Rufinamide add‐on therapy for drug‐resistant epilepsy
Abstract
Background
Epilepsy is a central nervous system disorder (neurological disorder). Epileptic seizures are the result of excessive and abnormal cortical nerve cell electrical activity in the brain. Despite the development of more than 10 new antiepileptic drugs (AEDs) since the early 2000s, approximately a third of people with epilepsy remain resistant to pharmacotherapy, often requiring treatment with a combination of AEDs. In this review, we summarised the current evidence regarding rufinamide, a novel anticonvulsant medication, which, as a triazole derivative, is structurally unrelated to any other currently used anticonvulsant medication when used as an add‐on treatment for drug‐resistant epilepsy. In January 2009, rufinamide was approved by the US Food and Drug Administration for the treatment of children four years of age and older with Lennox‐Gastaut syndrome. It is also approved as an add‐on treatment for adults and adolescents with focal seizures.
This is an updated version of the original Cochrane Review published in 2018.
Objectives
To evaluate the efficacy and tolerability of rufinamide when used as an add‐on treatment for people with drug‐resistant epilepsy.
Search methods
We imposed no language restrictions. We contacted the manufacturers of rufinamide and authors in the field to identify any relevant unpublished studies.
Selection criteria
Randomised, double‐blind, placebo‐controlled, add‐on trials of rufinamide, recruiting people (of any age or gender) with drug‐resistant epilepsy.
Data collection and analysis
Two review authors independently selected trials for inclusion and extracted the relevant data. We assessed the following outcomes: 50% or greater reduction in seizure frequency (primary outcome); seizure freedom; treatment withdrawal; and adverse effects (secondary outcomes). Primary analyses were intention‐to‐treat (ITT) and we presented summary risk ratios (RRs) with 95% confidence intervals (CIs). We evaluated dose response in regression models. We carried out a risk of bias assessment for each included study using the Cochrane 'Risk of bias' tool and assessed the overall certainty of evidence using the GRADE approach.
Main results
The review included six trials, representing 1759 participants. Four trials (1563 participants) included people with uncontrolled focal seizures. Two trials (196 participants) included individuals with established Lennox‐Gastaut syndrome. Overall, the age of adults ranged from 18 to 80 years and the age of children ranged from 4 to 16 years. Baseline phases ranged from 28 to 56 days and double‐blind phases from 84 to 96 days. Five of the six included trials described adequate methods of concealment of randomisation, and only three described adequate blinding. All analyses were by ITT. Overall, five studies were at low risk of bias and one had unclear risk of bias due to lack of reported information around study design. All trials were sponsored by the manufacturer of rufinamide and therefore were at high risk of funding bias.
The overall RR for 50% or greater reduction in seizure frequency was 1.79 (95% CI 1.44 to 2.22; 6 randomised controlled trials (RCTs), 1759 participants; moderate‐certainty evidence), indicating that rufinamide (plus conventional AED) was significantly more effective than placebo (plus conventional AED) in reducing seizure frequency by at least 50% when added to conventionally used AEDs in people with drug‐resistant focal epilepsy. Data from only one study (73 participants) reported seizure freedom: RR 1.32 (95% CI 0.36 to 4.86; 1 RCT, 73 participants; moderate‐certainty evidence). The overall RR for treatment withdrawal (for any reason and due to AED) was 1.83 (95% CI 1.45 to 2.31; 6 RCTs, 1759 participants; moderate‐certainty evidence), showing that rufinamide was significantly more likely to be withdrawn than placebo. Most adverse effects were significantly more likely to occur in the rufinamide‐treated group. Adverse events significantly associated with rufinamide were headache, dizziness, somnolence, vomiting, nausea, fatigue, and diplopia. The RRs for these adverse effects were as follows: headache 1.36 (95% Cl 1.08 to 1.69; 3 RCTs, 1228 participants; high‐certainty evidence); dizziness 2.52 (95% Cl 1.90 to 3.34; 3 RCTs, 1295 participants; moderate‐certainty evidence); somnolence 1.94 (95% Cl 1.44 to 2.61; 6 RCTs, 1759 participants; moderate‐certainty evidence); vomiting 2.95 (95% Cl 1.80 to 4.82; 4 RCTs, 777 participants; low‐certainty evidence); nausea 1.87 (95% Cl 1.33 to 2.64; 3 RCTs, 1295 participants; moderate‐certainty evidence); fatigue 1.46 (95% Cl 1.08 to 1.97; 3 RCTs, 1295 participants; moderate‐certainty evidence); and diplopia 4.60 (95% Cl 2.53 to 8.38; 3 RCTs, 1295 participants; low‐certainty evidence). There was no important heterogeneity between studies for any outcomes. Overall, we assessed the evidence as moderate to low certainty due to wide CIs and potential risk of bias from some studies contributing to the analysis.
Authors' conclusions
For people with drug‐resistant focal epilepsy, rufinamide when used as an add‐on treatment was effective in reducing seizure frequency. However, the trials reviewed were of relatively short duration and provided no evidence for long‐term use of rufinamide. In the short term, rufinamide as an add‐on was associated with several adverse events. This review focused on the use of rufinamide in drug‐resistant focal epilepsy, and the results cannot be generalised to add‐on treatment for generalised epilepsies. Likewise, no inference can be made about the effects of rufinamide when used as monotherapy.
PICOs
Plain language summary
How well does rufinamide treat drug‐resistant epilepsy when given with another antiepileptic medicine?
What is drug‐resistant epilepsy?
Epilepsy is a condition in which sudden bursts of intense electrical activity happen in the brain and cause the brain's messages to get mixed up, resulting in a seizure. Seizures affect people in different ways: they may cause unusual sensations, movements or feelings, loss of awareness, falls, stiffness or jerking. Epileptic seizures can occur repeatedly and without any triggers. Seizures can happen anytime and anywhere; they can come on suddenly and can happen often.
