Jama E2120714 s003

Supplemental Online Content
Ospina-Tascón GA, Calderón-Tapia LE, García AF, et al; HiFLo-Covid Investigators. Effect of high-flow
oxygen therapy vs conventional oxygen therapy on invasive mechanical ventilation and clinical recovery
in patients with severe COVID-19: a randomized clinical trial. JAMA. Published December 7, 2021.
doi:10.1001/jama.2021.20714
eAppendix. Supplemental Methods

eTable 1. Seven-Point Ordinal Scale
eTable 2. Other Patient Characteristics at Randomization
eTable 3. Patient Characteristics 2-Hours and 4-Hours After the Start of Assigned Oxygenation Therapy
eTable 4. Time From Randomization to Intubation/Invasive Mechanical Ventilation Support/Additional Respiratory
Support Strategies/Additional Therapies
eTable 5. Causes of Intubation at Day-7 and Causes of Death at Day-28
eTable 6. Primary and Secondary Outcomes for All Patients and According to 7-Category Ordinal Scale
eTable 7. Seven-Category Ordinal Scale at Day 28
eTable 8. Post-Hoc Sensitivity Analysis Considering All Randomized Patients Who Provided Consent to Use Data
(N=212)
eTable 9. Post-Hoc Sensitivity Analysis Considering the Site-by-Treatment Effects (N=109)
eTable 10. Proportional Hazard Asssumption Test
eFigure 1. Time Course of PaO2/FIO2 Ratio for Study Groups
eFigure 2. Time Course of Oxygen Flow (L/min) for Study Groups
eFigure 3. Time Course of Multiple Organ Dysfunction According to SOFA Score for Study Groups
eFigure 4. Time Course of Extra-pulmonary Organ Dysfunction According to SOFA Score for Study Groups
eFigure 5. Kaplan Meier Estimates of Cumulative Intubation Events According to Initial PaO2/FIO2 < or ≥ 100
eFigure 7. Kaplan Meier Estimates of Cumulative Intubation Events According to Initial IL-6 < or ≥ 100 pg/mL
eFigure 8. Kaplan Meier Estimates of Clinical Recovery According to Initial PaO2/FIO2 < or ≥ 100
eFigure 9. Kaplan Meier Estimates of Clinical Recovery According to Age < or ≥ 60 Years Old
eFigure 10. Kaplan Meier Estimates of Clinical Recovery According to Initial IL-6 < or ≥ 100 pg/mL
eFigure 11. Time Course of Total Leucocyte Count for Study Groups
eFigure 12. Time Course of Neutrophil:Lymphocyte Ratio for Study Groups
eFigure 13. Time Course of Ferritin Levels for Study Groups
eFigure 14. Time Course of D-Dimer for Study Groups
eFigure 15. Time Course of Lactate Dehydrogenase Levels for Study Groups
eFigure 16. Time Course of Platelets Count for Study Groups
eFigure 17. Time Course of IL-6 for Study Groups
eReferences
This supplemental material has been provided by the authors to give readers additional
information about their work.
© 2021 American Medical Association. All rights reserved.

eAppendix. Supplemental Methods
Study Oversight
An independent data quality surveillance committee (DQSC) and the steering committee were
committed to guarantee for the wholeness and accuracy of the data and also to ensure
compliance with the protocol. To fulfill such assignment, meetings among members from the
DQSC, research assistants from the coordinating center and the steering committee were
regularly performed aiming to evaluate data quality, potential protocol deviations and adverse
events detected throughout the study period. Research assistants from the coordinating center
and DQSC members regularly monitored all participating centers checking for the accuracy of
information recorded in the electronic case-report form. Data inaccuracies, potential deviations
and adverse effects were immediately examined with the research members from the involved
participating center and later discussed during the data quality surveillance meeting in order
to correct data inaccuracies, to solve deviations (if possible), to prevent future failures and to
report predefined and potentially new adverse effects. All adverse events were communicated
to the respective Ethical and Research Committee within the time frame as stipulated by each
center (usually within 24 hours for major events and one week for minor ones). At the end of
the study, one event was catalogued as major violation: a patient allocated to conventional
oxygen therapy was switched to high-flow oxygen nasal cannula by decision of his attending
physician. Finally, he was analyzed within his original allocated group according to the planned
intention-to-treat basis.
Members Of Boards And Committees
- Steering Committee: Gustavo A. Ospina-Tascón, Alberto Federico García, and Alexandre Biasi
Cavalcanti.
- Data quality surveillance committee (DQSC): Liliana Vallecilla, Diana Marcela Martínez, and
David Pantoja.
- Data Safety Monitoring Board (DSMB): Daniel De Backer (Université Libre de Bruxelles,
Bruxelles, Belgium), Jan Bakker (New York University, New York), and Wim Rietdijk
(Rotterdam, The Netherlands).
- Independent Statistician (for Interim analysis): Wim Rietdijk (Rotterdam, The Netherlands).
- Independent Statistician (for all other statistical analysis): Diana Marcela Martínez (Centro de
Investigaciones Clínicas, Fundación Valle del Lili. Cali, Colombia)

