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Articles Awake prone positioning for COVID-19 acute hypoxaemic respiratory failure: a randomised, controlled, multinational, open-label meta-trial Stephan Ehrmann*, Jie Li*, Miguel Ibarra-Estrada*, Yonatan Perez*, Ivan Pavlov*, Bairbre McNicholas*, Oriol Roca*, Sara Mirza, David Vines, Roxana Garcia-Salcido, Guadalupe Aguirre-Avalos, Matthew W Trump, Mai-Anh Nay, Jean Dellamonica, Saad Nseir, Idrees Mogri, David Cosgrave, Dev Jayaraman, Joan R Masclans, John G Laffey, Elsa Tavernier, for the Awake Prone Positioning Meta-Trial Group† Summary Background Awake prone positioning has been reported to improve oxygenation for patients with COVID-19 in Lancet Respir Med 2021 retrospective and observational studies, but whether it improves patient-centred outcomes is unknown. We aimed to Published Online evaluate the efficacy of awake prone positioning to prevent intubation or death in patients with severe COVID-19 in a August 20, 2021 https://doi.org/10.1016/ large-scale randomised trial. S2213-2600(21)00356-8 See Online/Comment Methods In this prospective, a priori set up and defined, collaborative meta-trial of six randomised controlled open-label https://doi.org/10.1016/ superiority trials, adults who required respiratory support with high-flow nasal cannula for acute hypoxaemic S2213-2600(21)00368-4 respiratory failure due to COVID-19 were randomly assigned to awake prone positioning or standard care. Hospitals *Contributed equally from six countries were involved: Canada, France, Ireland, Mexico, USA, Spain. Patients or their care providers were †A complete list of the not masked to allocated treatment. The primary composite outcome was treatment failure, defined as the proportion investigators, collaborators, and of patients intubated or dying within 28 days of enrolment. The six trials are registered with ClinicalTrials.gov, contributors to the Awake Prone Positioning Meta-Trial Group is NCT04325906, NCT04347941, NCT04358939, NCT04395144, NCT04391140, and NCT04477655. in appendix 1 CHRU Tours, Médecine Findings Between April 2, 2020 and Jan 26, 2021, 1126 patients were enrolled and randomly assigned to awake prone Intensive Réanimation, positioning (n=567) or standard care (n=559). 1121 patients (excluding five who withdrew from the study) were CIC INSERM 1415, CRICS- included in the intention-to-treat analysis. Treatment failure occurred in 223 (40%) of 564 patients assigned to awake TriggerSep F-CRIN research network, Tours, France prone positioning and in 257 (46%) of 557 patients assigned to standard care (relative risk 0·86 [95% CI 0·75−0·98]). (Prof S Ehrmann PhD, Y Perez The hazard ratio (HR) for intubation was 0·75 (0·62−0·91), and the HR for mortality was 0·87 (0·68−1·11) with MD); and INSERM, Centre awake prone positioning compared with standard care within 28 days of enrolment. The incidence of prespecified d’étude des pathologies adverse events was low and similar in both groups. respiratoires, U1100, Université de Tours, Tours, France (Prof S Ehrmann); Interpretation Awake prone positioning of patients with hypoxaemic respiratory failure due to COVID-19 reduces the Department of incidence of treatment failure and the need for intubation without any signal of harm. These results support routine Cardiopulmonary Sciences, awake prone positioning of patients with COVID-19 who require support with high-flow nasal cannula. Division of Respiratory Care, Rush University, Chicago, IL, USA (J Li PhD, Prof D Vines PhD, Funding Open AI inc, Rice Foundation, Projet Hospitalier de Recherche Clinique Interrégional, Appel d’Offre 2020, S Mirza MD); Unidad de Terapia Groupement Interrégional de Recherche Clinique et d’Innovation Grand Ouest, Association pour la Promotion à Intensiva, Hospital Civil Fray Antonio Alcalde Guadalajara, Tours de la Réanimation Médicale, Fond de dotation du CHRU de Tours, Fisher & Paykel Healthcare Ltd. Jalisco, México (M Ibarra-Estrada MD, Copyright © 2021 Elsevier Ltd. All rights reserved. R Garcia-Salcido MD, Prof G Aguirre-Avalos PhD); Introduction in oxygenation, escalation of respiratory support, or Department of Emergency Medicine, Hôpital de Verdun, Severe illness characterised by progressive hypoxaemic mortality.12,13 Despite the paucity of large scale randomised Montréal, QC, Canada respiratory failure develops in a large number of patients controlled evidence evaluating patient-centred outcomes, (I Pavlov MD); Department of with COVID-19, resulting in the need for invasive awake prone positioning generated great interest in Anesthesia and Intensive Care Medicine, Galway University mechanical ventilation.1–3 In patients who are intubated the clinical and scientific communities, and it has Hospitals, HRB Galway Clinical and have moderate to severe acute respiratory distress been incorporated into clinical guidelines14 and expert Research Facility, Galway, syndrome, prone positioning is an effective intervention consensus statements.15,16 Awake prone positioning has Ireland (B McNicholas PhD, to improve oxygenation and reduce mortality.4–7 Awake been identified as a research priority by the Surviving D Cosgrave MD, Prof J G Laffey MD); School of prone positioning has been associated with improved Sepsis Research Committee.17 Medicine, National University oxygenation in observational studies of non-intubated We aimed to determine whether awake prone of Ireland, Galway, Ireland patients with acute respiratory distress syndrome8 and, positioning reduces the rate of treatment failure at (B McNicholas, D Cosgrave, more recently, in patients