Effect of Awake Prone Positioning on Endotracheal Intubation in Patients With COVID-19 and Acute Respiratory Failure: A Randomized Clinical Trial

Key Points

Question  Does prone positioning reduce endotracheal intubation in adults who were awake and not intubated and who had hypoxemic respiratory failure from COVID-19?

Findings  In this randomized clinical trial that included 400 adults with acute hypoxemic respiratory failure from COVID-19, awake prone positioning compared with usual care resulted in endotracheal intubation at 30 days in 34.1% vs 40.5% of participants, respectively. Although the hazard ratio was 0.81, the result was not statistically significant.

Meaning  Although the findings do not support prone positioning in this setting, the effect size for the primary study outcome was imprecise and does not exclude a clinically important benefit.

Importance  The efficacy and safety of prone positioning is unclear in nonintubated patients with acute hypoxemia and COVID-19.

Objective  To evaluate the efficacy and adverse events of prone positioning in nonintubated adult patients with acute hypoxemia and COVID-19.

Design, Setting, and Participants  Pragmatic, unblinded randomized clinical trial conducted at 21 hospitals in Canada, Kuwait, Saudi Arabia, and the US. Eligible adult patients with COVID-19 were not intubated and required oxygen (≥40%) or noninvasive ventilation. A total of 400 patients were enrolled between May 19, 2020, and May 18, 2021, and final follow-up was completed in July 2021.

Intervention  Patients were randomized to awake prone positioning (n = 205) or usual care without prone positioning (control; n = 195).

Main Outcomes and Measures  The primary outcome was endotracheal intubation within 30 days of randomization. The secondary outcomes included mortality at 60 days, days free from invasive mechanical ventilation or noninvasive ventilation at 30 days, days free from the intensive care unit or hospital at 60 days, adverse events, and serious adverse events.

Results  Among the 400 patients who were randomized (mean age, 57.6 years [SD, 12.83 years]; 117 [29.3%] were women), all (100%) completed the trial. In the first 4 days after randomization, the median duration of prone positioning was 4.8 h/d (IQR, 1.8 to 8.0 h/d) in the awake prone positioning group vs 0 h/d (IQR, 0 to 0 h/d) in the control group. By day 30, 70 of 205 patients (34.1%) in the prone positioning group were intubated vs 79 of 195 patients (40.5%) in the control group (hazard ratio, 0.81 [95% CI, 0.59 to 1.12], P = .20; absolute difference, −6.37% [95% CI, −15.83% to 3.10%]). Prone positioning did not significantly reduce mortality at 60 days (hazard ratio, 0.93 [95% CI, 0.62 to 1.40], P = .54; absolute difference, −1.15% [95% CI, −9.40% to 7.10%]) and had no significant effect on days free from invasive mechanical ventilation or noninvasive ventilation at 30 days or on days free from the intensive care unit or hospital at 60 days. There were no serious adverse events in either group. In the awake prone positioning group, 21 patients (10%) experienced adverse events and the most frequently reported were musculoskeletal pain or discomfort from prone positioning (13 of 205 patients [6.34%]) and desaturation (2 of 205 patients [0.98%]). There were no reported adverse events in the control group.

Conclusions and Relevance  In patients with acute hypoxemic respiratory failure from COVID-19, prone positioning, compared with usual care without prone positioning, did not significantly reduce endotracheal intubation at 30 days. However, the effect size for the primary study outcome was imprecise and does not exclude a clinically important benefit.

Trial Registration  ClinicalTrials.gov Identifier: NCT04350723

Hospitalizations due to COVID-19 strained critical care resources internationally.^1-3 Surges limited the availability of resources for critically ill patients, emphasizing a need for practical, widely available, and affordable interventions. Awake prone positioning arose as a potentially useful intervention to investigate during the pandemic.

