Oxcarbazepine versus phenytoin monotherapy for epilepsy

  • Review
  • Intervention

Authors


Abstract

Background

This is an updated version of the original Cochrane review published in The Cochrane Library 2006, Issue 2.

Worldwide, phenytoin is a commonly used antiepileptic drug. For the newer drugs such as oxcarbazepine, it is important to know how they compare with standard treatments.

Objectives

To review the best evidence comparing oxcarbazepine and phenytoin when used as monotherapy in participants with partial onset seizures or generalised tonic-clonic seizures with or without other generalised seizure types.

Search methods

We searched the Cochrane Epilepsy Group's Specialised Register (22 January 2013), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2012, Issue 12) and MEDLINE (1946 to 22 January 2013). We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators and experts in the field.

Selection criteria

Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of oxcarbazepine monotherapy with phenytoin monotherapy.

Data collection and analysis

This was an individual participant data review. Outcomes were time to (a) treatment withdrawal (b) 12-month remission (c) six-month remission and (d) first seizure post randomisation. We used Cox proportional hazards models to obtain study-specific estimates of hazard ratios (HR) with 95% confidence intervals (CI) with the generic inverse variance method used to obtain the overall pooled HR and 95% CI.

Main results

Individual participant data were available for 480 out of 517 participants (93%) from three included trials. For remission outcomes, a HR > 1 indicates an advantage to phenytoin and for first seizure and withdrawal outcomes a HR > 1 indicates an advantage to oxcarbazepine.

The main overall results (pooled HR, 95% CI) were: (i) time to withdrawal of allocated treatment 1.65 (1.08 to 2.52), (ii) time to 12-month remission 0.92 (0.68 to 1.24), (iii) time to six-month remission 0.90 (0.70 to 1.15), (iv) time to first seizure 1.07 (0.83 to 1.39). Results indicate a statistically significant advantage for oxcarbazepine over phenytoin for time to treatment withdrawal, but insufficient evidence to suggest a difference between the drugs for other outcomes. By epilepsy type, there is no significant advantage for either drug for generalised epilepsy, however there is a significant advantage for partial epilepsy with oxcarbazepine for time to treatment withdrawal (HR 1.95; 95% CI 1.15 to 3.33).

Authors' conclusions

For participants with partial onset seizures oxcarbazepine is significantly less likely to be withdrawn, but current data do not allow a statement as to whether oxcarbazepine is equivalent, superior or inferior to phenytoin in terms of seizure control. However, the design of the studies may have biased seizure outcomes and misclassification of epilepsy type may have biased withdrawal rates.

Plain language summary

Oxcarbazepine versus phenytoin monotherapy for epilepsy

Epilepsy is a disorder where recurrent seizures are caused by abnormal electrical discharges from the brain. Most seizures can be controlled by a single antiepileptic drug. Worldwide, phenytoin is a commonly used antiepileptic drug and oxcarbazepine is one of a newer generation of antiepileptic drugs. The review found that the new drug, oxcarbazepine, when used as a single treatment, is less likely than phenytoin to be withdrawn for reasons of efficacy (seizure control) or tolerability (adverse effects) for participants with partial epilepsy. There is no evidence of a difference between withdrawal rates of the two drugs for participants with generalised seizures. There is also no evidence of a difference between the two drugs in terms of seizure recurrence or remission for both partial and generalised epilepsy, however the design of the studies included in this review may have influenced these seizure and remission outcomes.

Laički sažetak

Okskarbazepin ili fenitoin kao pojedinačni lijek za epilepsiju

Epilepsija je poremećaj u kojem su ponavljani napadaji uzrokovani abnormalnim električnim pražnjenjem iz mozga. Većina se napadaja može kontrolirati jednim antiepileptičkim lijekom. Širom svijeta fenitoin se uobičajeno koristi kao antiepileptički lijek, a okskarbazepin je jedan od novije generacije antiepileptičkih lijekova. Cochrane sustavni pregled pokazuje da je manje vjerojatno da će novi lijek, okskarbazepin, kada se koristi kao pojedinačna terapija, biti povučen zbog učinkovitosti (kontrola napadaja) ili tolerancije (nuspojave) kod ispitanika s djelomičnom epilepsijom, nego fenitoin. Nema dokaza da postoji razlika stope odustajanja ispitanika između dva lijeka za sudionike s generaliziranim napadajima. Također nema dokaza o razlici između dva lijekova u smislu povratka napadaja ili remisije za obje varijante i djelomične i generalizirane epilepsije, no ustroj studija uključenih u ovaj pregled je mogao imati utjecaj na ishod napadaja i remisije.

Bilješke prijevoda

Prevela Ivana Miosic

Prevoditelj:: Croatian Branch of the Italian Cochrane Centre

Summary of findings(Explanation)

Summary of findings for the main comparison. 
  1. 1Pooled hazard ratio for all participants adjusted for epilepsy type.

    2Up to 29% of adult participants (in Bill 1997) may have had their epilepsy type wrongly classified and sensitivity analyses show misclassification has an impact on results and conclusions.

    3Sensitivity analysis for misclassification of epilepsy type shows similar results and unchanged conclusions so misclassification is unlikely to impact on results.

    4As participants who withdrew from the treatment were no longer followed up in the study, remission and seizure outcomes had to be censored at time of treatment withdrawal, therefore remission and seizure outcomes could not be analysed with an intention-to-treat approach.

Oxcarbazepine compared with phenytoin for epilepsy

Patient or population: adults and children with newly diagnosed epilepsy

Settings: outpatients

Intervention: oxcarbazepine

Comparison: phenytoin

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
PhenytoinOxcarbazepine

Time to withdrawal of allocated treatment - all participants

8-week titration period then 48-week maintenance period

Total: 56 weeks (392 days) follow-up

23 per 10014 per 100
(10 to 22)

HR 1.64

(1.06 to 2.54)1

476
(2 studies)
⊕⊕⊕⊝
moderate2
HR > 1 indicates a clinical advantage for oxcarbazepine

Time to withdrawal of allocated treatment

Stratified by epilepsy type - partial epilepsy

8-week titration period then 48-week maintenance period

Total: 56 weeks (392 days) follow-up

24 per 10013 per 100
(8 to 21)

HR 1.95

(1.15 to 3.33)

333
(2 studies)
⊕⊕⊕⊝
moderate2
HR > 1 indicates a clinical advantage for oxcarbazepine

Time to withdrawal of allocated treatment

Stratified by epilepsy type - generalised epilepsy

8-week titration period then 48-week maintenance period

Total: 56 weeks (392 days) follow-up

20 per 10017 per 100
(8 to 34)

HR 1.16

(0.54 to 2.46)

143
(2 studies)
⊕⊕⊕⊝
moderate2
HR > 1 indicates a clinical advantage for oxcarbazepine

Time to achieve 6-month remission - all participants

8-week titration period then 48-week maintenance period

Total: 56 weeks (392 days) follow-up

51 per 10049 per 100
(41 to 58)

HR 0.94

(0.74 to 1.21)1

468
(2 studies)
⊕⊕⊕⊝
moderate3,4
HR > 1 indicates a clinical advantage for phenytoin

Time to achieve 6-month remission

Stratified by epilepsy type - partial epilepsy

8-week titration period then 48-week maintenance period

Total: 56 weeks (392 days) follow-up

51 per 10045 per 100
(36 to 56)

HR 0.85

(0.63 to 1.15)

326

(2 studies)

⊕⊕⊕⊝
moderate3,4
HR > 1 indicates a clinical advantage for phenytoin

Time to achieve 6-month remission

Stratified by epilepsy type - generalised epilepsy

8-week titration period then 48-week maintenance period

Total: 56 weeks (392 days) follow-up

52 per 10059 per 100
(43 to 75)

HR 1.20

(0.76 to 1.89)

142

(2 studies)

⊕⊕⊕⊝
moderate3,4
HR > 1 indicates a clinical advantage for phenytoin

Time to achieve 12-month remission - all participants

8-week titration period then 48-week maintenance period

Total: 56 weeks (392 days) follow-up

32 per 10031 per 100
(24 to 40)

HR 0.95

(0.70 to 1.29)1

468
(2 studies)
⊕⊕⊕⊝
moderate3,4
HR>1 indicates a clinical advantage for phenytoin

Time to achieve 12-month remission

Stratified by epilepsy type - partial epilepsy

8-week titration period then 48-week maintenance period

Total: 56 weeks (392 days) follow-up

31 per 10029 per 100
(21 to 39)

HR 0.92

(0.64 to 1.33)

326

(2 studies)

⊕⊕⊕⊝
moderate3,4
HR > 1 indicates a clinical advantage for phenytoin

Time to achieve 12-month remission

Stratified by epilepsy type - generalised epilepsy

8-week titration period then 48-week maintenance period

Total: 56 weeks (392 days) follow-up

35 per 10036 per 100
(23 to 53)

HR 1.01

(0.59 to 1.73)

142

(2 studies)

⊕⊕⊕⊝
moderate3,4
HR > 1 indicates a clinical advantage for phenytoin

Time to first seizure - all participants

8-week titration period then 48-week maintenance period

Total: 56 weeks (392 days) follow-up

50 per 10048 per 100
(39 to 57)

HR 1.04

(0.80 to 1.35)1

468
(2 studies)
⊕⊕⊕⊝
moderate3,4
HR > 1 indicates a clinical advantage for oxcarbazepine

Time to first seizure

Stratified by epilepsy type - partial epilepsy

8-week titration period then 48-week maintenance period

Total: 56 weeks (392 days) follow-up

53 per 10050 per 100
(40 to 61)

HR 1.08

(0.80 to 1.47)

326

(2 studies)

⊕⊕⊕⊝
moderate3,4
HR > 1 indicates a clinical advantage for oxcarbazepine

Time to first seizure

Stratified by epilepsy type - generalised epilepsy

8-week titration period then 48-week maintenance period

Total: 56 weeks (392 days) follow-up

41 per 10042 per 100
(28 to 60)

HR 0.94

(0.56 to 1.56)

142

(2 studies)

⊕⊕⊕⊝
moderate3,4
HR > 1 indicates a clinical advantage for oxcarbazepine

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The assumed risk is calculated as the event rate in the Phenytoin treatment group
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).
The corresponding risk is calculated as the assumed risk x the relative risk (RR) of the intervention where:

RR = (1 - exp(HR x ln(1 - assumed risk)))/assumed risk
CI: confidence interval; RR: risk ratio; HR: hazard ratio; exp: exponential

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

This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (2006, Issue 2) on 'Oxcarbazepine versus phenytoin monotherapy for epilepsy' (Muller 2006).

Oxcarbazepine is one of the newer antiepileptic drugs and has similar chemical properties to its parent compound carbamazepine. It is licensed in a number of countries for use as both monotherapy and add-on (adjunctive) therapy. A review of oxcarbazepine as an add-on treatment in people with partial onset seizures has already been published (Castillo 2000), which provides reliable evidence that oxcarbazepine reduces seizure frequency compared to placebo when used as an add-on treatment.

The majority of people with epilepsy have their seizures controlled by a single drug (monotherapy) (Cockerell 1995). There are an ever increasing number of antiepileptic drugs to choose from and both clinicians and people with epilepsy need reliable evidence upon which to base their choice of medication. Such evidence will come from trials comparing one drug with another, rather than trials comparing drugs with placebo. For newer drugs such as oxcarbazepine, it is important to know how they compare with first-line standard treatments. Our aim in this systematic review is to overview existing evidence for the comparative efficacy and tolerability of oxcarbazepine and phenytoin (one of the standard antiepileptic drugs) when used as monotherapy.

Worldwide, phenytoin is a commonly used antiepileptic drug for participants with partial onset seizures and generalised onset tonic-clonic seizures. Although phenytoin is no longer considered as a first-line treatment in Europe (Wallace 1997) it is more commonly used in the USA (Wilder 1995). Phenytoin is associated with long-term cosmetic changes including gum hypertrophy, acne and coarsening of the facial features (Mattson 1985; Scheinfeld 2003) as well as low folic acid levels, predisposing participants to megaloblastic anaemia (Carl 1992). It can also cause a rash (Tennis 1997) in 5% to 10% of participants, which on rare occasions may be life threatening. It is also associated with congenital abnormalities (Gladstone 1992; Nulman 1997), where the risk is estimated to be two to three times that of the general population (Meador 2008). Phenytoin is also particularly associated with fetal hydantoin syndrome (Scheinfeld 2003).

When used as monotherapy, oxcarbazepine has been shown to be as effective in terms of seizure control as first line antiepileptic drugs carbamazepine (Dam 1989), phenytoin (Bill 1997; Guerreiro 1997) and sodium valproate (Christe 1997). Oxcarbazepine is generally well tolerated as monotherapy in adults (Beydoun 2000; Bill 1997; Dam 1989 Christe 1997; Schachter 1999) and children (Guerreiro 1997), with a low incidence of cosmetic side effects and serious adverse events such as allergic reactions (Kwan 2003), resulting in significantly lower discontinuation rates compared to carbamazepine in adults (Dam 1989) and phenytoin in adults (Bill 1997) and children (Guerreiro 1997).

Common adverse events, reported in more than 5% of participants receiving oxcarbazepine monotherapy, are similar in adults and children and include somnolence, headache, dizziness, nausea, vomiting, fatigue and rash (Bang 2003; Kwan 2003; Wellington 2001). Oxcarbazepine has been shown to be better tolerated than phenytoin in adults, particularly in terms of gum hyperplasia, tremor, diplopia and nystagmus (Bill 1997), and in children, particularly in terms of gum hyperplasia, nervousness, dizziness, hypertrichosis and ataxia (Guerreiro 1997).

There are difficulties in undertaking a systematic review of epilepsy monotherapy trials as the important efficacy outcomes require analysis of time-to-event data (for example, time to first seizure after randomisation). Although methods have been developed to synthesise time-to-event data using summary information (Parmar 1998; Williamson 2002), the appropriate statistics are not commonly reported in published epilepsy trials.

Furthermore, although seizure data have been collected in most epilepsy monotherapy trials, there has been no uniformity in the definition and reporting of outcomes. For example, trials may report time to 12-month remission but not time to first seizure or vice versa, or some trials may define time to first seizure from the date of randomisation but others may use date of achieving maintenance dose. Trial investigators have also adopted differing approaches to the analysis, particularly with respect to the censoring of time-to-event data. For these reasons, we performed this review using individual participant data (IPD) which helps to overcome these problems. This review is one in a series of IPD reviews investigating pair-wise monotherapy comparisons.

Objectives

To review the best evidence comparing oxcarbazepine and phenytoin when used as monotherapy in participants with partial onset seizures or generalised tonic-clonic seizures with or without other generalised seizure types.

Methods

Criteria for considering studies for this review

Types of studies

  1. Randomised controlled trials using either:

    1. an adequate method of allocation concealment (e.g. sealed opaque envelopes);

    2. a quasi method of randomisation (e.g. allocation by date of birth).

  2. Studies may be double-blind, single-blind or unblinded.

Types of participants

  1. Children or adults with partial onset seizures (simple partial, complex partial or secondary generalised tonic-clonic), or generalised tonic-clonic seizures (with or without other generalised seizure types).

  2. Individuals with a new diagnosis of epilepsy, or who had had a relapse following antiepileptic monotherapy withdrawal.

Types of interventions

Oxcarbazepine or phenytoin as monotherapy.

Types of outcome measures

Below is a list of outcomes investigated in this review. Reporting of these outcomes in the original trial report was not an eligibility requirement for inclusion in this review.

Primary outcomes

Time to withdrawal of allocated treatment (retention time). This is a combined outcome reflecting both efficacy and tolerability as treatment may be withdrawn due to continued seizures, adverse effects or a combination of both. This is an outcome to which the participant makes a contribution, and is the primary outcome measure recommended by the Commission on Antiepileptic Drugs of the International League Against Epilepsy (ILAE 2006).

Secondary outcomes
  1. Time to achieve 12-month seizure-free period (remission).

  2. Time to achieve six-month seizure-free period (remission).

  3. Time to first seizure post randomisation.

  4. Quality of life measure if available.

Search methods for identification of studies

Electronic searches

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

  1. Cochrane Epilepsy Group Specialised Register (22 January 2013) using the search terms 'oxcarbazepine' and 'phenytoin'.

  2. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2012, Issue 12) using the strategy outlined in Appendix 1.

  3. MEDLINE (Ovid, 1946 to 22 January 2013) using the strategy outlined in Appendix 2.

Searching other resources

In addition, we handsearched relevant journals, reviewed the reference lists of included studies to search for additional reports of relevant studies, contacted Novartis (manufacturers of oxcarbazepine) and Parke-Davis (manufacturers of phenytoin) and researchers in the field to seek any ongoing or unpublished studies.

Data collection and analysis

Selection of studies

Two of the authors (MM and SJN) independently assessed all identified trials for inclusion. Any disagreements were resolved by mutual discussion.

Data extraction and management

We requested the following individual participant data for all trials meeting our inclusion criteria.

  1. Trial methods

    1. Method of generation of random list

    2. Method of concealment of randomisation

    3. Stratification factors

    4. Blinding methods

  2. Participant covariates

    1. Sex

    2. Age

    3. Seizure types

    4. Time between first seizure and randomisation

    5. Number of seizures prior to randomisation (with dates)

    6. Presence of neurological signs

    7. Electroencephalogram (EEG) results

    8. Computerised tomography (CT)/magnetic resonance imaging (MRI) results

  3. Follow-up data

    1. Treatment allocation

    2. Date of randomisation

    3. Dates of follow-up

    4. Dates of seizures post randomisation or seizure frequency data between follow-up visits

    5. Dates of treatment withdrawal and reasons for treatment withdrawal

    6. Dose

    7. Dates of dose changes

For each trial for which individual participant data were not obtained, we carried out an assessment to see whether any relevant aggregate level data had been reported.

Assessment of risk of bias in included studies

Two authors (SJN and MM) assessed all included studies independently for risk of bias and resolved any disagreements by mutual discussion.

Measures of treatment effect

All outcomes in this review were measured as time-to-event outcomes. We calculated outcomes from IPD provided where possible or extracted from published studies.

Unit of analysis issues

  • For included trials with IPD provided (Bill 1997; Guerreiro 1997) seizure data were provided in terms of the mean number of seizures recorded per week in the titration period (first eight weeks) and the maintenance period (following 48 weeks) rather than specific dates of seizures. To enable time-to-event outcomes to be calculated, we applied linear interpolation to approximate the days on which seizures occurred. For example, if the mean number of seizures per week in the titration period was 0 and in the maintenance period was 0.02115 and the participant started treatment on 28 September 1993 and ended treatment on 19 October 1994 (interval of 387 days), then the date of first seizure would be approximately 165.5 days after the start of the maintenance period and thus 221.5 days after the start of treatment. This allowed an estimate of the time to six- and 12-month remission and the time to first seizure to be computed.

  • We calculated time to six- and 12-month remission from the date of randomisation to the date (or estimated date) the individual had first been free from seizures for six or 12 months respectively. If the participant had one or more seizures in the titration period, a six- or 12-month seizure-free period could also occur between the estimated date of the last seizure in the titration period and the estimated date of the first seizure in the maintenance period.

  • We calculated time to first seizure from the date of randomisation to the date that their first seizure was estimated to have occurred. If the mean number of seizures per week data were missing for the titration period (first eight weeks), the estimated time of the first seizure could not be calculated. Eight participants in total (five in Bill 1997 and three in Guerreiro 1997) had missing seizure data for the titration period (all eight also had missing seizure data for the maintenance period. The number of days on trial medication ranged between one and 36 days for these eight participants. They were excluded from analyses of time to first seizure, time to six-month remission and time to 12-month remission, but included in the analysis of time to withdrawal

  • If the mean 'number of seizures per week' data were missing for the maintenance period (but not for the titration period), the values for six- and 12-month remission would be censored at the end of the titration period (effectively excluding them from the analysis). These outcomes were also censored if the individual died or follow-up ceased prior to the occurrence of the event of interest.

