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Keywords:

  • clinical trials;
  • epilepsy;
  • refractory complex partial seizures;
  • review;
  • vigabatrin

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Proof-of-concept study (097-005): Browne et al. ()
  5. Pivotal Studies (C-024 and C-025): French et al. () and Dean et al. ()
  6. Conclusions
  7. Conflicts of interest
  8. Acknowledgments
  9. References

Faught E. Vigabatrin therapy for refractory complex partial seizures: review of clinical trial experience in the United States. Acta Neurol Scand: 2011: 124 (Suppl. 192): 29–35. © 2011 John Wiley & Sons A/S.

Vigabatrin is an antiepileptic drug used in more than 50 countries as adjunctive therapy for the treatment of refractory complex partial seizures (rCPS) in adults. First approved in the United Kingdom in 1989, vigabatrin was approved for use in the United States by the Food and Drug Administration in 2009. Although most clinical trials of vigabatrin have been conducted in Europe, three major trials, including two pivotal trials, were conducted in the United States. These trials have demonstrated efficacy and tolerability findings similar to those observed from the European trials. Results of the US trials have demonstrated vigabatrin to be an effective and generally well-tolerated therapy for rCPS in adults, with an optimal dosage of 3 g/day for most patients, and an onset of response generally within 2 weeks. This review focuses on the design and results of the three major US trials of vigabatrin in adults with rCPS.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Proof-of-concept study (097-005): Browne et al. ()
  5. Pivotal Studies (C-024 and C-025): French et al. () and Dean et al. ()
  6. Conclusions
  7. Conflicts of interest
  8. Acknowledgments
  9. References

Animal studies of vigabatrin as an antiepileptic drug (AED) were reported during the 1970s, and clinical development in Europe began shortly thereafter (1–3). Clinical development of vigabatrin in the United States began in 1980, but Food and Drug Administration (FDA) approval was delayed at several points because of safety concerns (4, 5). Although available for clinical use in many European countries since the 1980s, vigabatrin was finally approved by the FDA in 2009 as adjunctive therapy for adult patients with refractory complex partial seizures (rCPS) who have responded inadequately to several alternative treatments (6).

A detailed review of the clinical development of vigabatrin in Europe and well-controlled European trials for rCPS is provided by Ben-Menachem and Sander in this supplement (7). The major US clinical trial experience with vigabatrin in patients with rCPS comprised three randomized controlled trials — Study 097-005, a single-blind, historical control, proof-of-concept trial (8); and two double-blind, parallel, pivotal trials comparing vigabatrin with placebo (Studies C-024 [9] and C-025 [10]).

The first delay in US development, in 1983, was related to the observation of intramyelinic edema (IME) in certain areas of white matter in rodents and dogs receiving vigabatrin (4, 5). After a review of additional data revealed no evidence of IME in humans, US clinical trials resumed in 1990 (4, 5). The second delay in US approval was caused by the discovery of peripheral visual field defects (pVFDs) in vigabatrin-treated patients. This adverse effect was discovered well after the first regulatory approvals in Europe and after the initiation of the three major US trials. The first report of pVFDs in vigabatrin-treated patients in Europe was published in 1997 (11). FDA approval was then delayed until additional information on pVFDs could be gathered and analyzed (4, 5). Safety issues related to non-vision adverse events and pVFDs are discussed in separate reviews in this supplement (12, 13).

FDA approval of vigabatrin occurred in 2009 in conjunction with a comprehensive Risk Evaluation and Mitigation Strategy, which is administered through the Lundbeck Inc. Support, Help And Resources for Epilepsy (SHARE) program. The program, described in more detail in separate reviews (13, 14), is designed to mitigate the risk of permanent vision loss.

This review provides a detailed description of the three major US trials of vigabatrin in patients with rCPS (8–10). It is important to note that these trials were conducted before the post-marketing reports of pVFDs in Europe emerged and did not include visual testing beyond conventional neurologic examinations.

