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Comparison of twice- and three times daily tiagabine for the adjunctive treatment of partial seizures in refractory patients with epilepsy: an open label, randomised, parallel-group study Volume 3, issue 2, June 2001

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Epilepsy is the most common serious neurological condition of adults and children, occurring in approximately 50 million people worldwide [1]. Amongst the variety of different seizure types that are encountered, partial seizure is the most common [2]. Therapy for epilepsy has been available for many years but in about 30% of patients, drug treatment, often with multiple medications, fails to prevent seizures. There is therefore a continuing need to develop more effective treatments and add-on therapies with improved safety and tolerability profiles especially for refractory patients in whom seizure control is a particular problem [3, 4].

Tiagabine belongs to the new class of antiepileptic drugs (AED) and is indicated as an add-on medication for the treatment of partial seizure in patients over 12 years of age. Tiagabine increases synaptosomal concentrations of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) by blocking reuptake into both pre-synaptic neurones and glial cells, allowing GABA to remain at the site of action for longer periods. This increase in GABA concentration at the synapse results in potentiation of GABA-mediated inhibitory neurotransmission. Tiagabine, unlike several other AEDs, lacks significant affinity for other neurotransmitter receptor binding sites and/or uptake sites [5]. The fact that the mode of action of tiagabine is specific and well-defined offers clear advantages, as the importance of understanding the basic mechanisms of action of drugs has been acknowledged as a rational approach to selecting antiepileptic drugs [6].

Tiagabine is rapidly absorbed after oral administration, and its pharmacokinetics are linear. Extensive metabolism of the drug occurs in the liver mainly via the isoform CYP3A4 of the cytochrome P450 family and breakdown products are mostly excreted into the bile. Consequently, little tiagabine is excreted in the urine and renal impairment does not alter the elimination rate whereas the half-life is prolonged in patients with hepatic impairment. Tiagabine does not cause induction or inhibition of cytochrome P450. Conversely, the clearance of tiagabine is affected by the co-administration of hepatic enzyme-inducing antiepileptic drugs. The elimination half life of 7-9 hours in patients taking non-enzyme inducing medication decreases to 2-3 hours in patients taking enzyme-inducing medication. As a result of the rapid absorption and elimination, frequent dosing is necessary and the drug is required to be taken with food [7-9].

Tiagabine has proven efficacy in clinical trials and in general clinical use. A meta-analysis assessed experience of tiagabine treatment in five add-on, placebo-controlled trials and six non-comparative, open-label, long-term multicentre trials in Australia, Europe and the USA involving 2,261 patients of a wide age range [10]. Tiagabine was effective as an add-on therapy in patients in whom epilepsy was difficult to control with existing therapies. Efficacy was also maintained during long term therapy. A clear dose response was demonstrated; the recommended maintenance dose for tiagabine when combined with enzyme-inducing drugs is 30 to 50 mg/day [7]. In patients not taking enzyme-inducing drugs, the recommended maintenance dose is 15-30 mg/day. During long-term therapy with tiagabine, no new or more severe adverse events occurred.

To date, approximately 90,000 patients have been treated with tiagabine. Its safety profile is well known and no serious adverse events have been consistently associated with its use. Adverse events are generally mild and mainly neurological [11]. No cognitive, memory or psychomotor side effects on tiagabine treatment have been reported [12, 13]. The adverse events described were mostly transient and occurred mainly during the titration period; they resolved on adjustment of the dose or discontinuation.

A substantial proportion of patients in clinical trials with tiagabine have received four daily dosages (q.i.d.), but twice daily (b.i.d.) and three times daily (t.i.d.) regimens have been shown to be efficacious in add-on, placebo-controlled trials. In the open-label, long-term add-on studies, the majority of patients were maintained on effective and well-tolerated dose levels in a t.i.d. regimen [10, 14]. Thus t.i.d. is currently considered as the recommended dose frequency. As comparative data for tiagabine t.i.d. versus b.i.d. are currently not available, this study was designed to allow a direct comparison between the two regimens.

Methods

Patients

Patients were required to have been diagnosed with epilepsy with partial seizures, with or without secondary generalisation, at least six months prior to study entry and must have had at least four partial seizures during an eight-week period before study start. The patients were also required to be taking a stable regimen of one to four AEDs and to be at least 12 years of age. Males and females were included. Women of childbearing potential were required to be non-pregnant and practising contraception on a regular basis throughout the study. Patients were required to give written informed consent before starting the medication. The study was approved by an Ethics Review Committee and conducted according to Good Clinical Practice and the Declaration of Helsinki as amended.

