TOPIRAMATE (Page 2 of 11)

CLINICAL STUDIES

The studies described in the following sections were conducted using topiramate tablets.

Epilepsy

Monotherapy Controlled Trial

The effectiveness of topiramate as initial monotherapy in adults and children 10 years of age and older with partial onset or primary generalized seizures was established in a multicenter, randomized, double-blind, parallel-group trial.

The trial was conducted in 487 patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documented seizures during the 3-month retrospective baseline phase who then entered the study and received topiramate 25 mg/day for 7 days in an open-label fashion. Forty-nine percent of subjects had no prior AED treatment and 17% had a diagnosis of epilepsy for greater than 24 months. Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization. In the double-blind phase, 470 patients were randomized to titrate up to 50 mg/day or 400 mg/day. If the target dose could not be achieved, patients were maintained on the maximum tolerated dose. Fifty eight percent of patients achieved the maximal dose of 400 mg/day for ≥ 2 weeks, and patients who did not tolerate 150 mg/day were discontinued. The primary efficacy assessment was a between group comparison of time to first seizure during the double-blind phase. Comparison of the Kaplan-Meier survival curves of time to first seizure favored the topiramate 400 mg/day group over the topiramate 50 mg/day group (p=0.0002, log rank test; Figure 1). The treatment effects with respect to time to first seizure were consistent across various patient subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use.

topiramate-fig01
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Figure 1: Kaplan-Meier Estimates of Cumulative Rates for Time to First Seizure

Adjunctive Therapy Controlled Trials in Patients With Partial Onset Seizures

The effectiveness of topiramate as an adjunctive treatment for adults with partial onset seizures was established in six multicenter, randomized, double-blind, placebo-controlled trials, two comparing several dosages of topiramate and placebo and four comparing a single dosage with placebo, in patients with a history of partial onset seizures, with or without secondarily generalized seizures.

Patients in these studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In each study, patients were stabilized on optimum dosages of their concomitant AEDs during baseline phase lasting between 4 and 12 weeks. Patients who experienced a prespecified minimum number of partial onset seizures, with or without secondary generalization, during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline, or 3 for 4-week baseline) were randomly assigned to placebo or a specified dose of topiramate tablets in addition to their other AEDs.

Following randomization, patients began the double-blind phase of treatment. In five of the six studies, patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg or 200 mg/day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. In the sixth study (119), the 25 or 50 mg/day initial doses of topiramate were followed by respective weekly increments of 25 or 50 mg/day until the target dose of 200 mg/day was reached. After titration, patients entered a 4, 8, or 12-week stabilization period. The numbers of patients randomized to each dose, and the actual mean and median doses in the stabilization period are shown in Table 1.

Adjunctive Therapy Controlled Trial in Pediatric Patients Ages 2 to 16 Years With Partial Onset Seizures

The effectiveness of topiramate as an adjunctive treatment for pediatric patients ages 2 to 16 years with partial onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial, comparing topiramate and placebo in patients with a history of partial onset seizures, with or without secondarily generalized seizures.

Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In this study, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial onset seizures, with or without secondarily generalized seizures, during the baseline phase were randomly assigned to placebo or topiramate tablets in addition to their other AEDs.

Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 or 50 mg per day; the dose was then increased by 25 mg to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225, or 400 mg/day based on patients’ weight to approximate a dosage of 6 mg/kg per day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period.

Adjunctive Therapy Controlled Trial in Patients With Primary Generalized Tonic-Clonic Seizures

The effectiveness of topiramate as an adjunctive treatment for primary generalized tonic-clonic seizures in patients 2 years old and older was established in a multicenter, randomized, double-blind, placebo-controlled trial, comparing a single dosage of topiramate and placebo.

Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs.

Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 50 mg per day for four weeks; the dose was then increased by 50 mg to 150 mg/day increments every other week until the assigned dose of 175, 225, or 400 mg/day based on patients’ body weight to approximate a dosage of 6 mg/kg per day was reached, unless intolerance prevented increases. After titration, patients entered a 12-week stabilization period.

