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Keywords:

  • Levetiracetam;
  • Epilepsy;
  • Add-on therapy;
  • Partial-onset seizures;
  • Refractory seizu-res;
  • Chinese patients.

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Purpose: To evaluate efficacy and tolerability of levetiracetam (LEV; Keppra®) as add-on therapy in Chinese patients with refractory partial-onset seizures.

Methods: In this multicenter, double-blind, randomized, placebo-controlled trial, 206 patients aged 16–70 years with uncontrolled partial-onset seizures were randomized to receive LEV (n =103) or placebo (n =103); 202 patients (LEV, n =102; placebo, n = 100) comprised the intent-to-treat population. An 8-week historical baseline period confirmed eligibility according to seizure count. The 16-week treatment period consisted of a 4-week up-titration period (LEV, 1,000–3,000 mg/day in two equal divided doses) followed by a 12-week maintenance period. Efficacy assessments were based on weekly frequency of partial-onset seizures during the 16-week treatment period.

Results: LEV significantly decreased weekly partial-onset seizure frequency over placebo by 26.8% (p  < 0.001). Median percentage reductions in weekly partial-onset seizure frequency from historical baseline were 55.9% for LEV and 13.7% for placebo (p  < 0.001). The ≥50% responder rates were 55.9% for LEV, compared with 26.0% for placebo (p  < 0.001). Freedom from partial-onset seizures during treatment period was achieved by 11 LEV patients (10.8%) and 2 placebo patients (2.0%) (p = 0.012). Adverse events were reported by 65 LEV-treated patients (63.1%) and 62 placebo-treated patients (60.2%); most were of mild-to-moderate intensity. The most common adverse events were somnolence (LEV, 17.5%; placebo, 17.5%), decreased platelet count (LEV, 9.7%; placebo, 9.7%), and dizziness (LEV, 7.8%; placebo, 13.6%).

Discussion: Add-on LEV was effective and well-tolerated in Chinese patients with refractory partial-onset seizures.

Levetiracetam (LEV; Keppra®), (S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, is a newer antiepileptic drug (AED). Three pivotal double-blind, placebo-controlled clinical trials conducted in the U.S.A. and Europe have confirmed that LEV is effective and well-tolerated as add-on treatment of partial-onset seizures in adults (Ben-Menachem & Falter, 2000;  Cereghino et al., 2000;  Shorvon et al., 2000). More recently, add-on LEV has been shown to be effective in controlling treatment-resistant partial-onset seizures in children ≥4 years of age ( Glauser et al., 2006). As monotherapy, LEV was equivalent to controlled-release carbamazepine as a first treatment in adults newly diagnosed with epilepsy characterized by partial or  generalized tonic–clonic seizures ( Brodie et al., 2007). LEV has a broad spectrum of activity, supported by recent double-blind studies that demonstrated its effectiveness as add-on therapy in myoclonic seizures ( Noachtar et al., 2008) and primary generalized tonic–clonic seizures ( Berkovic et al., 2007) in patients with idiopathic generalized epilepsies.

The synaptic vesicle protein, SV2A, has been identified as the binding site for LEV ( Lynch et al., 2004). The unique pharmacologic profile of LEV in animal models of seizures and epilepsy indicates that it has a mechanism of action distinct from that of other AEDs ( Margineanu & Klitgaard, 2000;  De Smedt et al., 2007;  Kaminski et al., 2008). Therefore, it is assumed that the efficacy and tolerability profiles may differ from those of conventional AEDs.

Studies in healthy Western populations have established that LEV has a favorable pharmacokinetic profile with rapid and complete oral absorption, linear pharmacokinetics, and a low potential for clinically significant pharmacokinetic drug interactions ( Perucca et al., 2003;  Strolin Benedetti et al., 2003;  Patsalos, 2004). Comparisons of adult Chinese and Japanese populations with Western subjects have pointed to an absence of significant ethnic differences in the pharmacokinetics of LEV, suggesting a similar efficacy and tolerability profile in different ethnic populations ( Pigeolet et al., 2007;  Zhao et al., 2007). In support of this, a multicenter, open-label, single-arm trial confirmed that LEV was an effective and generally well-tolerated add-on therapy for Korean patients with refractory partial seizures ( Heo et al., 2007). In the current study, we report the efficacy and tolerability of LEV as add-on therapy in Chinese patients with refractory partial-onset seizures, with or without secondary generalization. This study was performed to confirm the results obtained from Caucasian populations in Chinese patients with epilepsy. This was the first placebo-controlled, randomized trial assessing efficacy and tolerability of LEV conducted in mainland China.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Study design