Proof-of-concept study (097-005): Browne et al. (8)

  1. Top of page
  2. Abstract
  3. Introduction
  4. Proof-of-concept study (097-005): Browne et al. ()
  5. Pivotal Studies (C-024 and C-025): French et al. () and Dean et al. ()
  6. Conclusions
  7. Conflicts of interest
  8. Acknowledgments
  9. References

Browne et al. (8) conducted a single-blind (i.e., investigators were unblinded but patients were blinded), multicenter, proof-of-concept study of patients ≥18 years of age with rCPS. Other seizure types were noted and considered in secondary analyses but were not considered in eligibility for enrollment or in analysis for the primary endpoint. There were four phases. The first phase was a 12-week baseline phase during which patients continued receiving their conventional AEDs, with placebo added in a single-blind fashion for the final 4 weeks of the phase. Up to three concomitant drugs were permitted. The second phase was a 4-week titration phase, during which patients received an initial dosage of 1 g/day of vigabatrin followed by weekly increases in dosage (1 g/week) until either a dosage of 50 mg/kg/day or 4 g/day (whichever was less) was reached or until a maximum tolerable dosage was achieved. The third phase was a 12-week maintenance phase, during which the final dosage of vigabatrin attained in the titration phase was continued. Finally, the fourth phase was a long-term, open-label, follow-up phase for patients who had successfully completed the single-blind study with a favorable response to vigabatrin.

Dosages of conventional AEDs remained constant through the first three phases of the study unless a modification was felt to be necessary because of a suspected drug interaction with vigabatrin. Safety assessments included clinical laboratory tests, neurologic examinations, and adverse event (AE) monitoring. At the end of the maintenance phase, upper extremity somatosensory evoked potentials (EPs), auditory EPs, and visual EPs were obtained. In addition, visual EPs were obtained every 3 months during the follow-up phase.

Results

Eighty-nine patients entered the study, and 84 completed the maintenance phase. The most common concomitant AEDs were carbamazepine (59 patients), phenytoin (53 patients), and phenobarbital and primidone (24 patients each).

Efficacy —  The difference in CPS frequency between the 12-week baseline phase and the 12-week maintenance phase was statistically significant (< 0.001). During the 12-week maintenance phase, 51% of patients had a ≥50% decrease in CPS frequency compared with the baseline phase, with 7% of patients achieving a 100% decrease in CPS frequency (i.e., they were seizure free; Table 1). During the last 4 weeks of the maintenance phase, 55% of patients had a ≥50% decrease in CPS frequency compared with the baseline phase, with 15% achieving a 100% decrease (Table 1).

Table 1.   Changes in CPS frequency during the maintenance phase of Study 097-005 compared with the baseline phase. Browne TR, Mattson RH, Penry JK, et al (8). Vigabatrin for refractory complex partial seizures: multicenter single-blind study with long-term follow-up. Neurology. 1987;37(2):184-189. Reprinted with permission, Wolters Kluwer Health
Changes in CPS frequency during maintenance phase (vigabatrin 3 g/day)12-Week maintenance phase, % (= 89)Last 4 weeks of maintenance phase, % (= 89)
100% decrease715
75–99% decrease1918
50–74% decrease2522
1–49% decrease3427
No change or increase <20%1012
Discontinued before end of study because of toxicity22
Discontinued before end of study because of increased seizure frequency or duration33

The median number of CPS per month for the 84 patients who completed the maintenance phase was 11.0 for each of the first two of three baseline months, 10.5 during the placebo month, 6.0 during the titration month, and 5.0 during each of the three maintenance-phase months. There was no parallel placebo arm during the maintenance phase. This was a historical control study in which each patient’s baseline seizure frequency was compared with that during the maintenance phase. However, the mean shift of seizure frequency for all patients was a decrease of 48.3%, which was significant when compared with a theoretical expected shift of 0% (= 12.44, < 0.001).

Safety —  The most frequently reported AEs were drowsiness, ataxia, headache, irritability, dizziness, and unsteadiness (Table 2). Additional AEs reported by more than three patients were increased appetite, mood swings, anxiety, speech disturbance, tremor, numbness/tingling, abdominal pain, gastric irritation, constipation, nausea and vomiting, visual blurring, diplopia, rash, and dry mouth. Most AEs appeared during the titration phase, and the incidence and severity progressively decreased during the maintenance phase, with only drowsiness present for >10% of patients by the end of the maintenance phase. One patient discontinued the study because of drowsiness.

