Pregabalin add-on for drug-resistant partial epilepsy

  • Review
  • Intervention

Authors

  • Jennifer Pulman,

    Corresponding author
    1. Institute of Translational Medicine, University of Liverpool, Department of Molecular and Clinical Pharmacology, Liverpool, Merseyside, UK
    • Jennifer Pulman, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Clinical Sciences Centre for Research and Education, Lower Lane, Fazakerley, Liverpool, Merseyside, L9 7LJ, UK. jennifer.pulman@liv.ac.uk.

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  • Karla Hemming,

    1. University of Birmingham, Public Health, Epidemiology and Biostatistics, Birmingham, UK
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  • Anthony G Marson

    1. Institute of Translational Medicine, University of Liverpool, Department of Molecular and Clinical Pharmacology, Liverpool, Merseyside, UK
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Abstract

Background

Epilepsy is a common chronic neurological disease with an estimated prevalence of 1% in the UK. Approximately one third of these people continue to have seizures despite drug treatment. In order to try to improve outcomes a number of new antiepileptic drugs have been developed and pregabalin is one of these. This review is an update of a previous Cochrane review (Pulman 2008); no further studies have been added since the previous update in 2012 and only one study has been identified as an ongoing trial.

Objectives

To summarise evidence from randomised controlled trials regarding the efficacy and tolerability of pregabalin when used as an add-on antiepileptic treatment in drug-resistant partial epilepsy. The definitions of drug resistance used were those employed by the authors of the included trials.

Search methods

We searched the Cochrane Epilepsy Group Specialized Register (Jan 2014), CENTRAL (the Cochrane Central Register of Controlled Trials, The Cochrane Library 2013, Issue 12), MEDLINE (Ovid, 1946 to 09/01/2014) and contacted Pfizer Ltd. (the manufacturers of pregabalin) to identify published, unpublished and ongoing trials.

Selection criteria

We included randomised controlled trials comparing pregabalin with placebo or an alternative antiepileptic drug for people with drug-resistant partial epilepsy. Outcomes included 50% or greater reduction in seizure frequency, seizure freedom, treatment withdrawal for any reason, treatment withdrawal for adverse events and nature of adverse events.

Data collection and analysis

Two review authors (JP and AGM) independently selected and assessed suitable trials and extracted data. Primary analyses were by intention-to-treat (ITT). Results are presented as risk ratios (RR) with 95% confidence intervals (CI). Included studies were assessed for risk of bias by two authors using the Cochrane 'Risk of bias' tool.

Main results

Six suitable industry-sponsored trials (2009 participants) were identified and included in the analysis. Trials tested doses of pregabalin ranging from 50 mg/day to 600 mg/day. For the primary outcome, 50% or higher seizure reduction was significantly more likely in patients randomised to pregabalin than to placebo (RR 2.61; 95% CI 1.70 to 4.01). A dose-response analysis suggested increasing effect with increasing dose. Pregabalin was significantly associated with seizure freedom (RR 2.59; 95% CI 1.05 to 6.36). Patients were significantly more likely to have withdrawn from pregabalin treatment than placebo treatment for any reason (RR 1.39; 95% CI 1.13 to 1.72) or for adverse effects (RR 2.69; 95% CI 1.88 to 3.86). Ataxia, dizziness, somnolence and weight gain were significantly associated with pregabalin. The odds of response doubled with an increase in dose from 300 mg/day to 600 mg/day (OR 2.12; 95% CI 1.76 to 2.54). Overall, the evidence was rated as low/unclear risk of bias due to the possibility of publication bias. The quality of the evidence was rated as moderate using the GRADE approach.

Authors' conclusions

Pregabalin, when used as an add-on drug for treatment-resistant partial epilepsy, is significantly more effective than placebo at achieving a 50% or greater seizure reduction and significantly increasing seizure freedom. Results demonstrate efficacy for doses from 150 mg/day to 600 mg/day, with increasing effectiveness at 600 mg doses. The trials included in this review were of short duration and longer-term trials are needed to inform clinical decision making better.

Résumé scientifique

Adjonction de prégabaline dans l'épilepsie partielle résistante aux médicaments

Contexte

L'épilepsie est une maladie neurologique chronique courante dont la prévalence est estimée à 1 % au Royaume-Uni. Environ un tiers de ces personnes continuent d'avoir des crises malgré le traitement médicamenteux. Afin d'essayer d'améliorer les résultats cliniques, un certain nombre de nouveaux médicaments antiépileptiques ont été développés, dont la prégabaline. Cette revue est une mise à jour d'une précédente revue Cochrane (Pulman 2008) ; aucune étude supplémentaire n'a été ajoutée depuis la dernière mise à jour en 2012 et un seul essai en cours a été identifié.

Objectifs

Résumer les preuves issues d'essais contrôlés randomisés concernant l'efficacité et la tolérance de la prégabaline lorsqu'elle est utilisée comme antiépileptique d'appoint dans l'épilepsie partielle résistante aux médicaments. Les définitions de la résistance aux médicaments utilisées étaient celles employées par les auteurs des essais inclus.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre spécialisé du groupe Cochrane sur l'épilepsie (janvier 2014), CENTRAL (le registre Cochrane des essais contrôlés, Bibliothèque Cochrane 2013, numéro 12), MEDLINE (Ovid, de 1946 au 09/01/2014) et avons contacté Pfizer Ltd. (fabricant de la prégabaline) pour identifier les essais publiés, non publiés et en cours.

Critères de sélection

Nous avons inclus les essais contrôlés randomisés comparant la prégabaline à un placebo ou à un autre médicament antiépileptique chez les personnes atteintes d'épilepsie partielle résistante aux médicaments. Les critères de jugement comprenaient une réduction de 50 % ou plus de la fréquence des crises, l'absence de crises, l'abandon du traitement pour toutes raisons confondues, l'abandon du traitement en raison d'événements indésirables et la nature des événements indésirables.

Recueil et analyse des données

Deux auteurs de la revue (JP et AGM) ont de manière indépendante sélectionné et évalué les essais acceptables et extrait les données. Les analyses principales ont été effectuées en intention de traiter (ITT). Les résultats sont présentés sous la forme de risques relatifs (RR) avec des intervalles de confidence (IC) à 95 %. Les études incluses ont été évaluées pour les risques de biais par deux auteurs à l'aide de l'outil Cochrane « Risque de biais ».

Résultats principaux

Six essais adéquats parrainés par le secteur (2 009 participants) ont été identifiés et inclus dans l'analyse. Les essais testaient des doses de prégabaline allant de 50 mg/jour à 600 mg/jour. Pour le critère de jugement principal, une réduction des crises de 50 % ou plus était significativement plus susceptible de se produire chez les patients randomisés dans le groupe sous prégabaline que dans le groupe sous placebo (RR 2,61 ; IC à 95 % 1,70 à 4,01). Une analyse de l'effet dose-réponse a suggéré une augmentation de l'effet avec l'augmentation de la dose. La prégabaline a été significativement associée à l'absence de crises (RR 2,59 ; IC à 95 % 1,05 à 6,36). Les patients ont été significativement plus susceptibles d'abandonner le traitement à la prégabaline que le traitement par placebo pour toutes raisons confondues (RR 1,39 ; IC à 95 % 1,13 à 1,72) ou en raison d'effets indésirables (RR 2,69 ; IC à 95 % 1,88 à 3,86). L'occurrence d'ataxie, de vertiges, de somnolence et de prise de poids a été associée significativement à la prégabaline. La probabilité de réponse a été multipliée par deux en passant d'une dose de 300 mg/jour à 600 mg/jour (RC 2,12 ; IC à 95 % 1,76 à 2,54). Globalement, les preuves ont été considérées comme à risque de biais faible/incertain en raison de la possibilité de biais de publication. La qualité des preuves était jugée modérée en utilisant l'approche GRADE.

Conclusions des auteurs

Lorsqu'elle est utilisée comme médicament d'appoint dans l'épilepsie partielle résistante au traitement, la prégabaline est significativement plus efficace que le placebo pour parvenir à une réduction des crises de 50 % ou plus et pour augmenter significativement l'absence de crises. Les résultats démontrent une efficacité pour des doses de 150 mg/jour à 600 mg/jour, avec une efficacité croissante à des doses de 600 mg. Les essais inclus dans cette revue étaient de courte durée et des essais à plus long terme sont nécessaires pour mieux éclairer la prise de décision clinique.

Plain language summary

Pregabalin add-on for drug-resistant partial epilepsy

Use of pregabalin in combination with other antiepileptic drugs can reduce the frequency of seizures, but has some adverse effects. The overall evidence for reducing seizures was rated as moderate in quality.

Approximately one in 400 people have epileptic seizures that continue despite antiepileptic drug treatment. This review summarises data from six trials that included a total of 2009 participants. In addition to their usual antiepileptic drugs, participants were randomised to take pregabalin (an antiepileptic drug) or control drug. Results showed that patients taking pregabalin were two to three times more likely to reduce their seizure frequency by more than 50% than those taking placebo and two to three times more likely to increase seizure freedom over a 12-week interval. Pregabalin was shown to be effective across a range of doses (150 mg to 600 mg) with increasing effectiveness at higher doses. There was also an increasing likelihood of treatment withdrawal. Side effects associated with pregabalin included co-ordination problems, dizziness, sleepiness, and weight gain.

All included studies were rated as low or unclear in risk of bias. Overall, the risk of bias was rated as unclear due to a suspicion of publication bias. Publication bias may occur when studies that report non-significant findings are not published. In this review, authors suspected this bias because all the included studies showed significant findings and they were all sponsored by the same drug company. Evidence was further rated as moderate in quality for the primary outcome of seizure reduction.

