Rationale and Design of the Awake Prone Position for Early Hypoxemia in COVID-19 Study Protocol: A Clinical Trial

Abstract

The unprecedented public health burdens of coronavirus disease (COVID-19) have intensified the urgency of identifying effective, low-cost treatments that limit the need for advanced life support measures and improve clinical outcomes. However, personal protective equipment and staffing shortages, disease virulence, and infectivity have created significant barriers to traditional clinical trial practices. We present the novel design of a pragmatic, adaptive, multicenter, international, prospective randomized controlled clinical trial evaluating the safety and effectiveness of awake prone positioning in spontaneously breathing patients with COVID-19 (APPEX-19 [Awake Prone Position for Early Hypoxemia in COVID-19]). Key innovations of this trial include 1 ) a novel smartphone-based communication process that facilitates rapid enrollment and intervention delivery while allowing social distancing and conservation of personal protective equipment, 2 ) Bayesian response-adaptive randomization to allow preferential assignment to the most effective intervention and expedite trial completion compared with frequentist designs, 3 ) remote electronic collection of patient-reported outcomes and electronic medical record data, and 4 ) pragmatic prospective use of patient-reported data and data collected as part of routine clinical care. Clinical trial registered with www.clinicaltrials.gov (NCT04344587).

Awake prone positioning for non-intubated patients with COVID-19-related acute hypoxaemic respiratory failure: a systematic review and meta-analysis

“…We excluded 112 full-text articles; therefore, 29 studies were included in the study ( figure 1 ). We included ten RCTs 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 (NCT04853979) that included a total of 1985 patients, and 19 observational studies that included a total of 2669 patients (the reference list for observational studies [non-RCTs] is available in the appendix pp 6–7 ).

Figure 1 Study flow diagram

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“…Among the 29 included studies, the awake prone positioning procedures were variable, and the targeted daily proning duration varied between 1 h and 16 h, or as long as the patients could tolerate. Different types of initial respiratory support were used in the ten RCTs, of which seven studies 12 , 13 , 15 , 16 , 17 , 18 , 19 included patients with a lower level of respiratory support (ie, conventional oxygen therapy), two studies 11 , 14 used advanced respiratory support (ie, high-flow nasal cannula or NIV), and one study ( NCT04853979 ) applied all the types of respiratory support. Patients were exclusively in an ICU setting in two RCTs, 16 , 17 exclusively in a general ward setting in six RCTs 12 , 13 , 15 , 18 , 19 ( NCT04853979 ), and in both settings in two RCTs.…”

“…The primary outcome was the cumulative intubation risk across RCTs; the measure of effect was risk ratio (RR; 95% CI). Secondary outcomes included the reported all-cause mortality; the need for escalating respiratory support, which was defined as progression to a higher level of oxygen or respiratory support (room air<conventional oxygen therapy<high-flow nasal cannula<non-invasive ventilation [NIV]<invasive ventilation) according to the included studies; 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 the duration of ICU and hospital stay; and safety outcomes, including cardiac arrest, vomiting, and central or arterial line dislodgement. We also performed a post-hoc analysis on ICU admission among patients who were not admitted to the ICU at enrolment and added it as a secondary outcome.…”

“…10 In August, 2021, an international randomised controlled meta-trial with more than 1100 patients found that awake prone positioning significantly reduced intubation need and treatment failure for patients with COVID-19-related acute hypoxaemic respiratory failure requiring support with high-flow nasal cannula. 11 However, before this publication, six randomised controlled trials (RCTs) with a smaller sample size than the meta-trial, 12 , 13 , 14 , 15 , 16 , 17 and two completed but unpublished multi-centre RCTs that enrolled 248 patients 18 and 293 patients, 19 respectively, did not find that awake prone positioning reduced the intubation need for patients with COVID-19; and, three RCTs 12 , 13 , 18 found that patients' adherence to awake prone positioning was low. In the two most recent meta-analyses that included RCTs, 20 , 21 Fazzini and colleagues included two RCTs 11 , 14 and 12 observational studies, and they reported uncertainty regarding the effects of awake prone positioning on intubation and survival, 20 whereas Beran and colleagues included five RCTs 11 , 12 , 13 , 14 , 16 and nine observational studies, and they reported that awake prone positioning has a benefit on mortality.…”

ERS clinical practice guidelines: high-flow nasal cannula in acute respiratory failure

“…(50)(51)(52)(53) The panel does not make a recommendation regarding the use of awake prone position in HFNC, recognizing there is little evidence and RCTs to address the question. (54)(55)(56)(57) PICO Question 2: Should HFNC or NIV be used in patients with acute hypoxemic respiratory failure? Recommendation 2: We suggest the use of HFNC over NIV in patients with acute hypoxemic respiratory failure (conditional recommendation, very low certainty of evidence).…”