Awake Prone Positioning to Reduce Invasive VEntilation in COVID-19 Induced Acute Respiratory failurE (APPROVE-CARE)

• ClinicalTrials.gov Identifier: NCT04347941
• Recruitment Status: Terminated
• First Posted: April 15, 2020
• Results First Posted: December 2, 2021
• Last Update Posted: December 2, 2021
• Sponsor: University College Hospital Galway
• Information provided by (Responsible Party): John Laffey, University College Hospital Galway

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Conditions: ARDS, Human; Mechanical Ventilation Complication; COVID19
• Interventions: Procedure: Prone Positioning; Procedure: Standard of care.
• Enrollment: 24

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Prone Positioning	Standard Care
Arm/Group Description	Intervention patients will remain up to 16 hours per day in Prone Positioning with 45 minutes breaks for meals Prone Positioning: Patient will be asked to remain for at least one hour and to a maximum total of 16 hours in prone position with 45 minutes breaks for meals. Immediately prior to proning, if spO2 <94% on FiO2 0.4, start on 100% O2 to ensure stability during proning. A nurse or assistant will assist patient to turn on side and then face down with the support of pillows as required for comfort, ensure that they are predominantly on their chest rather than on their side. Arms can be at side, in swimmer position and can be moved to patients' comfort, pillows under knees and chest for comfort and call bell to be at patient's arm's length. Vitals and work of breathing score will be measured before and at 1 hour into each proning session and at the end of each session. Total length of time in prone position will be recorded. Intervention to continue daily until oxygen requirement to maintain spO2 >94% is below FiO2 0.4 via venturi facemask or high flow nasal cannula	Control patients will receive full standard care. Prone Positioning as a rescue intervention is permitted and is recorded. Standard of care.: Standard of care. Prone positioning may be administered as a rescue therapy
Period Title: Overall Study
Started	12	12
Completed	12	12
Not Completed	0	0

Baseline Characteristics

Arm/Group Title		Prone Positioning	Standard Care	Total
Arm/Group Description		Intervention patients will remain up to 16 hours per day in Prone Positioning with 45 minutes breaks for meals Prone Positioning: Patient will be asked to remain for at least one hour and to a maximum total of 16 hours in prone position with 45 minutes breaks for meals. Immediately prior to proning, if spO2 <94% on FiO2 0.4, start on 100% O2 to ensure stability during proning. A nurse or assistant will assist patient to turn on side and then face down with the support of pillows as required for comfort, ensure that they are predominantly on their chest rather than on their side. Arms can be at side, in swimmer position and can be moved to patients' comfort, pillows under knees and chest for comfort and call bell to be at patient's arm's length. Vitals and work of breathing score will be measured before and at 1 hour into each proning session and at the end of each session. Total length of time in prone position will be recorded. Intervention to continue daily until oxygen requirement to maintain spO2 >94% is below FiO2 0.4 via venturi facemask or high flow nasal cannula	Control patients will receive full standard care. Prone Positioning as a rescue intervention is permitted and is recorded. Standard of care.: Standard of care. Prone positioning may be administered as a rescue therapy	Total of all reporting groups
Overall Number of Baseline Participants		12	12	24
Baseline Analysis Population Description		Patients with suspected or confirmed COVID-19 pneumonia requiring high flow nasal cannula oxygen were randomized to either awake prone positioning or standard of care. The primary outcome was the requirement for invasive mechanical or death post 28 days randomization.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	12 participants	12 participants	24 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	7 58.3%	7 58.3%	14 58.3%
	>=65 years	5 41.7%	5 41.7%	10 41.7%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	12 participants	12 participants	24 participants
	Female	3 25.0%	5 41.7%	8 33.3%
	Male	9 75.0%	7 58.3%	16 66.7%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	12 participants	12 participants	24 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	0 0.0%	0 0.0%
	White	12 100.0%	12 100.0%	24 100.0%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
Ireland	Number Analyzed	12 participants	12 participants	24 participants
		12	12	24

Outcome Measures

1. Primary Outcome

Title	The Effect of Prone Positioning on Requirement for Invasive Mechanical Ventilation or Death in Patients With COVID 19 Induced Respiratory Failure.
Description	A measure of effect of awake prone positioning in patients with confirmed or suspected COVID-19 acute hypoxemic respiratory failure undergoing supplemental oxygen via high flow nasal cannular oxygen on reducing requirement for invasive mechanical ventilation or death. Outcome measure is calculated as a count of the number of patients who went onto require invasive mechanical ventilation or died up to 28 days post randomization.
Time Frame	Up to 28 days post randomisation

Outcome Measure Data

Analysis Population Description

Number of patients who required invasive mechanical ventilation or who died in each group up to 28 days post randomization.

Arm/Group Title	Prone Positioning	Standard Care
Arm/Group Description:	Intervention patients will remain up to 16 hours per day in Prone Positioning with 45 minutes breaks for meals Prone Positioning: Patient will be asked to remain for at least one hour and to a maximum total of 16 hours in prone position with 45 minutes breaks for meals. Immediately prior to proning, if spO2 <94% on FiO2 0.4, start on 100% O2 to ensure stability during proning. A nurse or assistant will assist patient to turn on side and then face down with the support of pillows as required for comfort, ensure that they are predominantly on their chest rather than on their side. Arms can be at side, in swimmer position and can be moved to patients' comfort, pillows under knees and chest for comfort and call bell to be at patient's arm's length. Vitals and work of breathing score will be measured before and at 1 hour into each proning session and at the end of each session. Total length of time in prone position will be recorded. Intervention to continue daily until oxygen requirement to maintain spO2 >94% is below FiO2 0.4 via venturi facemask or high flow nasal cannula	Control patients will receive full standard care. Prone Positioning as a rescue intervention is permitted and is recorded. Standard of care.: Standard of care. Prone positioning may be administered as a rescue therapy
Overall Number of Participants Analyzed	12	12
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	2 16.7%

2. Secondary Outcome

Title	Length of Time Tolerating Prone Positioning
Description	description of duration of prone positioning in hours per day from day 0 to day 14 in trial
Time Frame	Daily during intervention up to 14 days post randomisation

Outcome Measure Data

Analysis Population Description

description of duration of prone positioning in hours per day from day 0 to day 14 in trial

Arm/Group Title	Prone Positioning	Standard Care
Arm/Group Description:	Intervention patients will remain up to 16 hours per day in Prone Positioning with 45 minutes breaks for meals Prone Positioning: Patient will be asked to remain for at least one hour and to a maximum total of 16 hours in prone position with 45 minutes breaks for meals. Immediately prior to proning, if spO2 <94% on FiO2 0.4, start on 100% O2 to ensure stability during proning. A nurse or assistant will assist patient to turn on side and then face down with the support of pillows as required for comfort, ensure that they are predominantly on their chest rather than on their side. Arms can be at side, in swimmer position and can be moved to patients' comfort, pillows under knees and chest for comfort and call bell to be at patient's arm's length. Vitals and work of breathing score will be measured before and at 1 hour into each proning session and at the end of each session. Total length of time in prone position will be recorded. Intervention to continue daily until oxygen requirement to maintain spO2 >94% is below FiO2 0.4 via venturi facemask or high flow nasal cannula	Control patients will receive full standard care. Prone Positioning as a rescue intervention is permitted and is recorded. Standard of care.: Standard of care. Prone positioning may be administered as a rescue therapy
Overall Number of Participants Analyzed	12	12
Mean (Standard Deviation); Unit of Measure: hours
	3.3 (2.7)	1.0 (2.5)

3. Secondary Outcome

Title	PaO2/FiO2 Ratio Measured Before Prone Positioning
Description	Measure of change in oxygenation before intervention in the patients assigned to awake prone positioning
Time Frame	Immediately before intervention

Outcome Measure Data

Analysis Population Description

paO2 to fiO2 ratio before prone positioning in the group assigned to undergo awake prone positioning

Arm/Group Title	Prone Positioning	Standard of Care
Arm/Group Description:	Intervention patients will remain up to 16 hours per day in Prone Positioning with 45 minutes breaks for meals Prone Positioning: Patient will be asked to remain for at least one hour and to a maximum total of 16 hours in prone position with 45 minutes breaks for meals. Immediately prior to proning, if spO2 <94% on FiO2 0.4, start on 100% O2 to ensure stability during proning. A nurse or assistant will assist patient to turn on side and then face down with the support of pillows as required for comfort, ensure that they are predominantly on their chest rather than on their side. Arms can be at side, in swimmer position and can be moved to patients' comfort, pillows under knees and chest for comfort and call bell to be at patient's arm's length. Vitals and work of breathing score will be measured before and at 1 hour into each proning session and at the end of each session. Total length of time in prone position will be recorded. Intervention to continue daily until oxygen requirement to maintain spO2 >94% is below FiO2 0.4 via venturi facemask or high flow nasal cannula	Patients with suspected or confirmed COVID-19 pneumonia who are randomized to not undergo awake prone positioning but receive otherwise identical care as the awake prone positioning group.
Overall Number of Participants Analyzed	12	12
Mean (Standard Deviation); Unit of Measure: ratio
	144 (52)	114 (40)

