Apostol George, Pakalnis Ann, Laforet Genevieve A, Robieson Weining Z, Olson Evelyn, Abi-Saab Walid M, Saltarelli Mario
Abbott, Abbott Park, IL 60064, USA.
Headache. 2009 Jan;49(1):36-44. doi: 10.1111/j.1526-4610.2008.01299.x. Epub 2008 Nov 24.
To evaluate the long-term safety and tolerability of divalproex sodium extended-release in the prophylaxis of migraine headaches in adolescents.
Divalproex sodium has been approved for migraine prophylaxis in adults. A previous double-blind, placebo-controlled study of the efficacy and safety of divalproex sodium extended-release for prevention of migraine in adolescents was followed by the present long-term extension trial, which was designed to collect additional safety and tolerability data.
This was a 12-month, Phase 3, open-label extension of a 3-month, double-blind, placebo-controlled, multicenter study of adolescents aged 12 to 17 years with migraine headaches who had either completed the previous study or had discontinued because of lack of efficacy. Subjects from the previous trial who had experienced serious adverse events possibly or probably related to study drug were excluded. Divalproex sodium extended-release 500 mg daily was administered for 15 days then increased to 1000 mg. Study visits were conducted at days 1 and 15 and months 1, 2, 3, 6, 9, and 12. Safety assessments included adverse event collection, laboratory testing, physical and neurological examinations, vital signs, and electrocardiograms, as well as reproductive endocrine analyses for postmenarchal female subjects. Efficacy was evaluated by sequential 4-week migraine headache rates calculated from subjects' headache diaries.
A total of 112 subjects enrolled in the trial. The most common adverse events were weight gain (15%), nausea (14%), somnolence (12%), upper respiratory tract infection (11%), increased ammonia (8%), and sinusitis (8%). Five (4%) subjects experienced serious adverse events, and 15 (13%) subjects prematurely discontinued because of an adverse event. Increased ammonia levels were noted in some individuals, and the mean ammonia level for all subjects increased 19.2 microm from baseline. No other clinically significant changes were observed in laboratory values, vital signs, or electrocardiograms. Improvement in mean and median 4-week migraine headache rates occurred by the fourth month and lasted for the duration of the trial.
In this long-term open-label extension study, the safety profile of divalproex sodium extended-release in adolescents with migraine was consistent with that observed in the preceding 3-month, double-blind trial and in previous adult studies. Overall, divalproex sodium extended-release was well-tolerated in adolescents aged 12 to 17 years.
评估丙戊酸镁缓释片在青少年偏头痛预防中的长期安全性和耐受性。
丙戊酸镁已被批准用于成人偏头痛的预防。此前一项关于丙戊酸镁缓释片预防青少年偏头痛疗效和安全性的双盲、安慰剂对照研究之后，开展了本次长期延申试验，旨在收集更多安全性和耐受性数据。
这是一项为期12个月的3期开放标签延申试验，其前身为一项为期3个月、双盲、安慰剂对照、多中心研究，研究对象为12至17岁患有偏头痛的青少年，这些青少年要么完成了之前的研究，要么因疗效不佳而停药。排除了之前试验中经历过可能或很可能与研究药物相关的严重不良事件的受试者。每天服用500毫克丙戊酸镁缓释片，持续15天，然后增加到1000毫克。在第1天和第15天以及第1、2、3、6、9和12个月进行研究访视。安全性评估包括不良事件收集、实验室检查、体格和神经检查、生命体征和心电图，以及对月经初潮后女性受试者的生殖内分泌分析。通过根据受试者头痛日记计算的连续4周偏头痛发生率来评估疗效。
共有112名受试者参与了该试验。最常见的不良事件是体重增加（15%）、恶心（14%）、嗜睡（12%）、上呼吸道感染（11%）、血氨升高（8%）和鼻窦炎（8%）。5名（4%）受试者经历了严重不良事件，15名（13%）受试者因不良事件提前停药。一些个体血氨水平升高，所有受试者的平均血氨水平较基线升高19.2微摩尔。在实验室检查值、生命体征或心电图方面未观察到其他具有临床意义的变化。平均和中位数4周偏头痛发生率在第4个月时有所改善，并在试验期间持续改善。
在这项长期开放标签延申研究中，丙戊酸镁缓释片在青少年偏头痛患者中的安全性与之前3个月的双盲试验以及之前成人研究中观察到的一致。总体而言，丙戊酸镁缓释片在12至17岁青少年中耐受性良好。
