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Trial of Therapeutic Hypothermia in Patients With ARDS (CHILL)

Primary Purpose

Respiratory Distress Syndrome, Adult

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Hypothermia
Neuromuscular Blocking Agents
Standard of care
Sponsored by
University of Maryland, Baltimore
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Respiratory Distress Syndrome, Adult focused on measuring ards, targeted temperature management

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 and FiO2≥0.6; 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 oxygen with well-fitting nasal cannula with flow ≥ 65 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 >0.2 mcg/kg/min of norepinephrine or equivalent dose of other pressors for >6 continuous hours prior to randomization)
  5. Core temperature <35.5°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
  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
  13. Not likely to remain intubated for ≥48h
  14. Physician of record unwilling to participate
  15. Severe underlying lung disease

    1. Needs ≥ 2 LPM home O2
    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
  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 interventional trial

Sites / Locations

  • Emory University
  • Rush University Medical Center
  • University of Illinois at ChicagoRecruiting
  • Loyola University ChicagoRecruiting
  • University of Maryland Medical CenterRecruiting
  • Johns Hopkins HospitalRecruiting
  • Cooper Health System
  • Cleveland ClincRecruiting
  • University of PennsylaviaRecruiting
  • Thomas Jefferson UniversityRecruiting
  • Temple UniversityRecruiting
  • Brooke Army Medical CenterRecruiting
  • Intermountain Healthcare (Utah)Recruiting
  • University of WisconsinRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Hypothermia + Neuromuscular blockade

Usual Temperature Management

Arm Description

Deep sedation and Neuromuscular blockade (NMB) and surface temperature management to maintain core temperature between 34 and 35°C for 48h, then rewarm to 36°C at 0.33°C per h and NMB discontinued when core temp reaches 35.5°C.

Acetaminophen and surface temperature management to maintain core temperature between 37°C and 38°C. Rewarming to 37°C for hypothermia ≤36°C with continuous renal replacement therapy.

Outcomes

Primary Outcome Measures

28-day ventilator-free days (VFDs)
Total number of days alive and not on a ventilator in the first 28 days after enrollment

Secondary Outcome Measures

28-day ICU-free days
Total number of days alive and not admitted to the ICU in the first 28 days after
Survival
28-day, 60-day, and 90-day mortality
non neurologic Sequential Organ Failure (SOFA) scores
SOFA score excluding neurologic component - based on PaO2/FiO2 (0-4), BP and pressor requirement (0-4), bilirubin level (0-4), platelet count (0-4), and creatinine (0-14) with total composite score 0-20
Oxygen saturation (SpO2)
Pulse ox reading
Plateau airway pressure
On ventilator-imitated breath; measured at enrollment, every 4 hours on enrollment day, then Measured at randomization and daily on study days 1, 2, 3, 4, and 7 or until extubation whichever occurs firstinitiated breath
Mean airway pressure
Measured from ventilator during machine initiated breath
Airway driving pressure
Plateau pressure - PEEP (machine initiated breath)
Oxygen saturation index
Mean airway pressure x 100 x FiO2/SpO2
Core temperature
Measured continuously from iv catheter, urinary catheter, or esophageal probe.
Urine output
24 hour urine volume
comprehensive metabolic panel blood test (includes sodium, potassium, chloride, bicarb, BUN, creatinine, glucose, albumin, total protein, AST, SLT, alkaline phosphatase, and bilirubin)
7 ml of blood collected in serum separator tubes; assay preformed in clinical lab
Complete blood count with differential count and platelet count
7 ml of blood collected in purple top tube; assay preformed in clinical lab
Plasma biomarkers measured by immunoassay and including IL-1ß, IL-6, IL-8, IL-18, surfactant protein D, soluble ICAM-1, MMP8, and soluble TNF receptor-I)
12 ml blood draw in two green top tubes
Serum electrolytes
performed in clinical lab
Fingerstick blood glucose level
POC blood glucose testing performed at bedside

