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Trial of Therapeutic Hypothermia in Patients With ARDS (CHILL)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04545424
Recruitment Status : Not yet recruiting
First Posted : September 11, 2020
Last Update Posted : September 11, 2020
Sponsor:
Collaborators:
US Department of Veterans Affairs Cooperative Studies Program
KAI Research
United States Department of Defense
Information provided by (Responsible Party):
Jeffrey Hasday, University of Maryland, Baltimore

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. 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.

Condition or disease Intervention/treatment Phase
Respiratory Distress Syndrome, Adult Device: Hypothermia Drug: Neuromuscular Blocking Agents Device: Standard of care Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 340 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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.
Primary Purpose: Treatment
Official Title: Cooling to Help Injured Lungs (CHILL) Phase IIB Randomized Control Trial of Therapeutic Hypothermia in Patients With ARDS
Estimated Study Start Date : October 1, 2020
Estimated Primary Completion Date : December 1, 2023
Estimated Study Completion Date : May 31, 2024


Arm Intervention/treatment
Experimental: Hypothermia + Neuromuscular blockade
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
Subjects will be cooled using either cooling blankets or gel-pad systems to maintain core temperature 34-35°C.
Other Name: targeted temperature management

Drug: Neuromuscular Blocking Agents
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.
Other Name: Paralytics

Active Comparator: Usual Temperature Management
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
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.
Other Name: Usual temperature managementl




Primary Outcome Measures :
  1. 28-day ventilator-free days (VFDs) [ Time Frame: Calculated at study day 28 or death (whichever occurs first) ]
    Total number of days alive and not on a ventilator in the first 28 days after enrollment


Secondary Outcome Measures :
  1. 28-day ICU-free days [ Time Frame: Calculated at study day 28 or death (whichever occurs first) ]
    Total number of days alive and not admitted to the ICU in the first 28 days after

  2. Survival [ Time Frame: calculated at 28, 60, and 90 days ]
    28-day, 60-day, and 90-day mortality

  3. non neurologic Sequential Organ Failure (SOFA) scores [ Time Frame: At enrollment and study days 1, 2, 3, 4, 7, and 28 ]
    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

  4. Oxygen saturation (SpO2) [ Time Frame: Measured at enrollment, every 2 hours on enrollment day, then once on day 2, 3, 4, 7 and 28 ]
    Pulse ox reading

  5. Plateau airway pressure [ 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 ]
    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

  6. Mean airway pressure [ 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 ]
    Measured from ventilator during machine initiated breath

  7. Airway driving pressure [ 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 ]
    Plateau pressure - PEEP (machine initiated breath)

  8. Oxygen saturation index [ 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 ]
    Mean airway pressure x 100 x FiO2/SpO2

  9. Core temperature [ Time Frame: Measured continuously and recorded at randomization and then every 2 hours through study day 4 ]
    Measured continuously from iv catheter, urinary catheter, or esophageal probe.

  10. Urine output [ Time Frame: Daily on study day 1, 2, 3, 4, and 7 ]
    24 hour urine volume

  11. comprehensive metabolic panel blood test (includes sodium, potassium, chloride, bicarb, BUN, creatinine, glucose, albumin, total protein, AST, SLT, alkaline phosphatase, and bilirubin) [ Time Frame: At randomization and each morning on study days 1, 2, 3, 4, and 7 ]
    7 ml of blood collected in serum separator tubes; assay preformed in clinical lab

  12. Complete blood count with differential count and platelet count [ Time Frame: At randomization and each morning on study days 1, 2, 3, 4, and 7 ]
    7 ml of blood collected in purple top tube; assay preformed in clinical lab

  13. 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) [ 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 ]
    12 ml blood draw in two green top tubes

  14. Serum electrolytes [ Time Frame: Performed each evening on study days 1, 2, and 3 ]
    performed in clinical lab

  15. Fingerstick blood glucose level [ Time Frame: every 6 hour from randomization through study day 3 ]
    POC blood glucose testing performed at bedside



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04545424


Contacts
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Contact: Carl B Shanholtz, MD 410-328-8141 cshanhol@som.umaryland.edu
Contact: Michael L Terrin, MD/MPH 410-706-6139 mterrin@som.umaryland.edu

