A randomised double-blind placebo-controlled crossover add-on trial of lamotrigine in patients with treatment-resistant partial seizures

Epilepsy Res., 7 (1990) 136-145

136

Elsevier

EPIRES 00351

A randomised double-blind placebo-controlled crossover add-on trial of lamotrigine in patients with treatment-resistant partial seizures

P. Loiseau a, A . W . C . Y u e n b, B. Duch6 a, T. M 6 n a g e r c and M . C . Arn6-B~,s d "Department of Neurology, UniversityHospital, Bordeaux (France), bWellcomeResearch Laboratories, Beckenham (U. K.), CWellcomeFrance, Paris (France), and dDepartmentof Neurology, University Hospital, Toulouse (France) (Received 18 April 1990; accepted 26 April 1990)

Key words: Lamotrigine; Partial epilepsy

Efficacy and safety of lamotrigine (LTG) as add-on therapy was assessed in a randomised double-blind placebo-controlled trial of this drug in 23 adult patients with refractory partial seizures, Fifteen patients showed an improvement on LTG treatment, with a greater than 50% decrease in total seizure count in 7 patients. Fourteen patients experienced fewer simple and complex partial seizures, with 8 patients beuefitting by more than a 50% decrease in seizure frequency. The drug was well tolerated over the 2 month treatment period. The plasma concentration of concomitant antiepileptic drugs remained unchanged. No hacmatological or chemical abnormalities were noted,

INTRODUCTION Lamotrigine (LTG), 3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine (BW430C) is a novel anticonvulsant developed by Wellcome Research Laboratories. It is structurally unrelated to antiepileptic drugs (AEDs) in current use. In animal models, it has a phenytoin-like profile that suggests potential utility in the treatment of both generalized and partial seizures 13. Its anticonvulsant action may be due to inhibition of glutamate release by an action at voltage-sensitive sodiumchannels n. Its pharmacokinetics in normal huCorrespondence to: Prof. P. Loiseau, H6pital Pellegrin/Tripode, Place Am~lie Raba-L~on, 33076 Bordeaux Cedex, France.

mans are as followsS: complete bioavailability, a very long plasma elimination half-life (24 + 5.7 h), first-order kinetics and approx. 55% binding to plasma protein. Data obtained in patients showed large half-life variation, ranging from 10 to 42 h. The classical enzyme-inducing antiepileptic drugs reduce LTG half-life, while valproate increases it7. Its antiepileptic efficacy was assessed in a number of studies. Single oral doses of LTG have been shown to reduce photosensitivity and interictal spikes4,s. Two 1 week add-on studies in refractory patients showed that LTG was well tolerated, and analysis of seizure frequencies indicated a reduction in complex partial seizures on LTG 2'1°. Four randomised, double-blind, placebo-controlled crossover trials of LTG as add-on therapy in patients with refractory seizures have been com-

0920-1211/90/$03.50 ('C-)1990 Elsevier Science Publishers B.V. (Biomedical Division)

137 pleted in Holland 3, Cardiff 9, Chalfont 15 and Bordeaux. All 4 trial designs were essentially similar, enabling combination of the data in a meta-analysis to provide an overview of the efficacy and safety of LTG by comparison with placebo (Johnson, in prep.). The present study is one of these. Its primary objectives were to assess the efficacy and safety of LTG as add-on therapy in patients with poorly controlled partial seizures. Its secondary objective was to examine possible pharmacokinetic interaction between LTG and co-administered other antiepileptic drugs. METHODS

