GABITRIL (Page 2 of 8)

CLINICAL STUDIES

The effectiveness of GABITRIL as adjunctive therapy (added to other antiepilepsy drugs) was examined in three multi-center, double-blind, placebo-controlled, parallel-group, clinical trials in 769 patients with refractory partial seizures who were taking at least one hepatic enzyme-inducing antiepilepsy drug (AED), and two placebo-controlled cross-over studies in 90 patients. In the parallel-group trials, patients had a history of at least six complex partial seizures (Study 1 and Study 2, U.S. studies), or six partial seizures of any type (Study 3, European study), occurring alone or in combination with any other seizure type within the 8-week period preceding the first study visit in spite of receiving one or more AEDs at therapeutic concentrations.

In the first two studies, the primary protocol-specified outcome measure was the median reduction from baseline in the 4-week complex partial seizure (CPS) rates during treatment. In the third study, the protocol-specified primary outcome measure was the proportion of patients achieving a 50% or greater reduction from baseline in the 4-week seizure rate of all partial seizures during treatment. The results given below include data for complex partial seizures and all partial seizures for the intent-to-treat population (all patients who received at least one dose of treatment and at least one seizure evaluation) in each study.

Study 1 was a double-blind, placebo-controlled, parallel-group trial comparing GABITRIL 16 mg/day, GABITRIL 32 mg/day, GABITRIL 56 mg/day, and placebo. Study drug was given as a four times a day regimen. After a prospective Baseline Phase of 12 weeks, patients were randomized to one of the four treatment groups described above. The 16-week Treatment Phase consisted of a 4-week Titration Period, followed by a 12-week Fixed-Dose Period, during which concomitant AED doses were held constant. The primary outcome was assessed for the combined 32 and 56 mg/day groups compared to placebo.

Study 2 was a double-blind, placebo-controlled, parallel-group trial consisting of an 8-week Baseline Phase and a 12-week Treatment Phase, the first 4 weeks of which constituted a Titration Period and the last 8 weeks a Fixed-Dose Period. This study compared GABITRIL 16 mg BID and 8 mg QID to placebo. The protocol-specified primary outcome measure was assessed separately for each group treated with GABITRIL.

The following tables display the results of the analyses of these two trials.

Table 1: Median Reduction and Median Percent Reduction from Baseline in 4-Week Seizure Rates in Study 1

Placebo

(N=91)

GABITRIL

16 mg/day

(N=61)

GABITRIL

32 mg/day

(N=87)

GABITRIL

56 mg/day

(N=56)

Combined

32 and 56

mg/day

(N=143)

Complex

Partial

Median Reduction

0.6

0.8

2.2*

2.9*

2.6*

Median % Reduction

9%

13%

25%

32%

29%

All

Partial

Median Reduction

0.2

1.2

2.7*

3.5*

2.9*

Median % Reduction

3%

12%

24%

36%

27%

* p < 0.05† Statistical significance was not assessed for median % reduction.

Table 2: Median Reduction and Median Percent Reduction from Baseline in 4-Week Seizure Rates in Study 2

Placebo

(N=107)

GABITRIL

16 mg BID

(N=106)

GABITRIL

8 mg QID

(N=104)

Complex Partial

Median Reduction

0.3

1.6

1.3*

Median % Reduction

4%

22%

15%

All Partial

Median Reduction

0.5

1.6

1.3

Median % Reduction

5%

19%

13%

* p < 0.027, necessary for statistical significance due to multiple comparisons.† Statistical significance was not assessed for median % reduction.

Figures 1 to 4 present the proportion of patients (X-axis) whose percent reduction from baseline in the all partial seizure rate was at least as great as that indicated on the Y axis in the three placebo-controlled adjunctive studies (Studies 1, 2, and 3). A positive value on the Y axis indicates an improvement from baseline (i.e., a decrease in seizure rate), while a negative value indicates a worsening from baseline (i.e., an increase in seizure rate). Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo.