Treatments for epilepsy focus on stopping or reducing the number of seizures a person has with as few unwanted effects as possible. Most seizures are controlled by taking a single antiepileptic medicine. But some people's epilepsy does not respond (drug‐resistant epilepsy) and they may need more than one medicine to control the seizures. Drug‐resistant epilepsy is more common if the seizures involve one area of the brain (focal epilepsy) rather than the whole outer area of the brain (generalised epilepsy).
Why we did this review
Rufinamide is an antiepileptic medicine. It is given in addition to other antiepileptic medicines as an ‘add‐on’ treatment for focal epilepsy in adults and adolescents.
We wanted to know how well add‐on rufinamide works to treat drug‐resistant epilepsy, including the potential benefits and any unwanted effects of treatment.
What did we do?
We searched for studies that investigated the use of rufinamide as an add‐on treatment for drug‐resistant epilepsy.
We looked for randomised controlled studies, in which the treatments people received were decided at random, because these studies usually give the most reliable evidence about the effects of a treatment. We assessed the evidence we found by looking at how the studies were conducted, the study sizes, and whether their findings were consistent.
Search date: we included evidence published up to 20 February 2020.
What we found
We found six studies in 1759 people (aged 4 to 80 years). Four studies included people with focal seizures and two studies included children with Lennox‐Gastaut syndrome (a type of epilepsy affecting children). They were short‐term studies: treatments were given for at most 96 days, and assessments continued for up to 3 to 6 months afterwards.
The studies assessed add‐on rufinamide treatment compared with an 'add‐on' dummy (placebo) treatment. The doses of rufinamide in the studies ranged from 200 mg to 3200 mg daily.
We were interested in how many seizures people had. We also wanted to find out if adding rufinamide would affect the number and types of unwanted effects.
What are the results of our review?
Adding rufinamide to another antiepileptic medicine probably reduced how often seizures happened more than an add‐on placebo did (6 studies). Add‐on rufinamide probably increased seizure freedom (no seizures) more than an add‐on placebo, although only one study measured this.
More people stopped taking add‐on rufinamide (because of unwanted effects or for any other reason) than stopped taking add‐on placebo treatment (6 studies). Unwanted effects were probably more common in people who received add‐on rufinamide rather than add‐on placebo. Unwanted effects that were reported included: feeling dizzy (3 studies), feeling tired (3 studies), feeling sick (3 studies), headache (3 studies), feeling drowsy or sleepy (6 studies), being sick (vomiting) (4 studies) and double vision (3 studies).
How reliable are these results?
We are moderately confident (certain) about our findings for the effects of add‐on rufinamide on how many seizures people had, and on some of the unwanted effects seen (dizziness, sleepiness, headaches, tiredness and feeling sick). Our results may change if further evidence becomes available.
We are less confident (uncertain) about the unwanted effects of vomiting and double vision seen with add‐on rufinamide, because the results for these effects varied widely. Our results are likely to change if further evidence becomes available.
All studies were conducted or sponsored by a pharmaceutical company that makes rufinamide: this may have affected how the studies were designed, carried out and reported. One study did not fully report its study design.
Conclusions
Adding rufinamide to an antiepileptic medicine probably reduced seizures more than a placebo, but probably caused more unwanted effects (in the short term); more people stopped add‐on rufinamide treatment.
Authors' conclusions
Summary of findings
| Rufinamide versus placebo for drug‐resistant focal epilepsy | ||||||
| Patient or population: people with drug‐resistant focal epilepsy Settings: outpatients Intervention: rufinamide Comparison: placebo | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo | Rufinamide | |||||
| 50% or greater reduction in seizure frequency ‐ ITT analysis | Study population | RR 1.79 (1.44 to 2.22) | 1759 | ⊕⊕⊕⊝ Moderatea | RR > 1 indicates outcome is more likely in rufinamide group | |
| 143 per 1000 | 256 per 1000 | |||||
| Seizure freedom | 103 per 1000 | 136 per 1000 (37 to 500) | RR 1.32 (0.36 to 4.86) | 73 (1 study) | ⊕⊕⊕⊝ Moderatea | RR > 1 indicates outcome is more likely in rufinamide group |
| Treatment withdrawal | Study population | RR 1.83 (1.45 to 2.31) | 1759 | ⊕⊕⊕⊝ Moderatea | RR > 1 indicates outcome is more likely in rufinamide group | |
| 112 per 1000 | 205 per 1000 | |||||
| Adverse effects: dizziness | Study population | RR 2.52 (1.90 to 3.34) | 1295 | ⊕⊕⊕⊝ Moderatea | RR > 1 indicates outcome is more likely in rufinamide group | |
| 108 per 1000 | 272 per 1000 | |||||
| Adverse effects: fatigue | Study population | RR 1.46 (1.08 to 1.97) | 1295 | ⊕⊕⊕⊝ Moderatea | RR > 1 indicates outcome is more likely in rufinamide group | |
| 112 per 1000 | 164 per 1000 | |||||
| Adverse effects: headache | Study population | RR 1.36 (1.08 to 1.69) | 1228 | ⊕⊕⊕⊝ Moderatea | RR > 1 indicates outcome is more likely in rufinamide group | |
| 196 per 1000 | 267 per 1000 | |||||
| Adverse effects: somnolence | Study population | RR 1.94 (1.44 to 2.61) | 1759 | ⊕⊕⊕⊝ Moderatea | RR > 1 indicates outcome is more likely in rufinamide group | |
| 82 per 1000 | 159 per 1000 | |||||
| Adverse effects: nausea | Study population | RR 1.87 (1.33 to 2.64) | 1295 | ⊕⊕⊕⊝ Moderatea | RR > 1 indicates outcome is more likely in rufinamide group | |
| 82 per 1000 | 153 per 1000 | |||||
| Adverse effects: vomiting | Study population | RR 2.95 (1.80 to 4.82) | 777 (4 studies) | ⊕⊕⊝⊝ Lowb | RR > 1 indicates outcome is more likely in rufinamide group | |
| 49 per 1000 | 145 per 1000 | |||||
| Adverse effects: diplopia | Study population | RR 4.60 (2.53 to 8.38) | 1295 (3 studies) | ⊕⊕⊝⊝ Lowb | RR > 1 indicates outcome is more likely in rufinamide group | |
| 24 per 1000 | 110 per 1000 | |||||
| *The basis for the assumed riskc (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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| aDowngraded once due to risk of bias: unclear methodological information provided for some included studies and all included studies pharmaceutical sponsored. bDowngraded once due to imprecision: wide confidence intervals. cAssumed risk is calculated as the event rate in the control group per 1000 people (number of events divided by the number of participants receiving control treatment). | ||||||
Background
This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (Panebianco 2018).
