UMIN-CTR Clinical Trial

Basic information
Public title	Early awake prone positioning combined with non-invasive oxygen therapy in patients with COVID-19
Acronym	APPearl
Scientific Title	Adaptive, multicenter, randomized, controlled, open trial of the use of early prone positioning in conscious patients with severe COVID-19 without invasive ventilatory support, to prevent invasive mechanical ventilation and death.
Scientific Title:Acronym	Adaptive, multicenter, randomized, controlled, open trial of the use of early prone positioning in conscious patients with severe COVID-19 without invasive ventilatory support, to prevent invasive mechanical ventilation and death (APPearl)
Region	North America South America

Condition
Condition	COVID-19, acute hypoxemic respiratory failure
Classification by specialty	Pneumology Intensive care medicine
Classification by malignancy	Others
Genomic information	NO

Objectives
Narrative objectives1	To evaluate efficacy of early awake prone positioning in patients with acute hypoxemic respiratory failure due to coronavirus disease (COVID-19) under non-invasive oxygen therapy to prevent intubation and mortality
Basic objectives2	Others
Basic objectives -Others	To evaluate safety and tolerance to awake prone positioning in patients with acute hypoxemic respiratory failure due to coronavirus disease (COVID-19) under non-invasive oxygen therapy, probability of transtition and occupation of 4 clinical states (non-invasive oxygen therapy, invasive mechanical ventilation, domiciliary discharge, and death), and improvement of oxygenation parameters.
Trial characteristics_1	Confirmatory
Trial characteristics_2	Explanatory
Developmental phase	Not applicable

Assessment
Primary outcomes	1. Proportion of patients with orotracheal intubation and invasive mechanical ventilation performed up to 28 days after randomization. 2. Proportion of patients who die up to 28 days after randomization.
Key secondary outcomes	1. Probability of transition and occupation of 4 clinical states (non-invasive oxygen therapy, invasive mechanical ventilation, domiciliary discharge, and death) up to day 28 after randomization. 2. Proportion of patients achieving a SpO2/FiO2 greater than or equal to 236 for at least 12 hours within 28 days after randomization. 3. Proportion of patients achieving the greater than or equal to 12 hours/day in the prone position during the duration of the intervention, up to 28 days after randomization 4. SpO2/FiO2 index at different times (Baseline, 1 hour, 6 hours, 24 hours, 48 hours, and 72 hours). 5. Proportion of patients with complications potentially associated to prone position (accidental vascular access dislodgement, vomit, falls, pressure lesions, and intolerance to prone position) up to 28 days after randomization 6. Proportion of patients who develop acute respiratory distress syndrome (up to 28 days after randomization). 7. Proportion of patients with de novo organic failure during hospital stay (up to 28 days after randomization). 8. Time (days) of hospital stay (up to 28 days after randomization). 9. Time (days) of stay in the intensive care unit (up to 28 days after randomization). 10. Total time (days) of invasive mechanical ventilation (up to 28 days after randomization). 11. Total time (days) of ventilator-free days (up to 28 days after randomization).

Base
Study type	Interventional

Study design
Basic design	Parallel
Randomization	Randomized
Randomization unit	Individual
Blinding	Open -no one is blinded
Control	Active
Stratification	YES
Dynamic allocation	YES
Institution consideration	Institution is not considered as adjustment factor.
Blocking	NO
Concealment	Central registration

