Trial of Therapeutic Hypothermia in Patients With ARDS
Trial of Therapeutic Hypothermia in Patients With ARDS
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.
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.

 Intervention: The study intervention is TH to core temperature 34°-35°C + NMB for 48h.
 Patients in the TH+NMB arm will receive deep sedation, treatment with a neuromuscular
 blocking agent, and mechanical ventilation for at least 48h. Decisions about transition to
 unassisted breathing, extubation, and transfer from ICU will be based on criteria in the
 CHILL study protocol.

 TH+NMB: Once sedation and NMB are confirmed, TH to 34°-35°C will be initiated using surface
 cooling. Temperature will be measured from a central probe. Once target temperature is
 reached, TH will be maintained for 48h. Patients will then be rewarmed to 35.5°C by 0.3°C/h
 and the cooling devices removed. Post-TH fever suppression is not part of the CHILL protocol
 and will be performed at the discretion of the primary ICU team. TH+NMB will be aborted for
 persistent severe bradycardia, uncontrolled bleeding, and intractable arrhythmias.

 Usual temperature management: Patients will receive light sedation (RASS 0 to -1). During the
 54h post-randomization treatment period, acetaminophen will be given for core temperature
 >38°C and surface cooling will be initiated if core temperature remains >38°C within ≥45
 minutes of receiving acetaminophen and adjusted to maintain core temperature ≤38°C. If core
 temperature ≤36°C, patients in this arm will receive surface warming to core temperature
 37°C. Following the 54h treatment period, temperature will be managed at the discretion of
 the primary ICU team.

 Concomitant Treatment: Since prone positioning independently improves survival in ARDS,
 starting and stopping rules for prone positioning have been protocolized.

 Primary and Secondary Endpoints:

 Primary endpoint: 28-day Ventilator-free days (VFDs). Decisions about ventilator weaning and
 extubation will be made based on criteria in the CHILL protocol. The 28-day VFDs will be
 calculated at day 28.

 Intermediate endpoint: The low and high core temperatures in each 2-hour period will be
 recorded for each of the first four study days. The time required to reach the target
 temperature and the percent of readings within the target range in the TH+NMB arm will be
 determined.

 Secondary endpoints:

 Clinical: (a) 28-day ICU-FDs: The 28-day ICU-FDs will be calculated at day 28; (b) baseline
 and day 1, 2, 3, 4, and 7 non-neurologic SOFA score; (c) Glasgow coma score at hospital
 discharge; (d) 60- and 90-day survival; (e) 60- and 90-day functional status. The Montreal
 Cognitive Assessment Tool (MOCA) will be administered at ICU and hospital discharge.

 Physiologic: (a) day-3 and -7 driving pressure; (b) day-3 and day-7 oxygen saturation index
 (OSI).

 Plasma Biomarker: Day 0, 1, 2, 3, 4, and 7 plasma IL-1ß, IL-6, IL-8, IL-18, soluble-RAGE,
 surfactant protein-D, soluble ICAM-1, MMP8, and soluble TNFRI.

 Safety:

 1. For the first 54h: (a) continuous cardiac monitoring for bradycardia with associated
 hypotension requiring i.v. fluid or vasopressors; (b) every 6h blood glucose
 measurement; (c) every 12 h potassium, magnesium and phosphate; (d) significant bleeding
 event (requiring ≥3u packed red blood cells or surgical or interventional radiologic
 intervention)

 2. For the first 7 days: (a) Ventilator-associated pneumonia (VAP); (b) other secondary
 infections; (c) monitor for SAEs

 Schedule of Clinical and Laboratory Evaluations:

 1. Definitions:

 1. Baseline period: 24h prior to randomization

 2. Comprehensive metabolic panel (CMP): includes basic electrolytes, BUN, creatinine,
 ALT, AST, alkaline phosphatase, bilirubin, calcium, magnesium, phosphate,
 C-reactive protein (CRP)

 3. CBC: complete blood count

 4. Driving Pressure = Plateau Pressure - PEEP with patient NOT making inspiratory
 effort (on NMB or post-NMB and observed RR at set ventilator rate)

 5. OSI = Mean airway pressure x 100 x FIO2/SpO2

 2. Clinical and Research laboratory testing: Two purple top (EDTA; 24 ml blood) tubes will
 be collected for biomarker analysis just prior to randomization and as close to 0800 as
 possible on study days 1, 2, 3, 4, and 7 . Clinical laboratory testing required for
 secondary clinical outcomes at baseline and on study days 1, 2, 3, 4, and will be
 performed as part of usual clinical care whenever possible).