Full Information

First Posted
August 25, 2020
Last Updated
April 12, 2023
Sponsor
University of Maryland, Baltimore
Collaborators
US Department of Veterans Affairs Cooperative Studies Program, KAI Research, United States Department of Defense
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1. Study Identification

Unique Protocol Identification Number
NCT04545424
Brief Title
Trial of Therapeutic Hypothermia in Patients With ARDS
Acronym
CHILL
Official Title
Cooling to Help Injured Lungs (CHILL) Phase IIB Randomized Control Trial of Therapeutic Hypothermia in Patients With ARDS
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 29, 2021 (Actual)
Primary Completion Date
March 31, 2024 (Anticipated)
Study Completion Date
June 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Maryland, Baltimore
Collaborators
US Department of Veterans Affairs Cooperative Studies Program, KAI Research, United States Department of Defense

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
Yes
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

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.
Detailed Description
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: 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) For the first 7 days: (a) Ventilator-associated pneumonia (VAP); (b) other secondary infections; (c) monitor for SAEs Schedule of Clinical and Laboratory Evaluations: 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 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). 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. Pregnancy testing in women of child-bearing years Obtain informed consent from patient or Legally Authorized Representative (LAR) depending on capacity Complete the screening and enrollment portion of the Screening, Enrollment and Randomization CRF. Enter data into the Medidata CHILL database, which will assign a unique subject ID. The subject ID and patient identifiers are entered into a secure screening log. 3. Randomization: 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. 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: Fill out Daily CRFs and enter into Medidata database Collect plasma for research testing. Measure Driving Pressure and OSI Make sure CBC and CMP sent every morning and a subsequent BMP, magnesium, and phosphate sent ~12h later. Rewarming starts 48h after initially reaching target temperature (34°-35°C) on day 3 Complete Unassisted Breathing Checklist form if applicable 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: Fill out Day 7 CRF and enter into Medidata database Collect plasma for research testing. Measure Driving Pressure and OSI Make sure CBC are CMP sent Complete Unassisted Breathing Checklist form if applicable 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: Complete Day 28 CRF 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Respiratory Distress Syndrome, Adult
Keywords
ards, targeted temperature management

