Losigamone add-on therapy in partialepilepsy: a placebo-controlled study

Bauer J, Dienel A, Elger CE, Losigamone Study Group. Losigamoneadd-on therapy in partial epilepsy: a placebo-controlled study.Acta Neurol Scand 2001: 103: 226–230. # Munksgaard 2001.

Objectives – To evaluate the efficacy and tolerability of losigamone(LSG). Patients and methods – Double-blind, placebo-controlled add-onstudy with 3r500 mg LSG/die for the treatment of chronic partialseizures in 203 patients (99 treated with LSG, 104 on placebo). Results –The median percent change of seizures was 14.9% (LSG) versus 6.7%(placebo) (P=0.004). Seizure frequency was decreased by more than50% in 22.3% (LSG) and 14.6% (placebo) of patients (P=0.13). Meanpercent change of seizures was best in patients with only one additionalanticonvulsant drug (LSG versus placebo, P=0.004). Adverse events(usually CNS-related side effects of mild to moderate intensity) werereported in 59.6% (LSG) and 37.5% (placebo) of patients. Conclusions –LSG proved to be an effective and well tolerated anticonvulsant drug forthe treatment of chronic partial seizures.

J. Bauer1, A. Dienel2, C. E. Elger1,and the Losigamone Study Group*1Department of Epileptology, University of Bonn,

Germany; 2Dr Willmar Schwabe GmbH, Karlsruhe,

Germany

Key words: losigamone; antiepileptic drugs; epilepsy;

drug therapy

J. Bauer, Universitatsklinik fur Epileptologie, Sigmund

Freudstr. 25, 53105 Bonn, Germany

Fax: 0049 228 287 6294

Accepted for publication January 15, 2001

We report on the results of an add-on double-blind,placebo-controlled treatment-study with the newantiepileptic drug losigamone (LSG) in patientswith chronic partial seizures. LSG belongs to thegroup of beta-methoxy-butenolides and is a struc-turally novel compound (1). It was chosen forfurther development, based on results of pharma-cological screening of tetronic acid derivates offive- and six-membered lactones, which occurnaturally in various plants of the Piper species (2).In rodents, LSG is effective in inhibiting the tonichindleg extension produced by electroshock and byvarious chemical convulsants. It is also effective inantagonizing clonic seizures induced by pentylene-tetrazole, bicuculline and picrotoxin. An overallassessment of electrophysiological effects of LSGsuggests that the drug may decrease neuronal

excitability by a non-synaptic or direct membraneaction, possibly involving inhibition of sodium, orcalcium currents or activation of potassium cur-rents. LSG proved to be quite effective in stimula-ting chloride uptake in cultured spinal cordneurons. While some studies point to a primarilypre-synaptic mode of action, the contribution ofpost-synaptic effects cannot be excluded. LSG doesnot bind to c-aminobutyric acid (GABA), picro-toxin or benzodiazepine receptors, but it has beenfound to enhance chloride uptake in mouse spinalcord neurons in the absence of GABA, and topotentiate the effects of GABA in this model. Theobservation that both these actions are antagonizedby tetrodotoxin and bicuculline suggests that atleast part of the anticonvulsant activity may bemediated by stimulation of GABAA receptor-regulated chloride channels (1–8).

LSG proved to be an effective and well-toleratedanticonvulsant agent when orally administered toanimals, primarily preventing seizure spread and, toa lesser degree, raising seizure threshold (3–6). Nosignificant animal cerebral, cardiovascular, orperipheral adverse effects have been observed, andno carcinogenicity or teratogenicity was identified(1).

* The Losigamone Study Group consisted of: G. Bauer, C.Baumgartner, D. Bechinger, V. Blankenhorn, B. Cebular, A.Czlonkowska, E. Deisenhammer, L. Dobrzynska, T. Domzal,C.E. Elger, C. Fryze, J. Groselj, H.-J. Heinze, J. Majkowski,B. Mamoli, H.-J. Meencke, G. Rabending, U. Runge, D.Rosciszewska, A. Sczudlik, H. Stefan, B. Steinhoff, S.R.Stodieck, J. Szanto, B. Tettenborn, F. Vajd and M. Zupan.

