Pregabalin add-on treatment in patients with partial seizures: A novel evaluation of flexible dose and fixed-dose treatment in a double-blind, placebo-controlled study
Elger C, Brodie MJ, Anhut H, Lee CM and Barrett JA;
Commented by , 17 Jan 2006
Background
Pregabalin is the latest AED to have been approved for the adjunctive therapy of refractory partial seizures (ref. 1). In previous controlled trials, the target dose of pregabalin was achieved either on day 1 (ref. 2) or day 7 (ref. 3; ref. 4).
Aim
To investigate whether outcome of pregabalin therapy can be improved by gradual dose titration and flexible dose-adjustment.
Methods
- In a double-blind 12-week, add-on trial, 341 adults with refractory partial seizures were randomised (1:2:2) to placebo, pregabalin fixed-dose (600 mg/day from day 1) or pregabalin flexible dose (150 and 300 mg/day for 2 weeks each; 450 and 600 mg/day for 4 weeks each).
- In the flexible dose group, dose could be adjusted based on tolerability and maintained when a 4-week seizure-free period was achieved.
- Primary efficacy parameter was reduction in seizure frequency from baseline.
Results
- Reduction in seizure frequency was greater in the fixed- and flexible-dose groups (49.3% and 35.4% respectively) than on placebo (10.6%). Responder rates (proportions achieving > or = 50% seizure reduction) were 45.3% on a fixed-dose, 31.3% on a flexible-dose and 11.0% on placebo. For both endpoints, fixed-dose was significantly superior to flexible-dose.
- The better efficacy of the fixed dose was mainly due to greater seizure reduction in the initial part of the assessment period, when the flexible-dose group was still receiving a low dose.
- Tolerability was far superior with flexible dosing. Discontinuations for adverse events were 6.8% on placebo, 12.2% on flexible-dose, and 32.8% on fixed-dose.
- Overall, gradual titration and flexible dosage provide a better efficacy/safety ratio.
Professor Perucca's comments
In regulatory trials, pregabalin was tested at doses of 50, 150, 300 and 600 mg/day. Responder rates were dose-proportional starting from the minimally effective dose of 150 mg/day (ref. 1; ref. 5). Titration, when used, was restricted to one week.
This is the first double-blind trial allowing gradual titration and flexible dose adjustment. At the end of the trial, patients in the flexible-dose group received a mean dose of 508 mg/day, and 47% had reached the target 600 mg dose.
Although, as expected, therapeutic response developed more gradually with dose titration, the efficacy at the end of the trial was similar in the two groups, and tolerability was far better with flexible dosing. In fact, the fixed dose was associated with an almost 3-fold greater rate of withdrawals for adverse events, and dizziness and ataxia were twice as common.
At first glance, the reader may be misled to conclude that the fixed dose was more efficacious because it yielded greater responder rates (45% vs 31% on flexible doses, ITT analysis).
In fact, in the last-observation carried-forward (LOCF) ITT analysis typically used in these studies, patients who cannot tolerate the treatment and withdraw after having had fewer seizures are still counted as responders.
Careful inspection of the data reveals that only 33 of 137 patients (24%) in the fixed-dose group were responders and completed treatment, compared with 34 of 131 patients (26%) in the flexible-dose group.
Thus, truly successful outcomes did not differ between groups, and the flexible-dose group was spared a great deal of adverse effects. It is also clear that the proportion of real successes was lower than apparent from the reported LOCF analysis.
Overall, the results of this study confirm that, as predicted, optimal treatment should involve starting with a low dosage, followed by gradual adjustments.
The optimal maintenance dose of pregabalin cannot be determined from this study, but tolerability concerns (particularly with weight gain) suggest that the best dose in many patients may be in the range of 300 to 500 mg/day.
The fact that pregabalin controlled trials (except this study) only allowed between 1 and 7 days to reach the target dose, and that only 90 out of 1026 patients randomized to pregabalin were allocated to a target dose above 150 mg/day but below 600 mg/day, illustrates how far regulatory trials may deviate from optimal treatment modalities in routine clinical practice (ref. 7; ref. 8; ref. 9).
References
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