Withdrawal-Related Adverse Events from Clinical Trials of Clobazam in Lennox-Gastaut Syndrome (LGS) (P06.106)

Abstract

Objective: We assessed rates of withdrawal-related events following abrupt discontinuation and gradual tapering of clobazam during Phase I–III studies. Background Clobazam, a 1,5-benzodiazepine, is under FDA review for LGS. Design/Methods: Potential withdrawal-related AEs following abrupt CLB discontinuation were assessed in 4 multiple-dosage Phase I trials (dosing 8−34 days). These studies employed therapeutic (20 and 40 mg/day) and supratherapeutic dosages (120 and 160 mg/day). These events were also assessed in Phase II/III studies (dosing ≤18 weeks) and their open-label extension (OLE) (≤5 years). In these studies, gradual tapering over 2–3 weeks was conducted. Withdrawal-related AEs included sedation, somnolence, insomnia, irritability, anxiety, and seizures. AEs must have occurred ≥1 day following last clobazam dose and within 30 days after last dose, or must have been deemed withdrawal symptoms by investigators. Results: Phase I participants received steady-state dosages of 20–160 mg/day, with the vast majority receiving ≥40 mg/day and ∼50% receiving ≥120 mg/day (≤4-times maximum daily dosage in Phase II/III). In contrast, LGS patients received ≤40 mg/day during Phase II/III and ≤80 mg/day in the OLE. 87 patients discontinued clobazam during Phase II/III and tapered drug. None reported withdrawal-related AEs. Abrupt discontinuation led to AEs consistent with withdrawal. 93 AEs were reported for 68 of 207 in Phase I studies. Nearly all AEs occurred after abrupt discontinuation of clobazam ≥40 mg/day, with ∼50% occurring at ≥120 mg/day. The majority of AEs following abrupt discontinuation were mild, and included headache, insomnia, anxiety, and tremor. No status epilepticus occurred during withdrawal/tapering. Conclusions: Withdrawal-related AEs did not occur during 2- to 3-week tapering at the conclusion of Phase II/III studies of clobazam. No withdrawal-related AEs have been observed with long-term therapy through 5 years In Phase I, abrupt withdrawal led to generally mild AEs at rates comparable to those observed for other benzodiazepines. Supported by: Lundbeck Inc. Disclosure: Dr. Tolbert has received personal compensation for activities with Lundbeck Research USA, Inc as an employee. Dr. Harris has received research support from Lundbeck Research USA, Inc. Dr. Bekersky has received personal compensation for activities with Lundbeck Research USA, Inc. as an employee. Dr. Owen has received personal compensation for activities with Lundbeck Research USA, Inc.