4
1114 Gabapentin in partial epilepsy UK GABAPENTIN STUDY GROUP* Gabapentin is an analogue of &ggr; aminobutyric acid (GABA) which has anticonvulsant properties in animals. In a multicentre, double-blind, placebo- controlled, parallel-group study of 1200 mg/day gabapentin as additional therapy in 127 patients with drug-resistant partial epilepsy, 25% of patients who received gabapentin had the number of partial seizures at least halved, compared with 9·8% of patients given placebo. The median reduction in partial seizure frequency during 12 weeks’ treatment was 29·2% with gabapentin compared with 12·5% with placebo. The mean adjusted response ratio for gabapentin (-0·192) was significantly better than the ratio of -0·060 for placebo by analysis of variance. 62% of patients who received gabapentin reported mostly mild or moderate adverse effects compared with 41% on placebo; no interactions were observed between gabapentin and other standard anticonvulsants. Gabapentin is an effective additional treatment for patients with partial epilepsy refractory to standard therapy, is fairly well tolerated, and appears to have a favourable efficacy-to-toxicity ratio. Lancet 1990; 335: 1114-17. Introduction The choice of drugs for treatment of partial epilepsy is limited, yet such patients are at greatest risk of chronic disabling epilepsy.12 There is a clear need for novel PATIENT CHARACTERISTICS AND REASONS FOR EXCLUSION *Mean (range). tMedian (range) anticonvulsants, more effective or associated with less risk of adverse events than those routinely used but since the introduction of sodium valproate in 1974 no major anticonvulsants were introduced into clinical practice in the UK until 1989. Gabapentin (1-[aminomethyl] cyclohexaneacetic acid) is an analogue ofy aminobutyric acid (GABA) that is absorbed rapidly, penetrates the blood-brain barrier, is neither metabolised nor protein-bound, and has been shown to be effective against various types of seizure in animals- especially those associated with interference in GABAergic transmission or provoked by excitatory aminoacids- although the mechanism of action of gabapentin remains unclear.4 An open-label, dose-ranging pilot study showed that daily doses of up to 1800 mg gabapentin at least halved seizure frequency in 15 of 52 evaluable patients, and both partial and generalised seizures appeared to respond.s A dose-related antiepileptic effect was observed during a double-blind, crossover study that compared daily doses of 300 mg, 600 mg, and 900 mg gabapentin for 2 months each as additional therapy to standard antiepileptic drugs in 25 patients with severe partial or generalised epilepsy. We set out to investigate further the efficacy of gabapentin in a multicentre, double-blind, placebo-controlled, parallel- group study. Patients and methods Patients with partial epilepsy resistant to treatment with one or two standard anticonvulsants were followed for 3 months to establish a baseline seizure frequency (recorded in a seizure diary) and drug plasma concentrations were measured at - 12, - 8, and - 4 weeks. Patients eligible for the study were those with at least 1 partial seizure per week, with or without secondary generalisation, despite adequate medication with one or two standard anticonvulsants. 127 patients entered the trial: 61 were randomised to receive gabapentin, 66 to placebo (see table). 19 had simple partial seizures, 88 had complex partial seizures, and 76 had secondarily generalised tonic-clonic seizures at screening; some patients had more than one type of seizure. There were no significant differences between the baseline variables for the two treatment groups by Wilcoxon or Fisher’s exact tests (see table). Patients were randomised to receive apparently identical capsules that contained either placebo or gabapentin. For the first 2 weeks patients received either 1 capsule of gabapentin (200 mg), or a placebo capsule, 3 times daily. For the next 12 weeks this intake was doubled. Seizure frequency, adverse events, routine biochemical *Participants and centres listed at end of article Correspondence to Dr D Chadwick, University Department of Neuroscience, Walton Hospital Liverpool L9 1AE, UK.