This study was a randomized, double-blind, placebo-controlled, parallel group study (study no. N01102; http://clinicaltrials.gov, identifier NCT00152373), which was conducted between July 2004 and May 2005 at six centers in China. LEV at a dose of 3,000  mg/day (1,500  mg twice daily) was compared with placebo as add-on therapy in patients with treatment-refractory partial-onset seizures, with or without secondary generalization. The study period lasted for 24  weeks (8-week historical baseline and 16-week treatment period) ( Fig.  1).

image

Figure 1.   Study design. LEV, levetiracetam.

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The 16-week treatment period comprised a 4-week up-titration phase and a 12-week maintenance phase. At the first visit, patients were evaluated for inclusion criteria; the date, number, duration, and type of seizures; also the measurement of vital signs. LEV or matched placebo was started with 500  mg (one tablet) twice daily and was up-titrated in twice-daily increments of 500  mg (one tablet) at 2-week intervals; the dose was increased to 2,000  mg/day after 2  weeks and to 3,000  mg/day after an additional 2  weeks. In patients with mild renal insufficiency, the maximum daily dose was 2,000  mg. In patients with poor tolerability at the highest dose, the daily dose could be decreased to 2,000  mg. Treatment then continued for the 12-week evaluation period. After 16  weeks of treatment, all patients either started a 4-week period of down-titration (2  weeks at 1,000  mg twice daily, followed by 2  weeks at 500  mg twice daily, then discontinuation) or switched at the investigators’ discretion to long-term, open-label LEV therapy with a 1,500  mg twice daily regimen during a 4-week conversion period ( Fig.  1). Compliance was assessed by medication count.

This study was conducted in accordance with Good Clinical Practice guidelines, the relevant regulations of China, and the amended Declaration of Helsinki ( European Commission, 1991). The ethics committee at Huashan Hospital, Fudan University approved the protocol. All study medications (LEV and placebo) used in this study were supplied and packaged by UCB Pharma SA (Brussels, Belgium).

Study population

Chinese subjects aged between 16 and 70 years with partial-onset seizures, with or without secondary generalization were eligible. In addition, they had to have been diagnosed at least 6 months prior to the selection visit. Patients had to present with treatment-resistant partial-onset seizures to be eligible and had to have experienced at least eight partial-onset seizures during the 8-week historical baseline period. Seizures were classified according to the International League Against Epilepsy (ILAE) criteria into simple partial, complex partial, and partial seizures with secondary generalization ( International League Against Epilepsy, 1981). Patients were allowed one or two concomitant marketed AEDs at the time of study entry. The AED regimen was required to be stable for at least 10  weeks prior to study entry. A stable regimen of benzodiazepines was considered as one of the concomitant AEDs. Women with childbearing potential could be enrolled in the study only if they were using a medically accepted method of contraception or if they had been surgically sterilized.

Individuals were excluded if they had a history of pseudoseizures or if they had status epilepticus in the 3 months before the study or clusters of seizures that could not be reliably and regularly counted. Other exclusion criteria included a history of recurrent psychotic or major affective disorder; alcohol or drug abuse within the previous year; or current cardiac, renal, hepatic dysfunction; questionable compliance with drug treatment; laboratory test  abnormalities; and the use of central nervous system (CNS)-influencing medication (other than concomitant AED therapy), unless patients had been stabilized on such medication for more than 1 month before the trial. Lactating women were excluded from the study, as were patients who participated in another clinical trial in the 3 months before the study, and any patients who had participated in a previous study of LEV. All patients gave written informed consent before study entry.