Description of the condition
Epilepsy is a central nervous system disorder (neurological disorder). The definition of epilepsy, as recommended by the International League Against Epilepsy (ILAE) Commission on Epidemiology, is as follows: "two or more unprovoked seizures occurring more than 24 hours apart" (ILAE Commission on Epidemiology and Prognosis 1993). Epileptic seizures are the result of excessive and abnormal cortical nerve cell electrical activity in the brain.
Epilepsy imposes a significant clinical, epidemiological, and economic burden on societies worldwide. Despite the development of more than 10 new antiepileptic drugs (AEDs) since the early 2000s, approximately a third of people with epilepsy remain resistant to pharmacotherapy, often requiring treatment with a combination of AEDs. The proportion of people with drug‐resistant seizures varies in the literature between 6% and 35% (Granata 2009). Therefore, the development of effective new therapies for treatment of drug‐resistant seizures is of considerable importance. Since the late 1990s, the introduction of several new drugs, which often are better tolerated and more manageable than the older ones, has certainly improved our ability to treat people with epilepsy (Panebianco 2015a). Studies have reported that 12% to 17% of treatment‐resistant people become seizure‐free with the addition of a previously untried, in most cases new‐generation, AED (Granata 2009).
Description of the intervention
Rufinamide (1‐(2,6‐difluoro‐phenyl)‐methyl‐1 hydro‐1,2,3‐triazole‐4 carboxamide) is a novel anticonvulsant medication that, as a triazole derivative, is structurally unrelated to any other currently used anticonvulsant medications. It was granted orphan drug status in 2004 for adjunctive treatment of people with Lennox‐Gastaut syndrome (LGS) in the United States, and it was released for use in Europe in 2007. In January 2009, rufinamide was approved by the US Food and Drug Administration for treatment of children aged four years and older with LGS (Coppola 2011; Hsieh 2013). It is also approved as adjunctive treatment for adults and adolescents with focal seizures. There has been renewed interest in the development of newer AEDs, as several of the standard ones are not always effective and are associated with adverse effects. In the first instance, new AEDs are tested in randomised controlled trials (RCTs) as an add‐on treatment for people with drug‐resistant focal epilepsy. Once a therapeutic effect is reported by these trials, new AEDs tend to be licenced for add‐on use before monotherapy trials have compared new AEDs versus standard treatments. Placebo‐controlled studies of rufinamide that have provided efficacy data include trials involving people with LGS, people with adult focal‐onset seizures (for both monotherapy and adjunctive therapy), children with focal‐onset seizures in need of adjunctive therapy, and people with drug‐resistant generalised tonic‐clonic seizures (Biton 2005).
How the intervention might work
The precise mechanisms by which rufinamide exerts its antiepileptic effects are unknown. In vitro studies suggest that a principal mechanism of action is the modulation of activity in sodium channels, particularly prolongation of the inactive state. In cultured cortical neurons from immature rats, rufinamide significantly slowed sodium channel recovery from inactivation after a prolonged prepulse and limited sustained repetitive firing of sodium‐dependent action potentials. Rufinamide has no effect on benzodiazepine or gamma‐aminobutyric acid (GABA) receptors, nor on adenosine uptake; it also has no significant interactions with glutamate, adrenergic tryptophan, histamine, or muscarinic cholinergic receptors (Wheless 2010). The overall tolerability of rufinamide is good. Most adverse events in clinical trials were mild to moderate, and they were often transient in nature, largely occurring during the titration phase (Wheless 2009).
Why it is important to do this review
The purpose of this review was to report evidence from RCTs on the efficacy and tolerability of rufinamide used as add‐on treatment for people with drug‐resistant epilepsy. This review aimed to address these issues to inform clinical practice and future research.
Objectives
To evaluate the efficacy and tolerability of rufinamide when used as an add‐on treatment for people with drug‐resistant epilepsy.
Methods
Criteria for considering studies for this review
Types of studies
Studies were required to meet all the following criteria.
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RCTs.
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Double‐ or single‐blinded trials.
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Placebo‐controlled trials, or trials providing an alternative AED or a range of rufinamide doses used as controls.
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Parallel‐group or cross‐over studies.
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Minimum treatment period of eight weeks.
Types of participants
We considered participants who satisfied both of the following criteria.
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Any age.
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Diagnosis of drug‐resistant epilepsy (i.e. experiencing simple focal, complex focal, or secondarily generalised tonic‐clonic seizures).
Types of interventions
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Active treatment, wherein participants received treatment with rufinamide in addition to conventional AED treatment.
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Control, wherein participants received a matched placebo/different dose/alternative AED in addition to conventional AED treatment.