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Page 1: Gabapentin in partial epilepsy

1114

Gabapentin in partial epilepsy

UK GABAPENTIN STUDY GROUP*

Gabapentin is an analogue of &ggr; aminobutyric acid(GABA) which has anticonvulsant properties inanimals. In a multicentre, double-blind, placebo-controlled, parallel-group study of 1200 mg/daygabapentin as additional therapy in 127 patientswith drug-resistant partial epilepsy, 25% ofpatients who received gabapentin had the numberof partial seizures at least halved, compared with9·8% of patients given placebo. The medianreduction in partial seizure frequency during 12weeks’ treatment was 29·2% with gabapentincompared with 12·5% with placebo. The meanadjusted response ratio for gabapentin (-0·192)was significantly better than the ratio of -0·060for placebo by analysis of variance. 62% of patientswho received gabapentin reported mostly mild ormoderate adverse effects compared with 41% onplacebo; no interactions were observed betweengabapentin and other standard anticonvulsants.Gabapentin is an effective additional treatment forpatients with partial epilepsy refractory to

standard therapy, is fairly well tolerated, andappears to have a favourable efficacy-to-toxicityratio.

Lancet 1990; 335: 1114-17.

Introduction

The choice of drugs for treatment of partial epilepsy islimited, yet such patients are at greatest risk of chronicdisabling epilepsy.12 There is a clear need for novel

PATIENT CHARACTERISTICS AND REASONS FOR EXCLUSION

*Mean (range).tMedian (range)

anticonvulsants, more effective or associated with less risk ofadverse events than those routinely used but since theintroduction of sodium valproate in 1974 no majoranticonvulsants were introduced into clinical practice in theUK until 1989.

Gabapentin (1-[aminomethyl] cyclohexaneacetic acid) isan analogue ofy aminobutyric acid (GABA) that is absorbedrapidly, penetrates the blood-brain barrier, is neithermetabolised nor protein-bound, and has been shown to beeffective against various types of seizure in animals-

especially those associated with interference in GABAergictransmission or provoked by excitatory aminoacids-

although the mechanism of action of gabapentin remainsunclear.4 An open-label, dose-ranging pilot study showedthat daily doses of up to 1800 mg gabapentin at least halvedseizure frequency in 15 of 52 evaluable patients, and bothpartial and generalised seizures appeared to respond.s Adose-related antiepileptic effect was observed during adouble-blind, crossover study that compared daily doses of300 mg, 600 mg, and 900 mg gabapentin for 2 months eachas additional therapy to standard antiepileptic drugs in 25patients with severe partial or generalised epilepsy. We setout to investigate further the efficacy of gabapentin in amulticentre, double-blind, placebo-controlled, parallel-group study.

Patients and methods

Patients with partial epilepsy resistant to treatment with one or twostandard anticonvulsants were followed for 3 months to establish abaseline seizure frequency (recorded in a seizure diary) and drugplasma concentrations were measured at - 12, - 8, and - 4 weeks.Patients eligible for the study were those with at least 1 partialseizure per week, with or without secondary generalisation, despiteadequate medication with one or two standard anticonvulsants. 127patients entered the trial: 61 were randomised to receive gabapentin,66 to placebo (see table). 19 had simple partial seizures, 88 hadcomplex partial seizures, and 76 had secondarily generalisedtonic-clonic seizures at screening; some patients had more than onetype of seizure. There were no significant differences between thebaseline variables for the two treatment groups by Wilcoxon orFisher’s exact tests (see table).

Patients were randomised to receive apparently identical capsulesthat contained either placebo or gabapentin. For the first 2 weekspatients received either 1 capsule of gabapentin (200 mg), or aplacebo capsule, 3 times daily. For the next 12 weeks this intake wasdoubled. Seizure frequency, adverse events, routine biochemical

*Participants and centres listed at end of article Correspondence to Dr DChadwick, University Department of Neuroscience, Walton HospitalLiverpool L9 1AE, UK.