Design

This study was an open label, randomised, parallel group study, with an initial fixed schedule titration period of add-on tiagabine in patients with partial seizures, followed by an open continuation phase and was conducted at 63 clinical centres in France.

Patients who fulfilled the inclusion criteria were randomised to receive tiagabine treatment either b.i.d. or t.i.d. Tiagabine (Gabitril®) was supplied by Novo Nordisk as 5, 10 and 15 mg tablets to make up the required dose; the medication was taken with food.

The study schedule is given in figure 1. The first 12 weeks was a fixed-schedule titration period. After the first dose of tiagabine, the patients attended the clinic every four weeks until Visit 4 during which time the dose was titrated from an initial 10 mg/day to a target 40 mg/day. This total daily dose was given as a b.i.d. or t.i.d. regimen and was increased in two 5 mg and then two 10 mg increments to achieve a daily dose of 30 mg within 3 weeks and 40 mg within 6 weeks. If patients were unable to tolerate a dose increase step, they were maintained on the highest dose level they could tolerate at the same dosing frequency.

After 12 weeks the patients entered a 12-week flexible continuation period during which the b.i.d. or t.i.d. regimens were continued at the same dose level. At this stage the dose could be altered for the benefit of the patient if it was considered necessary by the investigator, within the range of 30-70 mg/day. The protocol was also amended so that patients who experienced limiting adverse events at the lowest target dose could be permitted to continue the study at a lower dose (minimum 15 mg/day).

Pre-treatment general medical, neurological and psychiatric histories, epilepsy aetiologies and seizure history (including seizure type and frequency) were recorded for each patient. Seizure types were classified according to the guidelines of the International League Against Epilepsy [15]. All patients were given a complete physical and neurological examination. Concomitant medications and all previous anti-epileptic drugs were recorded. Blood samples were taken for screening standard laboratory parameters (biochemistry and haematology) and for the determination of plasma concentrations of concomitant medications if deemed appropriate by the investigator. An electroencephalogram (EEG) was also performed in those patients who did not have an EEG recording.

Seizure occurrence, seizure interval history, compliance, concomitant medications, concomitant illnesses and adverse events were monitored at every visit. Each patient with an adverse event was monitored until clinical recovery was complete or the condition had stabilised. Laboratory analyses, plasma levels of concomitant AEDs (where appropriate), physical and neurological examinations, and monitoring of seizure severity were performed at regular intervals.

Statistical analysis

There were two analysis populations, the intent-to-treat population (ITT) which was all patients randomised who received at least one dose of medication, and the patients with seizure data (PwSD) population who were those in the ITT population who provided seizure data for the entire fixed-schedule titration period of the study; this included patients with evidence of being seizure-free during the period.

The primary endpoint was the proportion of patients remaining in the study to the end of the fixed-schedule titration period (ITT population). The two treatments were compared using a logistic regression model including terms for region, inducer/non-inducer (i.e. whether one or more enzyme-inducing concomitant AEDs were prescribed), age and gender. The main secondary efficacy endpoint was the percentage change in seizure rate from baseline (as retrospectively assessed over the eight weeks prior to entry into the study) to 12 weeks (the PwSD population). The treatments were compared using van Elteren's method (stratifying by region). The seizure rate for a period was calculated as the number of seizures occurring in the period divided by the number of days in that period, then multiplied by 28 (i.e. the seizure rate is presented as seizures per 28 days). Other endpoints included the analysis of responders and seizure free patients for both categories, using Fisher's exact test (ITT population). The responders were defined as the patients who experienced a decrease in the rate of any type of seizure of at least 50% from baseline during the final four weeks of the fixed titration period. Seizure free patients were defined as the patients who experienced no seizures during the whole flexible continuation phase. Numbers of responders and seizure-free patients were also calculated for the last eight weeks of the flexible continuation phase. For the safety endpoints (all "time to" endpoints) the treatments were compared using a Cox semi-parametric regression, including the same terms as in the primary analysis. In addition, the number of withdrawals as a function of time, AED medication (history and concomitant), compliance assessment and mean dose by treatment group were analysed.