Adjunctive Therapy Controlled Trial in Patients With Lennox-Gastaut Syndrome

The effectiveness of topiramate as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome was established in a multicenter, randomized, double-blind, placebo-controlled trial comparing a single dosage of topiramate with placebo in patients 2 years of age and older.

Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients who were experiencing at least 60 seizures per month before study entry were stabilized on optimum dosages of their concomitant AEDs during a 4-week baseline phase. Following baseline, patients were randomly assigned to placebo or topiramate in addition to their other AEDs. Active drug was titrated beginning at 1 mg/kg per day for a week; the dose was then increased to 3 mg/kg per day for one week then to 6 mg/kg per day. After titration, patients entered an 8-week stabilization period. The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity.

Table 1: Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizuresb
Target Topiramate Dosage (mg/day)
Protocol Stabilization Dose Placeboa 200 400 600 800 1,000

a Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Protocol Y1, 4 tablets/day; Protocols YD and Y2, 6 tablets/day; Protocol Y3 and 119, 8 tablets/day; Protocol YE, 10 tablets/day.

b Dose-response studies were not conducted for other indications or pediatric partial onset seizures.

YD N 42 42 40 41
Mean Dose 5.9 200 390 556
Median Dose 6.0 200 400 600
YE N 44 40 45 40
Mean Dose 9.7 544 739 796
Median Dose 10.0 600 800 1,000
Y1 N 23 19
Mean Dose 3.8 395
Median Dose 4.0 400
Y2 N 30 28
Mean Dose 5.7 522
Median Dose 6.0 600
Y3 N 28 25
Mean Dose 7.9 568
Median Dose 8.0 600
119 N 90 157
Mean Dose 8 200
Median Dose 8 200

In all add-on trials, the reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are shown below in Table 2. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial.

Table 2: Efficacy Results in Double-Blind, Placebo-Controlled, Add-On Epilepsy Trials
Target Topiramate Dosage (mg/day)
Protocol Efficacy Results Placebo 200 400 600 800 1,000 ≈6mg/kg/day*

Comparisons with placebo: a p=0.080; b p<0.010; c p<0.001; d p<0.050; e p=0.065; f p<0.005;g p=0.071;

h Median % reduction and % responders are reported for PGTC Seizures;

i Median % reduction and % responders for drop attacks, i.e., tonic or atonic seizures;

j Percent of subjects who were minimally, much, or very much improved from baseline

* For Protocols YP and YTC, protocol-specified target dosages (<9.3 mg/kg/day) were assigned based on subject’s weight to approximate a dosage of 6 mg/kg per day; these dosages corresponded to mg/day dosages of 125, 175, 225, and 400 mg/day.

Partial Onset Seizures
Studies in Adults
YD N 45 45 45 46
Median % Reduction 11.6 27.2a 47.5b 44.7c
% Responders 18 24 44d 46d
YE N 47 48 48 47
Median % Reduction 1.7 40.8c 41.0c 36.0c
% Responders 9 40c 41c 36d
Y1 N 24 23
Median % Reduction 1.1 40.7e
% Responders 8 35d
Y2 N 30 30
Median % Reduction -12.2 46.4f
% Responders 10 47c
Y3 N 28 28
Median % Reduction -20.6 24.3c
% Responders 0 43c
119 N 91 168
Median % Reduction 20.0 44.2c
% Responders 24 45c
Studies in Pediatric Patients
YP N 45 41
Median % Reduction 10.5 33.1d
% Responders 20 39
Primary Generalized Tonic-Clonich
YTC N 40 39
Median % Reduction 9.0 56.7d
% Responders 20 56c
Lennox-Gastaut Syndromei
YL N 49 46
Median % Reduction -5.1 14.8d
% Responders 14 28g
Improvement in Seizure Severityj 28 52d

Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED.

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