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and haematological investigations, and plasma concentrations ofgabapentin and other anticonvulsants were monitored at 0, 2, 6,10,and 14 weeks. Doses of the other anticonvulsants remained constant

throughout the study; gabapentin concentrations were assayed byhigh-pressure liquid chromatography after completion of the trial.’Patients underwent a full clinical and neurological examination andelectroencephalography at weeks 0 and 14.The primary measures for evaluation of efficacy were responder

rate and response ratio. Responder rate was defined as the

percentage of patients in whom the number of partial seizures fell byat least 50% from that in the baseline assessment period. Responseratio (RR) was defined as

- (T - B)(T+B)

where B denotes the number of seizures per 28 days during thebaseline period and T denotes the number of seizures per 28 daysduring the 12 weeks of treatment. Use of the response ratio gives aless skewed distribution than calculation of percentage change, andcan allow for occasions where a seizure type is observed duringtreatment but not during preliminary assessment. A sample size of120 patients was calculated to have an 80% likelihood to observe asignificant difference between treatment groups, on assumption of aresponder rate of 15% with placebo and 45% with gabapentin, atype I error of 5%, and a drop-out rate of 20%. Distribution ofbaseline variables between treatment groups were compared bymeans of the Wilcoxon test or Fisher’s exact test. Fisher’s exact test(2-sided) was used to compare responder rates between treatmentgroups. A supplementary analysis used logistic regression withfactors for treatment and centre to explore if there was a centre effecton response or an interaction between treatment and centre. The

response ratio was analysed by an analysis-of-variance model thattook account of treatment, centre, and treatment-by-centreinteractions.

Results

Data from 14 patients were not evaluable for efficacyanalysis (see table); exclusion criteria were determinedbefore data analysis. Evaluation of efficacy showed that thefrequency of partial seizures was at least halved in 25-0% ofpatients treated with gabapentin compared with 9-8%treated with placebo (p=0-043, Fisher’s exact test). (Onintention-to-treat analysis, including all patients whoreceived at least one dose of study drug, 23 % of patients who

Fig 1-Distribution of patients by percentage change in partialseizure frequency compared with baseline for gabapentin(left) and placebo (right).Positive deflection represents decreased seizure frequency.A=over -75%; B--50 to -75%; C=-25 to -50%; D=0 to

- 24%; E=+1 to 25%; F=+26 to 50%; G=+51 to 74%; andH = over + 75%.

Fig 2-Median change in seizure frequency with time.

- 0-= gabapentin;-W-==p!acebo.

received gabapentin were responders by at least 50%reduction in fit frequency compared with 9% of patientswho received placebo [p = 0-049, Fisher’s exact test].) Fig 1shows the distribution of responders in 25-percentile groupsby change in partial seizure frequency. Logistic regressionanalysis showed treatment to be a significant variable(p = 0-041) whereas centre was not (p = 0653), but the fit ofthe model indicated that differences between placebo andgabapentin responder rates were not constant betweencentres. The mean adjusted response ratio for gabapentin( - 0 192) was significantly better than for placebo ( - 0-060;p=0 0056). Analysis of variance showed no overall centreeffect, but treatment-centre interaction did occur because 1centre found placebo to be superior to gabapentin.However, there was no indication from residual variablesthat the analysis-of-variance model was inappropriate.The median percentage change in partial seizure

frequency from baseline was greater with gabapentin(-29-2%) than with placebo (-12-5%). In both

gabapentin and placebo groups the median reduction inseizure frequency was greater for patients in whom partialseizures did not show secondary generalisation. Fig 2 showsthe time-course of the effect of treatment; the effect of

gabapentin was apparent by the end of the 2-week low-dosephase during which patients received 600 mg gabapentindaily, and persisted throughout the next 3 months oftreatment. No significant changes in plasma concentrationsof other anticonvulsants were observed during the study.Mean and median plasma gabapentin concentrations werehigher in responders than in non-responders. Whenresponse ratio was plotted against gabapentin plasmaconcentrations the negative slope obtained was significantlydifferent from zero, and indicated increased efficacy withincreased gabapentin plasma concentrations.

38 of 61 patients (62%) who received gabapentin and 27of 66 (41 %) who received placebo reported an adverse eventduring the study. The most frequent reports in the

gabapentin group were somnolence (14-8%), fatigue(13-1 %), dizziness (6-6%), and increased weight (4-9%). Inthe placebo group headache (9-1 %) was the most commonlyreported symptom, followed by dizziness (4-5%) andsomnolence (45%). Most such symptoms were rated asmild to moderate, were not disabling, and in the gabapentingroup resolved during the study.

