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Keywords:

  • Epilepsy;
  • Gabapentin;
  • Lamotrigine;
  • Monotherapy;
  • Noninferiority study

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. MEMBERS OF GABAPENTIN STUDY GROUP 945-212
  7. REFERENCES

Summary:  Purpose: This randomised, double-blind study compared the newer antiepileptic drugs (AEDs) gabapentin (GBP) and lamotrigine (LTG) as monotherapy in newly diagnosed epilepsy.

Methods: Patients with partial seizures with and/or without secondary generalization or primary generalized tonic–clonic seizures were randomized to either GBP or LTG. During 2- and 6-week titration periods, respectively, GBP dosage reached 1,800 mg/day, and LTG, 150 mg/day. In the subsequent 24-week maintenance phase, the dose could be adjusted based on seizure control or adverse events between 1,200 and 3,600 mg/day for GBP and 100 and 300 mg/day for LTG. The primary end point was time to exit, a composite of efficacy and tolerability. Evaluable patients were used for the primary efficacy analysis, whereas tolerability was examined on an intent-to-treat basis.

Results: A total of 309 patients was randomized, and 291 (148 GBP, 143 LTG) were included in the evaluable population. Nineteen patients in each group had an exit event. The median time to exit was 69 days for GBP and 48 days for LTG. The hazard ratio was estimated as 1.043 (90% confidence intervals, 0.602–1.809). Overall, 106 (71.6% of the evaluable population) GBP-treated and 96 (67.1%) LTG-treated patients completed the study. Of those, 80 (75.5%) patients taking GBP and 73 (76.0%) taking LTG remained seizure free during the final 12 weeks of treatment. Only 14 (8.9%) GBP-treated patients and 15 (9.9%) LTG-treated patients withdrew because of study drug–related adverse events.

Conclusions: GBP and LTG monotherapy were similarly effective and well tolerated in patients with newly diagnosed epilepsy.

The majority of patients with newly diagnosed epilepsy can be successfully treated with a single antiepileptic drug (AED) (1). A number of randomised, double-blind trials in this population compared a newer agent with a standard AED (2–9). Most used flexible dosing regimens. The exception was the trial undertaken by Chadwick et al. (7), principally a regulatory study, in which patients were randomised to fixed-dose double-blind treatment with 300, 900, or 1,800 mg gabapentin (GBP) daily or to open-label carbamazepine (CBZ; 600 mg daily). The lowest dose of GBP (300 mg/day) was clearly inferior to the other treatment modalities.

Few differences in efficacy among AEDs have been demonstrated in these studies. Time to first seizure was shorter with vigabatrin (VGB) than with CBZ, although time to withdrawal for lack of efficacy and/or adverse events did not differ among the groups (8). Oxcarbazepine (OCBZ) was shown to be better tolerated than phenytoin (PHT) in children (6) and adults (5). Similarly, in studies comparing CBZ and lamotrigine (LTG) in adults (3) and in the elderly (9), significantly more patients remained taking LTG treatment because of its better tolerability. We report the first double-blind comparison between two of the newer AEDs, LTG and GBP, in patients with recent onset partial and/or tonic–clonic seizures by using a flexible dose design to reflect clinical practice. The study aimed to prove noninferiority of GBP compared with LTG with respect to time to exit. We also present a discussion on how equivalence or noninferiority can be defined when the primary efficacy parameter is of the type “time to event”.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. MEMBERS OF GABAPENTIN STUDY GROUP 945-212
  7. REFERENCES

Patients

Patients were age 16 years or older with a diagnosis of epilepsy. All had either partial seizures with or without secondary generalization or primary generalized tonic–clonic seizures. The latter patient group had not been systematically studied in clinical trials with GBP (10). No patient had absence or myoclonic seizures as defined by the International League Against Epilepsy (ILAE) guidelines (11). Patients had either never been treated with an AED or were untreated in the preceding 6 months. Patients with newly diagnosed epilepsy were required to have a minimum of two seizures within the past 12 months or one seizure in addition to unequivocal supporting evidence of epilepsy [e.g., positive electroencephalogram (EEG), brain imaging]. Untreated patients with a previous diagnosis of epilepsy were required to have had at least one seizure within the past 3 months. Patients who had a treatment attempt with a single AED for <2 weeks without achieving steady-state or an acceptable therapeutic level could enter the study. The previous AED was discontinued at randomisation. Women of childbearing potential were required to have a negative pregnancy test and were requested to use a reliable method of contraception.

