day and 500 mg/day groups who had a stable-dose phase of 20 and 18 weeks respectively. Both sponsors of one trial were manufacturers of zonisamide (Lu 2011). Two studies extended the baseline period by four weeks if participants did not experience 15 or more seizures in the first four weeks of baseline, or 30 or more seizures in the first eight weeks of baseline (Sackellares 2004; Schmidt 1993). This manipulation may have artificially inflated the effect of zonisamide on seizure frequency making any reduction in seizures attributed to zonisamide of a greater magnitude by comparison. Conversely, this extension of the baseline period may have increased the likelihood of regression to the mean.

Effects of interventions

See: Summary of findings for the main comparison Zonisamide versus placebo for drug-resistant partial epilepsy

Efficacy: 50% or greater reduction in seizure frequency

The study of Faught 2001 allocated patients to placebo or to one of two zonisamide groups. Both groups were titrated up to 400 mg per day, but according to two different regimes. One group took 100 mg in weeks one to five, 200 mg in week six, 300 mg in week seven and 400 mg in weeks eight to 12. The second group took 100 mg in week one, 200 mg in weeks two to six, 300 mg in week seven and 400 mg in weeks eight to 12. Data from weeks two to five provide estimates of the response rates for 100 mg and 200 mg of zonisamide, whilst data from weeks eight to 12 provide an estimate of the response rate for 400 mg zonisamide.

For Schmidt 1993 and Sackellares 2004, patients allocated zonisamide had the dose titrated up to a median of 400 mg per day over weeks one to four, and then entered a stable-dose period over weeks five to 12. Similarly in Brodie 2005, doses were titrated up over six weeks and stable for a further 18 weeks. Lu 2011 utilised a four-week titration period where patients were taken up to the target dose of either 300 or 400 mg/day of zonisamide (dependent on which sponsor group they were in) before entering a 12-week stable-dose phase.

Analysis of participants who experienced a 50% or greater reduction in their seizure frequency (responders) included data from the whole treatment period (titration plus stable-dose phase). Given that the median dose was 400 mg in Schmidt 1993 and Sackellares 2004, the target dose in Faught 2001 was 400 mg, and the target dose in Lu 2011 was either 300 mg/day or 400 mg/day, analyses are presented which include data from all groups in Brodie 2005 (100 mg, 300 mg, 500 mg), as well as analyses excluding the 100 mg group in that study.

(1) Whole treatment period analysis

For the analysis using any dose of zonisamide there was no statistical heterogeneity among trials (I2 = 0%) and the overall risk ratio (RR) was 1.92 (95% confidence interval (CI) 1.52 to 2.42) indicating a significant effect of zonisamide. Results excluding the 100 mg group from Brodie 2005 are similar: RR 2.00 (95% CI 1.58 to 2.54). NNT calculations show that approximately 6 patients need to be treated with zonisamide for every additional patient with a 50% response.

Both analyses indicate a significant treatment effect (Analysis 1.1).

(2) Best and worst-case scenarios

We calculated these using data for the whole treatment period and for all doses of zonisamide. For the best-case scenario the overall RR was 2.23 (95% CI 1.78 to 2.79) and for the worst-case was 1.42 (95% CI 1.16 to 1.75) (Analysis 1.2; Analysis 1.3). These results are consistent with a significant effect of zonisamide.

(3) Dose response regression

Brodie 2005 and Faught 2001 provide data for differing doses of zonisamide. Due to differences in the design of the trials we thought it inappropriate to combine these data in a meta-analysis. For Brodie 2005 estimates are as follows: 100 mg (RR 1.70; 95% CI 0.98 to 2.97); 300 mg (RR 1.94; 95% CI 1.14 to 3.31) and 500 mg (RR 2.66; 95% CI 1.73 to 4.11). Estimates indicate increasing efficacy with increasing dose (Analysis 1.4). For Faught 2001 there is no clear relationship between dose and response: 100 mg (RR 1.93; 95% CI 0.96 to 3.91), 200 mg (RR 2.26; 95% CI 1.15 to 4.48) and 400 mg (RR 1.74; 95% CI 1.11 to 2.75) (Analysis 1.5).

