Abstract
We conducted a multicenter, double-blind, randomized, parallel, placebo-controlled trial in 190 patients to evaluate the safety and efficacy of three dosages of topiramate (600, 800, and 1,000 mg/day) as adjunctive therapy for patients with refractory partial epilepsy. During an 18-week double-blind treatment period, median percent reductions from baseline in average monthly seizure rates were 1% for placebo, 41% for topiramate 600 mg/day and topiramate 800 mg/day, and 38% for topiramate 1,000 mg/day. There was a 50% or greater reduction from baseline in seizure frequency in 9% of patients in the placebo group and in 44% for topiramate 600 mg/day, 40% for topiramate 800 mg/day, and 38% for topiramate 1,000 mg/day. No placebo patients were improved by 75 to 100% in seizure frequency, whereas 20% of the topiramate patients were improved to this degree. All intent-to-treat drug-placebo comparisons including seizure reduction, percent responders, and investigator and patient global evaluations significantly (p <or=to 0.02) favored topiramate. Treatment-emergent adverse events consisted mainly of neurologic symptoms commonly observed during antiepileptic drug (AED) therapy. Sixteen percent of patients on topiramate discontinued therapy due to adverse events. Results of this study indicate that topiramate is a highly efficacious and generally well tolerated new AED. When large groups of patients are compared, incremental efficacy in the add-on setting is not observed at topiramate dosages above 600 mg/day; however, higher doses may prove beneficial to individual patients who tolerate them.
NEUROLOGY 1996;46: 1678-1683
Topiramate is a novel sulfamate-substituted monosaccharide [1] that has shown considerable promise as an antiepileptic drug (AED). Early open-label experience with topiramate in resistant partial epilepsy showed a 50% reduction in seizures in 50% or more of patients, [2,3] and there were no major interactions during coadministration with carbamazepine, phenytoin, or valproate. [4,5] On the basis of these encouraging findings, double-blind placebo-controlled trials were instituted to better define the efficacy, safety, and appropriate dosage range of topiramate as adjunctive therapy in refractory partial epilepsy. The present study was designed to evaluate a mid-to-high dose range comprising daily target dosages of 600, 800, and 1,000 mg of topiramate.
Methods.
Subjects.
Men and women 18 to 65 years of age with a history of refractory partial epilepsy with or without secondary generalization were eligible for participation in the study. A 68-year-old patient and a 67-year-old patient were also admitted to the trial. Only patients in good physical health were selected, and women were required to be postmenopausal or otherwise incapable of becoming pregnant. Patients with a treatable cause of seizures or progressive neurologic condition were excluded from the trial, as were those with a history of status epilepticus, serious psychiatric disorder, nephrolithiasis, substance abuse, or a significant confounding acute or chronic disease. Also excluded were patients treated with another experimental drug within 60 days before the study, those with clinically significant laboratory abnormalities at baseline, and patients considered unable to maintain a seizure diary or having a history of poor compliance with AED therapy.
Required preentry confirmatory studies included an EEG within the last 5 years demonstrating an epileptiform pattern consistent with a diagnosis of partial epilepsy and a CT or MRI within the last 2 years to exclude the possibility of progressive neurologic disease. All patients provided informed written consent before entering the study.
Design and procedure.
This was a multicenter, randomized, parallel, double-blind comparison of three target dosages of topiramate (600, 800, and 1,000 mg/day) and placebo in outpatients. The study consisted of a 12-week baseline phase and an 18-week double-blind phase. For admission to the double-blind phase, patients were required to have experienced at least 12 partial seizures during the baseline phase while being maintained on one or two AEDs at therapeutic plasma concentrations. During that phase, the longest allowable seizure-free interval was 3 weeks and only one such interval was permitted. Qualifying patients were randomized, in equal proportions at each center, to treatment with one of the three dosages of topiramate or placebo while their background AED regimen was continued.
The 18-week double-blind study phase consisted of two sequential treatment periods, a 6-week titration period and a 12-week stabilization period. All patients were scheduled to eventually receive five tablets bid of topiramate or placebo in a combination that matched their dose assignment. Patients received either 100 mg of topiramate or one placebo tablet once daily during the first week of the titration period and 100 mg of topiramate or one placebo tablet bid during the second week. The subsequent dosage increment for each remaining titration week was 100 mg of topiramate bid or one placebo tablet bid until the lesser of the assigned dosage or the maximum tolerated dosage was reached. Patients were then followed on this regimen throughout the stabilization period. Topiramate and placebo tablets were identical in appearance and packaging.
