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Keywords:

  • Pregabalin;
  • Epilepsy;
  • Antiepileptic drugs;
  • Adjunctive therapy;
  • Partial seizures;
  • Efficacy;
  • Clinical trials;
  • Dose escalation;
  • Flexible dose;
  • Double-blind

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Summary: Purpose: To evaluate pregabalin as add-on therapy for patients with partial seizures administered as fixed dose or as flexible dose adjusted to optimal seizure reduction and tolerability.

Methods: Patients receiving antiepileptic drugs (98.8% between 1 and 3 AEDs; 1.2% on more than 3 AEDs) and experiencing ≥4 partial seizures during the 6-week baseline period and no 4-week seizure-free interval were randomized (1:2:2) to placebo (n = 73), pregabalin fixed dose (600 mg/day BID; n = 137), or pregabalin flexible dose (n = 131; 150 and 300 mg/day for 2 weeks each; 450 and 600 mg/day for 4 weeks each, BID) for 12 weeks. Dosage could be adjusted based on tolerability and maintained when a 4-week seizure-free period was achieved. Primary efficacy parameter was reduction in seizure frequency from baseline.

Results: Both pregabalin regimens significantly reduced seizure frequency compared with placebo, by 35.4%, for flexible dose (p = 0.0091) and 49.3% for fixed dose (p = 0.0001) versus 10.6% for placebo, and the fixed-dose group was superior to the flexible-dose group (p = 0.0337). Most adverse events were mild or moderate. Discontinuation rates due to adverse events were 6.8% (placebo), 12.2% (pregabalin flexible dose), and 32.8% (pregabalin fixed dose). Patients receiving pregabalin fixed dose discontinued due to adverse event earlier than other groups.

Conclusions: Pregabalin administered twice daily, either as fixed (600 mg/day), or as flexible (150–600 mg/day) dose, was highly effective and generally well-tolerated as add-on therapy for partial seizures with or without secondary generalization. Lower incidence of adverse events and discontinuations were achieved in patients receiving pregabalin when dosing was individualized to optimize efficacy and tolerability.

Although many new antiepileptic drugs (AEDs) have been introduced in the last decade, many patients continue to experience partial seizures that are refractory to AED treatment. Studies suggest that less than 50% of patients will become seizure-free with the first AED tried and only 60–70% will be controlled by monotherapy with either their first or second AED (1), while the remaining patients' seizures are difficult to control. Generally, these patients are treated with a combination of AED treatments and are thus exposed to issues of tolerability, drug interactions, and safety that may often affect patient compliance. There remains a clear need for new AEDs with improved efficacy, novel mechanisms of action, better tolerability, and improved pharmacokinetics that could provide effective combination treatment for patients with partial seizures.

In preclinical models, pregabalin has demonstrated anticonvulsant, analgesic, and anxiolytic effects that are believed to result from its action on an auxiliary subunit (the alpha2-delta or α2-δ subunit) of voltage-gated calcium channels in the CNS (2–4). Potent binding at this site attenuates depolarization-induced calcium influx at nerve terminals, with a subsequent reduction in the release of excitatory neurotransmitters, including glutamate, noradrenaline, and substance P (4–7). In preclinical studies, pregabalin exhibits potent activity against seizures induced by maximal electroshock, pentylenetetrazole, bicuculline, and picrotoxin (2,3,8,9). It is also effective in preventing seizures in kindled rats, and audiogenic seizures in genetically susceptible mice, although it is ineffective against spontaneous absence seizures (9,10).

Pregabalin demonstrates highly predictable and linear pharmacokinetics across the dose range (150–600 mg/day) with low intersubject variability (2,11–13). It is rapidly and extensively absorbed following oral dosing, with peak plasma concentrations occurring approximately 1 h after dosing, and steady state being achieved within 24–48 h following repeated administration (2,11,12,14). Oral bioavailability is high at ≥90% and the elimination half-life (t1/2) is approximately 6 h (14). Pregabalin is not hepatically metabolized, is excreted virtually unchanged by the kidneys (∼98%), and does not bind to plasma proteins (14). Furthermore, pregabalin appears to be devoid of enzyme-inducing or -inhibiting activity and it does not affect the pharmacokinetics of oral contraceptives (2,11,12). Specific studies have shown no pharmacokinetic interaction with pregabalin and concomitantly administered AEDs, including carbamazepine, phenytoin, lamotrigine, and valproate (2,15,16) and no pharmacokinetic drug interactions have been observed during clinical development. Pregabalin appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone and may potentiate the effects of ethanol and lorazepam. However, multiple oral doses of pregabalin coadministered with oxycodone, lorazepam, or ethanol did not result in clinically important effects on respiration. Overall, the pharmacological and pharmacokinetic profiles of pregabalin provide a consistent and predictable basis for its use in clinical practice as an add-on antiepileptic agent.

Three similarly designed well-controlled fixed-dose trials of pregabalin have been published and demonstrate the efficacy, safety, and tolerability of pregabalin as adjunctive therapy in patients with partial epilepsy (17–19). These studies investigated dosing regimens (BID and TID, with fixed-dose design), and dose–response across the range 50–600 mg/day. The randomized dose was achieved either on day 1 (17) or day 7 (18,19). Data from these studies indicated that pregabalin is effective and well-tolerated across the recommended dose range 150–600 mg/day, irrespective of whether pregabalin was administered twice (BID) or three times daily (TID), as both regimens were similarly effective. There was also a statistically significant dose–response effect, which has also been confirmed by an exposure–response analysis of the data (20).

