Lamotrigine XR Conversion to Monotherapy: First Study Using a Historical Control Group

Abstract

The efficacy and safety of lamotrigine extendedrelease tablets (LTG XR) as monotherapy for partial seizures were evaluated using the conversion-tomonotherapy design, and historical data as the control. This methodology was recently approved by the United States Food and Drug Administration, and this study is the first historical control design in epilepsy to complete enrollment. Patients ≥13 years old with uncontrolled partial epilepsy receiving monotherapy with valproate or a noninducing antiepileptic drug were converted to once-daily LTG XR (250 mg or 300 mg) as monotherapy and were followed up for 12 additional weeks. Efficacy was measured by the proportion of patients meeting predefined escape criteria for seizure worsening compared with aggregated pseudoplacebo control data from 8 previously conducted conversion-to-monotherapy trials. Nonoverlap of the 95% confidence limit for LTG XR and the 95% prediction interval of the historical control denotes efficacy.Of 226 randomized patients, 174 (93 in 300 mg/day group and 81 in 250 mg/day group) started withdrawal of the background AED and were evaluated for escape. In the historical control analysis population, the lower 95% prediction interval of the historical control (65.3%) was not overlapped by the upper 95% confidence limit of either LTG XR (300 mg/day; 37.2%) or LTG XR (250 mg/day; 43.4%). Adverse events were reported in 53% and 61% of patients receiving LTG XR (300 mg/day and 250 mg/day, respectively). LTG XR (250 mg or 300 mg once daily) is effective for conversion-to-monotherapy treatment of partial seizures in patients ≥13 years old.

Time to prerandomization monthly seizure count in perampanel trials

“…21 The withdrawal to monotherapy design, which is used to obtain a monotherapy indication, uses a time-to-event outcome whereby patients reach an endpoint based on clinically important seizure worsening. 22 A time to Nth seizure outcome has been proposed in the past, 23 whereby N is set at an arbitrary number (e.g., 1, 3, or 10) and patients exit the trial if they experience this number of seizures. However, although post hoc analyses have suggested that this approach is able to correctly identify efficacious treatments and shorten patient exposure to placebo, the estimated sample sizes required to run such a trial are large.…”

Update on once-daily zonisamide monotherapy in partial seizures

“…Although the European regulatory agencies use noninferiority trials for monotherapy approval, this trial design does not meet the FDA requirement for monotherapy approval in the USA. Currently, the FDA requires either a superiority trial design or a historical control monotherapy design 6,7. Of the drugs that are currently approved for monotherapy in the USA, the first-generation antiepileptic drugs were “grandfathered” by the FDA and did not go through the current approval criteria 34.…”

“…These include oxcarbazepine, felbamate, lamotrigine, and topiramate, with oxcarbazepine and topiramate having FDA approval as initial monotherapy 6. After acceptance of historical control conversion to monotherapy design by the FDA, lamotrigine extended-release was the first drug to obtain FDA approval using this trial design 7. Lacosamide is currently under review by FDA as a potential second drug using the historical control conversion to monotherapy design 35.…”

“…In the USA, the only indication approved by the US Food and Drug Administration (FDA) for zonisamide is adjunctive treatment of partial onset epilepsy. For monotherapy approval, the FDA requires either a superiority trial using a pseudo-placebo design (since placebo-controlled studies are considered unethical in epilepsy) or a conversion to monotherapy design using historical controls 6,7. No such trials exist for zonisamide, so zonisamide currently has no FDA-approved indications for monotherapy in the USA.…”

Lamotrigine Usage in Epileptic Patients

“…Bu yan etkiler literatürdeki verilerle uyumlu bulundu. [10,17,18] Lamotrijinin en korkulan yan etkisi olan deri döküntüsü geçmiş çalışmalarda %2.3-8.2 oranında bildirilmişdi. [10] Deri döküntüsünü 18 (%4.3) hastamızda gördük ve yan etkiye bağlı olan ilaç kesiminin tek nedeni oldu.…”