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Randomized (1:1) control (non-blinded) multicenter trial
Masking
None (Open Label)
Masking Description
Since it will be obvious to observers of the subjects whether they are in the treatment (TH+NMB) or control groups, the study is not masked but all treatments that determine outcome are protocolized.
Allocation
Randomized
Enrollment
340 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Hypothermia + Neuromuscular blockade
Arm Type
Experimental
Arm Description
Deep sedation and Neuromuscular blockade (NMB) and surface temperature management to maintain core temperature between 34 and 35°C for 48h, then rewarm to 36°C at 0.33°C per h and NMB discontinued when core temp reaches 35.5°C.
Arm Title
Usual Temperature Management
Arm Type
Active Comparator
Arm Description
Acetaminophen and surface temperature management to maintain core temperature between 37°C and 38°C. Rewarming to 37°C for hypothermia ≤36°C with continuous renal replacement therapy.
Intervention Type
Device
Intervention Name(s)
Hypothermia
Other Intervention Name(s)
targeted temperature management
Intervention Description
Subjects will be cooled using either cooling blankets or gel-pad systems to maintain core temperature 34-35°C.
Intervention Type
Drug
Intervention Name(s)
Neuromuscular Blocking Agents
Other Intervention Name(s)
Paralytics
Intervention Description
Subjects in the TH + NMB arm will be deeply sedated using agents at the discretion of the primary ICU team, then start continuous iv infusion of either cisatracurium, atracurium, or vecuronium titrated to 2 twitches on train of four monitoring and further titrated to ablate visible shivering.
Intervention Type
Device
Intervention Name(s)
Standard of care
Other Intervention Name(s)
Usual temperature managementl
Intervention Description
Subjects who are hypothermic (≤36°C) during CRRT will receive surface warming to restore core temperature to 37°C. Patients with core temperature >38°C will receive 650 mg acetaminophen and, if temperature remains >38°C, surface cooling will be initiated to return core temperature to 37-38°C.
Primary Outcome Measure Information:
Title
28-day ventilator-free days (VFDs)
Description
Total number of days alive and not on a ventilator in the first 28 days after enrollment
Time Frame
Calculated at study day 28 or death (whichever occurs first)
Secondary Outcome Measure Information:
Title
28-day ICU-free days
Description
Total number of days alive and not admitted to the ICU in the first 28 days after
Time Frame
Calculated at study day 28 or death (whichever occurs first)
Title
Survival
Description
28-day, 60-day, and 90-day mortality
Time Frame
calculated at 28, 60, and 90 days
Title
non neurologic Sequential Organ Failure (SOFA) scores
Description
SOFA score excluding neurologic component - based on PaO2/FiO2 (0-4), BP and pressor requirement (0-4), bilirubin level (0-4), platelet count (0-4), and creatinine (0-14) with total composite score 0-20
Time Frame
At enrollment and study days 1, 2, 3, 4, 7, and 28
Title
Oxygen saturation (SpO2)
Description
Pulse ox reading
Time Frame
Measured at enrollment, every 2 hours on enrollment day, then once on day 2, 3, 4, 7 and 28
Title
Plateau airway pressure
Description
On ventilator-imitated breath; measured at enrollment, every 4 hours on enrollment day, then Measured at randomization and daily on study days 1, 2, 3, 4, and 7 or until extubation whichever occurs firstinitiated breath
Time Frame
Measured at randomization and daily as close to 0800 as possible on study days 1 2, 3, 4, and 7 or until extubation whichever occurs first
Title
Mean airway pressure
Description
Measured from ventilator during machine initiated breath
Time Frame
Measured at randomization and daily as close to 0800 as possible on study days 1 2, 3, 4, and 7 or until extubation whichever occurs first
Title
Airway driving pressure
Description
Plateau pressure - PEEP (machine initiated breath)
Time Frame
Measured at randomization and daily as close to 0800 as possible on study days 1 2, 3, 4, and 7 or until extubation whichever occurs first
Title
Oxygen saturation index
Description
Mean airway pressure x 100 x FiO2/SpO2
Time Frame
Measured at randomization and daily as close to 0800 as possible on study days 1 2, 3, 4, and 7 or until extubation whichever occurs first
Title
Core temperature
Description
Measured continuously from iv catheter, urinary catheter, or esophageal probe.
Time Frame
Measured continuously and recorded at randomization and then every 2 hours through study day 4
Title
Urine output
Description
24 hour urine volume
Time Frame
Daily on study day 1, 2, 3, 4, and 7
Title
comprehensive metabolic panel blood test (includes sodium, potassium, chloride, bicarb, BUN, creatinine, glucose, albumin, total protein, AST, SLT, alkaline phosphatase, and bilirubin)
Description
7 ml of blood collected in serum separator tubes; assay preformed in clinical lab
Time Frame
At randomization and each morning on study days 1, 2, 3, 4, and 7
Title
Complete blood count with differential count and platelet count
Description
7 ml of blood collected in purple top tube; assay preformed in clinical lab
Time Frame
At randomization and each morning on study days 1, 2, 3, 4, and 7
Title
Plasma biomarkers measured by immunoassay and including IL-1ß, IL-6, IL-8, IL-18, surfactant protein D, soluble ICAM-1, MMP8, and soluble TNF receptor-I)
Description
12 ml blood draw in two green top tubes
Time Frame
Collected at randomization and as close to 0800 as possible on study days 1 2, 3, 4, and 7 or until extubation whichever occurs first
Title
Serum electrolytes
Description
performed in clinical lab
Time Frame
Performed each evening on study days 1, 2, and 3
Title
Fingerstick blood glucose level
Description
POC blood glucose testing performed at bedside
Time Frame
every 6 hour from randomization through study day 3

