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Pilot RCT of Therapeutic Hypothermia Plus Neuromuscular Blockade in COVID-19 Patients With ARDS (CHILL-pilot)

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: NCT03376854
Recruitment Status : Recruiting
First Posted : December 19, 2017
Last Update Posted : June 16, 2020
Sponsor:
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 investigators sought to evaluate whether TH combined with NMBA is beneficial in patients with ARDS. The investigators are scheduled to begin enrolling in a Department of Defense-funded Phase IIb multicenter RCT of TH (core temperature 34-35°C) + NMBA for 48h vs. usual temperature management in patients with ARDS with time on ventilator as the primary outcome. Since COVID-19 is now the most common cause of ARDS, we are conducting a pilot study to examine the safety and feasibility of including patients with COVID-19-associated ARDS in our upcoming trial. In this pilot, we will randomize 20 patients with COVID-19 and ARDS to either TH+NMBA for 48h or usual temperature management. The primary outcome is achieving and maintaining the target temperature. Secondary outcomes include safety, physiologic measures, mortality, hospital and ICU length of stay, and serum biomarkers collected on days 0, 1, 2, 3, 4, and 7.

Condition or disease Intervention/treatment Phase
Respiratory Distress Syndrome, Adult Sars-CoV2 Device: Hypothermia Drug: Neuromuscular Blocking Agents Device: Standard of Care Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized (1:1) control (non-blinded) 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: Pilot Randomized Clinical Trial of Therapeutic Hypothermia Plus Neuromuscular Blockade vs. Standard of Care in COVID-19 Patients With Moderate to Severe ARDS - the Cooling to Help Injured Lungs (CHILL) Pilot Study
Actual Study Start Date : May 1, 2018
Estimated Primary Completion Date : November 30, 2020
Estimated Study Completion Date : December 31, 2020


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: Standard of care
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 management




Primary Outcome Measures :
  1. Targeted temperature compliance [ Time Frame: Randomization through day 3 ]
    The total time in hours from beginning of cooling to beginning of rewarming during which the patient's core temperature was within the target range of 34-35°C.


Secondary Outcome Measures :
  1. Adverse event [ Time Frame: Randomization through study day 3 ]
    Adverse events expected during cooling, including hemorrhage, bradycardia, and hypotension.

  2. 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

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

  4. 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

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

  6. Plateau airway pressure [ Time Frame: Measured at enrollment, every 4 hours on enrollment day, then once on day 2, 3, 4, and 7 or until extubation whichever occurs first ]
    On machine initiated breath

  7. Mean airway pressure [ Time Frame: Measured at enrollment, every 4 hours on enrollment day, then once on day 2, 3, 4, and 7 or until extubation whichever occurs first ]
    Direct ventilator measurement on machine initiated breath

  8. Airway driving pressure [ Time Frame: Measured at enrollment, every 4 hours on enrollment day, then once on day 2, 3, 4, and 7 or until extubation whichever occurs first ]
    Plateau pressure - PEEP (machine initiated breath)

  9. Oxygen saturation index [ Time Frame: Measured at enrollment, every 4 hours on enrollment day, then once on day 2, 3, 4, and 7 or until extubation whichever occurs first ]
    Mean airway pressure x 100 x FiO2/SpO2

  10. Core temperature [ Time Frame: Measured continuously and recorded at enrollment, every 2 hours on the day of enrollment, and mornings on study day 2, 3, 4, and 7 ]
    Measured continuously from iv catheter, urinary catheter, or esophageal probe.

