Reevaluation Of Systemic Early Neuromuscular Blockade (ROSE)

This study evaluates whether giving a neuromuscular blocker (skeletal muscle relaxant) to a patient with acute respiratory distress syndrome will improve survival. Half of the patients will receive a neuromuscular blocker for two days and in the other half the use of neuromuscular blockers will be discouraged.

Study Overview

• Status: Completed
• Conditions: Acute Respiratory Distress Syndrome
• Intervention / Treatment: Drug: Cisatracurium Besylate

Detailed Description

PRIMARY OBJECTIVE:

To assess the efficacy and safety of early neuromuscular blockade in reducing mortality and morbidity in patients with moderate-severe ARDS, in comparison to a control group with no routine early neuromuscular blockade (NMB).

PRIMARY HYPOTHESIS:

Early neuromuscular blockade will improve mortality prior to discharge home before day 90, in patients with moderate-severe ARDS.

The trial will accrue a maximum of 1408 patients. Patients will be recruited from the emergency departments, intensive care units and other acute care areas of the PETAL Network Clinical Centers and randomized to the active (NMB) or control. The overall strategy is to screen, consent, and enroll early, every newly intubated, acutely ill or post-operative, eligible patient at each site, using clinically obtained pulse oximetry and blood gases.

By preventing active expiration, and/or patient ventilator dyssynchrony, neuromuscular blockade may create a more homogenous distribution of airway pressures and tidal volumes, preventing barotrauma/volutrauma and "atelectrauma" resulting in less ventilator-induced lung injury.

• Study Type: Interventional
• Enrollment (Actual): 1008
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Fresno, California, United States, 93701
      • UCSF Fresno
    • Los Angeles, California, United States, 90095
      • Ronald Reagan UCLA Medical Center
    • Sacramento, California, United States, 95817
      • UC Davis Medical Center
    • San Francisco, California, United States, 94143
      • UCSF Medical Center
    • Stanford, California, United States, 94305
      • Stanford University Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital
    • Aurora, Colorado, United States, 80045
      • Medical Center of Aurora
    • Denver, Colorado, United States, 80204
      • Denver Health Medical Center
    • Englewood, Colorado, United States, 80113
      • Swedish Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46220
      • Indiana University Methodist Hospital
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • University Medical Center
  • Maine
    • Portland, Maine, United States, 04102
      • Maine Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Springfield, Massachusetts, United States, 01199
      • Baystate Medical Center
    • Worcester, Massachusetts, United States, 01608
      • St. Vincent's Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
    • Detroit, Michigan, United States, 48025
      • Henry Ford Medical Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • New York, New York, United States, 10029
      • Mt. Sinai Hospital
  • North Carolina
    • Greensboro, North Carolina, United States, 27403
      • Wesley Long Hospital
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Medical Center
  • Ohio
    • Akron, Ohio, United States, 44304
      • Summa Akron City Hospital
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43210
      • Ohio State University Wexner Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
    • Pittsburgh, Pennsylvania, United States, 15261
      • UPMC Presbyterian/Mercy/Shadyside
  • Tennessee
    • Nashville, Tennessee, United States, 37221
      • Vanderbilt University Medical Center
  • Utah
    • Murray, Utah, United States, 84107
      • Intermountain Medical Center
    • Ogden, Utah, United States, 84403
      • McKay-Dee Hospital
    • Provo, Utah, United States, 84604
      • Utah Valley Regional Medical Center
    • Salt Lake City, Utah, United States, 84143
      • LDS Hospital
    • Salt Lake City, Utah, United States, 84132
      • University Hospital
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University or Virginia Health System
    • Richmond, Virginia, United States, 23298
      • VCU Medical Center
  • Washington
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center
    • Seattle, Washington, United States, 98122
      • Swedish Hospital First Hill
    • Seattle, Washington, United States, 98104
      • University of Washington Medical Center
    • Seattle, Washington, United States, 98122
      • Swedish Hospital Cherry Hill

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

1. Age > 18 years

2. Presence of all of the following conditions for < 48 hours:

   i. PaO2/FiO2 < 150 with PEEP >/= 8 cm H2O OR, if ABG not available, SaO2/FiO2 ratio that is equivalent to a PaO2/FiO2 < 150 with PEEP >/= 8 cm H2O , and a confirmatory SaO2/FiO2 ratio that is again equivalent 1-6 hours later

ii. Bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules.

iii. Respiratory failure not fully explained by cardiac failure or fluid overload; need objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor present.

Patients must be enrolled within 48 hours of meeting inclusion criteria.

