Adjunctive use of controlled‐release pregabalin in adults with treatment‐resistant partial seizures: A double‐blind, randomized, placebo‐controlled trial

Abstract

SUMMARYObjectives: To assess the efficacy and tolerability of add-on pregabalin controlledrelease formulation (PGB-CR) (doses of 165 or 330 mg/day) in patients with partialonset seizures (POS). Methods: This was a randomized, double-blind (DB), parallel-group study of PGB-CR once-daily as adjunctive treatment in adults with treatment-resistant partial seizures. After an 8-week baseline period, eligible patients were randomized (1:1:1) to placebo, PGB-CR 165 mg, or PGB-CR 330 mg for 14 weeks, including a 2-week dose escalation. Primary endpoint was the log e -transformed 28-day seizure rate for all POS with observable component during the full 14-week double-blind treatment phase. Secondary endpoints included the 50% responder rate and percent change from baseline in 28-day POS rate. Results: Three hundred twenty-three patients were randomized and received treatment; placebo (n = 110), PGB-CR 330 mg (n = 100), PGB-CR 165 mg (n = 113); and 287 (88.9%) completed the trial. The primary efficacy analysis result, expressed as percent reduction from placebo, was 13.1% and 1.0% for PGB-CR 330 mg and PGB-CR 165 mg, respectively, and was not statistically significant (p = 0.091, 0.908). The proportion of 50% responders was similar for placebo (35.8%) and 165 mg PGB-CR (37.8%) and nominally higher for 330 mg PGB-CR (45.9%, p = 0.125 compared to placebo). The LS mean estimates of the percent change from baseline for placebo (À5.7%) was nominally smaller than 165 mg PGB-CR (À15.0%, p = 0.540) and 330 mg PGB-CR (À31.5%, p = 0.079); however, the median percent changes from baseline were not as well differentiated (placebo, À35.4%; 165 mg PGB-CR, À38.0%; 330 mg PGB-CR À43.4%). Rates of adverse events (AEs) were low for placebo and study drug; the most frequent reported AEs were dizziness, somnolence, and fatigue, consistent with the immediate-release formulation. Significance: Results from this trial did not demonstrate that PGB-CR is effective in reducing seizure frequency below that of placebo. Both doses of PGB-CR were shown to be safe and well-tolerated.

Population Pharmacokinetics of Pregabalin Extended‐Release in Healthy Volunteers and Patients With Postherpetic Neuralgia, Fibromyalgia, and Partial‐Onset Seizures

“…The 3 phase 3 studies were performed to evaluate the efficacy and safety of pregabalin ER in patients with postherpetic neuralgia, 15 fibromyalgia, 16 and partialonset seizures. 17 Exposures for pregabalin ER tablets administered QD after an evening meal in all 3 trials were similar to those for comparative doses of prega-balin IR capsules. Both the primary efficacy end point (ie, time to loss of therapeutic response) and a key secondary end point (ie, mean change from baseline) in a double-blind, placebo-controlled, randomized withdrawal trial of pregabalin ER (165-660 mg) demonstrated the efficacy of pregabalin ER in patients with postherpetic neuralgia.…”

“…In a trial of similar design evaluating pregabalin ER (330‐495 mg) in adults with fibromyalgia, the primary efficacy end point (ie, time to loss of therapeutic response) was met, but the trial did not demonstrate efficacy in a key secondary end point (ie, mean change from baseline) . Similarly, a double‐blind, randomized, placebo‐controlled trial of pregabalin ER (165‐330 mg) in adults with partial onset seizures did not demonstrate that pregabalin is effective in reducing seizure frequency below that of placebo . In all 3 trials, the safety profile of pregabalin ER was comparable to that reported previously for the IR formulation.…”

“…The 3 phase 3 studies were performed to evaluate the efficacy and safety of pregabalin ER in patients with postherpetic neuralgia, fibromyalgia, and partial‐onset seizures . Exposures for pregabalin ER tablets administered QD after an evening meal in all 3 trials were similar to those for comparative doses of pregabalin IR capsules.…”

“…The model also included data from 9 phase 1 single‐ and multiple‐dose studies of both pregabalin IR capsules and pregabalin ER tablets in healthy adult volunteers (V5‐13) . Sparse PK data from 3 phase 3 clinical studies of pregabalin ER in patients with postherpetic neuralgia (PHN1), fibromyalgia (FM1), and partial‐onset seizures (E1) were also analyzed separately.…”

An update of the Hong Kong Epilepsy Guideline: consensus statement on the use of antiepileptic drugs in Hong Kong

“…One study evaluated the efficacy and tolerability of adjunctive PGB as a controlled-release formulation. The 50% responder rate (ie percentage of patients achieving 50% reduction in seizure frequency) was 45.9% for a daily dose of 330 mg. 98 Another randomised study tested PGB versus LEV in a head-to-head comparison in 409 patients. The drug PGB was non-inferior to LEV with a similar tolerability to LEV as adjunctive therapy.…”