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: endotracheal tube or tracheostomy in place and mechanically ventilated for ≤7 days; admitted to a participating ICU radiologic evidence of bilateral pulmonary infiltrates not fully explained by pleural effusions, atelectasis, or hydrostatic pulmonary edema 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: SpO2 values are 80-96% SpO2 is measured ≥10 min after any change in FIO2 PEEP is ≥ 8 cm H2O the pulse oximeter waveform tracing is adequate the qualifying inferred P/F ratio is confirmed 1-6h after initial determination. access to an LAR to provide consent. 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: 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. Missed NMB window: (>48 hrs) Missed mechanical ventilation window (>7 days) Refractory hypotension (continuous infusion of >0.3 mcg/kg/min of norepinephrine or equivalent dose of other vasopressors within 2 hours prior to randomization) Core temperature <35.5°C for ≥6 hours while not receiving CRRT on day of randomization Significant, active bleeding (>3u blood products and/or surgical/IR intervention) on day of randomization Platelets <10K/mm3 (uncorrected) on day of randomization Active hematologic malignancy Skin process that precludes cooling device Moribund, not likely to survive 72h Pre-morbid condition makes it unlikely that patient will survive 28 days Do Not Resuscitate status at time of randomization (excluding patients receiving full support EXCEPT CPR for cardiac arrest) Not likely to remain intubated for ≥48h Physician of record unwilling to participate Severe underlying lung disease Needs ≥ 2 LPM home O2 On BIPAP (except for OSA) Prior lung transplantation Pregnant at time of randomization BMI consistently >50 kg/m2 Known NYHA class IV heart disease Acute Coronary Syndrome (MI, unstable angina) within 30 days of randomization Cardiac arrest within 30 days of randomization Burns over >20% of the body surface Severe chronic liver disease (Child-Pugh score 12-15) Previously randomized in CHILL study Simultaneous enrollment in another interventional trial started during the current hospitalization. On ECMO during the current hospitalization.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Carl B Shanholtz, MD
Phone
410-328-8141
Email
cshanhol@som.umaryland.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Michael L Terrin, MD/MPH
Phone
410-706-6139
Email
mterrin@som.umaryland.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeffrey D Hasday, MD
Organizational Affiliation
University of Maryland, Baltimore
Official's Role
Principal Investigator
Facility Information:
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jonathan Sevransky, MD
Email
jonathan.sevransky@emoryhealthcare.org
First Name & Middle Initial & Last Name & Degree
Jonathan Sevransky, MD
Facility Name
Rush University Medical Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jared Greenberg, MD
Email
Jared_Greenberg@rush.edu
First Name & Middle Initial & Last Name & Degree
Mark Yoder, MD
Email
Mark_A_Yoder@rush.edu
First Name & Middle Initial & Last Name & Degree
Jared Greenberg, MD
First Name & Middle Initial & Last Name & Degree
Mark Yoder, MD
Facility Name
University of Illinois at Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sunit Singla, MD
Email
ssingl6@uic.edu
First Name & Middle Initial & Last Name & Degree
Sunit singla, MD
Facility Name
Loyola University Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60660
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sean Forsythe, MD
Email
SFORSY1@lumc.edu
First Name & Middle Initial & Last Name & Degree
Sean Forsythe, MD
Facility Name
University of Maryland Medical Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Samuel A Tisherman, MD
Phone
410-328-9781
Email
STisherman@som.umaryland.edu
First Name & Middle Initial & Last Name & Degree
Samuel A Tisherman, MD
Facility Name
Johns Hopkins Hospital
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Robert S Stephens, MD
Email
rsteph13@jhmi.edu
First Name & Middle Initial & Last Name & Degree
Robert S Stephens, MD
Facility Name
Cooper Health System
City
Camden
State/Province
New Jersey
ZIP/Postal Code
08103
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nitin Puri, MD