  • For both trials (Bill 1997; Guerreiro 1997) the date of and reason for the treatment withdrawal were provided directly (see Table 1 for reasons of premature discontinuation of treatment). Two of the review authors (MM and AGM) extracted detail about the reason for the treatment withdrawal from study case report forms (when necessary e.g. for death and protocol violation(s)). For the analysis of time to withdrawal of allocated treatment, an event was defined to be withdrawal of allocated treatment due to an adverse experience by the participant, unsatisfactory therapeutic effect, concomitant illness, participant non-compliance or abnormal laboratory values. The outcome was censored if treatment was withdrawn because of protocol violation(s), loss to follow-up or administrative problems, or if the individual was still on allocated treatment at the end of follow-up. For one participant a protocol violation was further specified as non-compliance and this was classified as an event. Two deaths were recorded. One was classified as a censored value, because the cause of death was unrelated to the treatment or the condition. The other death was classified as an event: the participant died after experiencing an episode of status epilepticus, but had been non-compliant and discontinued treatment before they died.

    Table 1. Reasons for premature discontinuation (withdrawal from allocated treatment)
    Principal reasonBill - oxcarbazepine (n = 143)Bill - phenytoin (n = 144)Guerreiro - oxcarbazepine (n = 97)Guerreiro - phenytoin (n = 96)Classification
    Adverse experience5 (3.5%)16 (11.1%)2 (2.1%)14 (14.6%)Event
    Unsatisfactory therapeutic effect1 (0.7%)1 (0.7%)4 (4.1%)3 (3.1%)Event
    Concomitant illness2 (1.4%)4 (2.8%)1 (1.0%)0Event
    Protocol violation(s)16 (11.2%)10 (6.9%)3 (3.1%)2 (2.1%)

    Censored. Except where the description of the violation was 'Non-compliance'

    then coded as 'Event' (n = 1 in Bill and n = 1 in Guerreiro)

    Participant non-compliance13 (9.1%)10 (6.9%)6 (6.2%)5 (5.2%)Event
    Abnormal laboratory values01 (0.7%)00Event
    Lost to follow-up9 (6.3%)12 (8.3%)8 (8.2%)9 (9.4%)Censored
    Administrative reasons10 (7.0%)5 (3.5%)00Censored
    Death02 (1.4%)00

    Non-compliance before episode of status epilepticus and death (n = 1): Event

    Caught in political violence (n = 1): Censored

    Discontinuation at baseline0001 (1.0%)Censored
    Total (premature discontinuation)56 (39.2%)61 (42.4%)24 (24.7%)34 (35.4%) 

Dealing with missing data

For each trial where IPD were supplied, we reproduced results from trial results where possible and performed consistency checks:

  1. we cross-checked trial details against any published report of the trial and contacted original trial authors if missing data, errors or inconsistencies were found;

  2. review of the chronological randomisation sequence: we checked the balance of prognostic factors, taking account of factors stratified for in the randomisation procedure.

Assessment of heterogeneity

We assessed heterogeneity statistically using the Q test and I2 statistic output produced using the generic inverse variance approach in RevMan 5 (RevMan 2012) and visually by inspecting forest plots.

Assessment of reporting biases

Two review authors (SJN and MM) undertook a full quality and 'Risk of bias' assessment. In theory, a review using individual participant data should overcome issues of reporting biases as unpublished data can be provided and unpublished outcomes calculated.

Data synthesis

  • We carried out the analysis on an intention-to-treat basis and included all randomised participants, analysed in the treatment group to which they were allocated, irrespective of which treatment they actually received. However, in the two trials included in meta-analysis, participants were not followed up after the randomised treatment had been withdrawn (see Table 1 for reasons for premature discontinuation of treatment). For most of these participants, the treatment withdrawal was an event for the time to treatment failure analysis. However, these participants had to be censored at the time of treatment withdrawal for the seizure outcomes, which contravenes the principle of intention-to-treat.

  • For all outcomes, we used Cox proportional hazards models to obtain study-specific estimates of log (hazard ratio) and associated standard errors in statistical software SAS version 9.2. (Copyright, SAS Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS Institute Inc., Cary, NC, USA.). We tested the proportional hazards assumption of the Cox model for each outcome of each study by testing the statistical significance of a time-varying covariate in the model. We evaluated overall estimates of hazard ratios (with 95% confidence intervals) via the generic inverse variance method in RevMan 5.

  • Results are expressed as a hazard ratio (HR) and 95% confidence interval, and by convention a HR > 1 indicates that an event is more likely to occur earlier on phenytoin than oxcarbazepine. Hence, for time to withdrawal of allocated treatment or time to first seizure a HR > 1 indicates a clinical advantage for oxcarbazepine (e.g. HR = 1.2 would suggest a 20% increase in risk of withdrawal from phenytoin compared to oxcarbazepine) and for time to six- and 12-month remission a HR > 1 indicates a clinical advantage for phenytoin.

Subgroup analysis and investigation of heterogeneity

To examine the potential impact of epilepsy type on results, we stratified all analyses by epilepsy type (partial versus generalised), according to the classification of main seizure type recorded at baseline. We classified partial seizures (simple or complex) and partial secondarily generalised seizures as partial epilepsy. We classified primarily generalised seizures as generalised epilepsy. We conducted a Chi2 test of interaction between treatment and epilepsy type.

If significant statistical heterogeneity was found to be present, we performed meta-analysis with a random-effects model in addition to a fixed-effect model and present the result of both models. We also performed sensitivity analyses investigating differences in study characteristics such as randomised participants, dosing protocols and trial design.

Sensitivity analysis

The included trials were double-blind. After completion of the maintenance period, some participants continued to be followed up taking 'open-label' (unblinded) treatment. The primary analyses included data from this open-label period. We repeated the analysis, including only data from the double-blind period of 392 days (eight-week titration period plus the 48-week maintenance period).

As misclassification of seizure type is a recognised problem in epilepsy (whereby some people with generalised seizures have been mistakenly classed as having partial onset seizures and vice versa), we investigated its potential impact on the results in a sensitivity analysis. Given clinical evidence that people with generalised onset seizures are unlikely to have an 'age of onset' greater than 25 to 30 years (Malafosse 1994), we examined the distribution of age at onset for people with generalised seizures. We undertook two sensitivity analyses to investigate misclassification.

  1. We reclassified all individuals with generalised seizure types and age at onset greater than 30 into an 'uncertain epilepsy type' group.

  2. We reclassified individuals with generalised seizures and age of onset greater than 30 as having partial epilepsy.

Results

Description of studies

We identified 69 records from the databases and search strategies outlined in Electronic searches. No further records were found via searching other resources. We removed 22 duplicate records and screened 47 records (title and abstract) for inclusion in the review. We excluded 39 records based on title and abstract and assessed eight full-text articles for inclusion in the review. Five studies were excluded from the review; one (Sabers 1995) was not fully randomised and four (D'Souza 2003; Guerreiro 2003; Schmidt 2007; Sturm 2003) were re-analyses or follow-up analyses of two studies (Bill 1997; Guerreiro 1997) included in the review (see Characteristics of excluded studies for detailed reasons for exclusion).

A total of three randomised controlled trials in which participants were randomised to oxcarbazepine or phenytoin were included in the systematic review (see Characteristics of included studies and Figure 1 for details of eligibility screening).

Figure 1.

PRISMA Study flow diagram.

IPD were available for all participants in two included studies (Bill 1997; Guerreiro 1997), therefore these two studies are included in the IPD meta-analysis. IPD has been pledged for the third study (Aikia 1992) and, if received, the data for 37 participants will be included in an updated version of this review.

For Bill 1997 and Guerreiro 1997, IPD were available for a total of 480 participants and computerised data were provided directly for both trials (see Characteristics of included studies).

Data were available for the following participant characteristics (percentage participants with data available): time between first seizure and randomisation (100%); seizure types (99.2%); age (99.8%); sex (100%); number of seizures prior to randomisation (100%); EEG results (97.7%); CT scan results (79.2%).

The two trials were similar in design and recruited participants with newly diagnosed and previously untreated epilepsy, however one trial recruited adults only (Bill 1997) and one trial recruited children and adolescents only (Guerreiro 1997), which is a potential source of heterogeneity. Both trials recruited participants with partial onset seizures (simple/complex partial or secondary generalised tonic-clonic) and participants with generalised tonic-clonic seizures without partial onset. In the trial including adults only (Bill 1997) 61% of participants were male (57% males in the oxcarbazepine group and 64% in the phenytoin group). In the trial including children and adolescents (Guerreiro 1997), 50% of participants were male (47% males in the oxcarbazepine group and 52% in the phenytoin group). To be included in the trials (Bill 1997; Guerreiro 1997) participants had to have a minimum of two seizures, separated by at least 48 hours, in the six months before entering the study. In both trials the baseline assessment included a medical and seizure history, physical examination, laboratory evaluations, electrocardiogram (ECG), electroencephalogram (EEG) and an optional cranial computed tomography (CT) scan to rule out any progressive neurological disorder such as a brain tumour. Seizures were classified according to the 1981 International Classification of seizure types (Bill 1997; Guerreiro 1997; ILAE 1981) and the 1989 classification of epilepsies and epileptic syndromes (Guerreiro 1997; ILAE 1989).

During the eight-week titration period, treatment was started with daily doses of:

  • 300 mg oxcarbazepine or 100 mg phenytoin (Bill 1997) and then increased bi-weekly (every two weeks) based on clinical response (for adults);

  • 150 mg oxcarbazepine or 50 mg phenytoin (Guerreiro 1997) and then increased gradually based on clinical response (for children and adolescents).

