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Awake prone positioning of hypoxaemic patients with COVID-19: protocol for a randomised controlled open-label superiority meta-trial

Introduction Prone positioning (PP) is an effective first-line intervention to treat patients with moderate to severe acute respiratory distress syndrome (ARDS) receiving invasive mechanical ventilation, as it improves gas exchanges and reduces mortality. The use of PP in awake spontaneous breathing patients with ARDS secondary to COVID-19 was reported to improve oxygenation in few retrospective trials with small sample size. High-level evidence of awake PP for hypoxaemic patients with COVID-19 patients is still lacking. Methods and analysis The protocol of this meta-trial is a prospective collaborative individual participant data meta-analysis of randomised controlled open label superiority trials. This design is particularly adapted to a rapid scientific response in the pandemic setting. It will take place in multiple sites, among others in USA, Canada, Ireland, France and Spain. Patients will be followed up for 28 days. Patients will be randomised to receive whether awake PP and nasal high flow therapy or standard medical treatment and nasal high flow therapy. Primary outcome is defined as the occurrence rate of tracheal intubation or death up to day 28. An interim analysis plan has been set up on aggregated data from the participating research groups. Ethics and dissemination Ethics approvals were obtained in all participating countries. Results of the meta-trial will be submitted for publication in a peer-reviewed journal. Each randomised controlled trial was registered individually, as follows: NCT04325906, NCT04347941, NCT04358939, NCT04395144 and NCT04391140.

whether the mouth is open or closed. HFNC works mainly by flushing the nasal airspaces, reducing anatomical dead space and providing a high FiO2. Secondly, HFNC is extremely well tolerated by delivering warm and well-humidified gas through the nostrils and avoiding the discomfort associated with wearing non-invasive ventilation (NIV) masks. 7 Lastly, HFNC can provide constant FIO2 by avoiding air entrainment since the gas flow can be set to exceed most patient's inspiratory flow. The major goal of HFNC in treating ARDS is to achieve a sufficient level of oxygenation. However, HFNC may be viewed as a partial support therapy, but it is not totally addressing the underlying pathology of ARDS sufficiently, such as the ventilation-BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) BMJ Open doi: 10.1136/bmjopen-2020-041520 :e041520. 10 2020; BMJ Open , et al. Tavernier E perfusion mismatching caused by alveolar collapse and consolidation in the dependent areas of the lung as this disease process worsens. 8 In this regard, combination therapy such as PP with HFNC may be considered to get better physiological effects by improving ventilation-perfusion mismatch in ARDS and a better homogeneity of lung mechanics.
The early application of PP with HFNC, especially in patients with moderate ARDS and baseline SpO2>95%, may help avoid intubation. In a preliminary study, PP was well tolerated with noninvasive respiratory supports, and the efficacy in terms of PaO2/FiO2 with HFNC + PP was higher than HFNC alone. Severe ARDS patients were not appropriate candidates for HFNC/NIV+PP, and a risk for delayed intubation should be noticed. A prospective RCT is warranted in the future in non-intubated moderate ARDS patients on the true benefits of PP before intubation. 9 Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that was first reported in Wuhan, China, and had subsequently spread worldwide, including in United States.
Twenty-nine percent of COVID-19 patients may develop ARDS, 30% of these ARDS patients could be successfully supported with HFNC or NIV, and 60% of the ARDS patients needed intubation and invasive mechanical ventilation, or even ECMO support 10 .
Based on the potential beneficial mechanisms of HFNC and PP mentioned above, early use of PP combined with HFNC to avoid the need for intubation in COVID-19 patients with moderate to severe ARDS needs to be further investigated. We hypothesize that early use of PP combined with HFNC can avoid the need for intubation in moderate to severe ARDS patients. The purpose of this RCT will be to evaluate the effects of PP combined with HFNC for improving oxygenation and reducing the need for intubation compared with HFNC support alone, as well as the safety of the PP therapy in non-intubated COVID-19 induced ARDS patients.

Primary Objectives
The primary outcome for the efficacy of PP combined with HFNC will be the treatment failure rate and intubation rate of HFNC or HFNC+PP support and clinical requirement for advanced respiratory support including NIV, invasive ventilation or ECMO.

Secondary Objectives
The secondary outcomes for the efficacy of PP combined with HFNC will be the improvement of SpO2/FIO2 or PaO2/FiO2 from HFNC alone to HFNC+PP. SpO2/FIO2 will be utilized to substitute PaO2/FiO2 as a means for evaluating oxygenation. [11][12][13][14] As a practical substitute to PaO2/ FIO2, SpO2/FIO2 has been shown to have a strong linear relationship in moderate to severe ARDS 14 and was recommended as a diagnostic tool for early enrollment in clinical trial. 13 FIO2 will be titrated to maintain SpO2 at 90-95%. Other secondary outcomes including the time duration for PP therapy, patients' comfort with PP, PP complications including skin break down, tube/I.V. dislodgement, and the threshold of SpO2/FIO2 for successful PP in COVID-19 induced ARDS cases, HFNC duration, ICU length of stay and ICU mortality rate.

STUDY METHODS
This is a multi-center randomized controlled trial, which will be approved by the Ethic Committees of all the participant hospitals. This trial is registered with ClinicalTrials.gov (NCT04325906).