A limitation of this review is that there are no data regarding the longer-term effectiveness of pregabalin and this should be investigated in future studies.

Résumé simplifié

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

L'utilisation de la prégabaline en combinaison avec d'autres médicaments antiépileptiques peut réduire la fréquence des crises, mais a certains effets indésirables. Globalement, les preuves pour la réduction des crises épileptiques ont été considérées comme étant de qualité modérée.

Chez une personne sur 400 environ, les crises épileptiques se poursuivent malgré un traitement aux médicaments antiépileptiques. Cette revue résume les données de six essais qui portaient sur un total de 2 009 participants. En plus de leurs médicaments antiépileptiques habituels, les participants étaient randomisés dans des groupes sous prégabaline (un médicament antiépileptique) ou sous un médicament témoin. Les résultats ont montré que les patients prenant de la prégabaline étaient deux à trois fois plus susceptibles de réduire la fréquence de leurs crises de plus de 50 % que ceux prenant un placebo et deux à trois fois plus susceptibles d'augmenter l'absence de crises sur une période de 12 semaines. La prégabaline s'est révélée efficace avec plusieurs doses (150 mg à 600 mg), avec une efficacité croissante à des doses plus élevées. Une augmentation du risque d'arrêt du traitement a également été observée. Les effets secondaires associés à la prégabaline comprenaient les problèmes de coordination, les vertiges, la somnolence et la prise de poids.

Toutes les études incluses ont été considérées à risque de biais faible ou incertain. Globalement, le risque de biais a été considéré comme incertain en raison d'une suspicion de biais de publication. Le biais de publication peut survenir lorsque les études rapportant des résultats non significatifs ne sont pas publiées. Dans cette revue, les auteurs ont suspecté la présence de ce type de biais parce que toutes les études incluses ont montré des résultats significatifs et elles avaient toutes été parrainées par le même laboratoire pharmaceutique. Par ailleurs, les preuves ont été considérées comme étant de qualité modérée pour le critère de jugement principal de la réduction des crises.

Cette revue est limitée par le fait qu'il n'existe aucune donnée concernant l'efficacité à plus long terme de la prégabaline et cela devrait être examiné dans les études futures.

Notes de traduction

Traduit par: French Cochrane Centre 8th July, 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. Pregabalin versus placebo: 50% seizure reduction - ITT for drug-resistant partial epilepsy
  1. 1 High heterogeneity statistic.
    2 All studies sponsored by the same pharmaceutical company all reporting significant findings.

Pregabalin versus placebo: 50% seizure reduction - ITT for drug-resistant partial epilepsy
Patient or population: patients with drug-resistant partial epilepsy
Settings:
Intervention: Pregabalin versus placebo: 50% seizure reduction - ITT
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Pregabalin versus placebo: 50% seizure reduction - ITT
50% responders, ITT - any dose pregabalin 15 per 100 40 per 100
(26 to 61)
RR 2.61
(1.7 to 4.01)
1868
(6 studies)
⊕⊕⊕⊝
moderate 1,2
 
*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; ITT: intention-to-treat; 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

Epilepsy is a common neurological chronic condition affecting up to 1% of the UK population (Hauser 1990). A single antiepileptic drug (AED) (monotherapy) will induce remission for the majority of those diagnosed. However, up to 30% of patients will fail to respond to monotherapy (Cockerell 1995). Their continuing attacks will result in reduced quality of life, and may also lead to injuries, social isolation and depression (Villeneuve 2004). This group poses a significant therapeutic problem, leading to the development of new AEDs as well as exploration of non-pharmacological treatment options, such as vagal nerve stimulation and epilepsy surgery.

Since the 1990s numerous new AEDs have become available, raising hope for more potent and better tolerated treatment of epilepsy. Pregabalin is one of these new compounds with antiepileptic, analgesic and anxiolytic (anxiety reducing) properties. It acts through binding to an auxiliary protein (alpha 2 delta) of the voltage-gated calcium channels. It has been shown to reduce calcium influx into nerve terminals resulting in reduced presynaptic release of glutamate. In addition, by acting on AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors it indirectly reduces synaptic noradrenaline release (Fink 2002). These actions are thought to mediate its antiepileptic, anxiolytic and analgesic properties. Pregabalin has favourable pharmacokinetics; it is not protein bound, is 90% bioavailable and reaches peak plasma concentrations within 1.5 hours of administration of an oral dose. With repeated doses, a steady state is achieved within 24 to 48 hours. Furthermore, 90% of the drug is eliminated, un-metabolised, by the kidneys and it has no drug interactions (Brodie 2005). Pregabalin was launched onto the UK market in 2004 as an add-on AED for partial-onset seizures, as well as a treatment for neuropathic pain, and more recently (2006) as an anxiolytic.

Clinical trials published on the antiepileptic properties of pregabalin so far have focused on patients with refractory partial-onset epilepsy. In these randomised placebo-controlled trials, patients are randomised to have either pregabalin or placebo added to their existing AED treatment. This is in keeping with international guidelines on the development of AEDs (ILAE Commission 1989). Once a drug has confirmed efficacy and safety as an add-on therapy, it can be tested as monotherapy. The use of pregabalin as monotherapy will be the subject of a future Cochrane review.

This review is an update of a previous Cochrane review and aims to summarise existing data regarding the effects of add-on pregabalin for patients with refractory partial-onset seizures. This review is one in a series in which the efficacy and tolerability of seven new AEDs (gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin, zonisamide and pregabalin) are investigated in patients with drug-resistant partial epilepsy. Findings from the previous review showed significant seizure reduction in users of pregabalin compared to controls. Seizure freedom was significantly increased with the use of pregabalin. Pregabalin users were more likely to withdraw from the study than controls and significant adverse events associated with pregabalin were ataxia, dizziness, somnolence and weight gain.

Objectives

To summarise evidence from randomised controlled trials regarding the efficacy and tolerability of pregabalin when used as an add-on antiepileptic treatment in drug-resistant partial epilepsy.The definitions of drug resistance used will be those employed by the authors of the included trials.

Methods

Criteria for considering studies for this review

Types of studies

To be included in our review, studies had to meet all of the following criteria:

  1. randomised controlled trials;

  2. double-blind or single-blinded trials;

  3. placebo-controlled; or

  4. active controlled;

  5. parallel group or cross-over studies.

Types of participants

People 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 pregabalin in addition to an existing AED regimen taken at time of randomisation.

  2. The control group received a matched placebo in addition to an existing AED regimen taken at time of randomisation.

  3. The control group received an active control in addition to an existing AED regimen taken at time of randomisation.

Types of outcome measures

Primary outcomes
50% or greater reduction in seizure frequency

The proportion of people with a 50% or greater reduction in seizure frequency in the treatment period compared to the pre-randomisation baseline period was chosen as the primary outcome. It was chosen because it is a commonly reported outcome, and can be calculated for studies that do not report this outcome provided that baseline seizure data were recorded.

Secondary outcomes
Seizure freedom

The proportion of patients with a complete cessation of seizures during the treatment period.

Treatment withdrawal

The proportion of people having treatment withdrawn for any reason during the course of the treatment period was used as a measure of global effectiveness. Treatment is likely to be withdrawn due to adverse effects, lack of efficacy or a combination of both, and this is an outcome to which the individual makes a direct contribution. In trials of short duration, it is likely that adverse effects will be the most common reason for withdrawal. We have also assessed the proportion of people having treatment withdrawn for adverse effects.

Adverse effects

(1) The proportion of individuals experiencing the following five adverse effects:

  • ataxia (co-ordination problems),

  • dizziness,

  • fatigue,

  • nausea,

  • somnolence (unusual drowsiness).

These adverse effects were chosen as we considered them to be common and important adverse effects of AEDs.

(2) The proportion of individuals experiencing the five most common adverse effects mentioned in the included trials if these differed from those listed in (1) above.

Search methods for identification of studies

Electronic searches

We searched:

  1. The Cochrane Epilepsy Group's Specialized Register (09 January 2014) using the search term 'pregabalin OR Lyrica';

  2. the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2013, Issue 12) using the search strategy outlined in Appendix 1;

  3. MEDLINE (Ovid, 1946 to 09/01/2014 ) using the search strategy outlined in Appendix 2.

We did not impose any language restrictions.

Searching other resources

We reviewed the reference lists of retrieved studies to check for additional reports of relevant studies. We also contacted Pfizer Ltd. (manufacturers of pregabalin), and colleagues in the field.

Data collection and analysis

Selection of studies

For the update, two review authors (JP and AM) independently assessed trials for inclusion. Any disagreements were resolved by discussion with a third author (KH). Two review authors (JP and AM) extracted data and assessed risk of bias; disagreements again were resolved by discussion.

Data extraction and management

The same two review authors extracted the following information from included trials. Again, disagreements were resolved by mutual discussion.

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

  2. Method of double-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 pregabalin 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.

For all trials sponsored by Pfizer Ltd. the following information was confirmed
  1. The method of randomisation.

  2. The total number randomised to each group.

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

  4. The number of participants 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

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

Assessment of risk of bias in included studies

Two review authors (JP and AM) independently made an assessment of the risk of bias for each trial using the Cochrane 'Risk of bias' tool as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We discussed and resolved any disagreements. We rated included studies as adequate, inadequate or unclear for six domains applicable to randomised controlled trials: randomisation method, allocation concealment, blinding methods, incomplete outcome data, selective outcome reporting and other sources of bias. We created 'Summary of findings' tables where the GRADE approach for assessing quality of evidence was employed.