11 of 127 patients withdrew from the study because ofadverse events. 7 patients who received gabapentinwithdrew because of: tiredness and poor memory; white cellcount below 3 x 109/1 in a patient also treated withcarbamazepine; loss of speech and weakness of one side after

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fits (not previously noted), vomiting and drowsiness;"jitteriness"; increased seizure frequency; and a mild

maculopapular rash. 4 patients withdrew during treatmentwith placebo because of: altered mental state; confusion, oddbehaviour, and paranoia; generalised seizures; and a generalfeeling of ill health. Haematological and biochemical

parameters monitored during treatment showed no

significant trends for any parameter, compared with

baseline, for either gabapentin or placebo.

Discussion

In this study addition of 1200 mg gabapentin daily toprevious anticonvulsant treatment had an additional

antiepileptic effect in patients with severe drug-resistantpartial epilepsy; these results are consistent with previousreports. In an open-label, dose-ranging, add-on study Baueret al5 showed that gabapentin treatment resulted in a medianreduction in partial seizures of 32% (29 patients) and amedian reduction in tonic-clonic seizures of 36% (20patients). Crawford and co-workers6 compared 3 doses ofgabapentin in a dose-ranging, double-blind study and foundthat the weekly frequency of partial seizures was reducedfrom 2-5 to 1.2 with 900 mg daily over 2 months (14patients), and median tonic-clonic seizure frequency wasreduced from 1 to 03 per week (11 patients). All threestudies show gabapentin reduces partial seizures andtonic-clonic seizures, but in our study the effects on partialseizures that did not become secondarily generalised weregreater than on partial seizures with secondarygeneralisation. The earlier studies included patients withprimary generalised tonic-clonic seizures and this mayaccount for the difference: Bauer et al’s results indicate that

gabapentin may have a significant effect on primarygeneralised seizures since there was a 49 % median reductionin absence seizures after administration of gabapentin in 10patients.The efficacy of gabapentin as additional therapy was not

attributable to any significant changes in serum

concentrations of other anticonvulsant drugs. Suchinteractions would be unexpected as, in man, gabapentindoes not bind to plasma proteins or serum albumin, and nometabolites have been observed in plasma or urine.8

Furthermore, gabapentin does not affect antipyrinemetabolism and does not appear to be an enzyme inducer,9and Anhut et al10 found no evidence that gabapentininterferes with phenytoin pharmacokinetics. The simplepharmacokinetics of gabapentin may make it a particularlysuitable additional drug in patients who require more thanone anticonvulsant. The antiepileptic effect of gabapentindoes not seem to be accompanied by significant toxicity.The most common side-effects with gabapentin have beensomnolence and fatigue. The low incidence of suchside-effects in patients already treated with one or twostandard antiepileptic drugs indicates a favourable

therapeutic to adverse effects ratio for gabapentin.This study is unusual in that a parallel-group design was

used to assess the efficacy of a novel antiepileptic drug asadditional treatment. Usually double-blind, crossover

designs have been used to assess potential antiepilepticeffects, but for treatment of epilepsy such crossover trialshave disadvantages-particularly the risk of period effectsand carry-over effects which may interfere with the

interpretation of results. Crossover studies are often claimedto be more efficient in the examination of patients’ responses

to drugs because they allow within-patient comparison but,for anticonvulsants, to satisfactorily exclude period andcarry-over effects would require studies of a similar sizewhether crossover or parallel-group design is used."

Furthermore, withdrawals during crossover studies areusually lost for evaluation, although the reasons for drop-outmay be clinically important. For evaluation of antiepilepticefficacy, we believe parallel-group studies to be preferable tocrossover studies, and hope that such trials will be morewidely used.How does the observed reduction in seizures on addition

of gabapentin in our patients compare with that of additionof standard antiepileptic drugs? Although direct comparisonagainst other anticonvulsants is needed to accurately assessrelative efficacy, results against placebo indicate that theeffect of gabapentin may be less striking than that observedfor some other potential antiepileptic drugs. In double-blind, crossover studies that compared vigabatrin to placeboas an additional agent,12 about 45 % of patients had at least ahalved seizure frequency. However, antiepileptic activity ofa drug as an additional treatment may not accurately reflectantiepileptic efficacy as a single agent. Schmidt13 showedthat only 5 of 30 patients with complex partial epilepsy hadseizures reduced by more than 50% after addition of

phenytoin, carbamazepine, or phenobarbitone to a singleantiepileptic drug given in adequate dosage but which failedto achieve satisfactory seizure control. Temkin and