with severe COVID-19.9–11 28 days, defined as either death or intubation, in patients Prof J G Laffey); Servei de Medicina Intensiva, Hospital Two small (n=30 and n=60) pilot trials studied the with severe COVID-19 acute hypoxaemic respiratory Universitari Vall d’Hebron, feasibility of awake prone positioning in non-intubated failure who require respiratory support with high-flow Barcelona, Spain (O Roca PhD); patients but did not have the power to show improvement nasal cannula. We prospectively designed a collaborative Ciber Enfermedades www.thelancet.com/respiratory Published online August 20, 2021 https://doi.org/10.1016/S2213-2600(21)00356-8 1 Articles Respiratorias (CIberes), Instituto de Salud Carlos III, Research in context Madrid, Spain (O Roca); The Iowa Clinic P.C. and Unity Evidence before this study of respiratory support, or mortality. We did not identify any Point Health-Des Moines, Awake prone positioning has been associated with improved randomised controlled trial designed to determine whether Des Moines, IA, USA oxygenation in observational studies of non-intubated patients awake prone positioning reduces the combined incidence of (M W Trump DO); Medical intensive care unit, Centre with acute respiratory distress syndrome and, more recently, in intubation or death in patients with severe COVID-19. Hospitalier Régional d’Orléans, patients with severe COVID-19. Whether these improvements Added value of this study Orléans, France (M-A Nay MD); translate into a reduced need for intubation or reduced mortality UR2CA Unité de Recherche In this prospectively designed, multicentre, international, remains unknown, and observational studies have shown Clinique Université Côte d’Azur, randomised, open-label meta-trial, with a large sample size Nice, France conflicting results. Moreover, there is concern that awake prone (1121 patients), we found that awake prone positioning (Prof J Dellamonica PhD); positioning might prove harmful if transient improvement of reduced the incidence of treatment failure within 28 days of Médecine Intensive oxygenation leads to false reassurance and delayed intubation. Réanimation—CHU de Nice, enrolment (the primary composite outcome of intubation or Nice, France We searched MEDLINE, EMBASE, and PubMed, Web of Science, death) in patients with acute severe hypoxaemic respiratory (Prof Jean Dellamonica); Pôle de Scopus, medRxiv, bioRxiv, and ClinicalTrials.gov for studies failure due to COVID-19 supported with high-flow nasal Médecine Intensive- published from Jan 1, 2020, to April 26, 2021, for completed Réanimation, CHU Lille, Lille, cannula. Adverse effects were mild, infrequent, and occurred at France (Prof S Nseir PhD); randomised controlled trials published in any language similar rates between awake prone positioning and standard Inserm U1285, University of evaluating the effect of awake prone positioning to treat care groups. Lille, CNRS, UMR 8576, Unité patients with COVID-19. The keywords (“prone position*” OR de Glycobiologie Structurale et “pron*”) AND (“COVID-19” OR “SARS” OR “coronavirus”) AND Implications of all the available evidence Fonctionnelle, Lille, France (“awake” OR “non-intubated” OR “conscious”) were used to Awake prone positioning is a safe intervention that reduces the (Prof S Nseir); Pulmonary and search the databases. We identified two small pilot trials (n=60 risk of treatment failure in hypoxaemic patients with COVID-19 Critical Care Medicine Division, Texas A&M School of Medicine, and n=30) that studied the feasibility of awake prone who require advanced respiratory support with high-flow nasal Baylor University Medical positioning comparing it with usual care among non-intubated cannula oxygen. Our findings support routine implementation Center, Dallas, TX, USA of awake prone positioning in those patients. (I Mogri MD); Division of Critical patients with COVID-19. Neither of these studies reported Care, McGill University significant differences in oxygenation improvement, escalation Healthcare Center Montréal, QC, Canada (D Jayaraman MD); Jewish General Hospital, Montréal, QC, Canada meta-trial, a novel multicentre trial design consisting studies still recruiting (due to slower recruitment given (D Jayaraman); Critical Care of a prospective, a priori set up and defined, individual geographical and unpredictable variations in pandemic Department, Hospital del Mar, IMIM (Hospital del Mar participant data meta-analysis of six randomised con­ waves) would be terminated for loss of equipoise. A Research Institute) Barcelona, trolled open-label superiority trials. sixth group conducting a trial with a similar and Spain (J R Masclans PhD); compatible research design (NCT04477655) joined the Departament de Medicina, Universitat Autònoma de Methods consortium shortly thereafter (on Aug 26, 2020).19 In total, Barcelona, Bellaterra, Spain Study design hospitals from six countries were involved: Canada, (J R Masclans); Clinical On April 29, 2020, the lead investigators of five national France, Ireland, Mexico, USA, Spain (appendix 1 pp 3–4). Investigation Center, randomised, controlled, open-label trials of awake prone This innovative meta-trial approach combined the INSERM 1415, CHRU Tours, Tours, France (E Tavernier PhD); positioning (NCT04325906, NCT04347941, NCT04358939, benefits of a prospective design, and the high power Methods in Patients-Centered NCT04395144, NCT04391140) agreed to participate in this of a large multinational trial with the convenience of Outcomes and Health Research, meta-trial. In each trial, awake prone positioning was faster setup times