Competition from other studies and initiation of a larger multi center trial

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.

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. A Department of Defense-funded Phase IIb multicenter trial of TH+NMB in patients with moderate to severe ARDS will begin enrolling in Fall, 2020. Since COVID-19 has become the most common cause of ARDS, it is important to understand whether patients with COVID-19-associated ARDS can be included in the multicenter trial.

Focus of Study: We will conduct a single-site feasibility and safety RCT pilot of TH+NMB for 48h vs. usual temperature management in 20 patients with COVID-19-associated ARDS. We will also analyze efficacy markers to help decide whether the treatment duration (48h) to be used in the multicenter trial is appropriate for patients with COVID-19-associated ARDS. The results of this pilot help us decide whether to include patients with COVID-19-associated ARDS in our planned multicenter trial of TH+NMB in ARDS from all causes or to pursue a separate trial focused on patients with COVID-19-associated ARDS.

Primary and secondary objectives: The primary objective is to assess the safety and feasibility of the 48h TH+NMB treatment protocol. The secondary objective is to compare the TH+NMB and control arms for efficacy markers to be used in the multicenter trial.

Study design: The CHILL trial is a single 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, continuous infusion of cisatracurium 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: 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 VFDs. The 28-day VFDs will be calculated at day 28. (b) 28-day ICU-FDs:. The 28-day ICU-FDs will be calculated at day 28; (c) day 0, 1, 2, 3, 4, and 7 non-neurologic SOFA score; (d) Glasgow coma score at hospital discharge; (e) 60- and 90-day survival; (f) 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 2u packed red blood cells or surgical or interventional radiologic intervention)
2. 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. Day 0: day of 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; 14 ml blood) tubes will be collected for biomarker analysis at randomization and on study days 1, 2, 3, 4, and 7 at 8:00-10:00 on study days 1, 2, 3, 4, and 7. Clinical laboratory testing required for secondary clinical outcomes at enrollment and on study days 1, 2, 3, 4, and will be performed as part of usual clinical care whenever possible) at 6:00-10:00 AM and 6:00-10:00 PM

3. Day -2 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 with COVID-19, receiving mechanical ventilation for ≤7 days and have bilateral pulmonary opacities not fully explained by pleural effusions, atelectasis, or hydrostatic pulmonary edema for <48h will be offered enrollment and will be randomized when P/F ratio is <200. In patients without arterial blood gas values, the P/F ratio will be inferred from SpO2 readings as described by Brown et al. (Chest 150:307; 2016).

   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 Screening, enrollment, and randomization CRFs.
   4. If P/F<200 at enrollment, proceed with randomization, otherwise follow until P/F < 200 or patient exits the 48 hr ARDS or 7 day mechanical ventilation windows.

3. Day 0 (Randomization day): Pt. identified in screen:

1. Obtain baseline plasma for research testing. If >8h since last CBC and CMP or >24 since last CRP, send new samples to lab.

2. Randomize.

3. If patient does not have a central temperature probe, place esophageal probe.

4. For TH+NMB arm, confirm adequate sedation (RASS -4) and NMB (Train of four ≤2 twitch) and initiate TH protocol.

5. Complete Randomization Worksheet and Randomization and Baseline Data CRFs

6. Note time cooling initiated and time patient first reached target temperature on 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 and CRP every 24h e. Rewarming starts after 48h cooling 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:

a. Fill out Day 7 CRF b. Collect plasma for research testing. c. Measure Driving Pressure and OSI d. Make sure CBC, CMP, and CRP sent e. Complete Unassisted Breathing Checklist form if applicable f. 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 COVID-19 diagnosed by PCR testing within previous 2 weeks and 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: The investigators will use a randomization protocol stratified for proning status using pre-generated random assignment lists. Assignments will be made using an in-house Excel-based assignment tool, which blinds the observer to the assignment list.

   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 within 6 months.

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

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.

All information will be available within one year of the publication of the main trial data.

Access will either be by email to Dr. Hasday or through a website to be developed.

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.