Patients were recruited in 41 centres in Europe (Austria, Belgium, France, Germany, Ireland, Spain, Switzerland, U.K.) and Australia with approval of the local ethics committees. All patients or their legal guardians gave written informed consent to their participation. Patients were excluded from the study if they had a history of status epilepticus, progressive central nervous system disease, had been previously treated with either GBP or LTG, or had received any investigational drug during the preceding 3 months. Also excluded were patients with seizures related to drugs, alcohol, acute medical illness, or head trauma, or patients with situation-related seizures.

Study design

This was a multicentre, double-blind, randomized, parallel-group study. At baseline visit, a medical history was obtained, physical and neurologic examinations were undertaken, and a routine EEG was performed. Patients maintained a seizure diary. All seizures were classified, and all adverse events were recorded. Physical and neurologic examinations were repeated at the final visit (week 30) or at study withdrawal.

Patients were randomized to treatment with either GBP or LTG. Masking was achieved by double-dummy dosing. Randomization was performed with permuted blocks, stratified within each center by seizure type according to whether patients had partial seizures or primary generalized tonic–clonic seizures. Treatment was started with GBP, 600 mg/day, or LTG, 25 mg/day. Doses were increased according to a fixed schedule to GBP, 1,800 mg/day, administered 3 times daily (600, 600, 600 mg), or LTG, 150 mg/day, administered twice daily (75, 0, 75 mg), respectively. Maintenance dosing with GBP was achieved within 2 weeks, whereas for LTG, this took 6 weeks, as recommended in the Data Sheet. During the following 24 weeks, patients continued on the initial maintenance dose (i.e., 1,800 mg/day for GBP or 150 mg/day for LTG) unless intolerable adverse events or further seizures occurred, when adjustment of dosage within the range of 1,200–3,600 mg/day for GBP or 100–300 mg/day for LTG was allowed while maintaining the blind (Fig. 1).

image

Figure 1. Dosage (mg/day) adjustment procedure. GBP, gabapentin; LTG, lamotrigine.

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The primary end point was the time to exit, calculated from the first dose of medication for one of the following events: (a) lack of efficacy at the highest tolerated dose, (b) occurrence of status epilepticus, (c) addition of another AED, or (d) the occurrence of an intolerable adverse event related to study medication. Secondary efficacy parameters included (a) percentage of completers, (b) time to first seizure, (c) percentage of patients who remained seizure free during the final 12 weeks of the 30-week evaluation period, and (d) withdrawal rate for adverse events.

Statistical analyses

The sample size was calculated for the percentage of patients completing the 30-week double-blind phase of the trial. LTG was defined to be the active comparator in this trial, and its survival rate after 6 months was assumed to be 0.65 (3). It was planned to show that the GBP survival rate was not worse than 0.5, corresponding to a hazard ratio of 1.61, which in the protocol was defined as noninferiority. For this, a sample size of 126 patients per group was needed to achieve a power of 95% with a one-sided test at the 5% level. Based on ILAE guidelines (12), the equivalence range was extended to 0.2, corresponding to a hazard ratio of 1.85 and inserted as an amendment to the protocol during the clinical phase of the trial.

Kaplan–Meier estimates were used to describe the distribution of time to exit. The proportional hazards model with treatment and cluster as covariates was used to compare treatment groups statistically. Clusters were generated by pooling study centres into geographic clusters of 20 patients. A center was considered a cluster if ≥20 patients were randomized. Based on this proportional hazards model, a two-sided 90% confidence interval for the ratio GBP/LTG of hazard rates (relative risk) was calculated. A ratio>1 has to be interpreted as favouring LTG. An upper limit of this confidence interval of ≤1.85 was equivalent to proving noninferiority of GBP compared with LTG statistically at the 5% level. In other words, this was equivalent to a rejection of the null hypothesis of inferiority of GBP at the 5% level (one-sided), because the upper limit of a two-sided 90% confidence interval is equal to the upper limit of a one-sided 95% confidence interval. In addition, a proportional hazards model with treatment, cluster, and seizure type (partial and generalized seizures) was fitted to the data.