of individual national trials, an INSERM UMR 1246, Nantes, compared with standard care in patients with acute important advantage during a pandemic.20 Its statistical France (E Tavernier) hypoxaemic respiratory failure due to COVID-19 and underpinnings have been previously reported.21 Correspondence to: Dr Jie Li, Department of undergoing high-flow nasal cannula support. A meta-trial Each individual national trial was approved by each Cardiopulmonary Sciences, protocol incorporating a collaborative prospective meta- participating centre’s ethics committee. The meta-trial Division of Respiratory Care, analysis of individual patient data from each randomised was supervised by a steering committee formed by Rush University, Chicago 60612, controlled trial was agreed. Inclusion and exclusion principal investigators of each national trial, assisted IL, USA jie_li@rush.edu criteria and the planned intervention were harmonised by two independent advisors. The meta-trial protocol across all five trials. Investigators identified a common set has been published18 and is available along with each See Online for appendix 1 of core data that could be extracted from each trial, individual trial protocol in appendix 2. For the protocol see Online for appendix 2 primary and secondary outcomes of the meta-trial which were agreed a priori and recorded identically across Patients trials, planned collaborative interim and final statistical All adults (>18 years old) with acute hypoxaemic analyses at the meta-trial level, and agreed to report the respiratory failure due to proven (or highly clinically findings jointly as a unified group of investigators, before suspected, pending microbiological confirmation) any reporting of individual trial results.18 A priori, the COVID-19 pneumonia were eligible for enrolment at investigators also agreed that once the meta-trial result participating hospitals. Acute hypoxaemic respiratory was known, provided it gave a clear answer, the individual failure was defined as a requirement of respiratory 2 www.thelancet.com/respiratory Published online August 20, 2021 https://doi.org/10.1016/S2213-2600(21)00356-8 Articles support with high-flow nasal cannula and a ratio of mental status.18 Among intubated patients, the peripheral arterial oxygen saturation (SpO2) to the subsequent management (including prone positioning) fraction of inspired oxygen (FiO2) [SpO2:FiO2] of 315 or was left at the treating physician’s discretion. less (which is equivalent to a ratio of partial pressure of arterial oxygen [PaO2] to FiO2 [PaO2:FiO2] ≤300 mmHg).22 Outcomes We excluded patients who were unable or refused to The primary outcome was treatment failure within 28 days provide informed consent, were haemo­ dynamically of enrolment, defined as intubation or death. The reason unstable, were severely obese with a body-mass index we combined a non-fatal outcome (intubation) with death higher than 40 kg/m², were pregnant, or had a is that they are competing and causally related outcomes. contraindication to awake prone positioning (trial Main secondary outcomes (all censored at 28 days after inclusion and exclusion criteria by country are presented enrolment) were: intubation; mortality; use of non- in appendix 1 pp 5–6). Written informed consent was invasive ventilation; length of hospital stay; time to high- obtained for all patients according to national regulations. flow nasal cannula weaning in patients with treatment success (defined as the patient being alive and not having Randomisation and masking required intubation within 28 days of enrolment); time to A statistician not involved in patient recruitment treatment failure; time to intubation; time to death; generated the allocation sequence for each individual duration of invasive mechanical ventilation in intubated trial. Patients were assigned to either the intervention patients surviving to day 28; mortality in invasively (awake prone positioning group) or standard care (control mechanically ventilated patients; predefined safety group) using a 1:1 computer-generated variable block size outcomes as prospectively recorded by investigators; and sequence. Allocation concealment at randomisation was physiological response to awake prone positioning, ensured by an online randomisation system or with including the ratio of SpO2:FiO2 to respiratory rate, known on-site opaque sealed envelopes, depending on the trial as the ROX index.23 (the research protocols for each trial are available in appendix 2). By the very nature of the intervention Statistical analysis and design, trial participants, care providers, outcome All analyses were done at the individual patient level. assessors, and data analysts could not be blinded to the Treatment failure was analysed in an intention-to-treat intervention. population comprising all patients recruited across all six trials and a prespecified, strictly defined per-protocol Procedures population (appendix 1 p 20). Individual trial analysis Patients in the awake prone positioning group were was planned to be done secondarily, after analysis of the instructed and assisted to lie in the prone position for as complete meta-trial population and will be published long and as frequently as possible each day. The duration later. of each proning session was recorded by bedside nurses. Relative risks were estimated for the primary outcome High-flow nasal cannula was initiated at maximally and all binary outcomes, in a mixed effect log-binomial tolerated flow setting, and the FiO2 was titrated to model with a random effect on the individual trial. All