Trial of Therapeutic Hypothermia in Patients With ARDS

Cooling to Help Injured Lungs (CHILL) Phase IIB Randomized Control Trial of Therapeutic Hypothermia in Patients With ARDS

Sponsors

Lead Sponsor: University of Maryland, Baltimore

Collaborator: US Department of Veterans Affairs Cooperative Studies Program
KAI Research
United States Department of Defense

Source 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.

Detailed Description

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. COVID-19 is currently the most common cause of ARDS and will likely remain so for at least the first year of enrollment. Since patients with COVID-19 may respond differently to TH than those with ARDS from other causes, a randomization strategy that limits COVID-19 patients will be used. 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 safety and efficacy 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, extubation, and transfer from ICU 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, 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: Since prone positioning independently improves survival in ARDS, starting and stopping rules for prone positioning have been protocolized.

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. The Montreal Cognitive Assessment Tool (MOCA) will be administered at ICU and hospital discharge.

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 IL-1ß, IL-6, IL-8, IL-18, soluble-RAGE, surfactant protein-D, soluble ICAM-1, MMP8, and soluble TNFRI.

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:

1. Baseline period: 24h prior to randomization

2. Comprehensive metabolic panel (CMP): includes basic electrolytes, BUN, creatinine, ALT, AST, alkaline phosphatase, bilirubin, calcium, magnesium, phosphate, C-reactive protein (CRP)

3. CBC: complete blood count

4. Driving Pressure = Plateau Pressure - PEEP with patient NOT making inspiratory effort (on NMB or post-NMB and observed RR at set ventilator rate)

5. OSI = Mean airway pressure x 100 x FIO2/SpO2

2. Clinical and Research laboratory testing: Two purple top (EDTA; 24 ml blood) tubes 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 65 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 for <48h will be offered enrollment even if they do not yet meet the P/F ratio criterion for 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.

3. Randomization:

a. If P/F<200 at enrollment, proceed with randomization, otherwise follow until P/F < 200 or patient exits the 48h ARDS or 7 day mechanical ventilation windows.

b. Once patient meets criterion for randomization: i. Obtain baseline plasma for research testing. If >8h since last CBC and CMP or >24 since last CRP, send new samples to lab.

ii. Obtain treatment assignment will be made by 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) and NMB (Train of four ≤2 twitch) and initiate TH protocol.

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

4.Day 1-4:

a. Fill out Daily CRFs b. Collect plasma for research testing. c. Measure Driving Pressure and OSI d. Make sure CBC and CMP sent every 12h e. Rewarming starts 48h after initially reaching target temperature (34°-35°C) on day 3 f. Complete Unassisted Breathing Checklist form if applicable g. Assess for adverse events

5. Days 5-6:

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

6. Day 7:

1. Fill out Day 7 CRF

2. Collect plasma for research testing.

3. Measure Driving Pressure and OSI

4. Make sure CBC, CMP, and CRP 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) <48h in duration.

Data Analysis: This is a pilot trial to determine whether patients with COVID-19-associated patients with ARDS should be included in a multicenter trial of TH+NMB in patients with ARDS from all causes. The data from this pilot will not be merged with data from the planned multicenter trial. The primary analysis of this pilot study will be to determine the effectiveness of the TH+NMB protocol in maintaining targeted temperature and to determine whether there are any safety issues with the TH+NMB protocol in this patient population.

Data Management: Data for this pilot RCT will be recorded on paper CRFs. Completion of all fields will be checked in real-time. The forms have been designed to be compatible with the electronic versions developed for the multicenter trial.

Randomization Plan: Patients with moderate to severe ARDS for ≤48h based on the Berlin criteria 1 will be randomized. Because prone positioning improves survival in ARDS 37 and patients with COVID-19 may respond differently to TH than other ARDS patients, randomization will be stratified by proning status, COVID-19 status, and clinical site and patients will be randomized within each stratum using a 1:1 assignment ratio in small blocks of randomly varying size. Patients without ABG data may be randomized based on a P/F ratio imputed from SpO2 data as described by Brown et al. 135. To facilitate randomization within the inclusion window, patients who meet all Berlin criteria but have not yet met the P/F <200 criterion will be consented, enrolled, and followed until the P/F ratio < 200 criterion is documented or they exit the 48 hr ARDS window. Just prior to randomization, a research blood sample will be drawn, an esophageal temperature probe will be placed if no other central temperature probe is present, and patients will be randomized to TH+NMB or usual temperature management. The web-based randomization system provided by CSPCC.

Subject Participation Duration: The duration of intervention, TH + NMB vs. usual temperature management, is 48h, followed by rewarming for 3-6h in the TH group. NMB will be discontinued and sedation reduced when subjects are rewarmed to core temperature ≥35.5°C. In the control group fever and hypothermia during continuous renal replacement therapy (CRRT) will be treated by protocol for 54h post-randomization. Physiologic and clinical parameters will be collected through study day 7. In hospital follow-up up to 90 days will include determination of 28-day VFDs and ICU-FDs, and day of hospital discharge. When the patient regains competence, consent for continued participation will be obtained

Study Duration: Completion of enrollment is anticipated by December 1, 2023 and study completion by May 31, 2024.