Supplementary analyses were also carried out: analyses on the proportions of seizure free patients and responders (ITT population) as well as the percentage change in seizure rate (PwSD population) were repeated for the different categories of seizure type, and for all seizure types, excluding status epilepticus to avoid the bias possibly introduced when counting status epilepticus as the reoccurrence of a given seizure type. Analysis were also performed for inducers and non inducers.

All statistical significance tests were two-sided with a significance level of 0.05. All data summaries and analyses were produced using SAS version 6.12 for Windows, with the exception of the exact analysis for the primary endpoint which was performed using LogXact version 2.1 [16, 17].

Results

Patient disposition

A total of 353 patients were randomised, of whom six did not receive any treatment. The ITT population was therefore 347 patients, 175 randomised to b.i.d. and 172 to t.i.d. tiagabine (figure 2). The PwSD population comprised 265 patients, 126 in the b.i.d. group, 139 in the t.i.d. group.

The overall study duration was 13 months. Table I summarises the patient characteristics at baseline. The treatment groups were well-matched. The most frequent type of seizure was complex partial, and the mean time since patients experienced their first seizure was 20.5 years in each group. Epilepsy cause was not specified in more than 50% patients; the most frequent epilepsy etiologies were ante- and peri-natal injury, congenital abnormality, infections, or genetic propensity. Most patients were taking 2 or 3 concomitant AEDs at baseline; 19 (10.9%) in the b.i.d. group and 20 (11.6%) patients in the t.i.d. group were taking only one AED at baseline.

Dosing and concomitant medications

The mean daily doses of tiagabine in the ITT population during the fixed-schedule titration period, for the b.i.d. and t.i.d. groups respectively, were 26.8 (range 10-36) mg/day and 27.5 (range 10-37) mg/day. The mean dose achieved at week 12 was 34.6 mg/day in the b.i.d. group and 35.5 mg/day in the t.i.d. group and then stabilised for the remaining 12-week treatment period. Daily doses at week 12 and during the flexible continuation phase for inducers and non-inducers are summarised in table II.

Compliance with study treatment was good, with only a few patients deemed non-compliant (1% of patients were found non-compliant at two visits).

After 12 and 24 weeks, doses of the most frequently taken concomitant AEDs were similar to those taken at baseline and were also similar in both treatment groups. The most frequent concomitant medications were carbamazepine, valproate, lamotrigine, phenobarbitone and vigabatrin. The numbers of patients taking each of these drugs was similar for the b.i.d. and t.i.d. groups.

Study discontinuations

A total of 77 patients (44%) on b.i.d. tiagabine and 58 (33.7%) on t.i.d. tiagabine withdrew from the study. Of these, 46 (26.3%) and 37 (21.5%) withdrew due to adverse events, 22 (12.6%) and 15 (8.7%) withdrew due to lack of efficacy and 9 (5.1%) and 6 (3.5%) withdrew for other reasons, for b.i.d. and t.i.d. dosing respectively. The total daily doses taken at withdrawal date for patients who withdrew from the study are summarised in table III. Although some patients tended to discontinue at lower doses in the b.i.d. group compared to the t.i.d. group, the dose at withdrawal was 30 mg daily or greater in most patients, with a large proportion of patients who discontinued the study receiving 40 mg daily or greater.

Proportion of patients completing the fixed-schedule titration period (primary end point)

A statistically significantly smaller proportion of patients in the b.i.d. group (128 patients, 73.1%) than in the t.i.d. group (140 patients, 81.4%) completed the 12-week fixed schedule titration period (odds ratio = 0.571, 95% CI: 0.331, 0.970, p = 0.0383) (figure 3).

Efficacy

The percentage changes in seizure rates for each patient during the fixed-schedule titration period are summarised in table IV. There were slightly greater reductions in the occurrence of all-seizure types, simple-partial seizures and complex-partial seizures in the t.i.d. than in the b.i.d. groups. None of these differences were statistically significant although statistical significance was approached for all seizure rate (p = 0.08). For secondary generalised tonic-clonic seizures the b.i.d. treatment group showed a slight decrease in seizure rate whereas the t.i.d. treatment group showed a slight increase (p = ns).

The median percentage decrease in the rate of all types of seizure (but excluding status epilepticus) during the 12-week fixed schedule titration period (PwSD population) was 27.3% for the b.i.d. and 34.1% for the t.i.d. groups (p = ns). During the flexible continuation phase, the seizure frequency contin-ued to decline slightly and the median seizure rates were 4.3 and 4.4 per patient in the b.i.d. and t.i.d. groups, respectively.