Study design This was a randomised double-blind, placebocontrolled, crossover trial of LTG added on to an existing regimen of standard antiepileptic drugs (AEDs) in patients with refractory partial seizures. The trial lasted 28 weeks in total, being divided into 5 phases as follows: baseline (a 4 week period, with constant AEDs dosage); treatment period 1 (an 8 week treatment period, with added LTG or placebo, at half dosage during the first week, and full dosage during the subsequent 7 weeks); washout 1 (a first washout period, the investigational drug being tapered during the first week, and the patient maintained on placebo during the subsequent 3 weeks); treatment period 2 (an 8 week treatment period, during which patients were crossed over to LTG or placebo, with a dosage schedule similar to treatment period 1 and washout 2 (similar to washout 1). Thus, in the LTG/placebo sequence group, LTG was given throughout the 8 weeks of treatment period 1, then reduced over the first week of washout 1. Placebo was given for the rest of the trial. In the placebo/LTG group, placebo was given through treatment period 1 and washout 1, with LTG through treatment period 2, reducing during the first week of washout 2. Placebo was then given for the final 3 weeks of washout 2. The study was conducted double blind throughout, except for the last 3 weeks of both washout periods, when the study was effectively

single blind, as all patients received placebo.

Study schedule At screening, the following were recorded: seizure history, seizure types, seizure frequency for the previous 3 months, medical history and an inventory of adverse experiences. Admission criteria were checked. Physical and neurological examinations were performed. Clinical laboratory tests and trough plasma AED levels were assessed. An electrocardiogram was recorded. Patients were seen at the end of baseline, then weekly for the first 2 weeks of each treatment period, again after 2 weeks and then 4 weeks later. During the washout periods patients were seen after the first week and again after 3 weeks. Vital signs, assessment of adverse experiences and laboratory tests were performed at each visit. Physical and neurological examination and electrocardiogram were performed at the end of each phase.

Drugs and dosages Throughout the entire study, all patients were maintained on their previous AED regimens. LTG or placebo were given twice a day, in the morning and in the evening, in the form of identical white capsules. Pharmacological studies in animals indicated that LTG would be efficacious at plasma concentrations of 1-3 #g/ml. Studies in volunteers and in patiel~ts showed that concen.ratmns up to 3/~g/ml were well tolerated and reduced photosensitivity and interictal spikes in patients. Hence the dosage strategy aimed at achieving trough plasma LTG concentrations of 1.5-2.5 pg/ml. Previous data showed that enzyme-inducing drugs reduce the half-life of LTG to approximately 12 h, while valproate, when in combination with these drugs, increases the half-life of LTG to approximately 30 h. For this reason, patients were divided in 2 groups, according to the existing therapy: one of 'induced' and one of 'inhibited' patients. The full daily dosage was 300 rag/day for 'induced' patients and 150 rag/day for 'inhibited' patients. All patients received half dosage during escalating and tapering weeks. In the event of an adverse experience that '

138 the investigator deemed attributable to trial medication, the dose could be reduced by 25% or 50%. Patients returned their capsule containers at each clinic visit. Returned capsules were counted for compliance check. Trough plasma LTG concentrations were measured at each visit during treatment periods.

Admission criteria Inclusion criteria were: (i) adult patients, age range 16-65 years; (ii) a confident diagnosis of epilepsy uncomplicated by suspected psychogenic attacks; (iii) partial seizures, easily recognizable by patient, attendants or relatives; seizures should be classifiable by the International Classification of Seizures (1981); (iv) a minimum of 4 partial seizures per month through each of the previous 3 months and baseline period; (v) seizure diaries with daily seizure counts for each seizure type, during the study and for the previous 3 months; (vi) antiepileptic medication unchanged for the previous 3 monthz; (vii) seizures resistant to AEDs of first choice to therapeutic plasma concentrations; (viii) written informed consent. Exclusion criteria were: (i) severe organic or psychiatric disease, severe mental subnormalities, and progressive neurological disease; (ii) abnormal values of laboratory screen considered to be of clinical significance and not attributable to enzyme induction; (iii) status epilepticus in the past 6 months or more than once in the past 2 years; (iv) use of investigational (unmarketed) drugs in the past 6 months and/or more than 2 AEDs (including drugs of 2nd and 3rd choice); (v) chronic medication other than AEDs or oral contraceptives, abuse of alcohol or other substances; (vi) inability to fulfil protocol requirements (i.e., poor compliance, non-attendance at clinics, failure of seizure/adverse experience documentation); (vii) pregnancy, lactation or current exposure to risk of pregnancy. Female patients were accepted if they were post-menopausal, had undergone hysterectomy, oophorectomy or sterilisation, used IUD or sufficient oral contraceptives.