Table 2.   Most frequent AEs in Study 097-005. Browne TR, Mattson RH, Penry JK, et al (8). Vigabatrin for refractory complex partial seizures: multicenter single-blind study with long-term follow-up. Neurology. 1987;37(2):184-189. Reprinted with permission, Wolters Kluwer Health
AETitration phase, % (= 89)Maintenance phase
Month 1, % (= 87)Month 2, % (= 85)Month 3, % (= 84)
Drowsiness40342620
Ataxia11967
Headache10966
Irritability8898
Dizziness8612
Unsteadiness6222
Any AE71615445

A psychosis characterized by agitation, paranoia, confusion, mood swings, and auditory hallucinations was experienced by two patients, one of whom had a history of similar events before vigabatrin treatment. This patient dropped out of the study. The other patient’s psychosis resolved after decreasing the dosage of vigabatrin.

Follow-up phase (15) —  After the maintenance phase, 66 patients entered the long-term follow-up phase (15) and were assessed every 3 months for a median of 43 months (range: 5–72 months). During this phase, vigabatrin dosages could be adjusted. Dosages of vigabatrin were increased in 16 patients and decreased in 10 patients. The median daily dosage of vigabatrin was 3 g and ranged from 1 to 4 g. One or more concomitant medications were stopped for 15 patients and added for two patients.

A sustained reduction in seizure frequency was observed. More than 60% of patients remaining in the study had a ≥50% decrease in CPS frequency compared with their baseline value at every 6-month evaluation (up to 64 months; Table 3).

Table 3.   Changes in CPS frequency during the follow-up phase of Study 097-005. Browne TR, Mattson RH, Penry JK, et al (15). Multicenter long-term safety and efficacy study of vigabatrin for refractory complex partial seizures: an update. Neurology. 1991;41(3):363-364. Reprinted with permission, Wolters Kluwer Health
Duration of vigabatrin therapy, monthsan≥50% seizure reductionb% patients
  1. aThe duration includes the 4 months of the single-blind study.

  2. bDecrease in seizure frequency reported during the 6-month period ending with indicated month, compared with seizure frequency during the baseline phase.

105461
164463
224060
283764
343473
523165
642673

However, during the follow-up phase, 37 of the 66 patients discontinued the study for the following reasons: benefit-to-risk evaluation after the concern about IME appeared (= 8), AEs (= 6), seizure increase (= 6), AEs plus seizure increase (= 5), and various administrative reasons (= 12). The most common AEs reported were headache, dizziness, drowsiness, nervousness, sinusitis, ataxia, back pain, chest pain, tremor, and abdominal pain.

Pivotal Studies (C-024 and C-025): French et al. (9) and Dean et al. (10)

  1. Top of page
  2. Abstract
  3. Introduction
  4. Proof-of-concept study (097-005): Browne et al. ()
  5. Pivotal Studies (C-024 and C-025): French et al. () and Dean et al. ()
  6. Conclusions
  7. Conflicts of interest
  8. Acknowledgments
  9. References

Two large pivotal clinical trials to evaluate the tolerability and efficacy of vigabatrin as adjunctive therapy for adults with rCPS were conducted in the United States (9, 10). Both had a double-blind, placebo-controlled, and parallel-group design with three main periods: baseline, titration, and maintenance. Patients aged 18–60 years with documented rCPS with or without secondary generalization were enrolled. All patients received their baseline AEDs throughout the studies, but only one or two concomitant AEDs were permitted (9, 10).

The primary efficacy endpoint for both studies was the monthly (28-day) frequency of CPS plus secondarily generalized tonic-clonic seizures during the last 8 weeks of the treatment phase compared with the last 8 weeks of the baseline period (9, 10). Secondary endpoints included the therapeutic success rate, defined as the proportion of patients with ≥50% reduction in seizures, number of seizure-free days, and physicians’ subjective evaluations of both therapeutic effect and global evaluation of efficacy and tolerability.

Safety assessments included AE monitoring, vital signs, complete medical and neurologic examination, and clinical laboratory tests. Brain magnetic resonance imaging (MRI), EP measurements, and detailed testing of psychosocial and cognitive functioning were performed at baseline and study completion. MRIs were read blindly by at least three physicians at each site. Vision was not formally monitored in these studies.