Wilensky14 found that the addition of or withdrawal ofcarbamazepine, phenytoin, or sodium valproate from aprevious drug regimen caused a halved or doubled seizurefrequency in approximately 27%, 11%, and 30% of

patients, respectively, and Crawford and Chadwick15 foundseizure frequency was halved in 37% of patients on additionof sodium valproate to one, two, or three other antiepilepticdrugs in patients resistant to treatment.Our observation that the seizure frequency in 25% of

severely refractory patients was at least halved afterintroduction of gabapentin indicates that gabapentin mayhave a similar efficacy to conventional antiepileptic drugsand may be better tolerated.

The UK Gabapentin Study Group comprised: J. Andrews, D. Chadwick(Walton Hospital, Liverpool); D. Bates, N. Cartlidge (Royal VictonaInfirmary, Newcastle upon Tyne); G. Boddie (North Staffordshire RoyalInfirmary, Stoke-on-Trent); P. Bolel, P. Cleland (Sunderland District

General Hospital, Sunderland); P. Crawford, D. Shepherd, G. Yuill (NorthManchester Hospital, Crumpsall); K. Cumming, A. Kennedy-Young(Withington Hospital, Manchester); M. Foot (Warner-Lambert ClinicalResearch [Northern Europe], Eastleigh); R. Knight, G. Venables (NorthernGeneral Hospital, Edinburgh); A. McKenna, P. Newman, M. Saunders(Middlesbrough General Hospital, Middlesbrough); V. Patterson (RoyalVictoria Infirmary, Belfast); W. Sauermann (Goedecke, D-7800 Freiburg,West Germany); and B. Schmidt (Facharzt fur Neurologie und Psychiatrie,Wittnau, West Germany).

REFERENCES

1. Rodin E. The prognosis of patient with epilepsy. Springfield, Illinois: CCThomas, 1968.

2. Reynolds EH. Early treatment and prognosis of epilepsy. Epilepsia 1987,28: 97-106.

3. Porter RJ, Meldrum BS. New anticonvulsant drugs. London: JohnLibby, 1988.

4. Schmidt B. Gabapentin. In: Levy R, ed. Antiepileptic drugs, vol 3. NewYork: Raven Press, 1989: 925-35.

5. Bauer G, et al. Gabapentin in the treatment of drug-resistant epilepticpatients. 17th Epilepsy International Congress, Jerusalem, 1987219-21.

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6. Crawford P, Ghadiali E, Lane R, Blumhardt L, Chadwick D.

Gabapentin as an antiepileptic drug in man. J Neural NeurosurgPsychiatry 1987; 50: 682-86.

7. Hengy H, Kolle E-U. Determination of gabapentin in plasma and urineby high performance liquid chromatography and precolumn labellingfor ultraviolet detection. J Chromatogr 1984; 341: 473-78.

8. Vollmer K-O, Von Hodenberg A, Kolle E-U. Pharmamkinetics andmetabolism of gabapentin in rat, dog and man. Arzneimittellforschung1986; 36: 830-39.

9. Allen E, Jawad B, Wroe S, Richens A. Does the anticonvulsantgabapentin lack enzyme-inducing properties? 17th EpilepsyInternational Congress, Jerusalem, 1987 (abstr).

10. Anhut H, Leppik I, Schmidt B, Thomann P. Drug interaction study of

the new anticonvulsant gabapentin with phenytoin in epileptic patients.Naunyn Schmiedebergs Arch Pharmacol 1988; 337 (suppl): 507 (abstr).