Measurements and evaluations (1) Efficacy parameters The total number of countable seizures during each phase was used as the main efficacy parameter and the total number of days during which seizures occurred was used as a secondary efficacy parameter. Furthermore, at the end of weeks 12 and 24, the investigator made a global evaluation of the patient's progress. (2) Safety parameters (i) Clinical criteria. Standard clinical and neurological examinations, including fundoscopy were performed at each phase of the study. Total number of adverse events, number of patients with adverse reactions and severity of adverse events were recorded. (ii) Biological criteria. Haematology, routine blood chemistry and urinalysis were measured at intervals during the trial. Statistical analysis Formal statistical analysis of seizure data was performed according to the methods proposed by Koch n. The seizure total for each phase was logtransformed to conform to the Koch model and the data then analysed using the non-parametric Wilcoxon rank-sum test. Percentage reduction in seizure count totals was derived from the LTG/placebe ratio. Approximate 95% confidence intervals for percentage reduction in seizure count attributable to LTG were derived using the binomial theorem applied to the LTG/placebo seizure count ratio order statistics ~4. For the laboratory safety data analysis, the confidence intervals for differences between medians were derived using the methods described by Hollander and Wolfe6. Confidence intervals between rates of occurrence of adverse experiences were derived according to the method described by Armitage ~. RESULTS The study was conducted as stated in the protocol. No protocol amendments were issued.

139 TABLE I

Basefine group characteristics Patient no.

Age (years)

Sex

Weight (kg)

Duration of seizures (years)

No. of seizure types

Epilepsy

51 49 62 67 61 68 61 63 56 56 50 74 64

18 10 15 20 45 10 16 19 13 31 15 12 7

3 3 1 2 1 1 1 2 2 1 1 1 2

C S S C S C C C S S S C S

PHT PB CBZ PHT, PB PHT, PB PHT, PB CBZ, CLB PHT PHT, PB CBZ, PB PB, VPA CBZ, VPA PHT, VPA

68 53 84 55 56 72 53 68 84 75

10 29 7 9 38 5 29 16 24 3

2 1 2 1 2 3 1 1 1 3

C C S C C C C C S C

CBZ, CBZ CBZ, CBZ CBZ, CBZ PHT, PB PHT, PHT,

AEDs at entry

aetiology

PlacebolLTGsequencegroup 2 4 5 8 9 12 15 16 17 19 21 22 33

41 20 22 29 49 23 52 24 37 43 20 25 21

F F M M F F M M M F F M M

L TG/placebo sequence group 1 23 M 3 6 7 10 11 18 20 23 34

50 49 31 39 50 42 22 54 21

F M F F M F F M M

PB CLB PB PB VPA VPA

Etiology: C = cryptogenic; S = symptomatic. AEDs: PHT = phenytoin; PB = phenobarbital; CBZ - carbamazepine; VPA = valproate; CLB = clobazam.

Twenty-five patients were entered into the study. Two patients did not complete the trial. One patient was withdrawn from the study because of a protocol violation. This patient was receiving another investigative drug and therefore should not have been entered. A second patient withdrew his consent during the first treatment period. Twenty-three patients completed the trial and were included in the efficacy analysis. Baseline population characteristics are given in Table I. The balanced randomisation code for this study was generated for 40 patients (block size 4). An equal number of patients should therefore have received LTG or placebo in the treatment phases. This assumption depended on patient numbers being consecutive. Complex numbering arrange-

ments between the two centres used in the study created an imbalance in the number of patients in the two treatment sequences. Thus among the patients who completed the study, 13 received placebo in the initial phase, whereas only ten received LTG. Summary statistics (Table If) show slight differences between the two groups. The total daily dose of LTG in the 23 patients ranged from 75 to 300 mg. Patients continued on their standard AEDs: 15 patients were on 2 AEDs and 8 were on 1 AED; 10 patients received carbamazepine, 10 phenytoin, 11 phenobarbital, 5 sodium valproate and 2 clobazam. Patients complied with admission criteria except for the following: 1 patient was prescribed other chronic medication (thyroxine for hypothyroidism)