Measures of treatment effect

We presented the primary outcome of seizure reduction as a risk ratio. We also presented the secondary outcomes, including seizure freedom, treatment withdrawal and adverse effects, as risk ratios.

Unit of analysis issues

There were no unit of analysis issues.

Dealing with missing data

We sought any missing data from the study authors. We carried out intention-to-treat, best-case and worst-case analysis on the primary outcome to account for any missing data. All analyses are presented in the main report.

Assessment of heterogeneity

We assessed clinical heterogeneity by comparing the distribution of important individual participant factors among trials (for example age, seizure type, duration of epilepsy, number of antiepileptic drugs taken at the time of randomisation) and trial factors (for example, randomisation concealment, blinding, losses to follow-up). We examined statistical heterogeneity using a Chi2 test and the I2 statistic for heterogeneity and, providing no significant heterogeneity was present (P > 0.10), we employed a fixed-effect model. In the event that heterogeneity was found, we planned to use a random-effects model analysis using the inverse variance method.

Assessment of reporting biases

We requested all protocols from study authors to enable a comparison of outcomes of interest. We planned to investigate outcome reporting bias using the ORBIT matrix system (Kirkham 2010). We also intended to examine asymmetry of funnel plots to establish any publication bias. However, there were insufficient number of studies to allow funnel plots to be used, therefore, a judgement was made based on the characteristics of the studies.

Data synthesis

We employed a fixed-effect model meta-analysis to synthesise the data. Comparisons we expected to carry out included:

  1. intervention group versus controls on seizure reduction;

  2. intervention group versus controls on seizure freedom;

  3. intervention group versus controls on treatment withdrawal;

  4. intervention group versus controls on adverse effects.

Each comparison was to be stratified by type of control group, that is placebo or active control, and study characteristics to ensure the appropriate combination of study data.

Our preferred estimator was the Mantel-Haenszel risk ratio (RR). For the outcomes 50% or greater reduction in seizure frequency and treatment withdrawal, we used 95% confidence intervals (CIs). For individual adverse effects we used 99% CIs to make an allowance for multiple testing.

Our analyses included all participants in the treatment group to which they had been allocated. For the efficacy outcome (50% or greater reduction in seizure frequency) we undertook three analyses.

  • Primary (intention-to-treat (ITT)) analysis: participants not completing follow-up or with inadequate seizure data were assumed non-responders. To test the effect of this assumption, we undertook the following sensitivity analyses. Analysis by ITT was done where this was reported by the included studies.

  • Worst-case analysis: participants not completing follow-up or with inadequate seizure data were assumed to be non-responders in the intervention group, and responders in the placebo group.

  • Best-case analysis: participants not completing follow-up or with inadequate seizure data were assumed to be responders in the intervention group, and non-responders in the placebo group.

Dose regression analysis

Dose-response analysis was evaluated using a generalised linear mixed model with the logit link function xtmelogit in STATA SE version 11. Study and dose were included as fixed effects and a random-effect was included for the treatment (no random-effect for the constant term) as described in Turner 2000. Dose was standardised by its standard deviation (277 mg). This method estimates an odds ratio (OR) as opposed to a RR.

Subgroup analysis and investigation of heterogeneity

We undertook subgroup analysis for adverse effects. We intended to investigate heterogeneity using sensitivity analysis if deemed appropriate.

Sensitivity analysis

We also intended to carry out sensitivity analysis if peculiarities were found between study quality, characteristics of participants, interventions and outcomes.

Results

Description of studies

Results of the search

Searches were carried out from the date of the previous search (May 2012) to 09/01/2014. In total, 37 new records were retrieved, 18 of which were duplicates and therefore removed. Eighteen of the remaining records were then excluded due to irrelevance leaving one new relevant record. This is an ongoing trial and no data are currently available (Bali 2012). See Figure 1 and Characteristics of ongoing studies.

Figure 1.

Study flow diagram. Date of search 9 January 2014.

Included studies

Six randomised, controlled, parallel trials are included in this review; these had been sponsored by the company Pfizer Ltd. A total of 2009 participants were randomised into these studies. All six of the included studies recruited participants with treatment-resistant partial seizures. Participants were taking between one and four AEDs and had at least three partial seizures per month in the pre-randomisation baseline period. Further details are given below and in the Characteristics of included studies.

Arroyo et al (Arroyo 2004) published a multicentre (45 sites in Europe, Australia and Africa) parallel trial in 2004 on 288 patients. Inclusion criteria were defined as patients 18 years or older with partial seizures. As an electroencephalogram (EEG) was not required to confirm the above, some of the 18 patients included who were stated to have 'generalised seizures' rather than secondary generalised, may have had primary generalised epilepsy. Treatment arms included 99 patients on 50 mg pregabalin three times daily (TDS) and 92 patients on 200 mg pregabalin TDS, while 97 patients were randomised to placebo. After a baseline assessment of eight weeks the trial was conducted over 12 weeks (including titration period of four and eight days). During the trial period patients were assessed weekly for the first two weeks and fortnightly thereafter. Median follow-up was 12 weeks (range one day to 12 weeks). Three time points were reported in the study, each at four-weekly intervals.

Baulac et al (Baulac 2010) conducted a multicentre (97 sites in Europe, Canada and Australia) parallel trial on 434 patients. Randomised patients were between 16 and 82 years of age and had undergone an EEG within two years prior to randomisation. Treatment arms were 150 mg to 300 mg pregabalin twice daily (BD) (n = 152), 150 mg to 300 mg lamotrigine twice daily (BD) (n = 141) and 141 patients were randomised to the placebo arm. Following a six-week baseline period, treatment was conducted over 12 weeks following a five-week titration phase (one week for pregabalin and five weeks for lamotrigine). The lamotrigine titration phase started four weeks prior to the pregabalin titration phase so all patients started the treatment phase on the same dose. Patient review time points and follow-up were not reported.

Beydoun et al (Beydoun 2005) randomised 313 patients aged 17 to 82 years from 43 US and Canadian centres. Parallel groups included 111 individuals on 200 mg pregabalin TDS, 104 on 300 mg pregabalin BD and 98 on placebo. After a baseline assessment of eight weeks the trial was conducted over 12 weeks (including a one-week titration period). Follow-up occurred on weeks two, four, eight and 12. Median follow-up was 12 weeks (range not reported). During the trial an interim analysis was carried out on 129 patients. This led to alteration of the statistical analysis.

Elger et al (Elger 2005) reported a multicentre (53 sites in Canada and Europe) parallel trial of 341 patients aged 17 to 78 years. Treatment arms were 150 to 600 mg pregabalin (n = 131) titrated to clinical response and adverse effects in 150 mg daily increments and fixed-dose pregabalin of 300 mg BD (n = 137). A total of 73 people received placebo. Patients were randomised to one of the three treatments using a 1:2:2 ratio. The trial ran over 12 weeks and followed a six-week baseline period. Patients were reviewed at two, four, eight and 12 weeks into the study. Median follow-up was 12 weeks and over 58% of patients completed the study in each arm. Range of follow-up was not reported.

French et al (French 2003) published a multicentre (76 sites in US and Canada) parallel trial including 455 patients. Randomised patients were between 12 and 70 years of age, but not all had EEG and imaging data. Those with absence seizures and Lennox-Gastaut syndrome were excluded; however, the inclusion of some patients with primary generalised epilepsy could not be ruled out. Participants were randomised into one of five treatment arms; 50 mg/day (n = 88), 150 mg/day (n = 88), 300 mg/day (n = 90) and 600 mg/day (n = 89) pregabalin in a BD regimen, and 100 patients were in the placebo group. Baseline assessment occurred over eight weeks and trial duration was 12 weeks with no titration period. Follow-up occurred on weeks two, four, eight and 12. Median follow-up was 12 weeks (range one day to 12 weeks). Around 83% of patients completed the study.

Lee et al (Lee 2009) conducted a multicentre (nine sites in Korea) parallel trial consisting of two treatment arms. A total of 178 patients, aged 18 years and above, were randomised to either 75 mg to 300 mg pregabalin BD (n = 119) or placebo (n = 59) using a 2:1 ratio. Following a six-week baseline period, treatment was conducted over 12 weeks with a one-week taper period at the end. Patients were assessed at weeks two, four, six, eight and 12 with a follow-up visit at week 13. Eighty-eight per cent of patients randomised completed the study.

Risk of bias in included studies

All six included studies were subject to an assessment of bias on six domains. See 'Risk of bias' tables for each study for further details and see Figure 2 for 'Risk of bias' graph.

Figure 2.

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

Allocation

Four of the six studies used an adequate method of sequence generation by using computer-generated identification numbers and block sizes of five or six. Two of the studies did not provide details of method of randomisation (Baulac 2010; Lee 2009). Methods employed to prevent foreknowledge of group assignment (allocation concealment) were not reported in any of the studies.

Blinding

All studies reported to be double-blind and used identical tablets with identical packaging for all treatment groups. Further information regarding the blinding of key study personnel, participants and outcome assessors was not provided for all studies.

Incomplete outcome data

All studies reported study attrition rates and all studies used an intention-to-treat analysis on randomised patients who took at least one dose of medication and using the last-observation-carried-forwards approach. That is, for participants failing to complete follow-up, seizure-frequency data were extrapolated from the last patient observation point for the whole treatment period, while for participants with no seizure data during the treatment period, baseline data were extrapolated. In the trial reports, a total of four patients were excluded from analyses, but these patients have been included in the denominator as non-responders for calculations in this review.