Prone positioning has been used since the 1970s in patients undergoing invasive mechanical ventilation for acute respiratory distress syndrome.⁴ Observational studies showed that prone positioning may result in increased lung volume,⁵ homogenized pleural pressure,⁶ and reduced shunting.⁷ Furthermore, randomized clinical trials found prone positioning to be associated with a lower risk of death in patients undergoing invasive mechanical ventilation for moderate to severe acute respiratory distress syndrome (relative risk, 0.74 [95% CI, 0.56-0.99]).^8,9

Awake prone positioning has been used widely for patients with COVID-19. Prior to the pandemic, there were no randomized clinical trials examining the effects of prone positioning in patients who were awake and not intubated and who had hypoxemic respiratory failure.¹⁰ A meta-analysis of 2 randomized clinical trials and 12 observational studies found no association of awake prone positioning with the risk of endotracheal intubation in patients with COVID-19.¹¹ In contrast, a meta-trial of 6 randomized clinical trials enrolling patients with COVID-19 found awake prone positioning to be safe and associated with a reduction in a composite outcome of endotracheal intubation or death within 28 days of enrollment.¹² However, the most current practice guideline concluded that there is insufficient evidence to issue a clinical recommendation on this strategy.¹³

The COVI-PRONE (Awake Prone Position in Hypoxemic Patients with Coronavirus Disease 19) trial aimed to assess the efficacy and adverse events of awake prone positioning in patients who were not intubated and who had COVID-19 with hypoxemic respiratory failure.

We conducted a pragmatic, unblinded randomized clinical trial at 21 hospitals in Canada, Kuwait, Saudi Arabia, and the US. Investigators obtained approval from their local research ethics review boards. The trial protocol (Supplement 1) and statistical analysis plan (Supplement 2) were published prior to trial completion.¹⁴ An independent data and safety monitoring committee reviewed the interim analysis at 50% recruitment of the original sample size and provided recommendations to the trial steering committee. Study research coordinators obtained a priori or deferred consent for all enrolled patients. Screening and enrollment occurred between May 19, 2020, and May 18, 2021 (eTable 1 and eFigure 1 in Supplement 3).

The trial included patients aged 18 years or older who were not intubated, who had suspected or confirmed COVID-19, and who required at least 40% oxygen (via low- or high-flow oxygen devices) or noninvasive positive pressure ventilation and were being treated in an intensive care unit (ICU) or a monitored acute care unit. Patients were excluded from the trial if they (1) had received invasive mechanical ventilation, (2) had contraindications to prone positioning, (3) were at risk of complications from prone positioning, or (4) had been self-prone positioning prior to enrollment. Details of the eligibility criteria appear in the eMethods in Supplement 3. Racial and ethnic categorization was used to reflect international enrollment and provide a description of racial and ethnic diversity in this study. Research coordinators abstracted race and ethnicity using prespecified fixed categories from medical records when available.

Using a web-based randomization system with undisclosed variable block sizes of 2, 4, and 6, allocation was 1:1 and stratified by hospital and by ratio of oxygen saturation as measured by pulse oximetry (Spo₂) to fraction of inspired oxygen (Fio₂) of greater than 150 or of 150 or less. The nature of the intervention precluded blinding of participating patients, families, the health care team, or research staff.

Patients randomized to the intervention group underwent awake prone positioning. The target duration of prone positioning was 8 h/d to 10 h/d with 2 to 3 breaks (1-2 hours each), if needed (Figure 1). Daily prone positioning sessions were protocolized to continue until 1 of the following stopping criteria was met: a relative improvement in the Fio₂ requirement by 40% from the baseline value that was sustained for 24 hours; endotracheal intubation; or discharge from the ICU or acute care unit. The treating team supervised patients who could move themselves during the prone positioning process and assisted the patients with positioning as required.

Patients randomized to the control group, and their treating team, were informed of their group assignment. Nurses instructed patients not to position themselves in the prone position.

Patients in the intervention and control groups received usual care at the discretion of the treating team. Daily data collection on co-interventions continued until the intervention stopping criteria were met. In both groups, nurses used prone positioning logs to document the number of prone positioning hours every day. Daily documentation of prone positioning hours continued until the day of meeting stopping criteria.

The primary outcome was endotracheal intubation within 30 days of randomization. The secondary outcomes included mortality at 60 days, days free from invasive mechanical ventilation or noninvasive ventilation at 30 days, days free from the ICU or hospital at 60 days, and adverse events. In this study, adverse events included both adverse events and serious adverse events. Further details appear in eTable 2 in Supplement 3.