In clinical practice, the dose adjustment of most AEDs is done gradually with the hope that it may enhance the tolerability of AEDs and allow for optimum effective dosing (21). The current study was undertaken to assess the efficacy, safety, and tolerability of pregabalin administered twice daily as add-on therapy in patients with partial epilepsy. Dosing regimens used included a novel flexible-dose regimen initiated with an effective starting dose of 150 mg/day, followed by a stepwise dose adjustment for those patients requiring greater doses in an effort to optimize both efficacy in seizure reduction and tolerability, or a fixed high-dose regimen. This type of study design may provide a more rational basis for predicting the performance of a drug in clinical practice than traditional fixed dose clinical trials.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

This study was conducted at 53 centers throughout Canada and Europe (Austria, France, Germany, Italy, Lithuania, Spain, and the United Kingdom) between March 2001 and July 2003. The study was approved by each participating center's Institutional Review Board or Ethics committee and was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice, the Declaration of Helsinki, and in compliance with United States Food and Drug Administration regulations for informed consent and protection of patient rights. Patients or their authorized representative gave written informed consent.

Study design

This was a 12-week, randomized, double-blind, placebo-controlled, parallel-group study performed in patients with partial seizures refractory to AED treatment. The 12-week treatment period immediately followed a 6-week baseline phase, in which patients were required to experience at least four seizures with no 28-day seizure-free period. Patients meeting the entry criteria were randomly assigned to adjunctive twice daily (BID) dosing with placebo, pregabalin fixed dose of 600 mg/day, or pregabalin flexible dose of 150–600 mg/day using a 1:2:2 randomization ratio and block sizes of 5. All patients randomized to the pregabalin fixed-dose group received 600 mg/day (300 mg BID) on day 1 and for the entire treatment period. Patients randomized to the pregabalin flexible-dose group started on the lowest therapeutic dose of 150 mg/day (75 mg BID) for the first 2 weeks, and then increased to 300 mg/day for the next 2 weeks. Those patients who were seizure-free during these first 4 weeks remained on 300 mg/day for the remainder of the study as directed by the investigator, while those still experiencing seizures increased their dose to 450 mg/day for the next 4 weeks. Similarly, at week 8, patients who had been seizure-free for the preceding 4 weeks remained on 450 mg/day for the remainder of the study, while those still experiencing seizures increased their dose to 600 mg/day. Patients who experienced intolerable adverse events could reduce their daily dose (e.g., the number of capsules taken daily) to the previous level (e.g., 450 to 300 mg/day, or 600 to 450 mg/day) for the remainder of the treatment period. While all patients could reduce the number of capsules of study medication, only those in the pregabalin flexible-dose group received an actual dose reduction. Blinding was maintained by presenting study medication in identical capsules of 75, 150, 225 mg or matching placebo, with study medication for patients in all treatment groups supplied to mimic the dosing schedule for the pregabalin flexible-dose group.

Throughout the study, patients were required to maintain their concomitant AEDs and at the same dosages administered during the baseline period. During the double-blind phase, coadministration of other CNS-active compounds was prohibited, with the exception of antidepressant monotherapy for mild depression, or no more than six doses of benzodiazepines as needed to treat occasional seizure exacerbation.

Patients were required to visit the study center at the randomization visit and then subsequently at weeks 2, 4, 8, and 12 of the 12-week double-blind period. After the double-blind phase, patients were given the option to continue pregabalin therapy in a long-term, open-label follow-on study.

Selection of patients

Male or female patients aged 18 years or older, weighing at least 50 kg, with a diagnosis of epilepsy with partial seizures (as defined in the International League Against Epilepsy Classification of Seizures) (22) and who had not previously received pregabalin were eligible for inclusion. Diagnosis was established by the patient's history, family history, and the results of electroencephalogram testing conducted within 2 years of randomization. In addition, within 2 years of randomization patients must have had magnetic resonance imaging or computed tomography scan with contrast enhancement of the head that demonstrated no progressive structural abnormality. They must have experienced at least 4 partial seizures during the 6-week baseline period with no 28-day period free of partial seizures, and to be currently receiving between 1 and 3 AEDs, which could include vagus nerve stimulator devices and any benzodiazepines regardless of their indication and dosage. Due to the similar pharmacology of pregabalin and gabapentin, patients receiving gabapentin were excluded from the study unless this was discontinued at least 1 week prior to the baseline period (which allowed for 5× half-lives plus an additional 5-day buffer for any prolonged pharmacodynamic activity). Patients currently taking felbamate or vigabatrin were also excluded, due to the safety profile of the drugs.

Exclusion criteria included seizures with a treatable cause, absence seizures, Lennox–Gastaut syndrome, or status epilepticus within the previous year. Patients with a history or clinical evidence of cardiovascular, hematologic, hepatic, or renal disease, or a history of clinically significant, progressive, or unstable medical or psychiatric conditions were also excluded. All patients were required to have an estimated creatinine clearance ≥60 ml/min and to have had a 12-lead electrocardiogram (ECG) without clinically significant abnormal findings prior to randomization. Women were not pregnant or breastfeeding and were using a reliable method of contraception.

Assessment methods

All patients were required to maintain daily seizure diaries throughout the 6-week baseline period and 12-week double-blind treatment period, with or without assistance of a caregiver. The frequency and types of seizures were determined from the diary entries.

