CHILL TRIAL

Background:

Despite recent advances in supportive care for patients with acute respiratory distress syndrome (ARDS), mortality remains >40%. Fever worsens and hypothermia mitigates animal models of ALI and in small non-randomized in patients with ARDS. Since hypothermia reduces oxygen utilization as long as shivering is blocked, TH may reduce injury in part by allowing lower levels of assisted ventilation. TH likely exerts additional lung protective effects by directly modifying temperature-dependent cellular processes in endothelium, epithelium, and leukocytes. Neuromuscular blockade (NMB) is the ultimate treatment to block shivering and is frequently used in patients with ARDS to facilitate ventilator management. Since the recently completed NHLBI PETAL ROSE trial showed that NMB caused conferred neither benefit nor harm in patients with moderate to severe ARDS, the investigators have bundled TH with NMB to reduce shivering. An open-label study of 8 ARDS patients showed that studying TH + NMB in patients with moderate to severe ARDS was feasible. Moreover, the patients treated with TH +NMB had more 28-day ventilator-free days (VFDs), ICU-free days (ICU-FDs) and greater hospital survival (75% vs. 25%; p = 0.027) than historical controls with ARDS and NMB but without TH. Within the limits of historical comparisons, these results support further study of TH in ARDS. COVID-19 is currently the most common cause of ARDS and will likely remain so for at least the first year of enrollment. Since patients with COVID-19 may respond differently to TH than those with ARDS from other causes, a randomization strategy that limits COVID-19 patients will be used. Our overall hypothesis is that TH is lung protective in ARDS. The hypothesis to be tested is that induced hypothermia (core temperature 34°-35°C) with NMB to prevent shivering is safe and beneficial in patients with moderate to severe ARDS (PaO2/FIO2 (P/F) ratio<200) who are receiving NMB.

Focus of Study: We will conduct a multicenter RCT pilot of TH+NMB for 48h vs. usual temperature management in 340 patients with ARDS in 14 clinical sites.

Primary and secondary objectives: The primary objective is to assess the safety and efficacy of 48h TH+NMB in patients with ARDS compared with a control arm receiving usual temperature management. Secondary objectives include: (1) generating data to inform a decision about whether to proceed with a subsequent civilian population Phase III clinical trial of TH to reduce mortality in ARDS and to direct its study design; (2) analyzing biomarker and physiologic data to determine the mechanism(s) through which TH+NMB might exert benefit in ARDS

Study design: The CHILL trial is a multi-center RCT.

Brief Summary- Study Description:

Acute Respiratory Distress Syndrome (ARDS) is a serious condition that occurs as a complication of medical and surgical diseases, has a mortality of ~40%, and has no known treatment other than optimization of support. Data from basic research, animal models, and retrospective studies, case series, and small prospective studies suggest that therapeutic hypothermia (TH) similar to that used for cardiac arrest may be lung protective in patients with ARDS; however, shivering is a major complication of TH, often requiring paralysis with neuromuscular blocking agents (NMBA) to control. Since the recently completed NHLBI PETAL ROSE trial showed that NMBA had no effect (good or bad) in patients with moderate to severe ARDS, the CHILL trial is designed to evaluate whether TH combined with NMBA is beneficial in patients with ARDS. This Phase IIb randomized clinical trial is funded by the Department of Defense to compare TH (core temperature 34-35°C) + NMBA for 48h vs. usual temperature management in patients in 14 clinical centers with the Clinical Coordination Center and Data Coordinating Center at University of Maryland Baltimore. Planned enrollment is 340 over ~3.5 years of the 4-year contract. Since COVID-19 is currently the most common cause of ARDS, randomization will be stratified on COVID-19 status and patients with COVID-19 limited to no more than one-third of budgeted enrollment per year. Primary outcome is 28-day ventilator-free days. Secondary outcomes include safety, physiologic measures, mortality, hospital and ICU length of stay, and serum biomarkers collected at baseline and on days 1, 2, 3, 4, and 7.

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT04545424