The proportions of responders and non-responders in each treatment group for the fixed-schedule titration and contin-uation phases are given in figure 4. In both cases, percentages of responders in the t.i.d. group (47.1% when looking at the last eight weeks of treatment) and in the b.i.d. group (42.3%) were not different (p = ns).

Five (2.9%) patients in the b.i.d. and ten (5.8%) patients in the t.i.d. group were seizure-free during the entire continuation phase (p = ns). During the last eight weeks of this phase, seven (4%) and 14 (8.1%) of patients in the b.i.d. and t.i.d. groups respectively were seizure free (p = ns).

Analyses of seizure free patients and responders were repeated for four categories of seizure type (excluding status epilepticus) and results are presented in table V. There were similar proportions of seizure-free patients with complex seizures in the b.i.d. and t.i.d. groups but slightly more seizure-free patients with simple seizures in the t.i.d. group, and slightly fewer seizure-free patients with secondary generalised seizures. Nevertheless, there were no significant differences between the treatment groups for these seizure types. Similarly, the proportions of responders were similar for both treatment groups for any of the seizure types.

The numbers of patients taking enzyme-inducing and non-enzyme-inducing medication (inducers and non-inducers) who completed the fixed-schedule titration period and the flexible continuation phase are also given in figure 2. For the inducers, 101 (78.9%) patients in the b.i.d. group completed the fixed-schedule titration period compared to 110 (89.4%) in the t.i.d. group. This difference was statistically significant (odds ratio = 0.431, 95% CI: 0.204, 0.874, p = 0.0192). For the non-inducers, there was no significant difference between the treatment groups with 27 (57.4%) patients in the b.i.d. group completing the fixed-titration compared to 30 (61.2%) non-inducers in the t.i.d. group. When analyses of responders and seizure free patients were repeated for inducers and non-inducers, both treatment groups remained comparable.

Safety

A total of 149 (85%) patients in the b.i.d. group and 141 (82%) in the t.i.d. group reported at least one adverse event (AE) during the fixed schedule titration period. In the b.i.d. and t.i.d. groups respectively, 49 (28%) and 38 (22%) patients had at least one AE which led to discontinuation. In the flexible continuation phase there were fewer AEs which occurred in 51 (29%) patients in the b.i.d. group and 52 (30%) patients in the t.i.d. group. Five (3%) patients in each group withdrew due to at least one AE during this phase.

Table VI lists the treatment-emergent AEs which occurred most frequently during the fixed-schedule titration period. AEs were generally evenly balanced between groups. The majority of AEs were CNS-related, somnolence, dizziness, asthenia and tremor being the most frequent. Adverse events that occurred during this period were most frequently mild or moderate. Twenty one (12%) patients in the b.i.d. group and 23 (13%) in the t.i.d. group reported AEs of a severe nature. For both treatment groups, the only severe AEs reported by more than one patient were events of the nervous system.

The most frequent AEs that started during the 12-week flexible continuation phase were also CNS-related, with 31 (18%) patients in the b.i.d. group and 37 (22%) patients in the t.i.d. group reporting at least one AE. All of the AEs that started in the flexible continuation phase were reported by fewer than 5% of patients in either group and were mainly mild. The most frequent AE was tremor (3 and 4% for the b.i.d. and t.i.d. groups respectively).

Further to the report of visual field defects associated with the use of vigabatrin, the possibility that GABAergic compounds may induce such toxicity has been largely debated and thus close attention has been paid to the review of ophthalmological adverse events. Only non-specific visual disturbances were reported during the fixed-schedule titration period: diplopia was reported in seven (4%) patients in each treatment group; abnormal vision (five [3%] patients in the b.i.d. group and four [2%] patients in the t.i.d. group); and amblyopia (three [2%] and four [2%] patients, respectively). During the continuation period, abnormal vision was reported by one patient (1%) in each group.

Analysis of time to withdrawal due to an AE in the fixed-schedule treatment phase revealed no difference between groups although statistical significance was approached (p = 0.07), nor did the analysis of time to experiencing an AE (p = ns). The median time to experiencing an AE was 22.0 days for each treatment group (figure 5). The probability of not experiencing an AE decreased sharply during the first 3-4 weeks of treatment starting at 1.0 and stabilizing at around 0.2 after approximately six weeks.