140 TABLE lI

Summary statisticsfor demographic data and seizure history Placebo/ L TG group No. of males females

7 6

L TG/ placebo group 5 5

Groups pools 12 11

Age (years) Min/max Mean Median S.D.

20-52 31.2 25 11.62

21-54 38.1 41 12.91

20-54 34.2 31 12.41

Weight Min/max Mean Median S.D.

49-74 60.2 61 7.49

53-84 66,8 68 12.14

49-84 63 62 10,11

Duration of seizures (years) Min/max Mean Median S.D.

7-45 17.8 15 10.14

3-38 17.0 13 12.17

3-45 17.4 15 10,81

No. of seizure types 1 2 3

7 4 2

5 3 2

12 7 4

Epilepsy aetiology Cryptogenic Symptomatic

6 7

8 2

14 9

No. of AEDs at entry 1 2

4 9

4 6

8 15

and 3 patients had fewer than 4 seizures/month in the baseline period. Compliance was good with most patients taking 86% or over of the prescribed daily capsules.

Evaluation of efficacy Table III shows the total seizure counts for each patient during the 8 week treatment periods on LTG and placebo. Fig. I shows the percentage reduction in total seizure counts for each patient.

The percentage change has been expressed relative to the larger of the 2 treatment period totals, a method which has clinical relevance. Fifteen out of 23 patients showed an improvement on LTG treatment, with 7 patients benefitting by a greater than 50% decrease in total seizure count. Seven patients were better on placebo, with 1 patient showing a greater than 50% decrease in total seizure count. One patient showed no difference in seizure count between LTG and placebo treatment. Analysis performed according to methods proposed by Koch u and using the Wilcoxon rank sum statistics showed that LTG significantly reduced the total seizure frequency (P < 0.05). Neither the treatment x period interaction nor the period effect was statistically significant (P > 0.20). On examination of the distribution of seizure frequency, a very skewed distribution was produced by 1 patient with a very high seizure frequency. It was considered difficult for a patient to count more than 30 seizures/day accurately and hence days with >30 seizures were arbitrarily considered as a serial seizure. Comparison of total seizure counts during the 4 weeks of the 2 washout periods shows no statistically significant differences (P > 0.20). The median change in seizure count on LTG was a 23 % reduction with a confidence interval of - 11% to 52% (confidence coefficient = 0.965). Fig. 2 shows the percentage reduction in simple and complex partial seizure frequency for each patient. The percentage change has been expressed relative to the larger of the 2 treatment period totals. Fourteen out of 23 patients showed an improvement on LTG treatment, with 8 benefitting by more than a 50% decrease in total simple and complex partial seizures. Seven patients were better on placebo and 2 showed no change between treatments. Neither the treatment × period interaction nor the period effect was statistically significant (P > 0.20). The test for treatment effect shows a statistically significant difference in favour of LTG (P < 0.05). Comparison of the partial seizure counts during the 4 weeks of the 2 washout periods showed no significant differences (P > 0.20). Only 4 patients experienced generalized seizures, an insufficient number to allow any formal comparison of treatment effects.

141

As for the total number of seizure days between the 2 treatment periods, 15 out of 23 patients showed an improvement on LTG treatment, 3 by greater than 50%. Neither the treatment x period

interaction nor the period effect was statistically significant (P > 0.20). The test for treatment effects showed a statistically significant difference in favour of LTG (P < 0.05).