Measurement of efficacy.
For assessment of drug efficacy, patients recorded the date, time, and description of each seizure in a diary. The investigator reviewed the diary at each visit and classified each seizure as simple partial, complex partial, or partial evolving to secondarily generalized. The principal efficacy variable was the percent reduction in the average seizure rate from the baseline phase to the double-blind phase. Other efficacy determinants included percent treatment responders (patients with a 50% or greater reduction in seizure frequency were considered to be responders), investigator's global evaluation of improvement, patient's overall assessment of the study medication, and percent reduction in secondarily generalized seizures. Ratings for the global evaluations were as follows: investigator's evaluation of improvement: (1) worse, (2) none, (3) minimal, (4) moderate, (5) marked; patient's assessment of medication: (1) poor, (2) fair, (3) good, (4) excellent.
Measurement of safety.
Safety studies performed at baseline and repeated during and at the conclusion of the study included physical and neurologic examinations, vital signs, and complete clinical laboratory battery. Ophthalmologic and audiometric examinations were conducted at the end of the baseline period and at the conclusion of the study. Samples for independent measurement of trough plasma concentrations of topiramate and other AEDs were taken at each visit during the double-blind phase.
Patients were evaluated for adverse events at each visit. A sign or symptom that occurred during the double-blind phase but was not present during the baseline phase or that was present at baseline but worsened during double-blind therapy was considered to be a treatment-emergent adverse event (TEAE). Adverse events were classified according to World Health Organization terminology, graded as to severity, and followed to resolution. The investigator's judgment concerning the relationship of the adverse event to study medication was also recorded.
Statistical analysis.
Intent-to-treat analyses of efficacy measures included all subjects entering the double-blind study phase and all seizure data from both the titration and stabilization periods. The baseline seizure rate was calculated as the average monthly seizure count during the 12-week baseline phase. For the principal efficacy variable, percent reductions in seizure rate from baseline to double-blind phase were computed, and pairwise comparisons of the three topiramate dosages to placebo were performed using three separate two-factor (treatment, center, treatment-by-center interaction) ANOVA on ranks. [6] Percent responders in the treatment groups were also compared using the Cochran-Mantel-Haenszel test, [7] whereas investigator and subject overall assessments were analyzed by Wilcoxon rank-sum tests. [8] Because there were few patients with generalized seizures, all topiramate groups were combined and compared with the placebo group using ANOVA on rank of percent generalized seizure reduction.
Results.
Demographics.
Of the 240 patients enrolled in the baseline phase of the trial, 190 patients met the qualification criteria and were randomized to the double-blind phase. Of this group, 48 patients were assigned to the topiramate 600-mg/day group, 48 to the topiramate 800-mg/day group, 47 to the topiramate 1,000-mg/day group, and 47 to the placebo group. Demographic characteristics for those randomized are summarized in Table 1. The population was predominantly white and male with a mean age of 35 years. Baseline median monthly seizure rates ranged from 9.3 for the placebo group to 16.2 for the topiramate 800-mg/day group. Over 90% of all patients randomized had a history of complex partial seizures, and more than 60% had also experienced secondarily generalized seizures. The groups were comparable with respect to baseline characteristics. Consistent with the principles of the primary intent-to-treat statistical analysis, all data from the 190 patients who entered the double-blind phase were included in the efficacy analyses and in the safety assessment. These analyses included a single patient with primary generalized tonic-clonic seizures.
Table 1. Baseline characteristics for randomized patients
Efficacy.
Target study medication dosages were not reached by all patients. For the double-blind stabilization period, actual mean daily topiramate dosages were 544 mg/day for the 600-mg/day group, 739 mg/day for the 800-mg/day group, and 799 mg/day for the 1,000-mg/day group. For placebo, the target dosage was 10 tablets/day; the actual mean dosage was 9.7 tablets/day during the stabilization period. The target dosage was reached by 91% of patients in the placebo group, 73% of patients in the topiramate 600-mg/day group, 69% of those in the 800-mg/day group, and 55% of those assigned to the 1,000-mg/day group.