Additional Details for Study population
An electronic written informed consent was always obtained from each participant, his / her
next of kin, or another surrogate decision maker as appropriate. A complete description about
the process to obtain such informed consent is provided in the study protocol (Supplement 1).
All signatures were electronically recorded in the formats approved by the Ethical and
Biomedical Research Committee at each participating center. After obtaining informed consent,
patients were included if they met ALL of the following eligibility criteria:
- Age 18 years or older;

- Suspected or confirmed infection by SARS-CoV-2;
- Acute respiratory distress with a ratio of the partial pressure of arterial oxygen to the
fraction of inspired oxygen (PaO2/FiO2) < 200;
- Clinical signs of respiratory failure: laborious breathing, use of accessory muscles and
respiratory rate greater than 25/min;
- Less than 6 hours from fulfilling the criteria of acute respiratory failure;
SARS-CoV-2 infection was confirmed by a positive reverse transcription polymerase-chain-

reaction (RT-PCR) assay result from any respiratory specimen. Patients with a positive RT-PCR
assay >72 hours at randomization and with progressive disease impairment consistent with
ongoing SARS-CoV-2 infection, were genomically tested for coexistent viral / bacterial germs.
Those patients with confirmed or highly suspected pulmonary bacterial infection (according to
the clinical judgment of the attending physician) were not selected for the study. The intention-
to-treat analysis was planned to include both confirmed and suspected cases of SARS-CoV-2
infection while the per-protocol analysis only would include those in who SARS-CoV-2 infection
was confirmed.
Patient status at enrollment was that defined in the categories 4 and 5 from the modified 7-
category ordinal scale: 4, hospitalized in general ward (not intensive care unit), requiring
supplemental oxygen / requiring ongoing medical care (Covid-19–related or other medical
conditions); 5, hospitalized in the intensive care unit, requiring any supplemental oxygen but
not invasive mechanical ventilation or extracorporeal membrane oxygenation.
Definition of Failure to Respiratory Support
Failure to respiratory support (high-flow or conventional oxygen therapy) was considered if at

least one of the following was present:
- PaO2 < 55 mmHg
- Fail to improve signs of respiratory distress
- Development of copious bronchial secretions

- SpO2 < 92% for more then five minutes (discarding signal problems or other technical
issues) while receiving the maximal support according to the group allocation
- Acidosis (metabolic / respiratory): pH < 7.25
- Development of shock state (any type)
- PaCO2 > 55 mmHg (accompanied by acidosis)
- Neurological deterioration
Intubation Criteria (for Patients included in the study)
Once the patient was allocated to his/her respective study group, predefined intubation criteria
were followed in order to avoid delayed invasive mechanical ventilation support. Intubation
criteria were applied under the assumption that patient was under the maximum possible
respiratory support provided by the therapy assigned (high-flow oxygen or conventional
oxygen therapy). Such criteria were as follows:
• Signs of persistent respiratory distress

- Respiratory rate > 40 / min
- No improvement of laborious breathing - use of accessory muscles
- Development of copious bronchial secretions / impossibility to manage bronchial
secretions
- Acidosis (metabolic / respiratory): pH < 7.25
- PaO2 < 55 mmHg
- PaCO2 > 55 mmHg (accompanied by acidosis)
- SpO2 < 92% for more then five minutes (discarding signal problems or other
technical issues)
• Signs of hemodynamic derangement

