Abstract：
BACKGROUND: CD8+ T regulatory (Treg) cells that recognize the nonclassical class 1b molecule Qa-1/human leukocyte antigen E (Q/E CD8+ Treg cells) are important in maintaining self-tolerance. We sought to investigate the role that these T cells play in type 1 diabetes (T1D) pathogenesis and whether an intervention targeting this mechanism may delay T1D progression.
METHODS: We conducted a phase 1/2, randomized, double-blind, placebo-controlled trial of the autologous dendritic cell therapy AVT001 that included participants at least 16 years of age, within 1 year of T1D diagnosis, and with ex vivo evidence of a defect in Q/E CD8+ Treg function. Patients were randomly assigned in a 2:1 ratio to AVT001 or placebo, which was administered in three monthly intravenous infusions. The primary end point was safety; efficacy end points included changes from baseline in C-peptide area under the curve (AUC) during a 4-hour mixed meal, hemoglobin A1c (HbA1c), and insulin dose.
RESULTS: Sixteen patients received AVT001, and nine received placebo. Similar rates and severity of adverse events were observed in both groups. None of the patients in the AVT001 group had serious adverse events through visit day 360. Compared with placebo, treatment with ATV001 was associated with less decline from baseline log-transformed C-peptide AUC (nmol/l), with the treatment effect between AVT001 and placebo at day 150 of 0.09 (95% confidence interval [CI], 0.03 to 0.15) and at day 360 of 0.10 (95% CI, 0.04 to 0.15). No clear differences in change in HbA1c and insulin dose from baseline were observed between groups. Estimated treatment effects of AVT001 versus placebo at day 360 were -0.17% (95% CI, -0.60 to 0.26%) for HbA1c and -0.06 U/kg/day (95% CI, -0.14 to 0.02) for daily insulin dose.
CONCLUSIONS: In this phase 1/2 trial, AVT001 did not result in dose-limiting adverse events. Potential signals of efficacy observed here warrant further evaluation in a fully powered trial. (Funded by Avotres Inc. and the Division of Diabetes, Endocrinology, and Metabolic Diseases; ClinicalTrials.gov number, NCT03895996.).
METHODS: We conducted a phase 1/2, randomized, double-blind, placebo-controlled trial of the autologous dendritic cell therapy AVT001 that included participants at least 16 years of age, within 1 year of T1D diagnosis, and with ex vivo evidence of a defect in Q/E CD8+ Treg function. Patients were randomly assigned in a 2:1 ratio to AVT001 or placebo, which was administered in three monthly intravenous infusions. The primary end point was safety; efficacy end points included changes from baseline in C-peptide area under the curve (AUC) during a 4-hour mixed meal, hemoglobin A1c (HbA1c), and insulin dose.
RESULTS: Sixteen patients received AVT001, and nine received placebo. Similar rates and severity of adverse events were observed in both groups. None of the patients in the AVT001 group had serious adverse events through visit day 360. Compared with placebo, treatment with ATV001 was associated with less decline from baseline log-transformed C-peptide AUC (nmol/l), with the treatment effect between AVT001 and placebo at day 150 of 0.09 (95% confidence interval [CI], 0.03 to 0.15) and at day 360 of 0.10 (95% CI, 0.04 to 0.15). No clear differences in change in HbA1c and insulin dose from baseline were observed between groups. Estimated treatment effects of AVT001 versus placebo at day 360 were -0.17% (95% CI, -0.60 to 0.26%) for HbA1c and -0.06 U/kg/day (95% CI, -0.14 to 0.02) for daily insulin dose.
CONCLUSIONS: In this phase 1/2 trial, AVT001 did not result in dose-limiting adverse events. Potential signals of efficacy observed here warrant further evaluation in a fully powered trial. (Funded by Avotres Inc. and the Division of Diabetes, Endocrinology, and Metabolic Diseases; ClinicalTrials.gov number, NCT03895996.).
摘要：
背景：识别非经典1b类分子Qa-1/人白细胞抗原E的CD8+T调节（Treg）细胞（Q/ECD8+Treg细胞）在维持自身耐受方面很重要。我们试图研究这些T细胞在1型糖尿病（T1D）发病机制中的作用，以及针对该机制的干预是否可以延迟T1D进展。
方法：我们进行了1/2阶段，随机，双盲,自体树突状细胞疗法AVT001的安慰剂对照试验，包括至少16岁的参与者，在T1D诊断的1年内，和离体证据的Q/ECD8+Treg功能缺陷。患者以2：1的比例随机分配到AVT001或安慰剂，这是三个月的静脉注射。主要终点是安全性；疗效终点包括4小时混合餐期间C肽曲线下面积（AUC）相对于基线的变化，血红蛋白A1c（HbA1c），和胰岛素剂量。
结果：16名患者接受了AVT001，9名患者接受了安慰剂。两组的不良事件发生率和严重程度相似。AVT001组中的患者在第360天没有出现严重的不良事件。与安慰剂相比，用ATV001治疗与基线对数转化的C肽AUC(nmol/l)下降较少相关，在第150天时AVT001和安慰剂之间的治疗效果为0.09（95％置信区间[CI]，0.03至0.15），并且在第360天为0.10（95％CI，0.04至0.15）。两组间HbA1c和胰岛素剂量相对于基线的变化没有明显差异。在第360天，对于HbA1c，AVT001与安慰剂的估计治疗效果为-0.17％（95％CI，-0.60至0.26％），对于每日胰岛素剂量为-0.06U/kg/天（95％CI，-0.14至0.02）。
结论：在本1/2期试验中，AVT001未导致剂量限制性不良事件。此处观察到的潜在功效信号值得在全功率试验中进一步评估。（由AvotresInc.和糖尿病部门资助，内分泌学,和代谢疾病；临床试验。gov编号，NCT03895996。).
方法：我们进行了1/2阶段，随机，双盲,自体树突状细胞疗法AVT001的安慰剂对照试验，包括至少16岁的参与者，在T1D诊断的1年内，和离体证据的Q/ECD8+Treg功能缺陷。患者以2：1的比例随机分配到AVT001或安慰剂，这是三个月的静脉注射。主要终点是安全性；疗效终点包括4小时混合餐期间C肽曲线下面积（AUC）相对于基线的变化，血红蛋白A1c（HbA1c），和胰岛素剂量。
结果：16名患者接受了AVT001，9名患者接受了安慰剂。两组的不良事件发生率和严重程度相似。AVT001组中的患者在第360天没有出现严重的不良事件。与安慰剂相比，用ATV001治疗与基线对数转化的C肽AUC(nmol/l)下降较少相关，在第150天时AVT001和安慰剂之间的治疗效果为0.09（95％置信区间[CI]，0.03至0.15），并且在第360天为0.10（95％CI，0.04至0.15）。两组间HbA1c和胰岛素剂量相对于基线的变化没有明显差异。在第360天，对于HbA1c，AVT001与安慰剂的估计治疗效果为-0.17％（95％CI，-0.60至0.26％），对于每日胰岛素剂量为-0.06U/kg/天（95％CI，-0.14至0.02）。
结论：在本1/2期试验中，AVT001未导致剂量限制性不良事件。此处观察到的潜在功效信号值得在全功率试验中进一步评估。（由AvotresInc.和糖尿病部门资助，内分泌学,和代谢疾病；临床试验。gov编号，NCT03895996。).
