Two clinical trials form the basis for US Food and Drug Administration approval of vigabatrin for IS: a relatively small, short-term placebo-controlled study by Appleton et al. (20), and a larger, longer dosage-comparison trial by Elterman et al. (9).
A randomized, double-blind, placebo-controlled, parallel-group study with an open follow-up period: Appleton et al. (20)
This international, multicenter, randomized, placebo-controlled study evaluated vigabatrin in 40 infants who had been recently diagnosed with IS. Patients were observed during a 2- to 3-day baseline period and then randomized to vigabatrin or placebo for 5 days. Subsequently, all infants continuing in the study were treated with open-label vigabatrin for at least 24 weeks, with other AEDs allowed during this phase of the study. Although lengthy placebo-controlled trials in infants with IS would be considered unethical because of the potential brain damage caused by continued seizures, this very short trial was deemed justifiable and feasible to confirm previous reports from open-label, retrospective, or comparative studies that indicated that vigabatrin was an efficacious treatment for IS (14, 16, 21, 22). The earlier reports suggested that the response to vigabatrin was likely to be very rapid, with a large majority (82%) of infants who responded showing improvement within 5–7 days (16, 35). Therefore, the study by Appleton et al. (20) required only a 5-day, double-blind period. Investigators agreed that a maximum delay of 7–8 days, which would include both the baseline and double-blind period, would not affect either long-term spasm control or developmental outcome in infants receiving placebo.
Patients were previously untreated infants between the ages of 1 and 20 months who were recently diagnosed with IS and who had classic or modified hypsarrhythmia, as measured by EEG. Patients were excluded if they used any AED such as prednisolone, hydrocortisone, or ACTH within a 2-month period before entry. The starting dosage of vigabatrin was 50 mg/kg/day, which was maintained for 24 h. If spasms did not stop completely, the dosage was increased to 100 mg/kg/day for another 48 h. The dosage could be increased to a maximum of 150 mg/kg/day thereafter. Once a dosage was established for more than 48 h, it could not be altered during the double-blind period except for safety reasons.
The primary endpoint was the average percentage change in seizure frequency. Seizures were counted by nurses and parents. Another principal endpoint was the percentage of patients who were spasm-free at the end of the double-blind phase and at the end of the 24-week open-label phase. Repeated EEG recordings were conducted at both times. The infants’ development was assessed with the Denver test at baseline and after the 24-week open-label treatment period.
Forty infants from five European countries and Canada were enrolled, with 20 in each treatment group. Etiologies of IS were 30% cryptogenic and 70% symptomatic. No infant had tuberous sclerosis. Twenty-eight patients had classic hypsarrhythmia, and 12 had modified hypsarrhythmia. The mean dosage of vigabatrin at the end of the double-blind phase was 133 mg/kg/day (placebo, 148 mg/kg/day). The maximum dosage of 150 mg/kg/day was given to 11 of 20 patients in the vigabatrin group and to 19 of 20 patients in the placebo group. All 40 patients completed the double-blind phase, and 36 patients enrolled in the 24-week open-label phase, with 29 completing it. Of those who did not complete the open-label phase, five withdrew for lack of response to vigabatrin and two were lost to follow-up.
During the double-blind, placebo-controlled phase, seven (35.0%) vigabatrin-treated patients vs two (10.0%) placebo-treated patients achieved complete spasm-freedom (P = 0.063). The percentage decrease in spasms was significantly greater for infants treated with vigabatrin compared with placebo (77.9% [95% confidence interval (CI): 55%, 89%] vs 25.9% [95% CI: −56%, 65%], P = 0.02). At the end of the 24-week open-label treatment period, 15 of the original 40 patients (37.5%) were spasm-free. Of those 15 patients, 9 (60.0%) had become spasm-free within 12 days of the start of vigabatrin treatment.
Developmentally, infants appeared to have a favorable response when treatment resulted in cessation of spasms. At baseline, only three patients had normal Denver developmental test results, but by the end of the study, seven had normal results. All seven patients with normal developmental test results were spasm-free with vigabatrin monotherapy, whereas all patients who continued to have spasms had abnormal test results at the end of the study.