The main differences between these two studies were the length of the titration period (4 weeks for Study C-024 vs 6 weeks for Study C-025) and vigabatrin dosages (3 g/day for Study C-024 vs 1, 3, or 6 g/day for Study C-025).

Design (Fig. 1)

image

Figure 1.  Study designs for Studies C-024 (9) and C-025 (10). VGB, vigabatrin.

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Patients in Study C-024 (9) were randomized to vigabatrin 1 g/day (= 92) or placebo (= 90) at the first visit of the titration phase, and dosages were increased to 1.5 g/day at Week 2, 2 g/day at Week 3, and 2.5 g/day at Week 4). The dosage was increased to 3 g/day at the beginning of the maintenance phase, and this dosage was maintained throughout the treatment period. In Study C-025 (10), patients were randomized to placebo (= 45) or vigabatrin 1 g/day (= 45), 3 g/day (= 43), or 6 g/day (= 41) during the 6-week titration period.

Results

There were no significant differences between treatment groups in baseline demographics, clinical characteristics, or concomitant AED medication for either Study C-024 (9) or C-025 (10). Patient disposition is provided in Table 4.

Table 4.   Disposition of patients in Study C-024 (9) and Study C-025 (10)
PatientsStudy C-024Study C-025
Enrolled, N203203
Discontinued, N2129
Received study drug182174
  Sex, N
  Men8083
  Women10291
 Mean age, years3435
Received ≥2 concurrent AEDs, n (%)113 (62)92 (53)
Completed study, n (%)170 (93)149 (86)

Efficacy: primary endpoint —  In both studies, vigabatrin was superior to placebo for the primary efficacy endpoint — the change in median monthly frequency of CPS plus partial seizures secondarily generalized from baseline to the end of the study. In Study C-024 (9), median monthly frequency of seizures was decreased by 0.8 seizures in the placebo group vs 3.0 in the vigabatrin 1 g/day group (= 0.0002; Fig. 2). In Study C-025 (10), median monthly frequency of seizures was decreased by 0.2 seizures in the placebo group vs 0.8 in the vigabatrin 1 g/day group (not significant), 4.3 in the 3 g/day group (= 0.0001), and 4.5 in the 6 g/day group (= 0.0001). A test for a linear trend across vigabatrin dosages in Study C-025 indicated an increased effect of vigabatrin with increasing dosage (= 0.0001). However, 6 g/day was not statistically superior to 3 g/day.

image

Figure 2.  Decrease in median monthly frequency of seizures in Studies C-024 (9) and C-025 (10). aP = 0.0002. bP = 0.0001. VGB, vigabatrin.

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Efficacy: secondary endpoints —  Vigabatrin therapy was associated with a significantly greater responder rate (defined as ≥50% decrease in seizure frequency from baseline) than placebo (Table 5). In C-024 (9), the responder rate was 43% in the vigabatrin 3 g/d group vs 19% in the placebo group. In C-025 (10), the responder rate was 24%, 51%, and 54% in the vigabatrin 1, 3, and 6 g/day groups, respectively, vs 7% in the placebo group.

Table 5.   Percentages of patients classified as therapeutic successes (≥50% decrease in seizure frequency) at the end of Studies C-024 (9) and C-025 (10). French JA, et al (9). Neurology. 1996;46:54-61. Adapted with permission. Dose-response study of vigabatrin as add-on therapy in patients with uncontrolled complex partial seizures. Dean C, et al (10). Copyright © 1999 Epilepsia. Reproduced with permission of John Wiley & Sons, Inc
Study C-024Study C-025
TreatmentTherapeutic success, n (%)TreatmentTherapeutic success, n (%)
  1. aP < 0.001 vs placebo.

  2. bP = 0.0248 vs placebo.

  3. cP < 0.0001 vs placebo.

Placebo17 (19)Placebo3 (7)
Vigabatrin 3 g/day40 (43)aVigabatrin 1 g/day11 (24)b
Vigabatrin 3 g/day22 (51)c
Vigabatrin 6 g/day22 (54)c

Vigabatrin significantly increased the mean number of seizure-free days per month and number of patients who achieved seizure freedom at study end (Table 6) (9, 10).