maintain SpO2 between 90% and 95%. The use of non- time to event outcomes were compared using survival invasive ventilation was not included in the trial protocol analyses with a frailty term on the individual trials. The but was recorded prospectively. Study endpoints at proportional hazards assumption was checked by a visual which awake prone positioning was ceased were inspection of the Kaplan-Meier curves, using a graphical weaning of high-flow nasal cannula (based on improved diagnostic based on the scaled Schoenfeld residuals. The oxygenation defined in each individual trial; appendix 1 primary outcome and mortality were analysed in a Cox p 7), discharge from hospital, intubation, or death. proportional hazard model. Intubation was analysed with Patients in the standard care group received standard death as a competing event using a Fine and Gray with care with high-flow nasal cannula. The use of awake proportional hazards model, and weaning of high-flow prone positioning as a so-called rescue intervention was nasal cannula was analysed with escalation to non-invasive discouraged in the standard care group and recorded as ventilation or treatment failure as competing events. a protocol violation. To harmonise triggers for intubation, Mean difference was estimated for duration of hospital initially slightly different across individual trials, stay and was analysed in a mixed-effect linear regression. predefined criteria for tracheal intubation were provided All estimates were reported with the two-sided in both groups at the meta-trial level and disseminated corresponding 95% CI. across participating centres, including worsening Interim analyses at the meta-trial level of aggregated respiratory failure (respiratory rate above 40 breaths data for the individual trials were planned, a priori, after per min, respiratory muscle fatigue, respiratory acidosis each 200 patients were enrolled. Prespecified multiplicity- with a pH below 7·25, copious tracheal secretions, adjustment methods were used to control the overall severe hypoxaemia with SpO2 below 90% despite an FiO2 one-sided type 1 error rate at 0·025. Based on previous of ≥0·8), haemodynamic instability, or deteriorating reports,24,25 we estimated the incidence of the primary www.thelancet.com/respiratory Published online August 20, 2021 https://doi.org/10.1016/S2213-2600(21)00356-8 3 Articles 2350 patients with COVID-19 acute hypoxaemic Awake prone Standard care group respiratory failure were screened in positioning (n=557) participating hospitals group (n=564) Age, years 61·5 (13·3) 60·7 (14·0) 1224 excluded* 391 refused or could not consent Female sex 184 (33%) 191 (34%) 329 required immediate tracheal Male sex 380 (67%) 366 (66%) intubation Body-mass index, kg/m² 29·7 (4·6) 29·7 (4·6) 157 contraindications to awake prone positioning Clinical parameters at enrolment 143 BMI >40 kg/m2 Respiratory rate, breaths/min 24·7 (5·1) 24·9 (5·6) 94 already enrolled in other trials 19 were pregnant Mean arterial pressure, mmHg 88·2 (12·1) 87·4 (11·4) 174 other reasons† SpO2:FiO2 147·9 (43·9) 148·6 (43·1) Recruitment of individual trials 1126 randomised Mexico 216 (38%) 214 (38%) France 200 (35%) 202 (36%) USA 112 (20%) 110 (20%) Spain 17 (3%) 13 (2%) 567 assigned to awake prone 559 assigned to standard care Ireland 12 (2%) 12 (2%) positioning Canada 7 (1%) 6 (1%) Coexisting illness 3 withdrew consent 2 withdrew consent Chronic heart disease* 120 (21%) 127 (23%) Chronic lung disease† 63 (11%) 64 (12%) 564 in the 28 day 557 in the 28 day Chronic kidney disease‡ 45 (8%) 35 (6%) intention-to-treat analysis intention-to-treat analysis Severe liver disease§ 8 (1%) 6 (1%) Diabetes (type 1 and 2) 176 (31%) 173 (3%) Figure 1: Screening, enrolment, randomisation, and follow-up of trial Obesity¶ 221 (39%) 231 (42%) participants Active malignancy 45 (8%) 31 (6%) BMI=body-mass index. *Could have more than one reason. †Other trial specific reasons for exclusion were: initiation of awake prone positioning on treating Confirmed COVID-19 557 (99%) 552 (99%) physicians’ orders before inclusion in the trial, physician decision not to include Use of glucocorticoids for 494 (88%) 492 (88%) the patient, respiratory support with high-flow nasal cannula for more than treatment of COVID-19 48 h before enrolment, no insurance coverage. Do-not-intubate order 44 (8%) 44 (8%) Location at enrolment outcome to be between 60% and 70% in the standard Intensive care unit 336 (60%) 339 (61%) care group. The meta-trial was designed to show Intermediate care unit 197 (35%) 189 (34%) superiority of awake prone positioning over standard Emergency department 5 (1%) 5 (1%) care with 90% power and a one-sided type 1 error rate General ward 26 (5%) 24 (4%) of 0·025. For an asymmetric two-sided group sequential analysis with five interim analyses (including the last Data are mean (SD), or n (%). SpO2=peripheral blood oxygen saturation. FiO2=fraction of inspired oxygen. *Heart failure or coronary artery disease or analysis), the sample size was 1000. We determined hypertension. †Obstructive or restrictive lung disease. ‡Estimated glomerular continuous stopping boundaries using the Kim-DeMets filtration rate <60 mL/min per 1·73 m² before hospital admission. §Cirrhosis or alpha-spending approach,26 with a Pocock superiority portal hypertension with history of variceal bleeding, or liver disease with Child- bound for efficacy and O’Brien-Fleming bound for Pugh score ≥10. ¶Data for obesity were missing for two patients. futility.17 Both bounds were binding, in the sense that Table 1: Characteristics of patients at