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

  12. comprehensive metabolic panel [ Time Frame: Daily on study day 1, 2, 3, 4, and 7 ]
    performed in clinical lab

  13. Complete blood count with differential count and platelet count [ Time Frame: Daily on study day 1, 2, 3, 4, and 7 ]
    preformed in clinical lab

  14. Biomarkers [ Time Frame: Daily on study day 1, 2, 3, 4, and 7 ]
    10 ml blood draw

  15. Serum electrolytes [ Time Frame: Every 8 hours until study hour 60 ]
    performed in clinical lab

  16. Blood glucose [ Time Frame: Every 4 hours until study hour 60 ]
    Beside blood glucose testing

  17. 28-day ventilator-free days [ 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



Information from the National Library of Medicine

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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 for Enrollment

  1. COVID-19 diagnosed by PCR within 3 weeks
  2. men and women
  3. any race/ethnicity
  4. 18-65 years of age
  5. endotracheal tube or tracheostomy in place and mechanically ventilated for < 7 days;
  6. radiologic evidence of bilateral pulmonary infiltrates not fully explained by hydrostatic pulmonary edema
  7. access to an LAR to provide consent (remote consent is permissible).

Additional inclusion criteria required for randomization:

  1. meet all inclusion/exclusion criteria for enrollment
  2. have a P/F ratio <200 with PEEP ≥8 cm H2O either from ABG or imputed from SpO2 as described by Brown et al (Chest 2016; 150:307).

Exclusion Criteria:

  1. Missed ARDS window (>48hrs)
  2. Missed mechanical ventilation window (>7 days)
  3. Refractory hypotension (> 0.2 mcg/kg/min of norepinephrine or equivalent dose for minimum of 6 h)
  4. Core temperature <35.5°C while not receiving CRRT
  5. Patient is unable to give consent and no legally authorized representative is available;
  6. Significant, active bleeding (>3u blood products and/or surgical/IR intervention)
  7. Platelets <10K/mm3 (uncorrected)
  8. Active hematologic malignancy
  9. Skin process 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
  13. Not likely to remain intubated for ≥48h
  14. Physician unwilling to participate
  15. Severe underlying lung disease

    1. On home O2
    2. On BIPAP (except for OSA)
    3. Prior lung transplantation
  16. BMI >45 kg/m2
  17. Known NYHA class IV heart disease
  18. Acute Coronary Syndrome past 30 days (MI, unstable angina)
  19. Cardiac arrest within 30 days of enrollment
  20. burns over >20% of the body surface
  21. severe chronic liver disease (Child-Pugh of 12-15)
  22. 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): NCT03376854


Contacts
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Contact: Jeffrey D Hasday, MD 410-328-8141 jhasday@som.umaryland.edu
Contact: Carl B Shanholtz, MD 410-328-8141 cshanohol@som.umaryland.edu

Locations
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United States, Maryland
University of Maryland Medical Center Recruiting
Baltimore, Maryland, United States, 21201
Contact: Jeffrey D Hasday, MD    410-328-8141    jhasday@som.umaryland.edu   
Contact: Carl B Shanholtz, MD    410-328-8141    cshanhol@som.umaryland.edu   
Sponsors and Collaborators
University of Maryland, Baltimore
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:
Informed Consent Form  [PDF] April 10, 2020
Statistical Analysis Plan  [PDF] May 19, 2020
Study Protocol  [PDF] May 6, 2020

Publications:

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Responsible Party: Jeffrey Hasday, Professor of Medicine, University of Maryland, Baltimore
ClinicalTrials.gov Identifier: NCT03376854    
Other Study ID Numbers: HP-00078506
First Posted: December 19, 2017    Key Record Dates
Last Update Posted: June 16, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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 and in ClinicalTrials.gov. Within one year of the publication of the main trial data (whichever occurs first, Dr. Hasday will make de-identified study data available to any individual who presents an appropriate question and analysis plan. The available information will include 1) descriptive documents (e.g. study protocol, code book/variable dictionary, data collection instruments, and de-identification methodology), and 2) de-identified data file.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: All information will be available within one year of the publication of the main trial data.
Access Criteria: Access will either be by email to Dr. Hasday or through a website to be developed.

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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:
COVID-19, 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
Signs and Symptoms
Lung Injury
Neuromuscular Blocking Agents
Neuromuscular Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs