Trial of Therapeutic Hypothermia in Patients With ARDS

NCT04545424 | Recruiting Phase 2 DMC FDA Drug FDA Device

• 1 other identifier: W81XWH2010432
• Study Type: interventional
• Target: 340
• Locations: 1 country
• Sites: 19

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.

Conditions

Respiratory Distress Syndrome, Adult

Keywords

ards; targeted temperature management

Outcome Measures

Primary Outcomes (1)

• 28-day ventilator-free days (VFDs)

  Total number of days alive and not on a ventilator in the first 28 days after enrollment

  Calculated at study day 28 or death (whichever occurs first)

Secondary Outcomes (15)

• 28-day ICU-free days

  Calculated at study day 28 or death (whichever occurs first)

• Survival

  calculated at 28, 60, and 90 days

• non neurologic Sequential Organ Failure (SOFA) scores

  At enrollment and study days 1, 2, 3, 4, 7, and 28

• Oxygen saturation (SpO2)

  Measured at enrollment, every 2 hours on enrollment day, then once on day 2, 3, 4, 7 and 28

• Plateau airway pressure

  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

Study Arms (2)

Hypothermia + Neuromuscular blockade

EXPERIMENTAL

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.

Device: Hypothermia; Drug: Neuromuscular Blocking Agents

Usual Temperature Management

ACTIVE COMPARATOR

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.

Device: Standard of care

Interventions

Hypothermia DEVICE

Subjects will be cooled using either cooling blankets or gel-pad systems to maintain core temperature 34-35°C.

Also known as: targeted temperature management

Hypothermia + Neuromuscular blockade

Neuromuscular Blocking Agents DRUG

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.

Also known as: Paralytics

Hypothermia + Neuromuscular blockade

Standard of care DEVICE

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.

Also known as: Usual temperature managementl

Usual Temperature Management

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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°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 and not expected to survive 6 months
• 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

Sponsors & Collaborators

• University of Maryland, Baltimore: lead
• US Department of Veterans Affairs Cooperative Studies Program: collaborator
• KAI Research: collaborator
• United States Department of Defense: collaborator

Study Sites (19)

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

NOT YET RECRUITING

Yale University

New Haven, Connecticut, 06520, United States

TERMINATED

Emory University

Atlanta, Georgia, 30322, United States

RECRUITING

Rush University Medical Center

Chicago, Illinois, 60612, United States

RECRUITING

Loyola University Chicago

Chicago, Illinois, 60660, United States

TERMINATED

University of Kentucky

Lexington, Kentucky, 40536, United States

NOT YET RECRUITING

University of Maryland Medical Center

Baltimore, Maryland, 21201, United States

RECRUITING

Johns Hopkins Hospital

Baltimore, Maryland, 21205, United States

TERMINATED

Henry Ford Hospital

Detroit, Michigan, 48202, United States

RECRUITING

Cooper Health System

Camden, New Jersey, 08103, United States

RECRUITING

University of Cincinnati

Cincinnati, Ohio, 45219, United States

RECRUITING

Cleveland Clinc

Cleveland, Ohio, 44195, United States

RECRUITING

Oregon Health & Science University

Portland, Oregon, 97239, United States

RECRUITING

University of Pennsylavia

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

RECRUITING

Temple University

Philadelphia, Pennsylvania, 19140, United States

RECRUITING

Brooke Army Medical Center

Fort Sam Houston, Texas, 78234, United States

TERMINATED

Intermountain Healthcare (Utah)

Salt Lake City, Utah, 84132, United States

RECRUITING

University of Wisconsin

Madison, Wisconsin, 53792, United States

TERMINATED

Related Publications (41)

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MeSH Terms

Conditions

Respiratory Distress Syndrome; Acute Lung Injury

Interventions

Hypothermia, Induced; Neuromuscular Blocking Agents

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Lung Injury

Intervention Hierarchy (Ancestors)

Cryotherapy; Therapeutics; Neuromuscular Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• Jeffrey D Hasday, MD

  University of Maryland, Baltimore

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Carl B Shanholtz, MD

CONTACT

410-328-8141; cshanhol@som.umaryland.edu

Michael L Terrin, MD/MPH

CONTACT

410-706-6139; mterrin@som.umaryland.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Model Details: Randomized (1:1) control (non-blinded) multicenter trial

Study Record Dates

• First Submitted: August 25, 2020
• First Posted: September 11, 2020
• Study Start: June 29, 2021
• Primary Completion (Estimated): August 31, 2026
• Study Completion (Estimated): October 31, 2026
• Last Updated: November 10, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• 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,
• 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.

Locations

US (19)