4. Secondary Outcome

Title	PaO2/FiO2 Ratio After 1 Hours of Prone Positioning
Description	Measure of change in oxygenation following patients being placed in the prone position for 1 hour
Time Frame	During intervention

Outcome Measure Data

Analysis Population Description

change in paO2 one hour after proning in the individuals who were in the intervention group and underwent awake prone positioning

Arm/Group Title	Prone Positioning
Arm/Group Description:	Intervention patients will remain up to 16 hours per day in Prone Positioning with 45 minutes breaks for meals Prone Positioning: Patient will be asked to remain for at least one hour and to a maximum total of 16 hours in prone position with 45 minutes breaks for meals. Immediately prior to proning, if spO2 <94% on FiO2 0.4, start on 100% O2 to ensure stability during proning. A nurse or assistant will assist patient to turn on side and then face down with the support of pillows as required for comfort, ensure that they are predominantly on their chest rather than on their side. Arms can be at side, in swimmer position and can be moved to patients' comfort, pillows under knees and chest for comfort and call bell to be at patient's arm's length. Vitals and work of breathing score will be measured before and at 1 hour into each proning session and at the end of each session. Total length of time in prone position will be recorded. Intervention to continue daily until oxygen requirement to maintain spO2 >94% is below FiO2 0.4 via venturi facemask or high flow nasal cannula
Overall Number of Participants Analyzed	12
Mean (Standard Deviation); Unit of Measure: ratio
	33 (32)

5. Secondary Outcome

Title	SpO2/FiO2 Ratio Measured Before Prone Positioning
Description	Measure of oxygenation using pulse oximetry before intervention where ABG not available
Time Frame	Immediately before intervention

Outcome Measure Data

Analysis Population Description

spO2 to fiO2 ratio at baseline prior to awake prone position in those undergoing awake prone position, and on the morning post enrolment for patients undergoing standard of care treatment

Arm/Group Title	Prone Positioning	Standard of Care
Arm/Group Description:	Intervention patients will remain up to 16 hours per day in Prone Positioning with 45 minutes breaks for meals Prone Positioning: Patient will be asked to remain for at least one hour and to a maximum total of 16 hours in prone position with 45 minutes breaks for meals. Immediately prior to proning, if spO2 <94% on FiO2 0.4, start on 100% O2 to ensure stability during proning. A nurse or assistant will assist patient to turn on side and then face down with the support of pillows as required for comfort, ensure that they are predominantly on their chest rather than on their side. Arms can be at side, in swimmer position and can be moved to patients' comfort, pillows under knees and chest for comfort and call bell to be at patient's arm's length. Vitals and work of breathing score will be measured before and at 1 hour into each proning session and at the end of each session. Total length of time in prone position will be recorded. Intervention to continue daily until oxygen requirement to maintain spO2 >94% is below FiO2 0.4 via venturi facemask or high flow nasal cannula	Patients with suspected or confirmed COVID-19 pneumonia requiring high flow nasal cannula oxygen who were randomized to not undergo awake prone positioning as part of their management and received otherwise identical treatment as the awake prone positioning arm.
Overall Number of Participants Analyzed	12	12
Mean (Standard Deviation); Unit of Measure: ratio
	193 (45)	178 (52)

6. Secondary Outcome

Title	SpO2/FiO2 Ratio After 1 Hour in Prone Positioning
Description	Measure of oxygenation 1 hour after intervention where ABG not available
Time Frame	During Intervention

Outcome Measure Data

Analysis Population Description

spO2 to fiO2 ratio following 1 hour in prone position

Arm/Group Title	Prone Positioning
Arm/Group Description:	Intervention patients will remain up to 16 hours per day in Prone Positioning with 45 minutes breaks for meals Prone Positioning: Patient will be asked to remain for at least one hour and to a maximum total of 16 hours in prone position with 45 minutes breaks for meals. Immediately prior to proning, if spO2 <94% on FiO2 0.4, start on 100% O2 to ensure stability during proning. A nurse or assistant will assist patient to turn on side and then face down with the support of pillows as required for comfort, ensure that they are predominantly on their chest rather than on their side. Arms can be at side, in swimmer position and can be moved to patients' comfort, pillows under knees and chest for comfort and call bell to be at patient's arm's length. Vitals and work of breathing score will be measured before and at 1 hour into each proning session and at the end of each session. Total length of time in prone position will be recorded. Intervention to continue daily until oxygen requirement to maintain spO2 >94% is below FiO2 0.4 via venturi facemask or high flow nasal cannula
Overall Number of Participants Analyzed	12
Mean (Standard Deviation); Unit of Measure: ratio
	247 (53)