Types of outcome measures
Primary outcomes
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Fifty per cent or greater reduction in seizure frequency: proportion of people with 50% or greater reduction in seizure frequency during the treatment period compared with the pre‐randomisation baseline period
Secondary outcomes
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Seizure freedom: proportion of people with complete cessation of seizures during the treatment period
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Treatment withdrawal: proportion of people with treatment withdrawn during the course of the treatment period 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 participants make a direct contribution. In trials of shorter duration, it is likely that adverse effects would be the most common reason for withdrawal
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Adverse effects: proportions of people who experienced the following adverse effects
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Dizziness
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Fatigue
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Headache
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Somnolence
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Nausea
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Vomiting
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Psychiatric adverse effects (anxiety, depression, panic attack, irritability, trouble sleeping, mood or behaviour changes)
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Loss of appetite
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Diplopia
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Fever
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Loss of co‐ordination
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Difficulty walking
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Allergic reaction
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Quality of life (QoL): difference between intervention and control group means for QoL measures used in individual studies
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Cognition: difference between intervention and control group means for cognitive assessments used in individual studies
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Mood: difference between intervention and control group means for mood assessments used in individual studies
Search methods for identification of studies
Electronic searches
Searches were run for the original review in September 2015. Subsequent searches were run in October 2017. For the latest update, we searched the following databases on 11 February 2020.
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Cochrane Register of Studies (CRS Web), using the search strategy set out in Appendix 1.
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MEDLINE (Ovid, 1946 to 10 February 2020), using the search strategy set out in Appendix 2.
CRS Web includes randomised and quasi‐randomised, controlled trials from PubMed; Embase; ClinicalTrials.gov; the World Health Organization International Clinical Trials Registry Platform (ICTRP); the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; and the Specialised Registers of Cochrane Review Groups, including the Epilepsy Group.
We applied no language restrictions.
Searching other resources
We checked reference lists of retrieved studies for additional reports of relevant studies. We contacted lead study authors for relevant unpublished material. We identified duplicate studies by screening reports according to title, study author names, location, and medical institute. We omitted duplicate studies.
We identified any grey literature studies published from 2012 to 2017 by searching:
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Zetoc database;
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Institute for Scientific Information (ISI) proceedings;
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International Bureau for Epilepsy (IBE) congress proceedings database;
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ILAE congress proceedings database; and
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abstract books of symposia and congresses, meeting abstracts, and research reports.
Data collection and analysis
Selection of studies
Two review authors (MP and HP) independently assessed all citations generated by the searches for inclusion. We resolved any disagreements by discussion with a third review author (AGM). Two review authors (MP and HP) independently extracted data and assessed risk of bias; we resolved disagreements by discussion with a third review author (AGM).
Data extraction and management
Two review authors (MP and HP) independently extracted data from each included study. We cross‐checked the data extracted. Review authors discussed disagreements (bringing in a third review author (AGM) to arbitrate if need be), documented decisions, and, if necessary, contacted trialists for clarification.
We extracted the following information for each trial using a pre‐standardised data extraction form.
Methodological and trial design
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Methods of randomisation and allocation concealment
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Method of blinding
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Whether any participants were excluded from reported analyses
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Length of baseline period
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Length of treatment period
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Dose(s) of rufinamide tested
Participant/demographic information
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Total number of participants allocated to each treatment group
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Age/sex
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Number with focal/generalised epilepsy
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Seizure types
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Seizure frequency during the baseline period
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Number of background drugs
Outcomes
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Number of people experiencing each outcome (see Types of outcome measures) per randomly assigned group
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Contact with authors of trials to ask for missing information
We collated multiple reports of the same study, so that each study rather than each report was the unit of interest in the review. We collected characteristics of the included studies in sufficient detail to populate a table of Characteristics of included studies.
Assessment of risk of bias in included studies
Two review authors (MP and HP) independently assessed the risk of bias of each included study. We cross‐checked risk of bias assessments and discussed and resolved any disagreements. We utilised the Cochrane 'Risk of bias' tool as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We rated included studies as having low, high, or unclear risk of bias for six domains applicable to RCTs: randomisation method, allocation concealment, blinding methods, incomplete outcome data, selective outcome reporting, and other sources of bias. We made an overall summary judgement of risk of bias for each study per outcome, followed by an overall judgement per outcome across studies. We incorporated risk of bias judgements into the analysis using sensitivity analysis, in that a secondary analysis of the data included only studies rated as having low risk of bias. We presented all results in the Results section of the review.
Measures of treatment effect
We presented the primary outcome of seizure reduction as risk ratios (RRs) and 95% confidence intervals (CIs). We presented secondary outcomes, including seizure freedom, treatment withdrawal, and adverse effects, as RRs and 95% CIs.
Dealing with missing data
We sought missing data from the study authors. We carried out intention‐to‐treat (ITT), best‐case, and worst‐case analyses on the primary outcome for missing data (see Data synthesis). We included all analyses in the main report.
Assessment of heterogeneity
We assessed clinical heterogeneity by comparing the distribution of important individual participant factors among trials (e.g. age, seizure type, duration of epilepsy, number of AEDs taken at the time of randomisation) and trial factors (e.g. randomisation concealment, blinding, losses to follow‐up). We examined statistical heterogeneity by using a Chi² test and the I² statistic for heterogeneity, and, provided no significant heterogeneity was present (P > 0.10), we employed a fixed‐effect model. In the event that there was heterogeneity, we performed a random‐effects model analysis using the inverse variance method.
Assessment of reporting biases
Protocol versus full study
We requested all protocols from study authors to enable a comparison of outcomes of interest. In the event that a protocol was not available, we investigated outcome reporting bias using the ORBIT matrix system (Kirkham 2010).
