Pilot RCT of Therapeutic Hypothermia in ARDS Patients Receiving Neuromuscular Blockade

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. A small non-randomized controlled trial of therapeutic hypothermia (TH) in
moribund patients with septic shock and ARDS showed improved survival (3 of 9 vs. 0 of 10) in
the TH group. However, the study preceded modern ARDS definition and management and mortality
in both groups was much higher than current experience. Since oxygen utilization decreases
~10% per 1°C reduction in core temperature, 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. However, cooling in critically ill patients is complicated by shivering and its
adverse metabolic consequences. Neuromuscular blockade (NMB) is increasingly used in patients
with ARDS to facilitate low tidal volume ventilation and prone positioning and based on
results of the ACURASYS trial. Since NMB is the ultimate anti-shivering treatment, such
patients offer a convenient population for an initial study of TH in ARDS. A retrospective
study of 58 ARDS patients treated with NMB showed that NMB alone does not cause hypothermia.
An open-label study of 8 ARDS patients showed that studying TH in NMB-treated ARDS patients
was feasible. In this study, the TH-treated patients had greater 28-day ventilator-free days
(VFDs), ICU-free days (ICU-FDs) and hospital survival (75% vs. 25%; p = 0.027) than
historical controls. Within the limits of historical comparisons, these results support
further study of TH in ARDS.

Focus of Study: The focus of the Cooling to Help Injured Lungs (CHILL) program is to test the
central hypothesis that TH reduces mortality and morbidity in patients with ARDS in a Phase
III randomized control trial (RCT). CHILL-RCT-pilot, a single-site Phase IIb RCT of TH vs
usual temperature management in NMB-treated ARDS patients is the next step toward achieving
this objective. CHILL-RCT-pilot has been started as a self-funded pilot with plans to
transition to an NHLBI R33/61-funded phase contingent on grant funding. The data from the
single-center study will provide additional data to support and plan a larger, more
definitive multicenter Phase IIb or III trial.

Primary and secondary objectives: The primary objective is to assess in an RCT whether mild
TH is beneficial in patients with ARDS. The single-center pilot will provide information for
planning a multicenter Phase IIb RCT TH vs. usual temperature management in patients with
moderate to severe ARDS (PaO2:FIO2 (P/F) ratio<150) who are receiving NMB as part of their
clinical management.

Study design: The CHILL trial is a single center RCT.

Intervention: The study intervention is TH to core temperature 34°-35°C for 48h using surface
cooling devices. As a prerequisite for randomization, all patients 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 arm: Once sedation and NMB are confirmed, TH to 34°-35°C will be initiated using either
cooling blankets or Arctic Sun Device based on availability. 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. Following ~54h treatment period,
patients will receive antipyretics and surface cooling or warming at the discretion of the
primary ICU team. Early stopping rules for TH include: persistent severe bradycardia,
uncontrolled bleeding, and intractable arrhythmias.

Usual temperature management arm: Patients will receive sedation and NMB as described for the
TH arm. During the 54h post-randomization/NMB 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. Patients in the usual temperature management arm with core temperature <36.5°C will
receive surface warming to restore core temperature to 37°C. Following the 54h treatment
period, patients will receive antipyretics and surface cooling or warming 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 VFDs. Decisions about transition to unassisted breathing 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 and the mean core temperature for each of the first four study days will be
calculated.

Secondary endpoints:

Clinical: (a) 28-day ICU-FDs: Decisions about transfer out of the ICU will be made based on
criteria in the CHILL protocol. The 28-day ICU-FDs will be calculated at day 28 and recorded
on the Day 28 case report form (CRF); (b) day 0, 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 day-7 driving pressure and change vs baseline; (b) day-3 and day-7
oxygen saturation index (OSI) and change vs. baseline OSI. These measurements will be
performed at the same time of day as the baseline values.

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 enrollment

2. Comprehensive metabolic panel (CMP): includes basic electrolytes, BUN, creatinine,
ALT, AST, alkaline phosphatase, bilirubin, calcium, magnesium, and phosphate

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: One purple top (EDTA; 7 ml blood) tube will be
collected for biomarker analysis at enrollment and on study days 1, 2, 3, 4, and 7
within 4h of randomization and 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 ARDS and P/F<200 for
<48h will be offered enrollment but will not be randomized until P/F ratio is <150 and
they begin NMB

1. Pregnancy testing in women of child-bearing years

2. Obtain informed consent from Legally Authorized Representative (LAR)

3. Complete Screening Worksheet and Screening and Enrollment CRFs

4. If patient meets randomization criteria, proceed to randomization, otherwise follow
until randomization criteria are met or patient exits the inclusion window (for
ARDS, mechanical ventilation, or NMB).

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

1. Randomize.

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

3. Confirm adequate NMB (Train of four ≤1 twitch).

4. If patient is randomized to the TH arm, initiate TH protocol.

5. Obtain baseline plasma for research testing. If >8h since last CBC and CMP, send.

h. Complete Randomization Worksheet and Randomization and Baseline Data CRFs i. Note time
cooling initiated and time patient first reached target temperature on Baseline Data CRF

4.Day 1-4:

1. Fill out Daily Data CRFs

2. Collect plasma for research testing (aliquot and store at -80°C).

3. Measure Driving Pressure and OSI

4. Make sure CBC and CMP sent every 12h

5. Rewarming starts after 48h cooling on day 3

6. Complete Unassisted Breathing Checklist form if applicable

5. Days 5-6:

a. Follow for ventilator status, ICU status, survival, SAEs b. Complete Unassisted Breathing
Checklist form if applicable

6. Day 7:

a. Fill out Daily Data - Day 7 CRF b. Collect plasma for research testing. c. Measure Driving
Pressure and OSI d. Make sure CBC and CMP sent e. Complete Unassisted Breathing Checklist
form if applicable

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 (make
sure to obtain contact information for follow up)

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
<48h in duration and who are receiving NMB for ≤12h at time of randomization.

Data Analysis: The group difference on the primary outcome variable, 28-day, will be
tested with a permutation test for the difference in group means with alpha = 0.05
(two-tailed). For secondary clinical outcomes, t-tests, Wilcoxon, or chi-square tests
for the comparison of two proportions will be used as appropriate. Mean differences will
be estimated using 95% confidence intervals for all outcomes to further inform the
decision whether to recommend proceeding to as well as to plan for a multicenter Phase
IIb or Phase III trial.

Data Management: Data for this pilot RCT will be recorded on paper CRFs by Drs. Hasday,
Shanholtz, or their designees. Completion of all fields will be checked in real-time by
Drs. Hasday and Shanholtz. The forms have been designed to allow smooth transition to
electronic data management to be provided by Axio Research, LLC once funding is
approved.

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 vs. usual temperature
management, is 48h, followed by rewarming for 3-6h in the TH group. NMB can be stopped
52h after enrollment in the usual temperature management control group and when subjects
are rewarmed to core temperature ≥35.5°C in the TH group. 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 2 years.

Inclusion Criteria for Enrollment

1. Men and women

2. Any race and ethnicity

3. 18-80 years old

4. Endotracheally intubated or have a tracheostomy in place, and mechanically ventilated

5. Admitted to a participating ICU

6. have a P/F ratio <200 with PEEP ≥5 cm H2O

7. have radiologic evidence of bilateral pulmonary infiltrates

8. Respiratory process has occurred within one week of a condition known to be associated
with ARDS

9. Respiratory process cannot be fully explained by hydrostatic pulmonary edema.

10. ARDS criteria must have been initially met within 48h of enrollment

11. have a Legally authorized representative (LAR) to provide consent

Additional inclusion criteria required for randomization:

1. receiving deep sedation and NMB for ≤12h by time of randomization and who will remain
on NMB for an additional ≥48h

2. have a P/F ratio <200 with PEEP ≥5 cm H2O

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 a
minimum of 6 h)

5. Core temperature <35.5°C while not receiving CRRT

6. No Legally authorized representative

7. Significant, active bleeding (>3u blood products and/or surgical or IR intervention)

8. Platelets <10K (uncorrected)

9. Active hematologic malignancy

10. Skin process 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 unwilling to participate

16. Severe underlying lung disease

1. On home O2

2. On BIPAP (except for OSA)

3. prior lung transplantation

17. BMI >45

18. Known NYHA class IV heart disease

19. Acute Coronary Syndrome (MI, unstable angina)

20. Cardiac arrest within 30 days of enrollment 21 Previously randomized in CHILL study