BACKGROUND

Currently, there are no clinically approved treatments for ischemia-reperfusion injury after lung transplantation. Pre-clinical animal models have demonstrated a promising efficacy of adenosine _2A receptor (A_2AR) agonists as a treatment option for reducing ischemia-reperfusion injury. The purpose of this human study, is to conduct a Phase I clinical trial for evaluating the safety of continuous infusion of an A_2AR agonist in lung transplant recipients.

METHODS

An adaptive, two-stage continual reassessment trial was designed to evaluate the safety of regadenoson (A_2AR agonist) in the setting of lung transplantation. Continuous infusion of regadenoson was administered to lung transplant recipients that was started at the time of skin incision. Adverse events and dose-limiting toxicities, as pre-determined by a study team and assessed by a clinical team and an independent safety monitor, were the primary end-points for safety in this trial.

RESULTS

Between January 2018 and March 2019, 14 recipients were enrolled in the trial. Of these, 10 received the maximum infused dose of 1.44 µg/kg/min for 12 hours. No dose-limiting toxicities were observed. The steady-state plasma regadenoson levels sampled before the reperfusion of the first lung were 0.98 ± 0.46 ng/ml. There were no mortalities within 30 days.

CONCLUSIONS

Regadenoson, an A_2AR agonist, can be safely infused in the setting of lung transplantation with no dose-limiting toxicities or drug-related mortality. Although not powered for the evaluation of secondary end-points, the results of this trial and the outcome of pre-clinical studies warrant further investigation with a Phase II randomized controlled trial.

中文翻译：

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人肺移植中的腺苷 A2A 受体激动剂（regadenoson）。

背景

目前，尚无临床批准的肺移植后缺血再灌注损伤的治疗方法。临床前动物模型已经证明了腺苷_2A受体 (A _2A R) 激动剂作为减少缺血再灌注损伤的治疗选择的有希望的功效。这项人体研究的目的是进行 I 期临床试验，以评估在肺移植受者中连续输注 A _2A R 激动剂的安全性。

方法

一项适应性、两阶段持续重新评估试验旨在评估 regadenoson（A _2A R 激动剂）在肺移植中的安全性。在皮肤切口时开始对肺移植受者连续输注regadenoson。由研究团队预先确定并由临床团队和独立安全监测员评估的不良事件和剂量限制性毒性是该试验安全性的主要终点。

结果

2018 年 1 月至 2019 年 3 月期间，共有 14 名接受者参加了试验。其中，10 人接受了 12 小时的最大输注剂量 1.44 µg/kg/min。未观察到剂量限制性毒性。在第一个肺再灌注之前采样的稳态血浆 regadenoson 水平为 0.98 ± 0.46 ng/ml。30天内无死亡病例。

结论

Regadenoson 是一种 A _2A R 激动剂，可以在肺移植的情况下安全输注，没有剂量限制性毒性或药物相关死亡率。尽管对次要终点的评估没有效力，但该试验的结果和临床前研究的结果值得通过 II 期随机对照试验进行进一步调查。