Inclusion criteria
The diagnostic criteria for COVID-19 pneumonia will be based on the CDC guidelines. .The diagnosis of ARDS will be assigned to patients who meet the Berlin definition criteria 15 : 1) Presence of acute hypoxemic respiratory failure; 2) Acute onset within 7 days of insult, or new (within 7 days) or worsening respiratory symptoms; 3) Bilateral opacities on chest x-ray or CT not fully explained by effusions, lobar or lung collapse, or nodules; 4) Cardiac failure not the primary cause of acute respiratory failure.
Patients are categorized into 3 mutually exclusive classes of ARDS severity using previous definitions based on degree of hypoxemia:

COVID-19 induced adult ARDS patients admitted to the medical ICU or step-down ICU
will be enrolled when their PaO2/FiO2 is less than 300mmHg or FIO2 ≥ 0.3 is required to maintain SpO2 at 88-93% on HFNC treatment.

Exclusion criteria
The exclusion criterion are

Recruiting and consent
All patients admitted with COVID-19 will be screened and patients with ARDS who will be selected by the inclusion and exclusion criteria are included.
All participating subjects provide written informed consent or telephone consent before randomization.

Randomization and masking
Randomization will be stratified on ARDS severity (moderate and severe) performed by permuted block methods using Fisher and Yates tables of random permutations using a centralized interactive contact system is used for randomization. The random block length is 4, and random numbers are generated by computer. All of the centers participating in this study are immediately put in contact with the central unit (Rush University Medical Center) to obtain a randomization number if a patient fulfills the inclusion criteria. Within 6 hr of fulfilling inclusion criteria, a patient will be randomly allocated either to the prone positioning group or the control group (HFNC alone with no prone positioning therapy).

Blinding and Quality Control
The trial will be overseen by a steering committee, and data quality control will be completed by independent data monitoring board. Clinicians and epidemiologists of above organization are not members of participating in our research group. Research coordinator will timely verify database and regularly monitored all the centers on site to ensure the accuracy of the data recorded. An investigator at each center is responsible for enrolling patients in the study, ensuring adherence to the protocol, and completing the electronic case-report form. Although the individual study assignments of the patients could not be blinded, the coordinating center and all the investigators will remain unaware of the study group outcomes until the data are unlocked.
All the analyses are performed by the study statistician not involved in study recruitment, and blind of randomization group until database lock.

Prone positioning implementation
PP will be performed before or 1 hour after meal. Before PP, all the I.V. lines and nasal cannula will be checked by clinicians. PP will be performed by patient under the supervision of clinicians. Assistance will be offered if needed. If tolerated, PP will be maintained for at least 30 minutes, until the patients feel tired to keep that position. PP will be performed minimum twice a day for the first 3 days after the patient's enrollment. Patients will be informed to maintain prone position as long as they can. FIO2 will be adjusted to maintain SpO2 at 92-95%.
Protocol for sedation and comfort evaluation during PP: No sedation will be used during the PP. The patients are monitored by bedside respiratory therapist and nurses for their comfort and tolerance for the PP at 5mins, 30 minutes after PP for the first PP in each day.
A diary will be given to patients to record the time for position change.

HFNC treatment
HFNC will be initiated at 50 L/min (AIRVO2 or Optiflow, Fisher &Paykel Health care Limited., Auckland, New Zealand) with temperature set at 37 o C. Nasal cannula size should be ≤ 50% of the patient's nostril size. FIO2 will be adjusted to maintain SpO2 at 90% to 95%. Flow and temperature will be adjusted based on patient's comfort and clinical response. Patients' vital signs, SpO2, oxygen device and FIO2 before HFNC will be recorded, Patients' vital signs, SpO2, HFNC flow and FIO2 at 30 mins, and 2 hour of HFNC will also be recorded for both groups.
HFNC will be continuously delivered after enrollment in the study for ≥16 hours a day in the first 3 days. Patient comfort to HFNC, will be assessed by means of a scale used and validated in previous studies that is defined as follows: 1, bad; 2, poor; 3, sufficient; 4, good; 5, very good.
Patients' vital signs, SpO2, HFNC flow and FIO2, as well as patient comfort will be documented every 4-6 hours. In order to prevent virus transmission, all the patients with HFNC treatments will wear a surgical mask over the face.

Treatment Failure Criteria
Failure criteria: treatment failure is defined as one of the following criteria 17 : (1) Signs of persisting or worsening respiratory failure, defined by at least two of the following criteria: For patients who meet the failure criteria in the HFNC and HFNC+PP groups, a trial of NIV might be allowed according to the physician's preference in patients with signs of persisting or worsening respiratory failure and no other organ dysfunction before performing endotracheal intubation and invasive ventilation. Reasons for intubation will be recorded as well.

Primary endpoint
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)

Comprehensive therapy
The treatment of COVID-19 is followed by the CDC protocol. Comprehensive therapy is provided by the ICU attending physicians based on published ARDS guidelines. Antivirus treatment and the use of steroids will be recorded as well.

Data collection
The following information of all patients is collected in a data file: patients' characteristics, including age, gender, medical history, diagnosis for COVID-19, the laboratory and microbiology findings, treatment and outcome. Complications including skin breakdown, IV line or nasal cannula dislodgement or desaturation during position change. The respiratory assessments before, during the treatments of HFNC or HFNC with prone position.

Statistical analysis
Definition of the two groups: The patients who receive the prone positioning are classified as prone positioning group. The patients who receive HFNC alone are classified as HFNC group.
Comparisons between the two groups: Quantitative continuous variables are given as either means (±SDs) or medians (with inter-quartile ranges) are compared using the unpaired Student's t test or the Mann-Whitney test. Qualitative or categorical variables are compared with the chi-