Completion rates were compared by using the Cochran–Mantel–Haenszel (CMH) χ2 test with adjustment for cluster and, additionally, for seizure type. Generalizability of the difference in completion rates across strata was examined with the Breslow–Day test. A two-sided 95% confidence interval for the difference in completion rates between GBP and LTG was calculated by using a normal approximation to the binomial distribution. Seizure-free rates defined for patients who completed the study and were seizure-free for ≥12 weeks, were compared between groups with the CMH χ2 test adjusting for cluster. Two-sided 95% confidence intervals were calculated for the difference in rates.

The intent-to-treat population was defined as the population of all patients who were randomized and treated with at least one dose of study medication. The evaluable population was defined as the population of all patients in the intent-to-treat population, excluding those with protocol violations (e.g., no diagnosis of epilepsy as defined in the protocol). The primary efficacy analysis was based on the evaluable population as recommended by the ILAE guidelines for noninferiority studies (12). Evaluability was determined by review of the blinded data and assigned before the code break. Tolerability was examined in the intent-to-treat population.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. MEMBERS OF GABAPENTIN STUDY GROUP 945-212
  7. REFERENCES

Patient population

From 315 screened patients, 309 patients were randomized and treated (Fig. 2). Six patients were excluded from the analysis (three were lost to follow-up, three never took the drug). All 309 patients had a follow-up after randomization and could be included in the intent-to-treat population, of which 158 received GBP and 151 received LTG. Of these 309 randomized patients, 10 and eight patients in the GBP and LTG groups, respectively, were excluded for protocol violations (Table 1). Thus 148 patients treated with GBP and 143 treated with LTG represented the evaluable population and were applicable for the appropriate efficacy assessment. The first day of study drug administration was 8 February 1997, and the last day was 9 April 1999. The code was broken on 8 June 1999. A total of 110 (106) patients taking GBP and 100 (96) patients taking LTG completed the study within the intent-to-treat (evaluable) population. Baseline patient characteristics are summarised in Table 2.

image

Figure 2. Trial profile. ITT, intent-to-treat.

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Table 1.  Patient disposition
 GabapentinLamotrigine
  • a

     Patients withdrew for lack of efficacy without dose increase.

Intent-to-treat population158151
Number excluded for reason108
 lack of efficacya53
 No evidence of epilepsy33
 Wrong diagnosis20
 Did not receive randomized treatment01
 Prior antiepileptic drug use01
Evaluable population148143
Completers (evaluable population)10696
Table 2.  Characteristics of evaluable population
VariableGabapentin (n = 148)Lamotrigine (n = 143)
  • a

     One patient was younger than 16 years.

Sex, n (%)  
 Male68 (45.9)84 (58.7)
 Female80 (54.1)59 (41.3)
Race, n (%)  
 White146 (98.6)140 (97.9)
 Asian2 (1.4)3 (2.1)
Age (yr)  
 Mean ± SD35.8 ± 16.437.9 ± 16.7
 Rangea13–7816–78
 Median seizure number34
Seizure type n (%)  
 Partial seizures117 (79.1)116 (81.1)
 Generalised seizures31 (20.9)27 (18.9)
Duration of epilepsy (mo)  
 Median0.30.3
 Range1–5401–66

Primary outcomes

Kaplan–Meier analysis (Fig. 3) of the time to exit, a composite of efficacy and safety, showed no difference between GBP and LTG. In the evaluable population, median time to an exit event was 69 days for GBP and 48 days for LTG. In the analysis using the proportional hazards model, with treatment and cluster as covariates, the ratio of hazard rates of GBP to LTG was estimated as 1.043, with a two-sided 90% confidence interval of 0.602–1.809. Because the upper limit of the confidence interval was ≥1.85 (defined as equivalent in the protocol amendment), GBP and LTG were shown to be statistically equivalent. When patients were stratified by seizure type (partial seizures or primary generalized tonic–clonic seizures), GBP and LTG were still equivalent (90% confidence interval, 0.604–1.807). In the GBP group, 14 (12.0%) of 117 patients with partial seizures and five (16.1%) of 31 patients with generalized seizures had exit events, whereas in the LTG group, 19 (16.4%) of 116 patients with partial seizures and none of 27 patients with primary generalized seizures had exit events.

image

Figure 3. Kaplan–Meier estimate of the time to exit from the study in the evaluable population (hazard ratio, 1.043; 95% confidence interval, 0.602–1.809).