TABLE IIl

Drug therapy, L TG dosage and total seizure counts in individual patients LTG, lamotrigine; CBZ, carbamazepine; CLB, clobazam; PHT, phenytoin; PB, phenobarbital; VPA, valproate; A, simple partial

seizures; B, complex partial seizures; C, partial seizures secondarily generalized; D, generalized seizures. Patient no.

Seizure types

Placebo/L TG sequence group 2 A+B 4 5

A,B,C B

8

B

9

B

12

B

15

B

16

A+C

17

A+B

19

B

21

B

22

B

33

B +D

L TG/placebo sequence group 1 A 3

B

6

A+B

7 10

B B

11 18

B+C B

20 23

B B

34

B+C

Drug therapy and daily dose (mg)

L TG total daily dose (mg) (modal)

No. of seizures With L TG

With placebo

PHT PB CBZ PHT PB PHT PB PHT PB CBZ CLB PHT PHT PB CBZ PB PB VPA CBZ VPA PHT VPA

400 200 1200 325 150 350 100 400 100 1200 10 325 325 150 1200 100 150 1500 900 1000 300 1500

300 300 300 300 300 300 300 300

50 18 25 35 35 0 0 7

77 22 31 21 21 5 5 16

300 300 300 300 300 225 225 150 150 150 150 150 150

15 15 5 34 34 6 6 7 7 3 3 25 25

48 48 4 28 28 10 10 19 19 8 8 17 17

CBZ PB CBZ CBZ CLB CBZ CBZ PB CBZ PHT PB PB PHT VPA PHT VPA

1400 150 800 1000 50 1000 1200 100 700 350 200 250 300 1500 300 1500

300 300 300 300 300 300 300 300 300 300 300 300 150 150 150 150

256 256 14 33 33 16 10 10 16 10 10 17 3 3 0 0

333 333 22 28 28 20 21 21 22 9 9 7 9 9 0 0

142 100 80 ..! e.

60 0

oE

.=.J ¢= m c u o o a.

40 20

9 10

0

21 2

9

8

G o

0

~=

20

=8m g[

40

IIit

21E

m c ¢ o

60 80

Fig. 1. Percentage modification in total seizures during the verum period as compared with the placebo period. Each bar represents an individual patient.

100 -

80 ~a m'.-

¢3

~E

ig

60 m

4o

0

g

20

9 101

4

l.I

8

1 2 ,! s 6

:P

1,9

21 22 23

M

40 6O Q

IO0

Fig. 2. Percentage modification in partial seizures during the verum period as compared with the placebo period. Each bar represents an individual patient.

143 On investigator global evaluation 10 out of 23 patients were considered better on LTG than placebo, 5 better on placebo than LTG and 8 no change from baseline for either treatment. Of the patients better on LTG, 3 were considered to have marked improvement, 5 a moderate improvement and 1 a mild improvement. One patient was unchanged on LTG, but was thought to have deteriorated on placebo.

Evaluation of safety (1) Adverse experiences (AEs) Twenty-eight reports, involving 15 different AEs, wore recorded during the trial. Eleven patients reported at least 1 AE. The 2 most frequently reported AEs throughout the study were nervousness and vertigo. All of the 28 reports were classified as non-serious. There was only one dose reduction at the request of the blind investigator (because of vertigo). No patient was withdrawn for AE. The 95% confidence intervals for the difference in rate of occurrence of AE between placebo and LTG are given in Table IV. Rate is defined as the total number of patients reporting an AE divided by the total number of patients in the

analysis. There is no evidence of any effect attributable to LTG.

(2) Clinical and laboratory safety data Vital signs and visual acuity data remained unchanged throughout the trial. Individual patient measurements showed numerous biological values outside predefined normal ranges for most of the variables measured. However, there were transient changes, without any clinical significance, or persistent changes due to liver enzyme inducing properties of the patients' concomitant AEDs. There were no marked or consistent increases in the number of abnormal values attributable to LTG treatment.

