UMIN-CTR Clinical Trial

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

COVID-19, acute hypoxemic respiratory failure

Classification by specialty

Pneumology

Intensive care medicine

Classification by malignancy

Others

Genomic information

NO

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

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).

Study type

Interventional

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

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

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

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

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

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

Institute

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

Institute

Department

Personal name

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

Co-sponsor

Name of secondary funder(s)

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

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

Date of disclosure of the study information

2021

Year

10

Month

27

Day

URL releasing protocol

https://www.protocols.io/view/appearl-protocolo-v1-0-bs5dng26

Publication of results

Unpublished

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

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 related information

Registered date

2021

Year

10

Month

27

Day

Last modified on

2021

Year

10

Month

28

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000052387