Tolerability: treatment withdrawal for any reason

We undertook analyses including and excluding the 100 mg group from Brodie 2005. For both analyses there was no statistical heterogeneity (I2 = 0%). For any dose of zonisamide the RR is 1.47 (95% CI 1.07 to 2.01)and excluding the 100 mg group from Brodie 2005 the RR is 1.64 (95% CI 1.20 to 2.25) (Analysis 1.6).

Patients are therefore significantly more likely to withdraw from zonisamide than from placebo.

Adverse effects

In addition to the reports of ataxia, dizziness, fatigue, nausea and somnolence, agitation and anorexia were among the five most common adverse effects and have therefore been included in this analysis. The confidence intervals for the following adverse effects do not include unity: ataxia (RR 3.77; 99% CI 1.28 to 11.11); somnolence (RR 1.83; 99% CI 1.08 to 3.11); agitation (RR 2.35; 99% CI 1.05 to 5.27) and anorexia (RR 2.71; 99% CI 1.29 to 5.69), indicating a statistically significant association between zonisamide and these symptoms. All symptoms were more frequent with zonisamide than placebo.

The CIs of the following adverse effects indicate that they are not significantly associated with zonisamide: dizziness (RR 1.46; 99% CI 0.88 to 2.44, P = 0.05); nausea (RR 1.21; 99% CI 0.61 to 2.40, P = 0.46) and fatigue (RR 1.41; 99% CI 0.76 to 2.62, P = 0.16) (Analysis 1.7).

NNT calculations show that approximately 21 patients need to be treated with zonisamide for every patient withdrawing compared to placebo.

Discussion

Summary of main results

Four trials included in this review were sponsored by industry (Dainippon or Elan Pharma). No sources of funding were used to assist in the conduct or preparation of Lu 2011, but the drug was provided for the trial by two different manufacturers of zonisamide (Eisai Co. Ltd and Shenzhen Zifu Co. Ltd).

All included studies were double-blind and four were at low risk of bias due to having used adequate methods of allocation concealment (Brodie 2005; Faught 2001; Lu 2011; Sackellares 2004), while this risk was unclear in one study (Schmidt 1993). The detailed internal company report of Schmidt 1993 indicates that 144 participants were randomised into this study, although the published paper indicates that 139 participants were randomised. The numbers of responders differs slightly because, for this review, we have considered only the eight weeks immediately before randomisation to constitute the baseline, rather than a varied period of between eight to 12 weeks. The incidence of adverse events of different types differs as we have used figures derived from a later application of an updated lexicon and correction of previous duplicate reporting.

The intention-to-treat analysis shows that zonisamide reduces seizure frequency in people with drug-resistant partial epilepsy. There is a large discrepancy between estimates derived from worst and best-case scenarios indicating that the estimates from the intention-to-treat analysis should be regarded with some caution, although this analysis gives the most pragmatic assessment of treatment effect as all participants withdrawing prematurely are regarded as non-responders. The data from Brodie 2005 provide some evidence of a dose response relationship, although minimal effective or maximal tolerated doses have not yet been defined. Treatment in the randomised controlled trials reviewed ranged from 12 to 18 weeks, so that no conclusions can be drawn about longer-term efficacy.

Results for the outcome 'withdrawal of allocated treatment' indicate that zonisamide is more likely to be associated with withdrawal than placebo, an effect that is likely to be related to a higher incidence of adverse effects with active drug treatment. Somnolence, anorexia, agitation and ataxia were the most common adverse effects that were statistically more likely to occur on zonisamide than placebo. These clinical trials do not provide meaningful information about important safety issues such as acute idiosyncratic drug reactions, chronic toxicity or teratogenicity.

While this review offers proof of the efficacy of zonisamide for partial epilepsy as adjunctive treatment, it does not allow comparison with other AEDs. Prospective, actively controlled studies will be necessary to address this question. Similarly this review provides no information to support the use of zonisamide as either monotherapy or in people with other epilepsy syndromes. None of the studies included in this review recruited significant numbers of children and some caution should be exercised in extrapolating the results from adult studies to children with partial epilepsy.