- Persistent systolic arterial pressure < 90 or mean arterial pressure < 60 mmHg, with
vasopressor support requirement (norepinephrine > 0.10 µgr.kg.min-1) in presence
of an adequate intravascular volume
- Clinical signs of severe tissue hypoperfusion: capillary refill time > 10 seconds;
Mottling score ≥ 4
- Arterial lactate ≥ 4.0 mmol/L in presence of any clinical sign of tissue hypoperfusion
(capillary refill time > 3 seconds; Mottling score ≥ 2)
• Signs of neurological derangement

- Neurological impairment (Glasgow coma scale ≤ 12)

Additional Details for Study and Follow-up Procedures
All participants were daily evaluated from the day-1 through day-28 (while remained
hospitalized) by the local study coordinators and research assistants. Multiple organ
dysfunction was assessed from day-1 through day-7, and then at day-10 and day-14 (if
remained hospitalized at such time points) by using the Sequential Organ Failure Assessment
Score (SOFA) score (1). The amount of resuscitation fluids and cumulative fluid balance were
also recorded during the first 7 days from randomization. Other adjuvant interventions for
management of hypoxemia such as prone position (both awake and under sedation / invasive
mechanical ventilation), neuromuscular paralysis or extracorporeal membrane oxygenation
were also registered.
Serious adverse events (SAE) and grade 3-4 adverse events (AE) were daily recorded during
the study period. All SAE were notified to the respective Ethical and Research Committee
(usually within the next 24 hours of their detection). The steering committee and the data
quality surveillance committee (DQSC) periodically conducted dedicated meetings aimed to
perform a complete evaluation of SAE and AE. Potential causality of study interventions on SAE
was always discussed and informed to the respective Ethical and Research Committee. A total
of thirteen adverse events were classified as serious (Table 2). Proportion of SAE was not
significantly different between groups and none of those was directly attributed to the allocated
intervention. Suspected bacterial pneumonia was reported in 13 allocated to high-flow oxygen
therapy and 17 patients allocated to conventional oxygen therapy.
No in-person visits were performed after hospital discharge according to the local infection
control authority recommendations. Thus, for discharged patients, research assistants carried
out a structured phone call on day 28 of follow-up, aiming to confirm health status of the
participant and to categorize him/her within the ordinal 7-category scale.
Blood samples were drawn for laboratory test as described in the main protocol. Meanwhile,
blood samples for Interleukin-6 (IL-6) measurements were drawn and adequately stored for
analysis once enrollment of patients was ended.

Additional Details for Sample Size Calculation and Statistical Analysis
Sample size was calculated under the assumption of an intubation rate of 60%, according to the
data obtained from the first 75 patients with Covid-19-related moderate and severe hypoxemic
respiratory failure treated in the coordinating center. Such proportion of intubation events was
in agreement with previous data from a randomized controlled trial testing high-flow oxygen
through nasal cannula in a mixed population of patients with acute hypoxemic respiratory
failure (2). In such a trial, maximal values of the 95% confidence intervals for intubation at day
28 in the groups subjected to standard oxygen therapy and non-invasive mechanical ventilation
were 57% and 59% independently of basal oxygenation, and 64% and 68% for those with an
initial PaO2/FiO2 ratio < 200. Consequently, estimating an intubation rate around 60% in
conventionally-treated patients, we calculated that enrollment of 196 patients would be
necessary to demonstrate an absolute reduction of 20% in the proportion of intubation and
requirement of invasive mechanical ventilation with an 80% power and two-side alpha level of
0.05. In addition, data obtained from the initial cohort of patients with Covid-19-related severe
hypoxemic respiratory failure treated in the coordinating center revealed a time to recovery of
14 (± 4.5) vs. 12 (± 4.0) days for the conventional oxygen and high-flow oxygen therapy groups
respectively. Thus, it was estimated that 160 patients (80 by arm) would be necessary to
demonstrate such a difference with an 80% power and two-side alpha level of 0.05.
Consequently, the sample size of 196 patients was primarily retained as the sample size target.
Nevertheless, due to the particular situation during pandemic, an important number of

