Results of the search

The initial search yielded 142 references after duplicates were removed. Thirty‐five references were potentially related after title or abstract screening. We excluded four of these (Li 1996; Sachdeo 1990; Theodore 1990; Wilder 1991) and listed the reasons for exclusion in Characteristics of excluded studies.

See Figure 1 for study flow selection diagram.

Figure 1

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Flow chart of study selection

Included studies

See Characteristics of included studies

Four studies met our inclusion criteria, with a total of 236 participants (Binelli 1999; Bourgeois 1993; Leppik 1991; Theodore 1991). All four studies were randomised, double‐blind, placebo‐controlled trials. Two were parallel‐group trials, the third was a three‐period cross‐over trial, and the fourth was a two‐period cross‐over trial. They utilised varying felbamate doses, varying treatment periods, differing baseline antiepileptic drugs, and differing methodology for assessment of efficacy. Participants randomised in the four studies had differing seizure frequency during baseline.

Binelli 1999 was a parallel group trial including 8‐week baseline period, a period of gradual increase of the drug to the maximum tolerated dose, and 8‐week maintenance phase. The inclusion criteria and exclusion criteria were not mentioned in the trial. Concomitant antiepileptic therapy could be made up of no more than two of the following drugs: carbamazepine, γ‐vinyl‐GABA, lamotrigine, gabapentin, benzodiazepine. But there was no description of which drugs the felbamate group or the placebo group received. During the 8‐week baseline period, more than eight seizures were required.

Bourgeois 1993 was a parallel‐group trial including 4‐week treatment period included 3‐day titration period. The study utilised strict diagnosis, inclusion and exclusion criteria. The diagnosis criteria were video/electroencephalogram (EEG)‐confirmed partial‐onset seizures. The inclusion criteria were seizure frequency not exceeding an average of four complex partial‐onset seizures per day or more than one secondarily generalised seizure per day during the last three days of the surgical evaluation; interictal duration of greater than two hours; minimum average of one seizure per day for the last three days of the surgical evaluation period; previous CT or MRI to confirm the absence of a progressive lesion; age at least 18 years and body weight at least 40 kg; and ECG and chest X‐ray without significant findings during the previous year. Exclusion criteria were status epilepticus in the last three months, significant medical disorders, recent history of psychiatric disorder, poor compliance with prior antiepileptic drug therapy, serious antiepileptic drug complication in the past, change in benzodiazepine dosing during the surgical evaluation phase, drug or alcohol abuse and seizure aetiology considered treatable or progressive. At the end of the four‐week outpatient baseline period, the participants underwent a routine evaluation for epilepsy surgery. The treatment period immediately followed the surgical evaluation period and consisted of eight hospital days and 21 outpatient days. The mean number of other antiepileptic drugs was 5.7 in the felbamate group and 5.5 in the placebo group. During the evaluation period, standard antiepileptic drugs were reduced or discontinued. Throughout the hospitalisation period, the participants continued the same antiepileptic drug regimen present on the last day of the surgical evaluation period. During the outpatient days, participants were on less than the full dosage of standard antiepileptic drug(s). One of the antiepileptic drugs or standard antiepileptic drug (if participants received one antiepileptic drug during their presurgical evaluation period) was returned to their presurgical evaluation dosage. All participants in the felbamate group were treated at the maximum dosage. There was no description of which baseline antiepileptic drugs were being taken, or which participants on which antiepileptic drugs were the best responders to felbamate.

Leppik 1991 was a two‐period cross‐over study which took place at the Epilepsy Research Center, University of Minnesota (UMN) and the University of Virginia Health Sciences Center (UVA). The trial was supported by a research grant from Carter‐Wallace, Inc., but the drug patent is now owned by Meda Pharmaceuticals. The trial included 8 to 10‐day titration period and 10‐week treatment period with 3‐week wash‐out period. Diagnosis of epilepsy was based on observation of at least one ictal event by trained personnel and supported by EEG. The inclusion criteria (requiring four or more partial seizures per month with no seizure‐free interval of more than 20 days despite stable plasma concentrations of both phenytoin and carbamazepine) and exclusion criteria (people with medical conditions other than epilepsy, non compliant or unable to accurately report seizures) were well described. The other antiepileptic drugs were phenytoin and carbamazepine. The final eight weeks of seizure data from the first and second treatment periods were used in the analyses of seizure frequency reduction (SFR), seizure frequency percentage reduction (SFPR), and truncated seizure frequency percentage reduction (TSFPR).

Theodore 1991 was a three‐period cross‐over study. There were four treatment sequences: felbamate‐placebo‐felbamate; felbamate‐placebo‐placebo; placebo‐felbamate‐placebo; placebo‐felbamate‐felbamate. The treatments were administered over the course of alternating titration and analysis periods, each lasting two weeks. The diagnosis was based on clinical (partial seizures with or without secondary generalisation), EEG (onset in one cortical region), and imaging (either focal imaging abnormality or normal scan) criteria. People who had at least six seizures and one or more seizures in every week were included. The exclusion criteria, acquired by contacting the first study author, included people with treatable causes of seizures, metastatic tumours except skin cancer, progressive neurological disorders, other serious medical or psychiatric disorders, gastrointestinal abnormalities, history of generalised tonic‐clonic status epilepticus within baseline and poor compliance, abusers of other drugs, people having received an investigational antiepileptic drug within three months prior to baseline or chronic therapy with non antiepileptic drugs, abnormal laboratory values. There was no description of mean baseline seizure frequencies. All but two participants received felbamate 3000 mg a day. The two exceptions received 2400 mg a day. One of the two was the participant who left the study owing to seizure exacerbation. Nine of the 30 participants randomised had the other antiepileptic drug carbamazepine decreased or increased. The mean seizure frequencies during baseline were not reported and were unavailable through contacting the first author of the study. During the first titration period, the participant received gradually increasing doses of felbamate or placebo. The target felbamate dosage was 3000 mg a day. During the analysis period, the participant was observed with a steady dose. The other antiepileptic drug was carbamazepine.