Selective reporting

Most of the included studies distinguished between the primary and secondary outcome variables. All studies reported their primary/secondary outcomes within the articles; however, no trial protocols were available for examination in order to compare reported outcomes.

Other potential sources of bias

In two of the studies, patients with primary generalised epilepsy may have been included in the trials possibly leading to bias within the results (Arroyo 2004; French 2003). All studies were sponsored by the same pharmaceutical company indicating the possibility of reporting bias.

Effects of interventions

See: Summary of findings for the main comparison Pregabalin versus placebo: 50% seizure reduction - ITT for drug-resistant partial epilepsy

Intention-to-treat analysis

As mentioned above, the six trials included a total of four patients who were randomised (one to placebo and three to treatment) but not included in the analysis, as neither took first dose of trial medication. In our primary intention-to-treat analysis, these participants are included in the denominator and assumed to be non-responders.

Pregabalin versus placebo control

Primary outcome measure: 50% seizure reduction

An intention-to-treat analysis pooling across doses (50 mg to 600 mg/day) (Analysis 1.1) shows evidence of heterogeneity (I2 74%). A sensitivity analysis showed two studies contributing largely to the heterogeneity (Baulac 2010; Lee 2009) therefore a random-effects model was employed for this outcome. See Discussion for further details. Those participants allocated pregabalin were significantly more likely to achieve a 50% or greater reduction in seizure frequency (risk ratio (RR) 2.61; 95% confidence interval (CI) 1.70 to 4.01) (Figure 3; Figure 4). Subgroup analyses assessing the effect of individual doses show no significant effect for 50 mg pregabalin (RR 1.06; 95% CI 0.52 to 2.12). Higher doses of pregabalin were significantly associated with a 50% or greater reduction in seizure frequency (150 mg: RR 2.22; 95% CI 1.36 to 3.63; 300 mg: RR 2.86; 95% CI 1.65 to 4.94; 600 mg: RR 2.86; 95% CI 2.32 to 3.54; titrated 150 to 600mg: RR 2.86; 95% CI 1.42 to 5.76) (Analysis 1.1; Analysis 1.2; Summary of findings for the main comparison).

Figure 3.

Forest plot of comparison: 1 Pregabalin versus placebo: 50% seizure reduction - ITT, outcome: 1.1 50% responders, ITT.

Figure 4.

Forest plot of comparison: 1 Pregabalin versus placebo: 50% seizure reduction - ITT, outcome: 1.2 50% responders (Random-effects).

A best-case analysis (all drop-outs assumed to be responders to treatment) pooling across doses (50 mg to 600 mg/day) showed participants allocated to pregabalin were significantly more likely to achieve a 50% or greater reduction in seizure frequency (RR 3.60; 95% CI 2.93 to 4.43) (Analysis 1.3; Analysis 1.4). Subgroup analyses assessing the effect of individual doses show significant effects for all pregabalin doses (50 mg: RR 1.87; 95% CI 1.03 to 3.40; 150 mg: RR 2.61; 95% CI 1.63 to 4.19; 300 mg: RR 4.37; 95% CI 2.61 to 7.29; 600 mg: RR 4.09; 95% CI 3.34 to 5.01; titrated 105 to 600mg: RR 5.02; 95% CI 2.56 to 9.82).

A worst-case analysis (all drop-outs assumed to be responders to control) pooling across doses (50 mg to 600 mg/day) showed no significant differences between pregabalin and placebo (RR 1.08; 95% CI 0.94 to 1.23 (Analysis 1.5). Subgroup analyses by dose showed one dose (50 mg) to be significantly associated with seizure reduction in the placebo group compared to pregabalin (RR 0.55; 95% CI 0.30 to 0.99). There were no significant differences between groups for all other doses (150 mg: RR 1.32; 95% CI 0.88 to 1.96; 300 mg: RR 1.48; 95% CI 0.98 to 2.23; 600 mg: RR 1.24; 95% CI 1.08 to 1.43; titrated 150 to 600mg: RR 0.35; 95% CI 0.27 to 0.46).

Dose regression analysis for 50% response

We fitted a generalised linear mixed model (logit link) to estimate the effect of dose (details in Data synthesis). This method estimates an odds ratio (OR) as opposed to an RR. Dose was standardised by its standard deviation (277 mg). The odds of response (50% reduction in seizure frequency) more than doubled (OR 2.12; 95% CI 1.76 to 2.54 with estimated between-study standard deviation of 0.49 (standard error (SE) 0.22)) for each 279 mg increase in dose of pregabalin. This translates into an estimated doubling of odds of response with an increase in dose from 300 mg to 600 mg.

Secondary outcome measures
Seizure freedom

Three trials (Arroyo 2004; Beydoun 2005; French 2003) gave data for the proportion of patients free of seizures for the last eight weeks of the treatment phase, while a fourth trial (Elger 2005) gave the number free of seizures for the last 12 weeks. Baulac 2010 provided percentages of patients free of seizures over the 17-week study period and Lee 2009 gave proportions over the 12-week double-blind period and any 28-day period. An analysis pooling across doses (50 mg/day to 600 mg/day) showed no evidence of heterogeneity (I2 0%). Pregabalin was significantly associated with freedom from seizures (RR 2.59; 95% CI 1.05 to 6.36; Analysis 2.1).

Treatment withdrawal for any reason

An analysis pooling across doses (50 mg/day to 600 mg/day) showed no evidence of heterogeneity (I2 0%). Participants allocated pregabalin were significantly more likely to have withdrawn from treatment (RR 1.39; 95% CI 1.13 to 1.72; Analysis 3.1). Subgroup analyses assessing the individual doses showed no significant effect for 50 mg/day pregabalin (RR 0.87; 95% CI 0.40 to 1.89), 150 mg/day pregabalin (RR 0.72; 95% CI 0.41 to 1.28), 300 mg/day daily dose (RR 1.62; 95% CI 0.85 to 3.10) and 150 to 600 mg titrated dose of pregabalin (RR 1.02; 95% CI 0.61 to 1.71). The only dose associated with significant withdrawal for all reasons was 600 mg/day (RR 1.65; 95% CI 1.33 to 2.04) (Analysis 3.1).

Treatment withdrawal due to adverse effects

An analysis pooling across doses (50 mg/day to 600 mg/day) showed no evidence of heterogeneity (I2 0%). Participants allocated pregabalin were significantly more likely to withdraw from treatment for adverse effects (RR 2.69; 95% CI 1.88 to 3.86; Analysis 4.1). Subgroup analyses assessing treatment withdrawal with differing doses of pregabalin showed a higher withdrawal rate with higher doses (50 mg/day: RR 1.36; 95% CI 0.43 to 4.31; 150 mg/day: RR 1.02; 95% CI 0.45 to 2.32; 300 mg/day: RR 2.89; 95% CI 1.07 to 7.78; 600 mg/day: RR 3.39; 95% CI 2.36 to 4.87; Analysis 4.1). In Elger 2005, one treatment group had the dose titrated up to 150/day to 600 mg/day according to clinical response. The RR for withdrawal for this group was 1.78 (95% CI 0.68 to 4.67; Analysis 4.1).

Adverse events

In addition to the five pre-specified adverse effects, weight gain and headache were among the most common adverse effects reported. Analyses pooling across doses (50 mg/day to 600 mg/day) indicated that ataxia (RR 3.90; 99% CI 2.05 to 7.42; Analysis 5.1), dizziness (RR 3.06; 99% CI 2.16 to 4.34; Analysis 5.3), somnolence (RR 2.08; 99% CI 1.45 to 2.99; Analysis 5.5) and weight gain (RR 4.92; 99% CI 2.41 to 10.03; Analysis 5.6) were significantly associated with pregabalin, while fatigue (RR 1.28; 99% CI 0.88 to 1.86; Analysis 5.2), headache (RR 0.75; 99% CI 0.52 to 1.08; Analysis 5.7) and nausea (RR 1.14; 99% CI 0.51 to 2.53; Analysis 5.4) were not.

Pregabalin versus lamotrigine

Only one included study (Baulac 2010) compared pregabalin with an active control drug (lamotrigine), therefore the pooling of data could not be undertaken for this comparison.

Primary outcome measure: 50% seizure reduction

Within this study, participants allocated to pregabalin were significantly more likely to achieve a 50% or greater reduction in seizure frequency (RR 1.47; 95% CI 1.03 to 2.12) than those allocated lamotrigine (Analysis 6.1). A best-case analysis (all drop-outs assumed to be responders to treatment) revealed a significant increase in seizure reduction in favour of the pregabalin group (RR 2.73; 95% CI 1.99 to 3.74). A worst-case analysis (all drop-outs assumed to be responders to control) revealed a significant increase in seizure reduction in favour of the control group (RR 0.68; 95% CI 0.52 to 0.88) (Analysis 6.6).

Secondary outcome measures
Seizure freedom

No significant differences were found between pregabalin and lamotrigine for seizure frequency (RR 1.39; 95% CI 0.40 to 4.83; Analysis 6.2).

Treatment withdrawal for any reason

No significant differences were found between pregabalin and lamotrigine for withdrawal from the study due to any reason (RR 1.07; 95% CI 0.75 to 1.52; Analysis 6.3).

Treatment withdrawal due to adverse effects

No significant differences were found between pregabalin and lamotrigine for withdrawal from the study due to adverse events (RR 0.89; 95% CI 0.53 to 1.48; Analysis 6.4).