No fixed titration schedule was used except that after eight weeks participants were to be on a tid (three times per day) regimen of oxcarbazepine or phenytoin with daily doses of 450 to 2400 mg and 150 to 800 mg, respectively. The daily dose range and tid regimen were to be continued during the subsequent 48-week maintenance period. However, adjustment of the daily dose according to clinical response was possible during this period. The median daily dose actually taken (with lower and upper quartiles) for oxcarbazepine was 900 mg (900; 1200) for Bill 1997 and 600 mg (450; 900) for Guerreiro 1997. The median daily dose (with lower and upper quartiles) for phenytoin was 300 mg (300; 300) for Bill 1997 and 200 mg (150; 300) for Guerreiro 1997.

Risk of bias in included studies

For further details, see Characteristics of included studies, Figure 2 and Figure 3.

Figure 2.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3.

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

Allocation

For Bill 1997 and Guerreiro 1997 randomisation numbers were sequentially assigned across centres within each country. A computer-generated randomisation scheme was used to provide balanced blocks of participant numbers for each of the two treatment groups within each centre. A block size of six was used (Pohlmann 2005).

The trial reports (Bill 1997; Guerreiro 1997) did not provide details on allocation concealment, but the trial statistician (Pohlmann 2005) explained that allocation concealment was achieved as follows: sequentially numbered packages were prepared which were identical and contained identical tablets. Recruiting clinicians were asked to allocate each participant the package with the lowest number available at the centre.

Participants were "randomly allocated" to treatment in Aikia 1992, however the methods of generation of a random sequence and of allocation concealment were not provided in the trial report.

Blinding

Bill 1997 and Guerreiro 1997 were double-blinded by using divisible tablets with identical appearance. Aikia 1992 was also double-blinded, however the method of achieving the double-blind was not provided in the trial report.

Incomplete outcome data

Analyses were not performed with an intention-to-treat approach in Aikia 1992: 29 participants who completed 12 months of follow-up were included in analyses, eight participants who experienced inadequate seizure control, adverse events or were non-compliant were withdrawn from the study and excluded from analysis.

For the studies for which IPD were provided (Bill 1997; Guerreiro 1997) analyses for time to six-month remission, time to 12-month remission and time to first seizure could not be performed with an intention-to-treat approach as participants who withdrew from both studies were not followed up after time of withdrawal (see Data synthesis).

The numbers for premature discontinuation in the titration period differ from the numbers reported in the publication (49 participants - 25 on oxcarbazepine and 24 on phenytoin in Bill 1997 and 31 participants - 15 on oxcarbazepine and 16 on phenytoin in Guerreiro 1997). The differences were followed up with the trial statistician (Pohlmann 2005) who proposed a possible explanation: it is likely that the raw premature discontinuation data (0 or 1) as collected in the CRF (clinical record file) was provided for this Cochrane review, but for the time to premature discontinuation analyses in the publication a derived premature discontinuation variable based on the "time under assessment" was created. If certain participants had empty records in the maintenance period, the created variable will indicate a premature discontinuation at the end of the titration period, although in the CRF they were coded as discontinuing during the maintenance period. If this was the case, it is possible that we find fewer participants who discontinued during the titration period, compared to the publication. (Note that the trial statistician who proposed this explanation was not the original trial statistician and could only explain how they handled data at the time of the trial (in the 1990s). The data used for the publication were not accessible at the time of our query).

Selective reporting

Protocols were not available for the three included studies (Aikia 1992; Bill 1997; Guerreiro 1997), however unpublished individual participant data were provided in order to calculate outcomes used in this review for Bill 1997 and Guerreiro 1997 and neuropsychological and cognitive outcomes were well reported in Aikia 1992.

Other potential sources of bias

In Bill 1997, 104 of the 287 participants randomised were classified as having generalised onset seizures, 30 of whom were over the age of 30 years at randomisation. Given that generalised onset seizures present primarily in childhood and adolescence (Malafosse 1994), it is possible that many of the latter participants were wrongly classified. Hence the generalised onset seizure subgroup could represent a combination of participants with generalised onset and participants with partial onset seizures. We performed sensitivity analyses to examine the effect of the potential misclassification for each outcome.

Effects of interventions

See: Summary of findings for the main comparison

The following results apply only to the two studies included in meta-analysis for which individual participant data (IPD) were provided (Bill 1997; Guerreiro 1997). IPD have been pledged for Aikia 1992 and if received will be included in an updated version of this review.

Details regarding the number of participants contributing to each analysis are given in Table 2. Four participants had missing data for the main seizure type at baseline (one in Bill 1997 and three in Guerreiro 1997) and therefore their epilepsy type could not be derived. These four participants are excluded from subgroup analyses according to epilepsy types. All results are summarised in Table 3 and forest plots. The survival curve plots can be found in Figure 4; Figure 5; Figure 6; Figure 7; Figure 8; Figure 9; Figure 10 and Figure 11. We produced all survival curve plots in Stata software version 11.2 (Stata 2009) using data from all trials providing IPD combined.

Figure 4.

Time to treatment withdrawal

Figure 5.

Time to treatment withdrawal - stratified by epilepsy type

Figure 6.

Time to 12-month remission

Figure 7.

Time to 12-month remission - stratified by epilepsy type

Figure 8.

Time to six-month remission

Figure 9.

Time to six-month remission - stratified by epilepsy type

Figure 10.

Time to first seizure

Figure 11.

Time to first seizure - stratified by epilepsy type

Table 2. Number of participants contributing to analysis - stratified by epilepsy type
  1. OXC: oxcarbazepine, PHT: phenytoin

TrialEpilepsy type Number randomised6-month remission12-month remissionTime to withdrawalTime to first seizure
OXCPHTOXCPHTOXCPHTOXCPHTOXCPHT
Bill 1997Partial84988197819784988197
 Generalised58465746574658465746
 Total classified142144138143138143142144138143
 Unclassified/missing1010101010
 TOTAL143144139143139143143144139143
            
Guerreiro 1997Partial73787276727673787276
 Generalised22172217221722172217
 Total classified95959493949395959493
 Unclassified/missing2121212121
 TOTAL97969694969497969694
TOTAL 237239235237235237237239235237
Table 3. Results of analysis (heterogeneity, overall effect and interaction)
  1. CI: confidence interval
    df: degrees of freedom of Chi2 distribution
    HR: hazard ratio

    P values < 0.05 are classified as statistically significant.

 StatisticTime to treatment withdrawalTime to 6-month remissionTime to 12-month remissionTime to first seizure
Test for heterogeneityChi2(df = 1)  0.25(df = 1) 0.19(df = 1) 0.19(df = 1) 0.31
P value0.620.660.660.58
I20%0%0%0%
Overall effectHR (95% CI)1.65 (1.08 to 2.52)0.90 (0.70 to 1.15)0.92 (0.68 to 1.24)1.07 (0.83 to 1.39)
P value0.020.380.580.60

Test for interaction between

treatment effect and epilepsy type

Chi2 (df = 1) 1.23 (df = 1) 1.56(df = 1) 0.09(df = 1) 0.23
P value 0.270.210.770.63
I219%35.8%0%0%
Overall effect adjusted for epilepsy typeHR (95% CI)1.64 (1.06 to 2.54)0.94 (0.74 to 1.21)0.95 (0.70 to 1.29)1.04 (0.80 to 1.35)

(1) Time to withdrawal of allocated treatment

Of the 287 participants who were randomised in Bill 1997 (143 to oxcarbazepine and 144 to phenytoin), 117 participants (56 (39.2%) in the oxcarbazepine group and 61 (42.2%) in the phenytoin group) discontinued prematurely from the trial (5 and 16 respectively for tolerability reasons). Of these participants, 37 (18 on oxcarbazepine and 19 on phenytoin) discontinued during the eight-week titration period. An additional 80 participants (38 on oxcarbazepine and 42 on phenytoin) discontinued during the 48-week maintenance period.

Of the 193 participants who were randomised in Guerreiro 1997 (97 to oxcarbazepine and 96 to phenytoin), 58 participants (24 (24.7%) in the oxcarbazepine group and 34 (35.4%) in the phenytoin group) discontinued prematurely from the trial (2 and 14 respectively for tolerability reasons). Of these participants, 27 (13 on oxcarbazepine and 14 on phenytoin) discontinued during the eight-week titration period. An additional 31 participants (11 on oxcarbazepine and 20 on phenytoin) discontinued during the 48-week maintenance period.

See Table 1 for a breakdown of reasons for premature discontinuation according to trial and treatment.

For this outcome, a hazard ratio (HR) > 1 indicates a clinical advantage of oxcarbazepine. Time to withdrawal of allocated treatment and reason for withdrawal were available for 480 participants from two trials (100% of participants from two trials providing IPD).

There was no evidence of statistical heterogeneity between trials (Chi2 = 0.25, df = 1, P = 0.62, I2 = 0%). The overall pooled HR and 95% confidence interval (CI) of 1.65 (95% CI 1.08 to 2.52, P = 0.02) suggests a clinical advantage of oxcarbazepine over phenytoin (see Analysis 1.1).

For four participants the type of seizures was not available (one in Bill 1997 and three in Guerreiro 1997) and therefore their epilepsy type could not be classified. Results stratified for epilepsy type (Analysis 1.2) show a summary HR of 1.16 (95% CI 0.54 to 2.46, I2 = 0%) for generalised onset tonic-clonic seizures (143 participants) indicating an advantage to oxcarbazepine which is not statistically significant (P = 0.71), and 1.95 (95% CI 1.15 to 3.33, I2 = 24%) for partial onset seizures (333 participants) indicating a statistically significant, clinically important advantage for oxcarbazepine (P = 0.01). The overall pooled HR (adjusted for epilepsy type in 476 participants) was 1.64 (95% CI 1.06 to 2.54, P = 0.03) indicating a statistically significant advantage for oxcarbazepine. However, there is no evidence of an association from the test of interaction of treatment effect and epilepsy type (Chi2 = 1.23 df = 1, P = 0.27, I2 = 19%).