All spontaneously reported or observed adverse events were recorded by the investigator and classified using the COSTART IV dictionary (23). The intensity of these adverse events (mild, moderate, severe) and their possible relationship with study treatment were also evaluated by the investigator. In the case of patients with a change in body weight ≥7%, investigators were asked to assess whether the body weight changes also needed to be reported as an adverse event. A full battery of clinical laboratory tests were performed by a central laboratory on blood and urine samples collected at screening, randomization, and weeks 2, 4, 8, and 12, and/or upon discontinuation. Physical and neurological examinations and a 12-lead ECG were conducted at screening and at the week 12 visit.

Statistical analyses

The sample size was calculated based on the primary intention-to-treat (ITT) population with efficacy estimates of Response Ratio (RRatio) based on results from previous pregabalin trials conducted by the sponsor. Assumptions were RRatio of −32 for pregabalin fixed dose, −25 for pregabalin flexible dose, and −3 for placebo treatment with a common standard deviation of 35. The randomization was 1:2:2 and it was estimated that 60 patients in the placebo group and 120 patients each per pregabalin group would give a power of ≥95% (pregabalin flexible dose) and ≥99% (pregabalin fixed dose) for comparing pregabalin treatments versus placebo (α= 0.025; two-sided). The estimated power for detecting difference between the two pregabalin treatment groups was 24%, assuming a 7-point RRatio difference.

The analysis of efficacy was based on the ITT population of patients who were randomly assigned and received at least one dose of study medication. All statistical tests were two-tailed with a statistical significance level of 0.05. For centers with fewer than 20 randomized patients, clustering was performed.

The primary efficacy measure was a reduction in the 28-day seizure rate for all partial seizures during the 12-week double-blind treatment period compared with the baseline period, as measured by RRatio. RRatio is defined as [(T − B)/(T + B)]× 100, where T is the 28-day seizure rate during double-blind treatment period and B is the 28-day seizure rate during baseline. RRatio, also known as the symmetrized percent change, is a direct monotonic transformation of percent change from baseline, ranging from −100 to 100, with negative values representing improvement in seizure rate (24). Thus, a zero value indicates no change in seizure frequency, while a value of −100 would indicate complete elimination of seizures, and a value of −33 is equivalent to 50% reduction in seizure frequency. RRatio transformation is a statistically robust way of looking at seizure reduction, as it considers a normally distributed data population rather than the skewed distribution of percent change from baseline. Thus, use of RRatio allows parametric statistical methods to be applied to the data.

The RRatio was ranked across all patients and analyzed using an analysis of variance (ANOVA) with treatment and center as main effects in the model and rank of RRatio as the dependent variable. Patients with no double-blind seizure diary data during treatment had their baseline seizure frequency carried forward. Consistency of treatment across centers was explored by adding a treatment-by-center interaction term to the ANOVA model, which was tested at a significance level of 0.15, considered as evidence of lack of generalizability. The primary efficacy outcomes were two pairwise comparisons: pregabalin flexible dose versus placebo; and pregabalin fixed dose versus placebo. Pairwise comparisons were performed according to the Hochberg procedure to maintain an overall 5% type I error.

For ease of clinical interpretation, seizure reduction based on percentage change from baseline is also shown, as this is more familiar to clinicians. The RRatio corresponds 1:1 with percent change from baseline and can be simply transformed into this measure using [(200 × RRatio)/(100 − RRatio)].

Secondary efficacy variables included the responder rate, percentage of patients free of seizures, reduction in the proportion of secondarily generalized tonic clonic seizures (SGTC), and the percentage of patients completing the study (ITT completers). The responder rate, defined as the percentage of patients with ≥50% reduction in 28-day seizure rate during treatment, was analyzed using Cochran–Mantel–Haenszel (CMH) chi-square test adjusted for center. The percentage of patients free of seizures during their last 28 days of treatment, the percentage of patients who showed a reduction from baseline to treatment in the proportion of SGTC seizures over all partial seizures, and the percentage of patients completing the study were both analyzed using Fisher's exact test. The proportion of SGTC responder analysis was based on the SGTC population defined as patients who had at least one SGTC seizure during either baseline or double-blind periods. In this analysis, patients who became seizure-free during double-blind treatment were excluded from the analysis due to noncalculable proportions (0 denominator). Seizure-free data for patients who completed the study (ITT completers) and who were seizure-free throughout the entire double-blind treatment period were also analyzed using Fisher's exact test. An analysis by seizure-type was also conducted for the efficacy parameters of RRatio, and responder rate. An analysis of RRatio adjusted for the number of concurrent AEDs taken during the study was also performed. An odds ratio analysis of patients with ≥50% reduction in 28-day seizure rate during the final 28 days of the double-blind treatment period (i.e., month 3) expressed as a percentage of the initial randomized ITT population who completed the study was also conducted as an ad hoc analysis.

All randomized patients who took at least one dose of study medication were included in the evaluation of safety data using descriptive statistical methods. A time to event analysis comparing the three treatments using Kaplan–Meier survival plots was performed for the parameter time to withdrawal due to adverse events.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Patients

In total, 400 patients entered the baseline phase and 341 were randomly assigned to treatment for the double-blind phase of the study (Fig. 1). Of these, 73 were assigned to placebo, 131 to the pregabalin flexible-dose group (150–600 mg/day), and 137 to a fixed dose of pregabalin (600 mg/day). All of these patients received at least one dose of study medication and were included in the ITT analysis.

image

Figure 1. Patient disposition by treatment group.