The original target sample size was 350 participants based on an assumption for an estimated absolute risk reduction of 15%, an endotracheal intubation rate of 60% in the control group, a power of 80%, and a 2-sided α level of 5% (α = .05). Due to lack of preexisting studies to inform the sample size calculation, these assumptions were based on discussion and consensus among steering committee members.

As the management of COVID-19 evolved, the threshold for endotracheal intubation of COVID-19 patients changed, and guidelines suggested a trial of other respiratory support modalities prior to endotracheal intubation.¹³ Therefore, the steering committee decided to increase the study sample size to 400 participants. This sample size increase allowed 80% power to detect an absolute reduction of 13.5% for endotracheal intubation, assuming an endotracheal intubation risk of 45% in the control group.

Due to the lack of evidence to inform the study sample size calculation, the decision to increase the sample size from 350 to 400 participants was based on discussion and consensus among the steering committee members; all members were blinded to the study outcomes and interim analysis results. In addition, this change was approved by the independent data and safety monitoring committee and by the local research ethics review boards.

Patient baseline characteristics are reported as percentages for categorical variables and as means (SDs) or medians (IQRs) for continuous variables as appropriate. The primary analyses were conducted with patients analyzed according to their randomization group; the full analysis set included all randomized patients. There were no missing outcome data. The main analysis for the primary outcome (ie, endotracheal intubation within 30 days of randomization), mortality at 60 days, and a post hoc composite outcome of endotracheal intubation or death at 30 days was an unadjusted Cox proportional hazards regression analysis with the results reported as hazard ratios (HRs) with 95% CIs. Graphical diagnostics based on the scaled Schoenfeld residuals showed that the proportionality assumption was met. In addition, we constructed Kaplan-Meier survival curves, including log-rank tests. To assess the effect of competing risk of death, we used the Fine and Gray subdistribution hazard model for the primary outcome.¹⁵

We conducted preplanned secondary analyses for binary outcomes (ie, endotracheal intubation at 30 days and mortality at 60 days) comparing the proportion of patients in the 2 groups using the χ² test or the Fisher exact test as appropriate and presented the results as relative risks and 95% CIs. We also conducted a preplanned secondary per-protocol analysis excluding patients with protocol deviations (ie, patients who did not participate in prone positioning in the intervention group and patients who participated in any prone positioning in the control group). To assess hospital site effect, we conducted a post hoc mixed-effects modeling analysis using hospital site as a random effect.

The primary analysis method for the continuous outcomes (ie, days free from invasive mechanical ventilation or noninvasive ventilation and days free from the ICU or hospital) was an unadjusted linear regression analysis in which the main independent variable was group allocation. In addition, for all study outcomes, we conducted secondary analyses adjusting for stratification variables (ie, recruiting hospital site and severity of hypoxemia). All primary and secondary analyses of the study outcomes used 2-sided testing and an α = .05.

We compared the primary outcome in prespecified subgroups with prespecified hypotheses and reported the corresponding P value for the interaction. In addition, we reported the false discovery rate to account for multiplicity by calculating the expected proportion of tests with false-positive results at a specified rank for a set of tests.¹⁶ Predefined subgroup analyses focused on the severity of hypoxemia (Spo₂:Fio₂ ≤ 150 vs Spo₂:Fio₂ > 150) and the threshold used was based on the median Spo₂:Fio₂ in a case series that was available during the trial design,¹⁷ the mode of respiratory support at baseline (low-flow oxygen [ie, oxygen delivery other than via high-flow nasal cannula or noninvasive ventilation regardless of the fraction of oxygen delivered to the patient], high-flow oxygen, or noninvasive positive pressure ventilation); age (<70 years vs ≥70 years); and sex (male or female). All analyses were conducted using SAS version 9.4 (SAS Institute Inc).

During the study period, a total of 4229 patients were screened and, of these, 595 met the eligibility criteria and 400 were randomized (205 to the awake prone positioning group and 195 to the control group; Figure 1). Final follow-up was completed in July 2021. Patient characteristics at randomization were similar between groups. The mean age was 56.8 years (SD, 12.5 years) in the prone positioning group and 58.3 years (SD, 13.2 years) in the control group and the mean body mass index (calculated as weight in kilograms divided by height in meters squared) was 29.7 (SD, 4.7) and 29.5 (SD, 4.9), respectively (Table 1 and eTable 3 in Supplement 3).