Three participants had a recorded time of withdrawal of allocated treatment greater than 392 days (two in Bill 1997 and one in Guerreiro 1997); one with generalised onset seizures and two with partial onset seizures. When values greater than 392 days were censored in the above mentioned analyses (overall analysis and analysis stratified by epilepsy type), the HRs and 95% CIs were very similar to the uncensored analyses and conclusions were unchanged (see Table 4).

Table 4. Sensitivity analysis of the double-blind period only (events censored at 392 days)
  1. P: partial epilepsy, G: generalised epilepsy, O: overall (all participants). Results are presented as pooled HR (95% CI) with fixed-effect.

    Chi2 : Chi2 test; df: degrees of freedom of Chi2 distribution.

    P: P value (P values < 0.05 are classified as statistically significant).

    3 participants with time to withdrawal of allocated treatment greater than 392 days (within open-label treatment phase); one with generalised epilepsy and two with partial epilepsy.

    15 participants with time to 12-month remission greater than 392 days (within open-label treatment phase); three with generalised epilepsy and 12 with partial epilepsy.

    No participants with six-month remission achieved or first seizure recorded in the open-label treatment phase.

    See Analysis 1.2; Analysis 1.6; Analysis 1.8 and Analysis 1.10 for original analyses of time to treatment withdrawal, time to six-month remission, time to 12-month remission and time to first seizure respectively. Forest plots for sensitivity analyses not presented as results were similar and conclusion unchanged.

 AnalysisTime to treatment withdrawalTime to 6-month remissionTime to 12-month remissionTime to first seizure
(i) All follow-up time

P: 1.95 (1.15 to 3.33)

G: 1.16 (0.54 to 2.46)

O: 1.64 (1.06 to 2.54)

P: 0.85 (0.63 to 1.15)

G: 1.20 (0.76 to 1.89)

O: 0.94 (0.74 to 1.21)

P: 0.92 (0.64 to 1.33)

G: 1.01 (0.59 to 1.73)

O: 0.95 (0.70 to 1.29)

P: 1.08 (0.80 to 1.47)

G: 0.94 (0.56 to 1.56)

O: 1.04 (0.80 to 1.35)

Events/total90/476250/468168/468227/468
(i) Test of interactionChi2 = 1.23 (df = 1), P = 0.27, I2 = 19.0%Chi2 = 1.56 (df = 1), P = 0.21, I2 = 35.8%Chi2 = 0.09 (df = 1), P = 0.77, I2 = 0%Chi2 = 0.23 (df = 1), P = 0.63, I2 = 19.0%
     
(ii) Double-blind period only (events censored at 392 days - 56 weeks)

P: 1.99 (1.16 to 3.44)

G: 1.23 (0.57 to 2.63)

O: 1.69 (1.09 to 2.64)

P: 0.85 (0.63 to 1.15)

G: 1.20 (0.76 to 1.89)

O: 0.94 (0.74 to 1.21)

P: 0.84 (0.57 to 1.24)

G: 1.03 (0.60 to 1.78)

O: 0.90 (0.65 to 1.23)

P: 1.08 (0.80 to 1.47)

G: 0.94 (0.56 to 1.56)

O: 1.04 (0.80 to 1.35)

Events/total87/476250/468153/468227/468
(ii) Test of interactionChi2 = 1.03 (df = 1), P = 0.31, I2 = 3.3%Chi2 = 1.56 (df = 1), P = 0.21, I2 = 35.8%Chi2 = 0.36 (df = 1), P = 0.55, I2 = 0%Chi2 = 0.23 (df = 1), P = 0.63, I2 = 19.0%

When seizure type was reclassified from generalised onset to (a) uncertain epilepsy type and (b) partial epilepsy for 30 participants from Bill 1997 (see Sensitivity analysis), substantially more heterogeneity was present between the studies, therefore results are presented with both fixed and random-effects (see Table 5 for results with fixed-effect).

Table 5. Sensitivity analysis - epilepsy type misclassification, fixed-effect analysis
  1. P: partial epilepsy, G: generalised epilepsy, O: overall (all participants). Results are presented as pooled HR (95% CI) with fixed-effect.

    Chi2 : Chi2 test; df: degrees of freedom of Chi2 distribution.

    P: P value (P values < 0.05 are classified as statistically significant).

    30 participants reclassified to partial epilepsy or uncertain epilepsy type for outcome time to treatment withdrawal.

    29 participants reclassified to partial epilepsy or uncertain epilepsy type for outcomes time to six-month and 12-month remission and time to first seizure.

    See Analysis 1.2; Analysis 1.6; Analysis 1.8 and Analysis 1.10 for original analyses of time to treatment withdrawal, time to six-month remission, time to 12-month remission and time to first seizure respectively.

    See Analysis 1.3 and Analysis 1.4 for forest plots of time to withdrawal sensitivity analyses for generalised and age at onset > 30 reclassified as uncertain epilepsy type and partial epilepsy respectively. Forest plots not presented for time to six-month remission, time to 12-month remission and time to first seizure sensitivity analyses as results were similar and conclusions unchanged.

 Time to treatment withdrawalTime to 6-month remissionTime to 12-month remissionTime to first seizure
(i) Original analysis

P: 1.95 (1.15 to 3.33)

G: 1.16 (0.54 to 2.46)

O: 1.64 (1.06 to 2.54)

P: 0.85 (0.63 to 1.15)

G: 1.20 (0.76 to 1.89)

O: 0.94 (0.74,1.21)

P: 0.92 (0.64 to 1.33)

G: 1.01 (0.59 to 1.73)

O: 0.95 (0.70 to 1.29)

P: 1.08 (0.80 to 1.47)

G: 0.94 (0.56 to 1.56)

O: 1.04 (0.80 to 1.35)

(i) Test of interactionChi2 = 1.23 (df = 1), P = 0.27, I2 = 19.0%Chi2 = 1.56 (df = 1), P = 0.21, I2 = 35.8%Chi2 = 0.09 (df = 1), P = 0.77, I2 = 0%Chi2 = 0.23 (df = 1), P = 0.63, I2 = 19.0%
     
(ii) Generalised and age at onset > 30 classified as uncertain

P: 1.95 (1.15 to 3.33)

G: 1.57 (0.68 to 3.59)

U: 0.27 (0.03 to 2.56)

O: 1.70 (1.10 to 2.64)

P: 0.85 (0.63 to 1.15)

G: 1.38 (0.82 to 2.35)

U: 0.66 (0.26 to 1.71)

O: 0.93 (0.73 to 1.20)

P: 0.92 (0.64 to 1.33)

G: 1.06 (0.69 to 1.62)

U: 0.49 (0.16 to 1.46)

O: 0.94 (0.72 to 1.23)

P: 1.08 (0.80 to 1.47)

G: 0.76 (0.42 to 1.37)

U: 2.61 (0.69 to 9.86)

O: 1.04 (0.80 to 1.36)

(ii) Test of interactionChi2 = 2.88 (df = 2), P = 0.24, I2 = 30.5%Chi2 = 3.00 (df = 2), P = 0.22, I2 = 33.3%Chi2 = 1.69 (df = 2), P = 0.43, I2 = 0%Chi2 = 2.99 (df = 2), P = 0.22, I2 = 33.3%
     

(iii) Generalised and age at onset > 30

reclassified as partial

P: 1.70 (1.02 to 2.83)

G: 1.57 (0.68 to 3.59)

O: 1.66 (1.08 to 2.57)

P: 0.84 (0.63 to 1.12)

G: 1.38 (0.82 to 2.35)

O: 0.94 (0.73 to 1.21)

P: 0.89 (0.63 to 1.27)

G: 1.06 (0.69 to 1.62)

O: 0.96 (0.73 to 1.25)

P: 1.15 (0.85 to 1.54)

G: 0.76 (0.42 to 1.37)

O: 1.06 (0.81 to 1.38)

(iii) Test of interactionChi2 = 0.03 (df = 1), P = 0.87, I2 = 0%Chi2 = 2.66 (df = 1), P = 0.10, I2 = 62.4%Chi2 = 0.37 (df = 1), P = 0.54, I2 = 0%Chi2 = 1.50 (df = 1), P = 0.22, I2 = 33.3%
(a) Generalised onset seizures and age at onset > 30 reclassified as uncertain epilepsy type

See Analysis 1.3.

  • For generalised onset seizures (114 participants): fixed-effect HR 1.57 (95% CI 0.68 to 3.59, P = 0.29, I2 = 60%) and random-effects HR 1.39 (95% CI 0.36 to 5.41, P = 0.11, I2 = 60%, tau2 = 0.58).

  • For partial onset seizures (333 participants): fixed-effect HR 1.95 (95% CI 1.15 to 3.33, P = 0.01, I2 = 24%) and random-effects HR 1.99 (95% CI 1.07 to 3.69, P = 0.03, I2 = 24%, tau2 = 0.05).

  • Overall (476 participants): fixed-effect HR 1.70 (95% CI 1.10 to 2.64, P = 0.02, I2 = 40%) and random-effects HR 1.59 (95% CI 0.85 to 2.94, P = 0.14, I2 = 40%, tau2 = 0.19).

  • Test for interaction between treatment effect and epilepsy type: fixed-effect: Chi2 = 2.88, df = 2, P = 0.24, I2 = 30.5% and random-effects: Chi2 = 2.91, df = 2, P = 0.23, I2 = 31.2%.

(b) Generalised onset seizures and age at onset > 30 reclassified as partial onset seizures

See Analysis 1.4.

  • For generalised onset seizures (114 participants): fixed-effect HR 1.57 (95% CI 0.68 to 3.59, P = 0.29, I2 = 60%) and random-effects HR 1.39 (95% CI 0.36 to 5.41, P = 0.11, I2 = 60%, tau2 = 0.58).

  • For partial onset seizures (362 participants): fixed-effect HR 1.70 (95% CI 1.02 to 2.83, P = 0.04, I2 = 56%) and random-effects HR 1.82 (95% CI 0.82 to 4.05, P = 0.13, I2 = 56%, tau2 = 0.19).

  • Overall (476 participants): fixed-effect HR 1.66 (95% CI 1.08 to 2.57, P = 0.02, I2 = 37%) and random-effects HR 1.68 (95% CI 0.94 to 3.01, P = 0.08, I2 = 37%, tau2 = 0.13).