enrolment recruitment was to stop once they were crossed, and was designed to allow for the best chance to stop early in case of shown superiority (aggressive upper bound), therefore heterogeneity between individual trials was assessed by enabling all subsequent patients to benefit from the calculating the I² statistic, using the DerSimonian and intervention, and to minimise the risk of premature Laird method. Analyses were done with R, version 3.6.3. interruption of the meta-trial without reaching good evidence of futility (conservative lower bound). Role of the funding source All outcomes were further analysed in subgroups The funder of the study had no role in study design, data determined a priori of severe (SpO2:FiO2 <190, equivalent collection, data analysis, data interpretation, or writing of to PaO2:FiO2 <150 mmHg22 at enrolment) versus less severe the report. (SpO2:FiO2 ≥190, equivalent to PaO2:FiO2 ≥150 mmHg22 at enrolment) hypoxaemia. To test the difference of Results treatment effect between the two subgroups, we added an The first randomised controlled trial began screening interaction term in the primary outcome model. Statistical patients on April 2, 2020, and enrolment for all trials was 4 www.thelancet.com/respiratory Published online August 20, 2021 https://doi.org/10.1016/S2213-2600(21)00356-8 Articles terminated on Jan 26, 2021, after the third interim analysis on 928 patients who had been followed-up for at A Treatment failure least 28 days, showed that the predefined statistical 1·0 Standard care criteria for efficacy were met (appendix 1 pp 8–9). A total Awake prone positioning Probability of survival without 0·8 Hazard ratio 0·78 (95% CI 0·65–0·93) of 2350 patients were assessed for eligibility, of whom Log-rank p=0·0069 1126 underwent randomi­sation, five withdrew consent 0·6 outcome after randomisation, and 564 patients assigned to the 0·4 awake prone positioning group and 557 to the standard care group were included in the intention-to-treat 0·2 analysis of the primary outcome (figure 1). The median time from hospital admission to enrolment was 1·0 day 0 0 7 14 21 28 (IQR 0·4 to 1·9) in the awake prone positioning group Number at risk and 1·0 day (0·4 to 1·5) in the standard care group. (number censored) Standard care 557 (0) 345 (0) 310 (0) 299 (0) 298 (298) Most patients were recruited in Mexico (n=430, 38%), Awake prone positioning 564 (0) 405 (0) 358 (0) 344 (0) 341 (341) France (n=402, 36%), and the USA (n=222, 20%); patients were also recruited from Spain (n=30, 3%), Ireland B Intubation (n=24, 2%), and Canada (n=13, 1%). Baseline demo­ 1·0 Hazard ratio 0·75 (95% CI 0·62–0·91) Probability of survival without Z-test p=0·0038 graphic and disease characteristics were well balanced 0·8 between the two groups of the meta-trial (table 1) and between the two groups of each individual randomised 0·6 outcome controlled trial (appendix 1 pp 10–15). In total 986 (88%) 0·4 of 1121 patients received glucocorticoids. At enrolment, the mean SpO2:FiO2 was 147·9 (SD 43·9) for the awake 0·2 prone positioning group versus 148·6 (43·1) for the 0 standard care group with similar high-flow nasal 0 7 14 21 28 cannula settings (median flow rate set at 50·0 L/min Number at risk (number censored) [IQR 40·0–55·0] versus 50·0 [40·0–50·0], and median Standard care 557 (0) 345 (0) 310 (0) 299 (0) 298 (298) FiO2 set at 0·6 [0·5–0·8] in both groups). Awake prone positioning 564 (0) 405 (0) 358 (0) 344 (0) 341 (341) In the intervention group, the median daily duration of awake prone positioning (recorded until day 14) was 5·0 h C Mortality (IQR 1·6–8·8), with variations among individual trials, 1·0 Hazard ratio 0·87 (95% CI 0·68–1·11) from a median daily awake prone positioning duration of Log-rank p=0·27 Probability of survival without 0·8 1·6 h in Spain to 8·6 h in Mexico (appendix 1 p 16). In the intention-to-treat population, the primary 0·6 outcome endpoint of treatment failure (intubation or death) 0·4 within 28 days of enrolment occurred in 223 (40%) of 564 patients randomly assigned to awake prone positioning 0·2 and in 257 (46%) of 557 patients randomly assigned to standard care (relative risk 0·86 [95% CI 0·75–0·98], 0 0 7 14 21 28 p=0·02; figure 2A; table 2). No statistical heterogeneity was Number at risk detected between individual trials estimates (I²=0%, (number censored) Standard care 557 (0) 543 (0) 491 (0) 446 (0) 425 (425) 95% CI 0–69; appendix 1 p 17). The number needed to treat Awake prone positioning 564 (0) 553 (0) 496 (0) 460 (0) 448 (448) to avoid one treatment failure was 15 (95% CI 8–156). We did not measure a statistically significant interaction D Weaning of high-flow nasal cannula between the SpO2:FiO2 at enrolment and the intervention 1·0 Hazard ratio 1·19 (95% CI 1·01–1·39) Cumulative probability of outcome Z-test p=0·035 effect with regards to the primary outcome, within the 0·8 limits of the trial not being powered for this purpose (p=0·62; appendix 1 p 19). 