In the placebo-controlled phase, AEs occurred in 12 (60.0%) vigabatrin-treated patients and six (30.0%) placebo-treated patients (Table 3). The most common AE with vigabatrin treatment was drowsiness (n = 8). One patient had marked irritability. In the open-label phase of the study, 24 (66.7%) patients experienced one or more AEs. None of the events were clinically serious and no patient withdrew as a result of AEs. Overall, vigabatrin was generally well-tolerated. The study design did not include vision or MRI assessments.
Table 3. Incidence of commonly reported AEs
|Appleton et al. (20) (N = 40)||Elterman et al. (9) (N = 222)||Chiron et al. (21) (N = 22)b||Vigevano and Cilio (22) (N = 42)||Lux et al. (25) (N = 107)|
|PBO (n = 20)||VGB (n = 20)||VGB (High + Low)||HC (n = 12)||VGB (n = 18)||ACTH (n = 19)||VGB (n = 23)||HT (n = 55)||VGB (n = 52)|
|Patients with ≥1 AE||6||12||110||9||5||7||3||30||28|
The study by Appleton et al. was key in that it was the first double-blind, randomized, placebo-controlled trial of vigabatrin for IS, and it demonstrated the drug’s efficacy in this patient population. More patients treated with vigabatrin were spasm-free at the end of the double-blind period compared with placebo-treated patients. However, the difference was not statistically significant (P = 0.063). The authors concluded that the short double-blind period and the absence of patients with IS with tuberous sclerosis, which is known to respond particularly well to vigabatrin, were the likely reasons for this occurrence. Another unique finding was that more originally placebo-treated patients (n = 11) than originally vigabatrin-treated patients (n = 4) were spasm-free at the end of the 24-week, open-label treatment with vigabatrin. This outcome suggests that a short delay in treatment (of up to 8 days) does not appear to negatively affect ultimate response to treatment. Response to vigabatrin was rapid, occurring within 12 days and confirming similar results of previous studies (16, 21, 22, 35).
A randomized, single-blind, dosage-comparison trial with open-label follow-up for up to 3 years: Elterman et al. (9)
This large randomized, single-blind study by Elterman et al. evaluated the effects of high- and low-dosage vigabatrin on spasm cessation in 221 patients with newly diagnosed IS. This dosage-comparison trial included an open-label follow-up phase of up to 3 years (9). Initially, infants with IS were randomly assigned to high (100–148 mg/kg/day) and low (18–36 mg/kg/day) dosages of vigabatrin for 14–21 days. Patients achieving spasm-freedom within the first 14 days remained on randomized therapy for an additional 7 days before entering the open-label phase. Patients not achieving spasm-freedom within the first 14 days entered the open-label phase after Day 14.
All patients had a diagnosis of IS of less than 3 months’ duration, were <2 years of age, weighed ≥3.5 kg, and could not have been treated previously with corticosteroids, ACTH, or valproic acid. Any investigational drugs other than vigabatrin — including ACTH, corticosteroids, valproic acid, and felbamate — were not allowed during the first 14 days. Stable dosages of AEDs used for other seizure types, such as phenobarbital and clonazepam, were permitted but dosage adjustments were not allowed during the first 21 days.
The primary outcome measure was spasm cessation, defined as 7 consecutive days of spasm-freedom beginning within the first 14 days. Spasm cessation was to be initially reported by caregivers and then confirmed by video-EEG within 3 days of the seventh day of the spasm-free period. As the study progressed, investigators realized that the 3-day video-EEG requirement was an extremely stringent condition that was difficult to meet logistically and had a negative impact on the primary efficacy end point. Therefore, alternate criteria were applied to make results more comparable to those of other IS trials (Fig. 2). The post-hoc primary criterion extended the time frame for video-EEG confirmation to 9 days, and the secondary criterion was defined as spasm-freedom based on caregiver assessment for 7 consecutive days at any time during the study with no relapse.