Table 6.   Seizure-free days per month and achievement of seizure freedom at the end of Studies C-024 (9) and C-025 (10)
Study C-024Study C-025
TreatmentMean seizure-free days/month, nSeizure-freedom at study end, n (%)TreatmentMean seizure-free days/month, nSeizure-freedom at study end, n (%)
  1. aP = 0.0024 vs placebo.

  2. bP = 0.0001 vs placebo.

Placebo0.50 (0)Placebo–0.10 (0)
Vigabatrin 3 g/day2.25 (4.5)aVigabatrin 1 g/day1.20 (0)
Vigabatrin 3 g/day2.09 (9.3)b
Vigabatrin 6 g/day3.25 (12.2)b

Results of the physician’s subjective evaluation of therapeutic effect were that 64% of the vigabatrin group (59 of 92 patients) and 30% of the placebo group (27 of 90 patients) demonstrated improvement during the study (< 0.001) in Study C-024 (9). For this measure in Study C-025, there was a significant dosage-response relationship (< 0.001) between increasing vigabatrin dosage and degree of improvement as demonstrated by moderate or better improvement in 32%, 40%, and 56% of patients in the vigabatrin 1, 3, and 6 g/day groups, respectively, compared with 20% of patients in the placebo group (10). Improvement with vigabatrin 3 and 6 g/day was significantly greater than improvement with placebo (= 0.004 and < 0.001, respectively) (10).

For the physician’s subjective global improvement rating, 49% of the vigabatrin group (45 of 92 patients) and 21% of the placebo group (19 of 90 patients) were perceived to show improvement during therapy in Study C-024 (9). In Study C-025, there was no significant difference between treatment groups for the physician’s global evaluation (10).

Safety —  AEs in Studies C-024 and C-025 were primarily central nervous system (CNS)–related (9, 10). The most frequently reported AEs are indicated in Table 7. Discontinuations during a treatment phase because of an AE occurred in 2% of patients randomized to placebo in Study C-024 and 8% of those randomized to vigabatrin 3 g/day (9). One patient in the vigabatrin group committed suicide, and another had a behavioral abnormality (hyperactivity, paranoia, and grandiose thoughts) that resolved upon vigabatrin discontinuation.

Table 7.   AEs occurring in ≥5% of vigabatrin-treated patients and more frequently than in placebo-treated patients in Studies C-024 (9) and C-025 (10) combined
AE (preferred term)Vigabatrin, n (%) (= 222)Placebo, n (%) (= 135)
Fatigue60 (27.0)22 (16.3)
Somnolence49 (22.1)18 (13.3)
Dizziness47 (21.2)23 (17.0)
Nystagmus34 (15.3)12 (8.9)
Tremor31 (14.0)11 (8.1)
Nasopharyngitis29 (13.1)14 (10.4)
Vision blurred25 (11.3)7 (5.2)
Diarrhea23 (10.4)10 (7.4)
Irritability23 (10.4)10 (7.4)
Memory impairment21 (9.5)4 (3.0)
Upper respiratory tract infection21 (9.5)7 (5.2)
Coordination abnormal19 (8.6)3 (2.2)
Diplopia19 (8.6)4 (3.0)
Nausea19 (8.6)11 (8.1)
Pharyngolaryngeal pain19 (8.6)7 (5.2)
Arthralgia18 (8.1)4 (3.0)
Weight increased17 (7.7)4 (3.0)
Vomiting16 (7.2)8 (5.9)
Depression15 (6.8)4 (3.0)
Dysmenorrhea15 (6.8)4 (3.0)
Gait disturbance15 (6.8)9 (6.7)
Constipation14 (6.3)4 (3.0)
Back pain13 (5.9)3 (2.2)
Confusional state13 (5.9)1 (0.7)
General symptom13 (5.9)4 (3.0)
Asthenia12 (5.4)2 (1.5)
Disturbance in attention12 (5.4)1 (0.7)

In Study C-025 (10), the percentage of patients who discontinued because of AEs increased with increasing vigabatrin dosage: one patient (2.2%) in the placebo group discontinued, compared with three (6.5%), five (11.4%), and eight (18.2%) patients in the 1, 3, and 6 g/day vigabatrin groups, respectively. The incidence of AEs categorized as severe increased with vigabatrin dosage, ranging from 2.2% (placebo) to 8.7%, 11.4%, and 15.9% (vigabatrin 1, 3, and 6 g/day, respectively) (10).