Three patients died during the study (two accidental injuries, one sudden death). None of these events were considered likely to be related to the study drug.

Five patients in the b.i.d. group and two patients in the t.i.d. group had a serious adverse event which was considered to be possibly or probably related to the study drug. These were confusion (2 patients), psychosis, depression and dysarthria (b.i.d.) and amblyopia and paranoid reaction (t.i.d.). Four patients in the b.i.d. group and two patients in the t.i.d. group had the study drug discontinued as a result of one or more SAEs. There was only one SAE that did not resolve completely (CNS neoplasia).

There were no notable changes in mean clinical chemistry values from the baseline visit to week 12 or week 24 for both treatment groups. No clinically significant changes in haematology values or vital signs were observed during the study.

Discussion

This study was designed to compare two dosing regimens, b.i.d. and t.i.d., of tiagabine given as add-on treatment to refractory patients with partial epilepsy. The primary endpoint (the proportion of patients in each treatment group completing the fixed-schedule titration period) contains both efficacy and safety components, and showed a significant difference in favour of the t.i.d. regimen. Statistical significance was not reached for any of the efficacy analyses comparing both dose regimens, although slight treatment differences were found. When looking at the decrease from baseline in seizure frequency during the fixed-schedule period, there was a trend in favour of the t.i.d. treatment regimen. The proportions of seizure-free patients and responders for all seizure types and for simple, complex and generalised seizures did not differ substantially between the treatment groups, whatever study period was considered. Overall, an improvement in seizure reduction was still observed during the flexible continuation phase, thus confirming that efficacy is maintained in the longer term.

The efficacy results reported in this large population of refractory patients are generally in agreement with those previously published for both long- and short-term administration of tiagabine in such patients [18]. With 42.3 and 47.1% of patients having a 50% decrease or more in the rate of any seizure in the b.i.d. and the t.i.d. groups respectively, and more than 60% of patients having a 50% decrease or more in the rate of complex partial seizure in both groups, these data confirm that tiagabine is a valuable add-on treatment and compares favourably with other new AEDs given as add-on treatment to refractory patients.

Percentage responders (>= 50% reduction in seizure rates) in a study comparing topiramate with placebo were 27-46% for topiramate over a dose range of 200-600 mg/day, and 18% for placebo [19]. Treatment with zonisamide for 12 weeks, with a mean dose of 7.0 mg/kg being achieved at the end of the study, resulted in 29.9% of patients recording a 50% reduction of all seizures compared to 9.4% for placebo [20]. A similar response rate was reported in a placebo-controlled study on gabapentin in which 22.9% of patients had a 50% reduction in seizure frequency when receiving 900 mg/day of gabapentin (the response rate increased to 28% in the 1,200 mg treatment group) [21]. In a recent study comparing divalproate with placebo, 38% of 74 divalproate-treated patients completed the study with a seizure reduction of at least 50%, compared to 19% of 63 receiving placebo, and six patients were seizure-free [22]. When the efficacy of lamotrigine (300 and 500 mg daily) as add-on therapy was assessed compared to placebo, seizure frequency decreased by 50% or more in one third of the 500 mg group and one-fifth of the 300 mg group [23].

There were no notable differences between the treatment groups with regard to their safety profile. The most common adverse events were CNS related and were most often of mild intensity. There were slightly more serious adverse events possibly or probably related to tiagabine in the b.i.d. group than in the t.i.d. group (5 respectively 2). The type of adverse events and their frequency of occurrence were as expected based on previous experience of tiagabine administration and were similar to those previously reported in the literature [11, 16].

The most frequent reason for premature discontinuation from the study was related to adverse events and tended to occur at rather high doses in both groups. The protocol had to be amended during the course of the study in order to allow patients experiencing limiting AEs at 30 mg/day to continue the study using doses as low as 15 mg/day.

The fact that there was a significant difference between treatment groups in the numbers of patients completing the study for inducers (who received higher doses) as opposed to non-inducers also tends to support the conclusion that the t.i.d. regimen seems to offer some advantages over the b.i.d. regimen more particularly when high doses are administered, while at lower doses, both regimens would appear similar.