 3. Day -7 to 0 (Screening and enrollment): To facilitate randomization within the inclusion
 window, we will consent and enroll based on partial fulfillment of randomization
 criteria and randomize once all criteria are met. Patients between 18 and 65 years old
 receiving mechanical ventilation for ≤7 days will be screened and those who have
 bilateral pulmonary opacities not fully explained by pleural effusions, atelectasis, or
 hydrostatic pulmonary edema for <48h will be offered enrollment even if they do not yet
 meet the P/F ratio criterion for randomization.

 1. Pregnancy testing in women of child-bearing years

 2. Obtain informed consent from patient or Legally Authorized Representative (LAR)
 depending on capacity

 3. Complete the screening and enrollment portion of the Screening, Enrollment and
 Randomization CRF.

 3. Randomization:

 a. If P/F<200 at enrollment, proceed with randomization, otherwise follow until P/F < 200 or
 patient exits the 48h ARDS or 7 day mechanical ventilation windows.

 b. Once patient meets criterion for randomization: i. Obtain baseline plasma for research
 testing. If >8h since last CBC and CMP or >24 since last CRP, send new samples to lab.

 ii. Obtain treatment assignment will be made by the automated, web-based randomization
 service provided by Cooperative Studies Program Coordinating Center (CSPCC).

 iii. If patient does not have a central temperature probe, place esophageal probe.

 iv. For TH+NMB arm, confirm adequate sedation (RASS -4) and NMB (Train of four ≤2 twitch) and
 initiate TH protocol.

 v. Complete the randomization section of the Screening, Enrollment, and Randomization CRF vi.
 Complete Baseline CRF

 4.Day 1-4:

 a. Fill out Daily CRFs b. Collect plasma for research testing. c. Measure Driving Pressure
 and OSI d. Make sure CBC and CMP sent every 12h e. Rewarming starts 48h after initially
 reaching target temperature (34°-35°C) on day 3 f. Complete Unassisted Breathing Checklist
 form if applicable g. Assess for adverse events

 5. Days 5-6:

 a. Follow for ventilator status, ICU status, survival, SAEs b. Follow CRP daily c. Complete
 Unassisted Breathing Checklist form if applicable d. Assess for adverse events

 6. Day 7:

 1. Fill out Day 7 CRF

 2. Collect plasma for research testing.

 3. Measure Driving Pressure and OSI

 4. Make sure CBC, CMP, and CRP sent

 5. Complete Unassisted Breathing Checklist form if applicable

 6. Assess for adverse events

 7. Day 8-27:

 a. Follow for ventilator status, ICU status, survival, SAEs b. Complete Unassisted Breathing
 Checklist form if applicable

 8. Day 28:

 1. Complete Day 28 CRF

 2. Calculate 28 day VFDs and ICU-FDs

 9. When patient is discharged from the ICU, complete ICU discharge CRF

 10. When patient is discharged from the hospital, complete Hospital discharge CRF.

 11. Day 60 and 90: Follow up about patient status. Complete phone follow-up CRF.

 Study population: Adult patients with moderate to severe ARDS based on Berlin criteria
 (P/F < 200 while on PEEP ≥8 cm H2O) <48h in duration.

 Data Analysis: This is a pilot trial to determine whether patients with
 COVID-19-associated patients with ARDS should be included in a multicenter trial of
 TH+NMB in patients with ARDS from all causes. The data from this pilot will not be
 merged with data from the planned multicenter trial. The primary analysis of this pilot
 study will be to determine the effectiveness of the TH+NMB protocol in maintaining
 targeted temperature and to determine whether there are any safety issues with the
 TH+NMB protocol in this patient population.

 Data Management: Data for this pilot RCT will be recorded on paper CRFs. Completion of
 all fields will be checked in real-time. The forms have been designed to be compatible
 with the electronic versions developed for the multicenter trial.

