Corticosteroids to Reduce Inflammation in Severe Pancreatitis (CRISP)

摘要 目前有有限的药物干预措施证明，以改善患者的结果，急性 严重的非自身免疫性胰腺炎是一种高度病态和潜在致命的疾病， 在美国每年有275，000名患者。[1]早期轻度胰腺炎通常自行消退;然而，15-20% 的病例[2]进展为以潜在致死性全身炎症反应为特征的严重形式 多器官损伤综合征和（经常）呼吸衰竭。进一步的临床恶化会导致 坏死性胰腺炎在临床上与脓毒症相似，据报道死亡率高达30%。[3-6] 虽然炎症是已知的疾病进展的关键驱动因素，但没有抗炎治疗。 迄今为止的研究显示出足够的疗效，可以成为常规临床实践的一部分。识别 因此，针对重症急性胰腺炎的可行药物治疗仍然是一个尚未满足的重大需求。在这 应用，我们建议可以通过早期提供短期生理剂量来满足这一需求。 皮质类固醇这种常用的抗炎疗法已被证明可以提供一个明确的病人 与其他引发全身炎症、多器官损伤和呼吸衰竭的疾病（例如， 脓毒症、急性呼吸窘迫综合征（ARDS）以及最近的COVID-19），但研究甚少 胰腺炎少数已发表的重症急性胰腺炎治疗的初步试验表明， 皮质类固醇可缩短休克持续时间，并可能改善死亡率，但这些结果必须在 在这种疗法被临床医生广泛接受之前，还需要一系列越来越大的、严格的临床试验。这里我们 我提出了合乎逻辑的第一步II期试验：一个盲法，随机临床试验的早期生理剂量 氢化可的松与安慰剂在86例重症急性胰腺炎ICU患者中的比较。审判将在 由复苏科学中心的国家认可的重症监护研究小组进行。我们假设 皮质类固醇将减弱胰腺炎的炎症反应，从而减轻疾病的严重程度 和器官损伤。我们的第二个假设是，死亡率会随之降低，尽管这一假设 将是后续III期试验的重点。基线评估后，入选者将接受100毫克的 氢化可的松或匹配的安慰剂以盲法方式每8小时静脉注射一次，持续72小时（300 mg/天）。 主要试验结局将是72小时内SOFA疾病严重程度评分的变化，根据这些数据， 我们将进行一项新的亚组研究，以确定皮质类固醇的疗效是否在特定的亚组中更好， 临床结果可能最不确定。次要结局将包括进展为ARDS、呼吸机- 无ICU和无住院天数、炎症生物标志物谱、胰腺损伤生物标志物，以及 不良事件。总体而言，这项研究将提供一个常用的，有效的抗- 炎症疗法作为治疗通常缺乏药物治疗选择的危重疾病。

ABSTRACT There are currently limited medicinal interventions demonstrated to improve outcomes in patients with acute severe non-autoimmune pancreatitis, a highly morbid and potentially fatal condition which is estimated to afflict up to 275,000 patients annually in the US.[1] Early-stage mild pancreatitis often self-resolves; however 15-20% of cases [2] progress to a severe form characterized by a potentially lethal systemic inflammatory response syndrome with injury to multiple organs and (frequently) respiratory failure. Further clinical deterioration can lead to necrotizing pancreatitis, which is clinically similar to sepsis and has a reported mortality of up to 30%. [3–6] Although inflammation is known to be a key driver of disease progression, no anti-inflammatory therapy investigated to date has shown sufficient efficacy to become part of routine clinical practice. Identification of a viable medicinal therapy for severe acute pancreatitis thus remains a significant unmet need. In this application, we propose this need can be met via early delivery of a short course of physiologic-dose corticosteroids. This commonly used anti-inflammatory therapy has been shown to provide a clear patient benefit with other diseases which trigger systemic inflammation, multi-organ injury, and respiratory failure (e.g. sepsis, Acute Respiratory Distress Disorder (ARDS), and most recently COVID-19), but has been poorly studied in pancreatitis. The few published pilot trials of this therapy for severe acute pancreatitis have shown corticosteroids shorten the duration of shock and may improve mortality, but these results must be validated in a series of increasingly large, rigorous clinical trials before this therapy is widely accepted by clinicians. Here we propose the logical first step Phase II trial: a blinded, randomized clinical trial of an early physiological dose of hydrocortisone vs. placebo in 86 ICU patients with severe acute pancreatitis. The trial will be conducted by the nationally recognized critical care research team at the Center for Resuscitation Science. We hypothesize that corticosteroids will attenuate the inflammatory response from pancreatitis resulting in mitigated disease severity and organ injury. We secondarily hypothesize there will be a concomitant reduction in mortality, though this hypothesis will be the focus of a follow-up Phase III trial. After baseline assessments, enrollees will receive either 100 mgs of hydrocortisone or matching placebo intravenously in a blinded fashion every 8 hours for 72 hours (300 mg/day). The primary trial outcome will be the change in SOFA disease severity score over 72 hours, and from these data we will conduct a novel sub-study to determine if corticosteroid efficacy is better in specific subgroups whose clinical outcomes may be the most uncertain. Secondary outcomes will include progression to ARDS, ventilator- free days, ICU- and hospital-free days, inflammatory biomarker profiles, biomarkers for pancreatic injury, and adverse events. Overall, this study will provide an initial assessment of a commonly used, and effective anti- inflammatory therapy as a treatment for a critical illness which generally lacks medicinal therapeutic options.