Acta Neurol Scand 2001: 103: 226–230Printed in UK. All rights reserved

Copyright # Munksgaard 2001

ACTA NEUROLOGICASCANDINAVICA

ISSN 0001-6314

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Previous studies in patients with pharmacoresis-tant partial epilepsy demonstrated the anticonvul-sant effect of LSG. In an unblind, ascending dosetolerance study 9 patients with chronic partialseizures received up to 2100 mg LSG/day, withtreatment periods of 5–6 weeks. In 7/9 patientsseizure frequency was reduced during LSG treat-ment showing a median reduction of 39% ofseizures as compared to baseline. A clear dose–response relationship was found for daily LSGdosages between 600 and 1500 mg, with a max-imum of seizure control at 1500 mg/day (1). In afurther open label study LSG was administered in afixed daily dose of 1500 mg (9). Twenty patientswith intractable partial seizures received LSG for 24weeks; 15 patients (75%) had a decrease of seizurefrequency during treatment when compared tobaseline. In 6 of these patients seizure frequencydecreased by at least 50% (9).

Patients and methods

Patients

In a multinational, multicenter study on the efficacyand tolerability of LSG 203 patients suffering fromchronic partial epilepsy were included into arandomized, placebo-controlled clinical trial.Patients had to be on a stable comedication withnot more than three antiepileptic drugs. At least oneof the antiepileptic-codrugs had to show serumlevels within the therapeutic range. They had tohave at least four simple-partial, complex-partial orsecondarily generalized tonic–clonic seizures within28 days during 4 consecutive months prior toinclusion. Antiepileptic drug comedication had tobe held stable in the 3 months prior to inclusion.Patients had to be older than 18 years, they had togive their written informed consent before onset ofthe study. A safe contraception was required forfemale patients (post-menopause, surgical steriliza-tion, intra-uterine pessar). A cranial magneticresonance imaging was required for all patients(to exclude chronic progressive disorders).

Patients with idiopathic generalized epilepsy,those with alcohol, drug or other medicationabuse, a progressive neurological disease, severenephrological, hepatic or cardiovascular diseasesand diseases with altered gastrointestinal absorp-tion of drugs were not included. Furthermore,patients had to be compliant and had to be able toreport on their seizures.

Therefore, inclusion was restricted to thosepatients who proved to be compliant (detected bymeasurement of antiepileptic drug serum levels)during the treatment period previous to the study.Slight increases of hepatic enzyme levels (within

two–three times the upper normal limit if stableduring the past 4 months) and slight decreases inleucocytes (leucocyte levels above 2000 mm3 withover 50% neutrophils) and thrombocytes (throm-bocyte levels above 100,000/mm3) (as often seen inanticonvulsive medication) were allowed.

Study procedure

Following a pre-study screening visit, the patientsunderwent an 8-week baseline phase (weeks x8through x1), after which they were randomized toeither LSG or placebo treatment. Patients receiveda single dose of 500 mg LSG on baseline day 1 todetermine LSG single dose kinetics (data not shownhere). The baseline was followed by 8 weeks ofdouble-blind treatment (weeks 1 through 8), duringwhich the LSG treated patients received 3r500 mg/day LSG in addition to their stable-held anti-convulsant comedication. LSG was administeredaccording the following schedule: first and secondday of the double blind phase 3r250 mg/day.From the third day on patients received 3r500 mg/day. Examinations were held at the beginning ofweek x8 and at the end of weeks x3, x1, 2, 4 and8. The number and type of seizures and thecircumstances under which they occurred (dateand time) were recorded in a patient diary on a dailybasis.

The primary outcome variable was the relativechange in the partial seizure frequency. This wasdefined as the comparison between the mean seizurefrequency within the baseline and the placebo-controlled study phase. Furthermore, the absolutechange in seizure frequency and responder rate (i.e.seizure reduction by at least 50%) were assessed.

