COVID-19 Patient Positioning Pragmatic Trial

Sponsor
Vanderbilt University Medical Center (Other)
Overall Status
Completed
CT.gov ID
NCT04359797
Collaborator
(none)
501
2
2
8.7
250.5
28.8

Study Details

Study Description

Brief Summary

This study aims to determine if provider-recommended guidance on supine (on back) vs. prone (on stomach) positioning of patients testing positive for COVID-19 requiring supplemental oxygen, but not yet mechanically ventilated, improves outcomes in the inpatient setting. This study will be performed as a pragmatic clinical trial.

Condition or Disease Intervention/Treatment Phase
  • Other: Prone
  • Other: Usual Care
N/A

Detailed Description

Disease Progression and Timing of Intervention The intervention described herein focuses on adjustment of patient positioning aimed at improving gas exchange and lung function in patients harboring COVID-19. This intervention will target the inpatient setting generally.

Scientific/Clinical Rationale for Approach Since emergence of the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) now designated coronavirus disease 2019 (COVID-19), one in six affected patients becomes seriously ill. The lung appears to be the most susceptible target organ, with a large swath of symptomatic patients struggling with mild upper respiratory tract illness and severe viral pneumonia resulting in respiratory failure. This respiratory failure is often fatal, with one study showing 28% non-survivors having experienced respiratory failure. Moreover, 81-97% of patients requiring mechanical ventilation do not survive.

Like its interaction with Severe Acute Respiratory Syndrome (SARS-CoV), angiotensin converting enzyme 2 (ACE2) is the functional receptor for COVID-19. Viral adherence to host-cell membrane associated ACE2 facilitates the proximity required for viral "spike" mediated genetic material injection. In COVID-19, this spike is 10-20 times more likely to bind ACE2 than SARS. ACE2 is expressed in 0.64% of all human lung cells, with 83% of those cells being alveolar epithelial type II. In addition, gene ontology enrichment analysis showed that the ACE2-expressing alveolar epithelial type II have high levels of multiple viral process-related genes, including regulatory genes for viral processes, viral life cycle, viral assembly, and viral genome replication, suggesting that the ACE2-expressing alveolar epithelial type II cells facilitate coronaviral replication in the lung. Thus, these cells likely serve as a ready reservoir for viral invasion. Perhaps more importantly, alveolar type II cells function to generate and recycle surfactant essential to respiratory activity. Surfactant defends against alveolar collapse at low lung volume and protects the lung from injuries/infections caused by inhaled particles and micro-organisms. In COVID-19, if these vital cells are being destroyed, alveolar failure may ensue with severe lung impairment. Thus, interventions that are aimed at improving pressure normalization and alveolar protection may be beneficial in these patients.

Prone positioning (PP) has long been used to combat hypoxemia in acute respiratory distress syndrome (ARDS). Improvements in gas exchange result from improved alveolar ventilation and blood flow redistribution with enhanced perfusion following. PP reduces lung over inflation and bolsters alveolar recruitment. PP also promotes uniformity of vertical pleural pressure gradients resulting in more uniform alveolar size. Considering these physiologic factors together, the investigators hypothesize PP serves to balance stress and strain within the lungs of non-critically ill patients with COVID-19 leading to improved outcomes compared to traditional supine positioning.

Prior Research Supporting the Positioning Model:

Multiple studies have been conducted that support the use of PP as a proactive treatment to combat hypoxemia in ARDS. Each year, approximately 170,000 people are diagnosed with ARDS, and those diagnosed face mortality rates between 25% and 40%. The use of PP stretches back to the 1970s, as providers began to search for ways to ameliorate ARDS symptomatology and reduce the then even higher levels of mortality associated with it. Following initial reports that PP significantly improved oxygenation in 70-80% of patients with ARDS, it was adopted as a standard treatment option. Initially, randomized clinical trials struggled to replicate these findings, citing multiple limitations to study enrollment and treatment standardization that made ascertaining conclusive results difficult. Only as RCT construction has been refined to accommodate for these limitations have the benefits of PP been more clearly demonstrated.

These beneficial effects have been recently upheld by the landmark PROSEVA study, a multicenter, prospective, randomized, controlled trial, that randomly assigned 466 patients with severe ARDS to undergo prone-positioning sessions of at least 16 hours or to be left in the supine position. Their results demonstrated a significant improvement in both 28- and 90-day mortality rates: "the 28-day mortality was 16.0% in the prone group and 32.8% in the supine group (P<0.001). The hazard ratio for death with prone positioning was 0.39 (95% confidence interval [CI], 0.25 to 0.63). Unadjusted 90-day mortality was 23.6% in the prone group versus 41.0% in the supine group (P<0.001), with a hazard ratio of 0.44 (95% CI, 0.29 to 0.67)".