participants (n=13, representing the 6.6% of the original sample size) were transferred to other
hospitals (by administrative reasons) within 72 hours from randomization at the time in which
the HiFLo-Covid protocol amendment 2.0 was constructed. After an extensive discussion with
the Ethical and Biomedical Research Committee from the coordinating center (Fundación Valle
del Lili - EBRC) and trying to favor the possibility that results of this trial keep sufficient power
and consequently, more reliable results, the number total of randomized patients was newly
adjusted up to complete a total of 220 participants.
All the analysis were planned to be performed on an intention-to-treat basis with no exclusion
after randomization except exclusions for withdrawn consent, according to the local
regulations. Nevertheless, in agreement with the recommendation stated by the Ethical and
Biomedical Research Committee from the coordinating center (Fundación Valle del Lili - EBRC),
patients transferred to other hospitals before to complete 72 hours of the enrollment were also
excluded from analysis because the limitation to provide further protocolized management and
impossibility to ensure an adequate follow-up.
Continuous variables were described as medians (interquartile ranges) and categorical

variables as proportions. No participants were excluded from analysis because of missing or
incomplete data. The effect of the treatment on the cumulative incidence of intubation /
invasive mechanical ventilation was calculated with a Cox proportional hazard model with

stratification by age (< or ≥ 60 years old), initial hypoxemia severity (continuous PaO2/FiO2
ratio), and comorbidities (a composite of arterial hypertension, diabetes, obesity [body mass
index > 30], chronic obstructive pulmonary disease, end-stage renal failure, heart failure,
cirrhosis Child-Pugh A-B). (see the Main Protocol, and Supplement 2 –Statistical Analysis Plan–
). The proportional hazards assumption was tested with the Grambsch and Therneau method
(3). Results are reported as hazard ratios with 95% confidence intervals and represented in
Kaplan-Meier curves.
Time to clinical improvement was defined as time elapsed from randomization until the first
day, during the 28 days after enrollment, on which a patient attained a reduction in two or more
points in the modified ordinal 7-category scale. The effect size of the allocated therapy on the
time to recovery was assessed by computing the hazard ratio with its 95% confidence interval
(CI) as estimated from Cox proportional hazard model adjusted by age, grade of hypoxemia,
and comorbidities (see Main Protocol - and Supplement 2 –Statistical Analysis Plan–). Such
analysis was constructed for the overall population and also stratified according to baseline 7-
category ordinal scale at enrollment (i.e., scores of 4 or 5), and plotted in Kaplan-Meier curves.
Hazard ratios for clinical recovery greater than 1 indicate a benefit with the high-flow oxygen
therapy. Meanwhile, hazard ratios for intubation events less than 1 indicate benefit with the
use of high-flow oxygen therapy. Hazard ratios estimated from Cox regression models were
displayed in forest plots for predefined subgroups according to initial PaO2/ FiO2 (≥ or < 100
mmHg), interleukin-6 levels (≥ or < 100 pg/mL), and age (≥ or < 60 years old).
Secondary outcomes included: the proportion of patients requiring early intubation and
mechanical ventilation at days 7 and 14; mechanical ventilation free-days within 28 days,
computing the number of days remaining both alive and free of mechanical ventilation from the
randomization date to day-28; renal replacement therapy-free days, computing the number of
days remaining both alive and free of renal replacement therapy from the randomization date
to day-28; hospital and intensive care unit length of stay; overall mortality by day 28; and the
proportion of adverse events (including major adverse events and proportion of patients with
bacterial / fungal infections).
Tertiary outcomes included: time-course of oxygen flow and PaO2/FiO2 ratio; time (in hours)
from randomization up to intubation; clinical evolvement of multiorgan dysfunction evaluated
by the Sequential Organ Failure Assessment Score (SOFA) score (1), calculated day-by-day from
randomization up to day-7 and then, at day-10 and 14 (if hospitalized at such time points);
evolvement of extra-pulmonary organ dysfunction evaluated by the extra pulmonary score
given by the Sequential Organ Failure Assessment Score (SOFA) score, calculated day-by-day
from randomization up to day-7 and then, at day-10 and 14 (if hospitalized at such time points);
relationship between HACOR and ROX scales and requirement of intubation; time-course of
some prespecified blood markers: IL-6, IL-8, leucocytes, neutrophil: lymphocyte ratio, platelet
count, lactate dehydrogenase, ferritin, D-Dimer.
Subgroup analysis included: time to and proportion of patients requiring intubation and