Safety analysis focused on the incidence ofadverse events. In addition, laboratory parameterswere monitored and neurological and physicalexaminations (including vital signs and ECG)were conducted. The influence of LSG on plasmalevels of antiepileptic drugs was assessed from bloodsamples taken on all visits prior to the a.m. intake ofthe drugs.

Biometric methods

We planned to achieve 144 patients (72 in eachtreatment group). To provide a drop-out rate of10%, 160 patients were planned to be randomized.Due to a high inclusion rate after opening newcenters finally 203 patients were randomized.Responder rates of P=0.10 in the placebo groupand P=0.30 in the LSG group were assumed. Thedifference between these reponder rates was alsoregarded as clinically relevant. The sample sizecalculation was based on the dichotomous criterion

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‘‘treatment response’’ (reduction of mean seizurefrequency per 4 weeks of at least 50%). A samplesize of at least 2r72 evaluable patients was plannedin order to have a power of 1xb=0.80 for therejection of the null hypothesis (null hypothesis: seebelow) and to get a two-sided type I error of a=0.05(10).

A comprehensive descriptive analysis of allparameters recorded in the seizure diaries and thecase record forms was conducted, computingdescriptive statistics adequate for the parametersof measurement. For the analysis of treatmentefficacy, the mean seizure frequency per 28 days wascalculated for the baseline and the double-blindtreatment phase. For each patient, the absolute andrelative change in seizure frequency from baseline todouble-blind treatment phase was determined(defined as: baseline-treatment/baseline r100).The following null hypothesis was tested: Theintra-individual relative difference in mean seizurefrequency per 28 days between the baseline periodand the therapy period is equal for patients treatedwith LSG and for patients treated with placebo. Theanalysis was performed with the stratifiedWilcoxon–Mann–Whitney test to a type I error ofalpha=0.05 (two sided). Stratified analysis wasused to adjust for the center effect. The analysis wasbased on the intent-to-treat population. Theanalysis of the efficacy parameters included thecomputation of 95% confidence intervals for themeans and medians.

Adverse events were coded according to theWHO Adverse Reaction Terminology (WHO-ART). In addition to counting and comparing thenumber of adverse events per treatment phase andgroup, an adverse events analysis was performedusing the TESS (Treatment Emergent Signs andSymptoms) method, i.e. only such adverse eventswhich occurred during the double-blind treatmentphase (i.e. which did not occur during the baselineperiod) or which aggravated during the double-blind treatment phase were counted.

The analysis of treatment efficacy was carried outaccording to the intent-to-treat mode, thus,included all patients, who had received the inves-tigational drug at least once and had any evaluablefollow-up data on seizure frequency available. Allpatients who did not have any major protocolviolations were entered into a supportive perprotocol analysis. The safety analysis included allpatients who had received the investigational drugat least once. For drop outs during treatment phasethe seizure frequency during 28 days of treatmentwas calculated on the basis of the days withavailable seizure data instead of using the totaltreatment period of 8 weeks.

Results

The study was performed between January 1, 1994(inclusion of the first patient) and June 15, 1995(completion of the last patient). A total of 224patients suffering from chronic partial epilepsieswere included into baseline; 21 patients droppedout. Reasons for discontinuation of these patientswere: central nervous system-related adverse eventsfollowing a single dose of LSG (to determine LSGsingle dose kinetics) (n=1), hospitalization withoutmention of relationship to LSG (n=2), abnormallaboratory values interfering with the study proto-col (n=3), violation of inclusion/exclusion criteria(n=4), increased seizure frequency (n=2), informedconsent revoked (n=3), others (n=1), unknown(n=5).

In all, 203 patients entered the double-blindtreatment phase: 99 patients (61 men, 38 women,aged between 18–63 years, mean age 36.1 years)were treated with LSG. Some 104 patients (58 menand 46 women, aged between 19–74 years, mean age35.2 years) were on placebo. The mean duration ofepilepsy since the occurrence of the first seizure was23.5 years in the LSG treated group and 22.0 yearsin the placebo group. The mean frequency of partialseizures per 28 days was 8.77 seizures (range7.8–11.7) in the losigamone group and 9.33 seizures(range 7.9–11.5) in the placebo group (P=0.85).