Funnel plot
Reporting biases arise when dissemination of research findings is influenced by the nature and direction of results (Higgins 2011; Sterne 2000). We used funnel plots in investigating reporting biases with awareness that they have limited power to detect small‐study effects. We did not use funnel plots for outcomes when 10 or fewer studies were included, or when all studies were of similar size. In other cases, when funnel plots were possible, we sought statistical advice on their interpretation.
Data synthesis
We employed a fixed‐effect model meta‐analysis to synthesise the data. We expected to carry out the following comparisons.
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Intervention group versus control group on 50% or greater reduction in seizure frequency.
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Intervention group versus control group on seizure freedom.
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Intervention group versus control group on treatment withdrawal.
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Intervention group versus control group on individual adverse effects.
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Intervention group versus control group on QoL.
We stratified each comparison by type of control group, that is, placebo or active control, and by types of study characteristics to ensure the appropriate combination of study data. Our preferred estimator was the Mantel‐Haenszel RR. For the outcomes 50% or greater reduction in seizure frequency, seizure freedom, and treatment withdrawal, we used 95% CIs. For individual adverse effects, we used 99% CIs to allow for multiple testing. Our analyses included all participants in the treatment groups to which they were allocated. For the efficacy outcome (50% or greater reduction in seizure frequency), we undertook three analyses.
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Primary (ITT analysis): participants not completing follow‐up or with inadequate seizure data were assumed to be non‐responders. To test the effect of this assumption, we undertook the following sensitivity analyses.
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ITT analysis: when this was reported by the included studies.
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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.
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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.
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We investigated effects of rufinamide at doses ranging between 200 mg per day and 3200 mg per day. When trials compared more than one dose, we pooled doses and compared rufinamide versus control.
We summarised selected models by expected response rates and expected differences in response rates by dose level compared with placebo.
Subgroup analysis and investigation of heterogeneity
We analysed different adverse effects separately. We aimed to assess clinical heterogeneity by comparing the distribution of important individual participant factors among trials (e.g. age, seizure type, duration of epilepsy, number of AEDs taken at the time of randomisation) and trial factors (e.g. randomisation concealment, blinding, losses to follow‐up).
Sensitivity analysis
We intended to carry out a sensitivity analysis if we found peculiarities between study quality, characteristics of participants, interventions, and outcomes (assessment of risk of bias in included studies). We reported the analysis for all studies and then compared it with an analysis including only studies at low risk of bias.
'Summary of findings' and assessment of the certainty of evidence
We used the GRADE approach to summarise findings, as detailed in the GRADE Handbook (Schünemann 2013). We imported data into GRADEpro GDT software from Review Manager 5 to create a 'Summary of findings' table (GRADEpro GDT; Review Manager 2014). We assessed the certainty of evidence for all the outcomes in summary of findings Table 1.
Results
Description of studies
Results of the search
The search yielded 137 records. After duplicates were removed, 95 records remained, and we screened all for inclusion in the review. We excluded 58 due to irrelevance, leaving 37 full‐text articles to be assessed for eligibility. Following this, we excluded 13 studies (see Figure 1 and Characteristics of excluded studies table for reasons of exclusion). We included a total of 24 studies in the review, six of which were included in meta‐analyses and 18 that were linked to included studies. We identified three conference abstracts and contacted the authors of these studies for more information, provided their contact details were available (see Figure 1 and Characteristics of included studies table).
Study flow diagram.
Included studies
Overall, two RCTs compared rufinamide to placebo in children and adults aged 4 to 63 years (Glauser 2008; Ohtsuka 2014); two RCTs examined rufinamide versus placebo in adolescents and adults aged 12 to 80 years (Biton 2011; Elger 2010); one study examined rufinamide versus placebo in children aged 4 to 16 years (Glauser 2005); and one trial compared rufinamide versus placebo in adults aged over 16 years (Brodie 2009). All trials were sponsored by Eisai Inc., and one of these was conducted by Novartis (Glauser 2008). In all trials, participants were eligible to take part in the double‐blind period of the trial if they had uncontrolled focal seizures with or without secondary generalisation (Biton 2011; Brodie 2009; Elger 2010; Glauser 2005), or if they had established LGS (Glauser 2008; Ohtsuka 2014), and if they were currently taking one to two or up to three AEDs. See Characteristics of included studies table.
One parallel, multi‐centre trial had a pre‐randomisation period of 56 days and a treatment period of 96 days (12‐day titration period followed by 84‐day maintenance phase), randomising 176 participants to rufinamide and 181 to placebo (Biton 2011). Participants were aged 12 to 80 years and had inadequately controlled focal‐onset seizures with or without secondary generalisation.
One multi‐centre, parallel trial enrolled 313 adults aged over 16 years with drug‐resistant focal seizures (Brodie 2009). This trial randomised 156 participants to rufinamide 3200 mg and 157 to placebo; it comprised an eight‐week baseline phase and a 13‐week treatment phase (two‐week titration period followed by 11‐week maintenance phase).
One multi‐centre parallel trial enrolled 647 adolescents and adults aged 15 to 65 years with drug‐resistant focal seizures with or without secondary generalisation. Participants were randomised to one of five treatment arms: rufinamide 200 mg (127 participants), rufinamide 400 mg (125 participants), rufinamide 800 mg (129 participants), rufinamide 1600 mg (133 participants), or placebo (133 participants) (Elger 2010). The baseline phase lasted 12 weeks, and this was followed by a treatment phase of 12 weeks.
One multi‐centre, parallel study included 268 children aged 4 to 16 years with drug‐resistant focal seizures. The study included two treatment arms: rufinamide 45 mg/kg (135 participants) and placebo (133 participants) (Glauser 2005). The baseline period was 56 days, and the treatment period was 91 days (14‐day titration phase followed by 77‐day maintenance phase).