Results of the analysis of efficacy variables are summarized in Table 2. Patients in the placebo group showed a median reduction from baseline in average monthly seizure rate of 1.2%, whereas patients in the topiramate 600-mg/day group showed a reduction of 40.7%, those in the 800-mg/day group demonstrated a 41.0% reduction, and patients assigned to the 1,000-mg/day group demonstrated a 37.5% reduction in seizure rate. The differences between placebo and active drug were highly statistically significant (p < 0.001) for all three topiramate dosages. The drug-placebo differences were also consistent across centers. No statistically significant treatment-by-center interactions were detected (p = 0.889), and the results favored topiramate 600 mg/day over placebo at all 17 centers and topiramate 800 mg/day and 1,000 mg/day over placebo at 16 of 17 centers.
Table 2. Results of efficacy variables
The analysis of treatment responders indicated that a 50% or greater reduction in seizure rate from baseline to double-blind phase was documented in 9% of patients who received placebo, 44% of patients in the topiramate 600-mg/day group, 40% of those assigned to the 800-mg/day group, and 38% of patients in the 1,000-mg/day groups. Again, these drug-placebo differences were highly significant (p <or=to 0.001) for all topiramate dosage groups. Higher degrees of seizure control were also examined, although they were not formal efficacy variables. A 75 to 100% reduction in seizure rate was not experienced by any patient in the placebo group but was observed in 23% of patients who received topiramate 600 mg/day and 13% of patients treated with topiramate 800 mg/day or 1,000 mg/day.
Analyses of seizure rate reductions and treatment responders were also conducted using only stabilization period data and including only patients who completed the trial at their assigned dosage. In both cases, the results were congruent with the intent-to-treat analysis.
The investigator's global evaluation of improvement and the patient's overall assessment of study medication were consistent with the seizure reduction data. On the investigator's global evaluation of improvement during double-blind therapy, 72% of patients in the topiramate 600-mg/day group, 85% in the 800-mg/day group, and 72% in the 1,000-mg/day group showed improvement over baseline compared with 28% in the placebo group. All three dosages, overall, were statistically superior to placebo (p <or=to 0.001) on the investigators' evaluation. Sixty-two percent of subjects in the 600-mg/day group, 57% in the 800-mg/day group, and 47% in the 1,000-mg/day group rated their medication as good to excellent compared with 26% in the placebo group. All three topiramate dosages, overall, were statistically superior to placebo (p <or=to 0.015) on the patient assessment.
Changes in generalized seizure rate for the subpopulation of patients who experienced generalized seizures during the baseline phase are shown in Table 3. Median percent reductions from baseline were 40.3% for the placebo group, 65.5% for patients who received topiramate 600 mg/day, 44.4% for the topiramate 800-mg/day group, and 78.0% for those in the topiramate 1,000-mg/day group. Similar drug-placebo differences were observed in the comparisons of patients experiencing a 50% or greater reduction in generalized seizures.
Table 3. Changes in secondarily generalized seizures for patients reporting generalized seizures during the baseline study phase
Safety.
The most common TEAEs reported during the double-blind study phase are presented in Table 4. The most frequent events were CNS symptoms, including dizziness, ataxia, somnolence, nystagmus, diplopia, confusion, thinking abnormal, and headache. Of these, nystagmus, somnolence, and diplopia appeared to be dose related, occurring at a higher frequency in the topiramate 800-mg/day and 1,000-mg/day groups than in the placebo or topiramate 600-mg/day groups. Weight loss was present in some patients with anorexia; however, weight was not measured at each visit, and a quantitative assessment of weight change is not available. The frequencies of most other adverse events were greater in each of the three topiramate groups than in the placebo group, but a dose relationship was not apparent. The frequency of headache was similar in the placebo and topiramate groups. Most events were rated as mild or moderate in severity. Twenty-four patients (13%) discontinued treatment due to a limiting adverse event, 1 in the placebo group, 10 in the topiramate 600-mg/day group, 5 in the topiramate 800-mg/day group, and 8 in the topiramate 1,000-mg/day group. Most of the patients who discontinued dropped out during the titration period, and most limiting events were CNS-related symptoms and included anxiety, abnormal thinking, and emotional liability. Four patients experienced adverse events that were considered to be serious or potentially serious. One patient in the topiramate 1,000-mg/day group reported abdominal pain and another patient in the same treatment group reported shortness of breath. These were considered by the investigator to be possibly drug related. One patient each in the topiramate 600-mg/day and placebo groups suffered accidental injuries that were considered by the investigator to be unrelated to study medication. There were no deaths during the trial. There were no clinically significant mean changes from baseline in any of the clinical laboratory tests, and no individual abnormality was considered to represent a clinically relevant drug-related change.