There were no clinically important changes noted in brain MRI (including no evidence of changes suggestive of IME), EPs, or other laboratory tests reported in either study, and no important drug interactions were noted (9, 10).

Results of cognitive testing were encouraging. In Study C-025 (10), for 42 cognitive and psychosocial subtests performed, significant linear trends were seen only in the Digit Cancellation Test, which patients performed less accurately with increasing vigabatrin dosage. However, the authors believed that these small changes would not likely affect daily cognitive function, and no changes in the other cognitive tests were found.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Proof-of-concept study (097-005): Browne et al. ()
  5. Pivotal Studies (C-024 and C-025): French et al. () and Dean et al. ()
  6. Conclusions
  7. Conflicts of interest
  8. Acknowledgments
  9. References

The results of the three major US trials (8–10) are consistent with results from European trials (7), demonstrating the significant efficacy of vigabatrin as an adjunctive treatment for patients with rCPS. Therapeutic success, defined as ≥50% decrease in CPS frequency, with vigabatrin dosages of 3 g/day or greater occurred in 43% of patients in Study C-024 (9) and ≥51% of patients in Studies 097-005 and C-025 (8, 10). Perhaps more importantly for these patients with very refractory epilepsy, some became seizure-free. No patients who received placebo or vigabatrin 1 g/day became seizure-free during these trials, but 4.5% (9) and 9.3% (10) achieved seizure freedom with vigabatrin 3 g/day. Moreover, 12.2% achieved seizure-freedom with vigabatrin 6 g/day (10). Response to treatment was rapid, with statistically significant seizure reduction occurring as early as 2 weeks following the start of treatment and was maintained throughout the treatment period (Fig. 3) (9, 10).

image

Figure 3.  Time course to therapeutic success (≥50% decrease in seizure frequency) in Studies C-024 (9) and C-025 (10). VGB, vigabatrin.

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In most US and European trials to date, vigabatrin 3 g/day was demonstrated to be the optimal dosage based on response and tolerability (7, 9, 10, 16). A few patients may receive additional benefit from a dosage of 6 g/day, although AEs increase at this dosage. In addition, vigabatrin 1 g/day may be effective for a subset of patients.

The most frequently reported AEs in US and European trials were CNS-related, most prominently drowsiness, headache, dizziness, and fatigue (7–10, 12, 16). These CNS effects appear to be dosage-related. Serious AEs were uncommon but included three instances of psychosis, about 1% of the 310 patients randomized to vigabatrin in these three trials. Formal cognitive testing suggested that vigabatrin is unlikely to produce clinically significant changes in cognitive function (10).

There were no clinically important changes in brain MRIs, EPs, or laboratory tests observed in either Study C-024 or Study C-025. No vision assessments, other than routine clinical bedside examinations, were performed in these studies (8–10). The benefit of improved seizure control must be balanced against potential risks associated with vigabatrin, including development of pVFDs.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Proof-of-concept study (097-005): Browne et al. ()
  5. Pivotal Studies (C-024 and C-025): French et al. () and Dean et al. ()
  6. Conclusions
  7. Conflicts of interest
  8. Acknowledgments
  9. References

Edward Faught wrote the first and last drafts of this manuscript. Medical writing and editorial assistance were provided by Beth Alley and Robin L. Stromberg, PhD, of Arbor Communications, Inc. (Ann Arbor, MI, USA) and Michael A. Nissen, ELS, of Lundbeck Inc. (Deerfield, IL, USA). This support was funded by Lundbeck.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Proof-of-concept study (097-005): Browne et al. ()
  5. Pivotal Studies (C-024 and C-025): French et al. () and Dean et al. ()
  6. Conclusions
  7. Conflicts of interest
  8. Acknowledgments
  9. References