  • Test for interaction between treatment effect and epilepsy type: fixed-effect: Chi2 = 0.03, df = 2, P = 0.87, I2 = 0% and random-effects: Chi2 = 0.11, df = 2, P = 0.74, I2 = 0%.

The original analysis (Analysis 1.1) suggests a clinical advantage to oxcarbazepine. Stratified analysis results (Analysis 1.2) suggest that this advantage for oxcarbazepine is present for participants with partial onset seizures but there is no statistically significant advantage for either drug for participants with generalised seizures. While an advantage for oxcarbazepine is still generally indicated in the sensitivity analyses (Analysis 1.3; Analysis 1.4), this advantage is no longer statistically significant overall or for participants with partial onset seizures when random-effects are used to account for the heterogeneity. Therefore it is difficult to make a conclusion regarding the comparative time to withdrawal of the two treatments due to variability and potential confounding from seizure misclassification.

(2) Time to achieve six-month remission

For this outcome, a HR > 1 indicates a clinical advantage for phenytoin. Data for 472 participants (98.3%) of those providing IPD from two trials were available for the analysis of this outcome. This outcome could not be calculated for eight participants (three in Bill 1997 and five in Guerreiro 1997) due to missing data (no data for mean frequency of seizures in the maintenance period as well as in the titration period; number of days on trial medication ranged between one and 36 days for these eight participants). Analyses could not be performed with an intention-to-treat approach as participants who withdrew from both studies were not followed up after time of withdrawal (see Data synthesis).

There was no evidence of statistical heterogeneity between trials (Chi2 = 0.19, df = 1, P = 0.66, I2 = 0%). The overall pooled HR and 95% confidence interval (CI) of 0.90 (0.70 to 1.15) suggests no clear clinical advantage of either drug (P = 0.38). See Analysis 1.5.

For four participants the type of seizures was not available (one in Bill 1997 and three in Guerreiro 1997) and therefore their epilepsy type could not be classified or included in this analysis. Results stratified for epilepsy type (Analysis 1.6) give a summary HR of 1.20 (95% CI 0.76 to 1.89, I2 = 0%) for generalised onset tonic-clonic seizures (142 participants), indicating a non-significant trend in favour of phenytoin (P = 0.42), and 0.85 (95% CI 0.63 to 1.15, I2 = 0%) for partial onset seizures (326 participants), indicating a non-significant trend in favour of oxcarbazepine (P = 0.29). The overall pooled HR (adjusted for epilepsy type in 466 participants) was 0.94 (95% CI 0.74 to 1.21, P = 0.66), indicating no clear advantage to either drug. There was no evidence of an association between treatment effect and epilepsy type (test of interaction: Chi2 = 1.56, df = 1, P = 0.21, I2 = 35.8%).

When we censored values greater than 392 days in the above mentioned analyses (overall analysis and analysis stratified by epilepsy type), the HRs and 95% CIs were identical to the uncensored analyses as no participants achieved six-month remission in the open-label treatment phase (see Table 4).

When we reclassified seizure type from generalised onset to (a) uncertain epilepsy type and (b) partial epilepsy for 29 participants from Bill 1997 (see Sensitivity analysis), the HRs and 95% CIs were very similar to the analyses with the original epilepsy type classifications and overall conclusions were unchanged (see Table 5).

(3) Time to achieve 12-month remission

For this outcome, a HR > 1 indicates a clinical advantage for phenytoin. Data for 472 participants (98.3%) were available for the analysis of this outcome. This outcome could not be calculated for eight participants (three in Bill 1997 and five in Guerreiro 1997) due to missing data (no data for mean frequency of seizures in the maintenance period as well as in the titration period; number of days on trial medication ranged between one and 36 days for these eight participants). Analyses could not be performed with an intention-to-treat approach as participants who withdrew from both studies were not followed up after time of withdrawal (see Data synthesis).

There was no evidence of statistical heterogeneity between trials (Chi2 = 0.19, df = 1, P = 0.66, I2 = 0%). The overall pooled HR and 95% confidence interval (CI) of 0.92 (0.68 to 1.24) suggests no clear clinical advantage of either drug (P = 0.58). See Analysis 1.7.

For four participants the type of seizures was not available (one in Bill 1997 and three in Guerreiro 1997) and therefore their epilepsy type could not be classified or included in this analysis. Results stratified for epilepsy type (Analysis 1.8) give a summary HR of 1.01 (95% CI 0.59 to 21.73, I2 = 0%) for generalised onset tonic-clonic seizures (142 participants), indicating an advantage to phenytoin which is not statistically significant (P = 0.34), and 0.92 (95% CI 0.64 to 1.33, I2 = 0%) for partial onset seizures (326 participants), indicating no clear clinical advantage to either drug. The overall pooled HR (adjusted for epilepsy type in 466 participants) was 0.95 (95% CI 0.70 to 1.29), indicating no clear advantage to either drug (P = 0.66). There is no evidence of an association between treatment effect and epilepsy type (Chi2 = 0.09 df = 1, P = 0.77, I2 = 0%).

Fifteen participants had a time to 12-month remission greater than 392 days (nine in Bill 1997 and six in Guerreiro 1997); three with generalised onset seizures and 12 with partial onset seizures. When we censored values greater than 392 days in the above mentioned analyses (overall analysis and analysis stratified by epilepsy type), the HRs and 95% CIs were very similar to the uncensored analyses and conclusions were unchanged (see Table 4).

When seizure type was reclassified from generalised onset to (a) uncertain epilepsy type and (b) partial epilepsy for 29 participants from Bill 1997 (see Sensitivity analysis), the HRs and 95% CIs were very similar to the analyses with original epilepsy type classifications and conclusions were unchanged (see Table 5)

(4) Time to first seizure post randomisation

For this outcome, a HR > 1 indicates a clinical advantage for oxcarbazepine. Data for 472 participants (98.3% of those providing IPD) from two trials were available for the analysis of this outcome. This outcome could not be calculated for eight participants (five in Bill 1997 and three in Guerreiro 1997) due to missing data (no data for mean frequency of seizures in the maintenance period as well as the titration period; number of days on trial medication ranged between one and 36 days for these eight participants). Analyses could not be performed with an intention-to-treat approach as participants who withdrew from both studies were not followed up after time of withdrawal (see Data synthesis).

There was no evidence of statistical heterogeneity between trials (Chi2 = 0.31, df = 1, P = 0.58, I2 = 0%). The overall pooled HR and 95% confidence interval (CI) of 1.07 (95% CI 0.83 to 1.39) suggests no clear clinical advantage of either drug (P = 0.60). See Analysis 1.9.

For four participants the type of seizures was not available (one in Bill 1997 and three in Guerreiro 1997) and therefore their epilepsy type could not be classified or included in this analysis. Results stratified for epilepsy type (see Analysis 1.10) give a summary HR of 0.94 (95% CI 0.56 to 1.56, P = 0.80, I2 = 0%) for generalised onset tonic-clonic seizures (142 participants), and 1.08 (95% CI 0.80 to 1.47, P = 0.61, I2 = 0%) for partial onset seizures (326 participants). There is no clear indication of advantage for either drug. The overall pooled HR (adjusted for epilepsy type in 466 participants) was 1.04 (95% CI 0.80 to 1.35) indicating no clear advantage to either drug (P = 0.76). There is no evidence of an association between treatment effect and epilepsy type (Chi2 = 0.23, df = 1, P = 0.63).

No participants had a time of first seizure greater than 392 days into the follow-up time, therefore results were identical for the analysis of the full follow-up and for the double-blind period only (see Table 4).

When seizure type was reclassified from generalised onset to (a) uncertain epilepsy type and (b) partial epilepsy for 29 participants from Bill 1997 (see Sensitivity analysis), the HRs and 95% CIs were very similar to the analyses with original epilepsy type classifications and conclusions were unchanged (see Table 5).

(5) Quality of life measures

Quality of life measures were not recorded in any trial; therefore, they could not be examined.

Discussion

In this review we have included individual participant data from 480 out of 517 participants (93%) from three trials in which participants were randomised to either oxcarbazepine or phenytoin. Individual participant data (IPD) for the 480 participants represents 100% of the data for two studies; the further 37 study participants from the third included study will be included in an updated meta-analysis if IPD can be obtained.

Both randomised controlled trials included in meta-analysis used adequate methods of randomisation and adequate methods of allocation concealment, both were double-blinded and attrition rates (loss to follow-up and exclusions) were similar in the oxcarbazepine and phenytoin groups, although there were more premature discontinuations for tolerability reasons of participants on phenytoin compared to oxcarbazepine in Guerreiro 1997 (see table Characteristics of included studies and Table 1). The main difference between the trials is that one recruited adults whilst the other recruited children, which is a potential source of heterogeneity. The majority (70%) of participants had partial epilepsy (n = 333) while 30% (n = 143) had generalised epilepsy and the two trials had relatively short follow-up periods given that epilepsy is a chronic condition often requiring many years of treatment.

The overall results indicate an advantage for oxcarbazepine over phenytoin for time to treatment withdrawal with a hazard ratio (HR) (adjusted for epilepsy type) of 1.64 (95% confidence interval (CI) 1.06 to 2.54). Results stratified by epilepsy type indicate no statistically significant advantage for either drug for participants with generalised onset seizures (HR 1.16; 95% CI 0.54 to 2.46), but a potentially important advantage for oxcarbazepine for participants with partial onset seizures (HR 1.95; 95% CI 1.15 to 3.33). However, it is possible that up to 29% of adult participants may have been wrongly classified as having generalised rather than partial epilepsy. Following sensitivity analysis in which these 29% of participants are reclassified from generalised epilepsy to partial epilepsy, substantial heterogeneity was observed between the trials (I2 is increased from 24% to 56% for the partial epilepsy subgroup and from 0% to 60% for the generalised epilepsy subgroup). When the analysis is repeated with a random-effects model to account for this increased heterogeneity, the advantage to oxcarbazepine is no longer statistically significant (overall HR for all participants stratified by epilepsy type 1.68 (95% 0.94 to 3.01, P = 0.08), partial onset seizures HR 1.82 (95% 0.82 to 4.05), P = 0.14). Unfortunately, there are too few studies in this review to further investigate the hypothesis of epilepsy type misclassification as a confounder and cause of heterogeneity.