Table 4. Treatment-emergent adverse events and discontinuations for limiting adverse events*
Discussion.
Complex partial seizures are frequently refractory to medical therapy, with up to 40% of patients demonstrating this seizure type considered difficult to manage. [9] Although there are some limitations in directly comparing responder rates across clinical trials, the responder rates of 38 to 44% achieved with topiramate in this study compare favorably with those reported in controlled trials of other new AEDs. For example, in recently reported dose-ranging studies of gabapentin [10] and lamotrigine, [11] maximum responder rates at any dose were 26% for gabapentin and 34% for lamotrigine. Consistency of results across centers was also impressive in the present topiramate trial.
The profile of individual adverse events seen throughout the topiramate dose range was predominantly CNS related, as expected for drugs of this class, especially when added to existing AED treatment. Although most of the topiramate-treated patients reported TEAEs in the present study, they did not limit treatment in most cases, and substantial numbers of patients entered into long-term topiramate treatment protocols.
As with a number of the individual TEAEs, there was no detectable correlation between the topiramate target dosage and the frequency of adverse events leading to discontinuation across the higher doses studied in the present trial; however, the frequency of discontinuations was notably greater for active drug groups than for placebo. We believe that the rate of drug titration in this study was clearly too rapid and that slower titration in future trials and in clinical practice is likely to improve the tolerability of topiramate.
In summary, results of the present study indicate that topiramate is a highly effective new AED when used as adjunctive therapy in patients with refractory partial seizures. When groups of patients are compared, dosages of topiramate greater than 600 mg/day do not appear to produce significant incremental efficacy and may result in a higher incidence and greater severity of adverse events. However, as with most AEDs, individuals who tolerate higher doses in the add-on setting may receive additional benefit. CNS-related TEAEs are the most common adverse events observed with topiramate as they are with other centrally acting agents. Clinicians should be aware of potential CNS adverse effects during rapid titration of topiramate as undertaken in this trial. Future studies to better characterize the CNS adverse effects, particularly the impact of slower titration in smaller dosage increments, are indicated. Based on experience with other AEDs, [12] the frequency of TEAEs may be significantly reduced and the well-tolerated dose range extended when topiramate is administered as monotherapy.
Acknowledgments
We thank the study coordinators at the sites and the monitors from R. W. Johnson Pharmaceutical Research Institute for collecting the huge amount of data in this trial.
The Topiramate YE Study Group comprises the following: B. Bourgeois, MD, Cleveland Clinic Foundation; G. Carter, MD, PhD, Dallas Veterans Administration Medical Center; J. Ferrendelli, MD, Washington University School of Medicine and Barnes Hospital (St. Louis, MO); R. Fincham, MD, The University of Iowa Hospitals (Iowa City, IA); G. Fromm, MD, Falk Clinic and University of Pittsburgh School of Medicine; B. Gallagher, MD, Medical College of Georgia (Augusta, GA); R. Harner, MD, Medical College of Pennsylvania (Philadelphia, PA); M. Holmes, MD, Neurology Associates (Boise, ID); R. Leroy, MD, Southwestern Medical School (Dallas, TX); J. Penry, MD, Bowman Gray School of Medicine (Winston-Salem, NC); M. Privitera, MD, University of Cincinnati Medical Center and University of Cincinnati Hospital (Cincinnati, OH); W. Rosenfeld, MD, Bethesda General Hospital and St. Louis University (St. Louis, MO); A. Rowan, MD, Mt. Sinai Medical School and Bronx Veterans Administration Medical Center (New York, NY); J. C. Sackellares, MD, University of Michigan Medical Center (Ann Arbor, MI); D. Smith, MD, Good Samaritan Hospital (Portland, OR); L. Willmore, MD, University of Texas (Houston, TX); and A. Wyler, MD, Epicare Center (Memphis, TN).
- Copyright 1996 by Advanstar Communications Inc.
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