invasive mechanical ventilation in predefined subpopulations classified according to initial
PaO2/ FiO2 (≥ or < 100 mmHg), interleukin-6 levels (≥ or < 100), and age (≥ or < 60). Time to
recovery and proportion of patients recovered within the 28 days after randomization were
also analyzed according to initial PaO2/ FiO2 (≥ or < 100 mmHg), interleukin-6 levels (≥ or <
100), and age (≥ or < 60).
Additional Details for Interim Analysis
A first and only interim analysis was conducted when the 28-day follow-up had been completed
for the first 100 randomized patients. Database was prepared and sent to the Members of the
Data Safety Monitoring Board (DSMB). An independent statistician (W.R.) performed the
analysis and discussed it with the DSMB, who later communicated the results to the Steering
Committee. By the time of the interim analysis, 9 events had been qualified as serious (SAE).
Eight of such SAEs corresponded to death and no one was apparently related or conditioned to
the assigned therapy itself. According to Haybittle–Peto stopping boundaries (4) proposed a
priori, a P-value threshold of less than 0.001 had been considered to interrupt the trial for safety
and a P-value threshold of less than 0.0001 to interrupt the trial for efficacy. Consequently, the
DSMB recommended continuing with the enrollment till the number of planned participants
was attained.
Registration at ClinicalTrials.gov
The study record was submitted to clinicaltrials.gov on September 24, 2020, and lastly posted
at clinicaltrials.gov by the 30th October 2020, time in which 24 patients have been enrolled.
The Ethical Research Committee and the Centro de Investigaciones Clínicas – FVL (Fundación
Valle del Lili, Cali - Colombia) verified the entire inscription process.

e Tables
eTable 1. Seven-Point Ordinal Scale
1 Discharged from the hospital, resuming complete day-life

activities
Recovered
2 Discharged from the hospital, but limitation of activities,

home oxygen requirement, or both
3 Hospitalized in general ward (not intensive care unit), not

(Only if starting
from 5 points)
Recovered
requiring supplemental oxygen and no longer requiring

ongoing medical care (used if hospitalization was extended
for infection-control reasons)
4 Hospitalized in General Ward (not intensive care unit),

requiring supplemental oxygen / requiring ongoing
medical care (COVID-19–related or other medical
Enrolled
conditions)
5 Hospitalized in the Intensive Care Unit, requiring

supplemental oxygen
6 Hospitalized in the Intensive Care Unit, requiring invasive

mechanical ventilation or Extra Corporeal Membrane
Oxygenation (ECMO)
7 Death.

eTable 2. Other patient characteristics at randomization
Characteristic High-Flow Oxygen Conventional Oxygen P

Therapy Therapy
(n=99) (n=100)
Symptoms
Fever - no. (%) 66 (66.7) 73 (73.0) .41

Odynophagia - no. (%) 10 (10.1) 20 (20.2) .07
Cough - no. (%) 69 (69.7) 75 (75.0) .50
Vomiting / diarrhea - no. (%) 24 (24.2) 26 (26.0) .90
Asthenia / adynamia - no. (%) 71 (71.7) 68 (68.0) .68
Anosmia / dysgeusia - no. (%) 15 (15.2) 16 (16) > .99
Odynophagia - no. (%) 66 (66.7) 73 (73.0) .41
Vital signs at admission, median (IQR)
Systolic arterial pressure, mmHg 123 (113 – 142) 127 (114 – 141) .93
Diastolic arterial pressure, mmHg 74 (65 – 85) 74 (67 – 81) .72
Mean arterial pressure, mmHg 92 (82 – 102) 91 [85 – 100) .80
Heart rate, beats/min 95 (83 – 111) 100 (90 – 112) .17
Respiratory rate, breaths/min 28 (22 – 36) 28 (22 – 33) .45
Laboratory, median (IQR)
pH 7.46 (7.43 – 7.48) 7.45 (7.43 – 7-48) .69

PaCO2, mmHg 32 (30 – 35) 32 (30 – 36) .68
PaO2, mmHg 78 (66 – 97) 73 (63 – 92) .28
HCO3-, mmol/L 23.7 (21.90 – 25.5) 24.0 (22.5 – 25.5) .47
Base excess, mmol/L -1.10 (-3.20 – 1.10) -1.05 (-2.52 – 0.90) .69