Figure 1 indicates that the proportion of patients achieving any particular level of reduction in seizure rate was consistently higher for the combined GABITRIL 32 mg and 56 mg groups compared to the placebo group in Study 1. For example, Figure 1 indicates that approximately 24% of patients treated with GABITRIL experienced a 50% or greater reduction, compared to 4% in the placebo group.

Figure 1: Study 1

figure01
(click image for full-size original)

Figure 2 also displays the results for Study 1, which was a dose-response study, by treatment group, without combining GABITRIL dosage groups. Figure 2 indicates a dose-response relationship across the three GABITRIL groups. The proportion of patients achieving any particular level of reduction in all partial seizure rates was consistently higher as the dose of GABITRIL was increased. For example, Figure 2 indicates that approximately 4% of patients in the placebo group experienced a 50% or greater reduction in all partial seizure rate, compared to approximately 10% of the GABITRIL 16 mg/day group, 21% of the GABITRIL 32 mg/day group, and 30% of the GABITRIL 56 mg/day group.

Figure 2: Study 1

figure02
(click image for full-size original)

Figure 3 indicates that the proportion of patients achieving any particular level of reduction in partial seizure rate was consistently greater in patients taking GABITRIL than in those taking placebo in Study 2 (Study 2 compared placebo to GABITRIL 32 mg/day; one of the GABITRIL groups received 8 mg QID, while the other GABITRIL group received 16 mg BID). For example, Figure 3 indicates that approximately 7% of patients in the placebo group experienced a 50% or greater reduction in their partial seizure rate, compared to approximately 23% of patients in the GABITRIL 8 mg QID group and 28% of patients in the GABITRIL 16 mg BID group.

Figure 3: Study 2

figure03
(click image for full-size original)

Study 3 was a double-blind, placebo-controlled, parallel-group trial that compared GABITRIL 10 mg TID (N=77) with placebo (N=77). In this trial, patients were followed prospectively during a 12-week Baseline Phase and then randomized to receive study drug during an 18-week Treatment Phase. During the first 6 weeks of treatment (Titration Period), patients were titrated to 30 mg/day, after which they were maintained on this dose during the 12-week Fixed-Dose Period. The protocol-specified primary outcome measure (proportion of patients who achieved at least a 50% reduction from baseline in partial seizure rate) did not reach statistical significance. However, analyses of the median reduction from baseline in 4-week partial seizure rate (the analyses presented above for Study 1 and Study 2) were performed and showed a statistically significant improvement compared to placebo in all partial and complex partial seizure rates (Table 3):

Table 3: Median Reduction and Median Percent Reduction from Baseline in 4-Week Seizure Rates in Study 3

Placebo

(N=77)

GABITRIL

30 mg/day

(N=77)

Complex Partial

Median Reduction

-0.1

1.3*

Median % Reduction

-1%

14%

All Partial

Median Reduction

-0.5

1.1*

Median % Reduction

-7%

11%

* p < 0.05
† Statistical significance was not assessed for median % reduction.‡ N=72 and 75 for placebo and GABITRIL, respectively.

Figure 4 indicates that the proportion of patients achieving any particular level of reduction in seizure activity was consistently higher in those taking GABITRIL than those taking placebo in Study 3. For example, Figure 4 indicates that approximately 5% of patients in the placebo group experienced a 50% or greater reduction in their partial seizure rate compared to approximately 10% of patients in the GABITRIL group.

Figure 4: Study 3

figure04
(click image for full-size original)

The two other placebo-controlled trials that examined the effectiveness of GABITRIL were small cross-over trials (N=46 and 44). Both trials included an open Screening Phase during which patients were titrated to an optimal dose and then treated with this dose for an additional 4 weeks. After this Open Phase, patients were randomized to one of two blinded treatment sequences (GABITRIL followed by placebo or placebo followed by GABITRIL). The Double-Blind Phase consisted of two Treatment Periods, each lasting 7 weeks (with a 3 week washout between periods). The outcome measures were median with-in patient differences between placebo and GABITRIL Treatment Periods in 4-week complex partial and all partial seizure rates. The reductions in seizure rates were statistically significant in both studies.

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