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Patient demographic characteristics at baseline are shown in Table 1. The majority of patients were white and there was an equal distribution of men and women in the study. Ages ranged from 18 to 78 years with a mean age of 41 years. Overall, the three treatment groups were well-matched in terms of demographic parameters of age, gender, race, and weight. The mean estimated creatinine clearance was 108 ml/min (range 53–232 ml/min), and this was also similar across the three treatment groups.

Table 1. Summary of patient characteristics by treatment group
Patient characteristicPlacebo (n = 73)Pregabalin flexible dose 150–600 mg/day (n = 131)Pregabalin fixed dose 600 mg/day (n = 137)
Age in yr
 Mean (SD)40.3 (12.5)40.0 (13.5)41.1 (12.2)
 Range18–6518–7818–71
Race, n (%)
 White 71 (97.3) 128 (97.7) 133 (97.1)
 Black0  0   1 (0.7)
 Other 2 (2.7) 3 (2.3) 3 (2.2)
Gender, n (%)
 Male 37 (50.7) 64 (48.9) 69 (50.4)
 Female 36 (49.3) 67 (51.1) 68 (49.6)
Weight (kg)
 Mean (SD)72.6 (15.6)74.0 (17.4)75.1 (16.3)
 Range45.0–115.046.0–129.545.0–135.0
Estimated creatinineb clearance (ml/min)
 Mean (SD)107.2 (28.9)109.4 (33.8)108.0 (31.7)
 Range57.0–184.053.0–224.059.0–232.0

The epilepsy history and seizure characteristics at baseline and the number of baseline AEDs for each treatment group are shown in Table 2. Overall, the mean age at diagnosis was 15 years (range 0–64 years) and the mean duration of epilepsy was 25 years (range 1–61 years). The median baseline seizure frequency was 9 per 28 days (range 1–7,014). The baseline seizure frequency and historical parameters were similar across all treatment groups. Although there were some minor differences in epilepsy etiology across the three treatment groups, there was no difference in the types of seizures that patients had experienced during baseline, and the majority of patients experienced no new seizure types after baseline. In total, 23% of patients took one concurrent AED during the study, 50% took two, and 26% took at least three concurrent AEDs. The number of concurrent AEDs was similar across the three treatment groups. The most commonly used AEDs (>10% of all patients) were carbamazepine (46%), lamotrigine (25%), levetiracetam (23%), oxcarbazepine (21%), topiramate (18%), and clobazam (15%). There were no patients using a vagus nerve stimulator. The most frequently used combinations of AEDs were carbamazepine plus topiramate, carbamazepine plus levetiracetam, and oxcarbazepine plus topiramate.

Table 2. Baseline epilepsy history and seizure characteristics of randomized patients by treatment group
CharacteristicPlacebo (n = 73)Pregabalin flexible dose 150–600 mg/day (n = 131)Pregabalin fixed dose 600 mg/day (n = 137)
  1. AED, antiepileptic drugs.

Age at diagnosis (yr)
 Mean (SD)16.2 (13.6)14.5 (12.8)15.5 (12.1)
 Range0–620—640–50
Duration of epilepsy (yr)
 Mean24.1 (15.6)25.5 (12.8)25.6 (13.3)
 Range1–554—612–60
Partial seizures with secondary generalization, n (%)55 (75.3%)93 (71.0%)92 (67.2%)
Baseline 28-day seizure rate
 Median8.79.3310.0
 Range2.7–3,356.71.3–7,013.72.0–305.1
Number of concomitant
 AEDs, n (%)
 118 (24.7%)26 (19.8%)35 (25.5%)
 239 (53.4%)68 (51.9%)65 (47.4%)
 315 (20.5%)37 (28.2%)34 (24.8%)
 >31 (1.4%) 0 (0%)   3 (2.2%) 

The 12-week double-blind treatment period was completed by 76.7% of patients in the placebo group, 76.3% in the pregabalin flexible-dose group, and 58.4% in the pregabalin fixed-dose group (Fig. 1). Of all patients finishing the double-blind period, 78% of the placebo group, 78% of the pregabalin flexible-dose group, and 64% of the pregabalin fixed-dose group chose to enter the subsequent open-label study.

For patients in the pregabalin flexible-dose group, 47% received a maximum daily dose of 600 mg/day and 31%, 16%, and 5% received a maximum daily dose of 450, 300, or 150 mg/day, respectively. The average daily dose in the last month of study in this treatment group was 508 mg/day. Most (92%) of the patients in the pregabalin fixed-dose group received a maximum daily dose of 600 mg/day, with an average daily dose of 588 mg/day during the final month.

Efficacy

Both pregabalin treatment regimens were significantly more effective than placebo in reducing the frequency of all partial seizures (Fig. 2). Mean RRatios for the pregabalin flexible-dose group (−21.5, p = 0.0091) and the pregabalin fixed-dose group (−32.7, p = 0.0001) were both significantly lower than for the placebo group (−5.6), indicating a greater reduction in seizure frequency (Fig. 2, right y-axis). The corresponding percentage reduction in seizure frequency between baseline and treatment was 35.4% for the pregabalin flexible-dose group, and 49.3% for the pregabalin fixed-dose group compared with 10.6% for the placebo group (Fig. 2, left y-axis). Differences in the treatment means (95% confidence intervals) compared with the placebo group were −15.8 (−27.4, −4.3) for the pregabalin flexible-dose (150–600 mg/day) group, and −27.0 (−38.5, −15.6) for the pregabalin fixed-dose group. The pregabalin fixed-dose group was significantly superior to the pregabalin flexible-dose (150–600 mg/day) group (p = 0.0337), with a mean RRatio treatment difference of −11.2 (−20.8, −1.6). There was no significant treatment by cluster interaction (p = 0.5363). Analysis of weekly RRatio data (Table 3) indicated that the pregabalin fixed-dose group was statistically superior to the pregabalin flexible-dose group for week 1 only; at all other time points the two pregabalin groups were not statistically different.