Intervention
No. of arms	2
Purpose of intervention	Treatment
Type of intervention	Maneuver
Interventions/Control_1	Intervention - Awake prone positioning. The intervention consists of self- or assisted positioning in the decubitus recumbent prone position (bed header at 0 grades) for as much as possible, with the possibility to alternate between complete prone position for 30 min to 2 hours, followed by lateral prone position for 30 min to 2 hours, followed by supine position (bed header 30-60 grades), followed by lateral prone position for 30 min to 2 hours, ending the cycle with 30 min to 2 hours in the prone position. These cycles are intended to increase patient comfort and can be repeated as many times as possible. Time in every position will be quantified. The intervention will be performed until the patient achieves a SpO2/FiO2 index greater than or equal to 235 with an oxygen device providing inspired oxygen fraction (FiO2) lower than 40%, for 12 continuous hours. If this happens, it will be considered as therapeutic success and the patient will be asked to interrupt prone positioning. If the patient does not meet these criteria during the 28-day follow-up, it will be considered as treatment failure. If the patient undergoes orotracheal intubation and invasive mechanical ventilation, it will also be considered as treatment failure and prone positioning will be performed unless the patient has contraindications hemodynamic instability.
Interventions/Control_2	Control - Supine recumbent position. Patients in the control group will be encouraged to remain in the decubitus recumbent supine position (bed header 30-60 grades) for as much as possible. Patients will be able to freely choose any other position. The number of hours spent in all positions will be quantified, including lateral and complete prone positions. Patients in the control group will not be advised to follow the positioning cycle described for the intervention group. If the patient achieves a SpO2/FiO2 index greater than or equal to 235 with an oxygen device providing inspired oxygen fraction (FiO2) lower than 40%, for 12 continuous hours, the patient will no longer be encouraged to remain in the supine recumbent position and this will be considered as success in the supine position. If the patient does not meet these criteria during the 28-day follow-up, it will be considered as failure. If the patient undergoes orotracheal intubation and invasive mechanical ventilation, it will also be considered as failure and prone positioning will be performed unless the patient has hemodynamic instability.
Interventions/Control_3
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Eligibility
Age-lower limit	18 years-old <
Age-upper limit	Not applicable
Gender	Male and Female
Key inclusion criteria	1. Patient hospitalized in non-critical wards, with at least 12 hours of hospital stay but no longer than 48 hours at the moment of randomization. 2. Severe COVID-19 according to the following criteria: a. Symptoms of COVID-19, with 1 or more of the following i. Tachypnea (greater than or equal to 30 breaths per minute) ii. Peripheral oxygen saturation (SpO2) at room air (FiO2 21%) lower than or equal to 93% at sea level (lower than or equal to 89% in Mexico City) at any moment of current hospitalization. iii. PaO2/FiO2 ratio <300 iv. Pulmonary infiltrates >50% in imaging study performed in the last 24 to 48 hours. 3. Oxygen therapy with a device providing a FiO2 greater than or equal to 40% a. Low-flow nasal cannula with at least 5 liters per minute. b. Non-rebreather mask c. High-flow nasal cannula without imminent requirement of orotracheal intubation (ROX index greater than or equal to 4.88) 4. The participant understands the intervention, randomization, follow-up and provides their written informed consent prior to randomization.
Key exclusion criteria	1. Patients in palliative care 2. Patients with imminent orotracheal intubation according to refractory hypoxemia with acute respiratory distress syndrome (ARDS), acute respiratory acidosis (pH < 7.15, PaCO2 >45 mmHg) with ARDS, requirement of airway protection. 3. Patients with unsolved shock (reanimation phase or norepinephrine dose greater than or equal to 0.15 mcg/kg/min). 4. Unstable arrythmias (bradycardia o tachycardia). 5. Mental agitation or altered mental state (Glasgow Comma Scale <10 points) that would impede cooperation to self-prone. 6. Instability of the pelvis, vertebral column, or femur due to recent surgery or trauma. 7. Anatomical alterations that limit the adoption of prone position (severe kyphoscoliosis, muscle contracture, or other). 8. Abdominal surgery in the last 15 days. 9. Thoracic lesion or surgery in the last 15 days. 10. Pregnancy 11. Intracranial hypertension 12. Deep vein thrombosis in the last 2 days. 13. Heart pacemaker surgery in the last 2 days. 14. Chest tube with air leak 15. Recent facial trauma or surgery 16. Morbid obesity (BMI >40 kg/m2) 17. Pressure lesions or ulcers
Target sample size	384

Research contact person
Name of lead principal investigator	1st name Jose Middle name de Jesus Last name Vidal-Mayo
Organization	Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Division name	Intensive Care Unit
Zip code	14080
Address	Av. Vasco de Quiroga 15, Col. Belisario Dominguez Seccion XVI, Tlalpan 14080, Mexico City, Mexico
TEL	+52(55)55737378
Email	interstrok@hotmail.com

Public contact
Name of contact person	1st name Jose Middle name de Jesus Last name Vidal-Mayo
Organization	Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Division name	Intensive Care Unit
Zip code	14080
Address	Av. Vasco de Quiroga 15, Col. Belisario Dominguez Seccion XVI, Tlalpan 14080, Mexico City, Mexico
TEL	+52(55)48158075
Homepage URL	https://www.incmnsz.mx/opencms/
Email	interstrok@hotmail.com

Sponsor
Institute	Mexican Secretariat of Health Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran. Intensive Care Unit
Institute
Department

Funding Source
Organization	Mexican Secretariat of Health Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran. Intensive Care Unit
Organization
Division
Category of Funding Organization	Government offices of other countries
Nationality of Funding Organization	Mexican

Other related organizations
Co-sponsor
Name of secondary funder(s)

IRB Contact (For public release)
Organization	Research and Ethics Committee of the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Address	Av. Vasco de Quiroga 15, Col. Belisario Dominguez Seccion XVI, Tlalpan 14080, Mexico City, Mexico
Tel	+52(55)55737378
Email	sergio.hernandez@incmnsz.mx

Secondary IDs
Secondary IDs	YES
Study ID_1	U1111-1270-7262
Org. issuing International ID_1	Universal Trial Number - World Health Organization
Study ID_2	SME-3394-20-20-1
Org. issuing International ID_2	Research and Ethics Committee of the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
IND to MHLW

Institutions
Institutions

Other administrative information
Date of disclosure of the study information	2021 Year 10 Month 27 Day

Related information
URL releasing protocol	https://www.protocols.io/view/appearl-protocolo-v1-0-bs5dng26
Publication of results	Unpublished

Result
URL related to results and publications
Number of participants that the trial has enrolled
Results
Results date posted
Results Delayed
Results Delay Reason
Date of the first journal publication of results
Baseline Characteristics
Participant flow
Adverse events
Outcome measures
Plan to share IPD
IPD sharing Plan description

Progress
Recruitment status	Enrolling by invitation
Date of protocol fixation	2021 Year 03 Month 09 Day
Date of IRB	2021 Year 03 Month 12 Day
Anticipated trial start date	2021 Year 09 Month 02 Day
Last follow-up date	2023 Year 09 Month 01 Day
Date of closure to data entry
Date trial data considered complete
Date analysis concluded

Other
Other related information

Management information
Registered date	2021 Year 10 Month 27 Day
Last modified on	2021 Year 10 Month 28 Day

Link to view the page
URL(English)	https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000052387