COVID-19 Patient Positioning Pragmatic 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.