image

Figure 2. Seizure reduction (percent change from baseline on left y-axis and mean response ratio (RRatio) on right y-axis) by treatment group for all partial seizures. RRatio values were −5.6, −21.5, and −32.7 for placebo, pregabalin flexible dose (150–600 mg/day), and pregabalin fixed dose (600 mg/day), respectively, which correspond to seizure-frequency reductions from baseline of 10.6%, 35.4%, and 49.3%. *p = 0.0091 and **p = 0.0001 versus placebo; p = 0.0337 for pregabalin fixed dose (600 mg/day) versus pregabalin flexible dose (150–600 mg/day).

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Table 3. Weekly RRatios for all partial seizures by treatment group
Week of double-blind treatment periodPlaceboPregabalin flexible dose 150–600 mg/dayPregabalin fixed dose 600 mg/day
Week 1 (n) 73 131 136
 RRatio−22.4 −34.5 −50.1
 Seizure frequency reduction 36.6%  51.3%  66.8%
Week 2 (n) 72 125 101
 RRatio−19.1 −35.8 −40.0
 Seizure frequency reduction 32.1%  52.7%  57.1%
Week 3 (n) 71 124  96
 RRatio−28.7 −41.0 −52.6
 Seizure frequency reduction 44.6%  58.2%  68.9%
Week 4 (n) 70 121  95
 RRatio−14.2 −35.3 −34.2
 Seizure frequency reduction 24.9%  52.2%  51.0%
Week 5 (n) 66 113  92
 RRatio−29.5 −47.9 −38.9
 Seizure frequency reduction 45.6%  64.8%  56.0%
Week 6 (n) 66 115  90
 RRatio−28.5 −40.1 −30.1
 Seizure frequency reduction 44.4%  57.2%  46.3%
Week 7 (n) 63 112  89
 RRatio−25.5 −32.8 −40.9
 Seizure frequency reduction 40.6%  49.4%  58.1%
Week 8 (n) 60 108  88
 RRatio−17.1 −34.9 −34.3
 Seizure frequency reduction 29.2%  51.7%  51.1%
Week 9 (n) 57  99  86
 RRatio−23.0 −36.9 −48.8
 Seizure frequency reduction 37.4%  53.9%  65.6%
Week 10 (n) 57 102  84
 RRatio−16.0 −37.7 −40.7
 Seizure frequency reduction 27.5%  54.8%  57.8%
Week 11 (n) 56 102  83
 RRatio−27.2 −39.7 −39.8
 Seizure frequency reduction 42.8%  56.8%  56.9%
Week 12 (n) 54 100  82
 RRatio−35.9 −47.3 −43.6
 Seizure frequency reduction 52.8%  64.2%  60.7%

Significantly more patients in the pregabalin flexible-dose group (76.3%) completed the trial than did patients in the fixed-dose group (58.4%; p = 0.0019) (Table 4). RRatios were also analyzed for the subpopulation of patients who completed the study. RRatios for the completers in the pregabalin flexible-dose group (−23.2, n = 100, p = 0.008) and the pregabalin fixed-dose group (−28.7, n = 80, p = 0.0004) were both significantly lower than for the completers in the placebo group (−8.1, n = 56) (Table 4). Corresponding values for percentage reduction in seizure frequency between treatment and baseline were 37.7% for the pregabalin flexible-dose group, 44.6% for the pregabalin fixed-dose group, and 15.0% for the placebo group. However, there was no significant difference between the two pregabalin groups in this population.

Table 4. Efficacy parameters (RRatios, corresponding seizure frequency reductions, and 50% responder rates) for the subpopulation of patients who completed the study
ParameterPlaceboPregabalin flexible dose 150–600 mg/dayPregabalin fixed dose 600 mg/day
  1. *p < 0.01 and **p = 0.0001 versus placebo.

  2. ap = 0.0019 for pregabalin flexible dose (150–600 mg/day) versus pregabalin fixed dose (600 mg/day).

Randomized patients73131137
Patients completing the study (%)56 (76.7%)100 (76.3%)a80 (58.4%)
RRatio in patients completing the study−8.1−23.2*−28.7*
Corresponding % reduction in seizure frequency in patients completing the study15.0%37.7%44.6%
50% responder rate in patients completing the study10.7%34.0%**41.3%**

Lack of efficacy resulted in the withdrawal of 2 patients (2.7%) from the placebo group, 5 patients (3.6%) from the fixed-dose group, and 6 patients (4.6%) from the flexible-dose group.

The responder rate (patients with ≥50% reduction in seizure frequency) was significantly greater in both the pregabalin flexible-dose group (31.3%, p = 0.001) and the pregabalin fixed-dose group (45.3%, p = 0.001) compared with the placebo group (11.0%) (Fig. 3). The responder rate for the pregabalin fixed-dose group was also significantly higher than the rate in the pregabalin flexible-dose group (p = 0.016). For those patients completing the study (n = 236), responder rates were also significantly higher for both pregabalin dosing groups (34.0%, p = 0.001 for flexible dose, and 41.3%, p = 0.001 for fixed dose) than for the placebo group (10.7%), although there was no significant difference between the two pregabalin groups in this population (Table 4).

image

Figure 3. Responder rate by treatment group for all partial seizures. Responder rate is defined as the percentage of patients with ≥50% reduction in 28-day partial seizure rate during treatment compared with baseline. **p ≤ 0.001 versus placebo; p = 0.016 for pregabalin fixed dose (600 mg/day) versus pregabalin flexible dose (150–600 mg/day).