Most enrolled patients had confirmed COVID-19 at the time of randomization (97.0%). The median percentage of Fio₂ at randomization was 70% (IQR, 55%-90%) in the awake prone positioning group and 70% (IQR, 52%-90%) in the control group and the median Spo₂:Fio₂ was 132 (IQR, 103-174) and 136 (IQR, 110-181), respectively. Approximately 60% of enrolled patients had an Spo₂:Fio₂ of 150 or less. The most prevalent comorbidities at baseline were chronic hypertension (48%) and diabetes (40%). Most patients received corticosteroids (95%) and prophylactic-dose anticoagulants (78%) at the time of enrollment.

In the awake prone positioning group, the median duration of prone positioning was 5.0 hours (IQR, 2.0-8.0 hours) on day 1. In the first 4 days after randomization, the median duration of prone positioning was 4.8 h/d (IQR, 1.8-8.0 h/d) in the awake prone positioning group vs 0 h/d (IQR, 0-0 h/d) in the control group (Figure 2 and eTable 4 in Supplement 3) and the mean between-group difference was 4.48 h/d (95% CI, 3.90-5.06 h/d; P < .001).

In the awake prone positioning group, the median number of prone positioning days was 3 (IQR, 1-5 days). Of the 205 patients in the prone positioning group, 21 (10.2%) did not undergo any prone positioning after randomization, mostly due to patient preference. Additional details appear in eTable 5 in Supplement 3. In the control group, 38 patients (19.5%) underwent prone positioning after randomization, mainly at the request of the care treating team or patient preference (eTable 5 in Supplement 3). The median duration of prone positioning for the 38 patients who underwent prone positioning in the control group was 0.9 h/d (IQR, 0.3-3.5 h/d). The duration of daily prone positioning and patient adherence appear in eFigures 2-4 in Supplement 3.

During the study intervention period, the use of pharmacological agents such as corticosteroids, immunomodulators, anticoagulants, vasoactive agents, and antivirals was similar between groups (eTables 3-4 and eTable 6 in Supplement 3). After randomization, 143 patients (69.8%) in the prone positioning group and 122 patients (62.6%) in the control group received low-flow oxygen and 176 patients (85.5%) vs 165 patients (84.6%), respectively, received high-flow oxygen. In contrast, 53 patients (25.9%) in the prone positioning group and 60 patients (30.8%) in the control group received noninvasive positive pressure ventilation after randomization (eTable 4 in Supplement 3). Details on the duration of each oxygenation mode used per group appear in eTable 7 in Supplement 3. Awake prone positioning was associated with modest improvement in both Spo₂:Fio₂ and Fio₂ compared with the values collected prior to prone positioning (eFigure 5 in Supplement 3). Changes in oxygenation parameters appear in eFigures 6-7 in Supplement 3.

By day 30, 70 of 205 patients (34.1%) were intubated in the prone positioning group vs 79 of 195 patients (40.5%) in the control group (HR, 0.81 [95% CI, 0.59 to 1.12], P = .20; absolute difference, −6.37% [95% CI, −15.83% to 3.10%]; Table 2 and Figure 3A). The preplanned per-protocol analysis was consistent with the primary analysis in that 62 of 184 patients (33.7%) were intubated in the prone positioning group vs 57 of 157 patients (36.3%) in the control group (HR, 0.89 [95% CI, 0.62 to 1.28], P = .54; Table 2). A competing risk analysis yielded an HR of 0.81 (95% CI, 0.59 to 1.10; P = .19).

