An interventional study of Prone and Usual Care in COVID-19, sponsored by Vanderbilt University Medical Center. Completed at 2 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2021-12-27.
Sponsored by Vanderbilt University Medical Center · Not applicable, Interventional, and Supportive care
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.
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.
7,640 studies on the registry are indexed under COVID-19; 488 are open to participants now.
This study's enrollment of 501 is above the median of 100 across 4,099 interventional studies indexed under COVID-19.
Browse COVID-19 studies →Vanderbilt University Medical Center is the lead sponsor of 824 studies on the registry; 164 are open to participants now.
Of its 122 completed or terminated interventional studies of FDA-regulated products, 91 (75%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
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
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
Also known as: Proning
No provider-recommendation, patients will remain in their natural choice of position
Number of Participants Categorized on the Modified WHO Ordinal Scale by the Highest Level of Support on Day 5
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
FIO2
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
| Milestone | Usual Care | Prone |
|---|---|---|
| Started | 243 | 258 |
| Completed | 243 | 258 |
| Not completed | 0 | 0 |
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
| Participants | Usual Care | Prone |
|---|---|---|
| Discharged | 109 | 99 |
| Room Air | 15 | 15 |
| Standard Nasal Cannula | 57 | 65 |
| High Flow Nasal Cannula | 16 | 16 |
| Non-invasive Ventilation | 26 | 24 |
| Mechanical Ventilation | 10 | 19 |
| ECMO | 1 | 1 |
| Death | 9 | 19 |
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.
| percentage of inspired oxygen | Usual Care | Prone |
|---|---|---|
| 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 |
Collected over 28 days. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Usual Care | 48/243 (19.8%) | 0/243 (0%) | 0/243 (0%) |
| Prone | 63/258 (24.4%) | 0/258 (0%) | 0/258 (0%) |
| Age, Continuous(years) | Usual Care | Prone | Total |
|---|---|---|---|
| Mean | 60.3 ± 15.2 | 61.6 ± 15.4 | 61.0 ± 15.3 |
| Sex: Female, Male(Participants) | Usual Care | Prone | Total |
|---|---|---|---|
| Female | 105 | 112 | 217 |
| Male | 138 | 146 | 284 |
| Race/Ethnicity, Customized(Participants) | Usual Care | Prone | Total |
|---|---|---|---|
| Race — White | 162 | 154 | 316 |
| Race — Black or African American | 43 | 56 | 99 |
| Race — American Indian or Alaska Native | 0 | 1 | 1 |
| Race — Asian | 6 | 8 | 14 |
| Race — Other race | 26 | 30 | 56 |
| Race — Unknown race | 6 | 9 | 15 |
| Race/Ethnicity, Customized(Participants) | Usual Care | Prone | Total |
|---|---|---|---|
| Ethnicity — Non-Hispanic/Latinx | 204 | 213 | 417 |
| Ethnicity — Hispanic/Latinx | 33 | 33 | 66 |
| Ethnicity — Unknown ethnicity | 6 | 12 | 18 |
| Region of Enrollment(participants) | Usual Care | Prone | Total |
|---|---|---|---|
| United States | 243 | 258 | 501 |
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — Individual participant data that underlie the results reported will be made available (including data dictionaries) after de-identification.
Supporting information: Study protocol, Sap, Analytic code
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