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Odds ratio analysis of the number of randomized patients who completed the study with ≥50% reduction in seizure rate during the final 28 days of the double-blind treatment period (i.e., month 3) indicated that the odds of being a responder are 2.43 times higher for those patients in the fixed-dose group than those patients in the placebo group (p = 0.0280), while the odds of being a responder are 2.08 times higher for patients in the flexible-dose group than placebo-treated patients (p = 0.0557) (Table 5). The odds of being a responder is 1.17 times higher for patients in the fixed-dose group than patients in the flexible-dose group, although this difference was not statistically significant (p = 0.6333) (Table 5).

Table 5. Odds ratios for randomized patients with ≥50% reduction in seizure rate during the final 28 days of the double-blind treatment period
ComparisonOdds ratio for comparisonNominal p-value for comparison
Fixed dose pregabalin versus placebo2.430.0280
Flexible dose pregabalin versus placebo2.080.0557
Fixed dose pregabalin versus flexible dose pregabalin1.170.6333

During the last 28 days of treatment, 16 (12.2%) patients in the pregabalin flexible-dose group, 17 (12.4%) in the pregabalin fixed-dose group, and 6 (8.2%) in the placebo group were completely free of seizures (Table 6). Of patients completing the study (n = 236), 4 (5%) patients in the pregabalin fixed-dose group were completely free of seizures during the entire double-blind treatment period, as were 4 (4%) in the pregabalin flexible-dose group, and just 1 (2%) in the placebo group (Table 6). There was no statistically significant difference between either pregabalin treatment group and placebo for these parameters.

Table 6. Seizure-free rates by treatment group for all partial seizures
ParameterPlaceboPregabalin flexible dose 150–600 mg/dayPregabalin fixed dose 600 mg/day
Patients who were seizure-free for at least the last 28 days of treatment (ITT population)
   n73131137
   Seizure-free (%)6 (8.2%)16 (12.2%)17 (12.4%)
Patients completing the study who were seizure-free throughout the entire 84-day treatment period
   n5610080
   Seizure-free (%)1 (2%)4 (4%)4 (5%)

Compared with the placebo group (33%, n = 27), a higher proportion of patients in both the pregabalin flexible-dose group (53%, n = 28) and pregabalin fixed-dose group (68%, n = 45) exhibited a decrease in the proportion of SGTC seizures by 28-day seizure rates for all partial seizures with the difference between the pregabalin fixed dose and placebo reaching statistical significance (p = 0.015).

Analysis of RRatio and responder rates according to seizure type (simple partial, complex partial, partial seizures with generalization, partial seizures without generalization, and SGTC seizures) was consistent with the results for all partial seizures combined, favoring treatment with pregabalin over placebo.

Analysis of RRatios adjusted for the number of concurrent AEDs found that the number of AEDs taken by patients during the study had no statistically significant effect on the RRatio.

Tolerability and safety

A summary of treatment-emergent adverse events and associated discontinuation rates is provided in Table 7. Most patients reported adverse events that were mild or moderate in intensity which tended to resolve with continued treatment; however, a higher proportion of patients in the pregabalin 600 mg/day dose group (23%) experienced events that were characterized as severe by the investigator, compared with patients in the pregabalin flexible-dose group (10%), or placebo group (4%).

Table 7. Summary of treatment-emergent adverse eventsa and associated discontinuation rates
Adverse event categoryFrequency of adverse eventDiscontinuations due to event
Placebo (n = 73)Pregabalin flexible dose 150–600 mg/day (n = 131)Pregabalin fixed dose 600 mg/day (n = 137)Placebo (n = 73)Pregabalin flexible dose 150–600 mg/day (n = 131)Pregabalin fixed dose 600 mg/day (n = 137)
  1. aAll causality adverse events under treatment with study drug.

  2. bAdverse events reported by ≥10% of patients in any treatment group.

  3. cWeight gain adverse events were not exclusively spontaneously generated; a query was generated for patients with a change in weight ≥7% to assess whether the body weight changes also needed to be reported as an adverse event.

Overall adverse events (%)63.086.387.66.812.232.8
Frequency of most common adverse events (%)b
 Dizziness 8.224.443.10  5.313.9
 Ataxia 4.1 9.221.21.43.113.1
 Weight gainc 6.819.120.40  0   0  
 Asthenia13.716.818.20  0.8 2.2
 Somnolence 8.219.117.51.41.5 6.6
 Vertigo 2.710.713.90  2.3 6.6
 Diplopia 1.4 6.111.70  1.5 4.4
 Amblyopia (blurred vision) 1.4 2.310.20  0.8 1.5
 Headache11.013.7 7.30  0   2.2

The five most frequently reported treatment-emergent adverse events were dizziness, ataxia, weight gain, asthenia, and somnolence, and these all occurred more frequently in both pregabalin treatment groups than in the placebo group (Table 7). Pairwise comparisons indicated that dizziness and ataxia occurred more frequently in the pregabalin fixed-dose group than in the pregabalin flexible-dose group.