7. Secondary Outcome

Title	Number Requiring Increase in Ventilatory Assistance
Description	Number of patients in each group requiring an increase in the respiratory support from baseline high flow nasal cannula oxygen post randomization up to 28 days later, defined as need for continuous positive airway pressure (CPAP), bilevel positive airway pressure (biPAP)
Time Frame	Up to 28 days post randomisation

Outcome Measure Data

Analysis Population Description

Number of patients in each group requiring an increase in the respiratory support from baseline high flow nasal cannula oxygen post randomization up to 28 days later, defined as need for continuous positive airway pressure (CPAP), bilevel positive airway pressure (biPAP)

Arm/Group Title	Prone Positioning	Standard Care
Arm/Group Description:	Intervention patients will remain up to 16 hours per day in Prone Positioning with 45 minutes breaks for meals Prone Positioning: Patient will be asked to remain for at least one hour and to a maximum total of 16 hours in prone position with 45 minutes breaks for meals. Immediately prior to proning, if spO2 <94% on FiO2 0.4, start on 100% O2 to ensure stability during proning. A nurse or assistant will assist patient to turn on side and then face down with the support of pillows as required for comfort, ensure that they are predominantly on their chest rather than on their side. Arms can be at side, in swimmer position and can be moved to patients' comfort, pillows under knees and chest for comfort and call bell to be at patient's arm's length. Vitals and work of breathing score will be measured before and at 1 hour into each proning session and at the end of each session. Total length of time in prone position will be recorded. Intervention to continue daily until oxygen requirement to maintain spO2 >94% is below FiO2 0.4 via venturi facemask or high flow nasal cannula	Control patients will receive full standard care. Prone Positioning as a rescue intervention is permitted and is recorded. Standard of care.: Standard of care. Prone positioning may be administered as a rescue therapy
Overall Number of Participants Analyzed	12	12
Measure Type: Count of Participants; Unit of Measure: Participants
	4 33.3%	4 33.3%

8. Secondary Outcome

Title	Work of Breathing Assessment (Respiratory Distress Scale)
Description	Measure of work of breathing in COVID-19 based on Oxygen Delivery Device, Oxygen Saturation and respiratory rate and accessory muscle use with 0-3 Mild, 4-6 Moderate and 7-10 Severe
Time Frame	Immediately before and during intervention

Outcome Measure Data

Analysis Population Description

We did not carry out this aspect of the study due to constraints related to the Pandemic

Arm/Group Title	Prone Positioning	Standard Care
Arm/Group Description:	Intervention patients will remain up to 16 hours per day in Prone Positioning with 45 minutes breaks for meals Prone Positioning: Patient will be asked to remain for at least one hour and to a maximum total of 16 hours in prone position with 45 minutes breaks for meals. Immediately prior to proning, if spO2 <94% on FiO2 0.4, start on 100% O2 to ensure stability during proning. A nurse or assistant will assist patient to turn on side and then face down with the support of pillows as required for comfort, ensure that they are predominantly on their chest rather than on their side. Arms can be at side, in swimmer position and can be moved to patients' comfort, pillows under knees and chest for comfort and call bell to be at patient's arm's length. Vitals and work of breathing score will be measured before and at 1 hour into each proning session and at the end of each session. Total length of time in prone position will be recorded. Intervention to continue daily until oxygen requirement to maintain spO2 >94% is below FiO2 0.4 via venturi facemask or high flow nasal cannula	Control patients will receive full standard care. Prone Positioning as a rescue intervention is permitted and is recorded. Standard of care.: Standard of care. Prone positioning may be administered as a rescue therapy
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

9. Secondary Outcome

Title	Changes in Bioimpedance Measures of Lung Edema in Patients in PP
Description	Substudy examining use of bioimpedance as a surrogate measure of lung edema following prone positioning
Time Frame	During intervention

Outcome Measure Data

Analysis Population Description

Due to constraints related to the pandemic, this aspect of the study was not carried out.