Criteria for evaluation

Efficacy

Efficacy data were collected by means of self-reported seizure diaries in which patients noted the date, duration, and description of each seizure. At each study visit, the investigator recorded the number of seizures and classified each according to the ILAE criteria. The primary efficacy variable was weekly frequency of partial-onset seizures over the entire 16-week treatment period ( titration and maintenance phases). Secondary efficacy variables were also assessed over the 16-week treatment period and included: weekly frequency of all seizures; absolute and percentage reduction from historical baseline in weekly  frequency of partial-onset and all seizures; responder rate, defined as percentage of patients with ≥50% reduction from historical baseline in weekly frequency of partial-onset, and all seizures; and seizure freedom rate, defined as percentage of patients who experienced no partial-onset or all seizures during the entire 16-week treatment period.

At the final visit, the investigator completed the global evaluation scale (GES) to assess the overall change in the severity of the patient's illness compared to the start of study medication. The rating was based on overall clinical impression (marked, moderate, or slight improvement; no change; slight, moderate, or marked worsening).

Tolerability and safety

Tolerability was assessed by monitoring all adverse events, defined as any undesirable experience occurring to the patient, whether or not it was considered related to study treatment. Investigators rated each adverse event by severity as mild, moderate, or severe, and by causal relationship to study treatment as highly probable, probable, possible, unlikely, or not probable. At baseline and each study visit, patients underwent physical and neurological examinations, clinical laboratory assessments (hematology, blood chemistry, urinalysis), and vital signs and body weight assessments. The proportion of patients who experienced an increase of ≥25% from historical baseline in the weekly frequency of partial-onset seizures over the 16-week treatment period was calculated. Adverse event data were obtained for all patients in the LEV and placebo groups, not only for those who experienced a ≥25% reduction in seizure frequency.

Statistical analysis

The tolerability analyses were based on the safety population, which included all randomized patients who received at least one dose of study medication. The efficacy analyses were based on the intent-to-treat (ITT)  population, which included all patients in the safety population who had at least one postbaseline efficacy evaluation. An analysis of covariance (ANCOVA) model was used to assess the superiority of LEV over placebo with respect to the primary efficacy variable (weekly partial-onset seizure frequency). Because seizure frequency did not follow a normal distribution, logarithmic transformation [loge(x  + 1)] was applied. The ANCOVA model  included the treatment group and center as factors and  historical baseline seizure frequency as a covariate. The difference in treatment least square means (LSmean) with two-sided 95% confidence intervals (CIs) was determined and expressed as a percentage reduction over placebo.

The following two-sided tests were performed to assess LEV superiority over placebo regarding absolute and percentage decreases from historical baseline in weekly seizure frequency (Wilcoxon rank sum test), responder rate (logistic regression model), and seizure freedom rate (Cochran-Mantel-Haenszel test). All demographic and baseline characteristics and tolerability and safety variables are summarized descriptively.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Patient disposition

All 206 randomized patients (103 LEV; 103 placebo) received study medication and were included in the safety population ( Fig.  2). One patient in the LEV group (lost to follow-up) and three patients in the placebo group (two lost to follow-up; one adverse event) were excluded from the ITT population because they had no postbaseline efficacy evaluations; thus, 202 patients (102 LEV; 100 placebo) were included in the ITT population. From the ITT population, in the LEV group, one patient was lost to follow-up and three withdrew consent, while in the placebo group, one patient discontinued due to an adverse event (schizophrenia), five withdrew consent, two were lost to follow-up, and one withdrew due to poor compliance (other reason). Therefore, 98 of 103 patients (95.1%) randomized to LEV, and 91 of 103 patients (88.3%) randomized to placebo completed the study.

image

Figure 2.   Patient disposition. LEV, levetiracetam; ITT, intent-to-treat. *Patients in the safety population were excluded from the ITT population if they had no postbaseline efficacy evaluations.