Quality of the evidence

We used the GRADE approach to assess the quality of evidence of the included studies and this information is displayed in a 'Summary of findings' table (Summary of findings for the main comparison). No studies were downgraded from high quality.

Authors' conclusions

Implications for practice

People with drug-resistant partial epilepsy were twice as likely to experience at least a 50% reduction in the frequency of their seizures when they took 300 to 500 mg/day of zonisamide compared to a placebo group, when treated over a stable-dose period of up to 18 weeks. For the patients entered into the trials, approximately six patients needed to be treated with zonisamide for every additional patient with a 50% response compared to placebo, i.e. for the population recruited into the trials, the number needed to treat was six.

Ataxia, somnolence, agitation and anorexia were the most common adverse effects attributable to zonisamide. Patients treated with zonisamide were more likely to have treatment withdrawn. For the patients entered into the trials, approximately 21 needed to be treated with zonisamide for every additional patient withdrawing compared to placebo, i.e. for the population recruited into the trials, the number needed to treat for an additional harmful outcome was 21.

Implications for research

There is a need for studies that more adequately explore the dose response relationship for zonisamide in partial and other epilepsy syndromes. Zonisamide should be compared to other new and standard AEDs as both add-on and monotherapy. With regards to the design of trials, thought should be given to the dynamics of the baseline period in order to prevent over-estimating the efficacy of the drug.

Acknowledgements

We thank Dainippon, Elan Pharma and Eisai for sharing unpublished and additional data for this review. We acknowledge David Chadwick for conducting the previous review.

Data and analyses

Download statistical data

Comparison 1. Zonisamide versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 50% responder rate - whole treatment period5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Any dose5949Risk Ratio (M-H, Fixed, 95% CI)1.92 [1.52, 2.42]
1.2 300 to 500 mg zonisamide5891Risk Ratio (M-H, Fixed, 95% CI)2.00 [1.58, 2.54]
2 50% responder rate - best-case5949Risk Ratio (M-H, Fixed, 95% CI)2.23 [1.78, 2.79]
3 50% responder rate - worst-case5949Risk Ratio (M-H, Fixed, 95% CI)1.42 [1.16, 1.75]
4 50% responder rate - dose effect Brodie 20051 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4.1 100 mg per day1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 300 mg per day1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.3 500 mg per day1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5 50% responder rate - dose effect Faught 20011 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
5.1 100 mg per day1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5.2 200 mg per day1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5.3 400 mg per day1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Withdrawal rates5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
6.1 Any dose5949Risk Ratio (M-H, Fixed, 95% CI)1.47 [1.07, 2.01]
6.2 300 to 500 mg zonisamide5892Risk Ratio (M-H, Fixed, 95% CI)1.64 [1.20, 2.25]
7 Adverse effects5 Risk Ratio (M-H, Fixed, 99% CI)Subtotals only
7.1 Ataxia3494Risk Ratio (M-H, Fixed, 99% CI)3.77 [1.28, 11.11]
7.2 Dizziness5949Risk Ratio (M-H, Fixed, 99% CI)1.46 [0.88, 2.44]
7.3 Nausea4598Risk Ratio (M-H, Fixed, 99% CI)1.21 [0.61, 2.40]
7.4 Fatigue4598Risk Ratio (M-H, Fixed, 99% CI)1.41 [0.76, 2.62]
7.5 Somnolence5949Risk Ratio (M-H, Fixed, 99% CI)1.83 [1.08, 3.11]
7.6 Agitation/irritability4598Risk Ratio (M-H, Fixed, 99% CI)2.35 [1.05, 5.27]
7.7 Anorexia3494Risk Ratio (M-H, Fixed, 99% CI)2.71 [1.29, 5.69]
Analysis 1.1.

Comparison 1 Zonisamide versus placebo, Outcome 1 50% responder rate - whole treatment period.

Analysis 1.2.

Comparison 1 Zonisamide versus placebo, Outcome 2 50% responder rate - best-case.

Analysis 1.3.

