Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes
Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes
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DOI：
10.1016/j.jdiacomp.2004.12.003
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发表时间：
2005-07-01
影响因子：
3
通讯作者：
Lernmark, Å
中科院分区：
文献类型：
--
作者：
Agardh, CD;Cilio, CM;Lernmark, Å
这项11期研究的目的是评价明矾配制的人重组GAD 65是否安全且不损害β细胞功能。该研究是一项随机、双盲、安慰剂对照、剂量递增的临床试验，共有47名成人隐匿性自身免疫性糖尿病（LADA）患者在第1周和第4周接受安慰剂或4、20、100或500 μ g Diamyd皮下注射。在24周内反复评估安全性评价，包括神经学、β细胞功能试验、糖尿病状态评估、血液学、生物化学以及细胞和不道德免疫学标志物。所有患者均未发生显著的研究相关不良事件（AE）。与安慰剂组相比，20 μ g组24周时空腹C肽水平升高（P = 0.0015），但其他剂量组无此变化。此外，在20 μ g剂量组中，空腹（P = 0.0081）和刺激（P = 0.0236）C-肽水平从基线到24周均增加。GADA对数水平明显增加（P = 0.0002），响应于500 μ g Diamyd。在20 μ g组中，24周时CD 4（+）CD 25（+）/CD 4（+）CD 25（-）细胞比率增加（P = 0.0128）。在任何剂量组中均未观察到HbA（1c）或血糖突然升高或β细胞功能降低。这些临床安全性的积极发现进一步支持了Diamyd作为预防自身免疫性糖尿病的治疗药物的临床开发。(c)2005年爱思唯尔公司All rights reserved.
The purpose of this Phase 11 study was to evaluate if alum-formulated human recombinant GAD65 is safe and does not compromise beta cell function. The study was conducted as a randomized, double blind, placebo-controlled, dose-escalation clinical trial in a total of 47 Latent Autoimmune Diabetes in Adults (LADA) patients who received either placebo or 4, 20, 100, or 500 mu g Diamyd subcutaneously at Weeks 1 and 4. Safety evaluations, including neurology, beta cell function tests, diabetes status assessment, hematology, biochemistry, and cellular and Immoral immunological markers, were repeatedly assessed over 24 weeks. None of the patients had significant study-related adverse events (AE). Fasting c-peptide levels at 24 weeks were increased compared with placebo (P = .0015) in the 20 mu g but not in the other dose groups. In addition, both fasting (P = .0081) and stimulated (P = .0236) c-peptide levels increased from baseline to 24 weeks in the 20 mu g dose group. GADA log levels clearly increased (P = .0002) in response to 500 mu g Diamyd. The CD4(+)CD25(+)/CD4(+)CD25(-) cell ratio increased (P = .0128) at 24 weeks in the 20 mu g group. No sudden increase in HbA(1c), or plasma glucose or decrease in beta cell function was observed in any of the dose groups. These positive findings for clinical safety further support the clinical development of Diamyd as a therapeutic to prevent autoimmune diabetes. (c) 2005 Elsevier Inc. All rights reserved.