Adverse events

Within this study, patients allocated to pregabalin were significantly more likely to experience dizziness (RR 2.94; 99% CI 1.32 to 6.52) than patients allocated lamotrigine (Analysis 6.5). No other differences were found for the remaining adverse events between pregabalin and lamotrigine (ataxia: RR 1.72; 99% CI 0.54 to 5.55; fatigue: RR 1.72; 99% CI 0.77 to 3.83; somnolence: RR 1.99; 99% CI 0.91 to 4.33; weight gain: RR 4.33; 99% CI 0.86 to 21.68; headache: RR 0.52; 99% CI 0.26 to 1.05; (Analysis 6.5)).

Discussion

Summary of main results

This systematic review is one in a series of reviews analysing effects of new AEDs on treatment-resistant localisation-related epilepsy. We identified six industry-sponsored (Pfizer Ltd.) randomised placebo-controlled parallel trials. All studies were of good methodological quality and most were randomised using suitable sequence generation methods; all studies did not report methods of concealing allocation; all were reported to be double-blinded and had few patients lost to follow-up. Summary trial data were taken from the relevant publications and individual patient data were not obtained. The approach to analysis for all of the included trials used the last-observation-carried-forwards. For participants failing to complete follow-up, seizure frequency data were extrapolated to the whole treatment period, while for participants with no seizure data during the treatment period, baseline data were extrapolated. While this approach may help minimise bias due to losses to follow-up (and is preferred by drug regulatory authorities), its use must be taken into consideration when interpreting the results of this systematic review.

The included studies tested doses ranging from 50 mg/day to 600 mg/day. The results showed that pregabalin, when used as add-on treatment, can reduce seizure frequency in individuals with treatment-resistant localisation-related epilepsy. In the analysis, when all doses of pregabalin were pooled, the RR for a 50% or greater reduction in seizure frequency was 2.61 (95% CI 1.70 to 4.01), thus demonstrating that out of 100 people with refractory epilepsy 40 are likely to have their seizures reduced when taking pregabalin compared to 15 out of 100 people not taking pregabalin. The large heterogeneity statistic associated with this result led to a sensitivity analysis that revealed two studies to be contributing largely. There were three main reasons for this: one study Lee 2009 was conducted in Korea and used a non-Western population sample and both studies, Baulac 2010 and Lee 2009, were conducted at later times and therefore treatment regimens may have been different from earlier therapies. Both of these trials had the 150 mg/day to 300 mg/day BD and 75 mg/day to 300 mg/day BD treatment arms, therefore heterogeneity could also be due to the range of doses administered within the studies. Heterogeneity between studies was not found for any of the other outcomes.

A generalised linear mixed-model analysis showed evidence of a dose effect, suggesting that using pregabalin as an add-on treatment at 600 mg dose doubles the odds of reducing seizures compared to 300 mg. Participants taking pregabalin were also found to be more likely to be free of seizures than controls.

Participants were more likely to withdraw for any reason or because of adverse effects from pregabalin than from placebo. In both cases, treatment withdrawal was more likely on higher doses. Although the assessment of adverse events showed that ataxia, dizziness, somnolence and weight gain were significantly associated with pregabalin, these adverse events were not documented using a checklist or other systematic approach, but required physician reporting, so event rates may have been underestimated.

The one study (Baulac 2010) that examined the effectiveness of pregabalin in comparison to another add-on drug (lamotrigine) showed that pregabalin was more effective in reducing seizure frequency than lamotrigine. Participants taking pregabalin were no more likely to be free of seizures than participants taking lamotrigine. Participants taking pregabalin were not more likely to withdraw from the study than participants taking lamotrigine. This was found for both any reason for withdrawal and due to adverse events. Only dizziness was found to be significantly more prevalent when taking pregabalin.

In summary, pregabalin (150 mg/day to 600 mg/day) as an add-on drug can effectively reduce seizures by 50% or more in people with partial epilepsy. The addition of pregabalin doubled seizure freedom, however was found to have four significant adverse effects, ataxia, dizziness, somnolence and weight gain.

Quality of the evidence

The evidence for the primary outcome of seizure reduction was assessed for quality using the GRADE approach and presenting in Summary of findings for the main comparison. Overall, the evidence was rated as moderate evidence due to large statistical heterogeneity and the possibility of publication bias.

Authors' conclusions

Implications for practice

In the short term (12 weeks) 150 mg/day to 600 mg/day of pregabalin given in a twice or three times daily regimen can significantly reduce seizure frequency and significantly increase seizure freedom rates in people with treatment-resistant partial epilepsy. Adverse events significantly associated with pregabalin were ataxia, dizziness, somnolence and weight gain. There are currently no data regarding cost-effectiveness, longer-term effectiveness of pregabalin versus placebo and, more importantly, versus other adjunctive treatments.

Implications for research

To improve clinical decisions, further clinical trials are required in adults or children, or both with drug-refractory partial epilepsy. These trials should:

  1. compare efficacy and tolerability of pregabalin with other adjunctive treatments;

  2. be of long-term duration (at least 12 months);

  3. assess seizure freedom rates, quality of life and health economic outcomes;

  4. establish cost-effectiveness and compare it with that of other AEDs.

Further data are also necessary regarding pregnancy outcomes, which will require the recruitment of women taking pregabalin to ongoing pregnancy registries.

Acknowledgements

We acknowledge Dora Lozsadi for contributions made in the original review.

Data and analyses

Download statistical data

Comparison 1. Pregabalin versus placebo: 50% seizure reduction - ITT
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 50% responders, ITT6 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 50 mg pregabalin1188Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.52, 2.12]
1.2 150 mg pregabalin2384Risk Ratio (M-H, Fixed, 95% CI)2.22 [1.36, 3.63]
1.3 300 mg pregabalin1190Risk Ratio (M-H, Fixed, 95% CI)2.86 [1.65, 4.94]
1.4 600 mg pregabalin61372Risk Ratio (M-H, Fixed, 95% CI)2.86 [2.32, 3.54]
1.5 Titrated dose of pregabalin (150-600 mg)1204Risk Ratio (M-H, Fixed, 95% CI)2.86 [1.42, 5.76]
1.6 Any dose pregabalin61868Risk Ratio (M-H, Fixed, 95% CI)2.55 [2.06, 3.16]
2 50% responders (Random-effects)61868Risk Ratio (M-H, Random, 95% CI)2.61 [1.70, 4.01]
3 50% responders, Best-Case Analysis64206Risk Ratio (M-H, Fixed, 95% CI)3.72 [3.27, 4.23]
3.1 50mg pregabalin1188Risk Ratio (M-H, Fixed, 95% CI)1.87 [1.03, 3.40]
3.2 150mg pregabalin2384Risk Ratio (M-H, Fixed, 95% CI)2.61 [1.63, 4.19]
3.3 300 mg pregabalin1190Risk Ratio (M-H, Fixed, 95% CI)4.37 [2.61, 7.29]
3.4 600 mg pregabalin61372Risk Ratio (M-H, Fixed, 95% CI)4.09 [3.34, 5.01]
3.5 Titrated dose of pregabalin (150-600mg)1204Risk Ratio (M-H, Fixed, 95% CI)5.02 [2.56, 9.82]
3.6 Any dose pregabalin61868Risk Ratio (M-H, Fixed, 95% CI)3.60 [2.93, 4.43]
4 50% responders, Best-Case Analysis Random-effects63240Risk Ratio (M-H, Random, 95% CI)1.50 [0.92, 2.45]
4.1 600 mg pregabalin61372Risk Ratio (M-H, Random, 95% CI)1.64 [0.78, 3.44]
4.2 Any dose pregabalin61868Risk Ratio (M-H, Random, 95% CI)1.40 [0.65, 3.00]
5 50% responders, Worst-Case Analysis64206Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.96, 1.14]
5.1 50 mg pregabalin1188Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.30, 0.99]
5.2 150 mg pregabalin2384Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.88, 1.96]
5.3 300 mg pregabalin1190Risk Ratio (M-H, Fixed, 95% CI)1.48 [0.98, 2.23]
5.4 600 mg pregabalin61372Risk Ratio (M-H, Fixed, 95% CI)1.24 [1.08, 1.43]
5.5 Titrated dose of pregabalin (150-600 mg)1204Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.27, 0.46]
5.6 Any dose pregabalin61868Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.94, 1.23]
Analysis 1.1.

Comparison 1 Pregabalin versus placebo: 50% seizure reduction - ITT, Outcome 1 50% responders, ITT.

Analysis 1.2.

Comparison 1 Pregabalin versus placebo: 50% seizure reduction - ITT, Outcome 2 50% responders (Random-effects).

Analysis 1.3.

Comparison 1 Pregabalin versus placebo: 50% seizure reduction - ITT, Outcome 3 50% responders, Best-Case Analysis.

Analysis 1.4.

Comparison 1 Pregabalin versus placebo: 50% seizure reduction - ITT, Outcome 4 50% responders, Best-Case Analysis Random-effects.

Analysis 1.5.

Comparison 1 Pregabalin versus placebo: 50% seizure reduction - ITT, Outcome 5 50% responders, Worst-Case Analysis.

Comparison 2. Pregabalin versus placebo: seizure freedom - ITT
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Seizure freedom post titration6 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 50 mg pregabalin1188Risk Ratio (M-H, Fixed, 95% CI)3.40 [0.14, 82.52]
1.2 150 mg pregabalin2384Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 7.92]
1.3 300 mg pregabalin1190Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.4 600 mg pregabalin61880Risk Ratio (M-H, Fixed, 95% CI)2.45 [1.02, 5.91]
1.5 Titrated dose of pregabalin (150-600mg)1204Risk Ratio (M-H, Fixed, 95% CI)5.05 [0.28, 92.42]
1.6 Any dose pregabalin61868Risk Ratio (M-H, Fixed, 95% CI)2.59 [1.05, 6.36]
Analysis 2.1.