For the seizure outcomes which included time to six- and 12-month remission from seizures and time to a first seizure after randomisation, no significant differences were found in the overall or subgroup analyses. However there are consistent trends in all of the analyses indicating a potential advantage for oxcarbazepine for participants with partial onset seizures. Therefore the overall advantage for oxcarbazepine for time to treatment withdrawal presumably represents a combination of better tolerability and improved seizure control, the latter primarily in participants with partial onset seizures.

A major methodological issue in both of the trials is that participants were no longer followed up after the allocated treatment was withdrawn, and hence had to be censored at the time of treatment withdrawal for the analyses of seizure and remission outcomes. Failure to follow participants up after the withdrawal of allocated treatment violates the principle of intention-to-treat and may bias the seizure and remission analyses as treatment may have been withdrawn for differing reasons which may have lead to informative censoring. For these reasons the analyses of seizure and remission outcomes require cautious interpretation, although no statistically significant differences between treatments or between epilepsy types were found in any case.

Furthermore, although individual participant data were provided for 480 participants we did not have precise dates of seizures. We did have information regarding the mean number of seizures per week in the titration (eight weeks) and maintenance phases (48 weeks) for both trials. Using these data we were able to interpolate the dates of seizures assuming a uniform distribution so that the outcomes time to first seizure and time to six- and 12-month remission could be calculated.

Authors' conclusions

Implications for practice

The results of this review suggest that oxcarbazepine may be preferable to phenytoin for initial monotherapy for patients with partial epilepsy. Further data comparing oxcarbazepine with other standard antiepileptic drugs will be required to inform a choice among all alternatives. Guidelines currently recommend carbamazepine as a first-line treatment for partial epilepsy.

For participants with generalised onset tonic-clonic seizures, valproate is considered the first-line standard treatment and the results of this review do not inform current treatment policy.

Implications for research

This review highlights the need for comparative antiepileptic drug monotherapy trials that measure longer-term outcomes, as well as the need to continue to follow participants up after randomised treatment has been withdrawn in order to comply with the principle of intention-to-treat and to avoid the problems of informative censoring. Furthermore, more precise evidence is required regarding the comparative effects of both oxcarbazepine and carbamazepine and oxcarbazepine and lamotrigine to further inform policy regarding first-line treatment for partial onset seizures. A network meta-analysis comparing all direct and indirect evidence from oxcarbazepine, phenytoin and other standard and new antiepileptic drugs licensed for monotherapy is needed to best inform policy regarding first-line treatments.

Acknowledgements

We are grateful to Jennifer Pulman for providing support and advice in 'Risk of bias' and quality assessments for the review update, to Paula Williamson for contributions to the original review and to the Cochrane Epilepsy Group Trials Search Co-ordinators, Alison Beamond and Graham Chan, for performing all the electronic searches.

We are greatly indebted to the original trial investigators for providing individual participant data for this review and to Harald Pohlmann who very kindly responded to our requests for additional information and data.

Data and analyses

Download statistical data

Comparison 1. Oxcarbazepine versus phenytoin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Time to withdrawal of allocated treatment2480Hazard Ratio (Fixed, 95% CI)1.65 [1.08, 2.52]
2 Time to withdrawal of allocated treatment - stratified by epilepsy type2476Hazard Ratio (Fixed, 95% CI)1.64 [1.06, 2.54]
2.1 Partial epilepsy2333Hazard Ratio (Fixed, 95% CI)1.95 [1.15, 3.33]
2.2 Generalised epilepsy2143Hazard Ratio (Fixed, 95% CI)1.16 [0.54, 2.46]
3 Time to withdrawal of allocated treatment - epilepsy type reclassified to uncertain for generalised and age > 30 years2476Hazard Ratio (Fixed, 95% CI)1.70 [1.10, 2.64]
3.1 Partial epilepsy2333Hazard Ratio (Fixed, 95% CI)1.95 [1.15, 3.33]
3.2 Generalised epilepsy2114Hazard Ratio (Fixed, 95% CI)1.57 [0.68, 3.59]
3.3 Uncertain129Hazard Ratio (Fixed, 95% CI)0.27 [0.03, 2.56]
4 Time to withdrawal of allocated treatment - epilepsy type reclassified to partial for generalised and age > 30 years2476Hazard Ratio (Random, 95% CI)1.68 [0.94, 3.01]
4.1 Partial epilepsy2362Hazard Ratio (Random, 95% CI)1.82 [0.82, 4.05]
4.2 Generalised epilepsy2114Hazard Ratio (Random, 95% CI)1.39 [0.36, 5.41]
5 Time to achieve 6-month remission2472Hazard Ratio (Fixed, 95% CI)0.90 [0.70, 1.15]
6 Time to achieve 6-month remission - stratified by epilepsy type2468Hazard Ratio (Fixed, 95% CI)0.94 [0.74, 1.21]
6.1 Partial epilepsy2326Hazard Ratio (Fixed, 95% CI)0.85 [0.63, 1.15]
6.2 Generalised epilepsy2142Hazard Ratio (Fixed, 95% CI)1.20 [0.76, 1.89]
7 Time to achieve 12-month remission2472Hazard Ratio (Fixed, 95% CI)0.92 [0.68, 1.24]
8 Time to achieve 12-month remission - stratified by epilepsy type2468Hazard Ratio (Fixed, 95% CI)0.95 [0.70, 1.29]
8.1 Partial epilepsy2326Hazard Ratio (Fixed, 95% CI)0.92 [0.64, 1.33]
8.2 Generalised epilepsy2142Hazard Ratio (Fixed, 95% CI)1.01 [0.59, 1.73]
9 Time to first seizure2472Hazard Ratio (Fixed, 95% CI)1.07 [0.83, 1.39]
10 Time to first seizure - stratified by epilepsy type2468Hazard Ratio (Fixed, 95% CI)1.04 [0.80, 1.35]
10.1 Partial epilepsy2326Hazard Ratio (Fixed, 95% CI)1.08 [0.80, 1.47]
10.2 Generalised epilepsy2142Hazard Ratio (Fixed, 95% CI)0.94 [0.56, 1.56]
Analysis 1.1.

Comparison 1 Oxcarbazepine versus phenytoin, Outcome 1 Time to withdrawal of allocated treatment.

Analysis 1.2.

Comparison 1 Oxcarbazepine versus phenytoin, Outcome 2 Time to withdrawal of allocated treatment - stratified by epilepsy type.

Analysis 1.3.

Comparison 1 Oxcarbazepine versus phenytoin, Outcome 3 Time to withdrawal of allocated treatment - epilepsy type reclassified to uncertain for generalised and age > 30 years.

Analysis 1.4.

Comparison 1 Oxcarbazepine versus phenytoin, Outcome 4 Time to withdrawal of allocated treatment - epilepsy type reclassified to partial for generalised and age > 30 years.

Analysis 1.5.

Comparison 1 Oxcarbazepine versus phenytoin, Outcome 5 Time to achieve 6-month remission.

Analysis 1.6.

Comparison 1 Oxcarbazepine versus phenytoin, Outcome 6 Time to achieve 6-month remission - stratified by epilepsy type.

Analysis 1.7.

Comparison 1 Oxcarbazepine versus phenytoin, Outcome 7 Time to achieve 12-month remission.

Analysis 1.8.

Comparison 1 Oxcarbazepine versus phenytoin, Outcome 8 Time to achieve 12-month remission - stratified by epilepsy type.

Analysis 1.9.

Comparison 1 Oxcarbazepine versus phenytoin, Outcome 9 Time to first seizure.

Analysis 1.10.

Comparison 1 Oxcarbazepine versus phenytoin, Outcome 10 Time to first seizure - stratified by epilepsy type.

Appendices

Appendix 1. CENTRAL search strategy

#1 (epilep* or seizure* or convulsion*)
#2 MeSH descriptor Epilepsy explode all trees
#3 MeSH descriptor Seizures explode all trees
#4 (#1 OR #2 OR #3)
#5 MeSH descriptor Phenytoin explode all trees
#6 (phenytoin or diphenylhydantoin or epanutin)
#7 (#5 OR #6)
#8 (oxcarbazepine or trileptal)
#9 (#7 AND #8)
#10 (#4 AND #9)

Appendix 2. MEDLINE search strategy

The following search is based on the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE (Lefebvre 2011).

1. randomized controlled trial.pt.

2. controlled clinical trial.pt.

3. randomized.ab.

4. placebo.ab.

5. clinical trials as topic.sh.

6. randomly.ab.

7. trial.ti.

8. 1 or 2 or 3 or 4 or 5 or 6 or 7

9. exp animals/ not humans.sh.

10. 8 not 9

11. exp Epilepsy/

12. exp Seizures/

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

14. 11 or 12 or 13

15. exp Phenytoin/

16. (phenytoin or diphenylhydantoin or epanutin).tw.

17. (oxcarbazepine or trileptal).tw.

18. (15 or 16) and 17

19. 10 and 14 and 18

Earlier versions of this review used the following search strategy, based on the previous Cochrane Highly Sensitive Search Strategy for MEDLINE as set out in Appendix 5b of the Cochrane Handbook for Systematic Reviews of Interventions (version 4.2.4, updated March 2005) (Higgins 2005).

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. phenytoin/ or (phenytoin or diphenylhydantoin).tw.

19. (oxcarbazepine or trileptal).tw.

20. exp epilepsy/ or epilep$.tw.

21. exp seizures/ or seizure$.tw.

22. convulsion$.tw.