Per these positive findings, PP has been consistently shown to be an effective mechanism to increase oxygenation in patients with ARDS when implemented under the following conditions: early enlisting of treatment and its consistent maintenance for at least 16 hours per day, and with concurrent use of lung-protective therapies. Translating these findings towards treatment of COVID-19 positive patients seems promising given the similarity of manifested symptoms and complications.

Study Design

Study Type:
Interventional
Actual Enrollment :
501 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
This study will be performed as a pragmatic controlled clinical trial with parallel group assignment.This study will be performed as a pragmatic controlled clinical trial with parallel group assignment.
Masking:
Single (Outcomes Assessor)
Masking Description:
Patients and providers will necessarily be unblinded, but outcomes will be analyzed by a blind assessor.
Primary Purpose:
Supportive Care
Official Title:
Pragmatic Trial Exploring Impact of Patient Positioning in the Management of Patients Infected With COVID-19: Supine vs. Prone
Actual Study Start Date :
Apr 27, 2020
Actual Primary Completion Date :
Dec 17, 2020
Actual Study Completion Date :
Jan 17, 2021

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Usual Care

Participants randomized to this arm will remain in their natural choice of position, which is anticipated to favor a supine, semi-recumbent position.

Other: Usual Care
No provider-recommendation, patients will remain in their natural choice of position

Active Comparator: Prone

Participants randomized to this arm will be encouraged to lay in a completely prone position for as much time as is tolerable during hospitalization.

Other: Prone
Provider-recommended guidance on prone positioning of patients
Other Names:
  • Proning
  • Outcome Measures

    Primary Outcome Measures

    1. Number of Participants Categorized on the Modified WHO Ordinal Scale by the Highest Level of Support on Day 5 [5 days post-randomization]

      The highest level of support on the 5th day after enrollment according to the following scale adjusted for patient status at enrollment according to the same scale and ranked by mean FIO2 within each category, as appropriate. Death ECMO Mechanical ventilation (ranked by mean FIO2) Non-invasive ventilation such as BiPAP (ranked by mean FIO2) High flow nasal cannula, e.g. Optiflow, Vapotherm or other similar device (titrated by FiO2%) (ranked by mean FIO2) Standard nasal cannula (titrated by L/min up to 15 L/min) or face mask (ranked by mean FIO2) Room air

    Secondary Outcome Measures

    1. FIO2 [First 5 days post-randomization]

      For each day, the investigators will record the most intensive oxygen delivery mode and then, for that highest level of oxygen support device, the max FiO2 while exposed to that device.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • This study will enroll all patients admitted to VUMC who test positive for COVID-19 and require supplemental oxygen, but are not yet mechanically ventilated.
    Exclusion Criteria:
    • Patients admitted on mechanical ventilation will be excluded from enrollment.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 NorthShore University HealthSystem Highland Park Illinois United States 60035
    2 Vanderbilt University Medical Center Nashville Tennessee United States 37232

    Sponsors and Collaborators

    • Vanderbilt University Medical Center

    Investigators

    • Principal Investigator: Todd W Rice, MD, MSc, Vanderbilt University Medical Center

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    Todd Rice, MD, MSc, Associate Professor, Department of Medicine, Vanderbilt University Medical Center
    ClinicalTrials.gov Identifier:
    NCT04359797
    Other Study ID Numbers:
    • 200727
    First Posted:
    Apr 24, 2020
    Last Update Posted:
    Dec 27, 2021
    Last Verified:
    Dec 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Usual Care Prone
    Arm/Group Description Participants randomized to this arm will remain in their natural choice of position, which is anticipated to favor a supine, semi-recumbent position. Usual Care: No provider-recommendation, patients will remain in their natural choice of position Participants randomized to this arm will be encouraged to lay in a completely prone position for as much time as is tolerable during hospitalization. Prone: Provider-recommended guidance on prone positioning of patients
    Period Title: Overall Study
    STARTED 243 258
    COMPLETED 243 258
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title Usual Care Prone Total
    Arm/Group Description Participants randomized to this arm will remain in their natural choice of position, which is anticipated to favor a supine, semi-recumbent position. Usual Care: No provider-recommendation, patients will remain in their natural choice of position Participants randomized to this arm will be encouraged to lay in a completely prone position for as much time as is tolerable during hospitalization. Prone: Provider-recommended guidance on prone positioning of patients Total of all reporting groups
    Overall Participants 243 258 501
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    60.3
    (15.2)
    61.6
    (15.4)
    61.0
    (15.3)
    Sex: Female, Male (Count of Participants)
    Female
    105
    43.2%
    112
    43.4%
    217
    43.3%
    Male
    138
    56.8%
    146
    56.6%
    284
    56.7%
    Race/Ethnicity, Customized (Count of Participants)
    White
    162
    66.7%
    154
    59.7%
    316
    63.1%
    Black or African American
    43
    17.7%
    56
    21.7%
    99
    19.8%
    American Indian or Alaska Native
    0
    0%
    1
    0.4%
    1
    0.2%
    Asian
    6
    2.5%
    8
    3.1%
    14
    2.8%
    Other race
    26
    10.7%
    30
    11.6%
    56
    11.2%
    Unknown race
    6
    2.5%
    9
    3.5%
    15
    3%
    Race/Ethnicity, Customized (Count of Participants)
    Non-Hispanic/Latinx
    204
    84%
    213
    82.6%
    417
    83.2%
    Hispanic/Latinx
    33
    13.6%
    33
    12.8%
    66
    13.2%
    Unknown ethnicity
    6
    2.5%
    12
    4.7%
    18
    3.6%
    Region of Enrollment (participants) [Number]
    United States
    243
    100%
    258
    100%
    501
    100%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants Categorized on the Modified WHO Ordinal Scale by the Highest Level of Support on Day 5
    Description The highest level of support on the 5th day after enrollment according to the following scale adjusted for patient status at enrollment according to the same scale and ranked by mean FIO2 within each category, as appropriate. Death ECMO Mechanical ventilation (ranked by mean FIO2) Non-invasive ventilation such as BiPAP (ranked by mean FIO2) High flow nasal cannula, e.g. Optiflow, Vapotherm or other similar device (titrated by FiO2%) (ranked by mean FIO2) Standard nasal cannula (titrated by L/min up to 15 L/min) or face mask (ranked by mean FIO2) Room air
    Time Frame 5 days post-randomization

