Reevaluation Of Systemic Early Neuromuscular Blockade (ROSE)

Study Description

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Brief Summary:

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 .

Condition or disease	Intervention/treatment	Phase
Acute Respiratory Distress Syndrome	Drug: cisastracurium besylate	Phase 3

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	1006 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Reevaluation Of Systemic Early Neuromuscular Blockade
Actual Study Start Date :	January 4, 2016
Estimated Primary Completion Date :	May 4, 2018
Estimated Study Completion Date :	April 4, 2019

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Early Neuromuscular Blockade (NMB); Patients will receive cisastracurium besylate for the first 48 hours of the trial.	Drug: cisastracurium besylate; Patients randomized to the early neuromuscular blockade arm will receive a cisastracurium 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 Name: Nimbex
No Intervention: Control: No Routine Early NMB; Use of non-study NMB will be discouraged.

Outcome Measures

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Primary Outcome Measures :

1. Hospital Mortality to day 90 [ Time Frame: 90 days after randomization ]
   The percentage of subjects alive at study day 90. Those subjects discharged home prior to day 90 were counted as alive at day 90.

Secondary Outcome Measures :

1. Mean Ventilator Free Days to day 28 [ Time Frame: 28 days after randomization ]
   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.
2. Mean Organ Failure Free days to day 28 [ Time Frame: 28 days after randomization ]
   A patient will be considered failure free on each day alive with SOFA scores for all organ systems below 2.
3. ICU Free Days to day 28 [ Time Frame: 28 days after randomization ]
   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).
4. Mean Hospital Free Days to days 28 [ Time Frame: 28 days after randomization ]
   Hospital free days are days alive post hospital discharge through day 28. Patients who die on or prior to day 28 are assigned zero hopsital free days.
5. Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL) [ Time Frame: 12 months after randomization ]
   Assesses whether individual can living independantly
6. EuroQol (EQ-5D-5L): Health Related Quality of Life [ Time Frame: 12 months after randomization ]
   Using a standardized scale, do health reasons limit the person's ability to enjoy their life?
7. PTSS-14: Post-traumatic Stress-like Symptoms [ Time Frame: 12 months after randomization ]
   Does the patient have symptoms of anxiety and stress from their ICU stay?
8. MoCA-Blind: Montreal Cognitive Assessment [ Time Frame: 12 months after randomization ]
   How clearly can patient think and recall things?

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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)

Contacts and Locations

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Sponsors and Collaborators

Massachusetts General Hospital

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

Principal Investigator:	David A. Schoenfeld, PhD	Massachusetts General Hospital

More Information

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Additional Information:

Website for the PETAL Network 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Responsible Party:	David Alan Schoenfeld, Prinicipal Investigator PETAL CCC, Massachusetts General Hospital
ClinicalTrials.gov Identifier:	NCT02509078 History of Changes
Other Study ID Numbers:	PETAL01ROSE; 1U01HL123009-01 ( U.S. NIH Grant/Contract )
First Posted:	July 27, 2015
Last Update Posted:	April 18, 2018
Last Verified:	April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
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.

Keywords provided by David Alan Schoenfeld, Massachusetts General Hospital:

ARDS; neuromuscular blocker; cisatracurium

Additional relevant MeSH terms:

Respiratory Distress Syndrome, Newborn; Respiratory Distress Syndrome, Adult; Acute Lung Injury; Lung Diseases; Respiratory Tract Diseases	Respiration Disorders; Infant, Premature, Diseases; Infant, Newborn, Diseases; Lung Injury