Comparison 1 Zonisamide versus placebo, Outcome 3 50% responder rate - worst-case.

Analysis 1.4.

Comparison 1 Zonisamide versus placebo, Outcome 4 50% responder rate - dose effect Brodie 2005.

Analysis 1.5.

Comparison 1 Zonisamide versus placebo, Outcome 5 50% responder rate - dose effect Faught 2001.

Analysis 1.6.

Comparison 1 Zonisamide versus placebo, Outcome 6 Withdrawal rates.

Analysis 1.7.

Comparison 1 Zonisamide versus placebo, Outcome 7 Adverse effects.

Appendices

Appendix 1. Cochrane Epilepsy Group Specialised Register search strategy

#1 Zonisamide or Zonegran or Excegran

#2 monotherap* not (adjunct* or "add-on" or "add on")

#3 #1 NOT #2

Appendix 2. CENTRAL search strategy

#1 (zonisamide or zonegran or excegran):ti,ab,kw (Word variations have been searched)

#2 (monotherap* not (adjunct* or "add-on" or "add on")):ti,ab,kw  (Word variations have been searched)

#3 #1 not #2

#4 (epilep* or seizure* or convuls*):ti,ab,kw  (Word variations have been searched)

#5 MeSH descriptor: [Epilepsy] explode all trees

#6 MeSH descriptor: [Seizures] explode all trees

#7 (#4 or #5 or #6) in Trials

#8 #3 and #7

Appendix 3. MEDLINE search strategy

The following search strategy was used in updating the searches from February 2013 onwards. It is based on the Cochrane Highly Sensitive Search Strategy for identifying randomised trials published in Lefebvre 2009.

1. (randomized controlled trial or controlled clinical trial).pt. or (randomized or placebo or randomly).ab.

2. clinical trials as topic.sh.

3. trial.ti.

4. 1 or 2 or 3

5. exp animals/ not humans.sh.

6. 4 not 5

7. exp Epilepsy/

8. exp Seizures/

9. (epilep$ or seizure$ or convuls$).tw.

10. 7 or 8 or 9

11. exp Pre-Eclampsia/ or exp Eclampsia/

12. 10 not 11

13. (Zonisamide or Zonegran or Excegran).tw.

14. (monotherap* not (adjunct* or "add-on" or "add on")).tw.

15. 13 not 14

16. 6 and 12 and 15

---------------------

The search strategy below is the original MEDLINE strategy that was used for earlier versions of this review:

1. randomized controlled trial.pt.

2. controlled clinical trial.pt.

3. exp Randomized Controlled Trials/

4. exp Random Allocation/

5. exp Double-Blind Method/

6. exp Single-Blind Method/

7. clinical trial.pt.

8. Clinical Trial/

9. (clin$ adj trial$).ab,ti.

10. ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).ab,ti.

11. exp PLACEBOS/

12. placebo$.ab,ti.

13. random$.ab,ti.

14. exp Research Design/

15. or/1-14

16. (animals not humans).sh.

17. 15 not 16

18. (zonisamide or zonegran).tw.

19. exp EPILEPSY/

20. exp SEIZURES/

21. (epilep$ or seizure$ or convulsion$).tw.