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Secondary outcomes

Overall, 148 (93.7%) of 158 GBP and 143 (94.7%) of 151 LTG patients were evaluable (Table 3). A total of 106 (71.6% of the evaluable population) GBP-treated and 96 (67.1%) LTG-treated patients completed the study [95% confidence interval for differences in rates GBP–LTG (–6.1%; 15.1%)]. Among completers (intent-to-treat population), 74.3% of GBP-treated patients were taking 1,800 mg daily, and 66.7% of patients taking LTG were taking 150 mg daily (Table 4). The highest dose levels (GBP, 3,600 mg/day, or LTG, 300 mg/day) were reached by four (3.7%) and nine (9.1%) patients, respectively. By the end of the study (30 weeks), 80 (75.5%) [(ITT, 83 (76.1%)] patients taking GBP and 73 (76.0%) [ITT, 76 (76.8)] taking LTG remained seizure free during the last 12 weeks of double-blind treatment [95% confidence interval for difference in rates gabapentin–lamotrigine, –12.4%; 11.3% (ITT, –12.2%; 10.9%)].

Table 3.  Completion rate and exist events for the evaluable population
 GabapentinLamotrigine
Evaluable patients148143
Completers10696
Exist events1919
 Lack of efficacy32
 Related adverse event(s)1415
 Status epilepticus00
 Addition of another drug21
 Addition of another drug and   related adverse event(s)01
Other withdrawals2328
 Lack of compliance1214
 Unrelated adverse events37
 Other87
Table 4.  Dosage levels in completers (intent-to-treat population)
DosageGabapentin (n = 109)Lamotrigine (n = 99)
Level 11,200 mg5 (4.6)100 mg5 (5.1)
Level 21,800 mg81 (74.3)150 mg66 (66.7)
Level 32,400 mg19 (17.4)200 mg19 (19.2)
Level 43,600 mg4 (3.7)300 mg9 (9.1)

Kaplan–Meier analysis was undertaken in three of the four secondary outcome parameters (Fig. 4). No difference was evident between GBP and LTG in terms of percentage of completers, time to first seizure, and withdrawal due to adverse events. Such an analysis was not feasible for the percentage of patients remaining seizure free during the last 12 weeks, because this parameter is not event related.

image

Figure 4. Kaplan–Meier estimates from the intent-to-treat population of (a) time to any withdrawal (hazard ratio, 0.899; 95% confidence interval, 0.603–1.342); (b) time to first seizure (hazard ratio, 1.061, 95% confidence interval, 0.758–1.485); and (c) withdrawal rate for adverse events (difference of rates, gabapentin – lamotrigine, 12.0–3.0%).

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Adverse Events

Analysis of tolerability was undertaken in the intent-to-treat population. At least one adverse event was reported by 119 (75.3%) GBP-treated and 114 (75.5%) LTG-treated patients. Severe adverse events were reported in 17 (10.8%) patients taking GBP and 14 (9.3%) patients taking LTG. A total of 16 [14]“serious adverse events” with GBP [LTG] were reported among eight [eight] patients; however, only two were considered related to study drug [one “overdose” on GBP; one “convulsions” (assessed as adverse event by the investigator), with LTG]. The most frequent treatment-related adverse events in both treatment groups were dizziness, asthenia, and headache. Seventeen (10.8%) GBP-treated patients and 23 (15.2%) LTG-treated patients withdrew because of adverse events [95% confidence interval for the difference in rates gabapentin–lamotrigine (–12%; 3%)]. Of these, 14 (8.9%) GBP-treated patients and 15 (9.9%) LTG-treated patients were thought to have had study drug–related adverse events.