Comparison 2 Pregabalin versus placebo: seizure freedom - ITT, Outcome 1 Seizure freedom post titration.

Comparison 3. Pregabalin versus placebo: treatment withdrawal (any reason) - ITT
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Treatment withdrawal any reason6 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 50 mg pregabalin1188Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.40, 1.89]
1.2 150 mg pregabalin2384Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.41, 1.28]
1.3 300 mg pregabalin1190Risk Ratio (M-H, Fixed, 95% CI)1.62 [0.85, 3.10]
1.4 600 mg pregabalin61372Risk Ratio (M-H, Fixed, 95% CI)1.65 [1.33, 2.04]
1.5 Titrated dose of pregabalin (150-600 mg)1204Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.61, 1.71]
1.6 Any dose pregabalin61868Risk Ratio (M-H, Fixed, 95% CI)1.39 [1.13, 1.72]
Analysis 3.1.

Comparison 3 Pregabalin versus placebo: treatment withdrawal (any reason) - ITT, Outcome 1 Treatment withdrawal any reason.

Comparison 4. Pregabalin versus placebo: treatment withdrawal (adverse events) - ITT
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Treatment withdrawal for adverse events6 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 50 mg pregabalin1188Risk Ratio (M-H, Fixed, 95% CI)1.36 [0.43, 4.31]
1.2 150 mg pregabalin2384Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.45, 2.32]
1.3 300 mg pregabalin1190Risk Ratio (M-H, Fixed, 95% CI)2.89 [1.07, 7.78]
1.4 600 mg pregabalin61372Risk Ratio (M-H, Fixed, 95% CI)3.39 [2.36, 4.87]
1.5 Titrated dose of pregabalin (150-600 mg)1204Risk Ratio (M-H, Fixed, 95% CI)1.78 [0.68, 4.67]
1.6 Any dose pregabalin61868Risk Ratio (M-H, Fixed, 95% CI)2.69 [1.88, 3.86]
Analysis 4.1.

Comparison 4 Pregabalin versus placebo: treatment withdrawal (adverse events) - ITT, Outcome 1 Treatment withdrawal for adverse events.

Comparison 5. Pregabalin versus placebo: adverse effects
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Ataxia6 Risk Ratio (M-H, Fixed, 99% CI)Subtotals only
1.1 50 mg pregabalin1188Risk Ratio (M-H, Fixed, 99% CI)1.14 [0.14, 9.00]
1.2 150 mg pregabalin2384Risk Ratio (M-H, Fixed, 99% CI)1.98 [0.56, 7.01]
1.3 300 mg pregabalin1190Risk Ratio (M-H, Fixed, 99% CI)3.33 [0.62, 17.81]
1.4 600 mg pregabalin61372Risk Ratio (M-H, Fixed, 99% CI)4.93 [2.56, 9.48]
1.5 Titrated dose of pregabalin (150-600 mg)1204Risk Ratio (M-H, Fixed, 99% CI)2.23 [0.44, 11.26]
1.6 Any dose pregabalin61868Risk Ratio (M-H, Fixed, 99% CI)3.90 [2.05, 7.42]
2 Fatigue6 Risk Ratio (M-H, Fixed, 99% CI)Subtotals only
2.1 50 mg pregabalin1188Risk Ratio (M-H, Fixed, 99% CI)0.71 [0.17, 2.94]
2.2 150 mg pregabalin2384Risk Ratio (M-H, Fixed, 99% CI)1.09 [0.50, 2.39]
2.3 300 mg pregabalin1190Risk Ratio (M-H, Fixed, 99% CI)1.53 [0.49, 4.76]
2.4 600 mg pregabalin61503Risk Ratio (M-H, Fixed, 99% CI)1.32 [0.89, 1.95]
2.5 Titrated dose of pregabalin (150-600 mg)1204Risk Ratio (M-H, Fixed, 99% CI)1.23 [0.49, 3.04]
2.6 Any dose pregabalin61868Risk Ratio (M-H, Fixed, 99% CI)1.28 [0.88, 1.86]
3 Dizziness6 Risk Ratio (M-H, Fixed, 99% CI)Subtotals only
3.1 50 mg pregabalin1188Risk Ratio (M-H, Fixed, 99% CI)1.01 [0.31, 3.33]
3.2 150 mg pregabalin2384Risk Ratio (M-H, Fixed, 99% CI)2.04 [0.99, 4.22]
3.3 300 mg pregabalin1190Risk Ratio (M-H, Fixed, 99% CI)3.46 [1.39, 8.62]
3.4 600 mg pregabalin61372Risk Ratio (M-H, Fixed, 99% CI)3.57 [2.50, 5.09]
3.5 Titrated dose of pregabalin (150-600 mg)1204Risk Ratio (M-H, Fixed, 99% CI)2.97 [1.01, 8.77]
3.6 Any dose pregabalin61868Risk Ratio (M-H, Fixed, 99% CI)3.06 [2.16, 4.34]
4 Nausea3 Risk Ratio (M-H, Fixed, 99% CI)Subtotals only
4.1 150 mg pregabalin1196Risk Ratio (M-H, Fixed, 99% CI)1.31 [0.34, 5.00]
4.2 600 mg pregabalin3712Risk Ratio (M-H, Fixed, 99% CI)1.18 [0.51, 2.75]
4.3 Titrated dose of pregabalin (150-600 mg)1204Risk Ratio (M-H, Fixed, 99% CI)1.11 [0.12, 10.05]
4.4 Any dose pregabalin3942Risk Ratio (M-H, Fixed, 99% CI)1.14 [0.51, 2.53]
5 Somnolence6 Risk Ratio (M-H, Fixed, 99% CI)Subtotals only
5.1 50 mg pregabalin1188Risk Ratio (M-H, Fixed, 99% CI)0.93 [0.31, 2.78]
5.2 150 mg pregabalin2384Risk Ratio (M-H, Fixed, 99% CI)1.26 [0.58, 2.74]
5.3 300 mg pregabalin1190Risk Ratio (M-H, Fixed, 99% CI)1.62 [0.63, 4.12]
5.4 600 mg pregabalin61372Risk Ratio (M-H, Fixed, 99% CI)2.42 [1.68, 3.50]
5.5 Titrated dose of pregabalin (150-600 mg)1204Risk Ratio (M-H, Fixed, 99% CI)2.32 [0.77, 7.04]
5.6 Any dose pregabalin61868Risk Ratio (M-H, Fixed, 99% CI)2.08 [1.45, 2.99]
6 Weight gain6 Risk Ratio (M-H, Fixed, 99% CI)Subtotals only
6.1 50 mg pregabalin1188Risk Ratio (M-H, Fixed, 99% CI)3.40 [0.05, 224.69]
6.2 150 mg pregabalin2384Risk Ratio (M-H, Fixed, 99% CI)3.85 [0.64, 23.35]
6.3 300 mg pregabalin1190Risk Ratio (M-H, Fixed, 99% CI)14.43 [0.34, 620.87]
6.4 600 mg pregabalin61372Risk Ratio (M-H, Fixed, 99% CI)5.61 [2.74, 11.47]
6.5 Titrated dose of pregabalin (150-600 mg)1204Risk Ratio (M-H, Fixed, 99% CI)2.79 [0.84, 9.29]
6.6 Any dose pregabalin61868Risk Ratio (M-H, Fixed, 99% CI)4.92 [2.41, 10.03]
7 Headache6 Risk Ratio (M-H, Fixed, 99% CI)Subtotals only
7.1 50 mg pregabalin1188Risk Ratio (M-H, Fixed, 99% CI)0.52 [0.16, 1.77]
7.2 150 mg pregabalin2384Risk Ratio (M-H, Fixed, 99% CI)0.53 [0.24, 1.17]
7.3 300 mg pregabalin1190Risk Ratio (M-H, Fixed, 99% CI)0.43 [0.12, 1.57]
7.4 600 mg pregabalin61372Risk Ratio (M-H, Fixed, 99% CI)0.77 [0.51, 1.15]
7.5 Titrated dose of pregabalin (150-600 mg)1204Risk Ratio (M-H, Fixed, 99% CI)1.25 [0.45, 3.50]
7.6 Any dose pregabalin61868Risk Ratio (M-H, Fixed, 99% CI)0.75 [0.52, 1.08]
Analysis 5.1.

Comparison 5 Pregabalin versus placebo: adverse effects, Outcome 1 Ataxia.

Analysis 5.2.

Comparison 5 Pregabalin versus placebo: adverse effects, Outcome 2 Fatigue.

Analysis 5.3.

Comparison 5 Pregabalin versus placebo: adverse effects, Outcome 3 Dizziness.

Analysis 5.4.

Comparison 5 Pregabalin versus placebo: adverse effects, Outcome 4 Nausea.

Analysis 5.5.

Comparison 5 Pregabalin versus placebo: adverse effects, Outcome 5 Somnolence.

Analysis 5.6.

Comparison 5 Pregabalin versus placebo: adverse effects, Outcome 6 Weight gain.

Analysis 5.7.

Comparison 5 Pregabalin versus placebo: adverse effects, Outcome 7 Headache.