The number of concomitant antiepileptic drugsdid not differ significantly between patients treatedwith LSG and those on placebo: patients receivedone (28.7% vs 24.3%), two (48.9% vs 55.3%) or three(22.3% vs 20.4%) additional antiepileptic drugs.

Of the 203 patients, 171 finished the study; 21patients dropped out during treatment with LSG,and 11 drop-out patients were on placebo. Reasonsfor drop-out in the LSG-group were central nervoussystem-related adverse events (n=11), car accident(n=1), informed consent revoked (n=2), poorcompliance (n=3), intoxication from a co-drug(n=1), lack of efficacy (n=1) and increase of seizurefrequency (n=2).

Reasons for drop-out under placebo treatmentwere poor compliance (n=2), status epilepticus/prolonged seizures (n=2), sudden death (n=1),paresthesia (n=1), lack of efficacy (n=3), throm-bosis of the deep veins (n=1) and sedation (n=1).

Efficacy

Outcome variable was the relative reduction of themean frequency of partial seizures comparedbetween baseline and placebo-controlled treatmentphase (note: In this section, negative percentagesalways denote seizure increases, while positivepercentage values denote a decrease of seizures).

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The median percent change of seizures was 14.9%in patients on LSG and 6.7% in patients on placebo(statistically significant two-sided P-value ofP=0.004 for the stratified Wilcoxon–Mann–Whitney test in the intent-to-treat population).

The main secondary efficacy variable was theresponder rate, defined as an at least 50%-reductionof the mean seizure frequency. An at least 50%reduction of seizures was achieved in 22.3% ofpatients in the LSG-treated group and in 14.6% ofpatients in the placebo group (P=0.14; chi-quad-rat-test, two-sided).

The responder rates (e.g. number of patients witha relative difference of seizures between baseline andtreatment phase of at least 50%/total number ofpatients) were 22.2% (LSG) and 12.0% (placebo),respectively (P=0.33, chi-quadrat-test, two-sided).

Subgroup analysis showed a superior anticon-vulsant efficacy of LSG in patients treated with onlyone concomitant anticonvulsant drug. In suchpatients the median percent change of seizures(e.g. [mean seizure frequency during baselinexmean seizure frequency during treatment phase/mean seizure frequency during baseline]r100) was20.8% in the LSG-treated group and x1.8% in theplacebo-group (P=0.004, two-sided, Wilcoxon–Mann–Whitney test).

Analysis of seizure types did not show a shiftfrom one seizure type to another during thetreatment phase.

Tolerability

Safety was investigated by analysis of adverseevents, laboratory, physical and neurologicalparameters. Treatment emergent signs and symp-toms (TESS) were more often reported during LSG-treatment (59 patients=59.6%) than in the placebo-group (39 patients=37.5%). Classified by WHOBody System Organ Classes the main symptomclass was ‘‘central and peripheral nervous systemdisorders’’ (40 patients under LSG, 25 underplacebo). The most frequent individual symptomwas dizziness (27 patients under LSG, 10 underplacebo) (Table 1). No other specific adverse eventoccurred in more than 10% of patients duringtreatment with losigamone or placebo. Eight seriousadverse events in 5 patients occurred under treat-ment with LSG. One patient had a car accident, 1patient experienced gait ataxia, dizziness, headacheand somnolence, in 3 patients seizure increase ormanifestation of a generalized tonic–clonic seizurewas reported. Under placebo low back pain (duringbaseline), sudden death (heart attack suspected),thrombosis and status epilepticus or prolongedseizures (in 2 patients) were documented as seriousadverse events.

The only laboratory parameter showing adifference between treatment groups was gamma-GT: changes from normal values during baseline tovalues higher than normal range during treatmentperiod were measured in 15 patients receiving LSGand in 3 patients receiving placebo. Blood levelmeasurements of concomitant antiepileptic drugsdid not show an influence of LSG on suchparameters.

Discussion

We report on a study with LSG, a new antiepilepticdrug with an anticonvulsant mode of actiondifferent from that of other available antiepilepticdrugs (1). The median percent change of seizureswas significantly different in patients treated withLSG (14.9%) and patients on placebo (6.7%)(P=0.004).