Overall Status Not yet recruiting
Start Date October 1, 2020
Completion Date May 31, 2024
Primary Completion Date December 1, 2023
Phase Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
28-day ventilator-free days (VFDs) Calculated at study day 28 or death (whichever occurs first)
Secondary Outcome
Measure Time Frame
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
Mean 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
Airway driving 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
Oxygen saturation index 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
Core temperature Measured continuously and recorded at randomization and then every 2 hours through study day 4
Urine output Daily on study day 1, 2, 3, 4, and 7
comprehensive metabolic panel blood test (includes sodium, potassium, chloride, bicarb, BUN, creatinine, glucose, albumin, total protein, AST, SLT, alkaline phosphatase, and bilirubin) At randomization and each morning on study days 1, 2, 3, 4, and 7
Complete blood count with differential count and platelet count At randomization and each morning on study days 1, 2, 3, 4, and 7
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) 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
Serum electrolytes Performed each evening on study days 1, 2, and 3
Fingerstick blood glucose level every 6 hour from randomization through study day 3
Enrollment 340
Condition
Intervention

Intervention Type: Device

Intervention Name: Hypothermia

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

Arm Group Label: Hypothermia + Neuromuscular blockade

Other Name: targeted temperature management

Intervention Type: Drug

Intervention Name: Neuromuscular Blocking Agents

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.

Arm Group Label: Hypothermia + Neuromuscular blockade

Other Name: Paralytics

Intervention Type: Device

Intervention Name: Standard of care

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.

Arm Group Label: Usual Temperature Management

Other Name: Usual temperature managementl

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 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

Gender: All

Minimum Age: 18 Years

Maximum Age: 65 Years

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Jeffrey D Hasday, MD Principal Investigator University of Maryland, Baltimore
Overall Contact

Last Name: Carl B Shanholtz, MD

Phone: 410-328-8141

Email: [email protected]

Location
Facility: Contact: Contact Backup: Investigator:
Christiana Medical Center | Newark, Delaware, 19718, United States Matthew Barrett, DO 302-668-5823 [email protected] Matthew Barrett, DO Principal Investigator Luis Cardenas, DO/PhD Sub-Investigator
Emory University | Atlanta, Georgia, 30322, United States Jonathan Sevransky, MD [email protected] Jonathan Sevransky, MD Principal Investigator
Rush University Medical Center | Chicago, Illinois, 60612, United States Jared Greenberg, MD [email protected] Jared Greenberg, MD Principal Investigator Mark Yoder, MD Sub-Investigator
University of Illinois at Chicago | Chicago, Illinois, 60612, United States Sunit Singla, MD [email protected] Sunit singla, MD Principal Investigator
University of Chicago | Chicago, Illinois, 60637, United States Bhakti Patel, MD [email protected] Bhakti Patel, MD Principal Investigator
Loyola University Chicago | Chicago, Illinois, 60660, United States Sean Forsythe, MD [email protected] Sean Forsythe, MD Principal Investigator
University of Maryland Medical Center | Baltimore, Maryland, 21201, United States Samuel A Tisherman, MD 410-328-9781 [email protected] Samuel A Tisherman, MD Principal Investigator
Johns Hopkins Hospital | Baltimore, Maryland, 21205, United States Robert S Stephens, MD [email protected] Robert S Stephens, MD Principal Investigator
Mayo Clinic Rochester Minnesota | Rochester, Minnesota, 55902, United States Lioudmila Karnatovskaia, MD [email protected] Lioudmilla Karnatovskaia, MD Principal Investigator Richard Oekler, MD/PhD Sub-Investigator
Cleveland Clinc | Cleveland, Ohio, 44195, United States Rachel Scheraga, MD 216-296-4921 [email protected] Rachel Scheraga, MD Principal Investigator Abhijit Duggal, MD/MSc/MPH Sub-Investigator
University of Pennsylavia | Philadelphia, Pennsylvania, 19104, United States John Reilly, MD [email protected] John Reillt, MD Principal Investigator
Thomas Jefferson University | Philadelphia, Pennsylvania, 19107, United States Michael Baram, MD [email protected] Michael Baram, MD Principal Investigator
Temple University | Philadelphia, Pennsylvania, 19140, United States Gerard Criner, MD 215-510-6570 [email protected] Gerarad Criner, MD Principal Investigator Nathaniel Marchetti, DO Sub-Investigator
Brooke Army Medical Center | Fort Sam Houston, Texas, 78234, United States Whittney Warren, DO [email protected] Whittney Warren, DO Principal Investigator Robert Walter, MD Sub-Investigator
Location Countries

United States

Verification Date

September 2020

Responsible Party

Type: Principal Investigator

Investigator Affiliation: University of Maryland, Baltimore

Investigator Full Name: Jeffrey Hasday

Investigator Title: Professor of Medicine

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Hypothermia + Neuromuscular blockade

Type: Experimental

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.

Label: Usual Temperature Management

Type: Active Comparator

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.

Acronym CHILL
Patient Data Yes
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

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

Primary Purpose: Treatment

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.

Source: ClinicalTrials.gov