Figure 2. Vigabatrin effect on spasm cessation by different criteria for spasm cessation. The effect of high-dosage vigabatrin was consistently greater than low-dosage vigabatrin when different criteria for spasm cessation were applied. Primary criteria (which were determined by investigators to be overly stringent during course of the study) were defined as spasm-free by both caregiver assessment and video-EEG confirmation within 3 days of the seventh day of spasm freedom. Post-hoc criteria were defined as spasm-free by both caregiver assessment and video-EEG confirmation during a subsequent visit. Secondary criteria were defined as spasm-free for 7 consecutive days at any time during the study and remained spasm-free for the duration of the study period based on caregiver assessment. Elterman RD, Shields WD, Bittman RM, et al. J Child Neurol. Vol. 25, Issue 11, pp. 1340-1307, copyright © 2010 by SAGE Publications. Reprinted by Permission of SAGE Publications.
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The modified intention-to-treat cohort of 221 patients was evaluated for vigabatrin efficacy. One additional patient, who had received an unknown dosage of study drug and was therefore excluded from efficacy evaluations, was included in the safety population. Two patients discontinued during the 21-day single-blind phase because of non-compliance and were evaluated as treatment failures. The majority of patients were not followed through the entire 3-year open-label period (183 of 221; 82.8%). Most patients left the study early for lack of efficacy (49 of 221; 22.2%), other reasons (36 of 221; 16.3%), or administrative reasons (35 of 221; 15.8%). Nineteen (8.6%) patients discontinued over the 3-year period because of serious or severe AEs.
The mean (SD) durations of vigabatrin exposure were 423.3 (317.2) days in the high-dosage group and 512.0 (372.1) days in the low-dosage group. Duration of exposure varied considerably between patients, with infants who responded to vigabatrin therapy but who had no other access to the medication staying in the study longer.
Based on the most stringent definition of spasm-freedom, 17 of 107 patients (15.9%) in the high-dosage group and 8 of 114 patients (7.0%) in the low-dosage group achieved spasm cessation (P < 0.0375; Fig. 2). However, when spasm cessation was defined as video-EEG confirmation within 9 days of spasm cessation, the response rates were nearly double in each group: 30.8% in the high-dosage group vs 13.2% in the low-dosage group (P < 0.0014). Applying the criterion of caregiver-reported spasm-freedom at any time during the study with no video-EEG requirement produced even greater rates of spasm cessation for both groups: 68.2% for the high-dosage group vs 51.8% for the low-dosage group (P < 0.0126). Regardless of the definition of spasm cessation, significantly more patients receiving the greater dosage of vigabatrin achieved spasm cessation.
During follow-up, 39 of 171 patients (22.8%) relapsed, but 28 of the 39 (71.7%) achieved freedom from spasms again. Significantly more patients in the high-dosage group achieved spasm cessation within 1 week of treatment initiation compared with the low-dosage group (P = 0.0016), with median times to spasm cessation being 6 and 13 weeks, respectively. Response to vigabatrin varied slightly by etiology of IS, although between-group differences were not statistically significant. Of patients with symptomatic IS due to tuberous sclerosis, 21.1% (8 of 38) achieved spasm-free status, whereas 7.9% (10 of 126) of patients with other symptomatic etiologies and 12.3% (7 of 57) of patients with cryptogenic etiologies achieved spasm-free status.
Over the course of the entire 3-year study, 115 of 222 patients (51.8%) experienced at least one AE, although only 13.8% of AEs were considered to be related to vigabatrin. The most common vigabatrin-related AEs occurring for at least 10% of patients were sedation (16.7%), somnolence (13.5%), and irritability (9.9%; Table 3). Like the study by Appleton et al. (20), this study design did not include the assessments of vision or imaging.
Based on these findings, Elterman et al. concluded that vigabatrin decreased IS in a dosage-dependent manner. Spasm cessation occurred quickly and was maintained in most infants who responded to vigabatrin. An interim analysis of the first 142 patients in this study was published in 2001 by Elterman et al. (23), and the results from the final analysis reported here are consistent with those from the earlier analysis, in which 36% (24 of 67) of patients in the high-dosage group achieved spasm cessation within 14 days of starting treatment compared with 11% (8 of 75) in the low-dosage group (P < 0.001). IS of all etiologies improved with treatment, although a trend toward a greater response rate and shorter time to response was observed in infants with tuberous sclerosis compared with other etiologies. This is consistent with previous studies (4, 22). Vigabatrin was well-tolerated by the majority of patients, and AEs were generally mild to moderate.