The patients participating in the study sufferedfrom chronic partial epilepsy with an averagehistory of seizures of 22 years. LSG was adminis-tered add-on in patients treated with up to threeadditional antiepileptic drugs (about 75% ofpatients were on more than one additional anti-epileptic drug). Quite interestingly, the anticonvul-sant efficacy of LSG was best in such patients whoreceived only one additional antiepileptic drug.

Apart from central nervous system-relatedadverse events LSG did not exhibit prominentadverse reactions in the reported study. The overallgood tolerability of LSG, even at higher dosages(2100 mg LSG/day), was also described by others(1). In the study performed by Morris et al. (1), the

Table 1. Adverse events during treatment with losigamone or placebo listed

according to Treatment Emergent Signs and Symptoms (TESS) classification

WHO body system organ class

Losigamone

(N=99)

Placebo

(N=104)

Central and peripheral nervous system disorders 40 (40.4%) 25 (24%)

Body as a whole – general considerations 15 (15.2%) 8 (7.7%)

Vision disorders 14 (14.1%) 10 (9.6%)

Psychiatric disorders 10 (10.1%) 6 (5.8%)

Gastro-intestinal system disorders 11 (11.1%) 7 (6.7%)

Respiratory system disorders 3 (3%) 4 (3.9%)

Metabolic and nutritional disorders 2 (2%) 1 (1%)

Resistance mechanism disorders 2 (2%) –

Musculo-skeletal disorders 1 (1%) 3 (2.9%)

Hearing and vestibular disorders 1 (1%) 1 (1%)

Myo-, endo, pericardial and valve disorders 1 (1%) –

Vascular (extracardial) disorders 1 (1%) –

Platelet, bleeding and clotting disorders 1 (1%) 1 (1%)

Urinary system disorders 1 (1%) –

Skin and appendages disorders – 5 (4.8%)

Cardiovascular disorders, general – 1 (1%)

Heart rate and rhythm disorders – 1 (1%)

Total patients with TESS events 59 (59.6%) 39 (37.5%)

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most often reported adverse events were centralnervous system-related complaints (e.g. dizzinessand headache). All adverse events subsided whenLSG dosage was reduced or discontinued. Adverseevents tended to occur more frequently in patientsreceiving daily dosage beyond 1500 mg/day.

In the LSG study reported by Runge et al. (9) 6patients (30%) experienced adverse events (predo-minantly central nervous system-related). Almost90% of the adverse events ocurred during the firstweek of treatment, and adverse events were notreported after week 8.

Adverse events have regularily been reportedduring treatment with newly developed anticonvul-sant drugs. In a systematic review of publishedtreatment studies with anticonvulsant drugsMarson et al. (11) statistically analysed thenumber of patients who withdrew from the studies(for any reason) and the number of patients whoreported on central nervous related side effects (i.e.ataxia, dizziness, fatigue, nausea, somnolence).There was insufficient evidence to conclude thatpatients are more likely to discontinue gabapentinor lamotrigine than placebo. However, patientswere significantly more likely to discontinue tiaga-bine, topiramate or vigabatrin than placebo. Sideeffects were significantly more often reported duringtreatment with gabapentin, lamotrigine, tiagabineor topiramate than with placebo. However, therewas no conclusive evidence that such side effectswere more likely to occur with vigabatrin ratherthan placebo.

In the reported study LSG proved to be aneffective and well tolerated antiepileptic drug ableto improve the treatment of chronic partial seizures.Failure of clinically significant interactions withother anticonvulsant drugs allow to use LSG as awell tolerated comedication. Its new mode ofanticonvulsant action enlarges the therapeuticapproaches in the control of partial seizures.

It is difficult to compare LSG to other newlydeveloped drugs. Although their anticonvulsantefficacy varies, good tolerability proved to be ofmajor importance to maintain the anticonvulsant

treatment (12, 13). Therefore, due to the results ofthis study one should expect that LSG is a usefulnew antiepileptic drug.

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