22. 19 or 20 or 21

23. 17 and 18 and 22

Appendix 4. SCOPUS search strategy

((TITLE-ABS-KEY(Zonisamide or Zonegran or Excegran)) and not (TITLE-ABS-KEY(monotherap* AND NOT (adjunct* or "add-on" or "add on")))) and (((TITLE-ABS-KEY(epilep* OR "infantile spasm" OR seizure OR convuls* OR (syndrome W/2 (aicardi OR angelman OR doose OR dravet OR janz OR jeavons OR "landau kleffner" OR "lennox gastaut" OR ohtahara OR panayiotopoulos OR rasmussen OR rett OR "sturge weber" OR tassinari OR "unverricht lundborg" OR west)) OR "ring chromosome 20" OR "R20" OR "myoclonic encephalopathy" OR "pyridoxine dependency") AND NOT (TITLE(*eclampsia) OR INDEXTERMS(*eclampsia))) OR (TITLE-ABS-KEY(lafora* W/4 (disease OR epilep*)) AND NOT (TITLE(dog OR canine) OR INDEXTERMS(dog OR canine)))) and (TITLE-ABS-KEY(refractor* OR resist* OR nonrespons* OR non-respons* OR intractable))) and (TITLE((randomiz* OR randomis* OR controlled OR placebo OR blind* OR unblind* OR "parallel group" OR crossover or cross-over) PRE/2 (trial OR method OR procedure OR study)) OR ABS((randomiz* OR randomis* OR controlled OR placebo OR blind* OR unblind* OR "parallel group" OR crossover or cross-over) PRE/2 (trial OR method OR procedure OR study))) AND ( EXCLUDE(EXACTKEYWORD,"Animal experiment" ) OR EXCLUDE(EXACTKEYWORD,"Animal model" ) )

What's new

Last assessed as up-to-date: 12 February 2013.

DateEventDescription
12 February 2013New citation required and conclusions have changedOne new study has been included. Some adverse effects conclusions have changed.
12 February 2013New search has been performedSearches updated 12 February 2013.

History

Protocol first published: Issue 1, 1999
Review first published: Issue 2, 2000

DateEventDescription
15 February 2008AmendedWe re-ran our searches on 15 July 2007; several new potentially relevant studies were identified. These have been added to the 'studies awaiting classification' section and will be assessed for inclusion in the near future.
1 August 2005New citation required and conclusions have changedWe re-ran our searches on 1 August 2005, which identified one new study (Brodie 2005). This has been added to the review. 

Contributions of authors

Katie Carmichael and Jen Pulman independently assessed trials for inclusion and Katie Carmichael, Shaheen Lakhan and Prachi Parikh independently extracted data. Anthony Marson supervised the entire review process and provided advice and guidance.

Declarations of interest

Professor Marson has received hospitality from Eisai. No other declarations of interest.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • National Institute for Health Research, UK.

    The review presents independent research commissioned by the National Institute for Health Research (NIHR). The views expressed in this publication are those of the authors(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

Differences between protocol and review

We considered head-to-head drug trials for inclusion in this review update. However, no such trials met the inclusion criteria.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Brodie 2005

MethodsRandomised, double-blind, placebo-controlled, parallel-group study
Allocation concealment using telephone randomisation
Random permuted blocks of 6 per participating centre
Blinded using identical tablets and packaging
12 week pre-randomisation baseline period, 24-week treatment period including 6-week dose titration
ParticipantsMulticentre study, 49 centres in Europe and 5 in South Africa
351 participants. At least 12 seizures during 12-week baseline period, with no period of more than 3 weeks seizure-free
Taking 1 to 3 AEDs
Aged 12 to 77
51% male
InterventionsPlacebo, 100 mg, 300 mg or 500 mg placebo, randomised in 2:1:1:2 ratio
OutcomesReduction in seizure frequency, proportion with a 50% or greater reduction in seizure frequency
Adverse events
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Patients were randomised sequentially in blocks of six"
Allocation concealment (selection bias)Unclear riskInsufficient details were provided
Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Treatments were blinded using a double dummy technique throughout the study"
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient details about blinding of outcome assessors was provided
Incomplete outcome data (attrition bias)
All outcomes
Low riskA modified ITT analysis was conducted as "all patients who received at least one dose of study drug were included in the safety analysis". 4 participants not included in the analysis were spread fairly evenly among groups (1 participant lost from 2 groups, 2 participants lost from 1 group)
Selective reporting (reporting bias)Low riskThis study was deemed to be at a low risk of selective reporting
Other biasLow riskAllocation to groups led to different durations of stable-dose phase

