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. COVID-19 is considered an ARDS risk-factor and patients with ARDS secondary to COVID-19 pneumonia will be eligible for enrollment. 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.

Brief summary:

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. COVID-19 is considered an ARDS risk-factor and patients with ARDS secondary to COVID-19 pneumonia will be eligible for enrollment. 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. Since COVID-19 is currently the most common cause of ARDS and will likely remain so for much of the CHILL enrollment period, patients with ARDS secondary to COVID-19 pneumonia are eligible for enrollment in CHILL. 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 efficacy and safety 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 and extubation 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 with hypotension, 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: Proning and corticosteroid therapy is allowed.

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.

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 will be collected and analyzed in the University of Maryland Cytokine Core Lab using in-house ELISAs (IL-1ß, IL-6, IL-8, IL-18, and sTNFR1) or ELISA kits purchased from R\&D Systems (sRAGE, SP-D, sICAM-1, MMP8) and Helena Laboratories (Protein C).

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:

   a. Baseline period: 24h prior to randomization b. Comprehensive metabolic panel (CMP): includes basic electrolytes, BUN, creatinine, ALT, AST, alkaline phosphatase, bilirubin, calcium, magnesium, phosphate, C-reactive protein (CRP) c. CBC: complete blood count d. Driving Pressure = Plateau Pressure - PEEP with patient NOT making inspiratory effort (on NMB or post-NMB and observed RR at set ventilator rate) e. OSI = Mean airway pressure x 100 x FIO2/SpO2
2. Clinical and Research laboratory testing: Two purple/pink top tubes (EDTA; 12 ml blood total) 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 75 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 and a qualifying P/F ratio (P/F ≤200 with PEEP ≥8) for \<72h will be enrolled and randomized. Patients who meet the criteria for pulmonary opacities but have not yet had a qualifying P/F ratio may be enrolled and monitored for potential 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.
   4. Enter data into the Medidata CHILL database, which will assign a unique subject ID.
   5. The subject ID and patient identifiers are entered into a secure screening log.

3. Randomization:

1. If the patient has had a qualifying P/F ratio at the time of enrollment, proceed with randomization, otherwise follow until the patient has a qualifying P/F ratio, exits the 48h NMBA window or the 7 day mechanical ventilation window, or develops an exclusion.
2. Once patient meets criterion for randomization:

i. Obtain baseline plasma for research testing. If \>24h since last CBC and CMP, send new samples to lab.

ii. Obtain treatment assignment from 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 to -5) and NMBA(Train of four ≤2 twitch) and initiate TH protocol using surface cooling as soon as possible.

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

4.Day 1-4:

1. Fill out Daily CRFs and enter into Medidata database
2. Collect plasma for research testing.
3. Measure Driving Pressure and OSI
4. Make sure CBC and CMP sent every morning and a subsequent BMP, magnesium, and phosphate sent \~12h later.
5. Rewarming starts 48h after initially reaching target temperature (34°-35°C) on day 3
6. Complete Unassisted Breathing Checklist form if applicable
7. Assess for adverse events

   5. Days 5-6:

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

6. Day 7:

1. Fill out Day 7 CRF and enter into Medidata database
2. Collect plasma for research testing.
3. Measure Driving Pressure and OSI
4. Make sure CBC are CMP 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) \<72h in duration.

   Data Analysis (see protocol for full description): Primary and secondary analyses will be performed according to the principle of intention-to-treat. The randomization is stratified only by site, which will be accounted for in the primary efficacy analysis. Three interim analyses will be performed after \~25%, \~50%, and \~75% of planned enrollment and a decision to halt the study for efficacy or harm will be made.

   Primary and Secondary efficacy endpoints will be analyzed using Wilcoxon-Mann-Whitney rank sum test extended to account for stratification by site. Sub-group analysis will test for significant interaction between treatment effect and a priori established baseline characteristics (proning status, shock, COVID, P/F ratio, age, time between meeting ARDS criteria and randomization, and baseline biomarkers (IL-6, bicarb, and protein C)).

   Data Management (see protocol for full description): Data for this RCT will be recorded on paper CRFs and entered into the Medidata database containing multiple automatic crosschecks.

   Randomization Plan: Patients will be randomized by the web-based automated system operated by CSPCC using a 1:1 assignment ratio in small blocks of randomly varying size prepared for each site.

   Subject Participation Duration: The duration of intervention is \~54h including time for cool down and rewarming. Physiologic and clinical parameters will be collected through study day 7. In hospital follow-up will include determination of 28-day VFDs and ICU-FDs, and day of hospital discharge and 60- and 90-day phone follow-up. When the patient regains competence, consent for continued participation will be obtained.

   Study Duration: Completion of enrollment is anticipated by March 31, 2025 and study completion by July 1, 2025.

Eligibility Criteria:
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 72h of enrollment and randomization, not be fully explained by hydrostatic pulmonary edema, and must have occurred within 7 days of exposure to an ARDS-risk factor (including continuous exposure to persistent processes (e.g. sepsis, pneumonia, COVID-19).

   * 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 72h of randomization). Patients on high flow nasal oxygen or non-invasive pressure ventilation may be consented if they meet criteria for starting the 72h ARDS window but may not be enrolled and randomized until they are intubated.

Exclusion Criteria:

1. Missed moderate-severe ARDS window (\>72hrs) - Window starts when patient is intubated with a qualifying P/F ratio of ≤ 200 with PEEP ≥ 8 cm H2O or on high flow nasal oxygen with well-fitting nasal cannula with flow ≥ 40 LPM and FiO2 ≥ 0.65 or on non-invasive pressure ventilation with PEEP ≥ 8 cm H2O and FiO2 ≥ 0.6.
2. Missed NMB window: (\>48 hrs)
3. Missed mechanical ventilation window (\>7 days)
4. Refractory hypotension (continuous infusion of \>0.3 mcg/kg/min of norepinephrine or equivalent dose of other vasopressors within 2 hours prior to randomization)
5. Core temperature \<35°C for ≥6 hours while not receiving CRRT on day of randomization
6. Significant, active bleeding (\>3u blood products and/or surgical/IR intervention) on day of randomization
7. Platelets \<10K/mm3 (uncorrected) on day of randomization
8. Active hematologic malignancy and not expected to survive 6 months
9. Skin process that precludes cooling device
10. Moribund, not likely to survive 72h
11. Pre-morbid condition makes it unlikely that patient will survive 28 days
12. Do Not Resuscitate status at time of randomization (excluding patients receiving full support EXCEPT CPR for cardiac arrest)
13. Not likely to remain intubated for ≥48h
14. Physician of record unwilling to participate
15. Severe underlying lung disease

    1. Needs \> 2 LPM or \>28% continuous home O2 (adjusted for altitude)
    2. On BIPAP (except for OSA)
    3. Prior lung transplantation
16. Pregnant at time of randomization
17. BMI consistently \>50 kg/m2
18. Known NYHA class IV heart disease
19. Acute Coronary Syndrome (MI, unstable angina) within 30 days of randomization
20. Cardiac arrest within 30 days of randomization with sequelae likely to increase mortality and/or time to ventilator liberation.
21. Burns over \>20% of the body surface
22. Severe chronic liver disease (Child-Pugh score 12-15)
23. Previously randomized in CHILL study
24. Simultaneous enrollment in another inpatient interventional trial started during the current hospitalization.
25. On ECMO during the current hospitalization.