Comparison 6. Pregabalin versus Lamotrigine
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 50% responders, ITT1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2 Seizure freedom1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3 Treatment withdrawal (any reason)1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4 Treatment withdrawal (adverse events)1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
5 Adverse events1 Risk Ratio (M-H, Fixed, 99% CI)Subtotals only
5.1 Ataxia1293Risk Ratio (M-H, Fixed, 99% CI)1.72 [0.54, 5.55]
5.2 Fatigue1293Risk Ratio (M-H, Fixed, 99% CI)1.72 [0.77, 3.83]
5.3 Dizziness1293Risk Ratio (M-H, Fixed, 99% CI)2.94 [1.32, 6.52]
5.4 Somnolence1293Risk Ratio (M-H, Fixed, 99% CI)1.99 [0.91, 4.33]
5.5 Weight gain1293Risk Ratio (M-H, Fixed, 99% CI)4.33 [0.86, 21.68]
5.6 Headache1293Risk Ratio (M-H, Fixed, 99% CI)0.52 [0.26, 1.05]
6 50% responders, Best- and Worst-Case Analysis1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
6.1 Best-Case1293Risk Ratio (M-H, Fixed, 95% CI)2.73 [1.99, 3.74]
6.2 Worst-Case1293Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.52, 0.88]
Analysis 6.1.

Comparison 6 Pregabalin versus Lamotrigine, Outcome 1 50% responders, ITT.

Analysis 6.2.

Comparison 6 Pregabalin versus Lamotrigine, Outcome 2 Seizure freedom.

Analysis 6.3.

Comparison 6 Pregabalin versus Lamotrigine, Outcome 3 Treatment withdrawal (any reason).

Analysis 6.4.

Comparison 6 Pregabalin versus Lamotrigine, Outcome 4 Treatment withdrawal (adverse events).

Analysis 6.5.

Comparison 6 Pregabalin versus Lamotrigine, Outcome 5 Adverse events.

Analysis 6.6.

Comparison 6 Pregabalin versus Lamotrigine, Outcome 6 50% responders, Best- and Worst-Case Analysis.

Appendices

Appendix 1. CENTRAL search strategy

#1 (pregabalin or Lyrica)

#2 MeSH descriptor Epilepsy explode all trees

#3 MeSH descriptor Seizures explode all trees

#4 epilep* or seizure* or convulsion*

#5 (#2 OR #3 OR #4)

#6 (#1 AND #5)

Appendix 2. MEDLINE search strategy

The most recent version of this review used the following search strategy, which is based on the Cochrane Highly Sensitive Search Strategy for identifying randomised trials (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. (pregabalin or lyrica).tw.

16. 10 and 14 and 15

Earlier versions of this review employed the following search strategy. It was based on the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE as described in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0, updated March 2011) (Higgins 2011).

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

8. (animals not humans).sh.

9. 7 not 8

10. clinical trial.pt.

11. Clinical Trial/

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

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

14. exp PLACEBOS/

15. placebo$.ab,ti.

16. random$.ab,ti.

17. exp Research Design/

18. 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17

19. (animals not humans).sh.

20. 18 not 19

21. 9 or 20

22. epilep$.tw.

23. exp EPILEPSY/

24. seizure$.tw.

25. exp SEIZURES/

26. convulsion$.tw.

27. 22 or 23 or 24 or 25 or 26

28. Lyrica.tw.

29. pregabalin.tw.

30. 28 or 29

31. 21 and 27 and 30

 

What's new

DateEventDescription
9 January 2014New citation required but conclusions have not changedConclusions remain the same.
9 January 2014New search has been performedSeaches updated 9th January 2014; one ongoing study (Bali 2012) has been added to the review.

History

Protocol first published: Issue 1, 2006
Review first published: Issue 1, 2008

DateEventDescription
12 June 2012New search has been performedTwo new studies were included in this update of the original review
7 August 2009AmendedCopyedits made at editorial base.
16 September 2008AmendedConverted to new review format.

Contributions of authors

JP carried out and completed the update of this review. AM assessed trials for eligibility and data extraction and provided supervision throughout the review process. KH conducted the dose-regression analysis.

Declarations of interest

AM has been sponsored to attend a conference and has had research funding from Pfizer Ltd. Also a consortium of pharmaceutical companies (GSK, EISAI, UCB Pharma) funded the National Audit of Seizure Management in Hospitals (NASH) through grants paid to University of Liverpool.
JP has no conflict of interest.
KH has acted as expert witness as a statistician in a number of legal cases including anti-epileptic drug cases.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • National Institute for Health Research, UK, Other.

    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

Protocol for last up-to-date review was amended for this review to include interventions comparing pregabalin to other active AEDs.

The method of analysis for examining dose-regression has been changed for this review due to advances in techniques for analysis binary data. A generalised linear mixed model using the software package STATA SE version 11 was employed as opposed to the generalised linear model using Splus.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Arroyo 2004

MethodsRandomised double-blind PCB-controlled parallel multicentre (45 in Europe, Australia and South Africa) trial. 3 treatment arms: 1 PCB, 2 PGB. Patients randomised in blocks of 6, each allocated unique ID number. All patients received 2 capsules TDS but 2 capsule sizes were used (no further information available). Duration of baseline period: 8 weeks. 12-week treatment period included 4- to 8-day titration period
ParticipantsAdults aged 17 to 73 years (mean 37 years), 50.5% male, all with treatment-resistant partial epilepsy. Patients were on 1 to 4 baseline AEDs. 344 patients screened, 288 patients randomised: 97 patients to PCB (mean baseline 28-day seizure frequency: 23.5), 99 patients to 50 mg/day PGB TDS (mean baseline 28-day seizure frequency: 26.2) and 92 patients to 200 mg/day PGB TDS (mean baseline 28-day seizure frequency: 19.3)
InterventionsGroup 1: PCB
Group 2: PGB 50 mg TDS (4-day titration phase)
Group 3: PGB 200 mg TDS (8-day titration phase)
Outcomes

Primary outcome: reduction in seizure frequency compared to baseline (response ratio)

Secondary outcomes: responder rate, seizure freedom, change in seizure frequency, adverse events

NotesStudy used capsules of 2 sizes, containing 25 mg PGB or PCB (size 1# = small capsules); and 100 mg PGB or PCB (size 4# = large capsules). It is stated that patients received 2 capsules TDS. One patient excluded from ITT in PCB arm, as failed to take study drugs
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom computer-generated code used stratified by centre using block size of 6
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Low riskMedication presented in identical capsules
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition rates reported. ITT analysis performed
Selective reporting (reporting bias)Unclear riskAll outcomes stated in methods section of paper were reported in the results; however, there was no protocol available to check a priori outcomes
Other biasHigh risk

As an EEG was not required to confirm the above, some of the 18 patients included who were stated to have 'generalised seizures' rather than secondary generalised, may have had primary generalised epilepsy

Sponsored by the same pharmaceutical company (Pfizer Ltd.) as with all the other included trials

Baulac 2010

MethodsRandomised double-blind PCB- and active drug-controlled parallel multicentre (97 in Europe, Canada and Australia) trial. 3 treatment arms: 1 PCB, 1 PGB and 1 LTG. Patients randomised to 1 of 3 treatment arms (no further information available). Duration of baseline period: 6 weeks. 12-week treatment period with 5-week titration phase before treatment (1 week of titration for PGB and 5 weeks of titration for LTG)
ParticipantsAdults aged 16 to 82 years (mean 39.4 years), 48.5% male, all with treatment-resistant partial epilepsy confirmed by history and recent EEG. Patients were on 1 to 3 baseline AEDs. 546 patients screened, 434 patients randomised: 141 patients to PCB (mean baseline 28-day seizure frequency: 16.38), 152 patients to 150 mg to 300 mg PGB BD (mean baseline 28-day seizure frequency: 21.32), and 141 patients to 150 mg to 300 mg LTG BD (mean baseline 28-day seizure frequency: 21.80)
Interventions

Group 1: PCB

Group 2: PGB 150 mg to 300 mg BD (1-week titration phase)

Group 3: LTG 150 mg to 300 mg BD (5-week titration phase)

Outcomes

Primary outcome: change in seizure frequency compared to baseline (response ratio)

Secondary outcomes: responder rate, seizure freedom, adverse events

NotesOne patient randomised to the PCB group failed to take > 1 dose of medication, and therefore was excluded from ITT analysis. No information provided on methods of randomisation, concealment or blinding
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo details of method of randomisation
Allocation concealment (selection bias)Unclear riskNo details of concealment of allocation
Blinding (performance bias and detection bias)
All outcomes
Unclear riskSame number of capsules administered per study day per group. No further details provided
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition rates reported. ITT analysis employed
Selective reporting (reporting bias)Unclear riskAll outcomes stated in methods section of paper were reported in the results; however, there was no protocol available to check a priori outcomes
Other biasHigh riskSponsored by same pharmaceutical company (Pfizer Ltd.) as with all the other included trials

Beydoun 2005

MethodsRandomised double-blind PCB-controlled parallel multicentre (43 in USA and Canada) trial. 3 treatment arms: 1 PCB, 2 PGB. Patients randomised in blocks of 6, each allocated unique ID number. All patients received TDS regimen of blinded capsules (no further information available). Duration of baseline period: 8 weeks. 1-week titration period and 11-week treatment period
ParticipantsAdults aged 17 to 82 years (mean 39.1 years), 50.2% male, all with treatment-resistant partial epilepsy confirmed by history and recent EEG. Patients were on 1 to 4 baseline AEDs. 378 patients screened, 313 patients randomised: 98 patients to PCB (mean baseline 28-day seizure frequency: 25.1), 104 patients to 300 mg PGB BD (mean baseline 28-day seizure frequency: 21.5), and 111 patients to 200 mg PGB TDS (mean baseline 28-day seizure frequency: 21.3)
InterventionsGroup 1: PCB
Group 2: 300 mg PGB BD (1-week titration phase)
Group 3: 200 mg PGB TDS (1-week titration phase)
Outcomes