Withdrawal due to an adverse event was 33% in the pregabalin fixed-dose group followed by the pregabalin flexible-dose group (12%), and placebo group (7%) (Table 7). Although the majority of patients in each treatment group reported at least one adverse event during the course of the trial, relatively few led to discontinuation. Most of the withdrawals were due to adverse events that the investigator considered related to study medication. Withdrawals due to dizziness, ataxia, somnolence, vertigo, nausea, and diplopia occurred more frequently in the pregabalin fixed-dose group than in the pregabalin flexible-dose group.

Kaplan–Meier analysis of time to exit data indicated that a significantly higher withdrawal rate due to adverse events was reported during the first week of double-blind treatment in the pregabalin fixed-dose group (24%) as compared to the pregabalin flexible-dose (3%; p = 0.0001) or placebo (0%; p = 0.0001) groups. After the first 10 days, the withdrawal rates due to adverse events in the three treatment groups were essentially parallel (Fig. 4).

image

Figure 4. Kaplan–Meier survival plot of time to withdrawal due to an adverse event for placebo, pregabalin flexible-dose (150–600 mg/day), and pregabalin fixed-dose (600 mg/day) treatment groups.

Download figure to PowerPoint

Weight gain reported as an adverse event occurred at a similar rate in both pregabalin treatment groups (Table 7). No patients discontinued the trial due to weight gain. Weight gain was also objectively assessed between baseline and termination. Weight gain of ≥7% was observed in 25 patients (19%) in the pregabalin flexible-dose group, 21 patients (16%) in the pregabalin fixed-dose group, and 2 patients (3%) in the placebo group. In addition, 3 patients experienced a ≥7% decrease in weight gain with pregabalin treatment. A higher percentage of patients in the pregabalin fixed-dose group (28%, n = 38) and pregabalin flexible-dose group (16%, n = 21) reported new or intensified neurological findings between baseline and termination compared with the placebo group (9%).

There were no clinically relevant changes in vital signs. Similarly, a review of clinical laboratory parameters revealed no changes of any clinical significance. Of the 272 patients with ECGs at both baseline and termination, none had any clinically significant abnormal findings at termination. No deaths occurred during the trial.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

These results indicate that pregabalin administered twice daily is highly effective and well-tolerated as add-on therapy for controlling partial seizures in patients with or without secondary generalization.

In general practice, the clinician adjusts doses to optimal efficacy and tolerability according to individual patient needs (21). Thus, the current study was designed to explore whether a flexible dosing regimen would enhance tolerability of pregabalin while achieving efficacy. Patients in the pregabalin flexible-dose group were initiated with the effective starting dose of 150 mg/day followed by an opportunity for stepwise dose adjustment for those patients requiring increased doses to optimize efficacy and tolerability. Patients in the pregabalin fixed-dose group received a dose of 600 mg/day for the duration of the trial.

In terms of the primary efficacy measure of seizure reduction (as indicated by RRatio), both pregabalin dosing regimens were significantly superior to placebo (p ≤ 0.01). The reduction in seizure frequency observed for the fixed 600 mg/day dose group in this study, which corresponds to a mean reduction from baseline of 49.3%, is consistent with the observed efficacy of this dose (BID or TID) in previous add-on studies where seizure reduction ranged from 44% to 54% (17–19). In the present study, the RRatio values also indicated a significantly greater reduction in seizures (p = 0.034) with the fixed dosing compared with the flexible-dose regimen. This finding is not that surprising, however, given that patients in the flexible-dose group only achieved their optimal dose by week 8, as per protocol. Indeed, analysis of weekly RRatio data found that statistically significant differences between the fixed-dose and flexible-dose groups were only present at week 1. This suggests that the overall superiority of the fixed-dose group in the ITT analysis is probably based on differences during the early weeks of treatment when patients in the flexible-dose group were only receiving the minimum effective dose of 150 mg/day. In fact, when RRatio data were analyzed for the subpopulation of patients completing the study, both pregabalin treatment groups were clearly superior to placebo and there was no longer any statistical difference between the two groups.

In general, analysis of data for the secondary efficacy parameters corroborated the findings of the primary efficacy analysis, with both pregabalin dosing regimens being superior to placebo on most of these measures.

An odds ratio analysis of the number of randomized patients who completed the study with ≥50% reduction in seizure rate during the final 28 days of the double-blind treatment period (i.e., month 3) indicated that patients in the fixed-dose group were 1.17 times more likely to respond to treatment than patients in the flexible-dose group, although this difference did not reach statistical significance. These data add further support to the theory that the apparent overall superiority of the fixed dose is based on differences during the early weeks of treatment when there is a large dose difference between the two groups.

For patients in the pregabalin flexible-dose group, 47% received a maximum daily dose of 600 mg/day and the average daily dose in the last month of study in this treatment group was 508 mg/day. While this may be considered by some to be a relatively high dose, one must bear in mind the refractoriness of the seizures in this population and the fact that more than 75% of patients were uncontrolled on two or more concomitant AEDs. According to the protocol, patients in the flexible group remained on a particular dose once they had achieved seizure freedom. According to Brodie and Kwan, it is estimated that the chance of this refractory patient population becoming seizure-free was approximately 10% (1). In clinical practice it is possible that lower doses of pregabalin will be effective in patients with less refractory partial seizures.