PaO2/FiO2 ratio 78 (66 – 97) 74 (63 – 89) .23
Lactate, mmol/L 1.32 [1.07, 1.71] 1.28 [1.00, 1.61] .15
Hemoglobin, gr/dL 14.2 (12.9 – 15.3) 14.0 (13.0 – 15.3) .60
Hematocrit, % 40.9 (38.2 – 45.4) 41.4 (38.22 – 44.3) .96
Platelets, /mm3 263,000 (221,000 – 332,000) 262,000 (209,500 – 318,500) .69
Protrombin Time – PT, sec 12.7 (11.50 – 13.3) 12.9 (12.2 – 13.9) .03
Activated Partial Thromboplastin Time –
30.2 (27.8 – 33.6) 31.1 (28.2 – 33.6) .33
aPTT, sec
Fibrinogen, mg/dL 651 (540 – 835) 722 (597 – 868) .05
Leucocytes, /mm3 10,390 (7,850 – 13,930) 9,530 (6,690 – 13,180) .13
Neutrophils, /mm3 8,870 (6,265 – 12,100) 7,875 (5,030 – 11,373) .09
Lymphocytes, /mm3 930 (690 – 1,185) 925 (610 – 1,203) .95
Macrophages, /mm3 380 (280 – 655) 475 (320 – 655) .22
Neutrophil: Lymphocyte Ratio 9.4 (5.90 – 15. 9) 7.6 (5.30 – 14.7) .13
Bilirubin, mg/dL 0.52 (0.39 – 0.75) 0.56 (0.39 – 0.76) .67
Aspartate Amino Transferase – AST, IU/L 43.9 (31.9 – 67.4) 41.7 (31.9 – 63.4) .75
Alanine Amino Transferase – ALT, IU/L 45.8 (31.8 – 71,5) 43.9 (25.6 – 65.3) .18
C-Reactive Protein – CRP, mg/L 12.5 (7.4 – 23.0) 14.5 (7.8 – 24.6) .68
Lactate dehydrogenase – LDH, U/L 426 (353 – 517) 390 (327 – 466) .03
Ferritin, ng/mL 1,051 (696 – 2,247) 975 (650 – 1,456) .06
D-dimer, µg/mL 1.13 (0.73 – 1.82) 0.92 (0.63 – 1.52) .07
IL-6 8.14 (0.00 - 40.37) 11.71 (1.80 - 40.81 .29
Creatinine, mg/dL 0.9 (0.8 – 1.1) 0.9 (0.8 – 1.1) .92
Blood Nitrogen Urea – BUN, mg/dL 18.4 (14.8 – 24.9) 16.9 (13.10 – 22.2) .12
Troponin, ng/mL 6.80 (2.70 – 14.75) 5.35 (3.07 – 18.20) .92

eTable 3. Patient characteristics 2-hours and 4-hours after the start of assigned oxygenation therapy
High-Flow Oxygen Conventional Oxygen P

Therapy Therapy
(n=99) (n=100)
Respiratory support 2-Hours post

randomization, median (IQR)
Flow, L/min 60 (60 – 60) 15 (15 – 15) < .001
pH 7.44 (7.42 – 7.47) 7.43 (7.41 – 7.45) .03
PaO2, mmHg 78 (69 – 95) 79 (66 – 93) .58
FiO2 60 (60 – 70) 85 (85 – 85) < .001
PaO2/FiO2 ratio 127 (106 – 174) 97 (80 – 133) < .001
SaO2 96 (95 – 98) 97 (94 – 98) .41
Respiratory Rate, breaths/min 24 (21 – 28) 28 (23 – 32) < .001
Heart Rate, beats/min 80 (70 – 91) 78 (70 – 89) .99
SpO2 95 (93 – 97) 95 (93 – 98) .43
Respiratory distress signs, yes, no. (%) 9 (9.1)) 19 (19.0) .07
Tracheal Intubation, yes, no. (%) 1 (1.0) 3 (3.0) .62
BORG scale 2 (1 – 4) 3 (2 – 4) .09
Glasgow Coma Scale 15 (15 – 15) 15 (15 – 15) .99
HACOR score 5 (3 – 6) 6 (5 – 6) < .001
ROX score 6.36 (5.08 – 7.72) 4.20 (3.48 – 5.29) < .001
Respiratory support 4-Hours post

randomization, median (IQR)
Flow, L/min 60 (60 – 60) 15 (15 – 15) < .001
pH 7.43 (7.41 – 7.46) 7.42 (7.39 – 7.44) .004