Faught 2001

MethodsRandomised, double-blind, placebo-controlled, parallel-group study. 2 treatment arms: 1 placebo and 1 zonisamide
Randomisation concealment by allocated sequentially numbered, sealed packages. Random list generated by random permuted blocks. Blinding by identical packing and tablets
All participants received placebo during 28-day prospective baseline. Treatment period was 12 weeks. Participants receiving zonisamide were divided into 2 groups, 1 (group B1) of which received 100 mg/day during weeks 1 to 5, the second (group B2) of which received 100 mg/day during week 1 followed by 200 mg/day during weeks 2 to 5. Both groups received an escalating dose of zonisamide for weeks 5 to 7 followed by 400 mg/day during weeks 8 to 12
ParticipantsMulticentre (20) US study
Total randomised: 203 participants between April 1994 and March 1996 with at least 4 partial seizures/month taking 1 or 2 AEDs, 85 to placebo, 60 to group B1, 58 to group B2
Ages 13 to 68 years, 104 male, 99 female
Median monthly seizure frequency for the randomised groups during baseline ranged between 11.2 and 13 seizures/month
InterventionsZonisamide 400 mg/day or placebo (weeks 8 to 12)
Zonisamide 100 mg/day or 200 mg/day or placebo (weeks 1 to 5)
All treatments and packaging were identical
OutcomesPrimary: median percentage reduction from baseline of all partial seizures
Secondary: proportion of participants showing a 50% reduction in all partial seizures from baseline
Adverse events
NotesOf the randomised participants 8 failed to complete week 5 in the placebo group, 15 in the zonisamide group
By the end of week 12, 13 participants had withdrawn from the placebo group, 23 from zonisamide
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomization codes were generated centrally, with separate randomization sequences for each site."
Allocation concealment (selection bias)Low risk"Each investigator had a sealed copy of the code to be opened in an emergency. Otherwise, assignments were not revealed until all patients at all sites had completed the study." 
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficient detail was provided about blinding of personnel
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient detail was provided about blinding of outcome assessors
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe analysis for "the primary populations was a modified ITT" as it included participants who had received at least one dose of study medication
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasLow riskNo evidence of any other source of bias

Lu 2011

MethodsRandomised, double-blind, placebo-controlled, parallel trial. 12-week baseline phase, 4-week titration phase, 12-week stable treatment phase. Placebo or zonisamide treatment interventions
ParticipantsSingle centre in China. 104 participants randomised, 53 received zonisamide (29 M:24 F) and 51 received placebo (32 M: 19 F). Mean age of zonisamide group = 36.83 years +/- 10.77 and mean age in placebo group = 29.81 years +/- 8.24. All participants had simple partial seizures, complex partial seizures or secondary generalised seizures
InterventionsPlacebo or zonisamide (titrated to 300 mg/day or 400 mg/day)
Outcomes

The following outcomes were measured:

1. Responder rate (50% or greater reduction in seizures frequency during treatment phase compared to baseline)

2. Seizure freedom

3. Adverse effects

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information given other than "zonisamide and placebo were assigned to our centre in a ratio of 1:1" (page 223)
Allocation concealment (selection bias)Low risk"Random allocation of patients to their treatment group was concealed via the use of numbered containers" Comment: it is not explicitly stated whether the containers were opaque or not
Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Investigators were blind to treatment each patient received until the end of the study" and "Zonisamide and placebo tablets had the same size, colour and shape. The tablets were randomly numbered by the study sponsors"
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskIt is unclear whether the investigators who were blinded were also the outcome assessors or not
Incomplete outcome data (attrition bias)
All outcomes
Low riskOne patient was lost from each group, therefore missing data were balanced between groups
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasLow riskBoth providers of zonisamide were manufacturers of the drug