One parallel study randomised 139 participants (but one of these did not receive medication) aged 4 to 30 years with a diagnosis of LGS (Glauser 2008). This study consisted of two treatment arms including rufinamide 45 mg/kg (dose by body weight: 1000 mg, 1800 mg, 2400 mg, and 3200 mg) per day (74 participants) and placebo (64 participants). The baseline phase lasted 28 days, and a double‐blind treatment phase consisted of 84 days.
One multi‐centre, parallel trial in Japan included 59 participants (but one participant in the rufinamide group was excluded from the efficacy analysis due to inappropriate diagnosis) aged 4 to 30 years with LGS (Ohtsuka 2014). The trial had two treatment arms: rufinamide 45 mg/kg (28 participants) (dose by body weight: 1000 mg, 1800 mg, 2400 mg, and 3200 mg) and placebo (30 participants). It consisted of a four‐week baseline phase, followed by a 12‐week treatment phase (two‐week titration followed by 10‐week maintenance phase) and a further phase that involved either a follow‐up visit or entry into an open‐label extension.
Overall, the six RCTs recruited 1759 participants and between them tested rufinamide doses of 200 mg, 400 mg, 800 mg, 1000 mg, 1600 mg, 1800 mg, 2400 mg, and 3200 mg per day. For further information on each trial, see the Characteristics of included studies table.
Excluded studies
We excluded 13 RCTs for the following reasons: five studies had ineligible populations (Biton 2005; Critchley 2005; Madeddu 2013; Palhagen 2001; Xu 2016), four were not RCTs (Benedict 2010; Kim 2012; Kluger 2007; Knupp 2016), two had no rufinamide in add‐on (Lesser 2005; Todorov 2005), and one was described in conference proceedings that provided no data (Racine 2000). In addition, we found one ongoing study (Arzimanoglou 2016).
Risk of bias in included studies
See Figure 2 and Figure 3 for a summary of the 'Risk of bias' in each included study. We allocated each study an overall rating for risk of bias. All studies included in the review were individually rated as either low risk of bias or unclear risk of bias. See below for specific domain ratings.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Allocation
In five trials, we rated the methods by which allocation was concealed at low risk of bias (Biton 2011; Brodie 2009; Elger 2010; Glauser 2008; Ohtsuka 2014). One trial did not provide information and was at unclear risk of bias for this domain (Glauser 2005). For sequence generation, we rated five studies at low risk of bias due to the use of a computer‐generated randomisation schedule or random permuted blocks (Biton 2011; Brodie 2009; Elger 2010; Glauser 2008; Ohtsuka 2014). We rated one study at unclear risk of bias due to lack of details on the methods used (Glauser 2005).
Blinding
We rated blinding of participants and personnel at low risk of bias in four studies (Biton 2011; Brodie 2009; Glauser 2008; Ohtsuka 2014); no details were available for the remaining two studies, which we rated at unclear risk of bias (Elger 2010; Glauser 2005). Blinding of the outcome assessor was difficult to judge due to lack of detail provided for three trials (Elger 2010; Glauser 2005; Glauser 2008); therefore we rated these as unclear in terms of bias. We rated the other three studies at low risk of bias for blinding of the outcome assessor (Biton 2011; Brodie 2009; Ohtsuka 2014). In five trials (Biton 2011; Brodie 2009; Elger 2010; Glauser 2005; Ohtsuka 2014), blinding was achieved by using identical medication within rufinamide and placebo groups.
Incomplete outcome data
We rated five studies at low risk for attrition bias due to the ITT analyses undertaken by study authors (Biton 2011; Brodie 2009; Elger 2010; Glauser 2008; Ohtsuka 2014). One study was at unclear risk of bias (Glauser 2005).
Selective reporting
We requested the protocols for all included studies to compare a priori methods and outcomes against the published report, but these were unavailable. We rated all included studies at low risk of bias for this domain, as there was no suspicion of selective outcome reporting bias: all expected outcomes were reported in each of the publications.
Other potential sources of bias
All studies were sponsored by Eisai Inc., the manufacturer of rufinamide; therefore, we rated all studies as having high risk of funding bias. We found no evidence of further bias in any of the included studies.
Effects of interventions
See: Summary of findings 1 Rufinamide versus placebo for drug‐resistant focal epilepsy
See Summary of main results for the main comparison rufinamide versus placebo for drug‐resistant epilepsy.
The data were not heterogeneous, and we performed no 'best‐case' or 'worst‐case' analyses.
Fifty per cent or greater reduction in seizure frequency
Six RCTs (1759 participants) reported 50% or greater reduction in seizure frequency. A Chi² test for heterogeneity in response to rufinamide showed no significant heterogeneity between trials (Chi² = 5.76, degrees of freedom (df) = 5, P = 0.33). Participants allocated rufinamide were significantly more likely to achieve 50% or greater reduction in seizure frequency (223/1067 participants with rufinamide versus 99/692 participants with placebo). Based on the fixed‐effect model, the overall RR was 1.79 (95% CI 1.44 to 2.22; Analysis 1.1; Figure 4 moderate‐certainty evidence).
Rufinamide versus placebo, outcome: 1.1 50% reduction in seizure frequency.
Seizure freedom
Data from only one study (73 participants) showed seizure freedom. There was seizure freedom in 6/44 participants with rufinamide versus 3/29 participants with placebo (RR 1.32, 95% CI 0.36 to 4.86; Analysis 1.2; moderate‐certainty evidence).