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Demographics

At baseline, the two groups comprising the ITT population had comparable demographic characteristics ( Table  1). The mean duration of epilepsy in the LEV group was 16.5 years, similar to 17.3 years in the placebo group. The mean age of epilepsy onset was 16.0 years in the LEV group and 15.2 years in the placebo group. For more than half of the patients (71%), the cause of epilepsy was unknown. At baseline, 29.7% of patients had simple partial seizures, 58.4% had complex partial seizures, and 51.5% had partial seizures with secondary generalization, while 1.5% had generalized seizures. All patients were taking at least one concomitant AED, apart from two patients with missing information who were lost to follow-up. The number of concomitant AEDs taken by patients at baseline was comparable among the treatment groups. The most commonly used concomitant AEDs were carbamazepine (55.0%), valproate (30.2%), topiramate (26.7%), and gabapentin (13.9%).

Table 1.   Baseline demographic characteristics and history of epilepsy (intent-to-treat population)
 PlaceboLEV
 (n = 100)(n = 102)
  1. an  = 99.

  2. bUsed by ≥5% of patients in either treatment group.

  3. AED, antiepileptic drug; LEV, levetiracetam; SD, standard deviation.

Age (years), mean (sd)32.8 (11.9)32.7 (13.4)
 Range16–6415–70
Gender, male, n (%)54 (54.0)51 (50.0)
Weight (kg), mean (sd)63.2 (13.6)60.7 (11.6)
Age at onset of epilepsy (years), mean (sd)15.2 (10.9)a16.0 (11.0)
Duration of epilepsy (years), mean (sd)17.3 (12.1)a16.5 (12.7)
Seizure type at baseline, n (%)
 Simple partial30 (30.0)30 (29.4)
 Complex partial61 (61.0)57 (55.9)
 Secondarily generalized48 (48.0)56 (54.9)
 Primary generalized2 (2.0)1 (1.0)
Concomitant AEDs,b n (%)
 Carbamazepine52 (52.0)59 (57.8)
 Valproate30 (30.0)31 (30.4)
 Topiramate25 (25.0)29 (28.4)
 Gabapentin16 (16.0)12 (11.8)
 Phenytoin9 (9.0)9 (8.8)
 Clonazepam9 (9.0)7 (6.9)
 Phenobarbital9 (9.0)6 (5.9)
 Lamotrigine5 (5.0)3 (2.9)

Efficacy

All patients recruited to the study experienced partial-onset seizures at baseline, with a small number (1 LEV; 2 placebo) also reporting primary generalized seizures ( Table  1). Thus, the efficacy results for all seizures were similar to those for partial-onset seizures and only the results for partial-onset seizures are presented.

Primary efficacy variable

The median (Q1–Q3) weekly frequency of partial-onset seizures during the 16-week treatment period was 0.85 (0.25–2.54) in the LEV group compared with 1.74 (0.90–3.67) in the placebo group ( Table  2). LEV was statistically significantly superior to placebo, with a percentage reduction over placebo in weekly partial-onset seizure frequency of 26.8% (95% CI, 14.0–37.7; p  < 0.001).

Table 2.   Weekly frequency of partial-onset seizures during historical baseline and 16-week treatment periods, and absolute and percentage reduction from historical baseline in partial-onset seizure frequency over 16-week treatment period (intent-to-treat population)
 PlaceboLEV 
 (n  = 100)(n  = 102)p-value
  1. CI, confidence interval; LEV, levetiracetam; LSmean, least-squares mean.

Historical baseline weekly seizure frequency
 Median (Q1–Q3)1.75 (1.13–4.00)1.81 (1.13–3.38) 
Treatment period weekly seizure frequency
 Median (Q1–Q3)1.74 (0.90–3.67)0.85 (0.25–2.54) 
 Transformed LSmean1.230.92 
 Percentage reduction over placebo (95% CI)26.8% (14.0–37.7)<0.001
Absolute reduction in weekly seizure frequency from historical baseline
 Median (Q1–Q3)0.29 (−1.25–0.81)0.91 (0.02–1.75)<0.001
Percentage reduction in weekly seizure frequency from historical baseline
 Median (Q1–Q3)13.7 (−38.8–50.4)55.9 (0.9–87.6)<0.001

Secondary efficacy variables

Over the 16-week treatment period, compared with placebo, LEV was associated with a significantly greater median absolute (p  < 0.001) and percentage (p  < 0.001) reduction from historical baseline in the weekly frequency of partial-onset seizures ( Table  2).