Arm/Group Title	Prone Positioning	Standard Care
Arm/Group Description:	Intervention patients will remain up to 16 hours per day in Prone Positioning with 45 minutes breaks for meals Prone Positioning: Patient will be asked to remain for at least one hour and to a maximum total of 16 hours in prone position with 45 minutes breaks for meals. Immediately prior to proning, if spO2 <94% on FiO2 0.4, start on 100% O2 to ensure stability during proning. A nurse or assistant will assist patient to turn on side and then face down with the support of pillows as required for comfort, ensure that they are predominantly on their chest rather than on their side. Arms can be at side, in swimmer position and can be moved to patients' comfort, pillows under knees and chest for comfort and call bell to be at patient's arm's length. Vitals and work of breathing score will be measured before and at 1 hour into each proning session and at the end of each session. Total length of time in prone position will be recorded. Intervention to continue daily until oxygen requirement to maintain spO2 >94% is below FiO2 0.4 via venturi facemask or high flow nasal cannula	Control patients will receive full standard care. Prone Positioning as a rescue intervention is permitted and is recorded. Standard of care.: Standard of care. Prone positioning may be administered as a rescue therapy
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

10. Secondary Outcome

Title	Use of Awake Prone Positioning as a Rescue Intervention in Control Patients
Description	Number of patients who underwent rescue awake prone positioning in control patients by physicians in response to hypoxia
Time Frame	Up to 28 days post randomisation

Outcome Measure Data

Analysis Population Description

Number of patients who underwent awake prone positioning in the control arm of the study as a rescue manoeuvre in response to hypoxia.

Arm/Group Title	Standard Care
Arm/Group Description:	Control patients will receive full standard care. Prone Positioning as a rescue intervention is permitted and is recorded. Standard of care.: Standard of care. Prone positioning may be administered as a rescue therapy
Overall Number of Participants Analyzed	12
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%

Adverse Events

Time Frame	hospital discharge or 28 days
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Prone Positioning	Standard Care
Arm/Group Description	Intervention patients will remain up to 16 hours per day in Prone Positioning with 45 minutes breaks for meals Prone Positioning: Patient will be asked to remain for at least one hour and to a maximum total of 16 hours in prone position with 45 minutes breaks for meals. Immediately prior to proning, if spO2 <94% on FiO2 0.4, start on 100% O2 to ensure stability during proning. A nurse or assistant will assist patient to turn on side and then face down with the support of pillows as required for comfort, ensure that they are predominantly on their chest rather than on their side. Arms can be at side, in swimmer position and can be moved to patients' comfort, pillows under knees and chest for comfort and call bell to be at patient's arm's length. Vitals and work of breathing score will be measured before and at 1 hour into each proning session and at the end of each session. Total length of time in prone position will be recorded. Intervention to continue daily until oxygen requirement to maintain spO2 >94% is below FiO2 0.4 via venturi facemask or high flow nasal cannula	Control patients will receive full standard care. Prone Positioning as a rescue intervention is permitted and is recorded. Standard of care.: Standard of care. Prone positioning may be administered as a rescue therapy
All-Cause Mortality
	Prone Positioning	Standard Care
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/12 (0.00%)	0/12 (0.00%)
Serious Adverse Events
	Prone Positioning	Standard Care
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/12 (0.00%)	0/12 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Prone Positioning	Standard Care
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/12 (0.00%)	0/12 (0.00%)

Limitations and Caveats

Study was terminated after an interim analysis of a prospective meta-trial in which the patients reached statistical criteria for efficiency

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Dr Bairbre McNicholas
• Organization: National University of Ireland, Galway
• Phone: +35391893063
• EMail: bmcnicholas@nuigalway.ie

Publications of Results:

Tavernier E, McNicholas B, Pavlov I, Roca O, Perez Y, Laffey J, Mirza S, Cosgrave D, Vines D, Frat JP, Ehrmann S, Li J. Awake prone positioning of hypoxaemic patients with COVID-19: protocol for a randomised controlled open-label superiority meta-trial. BMJ Open. 2020 Nov 11;10(11):e041520. doi: 10.1136/bmjopen-2020-041520.

Other Publications:

Ehrmann S, Li J, Ibarra-Estrada M, Perez Y, Pavlov I, McNicholas B, Roca O, Mirza S, Vines D, Garcia-Salcido R, Aguirre-Avalos G, Trump MW, Nay MA, Dellamonica J, Nseir S, Mogri I, Cosgrave D, Jayaraman D, Masclans JR, Laffey JG, Tavernier E; Awake Prone Positioning Meta-Trial Group. Awake prone positioning for COVID-19 acute hypoxaemic respiratory failure: a randomised, controlled, multinational, open-label meta-trial. Lancet Respir Med. 2021 Dec;9(12):1387-1395. doi: 10.1016/S2213-2600(21)00356-8. Epub 2021 Aug 20.

• Responsible Party: John Laffey, University College Hospital Galway
• ClinicalTrials.gov Identifier: NCT04347941
• Other Study ID Numbers: APPROVE-CARE-2020
• First Submitted: April 8, 2020
• First Posted: April 15, 2020
• Results First Submitted: November 20, 2021
• Results First Posted: December 2, 2021
• Last Update Posted: December 2, 2021