Treatment withdrawal (for any reason or due to adverse effects)
Six RCTs (1759 participants) reported treatment withdrawal. A Chi² test for heterogeneity suggested no significant statistical heterogeneity between trials (Chi² = 5.85, df = 5, P = 0.32). Participants allocated rufinamide were significantly more likely to withdraw from treatment (247/1067 participants with rufinamide versus 78/692 participants with placebo). The overall RR for withdrawal for any reason and due to AED was 1.83 (95% CI 1.45 to 2.31; Analysis 1.3; Figure 5 moderate‐certainty evidence).
Forest plot of comparison: 1 Rufinamide versus placebo, outcome: 1.3 Treatment withdrawal.
Adverse effects
The RRs for more common adverse effects were as follows (no significant statistical heterogeneity between trials) (Analysis 1.4; Figure 6).
Rufinamide versus placebo: 1 Rufinamide versus placebo: 1.4 Adverse effects.
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Dizziness (three RCTs, 1295 participants) in 181/830 participants with rufinamide versus 50/465 participants with placebo (RR 2.52, 99% CI 1.90 to 3.34; moderate‐certainty evidence).
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Fatigue (three RCTs, 1295 participants) in 148/830 participants with rufinamide versus 52/465 participants with placebo (RR 1.46, 99% CI 1.08 to 1.97; moderate‐certainty evidence).
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Headache (three RCTs, 1228 participants) in 214/805 participants with rufinamide versus 83/423 participants with placebo (RR 1.36, 99% CI 1.08 to 1.69; moderate‐certainty evidence).
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Somnolence (six RCTs, 1759 participants) in 144/1067 participants with rufinamide versus 57/692 participants with placebo (RR 1.94, 99% CI 1.44 to 2.61; moderate‐certainty evidence).
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Nausea (three RCTs, 1295 participants) in 106/830 participants with rufinamide versus 38/465 participants with placebo (RR 1.87, 99% CI 1.33 to 2.64; moderate‐certainty evidence).
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Vomiting (four RCTs, 777 participants) in 59/393 participants with rufinamide versus 19/384 participants with placebo (RR 2.95, 99% CI 1.80 to 4.82; low‐certainty evidence).
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Diplopia (three RCTs, 1295 participants) in 82/830 participants with rufinamide versus 11/465 participants with placebo (RR 4.60, 99% CI 2.53 to 8.38; low‐certainty evidence).
Only one RCT reported the remaining adverse effects.
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Psychiatric adverse effects (anxiety, depression, panic attack, irritability, trouble sleeping, mood or behaviour changes).
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Loss of appetite.
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Fever.
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Loss of co‐ordination.
Discussion
Summary of main results
The review included six trials, with 1759 participants included in the analysis. Four trials (1563 participants) included people with uncontrolled focal seizures. Two trials (196 participants) included individuals with established Lennox‐Gastaut syndrome (LGS). Overall, adults were aged from 18 to 80 years, and children from 4 to 16 years. The baseline phase in all trials ranged from 28 to 56 days, and the treatment phase from 84 to 96 days. Five of the six included trials described adequate methods of concealment of randomisation. Three studies reported effective blinding. All analyses were done by intention‐to‐treat (ITT). The manufacturer of rufinamide (Eisai Inc.) sponsored all trials; therefore, we rated them at high risk of bias. Overall, five studies were at low risk of bias and one had unclear risk of bias due to lack of reported information around study design.
This meta‐analysis suggested that rufinamide was more effective than placebo in reducing seizure frequency by at least 50% when used in combination with other antiepileptic drugs (AEDs) (from one to three) in people with drug‐resistant focal epilepsy. We were unable to examine dose effects in the planned subgroup analyses, but results suggest increased efficacy with an increased dose. Only one study recruited children; we have no evidence from this study to indicate whether rufinamide is more or less effective in infants and children than in adults. The use of 50% or greater reduction in seizure frequency as a measure of efficacy could be criticised, given that seizure freedom would be a more relevant clinical measure. However, only one study reported data on seizure freedom; therefore, this finding must be interpreted with caution.
Results for treatment withdrawal (for any reason and due to adverse effects) show that rufinamide was significantly more likely to be withdrawn than placebo. In trials of relatively short duration, such as those reviewed here, this is likely to represent problems with tolerability rather than poor seizure control. Most of the adverse effects were significantly more likely to occur in the rufinamide‐treated group.
This review focused on the use of rufinamide in drug‐resistant focal epilepsy, and the results cannot be generalised to add‐on treatment for generalised epilepsies. Likewise, no inference can be made about the effects of rufinamide when used as monotherapy.
Review findings were not compared with other published evidence because we found no previous reviews and no published information on this topic.
Overall completeness and applicability of evidence
Caution is required when the results of clinical trials are translated into everyday practice because the participants in trials are a highly selected population that may be better motivated and are closely followed and monitored; participants who are unco‐operative and non‐compliant and those who are likely to have adverse effects and fewer benefits are excluded. The results of this review cannot be extrapolated to people with generalised epilepsies, about whom there is a great paucity of data. Tolerabliity of rufinamide during pregnancy and lactation cannot be ascertained from this review. The duration of the studies included in this review was insufficient to reveal changes in cognition, social problems, or long‐term adverse effects. Rare phenomena such as habituation and tolerance may not be evident in short‐term trials. The economic aspects of rufinamide therapy also need to be examined.
Certainty of the evidence
Overall, five studies were at low risk of bias and one at unclear risk of bias due to lack of reported information around study design. Only three studies had effective blinding of rufinamide. We rated all included studies at low risk of bias for incomplete outcome data due to the ITT analyses undertaken by study authors.
We used the GRADE approach to rate the certainty of evidence for each outcome; we have presented this information in summary of findings Table 1. For the main outcome of 50% or greater reduction in seizure frequency, the certainty of evidence was moderate (six studies contributed to the analysis). For the outcome of seizure‐free, the certainty of evidence was moderate (only one study contributed to the analysis). Tolerability outcomes (withdrawal and adverse effects) were at moderate to low certainty due to wide confidence intervals (CIs) and potential risk of bias from some studies contributing to the analysis.