Reduction in seizure frequency of 50% or more

Binelli 1999 reported that in the group treated with felbamate, 38% of participants had a greater than 50% reduction in seizures and of these 11% were completely controlled.

Absolute or percentage reduction in seizure frequency

Binelli 1999 reported that, in the felbamate group, there was a reduction in seizures of 35.8% in the maintenance period, and in the placebo group there was an increase in seizures of 3.3%.

Leppik 1991 reported that the mean seizure frequency was 34.4 seizures per eight weeks during felbamate treatment and 40.2 seizures per eight weeks during placebo treatment. Felbamate was statistically significantly better than placebo for absolute reduction in seizure frequency (felbamate: 4.95 ± 24.55, placebo: ‐0.36 ± 27.19, P = 0.046), and for percentage reduction in seizure frequency (felbamate: 4.24 ± 55.61, placebo: ‐19.14 ± 79.70, P = 0.018). The analyses described in the study were based on the 56 participants who completed the study. The other three participants who dropped out of the study were included by considering their felbamate period seizure frequencies as eight‐week frequencies and placebo period seizure frequency as zero. The resulting P values were identical. An additional analysis was done using the data from the last 10 weeks of each treatment period, with similar results.

Neither Bourgeois 1993 nor Theodore 1991 presented these results.

Treatment withdrawal

Binelli 1999 reported that four participants receiving felbamate withdrew from the study. In two cases treatment discontinuation was caused by adverse events (diplopia in one case, asthenia and collapse in the other). One participant died from the consequences of a seizure, the fourth withdrew consent to continue the trial. Eight participants treated with placebo did not complete the study.

Bourgeois 1993 reported that two participants in the felbamate group dropped out due to adverse clinical events. One participant in the placebo group withdrew consent.

Leppik 1991 reported that three participants discontinued the trial during the felbamate period because of diplopia, nausea and vomiting, and fever with malaise, respectively.

Theodore 1991 reported that two participants left the study during the felbamate analysis period, one owing to seizure exacerbation and the other owing to hyponatraemia, which might be related to carbamazepine therapy.

Adverse effects

Binelli 1999 reported 26 adverse events in the group of participants treated with felbamate. The adverse events were central nervous system events such as headache, dizziness, ataxia, diplopia, confusion, depression, sedation, and paraesthesia, and gastrointestinal tract events such as stomach pain, nausea, vomiting and loss of appetite. Only 4.9% (2/41) discontinued the treatment for the occurrence of side effects. In the group of participants treated with felbamate significant weight loss occurred (mean reduction from 72.9 kg to 71.4 kg) and in 19.5% (8/41), the decrease in weight was of 5 kg to 7 kg, justifiable in two cases because of gastrointestinal side effects. 2.4% (1/41) suffered a modest and transient reduction in the value of leukocytes. There was no description of adverse effects in the group of participants treated with placebo.

Bourgeois 1993 reported that the most commonly occurring adverse experience in both treatment groups was headache (40% felbamate and 12% placebo). Other commonly occurring adverse experiences in the felbamate group were insomnia (37%), nausea (37%), dizziness (23%), fatigue (20%), constipation (20%), anorexia (20%), dyspepsia (17%), anxiety (13%), and vomiting (13%). The most common adverse experiences in the placebo group were dizziness (15%), dyspepsia (9%), somnolence (9%), insomnia (6%), fatigue (6%), anxiety (6%), nausea (3%), constipation (3%), and vomiting (3%). Only one participant in the felbamate group had a severe adverse experience: stupor and confusion. Two participants in the felbamate group failed to complete the trial due to adverse experiences.

Leppik 1991 reported that the most frequent adverse effects were in the central nervous system and gastrointestinal tract, of which headache (36% felbamate and 3% placebo), dizziness (36% felbamate and 5% placebo), diplopia (36% felbamate and 2% placebo), blurred vision (22% felbamate and 5% placebo), ataxia (32% felbamate and 2% placebo), nausea (39% felbamate and 7% placebo), and vomiting (25% felbamate and 3% placebo) were noted.

Theodore 1991 reported that 87% (26/30) suffered headache, 57% (17/30) suffered nausea, 50% (15/30) suffered dizziness, 33% (10/30) suffered diplopia, 33% (10/30) suffered vomiting, 30% (9/30) suffered blurred vision, 17% (5/30) suffered fatigue, and 10% (3/30) suffered poor balance. Nausea, double vision and blurred vision were significantly associated with periods during which felbamate was administered. Felbamate led to a decrease in both blood urea nitrogen and white blood count.

Quality of life

Bourgeois 1993 was the only study to describe quality of life. During the four‐week outpatient baseline period each participant's vital signs were obtained and the Short Neuropsychological Test was administered. For those who had the Short Neuropsychological Test and completed the treatment period, motor skills and memory skills remained the same or were improved. However, no detailed data were provided.

Theodore 1991 failed to detect a significant effect of felbamate on seizure frequency at the 0.05 level. In Bourgeois 1993, the primary efficacy analysis was the mean rank according to seizure frequency. The difference between felbamate and placebo was statistically significant in favour of felbamate. The secondary analysis was the time to the fourth seizure, it was indicated in the fourth seizure survival curves for the two treatments that participants in the placebo group experienced a fourth seizure more frequently and earlier than participants in the felbamate group.