At 60 days, 46 of 205 patients (22.4%) died in the prone positioning group and 46 of 195 patients (23.6%) died in the control group (HR, 0.93 [95% CI, 0.62 to 1.40], P = .72; absolute difference, −1.15% [95% CI, −9.40% to 7.10%]; Figure 3B). At 30 days, patients in the prone positioning group had a mean of 21.6 days (SD, 12.4 days) free from invasive mechanical ventilation compared with a mean of 19.6 days (SD, 13.1 days) in the control group (mean difference, 2.03 days [95% CI, −0.47 to 4.54 days], P = .11). The between-group differences were not statistically significant for ventilation-free days (invasive mechanical or noninvasive) at 30 days (mean difference, 2.04 days [95% CI, −0.50 to 4.59 days], P = .12), ICU-free days at 60 days (mean difference, 4.07 days [95% CI, −0.67 to 8.81 days], P = .09), and hospital-free days at 60 days (mean difference, 3.52 days [95% CI, −1.05 to 8.08 days], P = .13; Table 2). The adjusted linear regression analysis for secondary continuous outcomes yielded consistent results that were not statistically significant (eTable 8 in Supplement 3).

No serious adverse events were reported in either group; however, 26 adverse events were reported in 21 patients in the prone positioning group and no events were reported in the control group. Most reported adverse events were musculoskeletal pain or discomfort from prone positioning (13 of 205 patients [6.34%]) and desaturation (2 of 205 patients [0.98%]). Unintentional removal of intravenous access occurred in 1 patient (Table 3 and eTable 2 in Supplement 3).

A prespecified subgroup analysis by severity of hypoxemia yielded an HR of 0.44 (95% CI, 0.23 to 0.87; absolute difference, −16.58% [95% CI, −29.50% to −3.65%]) for endotracheal intubation in patients with Spo₂:Fio₂ greater than 150 at baseline and an HR of 1.02 (95% CI, 0.70 to 1.48; absolute difference, 0.95% [95% CI, −11.72% to 13.63%]) in patients with Spo₂:Fio₂ of 150 or less at baseline (P = .03 for interaction and P = .12 for false discovery rate). The subgroup analysis by oxygen delivery modality yielded an HR of 0.61 (95% CI, 0.42 to 0.88; absolute difference, −16.13% [95% CI, −27.55% to −4.72%]) for endotracheal intubation in patients who received high-flow oxygen at baseline, an HR of 3.69 (95% CI, 1.07 to 12.70; absolute difference, 38.33% [95% CI, 5.39% to 71.28%]) in patients who received noninvasive positive pressure ventilation at baseline, and an HR of 1.35 (95% CI, 0.60 to 3.05; absolute difference, 7.86% [95% CI, −10.65% to 26.36%]) in patients who received low-flow oxygen at baseline (P = .54 for interaction and P = .73 for false discovery rate). Similarly, there was no evidence of heterogeneity of treatment effect in other subgroups (eTable 9 in Supplement 3). We were unable to conduct a prespecified subgroup analysis by COVID-19 status because almost all enrolled patients had confirmed COVID-19 at baseline.

A post hoc analysis showed that 74 of 205 patients (36.1%) in the prone positioning group and 89 of 195 patients (45.6%) in the control group were intubated or died within days 30 after randomization (HR, 0.75 [95% CI, 0.55 to 1.02], P = .07; absolute difference, −9.54% [95 CI, −19.14% to 0.05%]). For the primary outcome, a post hoc mixed-effects modeling analysis, using hospital site as a random effect, yielded an HR of 0.80 (95% CI, 0.58 to 1.11, P = .18; eTable 8 in Supplement 3).

In this international, pragmatic, unblinded randomized clinical trial enrolling 400 patients who were not intubated and who had confirmed or suspected COVID-19, awake prone positioning compared with usual care did not show a statistically significant difference in endotracheal intubation within 30 days after randomization or for the secondary outcomes.

Several small trials have assessed awake prone positioning in patients with COVID-19; however, none of which individually showed a reduction in endotracheal intubation or death.^18-23 Another 6 randomized clinical trials were prospectively analyzed and published collectively as a meta-trial¹² and showed a reduced risk of endotracheal intubation at 28 days with awake prone positioning. However, these trials differed by the inclusion criteria and the prone positioning protocols used, and most achieved short durations (<3 h/d) of prone positioning. In addition, the effect sizes of the individual studies were inconsistent, and the pooled estimate seemed to be primarily driven by the results from 1 trial (NCT04477655).