Most AEs started during the initial period of the study (around 3 weeks) and nearly all discontinuations due to AEs occurred during this fixed-scheduled titration period thus indicating improved patient tolerance after an initial adjustment period. No statistically significant differences between groups were evident although observed treatment differences tended to favour the t.i.d. regimen with b.i.d. patients tending to discontinue due to AEs earlier than t.i.d. patients. Of interest was that few discontinuations occurred in the t.i.d. group until a daily dose of 30 mg was achieved, while in the b.i.d. group, 20% discontinuations were recorded at the 20 mg dose level (compared to 6.9% in the t.i.d. group). These findings confirm that a careful titration of patients commencing tiagabine therapy may be necessary for the drug to achieve its full therapeutic potential. Indeed, when initiating therapy with tiagabine, it is critical that each patient is titrated by a gradual increase in dose to a tolerable target level. If the patient reacts to an increased dose, it is important that the dose is temporarily reduced to a tolerable level before possible further titration at smaller increments or maintenance of the existing dose. This is a more rational strategy than stopping tiagabine treatment and changing to an alternative therapy which also may require titration and adjustment. Prescribers who are now familiar with tiagabine advocate use of a slower titration scheme than the one formally recommended, i.e. initiation of treatment with 5 mg daily, and then to gradually increase the dose by weekly increments of 5 mg [24]. Should such recommendations have been implemented in our study and the use of lower doses permitted from the beginning, it seems probable that the overall tolerability would have improved, particularly for those patients who received the drug twice daily and were therefore more likely to be exposed to higher plasma concentrations. If the use of several divided doses should remain the rule in patients receiving high doses of tiagabine, our results confirm that patients who are maintained at daily doses around 30 mg or less can benefit from the use of b.i.d. regimen. In a group of patients who are not always willing or competent to adhere to frequent medication regimens, being able to reduce the number of daily intakes of the drug even at high doses would undoubtedly lead to greater convenience and potentially better compliance and some authors have actually previously underlined the need for a slow release formulation [1]. These results confirm that tiagabine given either b.i.d. or t.i.d. is effective and well tolerated as add-on treatment in refractory patients with partial seizures provided appropriate dosing recommendations are carefully followed.

CONCLUSION

Acknowledgements: We acknowledge the contribution of the following Study Group participants: C. Allaire, Rennes; L. Arbus, Toulouse; A. Autret, Tours; N. Ayrivie, La Rochelle; M. Baldy-Moulinier, Montpellier; M. Baulac, Paris; C. Belin, Bobigny; C. Billard, Tours; J. Boulliat, Bourg-en-Bresse; T. de Broucker, Saint-Denis; P. Chauvel, Rennes; J.-P. Chodkiewicz, Paris; P. Contis, Colomiers; P. Convers, Saint-Étienne; C. Degos, Paris; P. Derambure, Lille; B. Duche, Talence; O. Dulac, Paris; B. Dupuy, Cherbourg; G. Durand, Nice; G. Fanjaud, Castres; D. Felten, Paris; M. Fohlen, Paris; A. Garde, Lyon; S. Garrel, Grenoble; J.-L. Gastaut, Marseille; C. Gauthier, Paris; P. Genton, Marseille; R. Gil, Poitiers; P.-M. Gonnaud, Pierre-Bénite; O. Guard, Dijon; B. Gueguen, Paris; M. Haguenau, Paris; M. Helias, Mortagne-au-Perche; H. Isnard, Lyon; H. Jeudi de Grissac, Chateaulin; M. Mann, Paris; C. Marchal, Bordeaux; C. Marescaux, Strasbourg; F. Mauguière, Lyon; B. Montagne, Roubaix; J. Motte, Reims; D. Parain, Rouen; J.-C. Pechadre, Clermont-Ferrand; J.-M. Pedespan, Bordeaux; M.-C. Perrier, Leguevin; J.-M. Pinard, Garches; J. Reis, Sarreguemines; C. Remy, Roman; M. Rey, Marseille; M. Serre, Corbeil-Essonnes; C. Tannier, Carcassonne; P. Tapie, Limoges; P. Thomas, Nice; L. Vallée, Lille; H. Vespignani, Nancy; M. Vidart, Créteil.

We gratefully acknowledge L. Merlet for the statistical analysis and M.-C. Minjoulat-Rey, MD for coordinating the manuscript.

This study was sponsored by Sanofi-Synthelabo.

Received February 23, 2001 - Accepted May 7, 2001