11. Hills M, Armitage P. The two-period cross-over clinical trial. Br J ClinPharmacol 1979; 8: 7-20.

12. Mumford JP. A profile of vigabatrin. Br J Clin Pract 1988; 42 (suppl 61):7-9.

13. Schmidt D. Two antiepileptic drugs for intractable epilepsy withcomplex-partial seizures. J Neurol Neurosurg Psychiatry 1982; 45:1119-24.

14. Temkin NR, Wilensky AJ. New AEDs: are the compounds or the studiesineffective?. Epilepsia 1986; 27: 644-45.

15. Crawford P, Chadwick D. A comparative study of progabide, valproateand placebo as add-on therapy in patients with refractory epilepsy.J Neurol Neurosurg Psychiatry 1986; 49: 1251-57.

Hepatitis C antibody and chronic liver disease inhaemophilia

ADDRESSES Departments of Haematology (M. Makris, MRCP,Prof F E. Preston, MD), Medicine (D. R. Triger, FRCP), and Pathology(J. C. E. Underwood, MD), Royal Hallamshire Hospital, Sheffield,UK; and Chiron Corporation, Emeryville, California, USA(Q. L. Choo, PhD, G Kuo, PhD, M. Houghton, PhD) Correspondence toProf F E. Preston, Department of Haematology, Royal HallamshireHospital, Sheffield S10 2JF, UK.

A radioimmunoassay was used to detectantibodies to hepatitis C virus (anti-HCV) in 154patients with haemophilia. Prevalence of anti-HCV was associated with exposure to clottingfactor concentrates. 76 of 129 (59%) who hadreceived factor VIII or IX had anti-HCV: 42 of 55(76%) who required over 10 000 units ofconcentrate annually had anti-HCV, comparedwith 34 of 74 (46%) who required less, and 0 of 25patients who had never received concentrates.Anti-HCV were significantly more common in

patients seropositive for antibodies against humanimmunodeficiency virus (anti-HIV) or withmarkers of previous hepatitis B infection than inthose without anti-HIV or hepatitis B markers(88% vs 39% and 75% vs 46%, respectively). 5 of 23(22%) haemophiliacs treated only with heatedconcentrates had anti-HCV compared with 71 of106 (67%) patients who received unmodifiedproducts. 35 patients with chronic liver diseaseunderwent liver biopsy: histological examinationshowed features associated with post-transfusionhepatitis in 24, all of whom were anti-HCV-positive; of the other 11 patients with no

histological features of non-A, non-B hepatitis, 5were anti-HCV-positive. HCV appears to be themajor predisposing factor for most non-A, non-Bhepatitis and chronic liver disease in haemophilia.

Lancet 1990; 335: 1117-19.

Introduction

Before heat treatment of clotting factor concentrates, almostall patients who were treated with factor VIII for the firsttime acquired non-A, non-B (NANB) hepatitis,l of whom

70 % would show chronic liver enzyme abnormalities2 and atleast 20% would develop cirrhosis.3 End-stage liver failureis now recognised to be a major cause of morbidity andmortality in haemophilia 4 Although it has been widelyassumed that such liver disease is caused by a virus orviruses, in the absence of a serological marker it has beenimpossible to identify the agent or agents responsible. Wereport serological evaluation of a novel marker for hepatitisC5,6 in relation to clinical, biochemical, and histologicalchanges in a population of haemophilia patients.

Patients and methods

Sera from 154 adults (aged 17-91 years) with coagulation disorderswho attended the Sheffield Haemophilia Centre were tested for thepresence of antibody to hepatitis C virus (anti-HCV). All 46patients with severe haemophilia (less than 2 IU/dl factor VIII orIX plasma concentrations) were included, as were a randomlyselected group of patients with less severe haemophilia, 18 withvon Willebrand’s disease, and 9 with other familial coagulationdisorders. 129 (84%) of the patients had received either factor VIIIor IX concentrate. All samples were kept frozen at - 20°C untiltested. The presence of chronic liver disease was defined

biochemically as a raised serum alanine aminotransferase (ALT;above 45 U/1) for more than 6 months. ALT concentrations wereconsidered persistently raised when all 3 most recent measurementswere high, intermittently raised when 1 or 2 of the last 3 values were