Sackellares 2004

MethodsRandomised, double-blind, placebo-controlled, parallel-group study
2 treatment arms, 1 placebo, 1 zonisamide. The initial target dose of zonisamide was 7 mg/kg/day, but when it became apparent that this was associated with a significant incidence of adverse effects, it was titrated over the first 4 weeks to 400 mg/day. Thereafter a non-blinded observer recommended dose adjustments to obtain plasma levels of 20 to 30 µg/ml. Median dosage in this group was 400 mg/day (range 200 to 600 mg/day)
Randomisation concealment by allocated sequentially numbered, sealed packages. Random list generated by random permuted blocks. Blinding by identical packing and tablets
Baseline was variable, between 8 and 12 weeks, being extended if frequency was below 4 partial seizures/month
Treatment period was 12 weeks
ParticipantsConducted at 4 US centres between August 1983 and July 1986
Total randomised: 152 participants, all with 4 or more partial seizures/month while taking 1 or 2 AEDs. 78 were randomised to zonisamide, 74 to placebo
Age 17 to 67 years, 101 male 51 female
Median monthly seizure frequency pre-baseline: 7.5 zonisamide, 11.1 placebo
InterventionsZonisamide median dosage 400 mg/day (100 mg capsules)
Placebo
Treatments and packaging were identical
OutcomesPrimary: median percentage reduction in seizure frequency of all partial seizures from baseline
Secondary: proportion of participants with a 50% reduction in all partial seizures from baseline
NotesBecause of the variable baseline periods, baseline seizure frequency was recalculated for the 8 weeks immediately before entry into the treatment period
14 people failed to complete the 12-week treatment period in the zonisamide group, 7 in the placebo group
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomisation codes were generated by the study sponsor". "Each patient who qualified to receive double-blind treatment was assigned a randomisation number and given zonisamide or placebo"
Allocation concealment (selection bias)Low risk"Random allocation of patients to their treatment groups was concealed via the use of numbered containers"
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThis study was deemed to be at low risk of performance bias
Blinding of outcome assessment (detection bias)
All outcomes
Low riskThis study was deemed to be at low risk of detection bias
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient or unclear details were provided with regard to attrition bias
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasLow riskBaseline period was extended if the frequency of seizures did not meet a prespecified threshold

Schmidt 1993

  1. a

    AED: antiepileptic drug
    F: female
    ITT: intention-to-treat
    M: male

MethodsRandomised, double-blind, placebo-controlled, parallel group study
2 treatment arms, 1 placebo, 1 zonisamide. The initial target dose of zonisamide was 7 mg/kg/day, but when it became apparent that this was associated with a significant incidence of adverse effects, it was titrated over the first 4 weeks to 400 mg/day. Thereafter a non-blinded observer recommended dose adjustments to obtain plasma levels of 20 to 30 µg/ml. Median dosage in this group was 400 mg/day
Randomisation concealment by allocated sequentially numbered, sealed packages. Random list generated by random permuted blocks. Blinding by identical packing and tablets
Baseline was variable, between 8 and 12 weeks, being extended if frequency was below 4 partial seizures/month
Treatment period was 12 weeks
ParticipantsParticipants from 10 European centres recruited between June 1984 and October 1986
Total randomised: 144 participants, all with 4 or more partial seizures/month while taking 1 or 2 AEDs. 73 were randomised to zonisamide, 71 to placebo
Age 17 to 60 years, 85 male 59 female
Median monthly seizure frequency pre-baseline: 11.3 zonisamide, 11.0 placebo
InterventionsZonisamide median dosage 400 mg/day (100 mg capsules)
Placebo
Treatments and packaging were identical
OutcomesPrimary: median percentage reduction in seizure frequency of all partial seizures from baseline
Secondary: proportion of participants with a 50% reduction in all partial seizures from baseline
NotesBecause of the variable baseline periods, baseline seizure frequency was recalculated for the 8 weeks immediately before entry into the treatment period
7 people failed to complete the 12-week treatment period in the zonisamide group, 2 in the placebo group
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Patients were randomised sequentially in blocks of four"
Allocation concealment (selection bias)Unclear riskInsufficient details provided
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficient details were provided about blinding of personnel
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessors was not detailed
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskA modified ITT analysis was conducted including patients who had received "at least 7 days of treatment"
Selective reporting (reporting bias)Low riskThis study was deemed to be at low risk of selective reporting
Other biasLow riskBaseline period was extended if the frequency of seizures did not meet a prespecified threshold

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Shimizu 1988No control group was used

Characteristics of studies awaiting assessment [ordered by study ID]

Anderson 1988

MethodsNo details
ParticipantsNo details
InterventionsZonisamide add-on versus sodium valproate add-on
OutcomesNo details
NotesNo details