PaO2, mmHg 75 (67 – 92) 79 (66 – 100) .17
FiO2 60 (60 – 70) 85 (85 – 85) < .001
PaO2/FiO2 ratio 128 (108 – 163) 99 (81 – 139) .001
SaO2 96 (94 – 98) 96 (94 – 98) .34
Respiratory Rate, breaths/min 23 (20 – 27) 25 (22 – 29) .004
Heart Rate, beats/min 78 (69 – 90) 80 (72 – 90) .41
SpO2 95 (93 – 97) 95 (92 – 97) .96
Respiratory distress signs, yes, no. (%) 9 (9.1) 19 (19.0) .07
Tracheal Intubation, yes, no. (%) 1 (1.0) 4 (4.0) .37
BORG scale 2 (1 – 4) 3 (1 – 4) .04
Glasgow Coma Scale 15 (15 – 15) 15 (15 – 15) .48
HACOR score 5 (3 – 6) 6 (5 – 6) < .001
ROX score 6.71 (5.51 – 8.25) 4.64 (3.85 – 5.77) < .001

eTable 4. Time from randomization to intubation / invasive mechanical ventilation support / additional respiratory
support strategies / additional therapies
High-Flow Oxygen Conventional Oxygen P value

Therapy Therapy
(n=99) (n=100)
No. of intubations by day 28, (%) .026 (a)

34 (34.3) 51 (51.0)
Time elapsed from randomization to

Intubation, hours 22.3 (13.2 – 60.7) 29.2 (14.4 – 58.3) .69
Time elapsed with FiO2 > 0.70 from

11.5 (4.2 – 21.0) 25.8 (13.5 – 46.5) < .001
randomization to Intubation, hours
Awake prone position, n (%) 74 (74.7) 64 (64.) .12
Time in awake prone position, hours
21 (8 – 40) 18 (8 – 35) .35
(interquartile range)
Prone position during mechanical ventilation,
21 (21.2) 32 (32.3) .08
n (%)
Time in prone position during mechanical
30 (18 – 39) 27 (18 – 60) .90
ventilation, hours (interquartile range)
Neuromuscular paralysis, n (% from total
30 (30.3) 44 (44.4) .04
populatin)
Other therapies
Hydroxichloroquine 0 (0) 0 (0) NA
Azytromicin 0 (0) 0 (0) NA

Ivermectin 7 (7.1) 4 (4.9) .35
Methylprednisolone 93 (93.9) 92 (92.0) .77
Dexametasone 18 (18.2) 19 (19.0) .85
Tocilizumab 0 (0) 0 (0) NA
Remdesivir 0 (0) 2 (2.0) .15
(a) P value obtained by X2 test

NA: non applicable

eTable 5. Causes of Intubation at day-7 and Causes of Death at day-28
High-Flow Oxygen Conventional Oxygen P value

Therapy Therapy
(n=99) (n=100)
Cause of intubation – no. / total of intubated at day-7 – No. (%)
Persistent signs of respiratory distress 31 / 31 (100) 47 / 47 (100) > .99
Hemodynamic derangement 0 / 31 (0) 1 / 47 (2.1) > .99
Neurologic derangement 3 / 31(9.7) 1 / 47 (2.1) .30
Other 0 / 31 (0) 2 / 47 (4.3) .51
Cause of death – No. / total of deceased at day-28 – No. (%)
Refractory hypoxemia 1 / 8 (12.5) 2 /16 (12.5) .99
Refractory shock 4 / 8 (50.0) 13 / 16 (81.3) .41
Cardiac arrest 1 / 8 (12.5) 2 / 16 (12.5) 1.00
Multiorgan failure 6 / 8 (75.0) 13 / 16 (81.3) 1.00

eTable 6. Primary and Secondary Outcomes for all patients and according to 7-category Ordinal Scale
Overall Seven-Category Ordinal Scale at Baseline
4 5
High-Flow Oxygen Conventional High-Flow Conventional High-Flow Conventional