0·6 0·4 0·2 Figure 2: Kaplan-Meier probabilities estimates in the intention-to-treat 0 population over 28 days after enrolment 0 7 14 21 28 (A) Probability of treatment failure (intubation or death). (B) Probability of Days since enrolment intubation. (C) Probability of survival. (D) Probability of successful weaning of Number at risk high-flow nasal cannula, with death, intubation, and non-invasive ventilation as (number censored) Standard care 556 (0) 186 (0) 36 (0) 11 (0) 5 (5) competing events. The criteria for weaning were protocolised in each individual Awake prone positioning 559 (0) 228 (0) 34 (0) 7 (0) 1 (1) trial and are described in the appendix 1 p 7. www.thelancet.com/respiratory Published online August 20, 2021 https://doi.org/10.1016/S2213-2600(21)00356-8 5 Articles Awake prone Standard care RR (95% CI), HR positioning group (n=557) (95% CI), or mean 170 group (n=564) difference (95% CI) Primary outcome SpO2:FiO2 160 Treatment failure at day 28 223/564 (40%) 257/557 (46%) RR 0·86 (0·75 to 0·98) (intubation or death) Secondary outcomes 150 Intubation rate at day 28 185/564 (33%) 223/557 (40%) ·· Mortality at day 28 All patients 117/564 (21%) 132/557 (24%) RR 0·87 (0·71 to 1·07) Invasively mechanically ventilated 79/185 (43%) 98/223 (44%) ·· 25 Respiratory rate, breaths per min patients Time to event analysis, median days* Treatment failure (intubation or 2·0 (1·0 to 4·3) 2·0 (1·0 to 3·8) HR 0·78 (0·65 to 0·93) 24 death) Intubation 2·3 (1·3 to 5·0) 2·0 (1·0 to 3·8) HR 0·75 (0·62 to 0·91) Death 12·0 (9·0 to 17·0) 14·0 (9·8 to 19·0) HR 0·87 (0·68 to 1·11) 23 Non-invasive ventilation, intubation 3·0 (1·0 to 7·4) 2·3 (1·0 to 5·0) HR 0·79 (0·67 to 0·94) or death Weaning of high-flow nasal cannula 6·9 (3·3 to 9·2) 6·0 (3·0 to 9·8) HR 1·19 (1·01 to 1·39) Mean duration, days Hospital length of stay 16·4 (10·5) 16·5 (9·7) Mean difference –0·2 8·0 (–1·3 to 1·0) Mechanical ventilation among 12·4 (9·0) 12·4 (8·4) Mean difference 0·2 7·5 ROX index intubated patients who survived (–1·9 to 2·3) until day 28 7·0 Safety outcomes Skin breakdown 8 (1%) 10 (2%) ·· 6·5 Vomiting 15 (3%) 18 (3%) ·· Central or arterial line dislodgement 26 (5%) 17 (3%) ·· 6·0 1 h to immediately 30 min to 1 h 30 min to 1 h after Cardiac arrest at any time† 3 (1%) 1 (0%) ·· before APP during APP return to supine Data are n (%), mean (SD), or median (IQR). HR=hazard ratio. RR=relative risk. All outcomes were censored at 28 days. Figure 3: Physiological effects of awake prone positioning *The median time to event is reported for patients who experienced the reported event in each group, while the Means are indicated by points, with standard deviation indicated by the shaded corresponding HRs are computed from the whole groups and reflect the difference in the incidence of those outcomes area. (A) Ratio of peripheral arterial oxygen saturation to the fraction of inspired over time. †No cardiac arrest occurred in prone position, nor during manoeuvres to place patients prone or supine. oxygen (SpO2:FiO2). (B) Respiratory rate in breaths per minute. (C) The ROX index is equal to SpO2:FiO2 divided by the respiratory rate. Lower values indicate Table 2: Primary and secondary outcomes more severe respiratory compromise. Values were recorded 1 h to immediately before the first awake prone positioning session, during the session 30 min to 1 h after the patient was placed into prone position and 30 min to 1 h after the The cumulative incidence of intubation at day 28 was patient had returned into the supine position. lower in the awake prone positioning group than in the standard care group (figure 2B, table 2). The number respiratory rate, and ROX index were all significantly needed to treat to avoid one intubation was 14 (95% CI improved during the first awake prone positioning 8–69). The 28 day mortality was not different between the session, which lasted a median of 3·0 h (IQR 1·2–4·0), awake prone positioning group versus the standard care and this improvement persisted after returning to the group (figure 2C, table 2). Among patients who were supine position (figure 3). Other secondary outcomes are invasively mechanically ventilated, the 28 day mortality reported in table 2. was similar between groups (table 2). Mean duration of Longer mean daily duration of awake prone positioning invasive mechanical ventilation was also similar between was reported more frequently in patients that ultimately groups among patients who were intubated and survived had treatment success at day 28 (figure 4). Treatment until day 28 (table 2). Non-invasive ventilation was used failure occurred in 25 (17%) of 151 patients who remained in 94 (17%) patients in the awake prone positioning in awake prone positioning for at least 8 h daily on group and 110 (20%) patients in the standard care average while on high-flow nasal cannula, compared group, in whom 77 (81%) of patients in the awake prone with 198 (48%) of 413 patients who remained in awake positioning group and 92 (84%) of patients in the prone positioning less than 8 h daily on average while on standard care group were intubated or died within high-flow nasal cannula. 28 days. Patients in the awake prone positioning group 64 (11%) of 557 patients of the standard care were more likely to be weaned from high-flow nasal group received at least one episode of awake prone cannula up to day 28 (figure 2D, table 2). The SpO2:FiO2, positioning. Intubation or death occurred in 36 (56%) of 6 www.thelancet.com/respiratory Published online August 20, 2021 https://doi.org/10.1016/S2213-2600(21)00356-8 Articles those patients within 28 days of enrolment. Among the 150 Treatment success 32 patients intubated after undergoing awake prone Treatment failure positioning in the standard care group, 19 (59%) patients died by day 28, and the median duration of invasive mechanical ventilation was 7·1 days (IQR 6·0–14·0) among survivors. 100 Number of patients The incidence of prespecified adverse events, including skin breakdown, vomiting, and central or arterial line dislodgement, was low and similar in both groups (table 2). No patient had a cardiac arrest during awake prone positioning or in relation to proning. Additional 50 results (patients’ characteristics in individual trials, awake prone positioning durations, and per-protocol and subgroup analyses) are provided in appendix 1. 