BACKGROUND/AIMS The motivating randomized controlled phase I trial evaluates three sodium nitroprusside doses in a novel sodium nitroprusside-enhanced cardiopulmonary resuscitation strategy for improved end-organ perfusion relative to local standard of care. Sodium nitroprusside is a vasodilator with an established safety profile in other indications, whereas the local standard of care uses vasoconstrictors, typically epinephrine. The purpose of the proposed trial is to identify the highest safe dose of sodium nitroprusside in this new context as excessive doses may cause severe hypotension with compromised end-organ perfusion. METHODS The proposed phase I trial design expands upon traditional dose-finding designs to include a randomized control arm, which is needed to assess safety through the relative increase in serum lactate on hospital admission. For guiding dose escalation, we propose and compare six Bayesian models which characterize expected serum lactate as a function of sodium nitroprusside dose and randomization group. Each model makes a different assumption about the expected change in serum lactate across control cohorts concurrently randomized with each dose. Model selection aims to minimize the expected number of times that a dose is incorrectly classified as safe or unsafe while sample size selection targets an expected number of incorrectly classified doses. Randomization is 1:1 for the initial cohort, and for subsequent cohorts is chosen to maximize the lower confidence bound. RESULTS The spike-and-slab model minimizes the expected number of times that a dose is incorrectly classified as safe or unsafe under the most scenarios in the motivating three-dose trial, but all six models exhibit relatively similar performance. A 2:1 randomization ratio for the second and third cohorts maximizes the lower confidence bound when using the spike-and-slab model. With the optimal design, on average, 70 individuals will ensure 1 incorrectly classified dose in 6 opportunities. CONCLUSION We recommend that the motivating trial use the spike-and-slab model with a 1:1 randomization ratio for the initial cohort and 2:1 randomization ratio for subsequent cohorts; however, the simpler fixed effects approaches performed similarly well.

中文翻译：

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随机控制剂量递增设计评估新型药理学心肺复苏策略的安全性。

背景/目的 这项激动人心的随机对照 I 期试验评估了一种新型硝普钠增强心肺复苏策略中的三种硝普钠剂量，以相对于当地护理标准改善终末器官灌注。硝普钠是一种血管扩张剂，在其他适应症中具有既定的安全性，而当地的护理标准使用血管收缩剂，通常是肾上腺素。拟议试验的目的是确定在这种新背景下硝普钠的最高安全剂量，因为过量剂量可能会导致严重低血压并损害终末器官灌注。方法 拟议的 I 期试验设计在传统剂量探索设计的基础上进行了扩展，纳入了随机对照组，需要通过入院时血清乳酸的相对增加来评估安全性。为了指导剂量递增，我们提出并比较了六种贝叶斯模型，这些模型将预期血清乳酸描述为硝普钠剂量和随机分组的函数。每个模型对每个剂量同时随机化的对照队列中血清乳酸的预期变化做出了不同的假设。模型选择的目的是最大限度地减少剂量被错误分类为安全或不安全的预期次数，而样本量选择的目标是错误分类剂量的预期次数。初始队列的随机化比例为 1:1，随后的队列选择最大化置信下限。结果 在激励性三剂量试验的大多数情况下，尖峰和平板模型最大限度地减少了剂量被错误分类为安全或不安全的预期次数，但所有六个模型都表现出相对相似的性能。使用尖峰平板模型时，第二组和第三组的 2:1 随机化比例可最大化置信下限。通过最佳设计，平均 70 个人将在 6 次机会中确保 1 次错误分类的剂量。结论 我们建议激励试验使用尖峰和平板模型，初始队列的随机化比例为 1:1，后续队列的随机化比例为 2:1；然而，更简单的固定效应方法同样表现良好。