The preplanned subgroup analysis showed a possible reduction in endotracheal intubation risk with prone positioning in patients with Spo₂:Fio₂ greater than 150 and in those receiving high-flow oxygen. It is possible that patients with more severe disease do not benefit from awake prone positioning. However, the false discovery rate did not reach statistical significance for any of the preplanned subgroups, therefore, these findings should be interpreted with great caution and considered hypothesis generating.²⁴

In this trial, 26 adverse events were reported, the majority (62%) of which were related to pain and discomfort from prone positioning (Table 3). These findings are congruent with other trials.¹² Long hours of awake prone positioning are challenging and highly influenced by patient comfort and preference in contrast to prone positioning of sedated (and often pharmacologically paralyzed) patients requiring invasive mechanical ventillation.⁸

In the current trial, the median duration of prone positioning per day (in the first 4 days after randomization) was approximately 5 hours for a median of 3 days. Although the median duration of prone positioning in our study was longer than in most published trials, the target of 8 h/d to 10 h/d was not universally achieved. The most common reason for interruption of prone positioning was patient request, which might have been related to overall subjective improvement or related to discomfort from prone positioning (eTable 10 in Supplement 3). Given the pragmatic design of this trial, these findings reflect the challenges with implementing prone positioning in awake patients with severe illness. Studying strategies to enhance prone positioning adherence is worthy of future investigation (eg, verbal support, anxiolytics, pain control, mechanical support devices).

Strengths of this study include enrollment of patients with severe COVID-19 in acute care settings, commensurate with a high median Fio₂ requirement of 70% at randomization; in this trial, 60% of patients had an Spo₂:Fio₂ of 150 or less. In addition, the international collaboration led to including patients with racial and ethnic diversity, enhancing the generalizability of the results.

This study has several limitations. First, although the study sample size was increased from 350 to 400 patients and a total of 149 endotracheal intubation events occurred, the effect size for the primary outcome was imprecise. The 95% CI included a 15.8% absolute reduction in endotracheal intubation but could not exclude a 3.1% absolute increase. It is also possible that the effect of prone positioning is heterogenous as suggested by subgroup analyses, further contributing to imprecision.

Second, patient preference and health care team request led to 19% of patients in the control group undergoing some prone positioning. However, the median duration of daily prone positioning in these patients was less than 1 hour, and the per-protocol analysis was consistent with the primary intention-to-treat analysis. Furthermore, 58% of these patients were intubated despite prone positioning, suggesting that the prone positioning was prompted by severe disease.

Third, the inability to keep the health care teams blinded to the study intervention and the lack of structured criteria for endotracheal intubation may have introduced bias. However, pharmacological and nonpharmacological interventions after randomization were similar in both groups (eTables 4 and 6 in Supplement 3).

In patients with acute hypoxemic respiratory failure from COVID-19, prone positioning, compared with usual care without prone positioning, did not significantly reduce endotracheal intubation at 30 days. However, the effect size for the primary study outcome was imprecise and does not exclude a clinically important benefit.

Corresponding Author: Waleed Alhazzani, MD, MSc, Department of Medicine and Department of Health Research Methods, Evidence, and Impact, McMaster University, 1200 Main St W, Hamilton, ON L8N 3Z5, Canada (waleed.al-hazzani@medportal.ca).

Accepted for Publication: April 26, 2022.

Published Online: May 15, 2022. doi:10.1001/jama.2022.7993

Author Contributions: Drs Alhazzani and Arabi had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Parhar, Weatherald, Al Duhailib, Fan, Lauzier, Rochwerg, Culgin, Nelson, Fiest, Stelfox, Solverson, Niven, Møller, Belley-Cote, Thabane, Cook, Arabi.

Acquisition, analysis, or interpretation of data: Alhazzani, Parhar, Weatherald, Al Duhailib, Alshahrani, Al-Fares, Buabbas, Cherian, Munshi, Fan, Al Hameed, Chalabi, Rahmatullah, Duan, Tsang, Lewis, Lauzier, Centofanti, Culgin, Nelson, Abdukahil, Fiest, Stelfox, Tlayjeh, Meade, Perri, Solverson, Lim, Møller, Belley-Cote, Thabane, Tamim, Cook.

Drafting of the manuscript: Alhazzani, Parhar, Weatherald, Al Duhailib, Chalabi, Lewis, Centofanti, Culgin, Nelson, Møller, Tamim, Arabi.