Locations
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United States, Delaware
Christiana Medical Center
Newark, Delaware, United States, 19718
Contact: Matthew Barrett, DO    302-668-5823    MBarrett@Christianacare.org   
Contact: Luis Cardenas, DO/PhD       LCardenas@ChristianaCare.org   
Principal Investigator: Matthew Barrett, DO         
Sub-Investigator: Luis Cardenas, DO/PhD         
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
Contact: Jonathan Sevransky, MD       jonathan.sevransky@emoryhealthcare.org   
Principal Investigator: Jonathan Sevransky, MD         
United States, Illinois
Rush University Medical Center
Chicago, Illinois, United States, 60612
Contact: Jared Greenberg, MD       Jared_Greenberg@rush.edu   
Contact: Mark Yoder, MD       Mark_A_Yoder@rush.edu   
Principal Investigator: Jared Greenberg, MD         
Sub-Investigator: Mark Yoder, MD         
University of Illinois at Chicago
Chicago, Illinois, United States, 60612
Contact: Sunit Singla, MD       ssingl6@uic.edu   
Principal Investigator: Sunit singla, MD         
University of Chicago
Chicago, Illinois, United States, 60637
Contact: Bhakti Patel, MD       bpatel@medicine.bsd.uchicago.edu   
Principal Investigator: Bhakti Patel, MD         
Loyola University Chicago
Chicago, Illinois, United States, 60660
Contact: Sean Forsythe, MD       SFORSY1@lumc.edu   
Principal Investigator: Sean Forsythe, MD         
United States, Maryland
University of Maryland Medical Center
Baltimore, Maryland, United States, 21201
Contact: Samuel A Tisherman, MD    410-328-9781    STisherman@som.umaryland.edu   
Principal Investigator: Samuel A Tisherman, MD         
Johns Hopkins Hospital
Baltimore, Maryland, United States, 21205
Contact: Robert S Stephens, MD       rsteph13@jhmi.edu   
Principal Investigator: Robert S Stephens, MD         
United States, Minnesota
Mayo Clinic Rochester Minnesota
Rochester, Minnesota, United States, 55902
Contact: Lioudmila Karnatovskaia, MD       Karnatovskaia.Lioudmila@mayo.edu   
Principal Investigator: Lioudmilla Karnatovskaia, MD         
Sub-Investigator: Richard Oekler, MD/PhD         
United States, Ohio
Cleveland Clinc
Cleveland, Ohio, United States, 44195
Contact: Rachel Scheraga, MD    216-296-4921    scherar@ccf.org   
Contact: Abhijit Duggal, MD/MSc/MPH       duggala2@ccf.org   
Principal Investigator: Rachel Scheraga, MD         
Sub-Investigator: Abhijit Duggal, MD/MSc/MPH         
United States, Pennsylvania
University of Pennsylavia
Philadelphia, Pennsylvania, United States, 19104
Contact: John Reilly, MD       John.Reilly@pennmedicine.upenn.edu   
Principal Investigator: John Reillt, MD         
Thomas Jefferson University
Philadelphia, Pennsylvania, United States, 19107
Contact: Michael Baram, MD       Michael.Baram@jefferson.edu   
Principal Investigator: Michael Baram, MD         
Temple University
Philadelphia, Pennsylvania, United States, 19140
Contact: Gerard Criner, MD    215-510-6570    Gerard.Criner@tuhs.temple.edu   
Contact: Nathaniel Marchetti, DO       Nathaniel.Marchetti@tuhs.temple.edu   
Principal Investigator: Gerarad Criner, MD         
Sub-Investigator: Nathaniel Marchetti, DO         
United States, Texas
Brooke Army Medical Center
Fort Sam Houston, Texas, United States, 78234
Contact: Whittney Warren, DO       whittney.a.warren.mil@mail.mil   
Contact: Robert Walter, MD       robert.j.walter26.mil@mail.mil   
Principal Investigator: Whittney Warren, DO         
Sub-Investigator: Robert Walter, MD         
Sponsors and Collaborators
University of Maryland, Baltimore
US Department of Veterans Affairs Cooperative Studies Program
KAI Research
United States Department of Defense
Investigators
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Principal Investigator: Jeffrey D Hasday, MD University of Maryland, Baltimore
  Study Documents (Full-Text)

Documents provided by Jeffrey Hasday, University of Maryland, Baltimore:
Statistical Analysis Plan  [PDF] July 30, 2020
Informed Consent Form  [PDF] July 30, 2020
Study Protocol  [PDF] July 24, 2020

Publications:

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Responsible Party: Jeffrey Hasday, Professor of Medicine, University of Maryland, Baltimore
ClinicalTrials.gov Identifier: NCT04545424    
Other Study ID Numbers: W81XWH2010432
First Posted: September 11, 2020    Key Record Dates
Last Update Posted: September 11, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame:
  • The Study Protocol and Statistical Analysis Plan will be included in a peer-reviewed article about the CHILL trial.
  • The informed consent form will be available from the CHILL trial website currently under construction and planned to be operational by August, 2020
  • 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.

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.


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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
Keywords provided by Jeffrey Hasday, University of Maryland, Baltimore:
ards
targeted temperature management
Additional relevant MeSH terms:
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Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Acute Lung Injury
Hypothermia
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Body Temperature Changes
Lung Injury
Neuromuscular Blocking Agents
Neuromuscular Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs