Pilot RCT of Therapeutic Hypothermia Plus Neuromuscular Blockade in COVID-19 Patients With ARDS

NCT03376854 | Withdrawn Phase 2 DMC FDA Drug FDA Device

• 1 other identifier: HP-00078506
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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.

Conditions

Respiratory Distress Syndrome, Adult; Sars-CoV2

Keywords

COVID-19, ARDS, targeted temperature management

Outcome Measures

Primary Outcomes (1)

• Targeted temperature compliance

  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.

  Randomization through day 3

Secondary Outcomes (17)

• Adverse event

  Randomization through study day 3

• 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 4 hours on enrollment day, then once on day 2, 3, 4, 7 and 28

Study Arms (2)

Hypothermia + Neuromuscular blockade

EXPERIMENTAL

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; Drug: Neuromuscular Blocking Agents

Standard of care

ACTIVE COMPARATOR

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

Interventions

Hypothermia DEVICE

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

Also known as: Targeted temperature Management

Hypothermia + Neuromuscular blockade

Neuromuscular Blocking Agents DRUG

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.

Also known as: Paralytics

Hypothermia + Neuromuscular blockade

Standard of Care DEVICE

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.

Also known as: Usual temperature management

Standard of care

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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).
• Missed ARDS window (\>48hrs)
• Missed mechanical ventilation window (\>7 days)
• Refractory hypotension (\> 0.2 mcg/kg/min of norepinephrine or equivalent dose for minimum of 6 h)
• Core temperature \<35.5°C while not receiving CRRT
• Patient is unable to give consent and no legally authorized representative is available;
• Significant, active bleeding (\>3u blood products and/or surgical/IR intervention)
• Platelets \<10K/mm3 (uncorrected)
• Active hematologic malignancy
• Skin process precludes cooling device
• Moribund, not likely to survive 72h
• Pre-morbid condition makes it unlikely that patient will survive 28 days
• Do Not Resuscitate status
• Not likely to remain intubated for ≥48h
• Physician unwilling to participate

Sponsors & Collaborators

• University of Maryland, Baltimore: lead

Study Sites (1)

University of Maryland Medical Center

Baltimore, Maryland, 21201, United States

Location

Related Publications (39)

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MeSH Terms

Conditions

Respiratory Distress Syndrome; COVID-19

Interventions

Hypothermia, Induced; Neuromuscular Blocking Agents

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections

Intervention Hierarchy (Ancestors)

Cryotherapy; Therapeutics; Neuromuscular Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• Jeffrey D Hasday, MD

  University of Maryland, Baltimore

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Model Details: Randomized (1:1) control (non-blinded) trial

Study Record Dates

• First Submitted: December 7, 2017
• First Posted: December 19, 2017
• Study Start: May 1, 2018
• Primary Completion: April 27, 2021
• Study Completion: April 27, 2021
• Last Updated: April 30, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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.

Locations

US (1)