Critical revision of the manuscript for important intellectual content: Alhazzani, Parhar, Weatherald, Al Duhailib, Alshahrani, Al-Fares, Buabbas, Cherian, Munshi, Fan, Al Hameed, Rahmatullah, Duan, Tsang, Lewis, Lauzier, Centofanti, Rochwerg, Culgin, Nelson, Abdukahil, Fiest, Stelfox, Tlayjeh, Meade, Perri, Solverson, Niven, Lim, Møller, Belley-Cote, Thabane, Cook, Arabi.

Statistical analysis: Alhazzani, Al Duhailib, Møller, Thabane, Tamim, Arabi.

Obtained funding: Alhazzani, Parhar, Weatherald, Al Duhailib, Duan, Lauzier, Culgin, Fiest, Stelfox, Meade, Perri, Solverson, Niven, Belley-Cote, Cook, Arabi.

Administrative, technical, or material support: Alhazzani, Parhar, Weatherald, Alshahrani, Al-Fares, Buabbas, Cherian, Munshi, Rahmatullah, Duan, Tsang, Centofanti, Rochwerg, Culgin, Nelson, Abdukahil, Fiest, Tlayjeh, Perri, Solverson, Belley-Cote, Cook, Arabi.

Supervision: Alhazzani, Parhar, Weatherald, Alshahrani, Al-Fares, Al Hameed, Duan, Culgin, Nelson, Møller, Thabane, Cook, Arabi.

Conflict of Interest Disclosures: Dr Parhar reported receiving Rapid COVID-19 grants from the Cumming School of Medicine at the University of Calgary and Alberta Innovates. Dr Weatherald reported receiving Rapid COVID-19 grants from the Cumming School of Medicine at the University of Calgary; receiving grants, personal fees, and nonfinancial support from Janssen, Actelion, and Bayer; and receiving personal fees from Acceleron and Merck. Dr Alshahrani reported receiving grants from King Abdullah International Medical Research Center. Dr Fan reported receiving personal fees from ALung Technologies, Baxter, Aerogen, Inspira, GE Healthcare, and Vasomune. Dr Belley-Cote reported receiving grants from Bayer, Bristol Myers Squibb-Pfizer Alliance, and Roche Diagnostics. No other disclosures were reported.

Funding/Support: The trial was supported by peer-review grants from the Canadian Institute of Health Research and King Abdullah International Medical Research Center in Saudi Arabia and a McMaster University COVID-19 research grant.

Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The COVI-PRONE Trial Investigators and the Saudi Critical Care Trials Group members are listed in Supplement 4.

Meeting Presentation: This was presented at the American Thoracic Society International Conference; May 15, 2022; San Francisco, California.

Data Sharing Statement: See Supplement 5.

Additional Contributions: We thank the patients and families participating in this trial. We also thank the collaborating research coordinators and investigators and the bedside clinicians who supported this work. We specifically thank Kelly Hassall, RRT (St Joseph’s Healthcare Hamilton; did not receive financial compensation), and France Clarke, RRT (McMaster University; did not receive financial compensation), who were instrumental in championing the trial with their respiratory therapy colleagues and respective societies, Joshua Piticaru, MD (McMaster University; did not receive financial compensation), for producing prone positioning educational material, and Tom Piraino, RRT (University of Toronto; did not receive financial compensation), for his contributions to the trial design. We thank Melanie Columbus, PhD (University of Calgary; received financial compensation), Olesya Dmitrieva, BHSc (University of Calgary; received financial compensation), and Cassidy Codan, BSc (University of Calgary; received financial compensation), for serving as research coordinators. We also thank Kelly Nelson, RN (St Joseph’s Healthcare Hamilton; received financial compensation), for her role in the methods center with data cleaning and Will Cullimore (St Joseph’s Healthcare Hamilton; received financial compensation) for creating the trial’s website and social media platforms. We are grateful to the Canadian Society of Respiratory Therapists, the Canadian Critical Care Society, and the Alberta Health Services Critical Care Strategic Clinical Network for endorsing and supporting the trial grant application.

Additional Information: Dr Alhazzani holds a McMaster University Department of Medicine Mid-Career Research Award. Dr Cook holds a Canada Research Chair.