23. 18 and 19

24. 20 or 21 or 22

25. 23 and 24

26. 17 and 25

What's new

DateEventDescription
12 March 2013New search has been performedSearches updated 22 January 2013; one new trial included (Aikia 1992). Conclusions remain unchanged.
22 January 2013New citation required but conclusions have not changedAnalyses and text updated. 'Risk of bias' assessments and 'Summary of findings' table added.

History

Protocol first published: Issue 2, 2002
Review first published: Issue 2, 2006

DateEventDescription
7 September 2010AmendedContact author's details updated.
7 August 2009AmendedCopy edits made at editorial base.
24 October 2008AmendedSearch strategy amended to comply with RevMan 5.
12 August 2008AmendedConverted to new review format.
12 August 2008New search has been performedSearches were re-run on 4 April 2008; no new studies were found.

Contributions of authors

SJ Nolan assessed risk of bias in all included studies, performed analyses in SAS version 9.2 and RevMan 5, added survival plots and the 'Summary of findings' table and updated the text of the review under the supervision of C Tudur Smith and AG Marson.

M Muller was the lead investigator on the original review and was involved in developing the original protocol, assessing eligibility of trials for inclusion in the review and obtaining, validating and checking individual participant data and assessing risk of bias in all included studies.

AG Marson was involved in obtaining individual participant data from original trial investigators and provided guidance with the clinical interpretation of results

Declarations of interest

None known.

Sources of support

Internal sources

  • University of Liverpool, UK.

  • South African Cochrane Centre, Medical Research Council, South Africa.

  • Biostatistics Unit, Medical Research Council, South Africa.

  • Institute for Maritime Technology, Simon's Town, South Africa.

External sources

  • Effective Health Care Alliance, UK.

  • National Health Service, Research and Development, UK.

  • Department for International Development, UK.

  • National Institute of Health Research (NIHR), UK.

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

Differences between protocol and review

Sensitivity analysis for misclassification of epilepsy type added.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Aikia 1992

Methods

Randomised, double-blinded, parallel-group study

Methods of randomisation and allocation concealment not stated

Participants

Adult participants with newly diagnosed epilepsy and "normal intellectual capacity" with a minimum of 2 seizures in the last 2 years or 1 seizure and an epileptiform EEG

Number randomised: total = 37, OXC = 19, PHT = 18

11 out of 29 included participants male (38%), 21 out of 29 included participants with partial epilepsy (72%) - see Notes

Interventions

Monotherapy with oxcarbazepine or phenytoin

4 to 8-week titration period until serum concentrations reached 30 to 120 μmol/litre for OXC and 40 to 80 μmol/litre for PHT followed by a maintenance phase of 12 months

Outcomes

Neuropsychological assessment and cognitive functioning in 3 major areas at baseline, 6 months and 12 months follow-up:

  • Verbal learning and memory

  • Sustained attention

  • Simple psychomotor speed

Notes

Participants experiencing inadequate seizure control, adverse events or those who were non-compliant were withdrawn from the study and excluded from analysis (5 from OXC group and 3 from PHT group). Results presented only for 29 participants (OXC = 14 and PHT = 15) completing the study.

IPD request pending on this study. Any IPD received will be included when the review is updated

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskParticipants were "randomly assigned" to treatment; no further information provided
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"The study followed a double blind design"; no further information provided regarding how the double-blind was achieved
Incomplete outcome data (attrition bias)
All outcomes
High riskIntention-to-treat approach not taken: results reported only for 29 participants (OXC = 14 and PHT = 15) who completed 12-month follow-up. 8 participants experiencing inadequate seizure control, adverse events or those who were non-compliant (OXC = 5 and PHT = 3) were excluded from analysis and results
Selective reporting (reporting bias)Low riskNo protocol available and outcomes chosen for this review not reported. Neuropsychological and cognitive outcomes well reported and treatment withdrawal rates reported
Other biasLow riskNone detected

Bill 1997

MethodsMulticentre, double-blind, parallel-group trial
A computer-generated randomisation scheme provided balanced blocks (size 6) of participant numbers for each of the 2 treatment groups sequentially assigned across centres/countries
Written informed consent obtained from participants or parents/guardians
Approved by local ethics committees
Conducted 1991 to first quarter of 1995
Participants

Participants aged between 16 and 65 years with newly diagnosed epilepsy with PS or GTCS

1 participant above the upper age limit (aged 91) included in efficacy and tolerability analyses

A minimum of 2 seizures, separated by at least 48 hours, within 6 months preceding trial entry

Centres in Argentina, Brazil, Mexico, South Africa

No previous AED, except emergency treatment of seizures for a maximum of 3 weeks prior to trial entry

Number randomised: total = 287, OXC = 143, PHT = 144

174 male (61%); 182 partial epilepsy (63%)

Interventions

Monotherapy with oxcarbazepine or phenytoin. 8-week titration period started with 300 mg OXC or 100 mg PHT, increased bi-weekly, based on clinical response

After 8 weeks participants were to be on a tid regimen with daily doses of 450 to 2400 mg OXC or 150 to 800 mg PHT

Continued during 48-week maintenance with adjustment according to clinical response

A third long-term, open-label extension phase followed the maintenance period. Double-blind results only are reported

OutcomesEfficacy: proportion of seizure-free participants who had at least 1 seizure assessment during the maintenance period
Tolerability: comparison of participants who prematurely discontinued because of adverse experiences
Clinical utility: comparing premature discontinuation
NotesIPD provided
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTreatment groups randomised in 1:1 ratio across centres via computer-generated randomisation numbers over balanced blocks of size 6
Allocation concealment (selection bias)Low riskAllocation concealment was achieved with sequentially numbered packages which were identical and contained identical tablets (information provided by trial statistician)
Blinding (performance bias and detection bias)
All outcomes
Low risk

Trial conducted in 2 phases: 56-week, double-blind phase followed by long-term, open-label extension Double-blind phase results reported only

Blind achieved with divisible OXC and PHT tablets identical in appearance

Incomplete outcome data (attrition bias)
All outcomes
High riskAttrition rates reported in both treatment phases, participants withdrawing from treatment were no longer followed up so seizure outcomes had to be censored at time of withdrawal and therefore analyses for remission and seizure outcomes could not adopt an ITT approach
Selective reporting (reporting bias)Low riskAll outcomes reported or calculated with IPD provided (see footnote 2)
Other biasHigh risk30 out of 104 (29%) participants may have been wrongly classified as having generalised onset seizures and therefore the subgroup could consist of a mixture of participants with both generalised and partial onset seizures

Guerreiro 1997

  1. a

    1Abbreviations:

    AED: antiepileptic drug
    EEG: electroencephalogram
    GTCS: generalised onset tonic-clonic seizures
    IPD: individual participant data
    ITT: intention-to-treat
    OXC: oxcarbazepine
    PHT: phenytoin
    PS: partial onset seizures
    tid: three times per day

    2For studies where IPD were provided for all randomised participants (Bill 1997; Guerreiro 1997), attrition and reporting bias are reduced as attrition rates and unpublished outcome data are requested.

    3See Figure 2 and Figure 3 for 'Risk of bias' presented graphically.

MethodsMulticentre, double-blind, parallel-group trial
A computer-generated randomisation scheme provided balanced blocks (size 6) of participant numbers for each of the 2 treatment groups sequentially assigned across centres/countries
Written informed consent obtained from participants or parents/guardians
Approved by local ethics committees
Conducted 1991 to first quarter of 1995
Participants

Participants aged 5 to 18 years with newly diagnosed epilepsy with PS or GTCS

A minimum of 2 seizures, separated by at least 48 hours, within 6 months preceding trial entry

Centres in Argentina and Brazil

No previous AED, except emergency treatment of seizures for a maximum of 3 weeks prior to trial entry

Number randomised: total = 193, OXC = 97, PHT = 96

96 male (50%); 151 partial epilepsy (78%)

Interventions

Monotherapy with oxcarbazepine or phenytoin. 8-week titration period started with 150 mg OXC or 50 mg PHT, increased bi-weekly, based on clinical response

After 8 weeks participants were to be on a tid regimen with daily doses of 450 to 2400 mg OXC or 150 to 800 mg PHT

Continued during 48-week maintenance with adjustment according to clinical response

A third long-term, open-label extension phase followed the maintenance period. Double-blind results only are reported

OutcomesEfficacy: proportion of seizure-free participants who had at least 1 seizure assessment during the maintenance period
Tolerability: comparison of participants who prematurely discontinued because of adverse experiences
Clinical utility: comparing the rate of premature discontinuation
NotesIPD provided
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTreatment groups randomised in 1:1 ratio across centres via computer-generated randomisation numbers over balanced blocks of size 6
Allocation concealment (selection bias)Low riskAllocation concealment was achieved with sequentially numbered packages which were identical and contained identical tablets (information provided by trial statistician)
Blinding (performance bias and detection bias)
All outcomes
Low risk

Trial conducted in 2 phases: 56-week, double-blind phase followed by long-term, open-label extension. Double-blind phase results reported only

Blind achieved with divisible OXC and PHT tablets identical in appearance

Incomplete outcome data (attrition bias)
All outcomes
High riskAttrition rates reported in both treatment phases, participants withdrawing from treatment were no longer followed up so seizure outcomes had to be censored at time of withdrawal and therefore analyses for remission and seizure outcomes could not adopt an ITT approach
Selective reporting (reporting bias)Low riskAll outcomes reported or calculated with IPD provided (see footnote 2)
Other biasLow riskNo other sources of bias detected

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    IPD: individual participant data

D'Souza 2003Abstract only, report of open-label, follow-up data for Bill 1997 and Guerreiro 1997. Open-label, follow-up data included in IPD provided for this review
Guerreiro 2003Abstract only, report of open-label, follow-up data for Guerreiro 1997. Open-label, follow-up data included in IPD provided for this review
Sabers 1995Not fully randomised: "The treatment was chosen at random unless the individual diagnoses required a specific drug"
Schmidt 2007Post hoc analysis of participant data from Bill 1997 and Guerreiro 1997
Sturm 2003Abstract only, report of open-label, follow-up data for Guerreiro 1997. Open-label, follow-up data included in IPD provided for this review