LTG-treated patients had slightly more withdrawals due to adverse events during titration [10 (43%) of 23 patients] compared with the GBP group [seven (41%) of 17 patients]. After titration, 10 (32%) of 31 withdrawals in the GBP group were due to adverse events, whereas in the LTG group, the equivalent figure was 13 (46%) of 28 (Fig. 2). Twenty-two (13.9% of the intent-to-treat population) patients in the GBP group and 10 (6.6% of the intent-to-treat population) in the LTG group experienced>7% increase in body weight from baseline. Seven (4.4% of the intent-to-treat population) patients in the GBP group and 16 (10.6% of the intent-to-treat population) taking LTG experienced a skin rash. All were benign, and none progressed to Stevens–Johnson syndrome. No significant changes from screening (before entry into study) were observed in either treatment group in mean heart rate or systolic or diastolic blood pressure.

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. MEMBERS OF GABAPENTIN STUDY GROUP 945-212
  7. REFERENCES

LTG has been compared with CBZ and PHT in randomised, double-blind trials in newly diagnosed patients with partial and generalised tonic–clonic seizures (3,9,13). These studies supported similar efficacy for LTG with better tolerability than for the standard AEDs. GBP also has been shown to be effective as monotherapy in adults with partial seizures (7,14,15). The present study demonstrated that GBP is similarly effective to LTG in terms of seizure control and tolerability in patients with partial seizures with or without secondary generalisation or primary generalised tonic–clonic seizures.

The trial design allowed dosage adjustment similar to that in clinical practice in accordance with the recommendations of the ILAE guidelines (12). The majority of patients were well controlled on the daily maintenance doses of 1,800 mg GBP or 150 mg LTG, whereas the maximal GBP and LTG dosages (3,600 mg and 300 mg daily, respectively) were required by only 3.7% of GBP and 9.1% of LTG patients. A reduction in dosage from maintenance was undertaken in only 4.6% of the patients treated with GBP and in 5.1% of those receiving LTG. The good tolerability profile of GBP was evident in an earlier monotherapy study in which only 6% of patients who received GBP withdrew because of adverse events, compared with 24% of patients taking CBZ (7). In other studies, GBP has been found to be well tolerated at daily doses of 2,400 to 4,800 mg (14–19). This study supports the recent observation that most patients responding to their first AED do so at moderate dosage (20).

Patients with newly diagnosed epilepsy cannot easily take part in placebo-controlled monotherapy studies for ethical reasons. Efficacy may be assumed if equivalence or noninferiority between the newer agent and a comparator can be established. By using an active-controlled design, it was expected that the sample size calculated for this study was large enough that a clinically meaningful difference between the two treatments, if present, could be detected. In a trial designed to show the equivalence of two treatments or noninferiority (one-sided equivalence) of a new treatment compared with a standard treatment for the primary outcome, the definition of “equivalence” must be stated in the trial protocol. The margin of clinical equivalence is then chosen by defining the largest difference that is clinically acceptable. If the parameter of interest is the time to a specified event (e.g., exit) as in the present study, there are several possible ways to define equivalence. The definition could be based on the proportion of patients “surviving” at time t (i.e., not having had the event up to time t; e.g., not withdrawn at time t); t would be the duration of the trial. If S1(t) is the proportion of patients surviving at time t for the standard treatment, and S2(t) is the corresponding survival rate for the new treatment, equivalence can be defined in absolute terms as

  • image

or in relative terms as:

  • image

As discussed by Chow and Liu (21), the equivalence range should be narrower for S1(t) (i.e., close to 1) than for the smaller S1(t).

Alternatively, the definition could be based on the probability distribution of the time to event. For this purpose, it is common to assume proportional hazards between the new and standard treatment. Then the following relation holds between the two survival functions.

  • image

where r is the (constant) ratio of hazard functions (the hazard ratio). Equivalence could then be defined as

  • image

Figure 5 shows the relation between the three relevant quantities S1(t), S2(t), and r. The lines correspond to a constant hazard ratio. Requiring the hazard to be between 0.8 and 1.2 in the definition of equivalence is much stricter than requiring the survival rates not to differ by>0.2. Furthermore, if the survival rate is close to 1, the definition via the hazard ratio is stricter than if it is close to 0.5. In the present study, the primary efficacy parameter was time to exit from the study, defined as withdrawal due to lack of efficacy or drug-related adverse events, a compound outcome.

image

Figure 5. Relation between three relevant quantities S1(t), S2(t), and r, where S1(t) is the proportion of patients surviving at time t for the standard treatment, S2(t) is the corresponding survival rate for the new treatment, and r is the (constant) ratio of hazard functions (the hazard ratio). The risk difference with a fixed difference of 0.2 also is presented.