Plasma levels of antiepileptic drugs (1) Lamotrigine Plasma LTG concentrations ranged from 0.3 ~.o 4.9/~g/ml. The mean plasma LTG concentrations in patients who responded to LTG appear to be slightly higher than in those patients who did not respond or showed no change (1.53/~g/ml, S.D. 0.652 and 1.37/~g/ml, S.D. 0.735), respectively. There was also a significa, t correlation between plasma LTG concentrations and a measure of treatment efficacy.

TABLE IV 95% confidence intervals for differences between rates of occur-

rence of adverse experience on placebo and lamotrigine (listed in descending order of incidence on lamotrigine) Adverse experience

Vertigo Nervousness Anomaly vascul. Acne Edema periph. Pain Conjunctivitis Asthenia Dizziness Somnolence Stupor Dry mouth Headache

Incidence on placebe (%)

Incidence on lamotrigine (%)

95% Cl for

0 4 0 0 0 0 0 0 0

13 9 4 4 4 4 4 4 4

-28%; 2% - 19%; 10% -13%; 4% -13%; 4% -13%; 4% -13%; 4% -13%; 4% -13%; 4% -13%; 4%

4 4 4 4

0 0 0 0

(2) Concomitant AEDs Phenytoin, carbamazepine and phenobarbital plasma levels were not modified by LTG comedication (Table V).

PLO-L TG TABLE V

-

4%; 4%; 4%; 4%;

13% 13% 13% 13%

Mean plasma concentration of concomitant AEDs during placebo and L TG treatment periods AEDs, antiepileptic drugs; LTG, lamotrigine.

AED

Carbamazepine (mg/l) Phenytoin (mg/l) Phenobarbital (rag/l)

Mean during placebo

Mean during L TG

95% CI estimate of difference (placebo/L TG)

8.87

8.68

-0.45; 0.83

19.71

19.86

-2.03; 1.72

25.39

25.59

-1.49; 1.09

144 DISCUSSION This double-blind placebo-controlled randomised crossover study was undertaken to assess the efficacy and safety of lamotrigine in a group of outpatients with therapy-resistant epilepsy. A crossover design makes the most efficient use of the limited number of patients available for such studies. This design allows within patient comparison of treatment effects and hence reduces the effect of large inter-individual differences in seizure frequencies. The trial aimed at obtaining a minimum of 20 completed patients, since twenty is considered to be the minimum number required to demonstrate a treatment effect using a crossover design. A treatment period of 8 weeks was used. Patients were required to have at least 4 seizures/ month to increase the likelihood of demonstrating a treatment effect during this short period. LTG was tapered over the first week of washout to avoid possible withdrawal seizures. The total 4 weeks washout period was considered sufficiently long to avoid carry over effects to the next treatment period. For practical and ethical reasons, new AEDs are initially tested by addition to existing drugs in patients with refractory ~¢.eizures. This situation intro-

REFERENCES 1 Armitage, P., Statistical Methods in MedictP Research, Blackwell, Oxtord, 1971. 2 Binnie, C.D,, Beiwema, D.J., Debets, R.M.C., Van Erode Boas, W., Meijer, J.W.A., Meinardi, H., Peck, A,W., Westendorp, A.M. and Yuen, W.C., Seven day administration of lamotrigine in epilepsy: add-on trial, Epilep. sy Res., 1 (1987) 202-208. 3 Binnie, C.D., Debets, R.M.C., Engelsman, M., Meijer, J.W.A., Meinardi, H., Overweg, J., Peck, A.W., Van Wieringen, A. and Yuen, W.C., Double-blind crossover trial of lamotrigine (Lamictal®) as add-on therapy in intractable epilepsy, Epilepsy Res., 4 (1989) 222-229. 4 Binnie, C.D., Van Erode Boas, W., Kasteleijn-Nolst Trenit6, D.G.A., De Korte, R.A., Meijer, J.W.A., Meinardi, H., Miller, A.A., Overweg, J., Peck, A.W., Van Wieringen, A, and Yuen, W.C., Acute effects of lamotrigine (BW 430C) in persons with epilepsy, Epilepsia, 27 (1986) 248-254. 5 Cohen, A.F., Land, G.S., Breimer, D.D., Yuen, W.C., Winton, C. and Peck, A.W., Lamotrigine, a new anticonvulsant. Pharmacokinetics in normal humans, Clin. Phar-