Email
puri-nitin@CooperHealth.edu
First Name & Middle Initial & Last Name & Degree
Nitin Puri, MD
Facility Name
Cleveland Clinc
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rachel Scheraga, MD
Phone
216-296-4921
Email
scherar@ccf.org
First Name & Middle Initial & Last Name & Degree
Abhijit Duggal, MD/MSc/MPH
Email
duggala2@ccf.org
First Name & Middle Initial & Last Name & Degree
Rachel Scheraga, MD
First Name & Middle Initial & Last Name & Degree
Abhijit Duggal, MD/MSc/MPH
Facility Name
University of Pennsylavia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
John Reilly, MD
Email
John.Reilly@pennmedicine.upenn.edu
First Name & Middle Initial & Last Name & Degree
John Reillt, MD
Facility Name
Thomas Jefferson University
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michael Baram, MD
Email
Michael.Baram@jefferson.edu
First Name & Middle Initial & Last Name & Degree
Michael Baram, MD
Facility Name
Temple University
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19140
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nathaniel Marchetti, DO
Phone
215-707-3336
Email
Gerard.Criner@tuhs.temple.edu
First Name & Middle Initial & Last Name & Degree
Nathaniel Marchetti, DO
Email
Nathaniel.Marchetti@tuhs.temple.edu
First Name & Middle Initial & Last Name & Degree
Gerard Criner, MD
First Name & Middle Initial & Last Name & Degree
Nathaniel Marchetti, DO
Facility Name
Brooke Army Medical Center
City
Fort Sam Houston
State/Province
Texas
ZIP/Postal Code
78234
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jess Anderson, DO
Email
jess.t.anderson.mil@mail.mil
First Name & Middle Initial & Last Name & Degree
Jess T Anderson, DO
Facility Name
Intermountain Healthcare (Utah)
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Daniel Knox, MD
Phone
303-601-1856
Email
Dan.Knox@imail.org
First Name & Middle Initial & Last Name & Degree
Daniel Knox, MD
Facility Name
University of Wisconsin
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Majid Afshar, MD
Phone
312-545-9462
Email
mafshar@medicine.wisc.edu
First Name & Middle Initial & Last Name & Degree
Majid Afshar, MD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
The CHILL trial will be registered with clinicaltrials.gov. Within the first year of the study, Dr. Hasday and colleagues will publish the rationale for and description of the CHILL trial in a peer-reviewed journal. At the completion of the study, Dr. Hasday and colleagues will present the results of the long-term outcomes at national meetings and publish them in peer-reviewed journals. Within two years of the end of the award period or one year of the publication of the main trial data (whichever occurs first, Drs. Hasday and colleagues will make available for sharing with qualified investigators and consumer advocacy communities the de-identified study data. Plasma samples will be stored for at least 2 years after study closure and be made available to qualified investigators based on the rationale of their intended use. Requests for the limited plasma samples will be prioritized by the CHILL Executive Committee.
IPD Sharing Time Frame
The Study Protocol and Statistical Analysis Plan will be included in a peer-reviewed article about the CHILL trial protocol. The informed consent form will be available from the CHILL trial website (CHILLtrial.org) The Clinical Study Report will be published within the first year of the CHILL trial. De-identified data will be made available within two years of the end of the award period or one year of the publication of the main trial data (whichever occurs first,
IPD Sharing Access Criteria
The consent form will be publicly available through the public accessible CHILL website portal (CHILLtrial.org) The Study Protocol, Statistical Analysis Plan, and Clinical study Report will be publicly available in a peer-review publication and will also be available on the CHILL website. -Access to de-identified data will be evaluated by the CHILL Executive Committee and made available to qualified investigators and consumer advocacy communities.
IPD Sharing URL
https://CHILLtrial.org
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Trial of Therapeutic Hypothermia in Patients With ARDS

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