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LTG was considered the standard treatment, and its survival rate after 6 months (3) was assumed to be 0.65 (left vertical line in Fig. 5). It was planned to show that the GBP survival rate was not worse than 0.5 (a risk difference of 0.15). This corresponds to a hazard ratio of 1.61, which was defined as noninferiority. Based on the recently published ILAE guidelines (12), the equivalence range was widened to 0.2, corresponding to a hazard ratio of 1.85 in an amendment to the protocol inserted before unblinding the trial. This widening of the hazard ratio was dependent on the interpretation of ILAE guidelines as excluding a risk difference of 0.20. These guidelines, however, do not specify whether the exclusion of a 20% variation in either risk difference or hazard ratio would be acceptable. On clinical grounds, the difference between 65% continuing on standard treatment at 6 months compared with 50% remaining on a new treatment could be regarded clinically as too large.

Results showed that the survival rates were ∼0.85 (right vertical line in Fig. 5). In this situation, a hazard ratio of 1.85 becomes a stricter requirement of noninferiority [S2(t) 0.74; i.e., at most 11% worse (0.85–0.74 = 0.11)] than if the survival rate for LTG had been 0.65 [S2(t) 0.45; i.e., at most 20% worse (0.65–0.45 = 0.20]. If the primary efficacy parameter had been time to withdrawal for any reason, the assumptions underlying the sample-size calculations would have been more appropriate. Clearly, there is a need for consensus around definitions for equivalence and noninferiority for the commonly used time-related outcomes in epilepsy trials.

The results of this study have implications for the management of newly diagnosed epilepsy. GBP, by virtue of its favourable tolerability profile and short titration period, can be considered an alternative to standard first-line AED therapy in patients with newly diagnosed partial and tonic–clonic seizures. From a statistical (i.e., more theoretic) point of view, the study also provides an insight into the importance of how to define equivalence or noninferiority in comparative monotherapy trials, when the primary efficacy parameter is of the type “time to event.”

MEMBERS OF GABAPENTIN STUDY GROUP 945-212

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. MEMBERS OF GABAPENTIN STUDY GROUP 945-212
  7. REFERENCES

S. Arroyo (Madrid, Spain), G. Bauer (Innsbruck, Austria), S. Berkovic (Heidelberg, Australia), M. J. Brodie (principal investigator; Glasgow, U.K.), D.W. Chadwick (Liverpool, U.K.), P. Cleland (Sunderland, U.K.), M. Cook (Fitzroy, Australia), G. Danta (Canberra, Australia), E. Deisenhammer (Linz, Austria), F. Donati (Bern, Switzerland), M. Dumas (Limoges, France), R. Duncan (Glasgow, U.K.), D. Flügel (Regensburg, Germany), G.H.P. Franck (Liège, Belgium), E. García-Albea (Alcala de Henares, Spain), J.L. Gastaut (Marseille, France), A. Gonzales (Valencia, Spain), J. Haan (Mönchengladbach, Germany), G. Herkes (Chatswood, Australia), P. Jallon (Geneva, Switzerland), M. Kerr (Cardiff, U.K.), A. Kowalik (Stuttgart, Germany), M. Maillet-Vioud (Montlucon, France), B. Mamoli (Wien, Austria), C. Marchal (Bordeaux, France), R. Massot (Tarragona, Spain), Z. Matkovic (Parkville, Australia), F. Mauguière (Lyon, France), D. McLaughlin (Herston, Australia), P.P.M. Menage (Tours, France), A. Molins (Girona, Spain), R. Murphy (Dublin, Ireland), S. Noachtar (München, Germany), B. Pohlmann-Eden (Mannheim, Germany), P. Rey Del Corral (La Coruna, Spain), E. Somerville (Westmead, Australia), S. Stodieck (Münster, Germany), T. Strauven (Wilrijk, Belgium), B. Wendtland (Grevenbroich, Germany), O. Witte (Düsseldorf, Germany), A. Zabala (Madrid, Spain)

Acknowledgment: The study was sponsored by Parke-Davis GmbH Freiburg (PD), a company of Pfizer Inc.

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. MEMBERS OF GABAPENTIN STUDY GROUP 945-212
  7. REFERENCES
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