Significantly more LEV than placebo patients (57 of 102, 55.9% versus 26 of 100, 26.0%) experienced a ≥50% reduction from historical baseline in the weekly frequency of partial-onset seizures (odds ratio 3.6; 95% CI, 2.0–6.5; p  < 0.001) ( Fig.  3). In the LEV group, 11 of 102 patients (10.8%) were free from partial-onset seizures during the 16-week treatment period, compared with 2 of 100 placebo patients (2.0%, p  = 0.012).

image

Figure 3.   Responder rate (≥50% reduction in weekly seizure frequency from historical baseline) and seizure freedom rate over the 16-week treatment period for partial-onset seizures (intent-to-treat population).

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According to the investigator-completed GES, 84 patients (82.4%) in the LEV group were rated as improved compared with 51 patients (51.0%) in the placebo group ( Fig.  4). Of these, marked improvement was observed in 36 patients (35.3%) in the LEV group and 12 (12.0%) in the placebo group. The differences between the LEV and placebo groups were statistically significant (p  < 0.001).

image

Figure 4.   Investigator-completed GES scores at the end of the 16-week treatment period (intent-to-treat population). GES, Global Evaluation Scale. *GES data unknown for two patients in the placebo group.

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Tolerability and safety

Overall, 65 patients (63.1%) in the LEV group and 62 (60.2%) in the placebo group reported at least one treatment-emergent adverse event, of whom 44 patients (42.7%) in the LEV group and 43 (41.7%) in the placebo group had adverse events that were considered by the investigator to be related to the study drug. None of the patients in the LEV group discontinued medication due to an adverse event, compared with two patients (1.9%) in the placebo group. One patient (1.0%) in the LEV group and two (1.9%) in the placebo group temporarily discontinued the study drug, while eight (7.8%) and two (1.9%) patients in the LEV and placebo groups, respectively, reduced the dosage because of adverse events. Serious adverse events were reported by three patients (2.9%) in LEV group (appendicitis, pregnancy, fracture) and two (1.9%) in the placebo group (schizophrenia, overdose). None of the serious adverse events was considered to be related to the study drug.

The overall incidence of adverse events was similar between the two groups. The most frequently reported adverse events (>5% in either of the treatment groups) were somnolence, decreased platelet count, dizziness, and headache ( Table  3). Adverse events were generally mild-to-moderate in intensity.

Table 3.   Treatment-emergent adverse events reported by at least 5% of patients in either treatment group (safety population)
 Number (%) of patients
 Placebo (n  = 103)LEV (n  = 103)
  1. LEV, levetiracetam; TEAE, treatment-emergent adverse event.

At least one TEAE62 (60.2)65 (63.1)
Somnolence18 (17.5)18 (17.5)
Decreased platelet count10 (9.7)10 (9.7)
Dizziness14 (13.6) 8 (7.8)
Headache 9 (8.7) 4 (3.9)

Some abnormal laboratory values were observed during the study, mostly decreased platelet count, decreased white blood cell count, increased alanine transaminase, and increased aspartate transaminase. The incidence of these abnormal values was comparable between the treatment groups, and most values returned to within normal limits after discontinuation of study medication. Any changes seen during the study in vital signs remained within the normal range. No clinically relevant changes from baseline were observed in physical and neurological examinations and body weight.

Over the 16-week treatment period, 19 patients (18.6%) in the LEV group and 33 patients (33.0%) in the placebo group experienced an increase of ≥25% from historical baseline in the weekly frequency of partial-onset seizures.