0 Discussion 0 to <2 2 to <5 5 to <8 8 to <11 11 to <13 ≥13 In this multicentre, international, randomised, open- Daily mean duration of awake prone positioning (h) label meta-trial, awake prone positioning decreased the Figure 4: Daily mean duration of prone positioning and outcomes in patients incidence of treatment failure (the primary composite allocated to awake prone positioning outcome of intubation or death) in patients with acute Each bar represents the total number of patients having received a mean daily severe hypoxaemic respiratory failure due to COVID-19 duration of awake prone positioning indicated on the horizontal axis in the population of patients with treatment success (patient was alive and did not supported with high-flow nasal cannula. Adverse effects require intubation after 28 days) and treatment failure (intubation or death by were mild, infrequent, and occurred at similar rates day 28). between the awake prone positioning and standard care groups. between patients and studies. The effect size of awake At 28 days, the incidence of intubation was significantly prone positioning on the primary outcome was greatest reduced with awake prone positioning compared with in the trial from Mexico, which also had the longest standard care. 14 patients needed to be treated with awake mean daily duration of awake prone positioning prone positioning to avoid one intubation. Mortality and (appendix 1 p 16). Longer awake prone positioning duration of invasive mechanical ventilation were similar sessions were associated with greater treatment success. between groups among intubated patients, suggesting no This study was not designed to evaluate the effect of signal for harm from awake prone positioning. Beyond awake prone positioning duration, and patients’ baseline individual benefits, reduced intubation might relieve severity and the response to awake prone positioning pressure on ventilator requirements and use of intensive might influence commitment to the awake prone care unit resources, whereas the hospital length of stay positioning procedure, thus awake prone positioning was not affected by awake prone positioning. Several duration data are to be considered primarily as hypothesis physiological mechanisms might underpin those favour­ generating. Future studies are needed to explore the able clinical outcomes. As observed during invasive dose-response effect. Given that longer durations of mechanical ventilation, prone positioning might induce a awake prone positioning were associated with a lower more homogenous distribution of pleural pressure risk of treatment failure, patients should be encouraged throughout lung regions, resulting in reduced regional to remain prone for as long as they can tolerate. Further lung stress and strain.8,9 Awake prone positioning trials could investigate modifiable factors to promote improves oxygenation, probably through reducing awake prone positioning. ventilation to perfusion mismatch and alveolar shunt. The major strengths of this meta-trial are the large Furthermore, the reduced respiratory rate also observed sample size and international scope, which allows during awake prone positioning might be indicative of generalisation to a variety of clinical settings. In addition, reduced respiratory drive and might result in reduced the meta-trial implemented a harmonised research transpulmonary pressure swings leading to reduced protocol to include a well-defined population of patient self-inflicted lung injury.27,28 Physiological studies patients suffering from severe COVID-19 induced acute are required to investigate those potential mechanisms. hypoxaemic respiratory failure, all undergoing high-flow In contrast to proning of patients who are intubated nasal cannula with the majority of patients receiving and sedated or even paralysed, effective awake prone glucocorticoid therapy. positioning implementation requires patients’ cooper­ The meta-trial concept, prospectively defined by the ation. Important variations in the duration of awake investigators of this project18,20 presents advantages in the prone positioning reflecting individual characteristics pandemic setting, beyond faster setup and lower cost such as age, body stature, tolerance, health-care team compared with a centralised international trial. Because support, and availability of escalation options existed of the cumulative sample size of several trials, it provides www.thelancet.com/respiratory Published online August 20, 2021 https://doi.org/10.1016/S2213-2600(21)00356-8 7 Articles adequate power for most effect sizes that are difficult to Contributors estimate early in a pandemic. The cumulative sample SE, JL, and ET designed the meta-trial project. MIE, YP, SE, JL, DV, SM, BM, JGL, DC, IP, and OR designed and conducted the individual trials. size also enables a coordinated prospective interim All authors significantly contributed to the conduct of the meta-trial, analysis plan to be set up (appendix 1 pp 8–9). This attending monthly web meetings. ET conducted data analysis. IP, BM, represents the key feature of the meta-trial concept and JL, YP, SE, ET, MIE, and OR had full access to the data, verified the data, leads to reducing the time to reach a conclusion and drafted the manuscript. All authors vouch for the accuracy and completeness of data and for adherence to the protocol. All authors compared with individually conducted trials. In contrast reviewed the manuscript for important intellectual