Potential biases in the review process
Although we requested all protocols, the time frames in which most studies were conducted made retrieval of these difficult. This could lead to potential bias through omitted information to which we did not have access.
All studies were sponsored by Eisai Inc., the manufacturer of rufinamide, and this could be a potential source of bias.
Agreements and disagreements with other studies or reviews
We found no reviews or published information on the use of rufinamide as add‐on therapy for drug‐resistant epilepsy.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Rufinamide versus placebo, outcome: 1.1 50% reduction in seizure frequency.
Forest plot of comparison: 1 Rufinamide versus placebo, outcome: 1.3 Treatment withdrawal.
Rufinamide versus placebo: 1 Rufinamide versus placebo: 1.4 Adverse effects.
Comparison 1: Rufinamide versus placebo, Outcome 1: ≥ 50% reduction in seizure frequency
Comparison 1: Rufinamide versus placebo, Outcome 2: Seizure freedom
Comparison 1: Rufinamide versus placebo, Outcome 3: Treatment withdrawal
Comparison 1: Rufinamide versus placebo, Outcome 4: Adverse effects
| Rufinamide versus placebo for drug‐resistant focal epilepsy | ||||||
| Patient or population: people with drug‐resistant focal epilepsy Settings: outpatients Intervention: rufinamide Comparison: placebo | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo | Rufinamide | |||||
| 50% or greater reduction in seizure frequency ‐ ITT analysis | Study population | RR 1.79 (1.44 to 2.22) | 1759 | ⊕⊕⊕⊝ Moderatea | RR > 1 indicates outcome is more likely in rufinamide group | |
| 143 per 1000 | 256 per 1000 | |||||
| Seizure freedom | 103 per 1000 | 136 per 1000 (37 to 500) | RR 1.32 (0.36 to 4.86) | 73 (1 study) | ⊕⊕⊕⊝ Moderatea | RR > 1 indicates outcome is more likely in rufinamide group |
| Treatment withdrawal | Study population | RR 1.83 (1.45 to 2.31) | 1759 | ⊕⊕⊕⊝ Moderatea | RR > 1 indicates outcome is more likely in rufinamide group | |
| 112 per 1000 | 205 per 1000 | |||||
| Adverse effects: dizziness | Study population | RR 2.52 (1.90 to 3.34) | 1295 | ⊕⊕⊕⊝ Moderatea | RR > 1 indicates outcome is more likely in rufinamide group | |
| 108 per 1000 | 272 per 1000 | |||||
| Adverse effects: fatigue | Study population | RR 1.46 (1.08 to 1.97) | 1295 | ⊕⊕⊕⊝ Moderatea | RR > 1 indicates outcome is more likely in rufinamide group | |
| 112 per 1000 | 164 per 1000 | |||||
| Adverse effects: headache | Study population | RR 1.36 (1.08 to 1.69) | 1228 | ⊕⊕⊕⊝ Moderatea | RR > 1 indicates outcome is more likely in rufinamide group | |
| 196 per 1000 | 267 per 1000 | |||||
| Adverse effects: somnolence | Study population | RR 1.94 (1.44 to 2.61) | 1759 | ⊕⊕⊕⊝ Moderatea | RR > 1 indicates outcome is more likely in rufinamide group | |
| 82 per 1000 | 159 per 1000 | |||||
| Adverse effects: nausea | Study population | RR 1.87 (1.33 to 2.64) | 1295 | ⊕⊕⊕⊝ Moderatea | RR > 1 indicates outcome is more likely in rufinamide group | |
| 82 per 1000 | 153 per 1000 | |||||
| Adverse effects: vomiting | Study population | RR 2.95 (1.80 to 4.82) | 777 (4 studies) | ⊕⊕⊝⊝ Lowb | RR > 1 indicates outcome is more likely in rufinamide group | |
| 49 per 1000 | 145 per 1000 | |||||
| Adverse effects: diplopia | Study population | RR 4.60 (2.53 to 8.38) | 1295 (3 studies) | ⊕⊕⊝⊝ Lowb | RR > 1 indicates outcome is more likely in rufinamide group | |
| 24 per 1000 | 110 per 1000 | |||||
| *The basis for the assumed riskc (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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| aDowngraded once due to risk of bias: unclear methodological information provided for some included studies and all included studies pharmaceutical sponsored. bDowngraded once due to imprecision: wide confidence intervals. cAssumed risk is calculated as the event rate in the control group per 1000 people (number of events divided by the number of participants receiving control treatment). | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 ≥ 50% reduction in seizure frequency Show forest plot | 6 | 1759 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.79 [1.44, 2.22] |
| 1.2 Seizure freedom Show forest plot | 1 | 73 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.32 [0.36, 4.86] |
| 1.3 Treatment withdrawal Show forest plot | 6 | 1759 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.83 [1.45, 2.31] |
| 1.4 Adverse effects Show forest plot | 6 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.4.1 Dizziness | 3 | 1295 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.52 [1.90, 3.34] |
| 1.4.2 Fatigue | 3 | 1295 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.46 [1.08, 1.97] |
| 1.4.3 Headache | 3 | 1228 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.36 [1.08, 1.69] |
| 1.4.4 Somnolence | 6 | 1759 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.94 [1.44, 2.61] |
| 1.4.5 Nausea | 3 | 1295 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.87 [1.33, 2.64] |
| 1.4.6 Vomiting | 4 | 777 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.95 [1.80, 4.82] |
| 1.4.7 Diplopia | 3 | 1295 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.60 [2.53, 8.38] |