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

The principal goal of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy and safety of LEV 3,000  mg/day in controlling refractory partial-onset seizures in Chinese adults aged between 16 and 70 years. The results clearly demonstrate that treatment with LEV significantly reduces the frequency of partial-onset seizures per week when administered as an add-on therapy. The percentage reduction in weekly partial-onset seizure frequency for LEV relative to placebo was 26.8% (p  < 0.001). The responder rates, defined as the percentage of patients with a ≥50% reduction in partial-onset seizure frequency, were 55.9% and 26.0% for the LEV and placebo groups, respectively (p  < 0.001). These values are somewhat higher than the ≥50% responder rates obtained by a combined analysis of data from the three double-blind, placebo-controlled pivotal studies of LEV in Caucasians with epilepsy: 28.5%, 34.3%, and 41.3% with LEV 1,000, 2,000, and 3,000  mg/day, respectively, and 13.1% with placebo ( Meencke & Buyle, 2006). This difference might be caused by the use of the highest dose in the recommended dose range in the current trial (3,000  mg/day). The ≥50% responder rate reported by an open-label study in Korean patients ( Heo et al., 2007) was 45.4%, which also compares favorably with the European and U.S. studies.

Importantly, 11 patients (10.8%) treated with LEV and 2 patients (2%) receiving placebo (p  = 0.012) became free from partial-onset seizures and remained seizure-free throughout the entire treatment period. These results are consistent with the three double-blind studies in Caucasian patients that reported seizure freedom rates of 4.7%, 6.3%, and 8.6% with LEV 1,000, 2,000, and 3,000  mg/day, respectively, and 0.8% with placebo ( Meencke & Buyle, 2006).

Results from the subjective rating scale completed by the investigator were consistent with the primary efficacy analysis. Overall, 82.4% of patients in the LEV group were reported to show some improvement compared with 51.0% of patients in the placebo group, with marked improvement observed for 35.3% of LEV patients (placebo 12.0%).

In previous clinical development studies, LEV has been shown to be well-tolerated, with adverse events typically related to the CNS ( Ben-Menachem & Falter, 2000;  Cereghino et al., 2000;  Shorvon et al., 2000). In the current study, the most frequently reported adverse events in both groups were somnolence, decreased platelet count, dizziness and headache, and they were generally mild-to-moderate in intensity. The study conducted in Korea reported a higher incidence of somnolence (36%) than had been observed in previous trials in the LEV groups, possibly indicating a greater sensitivity to LEV-induced somnolence in Korean patients ( Heo et al., 2007). In this study of Chinese patients, the incidence of somnolence was only slightly higher than that reported previously, but was identical in the LEV and placebo groups (17.5%). Neither the overall incidence of adverse events nor the incidence of discontinuation related to adverse events was significantly different between the LEV and placebo groups. Most adverse events resolved when the dosage of LEV was reduced or discontinued. Serious adverse events were very rare, and all those reported were considered unlikely to be related to the study drug. The tolerability profile of LEV in the present study was similar to that documented in the three earlier placebo-controlled studies ( Ben-Menachem & Falter, 2000;  Cereghino et al., 2000;  Shorvon et al., 2000) with no new or unexpected safety concerns. The present findings provide further support for the safety of LEV in patients with epilepsy.

In conclusion, results of the study suggest that LEV is an effective and well-tolerated add-on therapy for Chinese patients with partial-onset seizures. Treatment with LEV was superior to placebo in efficacy, with an adverse event profile comparable to that of placebo. Our findings support the use of LEV as a worthwhile addition to the drug armamentarium in the treatment of Chinese patients with epilepsy.

Acknowledgments

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

This study was sponsored by UCB Pharma SA. The authors would like to thank Jennifer Stewart for assistance with manuscript editing. The following investigators and clinical centers participated in this study: Huashan Hospital: Guoxing Zhu, Huan Yu, Xiantao Li, Peimin Yu; Peking University First Hospital: Weiwei Wang, Fengjun Liu, Wei Sun, Xinyu Li; Peking Xiehe Hospital: Xiangqing Zhou, Liankun Ren; The Affiliated Hospital of Chongqing University of Medical Sciences: Jingmei Li; West China Hospital: Linyu Tian, Bo Zhou; Shanghai Changzheng Hospital: Liuqing Huang, Ying Zhao, Guohong Tian, Hui Zhou.

Conflict of interest: We confirm that we have read Epilepsia’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. UCB Pharma had no financial or scientific input into the design or publication of this paper. However, all authors have received hospitality and their departments have received an unrestricted research grant from UCB. Pharma SA has no conflicts of interest.

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  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
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