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Usual Care Prone
    Arm/Group Description Participants randomized to this arm will remain in their natural choice of position, which is anticipated to favor a supine, semi-recumbent position. Usual Care: No provider-recommendation, patients will remain in their natural choice of position Participants randomized to this arm will be encouraged to lay in a completely prone position for as much time as is tolerable during hospitalization. Prone: Provider-recommended guidance on prone positioning of patients
    Measure Participants 243 258
    Discharged
    109
    44.9%
    99
    38.4%
    Room Air
    15
    6.2%
    15
    5.8%
    Standard Nasal Cannula
    57
    23.5%
    65
    25.2%
    High Flow Nasal Cannula
    16
    6.6%
    16
    6.2%
    Non-invasive Ventilation
    26
    10.7%
    24
    9.3%
    Mechanical Ventilation
    10
    4.1%
    19
    7.4%
    ECMO
    1
    0.4%
    1
    0.4%
    Death
    9
    3.7%
    19
    7.4%
    2. Secondary Outcome
    Title FIO2
    Description For each day, the investigators will record the most intensive oxygen delivery mode and then, for that highest level of oxygen support device, the max FiO2 while exposed to that device.
    Time Frame First 5 days post-randomization

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Usual Care Prone
    Arm/Group Description Participants randomized to this arm will remain in their natural choice of position, which is anticipated to favor a supine, semi-recumbent position. Usual Care: No provider-recommendation, patients will remain in their natural choice of position Participants randomized to this arm will be encouraged to lay in a completely prone position for as much time as is tolerable during hospitalization. Prone: Provider-recommended guidance on prone positioning of patients
    Measure Participants 243 258
    Day 1
    40.4
    (27.1)
    45.3
    (29.1)
    Day 2
    40.3
    (28.2)
    44.0
    (30.9)
    Day 3
    39.3
    (29.8)
    43.6
    (32.1)
    Day 4
    37.8
    (30.2)
    42.7
    (32.5)
    Day 5
    37.1
    (31.0)
    40.6
    (32.0)

    Adverse Events

    Time Frame 28 days
    Adverse Event Reporting Description Adverse event information was collected for any untoward or unfavorable medical occurrence in a participant, including any abnormal sign, symptom, or disease, temporally associated with the participant's participation in the research, whether or not considered related to the participant's participation in the research.
    Arm/Group Title Usual Care Prone
    Arm/Group Description Participants randomized to this arm will remain in their natural choice of position, which is anticipated to favor a supine, semi-recumbent position. Usual Care: No provider-recommendation, patients will remain in their natural choice of position Participants randomized to this arm will be encouraged to lay in a completely prone position for as much time as is tolerable during hospitalization. Prone: Provider-recommended guidance on prone positioning of patients
    All Cause Mortality
    Usual Care Prone
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 48/243 (19.8%) 63/258 (24.4%)
    Serious Adverse Events
    Usual Care Prone
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/243 (0%) 0/258 (0%)
    Other (Not Including Serious) Adverse Events
    Usual Care Prone
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/243 (0%) 0/258 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Edward T. Qian
    Organization Vanderbilt University Medical Center
    Phone 615-322-2386
    Email edward.t.qian@vumc.org
    Responsible Party:
    Todd Rice, MD, MSc, Associate Professor, Department of Medicine, Vanderbilt University Medical Center
    ClinicalTrials.gov Identifier:
    NCT04359797
    Other Study ID Numbers:
    • 200727
    First Posted:
    Apr 24, 2020
    Last Update Posted:
    Dec 27, 2021
    Last Verified:
    Dec 1, 2021