Short-Term Administration of Mycophenolate Is Well-Tolerated in CLN3 Disease (Juvenile Neuronal Ceroid Lipofuscinosis).
Short-Term Administration of Mycophenolate Is Well-Tolerated in CLN3 Disease (Juvenile Neuronal Ceroid Lipofuscinosis).
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DOI：
10.1007/8904_2018_113
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发表时间：
2019-01-01
期刊：
影响因子：
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通讯作者：
Marshall, Frederick J
中科院分区：
文献类型：
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作者：
Augustine, Erika F;Beck, Christopher A;Marshall, Frederick J
麦考酚酯是一种免疫抑制剂，通常在标签外用于治疗自身免疫性神经系统疾病。 CLN3 疾病是一种儿童时期的神经退行性疾病，临床前和临床数据表明，继发性自身免疫和整个中枢神经系统的炎症是发病机制的关键组成部分。我们测试了 CLN3 疾病个体对霉酚酸酯的短期耐受性，为该药物可能的长期疗效试验做准备。我们对 19 名患有 CLN3 疾病的流动个体进行了麦考酚酯的随机、双盲、安慰剂对照、交叉研究，以确定短期给药的安全性和耐受性 (NCT01399047)。该研究包括两个为期 8 周的治疗期以及为期 4 周的间歇期清除。麦考酚酯的耐受性良好。 89.5% 的参与者按照指定的研究剂量完成了霉酚酸酯组的治疗（95% CI：66.9-98.7%），霉酚酸酯组和安慰剂组之间的耐受率没有显着差异（10.5%；95% CI：-3.3-24.3%，p=0.21）。所有报告的不良事件的严重程度均为轻微；麦考酚酯最常见的不良事件是呕吐（31.6%；95% CI：12.6-56.6%）、腹泻（15.8%；95% CI：3.4-39.6%）和咳嗽（15.8%；95% CI：3.4-39.6%）。这些情况的发生频率并未显着高于安慰剂。短期给药对测量的自身免疫或临床结果没有明确的影响。需要进行长期暴露研究来测试霉酚酸酯对关键临床特征和 CLN3 疾病轨迹的影响。
Mycophenolate, an immunosuppressant, is commonly used off-label for autoimmune neurological conditions. In CLN3 disease, a neurodegenerative disorder of childhood, preclinical and clinical data suggest secondary autoimmunity and inflammation throughout the central nervous system are key components of pathogenesis. We tested the short-term tolerability of mycophenolate in individuals with CLN3 disease, in preparation for possible long-term efficacy trials of this drug. We conducted a randomized, double-blind, placebo-controlled, crossover study of mycophenolate in 19 ambulatory individuals with CLN3 disease to determine the safety and tolerability of short-term administration (NCT01399047). The study included two 8-week treatment periods with a 4-week intervening washout. Mycophenolate was well tolerated. 89.5% of participants completed the mycophenolate arm, on the assigned study dose (95% CI: 66.9-98.7%), and there were no significant differences in tolerability rates between mycophenolate and placebo arms (10.5%; 95% CI: -3.3-24.3%, p=0.21). All reported adverse events were mild in severity; the most common adverse events on mycophenolate were vomiting (31.6%; 95% CI: 12.6-56.6%), diarrhea (15.8%; 95% CI: 3.4-39.6%), and cough (15.8%; 95% CI: 3.4-39.6%). These did not occur at a significantly increased frequency above placebo. There were no definite effects on measured autoimmunity or clinical outcomes in the setting of short-term administration. Study of long-term exposure is needed to test the impact of mycophenolate on key clinical features and CLN3 disease trajectory.