content and approved to alternative designs, such as platform trials,29 the meta- the final manuscript. SE, JL, MIE, YP, IP, BM, and OR equally trial enables the equal and concurrent enrolment of the contributed to the overall project described in this article. SE and JL were control group, exactly as in a conventional randomised responsible for the decision to submit the manuscript. controlled trial. The meta-trial concept has recently been Declaration of interests adopted by other groups of investigators30 while others SE discloses consultancies from Aerogen Ltd, research support from Aerogen Ltd, Fisher & Paykel Healthcare Ltd, Hamilton medical, travel took similar approaches under the multiplatform trial reimbursements from Aerogen Ltd and Fisher & Paykel Healthcare Ltd. denomination.31 JL discloses research funding from Fisher & Paykel Healthcare Ltd, The present work has several limitations. First, the Aerogen Ltd, and Rice Foundation, and speaker fees from AARC and very nature of the intervention precluded blinding, and Fisher & Paykel Healthcare Ltd. IP discloses a research grant and speaker fees from Fisher & Paykel Healthcare Ltd. YP discloses research support we cannot exclude that at least part of the effect of from Fisher & Paykel Healthcare Ltd. OR discloses a research grant from awake prone positioning was mediated by influencing Hamilton Medical and speaker fees from Hamilton Medical, Ambu and the decision-making of treating physicians. Despite Aerogen Ltd, and non-financial research support from Timpel and the provision of clear criteria for intubation,18 clinicians Masimo Corporation. His institution received fees for consultancy from Hamilton Medical. DV discloses research funding from Teleflex Medical, could have refrained from intubation on the basis Inc and Rice Foundation, and speaker fees from Theravance Biopharma. of transient improvements of respiratory parameters MWT discloses consulting fees from Fisher and Paykel. JRM discloses during awake prone positioning or conversely have a research support from Fisher & Paykel, and speaker fees from Fisher & lower intubation threshold for patients in the standard Paykel, Gilead, Dextro, and Linet. JGL discloses consulting fees from Baxter Healthcare and Glaxosmithkline. All other authors have no care group. However, that awake prone positioning was competing interests to disclose. not associated either with longer duration of mechanical Data sharing ventilation or with higher mortality in intubated The research protocols for the meta-trial and each individual trial are patients would suggest that the physicians were available in the appendix 2. De-identified data will be available from influenced in the right direction, correctly identifying 9 months to 36 months after article publication to researchers who provide a methodologically sound and ethically approved proposal, for patients who did not require intubation. Similarly, a any purpose of analysis. bias towards excessive intubation in the control group Acknowledgments is unlikely. Overall, these considerations should not This meta-trial was funded by Open AI inc, Rice Foundation, Projet distract from the pragmatic finding that awake prone Hospitalier de Recherche Clinique Interrégional, Appel d’Offre 2020, positioning reduced intubation, regardless of the Groupement Interrégional de Recherche Clinique et d’Innovation Grand underlying mechanism of this effect. Second, in the Ouest, Association Pour la Promotion à Tours de la Réanimation Médicale, Fond de Dotation du CHRU de Tours, and Fisher & Paykel standard care group, one patient out of ten underwent Healthcare Ltd. The meta-trial was carried out with the support of the awake prone positioning. These protocol violations CRICS-TriggerSEP, a FCRIN endorsed research network, REVA could have led to an underestimation of the efficacy of network, and the Irish Critical Care Clinical Trials Network. We thank awake prone positioning in the intention-to-treat Richard Kallet (University of California, San Francisco at San Francisco General Hospital and Trauma Center, San Francisco, CA, USA) and population. Last, the meta-trial design has some Paolo Biselli (University Hospital, University of São Paulo, São Paulo, disadvantages compared with a multisite trial following Brazil) for acting as an independent advisory board of the meta-trial a common protocol at all sites, such as slightly different steering committee. We thank the members of the Awake Prone inclusion criteria between trials or the complexity of Positioning Meta-Trial Group (see appendix 1 for a complete list) for their contributions in conducting the meta-trial, and the patients and tracking the global inclusion rate across trials in relatives for their participation. real-time, which could contribute to overshoot planned References interim analysis or trial sample size in the case of 1 Intensive care national audit and research centre. ICNARC report efficient recruitment as observed in the present trial. on COVID-19 in critical care: England, Wales and Northern Ireland. These limits are outweighed by the benefit of setting 2021. https://www.icnarc.org/DataServices/Attachments/ Download/2d288f8e-728e-eb11-912f-00505601089b (accessed up very quickly an international randomised study April 14, 2021). generating high-level evidence in a short period of 2 Berlin DA, Gulick RM, Martinez FJ. Severe COVID-19. 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BMJ Open 2020; 10: e041520. www.thelancet.com/respiratory Published online August 20, 2021 https://doi.org/10.1016/S2213-2600(21)00356-8 9