Primary outcome: reduction in seizure frequency compared to baseline (response ratio)

Secondary outcomes: responder rate, median percentage change in seizure frequency

NotesOne patient randomised to the 300 mg BD group failed to take tablets, and therefore was excluded from ITT analysis. Blinding was broken with 1 patient in the PCB arm when she became pregnant
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskPatients randomised in blocks of 6 and allocated unique ID number
Allocation concealment (selection bias)Unclear riskNo details provided
Blinding (performance bias and detection bias)
All outcomes
Low riskAll patients received identical capsules
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition rates reported. ITT analysis employed
Selective reporting (reporting bias)Unclear riskAll outcomes stated in methods section of paper were reported in the results; however, there was no protocol available to check a priori outcomes
Other biasHigh riskSponsored by same pharmaceutical company (Pfizer Ltd.) as with all the other included trials

Elger 2005

MethodsRandomised double-blind PCB-controlled parallel multicentre (53 in Europe and Canada) trial. 3 treatment arms: 1 PCB, 2 PGB. Patients randomised in blocks of 5, each allocated unique ID number. All regimens mimicked control group using identical capsules (no further information available). Duration of baseline period: 6 weeks. 12-week treatment period
ParticipantsAdults aged 18 to 78 years (mean 40.5 years), 49.9% male, all with treatment-resistant partial epilepsy confirmed by personal and family history as well as recent EEG. Patients were on 1 to 5 baseline AEDs. 400 patients screened, 341 patients randomised: 73 patients to PCB (median baseline 28-day seizure frequency: 8.7), 137 patients to 300 mg PGB BD fixed (median baseline 28-day seizure frequency: 10), and 131 patients to PGB flexible dosing (median baseline 28-day seizure frequency: 9.33)
InterventionsGroup 1: PCB
Group 2: 300 mg PGB BD fixed dose
Group 3: 75 mg to 300 mg PGB BD flexible titration at physician's discretion
Outcomes

Primary outcome: reduction in seizure frequency compared to baseline (response ratio)

Secondary outcomes: responder rate, median percentage change in seizure frequency and reduction of GTCS in those completing the study, adverse events

NotesIn PGB titration and PCB groups, patients were included with seizure frequency of over 120 a day. Documenting seizures at this frequency is difficult and may be unreliable. Medium length of follow-up not reported
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskPatients randomised using a 1:2:2 ratio and block sizes of 5
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Low riskStudy medication presented in identical capsules
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition rates reported. ITT analysis employed
Selective reporting (reporting bias)Unclear riskAll outcomes stated in methods section of paper were reported in the results; however, there was no protocol available to check a priori outcomes
Other biasHigh riskSponsored by same pharmaceutical company as with all the other included trials

French 2003

MethodsRandomised double-blind PCB-controlled parallel multicentre (71 in the USA and 5 in Canada) trial. 5 treatment arms: 1 PCB, 4 PGB. Patients randomised in blocks of 5, each allocated unique ID number. Capsule sizes varied (no further information available). Duration of baseline period: 8 weeks. There was no titration; 12-week treatment period
ParticipantsPatients 12 years and above (range 12 to 75 years, mean 38.4 years), 48.1% male, all with treatment-resistant partial epilepsy. Patients were on 1 to 4 baseline AEDs. 586 patients screened, 455 patients randomised: 100 patients to PCB (mean baseline seizure frequency: 22.3); 88 patients to 50 mg PGB (mean baseline seizure frequency: 27.4); 88 patients to 150 mg PGB (mean baseline 28-day seizure frequency: 23.1); 90 patients to 300 mg PGB (mean baseline 28-day seizure frequency: 19.1) and 89 patients to 600 mg PGB (mean baseline 28-day seizure frequency: 18.6)
InterventionsGroup 1: PCB
Group 2: 50 mg PGB daily
Group 3: 150 mg PGB
Group 4: 300 mg PGB
Group 5: 600 mg PGB daily
Outcomes

Primary outcome: reduction in seizure frequency compared to baseline (response ratio)

Secondary outcomes: responder rate, pair-wise comparisons with PCB, adverse events

NotesBlinding broken for interim analysis (data obtained were only known to committee who were not involved in further running of study) and for 1 patient who developed visual field defect. 2 patients were excluded from ITT analysis (1 withdrew consent, 1 had AEDs changed during baseline period). Seizure frequency and responder rate were calculated from data collected from seizure diaries and mean calculated over a 4-week period
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskUsed a computer-generated randomised schedule using block sizes of 5
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskStudy medication presented in identical capsules
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition rates reported. ITT analysis employed
Selective reporting (reporting bias)Unclear riskAll outcomes stated in methods section of paper were reported in the results; however, there was no protocol available to check a priori outcomes
Other biasHigh risk

Possibility of the inclusion of patients with primary generalised epilepsy

Sponsored by same pharmaceutical company as with all the other included trials

Lee 2009

  1. a

    AED: antiepileptic drug; BD: twice daily; EEG: electroencephalogram; GTCS: generalised tonic-clonic seizures; ITT: intention-to-treat analysis; LTG: lamotrigine; PCB: placebo; PGB: pregabalin; TDS: three times a day

MethodsRandomised double-blind PCB-controlled parallel multicentre (9 in Korea) trial. 2 treatment arms: 1 PCB, 1 PGB. Patients randomised to 1 of 2 treatment arms (no further information available). Duration of baseline period: 6 weeks. 12-week treatment period (no further details provided)
ParticipantsPatients 18 years and above (mean 34.2 years), 48.3% male, all with treatment-resistant partial epilepsy. Patients were on 1 to 3 baseline AEDs. 209 patients screened, 178 patients randomised: 59 patients to PCB (mean baseline 28-day seizure frequency: 13.2) and 119 patients to 150 mg to 600 mg PGB (mean baseline 28-day seizure frequency 13.2)
Interventions

Group 1: PCB

Group 2: 150 mg/day to 600 mg/day

Outcomes

Primary outcome: change in seizure frequency (response ratio)

Secondary outcomes: responder rate, seizure freedom, anxiety/depression, sleep, quality of life, adverse events

NotesAll randomised patients included in ITT analysis. No information provided on methods of randomisation, concealment or blinding
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskPatients randomised using 2:1 ratio. No further information given
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information provided
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition rates reported. ITT analysis employed
Selective reporting (reporting bias)Unclear riskAll outcomes stated in methods section of paper were reported in the results; however, there was no protocol available to check a priori outcomes
Other biasHigh riskSponsored by same pharmaceutical company (Pfizer Ltd.) as with all the other included trials

Characteristics of studies awaiting assessment [ordered by study ID]

Russi 2006

MethodsRandomised observational controlled study. 4 treatment arms: 1 LEV fast rate, 2 LEV slow rate, 3 PGB fast rate, 4 PGB slow rate dosage
Participants128 patients with refractory partial epilepsy (32 in each treatment arm)
Interventions

Group 1: starting dose of 1000 mg BD LEV fast rate with weekly increments of 500 mg

Group 2: starting dose of 500 mg BD LEV slow rate with weekly increments of 250 mg

Group 3: starting dose of 300 mg BD PGB fast rate with weekly increments of 150 mg

Group 4: starting dose of 150 mg BD PGB slow rate with weekly increments of 75 mg

Outcomes

Rate of withdrawals and continuation to maximum dose

Incidence of adverse events

NotesStudy reported in abstract form only. Further details of study are unavailable

Tata 2007

  1. a

    AED: antiepileptic drug; BD: twice daily; LEV: levetiracetam; PGB: pregabalin;

MethodsRandomised cross-over trial consisting of 2 treatment arms: 1 PGB, 2 LEV. Patients randomised to groups using 1:1 ratio. Study was open-label. Long-term study duration of minimum 6 months
Participants28 adults aged 19 to 62 years, 54% male. Patients currently taking different AED without maintaining good seizure control, stabilised to therapeutic association of valproate and lamotrigine
Interventions

Group 1: starting dose of 150 mg to target dose of 600 mg PGB

Group 2: starting dose of 1000 mg to target dose of 3000 mg LEV

Outcomes

Seizure freedom

Seizure reduction

Withdrawals

Adverse events

NotesStudy reported in abstract only. Further details of study are unavailable

Characteristics of ongoing studies [ordered by study ID]

Bali 2012

  1. a

    RCT: randomised controlled trial

Trial name or titleComparison of the effect of Zonisamide and Pregabalin as adjunctive therapy in control of intractable epilepsy in children
MethodsA single-blind parallel RCT comparing Zonisamide to Pregabalin. Duration: 6 months.
Participants96 children aged 1-18 years with drug-resistant epilepsy
Interventions

Intervention group 1 treated with Zonisamide orally with dose of 2-12 mg per kg daily and after one month and six months.

Intervention group 2 treated with Pregablin orally with dose of 5-15mg per kg daily and after one month and six months.

Outcomes

1) > 50% seizure reduction.

2) Seizure severity.

Starting dateRecruitmanet start date: 01/04/2012.
Contact informationDr Mohammad Kazem Bakhshandeh Bali, Dr.MK.Bakhshandehbali@sbmu.ac.ir
NotesAuthor contacted, no response received.