 Randomization Plan: Patients with moderate to severe ARDS for ≤48h based on the Berlin
 criteria 1 will be randomized. Because prone positioning improves survival in ARDS 37
 and patients with COVID-19 may respond differently to TH than other ARDS patients,
 randomization will be stratified by proning status, COVID-19 status, and clinical site
 and patients will be randomized within each stratum using a 1:1 assignment ratio in
 small blocks of randomly varying size. Patients without ABG data may be randomized based
 on a P/F ratio imputed from SpO2 data as described by Brown et al. 135. To facilitate
 randomization within the inclusion window, patients who meet all Berlin criteria but
 have not yet met the P/F <200 criterion will be consented, enrolled, and followed until
 the P/F ratio < 200 criterion is documented or they exit the 48 hr ARDS window. Just
 prior to randomization, a research blood sample will be drawn, an esophageal temperature
 probe will be placed if no other central temperature probe is present, and patients will
 be randomized to TH+NMB or usual temperature management. The web-based randomization
 system provided by CSPCC.

 Subject Participation Duration: The duration of intervention, TH + NMB vs. usual
 temperature management, is 48h, followed by rewarming for 3-6h in the TH group. NMB will
 be discontinued and sedation reduced when subjects are rewarmed to core temperature
 ≥35.5°C. In the control group fever and hypothermia during continuous renal replacement
 therapy (CRRT) will be treated by protocol for 54h post-randomization. Physiologic and
 clinical parameters will be collected through study day 7. In hospital follow-up up to
 90 days will include determination of 28-day VFDs and ICU-FDs, and day of hospital
 discharge. When the patient regains competence, consent for continued participation will
 be obtained

 Study Duration: Completion of enrollment is anticipated by December 1, 2023 and study
 completion by May 31, 2024.
Inclusion Criteria:

 1. endotracheal tube or tracheostomy in place and mechanically ventilated for ≤7 days;

 2. admitted to a participating ICU

 3. radiologic evidence of bilateral pulmonary infiltrates not fully explained by pleural
 effusions, atelectasis, or hydrostatic pulmonary edema

 4. P/F ratio <200 with PEEP ≥8 cm H2O; If ABG values are not available, the P/F ratio may
 be inferred from SpO2 values based on Table 3 from Brown et al as long as following
 conditions are met:

 1. SpO2 values are 80-96%

 2. SpO2 is measured ≥10 min after any change in FIO2

 3. PEEP is ≥ 8 cm H2O

 4. the pulse oximeter waveform tracing is adequate

 5. the qualifying inferred P/F ratio is confirmed 1-6h after initial determination.

 5. access to an LAR to provide consent.

 6. Criteria 3 AND 4 must be met within 48h of enrollment and randomization, not be fully
 explained by hydrostatic pulmonary edema, and must have occurred within 7 days onset
 of a condition associated with ARDS.

 -  Patients may be enrolled and decision about randomization delayed if all criteria
 other than P/F ratio < 200 are met and then randomized if and when the P/F ratio
 < 200 (as long as this occurs within 48h of randomization).

 Exclusion Criteria:

 1. Missed ARDS window (>48hrs)

 2. Missed NMB window: (>12 hrs)

 3. Missed mechanical ventilation window (>7 days)

 4. Refractory hypotension (> 0.2 mcg/kg/min of norepinephrine or equivalent dose for 6 h
 or longer)

 5. Core temperature <35.5°C while not receiving CRRT

 6. Patient is unable to give consent and no Legally authorized representative is
 available

 7. Significant, active bleeding (>3u blood products and/or surgical/IR intervention)

 8. Platelets <10K/mm3 (uncorrected)

 9. Active hematologic malignancy

 10. Skin process that precludes cooling device

 11. Moribund, not likely to survive 72h

 12. Pre-morbid condition makes it unlikely that patient will survive 28 days

 13. Do Not Resuscitate status

 14. Not likely to remain intubated for ≥48h

 15. Physician of record unwilling to participate

 16. Severe underlying lung disease

 1. On home O2

 2. On BIPAP (except for OSA)

 3. Prior lung transplantation

 17. Pregnant

 18. BMI >50 kg/m2

 19. Known NYHA class IV heart disease

 20. Acute Coronary Syndrome past 30 days (MI, unstable angina)

 21. Cardiac arrest within 30 days of enrollment

 22. Burns over >20% of the body surface

 23. Severe chronic liver disease (Child-Pugh score 12-15)

 24. Previously randomized in CHILL study