The responder rates observed for pregabalin are very encouraging particularly when one considers that patients had a median baseline seizure rate of 9 per month despite the use of multiple concomitant AEDs. Although one should be cautious of comparing response rates across different trials, it is worth noting that these responder rates compare favorably with those seen for other AEDs tested as adjunctive therapy in similar patient populations. Previously, Cramer et al. (25) have compared adjunctive therapy trials of new AEDs using overall improvement rates (defined as treatment responder rate minus placebo responder rate) and these ranged from 11.4% to 30.4%. In comparison, both pregabalin dosing regimens are highly effective with overall improvement rates of 20.3% and 34.3% for pregabalin flexible-dose and fixed-dose groups, respectively. Furthermore, around 12% of patients in each of the pregabalin treatment groups (ITT population) were completely free of seizures during their last 28 days of treatment, and between 4% and 5% of pregabalin-treated patients completing the study (n = 236) were completely free of seizures during the entire double-blind treatment period.

Both pregabalin dosing regimens were generally well-tolerated, and as expected, there appears to be a tolerability advantage with flexible-dose adjustment. Overall, significantly more patients in the flexible-dose group completed the 3-month treatment period compared with those in the fixed-dose group. The overall incidence of adverse events in the two pregabalin treatment groups was similar, although patients in the fixed-dose group withdrew from the study sooner and at a greater rate than those in the flexible-dose group. Twenty-four percent of patients in the pregabalin fixed-dose group withdrew due to adverse events in the first week of treatment, compared with 3% in the flexible-dose and none in the placebo groups. Discontinuation rates due to adverse events were highest in the pregabalin fixed-dose group (33%) followed by the pregabalin flexible-dose group (12%) and the placebo group (7%). The most frequently reported adverse events associated with pregabalin treatment in this study were consistent with those reported in previous studies in similar patient populations (17–19), and generally affected the CNS. Of the most frequent adverse events, dizziness and ataxia occurred more frequently in the pregabalin fixed-dose group than in the pregabalin flexible-dose group. Withdrawals due to dizziness, ataxia, somnolence, vertigo, nausea, and diplopia occurred more frequently in the pregabalin fixed-dose group than in the pregabalin flexible-dose group. In contrast, weight gain occurred at a similar rate in both pregabalin treatment groups, and there were no discontinuations due to weight gain. While the adverse events experienced by most patients in this study were mild to moderate in intensity and resolved with continued treatment, more patients in the pregabalin fixed-dose group (23%) experienced adverse events that were characterized as severe, than those in the pregabalin flexible-dose group (10%).

The tolerability advantage of flexible dosing does not appear to be associated with any obvious penalty in terms of decreased efficacy, since the analysis of weekly RRatio values indicates that the overall efficacy differences between the flexible- and fixed-dose regimen is confined to the first week of treatment.

Taken together, these data suggest that the common clinical practice of adjusting the pregabalin dosage for the individual patient based on efficacy and tolerability within the therapeutic range of 150–600 mg/day may confer an overall treatment advantage.

In conclusion, robust efficacy, safety, and tolerability of twice daily pregabalin as adjunctive therapy for patients with partial seizures have been demonstrated in this study, confirming earlier observations (17–19). In addition, there is a clinical advantage to adjusting the dose of pregabalin within the therapeutic range according to the patient's optimal efficacy and tolerability.

Acknowledgments

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Acknowledgment:  The authors thank the patients who took part in this study and the principal investigators in the Pregabalin 1008-157 International Study Group (listed below by country): Austria: Prof. Dr. Gerhard Bauer, Prof. Dr. Christoph Baumgartner, Prim. Dr. Ulf Baumhackl, Prim. Dr. Berthold Kepplinger Canada: Dr. Warren T. Blume, Dr. Andre F. Gagnon, Dr. Alan Guberman, Dr. John Maher, Dr. Neelan Pillay, Dr. Robert Mark Sadler, Dr. Elout Starreveld, Dr. Samuel Wiebe, Dr. Michael Wyndham Jones France: Dr. Michel Baldy-Moulinier, Prof. Michel Baulac, Dr. Arnaud Biraben, Dr. Patrick Y. Chauvel, Dr. Patrick Edouard Contis, Dr. Philippe Derambure, Dr. Jean-Albert Gastaut, Dr. Pierre Genton, Dr. Olivier Guard, Prof. Eduard Hirsch, Dr. Philippe Ryvlin, Dr. Herve Vespignani Germany: Prof. Christian E. Elger, Prof. Dr. Andreas Hufnagel, Dr. Karsten Krakow, Dr. P.D. Holger Lerche, Prof. Heinz J. Meencke, Prof. Dr. Walter Paulus, Prof. Benrd Pohlmann-Eden, Dr. Felix Rosenow, Dr. P.D. Eva Bettina Schmitz, Dr. Andreas Schulze-Bonhage, Prof. Dr. Bernhard J. Steinhoff Italy: Dr. Patrizia D. Alessandro, Prof Luigi Murri, Dr. Giuseppe Neri, Dr. Raffaele Rocchi, Dr. Francesco Sasanelli, Dr. Gaetano Zaccara Lithuania: Dr. Valmantas Budrys, Dr. Aloyzas-Algimantas Skaringa Spain: Dr. Hari Bhathal, Dr. Maria del Mar Carreño Martinez, Dr. Antonio Gil-Nagel, Dr. José Félix Martí-Massó, Dr. Albert Molins I. Albanell, Dr. José María Serratosa United Kingdom: Prof. Martin Jeffrey Brodie, Prof. David William Chadwick, Dr. Pamela Mary Crawford Disclosures:Dr. Anhut, Ms. Lee, and Dr. Barrett are employees of Pfizer Inc.

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  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES
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