duces an important bias in the evaluation of drug efficacy. According to Schmidt and Richter 16, only 30% of patients resistant to one of the first-line AEDs benefit from a second first-line drug. All patients included in the present study were resistant to at least 2 first-line drugs. Many of them had been resistant to investigational drugs, such as progabide, zonisamide and gamma-vinyl GABA. In the very resistant epileptic population represented in this study, the use of LTG for 8 weeks as add-on therapy was effective in reducing total seizure frequencies by more than 50% in 7 out of 23 patients. With Schmidt's figure in mind, one may consider that lamotrigine is a promising novel drug. CONCLUSION Lamotrigine has demonstrated unequivocal efficacy as add-on therapy in patients with poorly controlled simple and complex partial seizures. The drug was well tolerated over the 2 month treatment period, There were no changes in laboratory safety measures considered to be attributable to lamotrigine. It did not affect the plasma concentration of concomitant antiepileptic drugs.

macol. Ther., 42 (1987) 535-541. 6 Hollander, M. and Wolfe, D.A., Nonparametric Statistical Methods, Wileyand Sons, New York, 1973. 7 Hubbell, J.P., Garnett, N.R., Pellock, J,M., Chern, W.H., Wargin, W.A., Lai, A. and Cloutier, G., Pharmacokinetics of lamotrigine (BW430C) in epileptic patients, Epilepsia, 26 (1985) 537. 8 Jawad, S., Oxley, J.R., Yuen, W.C. and Richens, A., Reduction of interictal electroencephalographic spikes by lamotrigine in epileptic patients, Br. J. Pharmacol., 85 (1985) 287-288. 9 Jawad, S., Richens, A., Goodwin, G. and Yuen, W.C., Controlled trial of lamotrigine (Lamictal®) for refractory partial seizures, Epllepsia, 30 (1989) 356-363. 10 Jawad, S., Yuen, W.C., Peck, A.W., Hamilton, M.J., Oxley, J.R. and Richens, A., Lamotrigine: single dose pharmacokinetics, and initial one week experience in refractory seizures, Epilepsy Res., 1 (1987) 194-201. 11 Koch, G.G., The use of non-parametric methods in the statistical analysis of a two-period change-over design, Biome. trics, 28 (1972) 577-584. 12 Leach, M.J., Marden, C.M. and Miller, A.A., Pharmaco. logical studies on lamotrigine, a novel potential antiepi-

145 leptic drug. II. Neurochemical studies on the mechanism of action, Epilepsia, 27 (1986) 490-497. 13 Miller, A.A., Wheatley, P., Sawyer, D.A., Baxter, M.G. and Roth, B., Pharmacological studies on lamotrigine, a novel antiepileptic drug: anticonvulsant profile in mice and rats, Epilepsia, 27 (1986) 483-489. 14 Mood, A.M., Graybill, F.A. and Boes, D.C., Introduction to the Theory of Statistics, McGraw Hill, New York, 1974.

15 Sander, J.W.A.S., Patsalos, P.N., Owley, J.R., Hamilton, M.J. and Yuen, W.C., A randomised double-blind placebo-controlled add-on trial of lamotrigine in patients with severe epilepsy, Epilepsy Res., 6 (1990) in press. 16 Schmidt, D. and Richter, K., Alternative single anticonvulsant drug therapy for refractory epilepsy, Ann. Neurol., 19 (1986) 85-87.