Tolbert Dwain, Harris Stuart I, Bekersky Ihor, Lee Deborah, Isojarvi Jouko
Lundbeck LLC, Deerfield, IL, USA.
SeaView Research, Inc., Miami, FL, USA.
Epilepsy Behav. 2014 Aug;37:11-5. doi: 10.1016/j.yebeh.2014.05.016. Epub 2014 Jun 18.
To assess withdrawal-related adverse event (AE) rates following abrupt clobazam discontinuation in Phase I trials and gradual clobazam tapering (2-3 weeks) following discontinuation from III trials met the criteria for potential/III trials, we evaluated AE data from four multiple-dosage Phase I trials (duration: 8-34 days). Therapeutic (20 and 40 mg/day) and supratherapeutic clobazam dosages (120 and 160 mg/day) were administered. Adverse events (AEs) were also assessed for patients with Lennox-Gastaut syndrome enrolled in Phase II (OV-1002) and Phase III (OV-1012) studies (duration ≤15 weeks) and in the open-label extension (OLE) trial OV-1004 (≤5 years). Potential withdrawal-related AEs were identified by preferred terms, provided that the AEs occurred ≥1 day following and ≤30 days after the last clobazam doses, or were deemed withdrawal symptoms by investigators. Clinical Institute Withdrawal Assessment for Benzodiazepines (CIWA-B) scale was used to evaluate withdrawal intensity in three of the four Phase I trials. A total of 207 participants in Phase I trials received steady-state clobazam dosages of 20-160 mg/day, 182 received clobazam dosages of ≥40 mg/day, and 94 received clobazam dosages of ≥120 mg/day. Abrupt clobazam discontinuation led to 193 withdrawal-related AEs for 68 Phase I participants. Nearly 50% of AEs occurred after discontinuation of clobazam dosages of ≥120 mg/day. Adverse events were mild or moderate and included headache (14% of Phase I participants), insomnia (12.6%), tremor (10.1%), and anxiety (8.7%). The CIWA-B scores varied (range: 0-59). Most scores were <30, indicating possible mild benzodiazepine withdrawal. III trials met the criteria for potential/III patients received clobazam dosages of ≤40 mg/day, and those in the OLE trial received clobazam dosages of ≤80 mg/day. Eighty-seven patients discontinued clobazam and were gradually tapered. No withdrawal-related AEs or incidences of status epilepticus were reported. Withdrawal-related AEs observed in Phase I studies following abrupt clobazam discontinuation at therapeutic and supratherapeutic dosages were generally mild. No withdrawal-related AEs occurred when dosages were tapered over 3 weeks, after short- or long-term clobazam use (≤5 years).
为了评估在I期试验中突然停用氯巴占后与撤药相关的不良事件（AE）发生率，以及在III期试验停药后逐渐减少氯巴占剂量（2 - 3周）是否符合潜在标准/III期试验，我们评估了四项多剂量I期试验（持续时间：8 - 34天）的AE数据。给予了治疗剂量（20和40毫克/天）和超治疗剂量的氯巴占（120和160毫克/天）。还对参加II期（OV - 1002）和III期（OV - 1012）研究（持续时间≤15周）以及开放标签扩展（OLE）试验OV - 1004（≤5年）的伦诺克斯 - 加斯托综合征患者的不良事件进行了评估。通过首选术语识别潜在的与撤药相关的AE，前提是这些AE在最后一剂氯巴占后≥1天且≤30天发生，或者被研究者视为撤药症状。在四项I期试验中的三项中，使用临床研究所苯二氮䓬类药物撤药评估（CIWA - B）量表来评估撤药强度。I期试验中共有207名参与者接受了20 - 160毫克/天的氯巴占稳态剂量，182名接受了≥40毫克/天的氯巴占剂量，94名接受了≥120毫克/天的氯巴占剂量。突然停用氯巴占导致68名I期参与者出现193例与撤药相关的AE。近50%的AE发生在停用≥120毫克/天的氯巴占剂量后。不良事件为轻度或中度，包括头痛（I期参与者的14%）、失眠（12.6%）、震颤（10.1%）和焦虑（8.7%）。CIWA - B评分各不相同（范围：0 - 59）。大多数评分<30，表明可能是轻度苯二氮䓬类药物撤药。III期试验符合潜在标准/III期患者接受的氯巴占剂量≤40毫克/天，OLE试验中的患者接受的氯巴占剂量≤80毫克/天。87名患者停用氯巴占并逐渐减量。未报告与撤药相关的AE或癫痫持续状态的发生率。在I期研究中，在治疗剂量和超治疗剂量下突然停用氯巴占后观察到的与撤药相关的AE通常较轻。在短期或长期（≤5年）使用氯巴占后，当剂量在3周内逐渐减量时，未发生与撤药相关的AE。