Exclusion Criteria:

1. Lack of informed consent
2. Continuous neuromuscular blockade at enrollment
3. Known pregnancy
4. Currently receiving ECMO therapy
5. Chronic respiratory failure defined as PaCO2 > 60 mm Hg in the outpatient setting
6. Home mechanical ventilation (non-invasive ventilation or via tracheotomy) except for CPAP/BIPAP used solely for sleep-disordered breathing
7. Actual body weight exceeding 1 kg per centimeter of height
8. Severe chronic liver disease defined as a Child-Pugh score of 12-15 (Appendix A2)
9. Bone marrow transplantation within the last 1 year
10. Expected duration of mechanical ventilation of < 48 hours
11. Decision to withhold life-sustaining treatment; except in those patients committed to full support except cardiopulmonary resuscitation if an actual cardiac arrest occurs
12. Moribund patient not expected to survive 24 hours; if CPR provided, assess for moribund status greater than 6 from CPR conclusion
13. Diffuse alveolar hemorrhage from vasculitis
14. Burns > 70% total body surface
15. Unwillingness to utilize the ARDS Network 6 ml/kg IBW ventilation protocol
16. Previous hypersensitivity or anaphylactic reaction to cisatracurium
17. Neuromuscular conditions that may potentiate neuromuscular blockade and/or impair spontaneous ventilation (Appendix A2)
18. Neurologic conditions undergoing treatment for intracranial hypertension
19. Enrollment in an interventional ARDS trial with direct impact on neuromuscular blockade and PEEP
20. >120 hours of mechanical ventilation
21. P/F < 200 mmHg at the time of randomization (if available)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Early Neuromuscular Blockade (NMB); Patients will receive cisatracurium besylate for the first 48 hours of the trial.	Drug: Cisatracurium Besylate; Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.; Other Names: Nimbex
No Intervention: Control: No Routine Early NMB; Use of non-study NMB will be discouraged.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital Mortality to Day 90	The percentage of subjects alive at study day 90. Those subjects discharged home prior to day 90 were counted as alive at day 90.	90 days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Ventilator Free Days to Day 28	Ventilator-free days is defined to be 28 days minus the duration of mechanical ventilation through day 28. Participants who do not survive to day 28 are assigned zero ventilator-free days.	28 days after randomization
Mean Organ Failure Free Days to Day 28	SOFA (Sepsis-related Organ Failure Assessment) was used to determine criteria for an organ failure free day. Scores were based on four of the six SOFA organ categories: Coagulation, Liver, Cardiovascular, and Renal. Each category was scored 0-4; 0 being normal functioning and 4 being the most abnormal. A patient was considered failure free on each day alive with SOFA scores below 2 for all four organ systems. Ref: Vincent, J.L., et al., The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med, 1996. 22(7): p. 707-10.	28 days after randomization
ICU Free Days to Day 28	ICU free days is defined as the number of days between randomization and day 28 in which the patient is in the ICU (for any part of a day).	28 days after randomization
Mean Hospital Free Days to Days 28	Hospital free days are days alive post hospital discharge through day 28. Patients who die on or prior to day 28 are assigned zero hospital free days.	28 days after randomization
Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL)	Assesses whether individual can living independently and assess a range of common functional activities, from walking and toileting to managing money and cooking meals. Data is a pooled estimates from patient survey and proxy survey. The total score is rated from 0 to 10 (MCID=1; 1 point=1 ADL); a higher score indicates having more difficulties in daily activities.	3 months after randomization
EuroQol (EQ-5D-5L): Health Related Quality of Life	Using a standardized scale, do health reasons limit the person's ability to enjoy their life? Pooled estimates from patient survey and proxy survey were used. Utility index was computed from a lookup table according to EQ-5D-5L response profiles; utility index ranges from -0.11 to 1.00 (higher scores are better; 1.00 is perfect health), minimal clinically important difference (MCID) is 0.07	3 months after randomization
PTSS-14: Post-traumatic Stress-like Symptoms Scores >/= 45	Does the patient have symptoms of anxiety and stress from their ICU stay? PTSS-14 is only asked at month 6 and month 12 in patient survey; total score is rated from 14 to 98 and a higher score indicates having more post-traumatic stress syndrome related symptoms. Participants with scores greater than or equal to 45 were reported.	6 months after randomization
MoCA-Blind: Montreal Cognitive Assessment	How clearly can patient think and recall things? MoCA-Blind is only asked in patient survey; total score is rated from 0 to 30 and a higher score indicates better cognitive performance. Normal range: 26 or greater.	3 months after randomization
Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL)	Assesses whether individual can living independently and assess a range of common functional activities, from walking and toileting to managing money and cooking meals. Data is a pooled estimates from patient survey and proxy survey. The total score is rated from 0 to 10 (MCID=1; 1 point=1 ADL); a higher score indicates having more difficulties in daily activities.	6 months after randomization
Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL)	Assesses whether individual can living independently and assess a range of common functional activities, from walking and toileting to managing money and cooking meals. Data is a pooled estimates from patient survey and proxy survey. The total score is rated from 0 to 10 (MCID=1; 1 point=1 ADL); a higher score indicates having more difficulties in daily activities.	12 months after randomization
EuroQol (EQ-5D-5L): Health Related Quality of Life	Using a standardized scale, do health reasons limit the person's ability to enjoy their life? Pooled estimates from patient survey and proxy survey were used. Utility index was computed from a lookup table according to EQ-5D-5L response profiles; utility index ranges from -0.11 to 1.00 (higher scores are better; 1.00 is perfect health), minimal clinically important difference (MCID) is 0.07	6 months after randomization
EuroQol (EQ-5D-5L): Health Related Quality of Life	Using a standardized scale, do health reasons limit the person's ability to enjoy their life? Pooled estimates from patient survey and proxy survey were used. Utility index was computed from a lookup table according to EQ-5D-5L response profiles; utility index ranges from -0.11 to 1.00 (higher scores are better; 1.00 is perfect health), minimal clinically important difference (MCID) is 0.07	12 months after randomization
MoCA-Blind: Montreal Cognitive Assessment	How clearly can patient think and recall things? MoCA-Blind is only asked in patient survey; total score is rated from 0 to 30 and a higher score indicates better cognitive performance. Normal range: 26 or greater.	6 months after randomization
MoCA-Blind: Montreal Cognitive Assessment	How clearly can patient think and recall things? MoCA-Blind is only asked in patient survey; total score is rated from 0 to 30 and a higher score indicates better cognitive performance. Normal range: 26 or greater.	12 months after randomization
PTSS-14: Post-traumatic Stress-like Symptoms Scores >/= 45	Does the patient have symptoms of anxiety and stress from their ICU stay? PTSS-14 is only asked at month 6 and month 12 in patient survey; total score is rated from 14 to 98 and a higher score indicates having more post-traumatic stress syndrome related symptoms. Participants with scores greater than or equal to 45 were reported.	12 months after randomization

