Trial NCT04325906, NCT04347941, NCT04358939, NCT04395144
Publication Ehrmann S, Lancet Respir Med, 2021 (published paper)
Dates: 2020-04-02 to 2021-01-26
Funding: Mixed (Open AI inc, Rice Foundation, Projet Hospitalier de Recherche Clinique Interrégional, Appel d'Offre 2020, Groupement Interrégional de Recherche Clinique et d'Innovation Grand Ouest, Association Pour la Promotion à Tours de la Réanimation Médicale, Fond de Dotation du CHRU de Tours, and Fisher & Paykel Healthcare Ltd.)
Conflict of interest: Yes
| Methods | |
| RCT Blinding: Unblinded | |
| Location :
Multicenter / Canada, France, Ireland, Mexico, USA, Spain Follow-up duration (days): 28 | |
| Inclusion criteria | Adults (>18 years old) with acute hypoxaemic respiratory failure due to proven (or highly clinically suspected, pending microbiological confirmation) COVID-19 pneumonia were eligible for enrolment at participating hospitals. Acute hypoxaemic respiratory failure was defined as a requirement of respiratorysupport with high-flow nasal cannula and a ratio of peripheral arterial oxygen saturation (SpO2) to the fraction of inspired oxygen (FiO2) [SpO2:FiO2] of 315 or less (which is equivalent to a ratio of partial pressure of arterial oxygen [PaO2] to FiO2 [PaO2:FiO2] ≤300 mmHg). Inclusion criteria and the planned intervention were harmonised across all five trials. |
| Exclusion criteria | Refused or could not consent; required immediate tracheal intubation; contraindications to awake prone positioning; BMI >40 kg/m2; already enrolled in other trials; pregnant; initiation of awake prone positioning on treating physicians’ orders before inclusion in the trial; physician decision not to include the patient; respiratory support with high-flow nasal cannula for more than 48 h before enrolment; no insurance coverage |
| Interventions | |
| Treatment
Prone position Instructed and assisted to lie in the prone position for as long and as frequently as possible each day until weaning of high-flow nasal cannula, discharge from hospital, intubation, or death. |
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| Control
Standard care ( / ) Definition of Standard care: Protocols: HFNC will be initiated at 50 L/min (AIRVO2 or Optiflow, Fisher & Paykel Healthcare Limited, Auckland, New Zealand) with temperature set at 37°C. Nasal cannula size will be determined by the patient’s nostril size (≤50%). FiO2 will be adjusted to maintain SpO2 at 92%–95%. Flow and temperature will be adjusted based on patient’s comfort and clinical response. (USA, Canada); Control patients will receive full standard care. (Ireland); HFNC adapted for an SpO2 of 90%–95%. Except in case of poor tolerance by the patient a minimum gas flow rate of 50 L/min will be set initially. Weaning of the HFNC will first be performed reducing FiO2 down to 0.4 before reducing the gas flow rate. In clinically stable patients with a FiO2 less than or equal to 0.4 and a gas flow rate less than or equal to 30 L/ min, an attempt will be made to switch to standard oxygen therapy at 4–6L/min. (France, Spain) | |
| Participants | |
| Randomized 1126 participants (n1=567 / n2= 559) | |
| Characteristics of participants N=1126 Mean age : 61.1 746 males Severity : Mild: n=0 / Moderate: n=0/ Severe: n=1121 Critical: n=0 | |
| Primary outcome | |
| In the register Therapeutic failure within 28 days of randomisation, defined as intubation (successful or attempted) or death. (harmonized protocol). Intubation rate [ Time Frame: 28 days ](Mexico); Therapeutic failure death or intubation [ Time Frame: 28 days within randomization ](Spain); Rate of Therapeutic failure, defined as a combined outcome of rate of intubation or death [ Time Frame: Up to 28 days after randomization ](Canada); Therapeutic failure within 14 days of randomization [ Time Frame: From randomization to day 14 ](France); The effect of prone positioning on requirement for invasive mechanical ventilation in patients with COVID 19 induced respiratory failure. [ Time Frame: Up to 28 days post randomisation ](Ireland); Treatment failure (intubation or death) [ Time Frame: 28 days ](USA) | |
| In the report Treatment failure within 28 days of enrolment, defined as intubation or death. | |
| Documents available |
Protocol Yes. In English Statistical plan Yes Data-sharing stated
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| Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review |
Some concerns |
| General comment | In addition to the published article, the trial registries, protocols, statistical analysis plans and supplementary appendices were used in data extraction and assessment of risk of bias. The article reports the combined results of six trials that were independently registered and conducted. There was some variations in outcomes included in the registries of individual trials, but all agreed on a harmonized overall protocol and that the combined analysis based on the harmonized protocol would be published first. Individual trial analyses will be published later. The primary outcome in the article reflects that in the harmonized protocol. There are no substantive differences in secondary outcomes. The trials were terminated following a third interim analysis on 928 patients who had been followed-up for at least 28 days showed that the predefined statistical criteria for efficacy were met. Ultimately the trials included 1126 who underwent randomization. |