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: David A. Schoenfeld, PhD, Massachusetts General Hospital

Publications and helpful links

General Publications

• National Heart, Lung, and Blood Institute PETAL Clinical Trials Network; Moss M, Huang DT, Brower RG, Ferguson ND, Ginde AA, Gong MN, Grissom CK, Gundel S, Hayden D, Hite RD, Hou PC, Hough CL, Iwashyna TJ, Khan A, Liu KD, Talmor D, Thompson BT, Ulysse CA, Yealy DM, Angus DC. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019 May 23;380(21):1997-2008. doi: 10.1056/NEJMoa1901686. Epub 2019 May 19.
• Sjoding MW, Schoenfeld DA, Brown SM, Hough CL, Yealy DM, Moss M, Angus DC, Iwashyna TJ; NHLBI Prevention and Early Treatment of Acute Lung Injury (PETAL) Network. Power Calculations to Select Instruments for Clinical Trial Secondary Endpoints. A Case Study of Instrument Selection for Post-Traumatic Stress Symptoms in Subjects with Acute Respiratory Distress Syndrome. Ann Am Thorac Soc. 2017 Jan;14(1):110-117. doi: 10.1513/AnnalsATS.201608-585OC.
• Huang DT, Angus DC, Moss M, Thompson BT, Ferguson ND, Ginde A, Gong MN, Gundel S, Hayden DL, Hite RD, Hou PC, Hough CL, Iwashyna TJ, Liu KD, Talmor DS, Yealy DM; Reevaluation of Systemic Early Neuromuscular Blockade Protocol Committee and the National Institutes of Health National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Network Investigators. Design and Rationale of the Reevaluation of Systemic Early Neuromuscular Blockade Trial for Acute Respiratory Distress Syndrome. Ann Am Thorac Soc. 2017 Jan;14(1):124-133. doi: 10.1513/AnnalsATS.201608-629OT.

Helpful Links

• Website for the PETAL Network

Study record dates

Study Major Dates

• Study Start (Actual): January 4, 2016
• Primary Completion (Actual): July 3, 2018
• Study Completion (Actual): April 4, 2019

Study Registration Dates

• First Submitted: July 24, 2015
• First Submitted That Met QC Criteria: July 24, 2015
• First Posted (Estimate): July 27, 2015

Study Record Updates

• Last Update Posted (Actual): August 13, 2019
• Last Update Submitted That Met QC Criteria: July 23, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: ARDS; cisatracurium; neuromuscular blocker
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Physiological Effects of Drugs; Peripheral Nervous System Agents; Neuromuscular Agents; Neuromuscular Blocking Agents; Cisatracurium
• Other Study ID Numbers: PETAL01ROSE; 1U01HL123009-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be collected electronically and stored at the Clinical Coordinating Center at MGH. A de-identified database of all data will be available for use 3 years after the primary publication. Data can be accessed at that point via the NHLBI BioLINCC data repository.