Therapy Oxygen Therapy Oxygen Oxygen Oxygen Oxygen
(n=99) (n=100) Therapy Therapy Therapy Therapy
(n=18) (n=20) (n=81) (n=80)
Primary Outcomes
Intubation over first

28 days
No. of intubations by
34 51 7 12 27 39
day 28
Hazard ratio (95%CI) 0.62 (0.39–0.96) [p= .03] a 0.63 (0.25–1.62) [p= .34]  a 0.61 (0.37-1.005) [p= .51]  a
for data through day
28
Clinical Recovery b
No. of recoveries 77 71 13 11 64 60
Median time to
recovery (95%CI) - 11 (9-14) 14 (11-19) 13 (7-25) 25 (10-28) 11 (9-14) 13 (11-16)
days

Hazard ratio (95%CI) 1.39 (1.00–1.92) [p= .047]  b 1.97 (0.80-4.83) [p= .14]  b 1.26 (0.89-1.80) [p= .19]  b
for data through day
28
Secondary Outcomes
Mortality
At day 14
No. of patients (%) 6 (6.1) 6 (6.0) 2 (11.1) 1 (5.0) 4 (4.9) 5 (6.3)
Hazard Ratio
(95%CI) for data 0.93 (0.29-2.93) [p=0.90]  a 2.27(0.17-30.77) [p=0.53]  a 0.72(0.19-2.74) [p=0.63]  a
through day 28
At day 28
No. of patients (%) 8 (8.1) 16 (16.0) 2 (11.1) 5 (25.0) 6 (7.4) 11 (13.8)
Hazard Ratio
(95%CI) for data 0.49 (0.21–1.16) [p= .11]  a 0.56 (0.10-3.09)[p= .50]  a 0.50 (0.18-1.38)[p= .18]  a
through day 28
Intubation
At day 7
No. of patients (%) 31 50 7 11 24 39

Hazard Ratio
(95%CI) for data 0.59 (0.38 – 0.94) [p= .03]  a 0.72 (0.27 – 1.90) [p= .51]  a 0.55 (0.33 – 0.92) [p= .02]  a
through day 28
Intubation
At day 14
No. of patients (%) 34 51 7 12 27 39
Hazard Ratio
(95%CI) for data 0.63 (0.41 – 0.97) [p= .04]  a 0.63 (0.24 – 1.62) [p= .34]  a 0.61 (0.37 – 1.01) [p= .048]  a
through day 28
Time elapsed from 23.1 (18.7 – 35 (22.3 - 21.4 (12.5 – 27.2 (11.2 –
randomization to 22.3 (13.2 – 60.7) 29.2 (14.4 – 58.3)
66.4) 107) 57.4) 56.5)
Intubation, hours
Adjusted odds ratio
(95% CI) for data 0.77 (0.33 – 1.68) [p= .52]  d 0.29 (0.04 – 1.92) [p= .20]  d 0.86 (0.36 – 2.06) [p= .73]  d
through day 28
Ventilation-free
days at day-28, days 28 (19 – 28) 24 (14 – 28) 28 (20 – 28) 19 (5 – 28) 28 (18 – 28) 27 (15 – 28)
(IQR)
Adjusted odds ratio
through day 28
Renal replacement
therapy-free days, , 28 (28 – 28) 28 (28 – 28) 28 (28 – 28) 28 (26 – 28) 28 (28 – 28) 28 (28 – 28)
days (IQR)

Adjusted odds ratio
through day 28
Length of Stay –
Intensive Care Unit, , 7 (5 – 13) 9 (5 – 18) 8 (4 – 11) 18 (7 – 24) 7 (5 – 14) 8 (5 – 15)
days (IQR)
Adjusted odds ratio
through day 28
Length of Stay – 12 (9 – 20) 14 (9 – 23) 12.5 (9 - 20) 18 (11 – 26) 12 (9 – 19) 13.5 (9 – 23)
Hospital, days (IQR)
Adjusted odds ratio
(95% CI) for data 0.77 (0.47 – 1.25) [p= .29]  d 0.55 (0.17 – 1.81) [p= .33]  d 0.85(0.49 – 1.46) [p= .56]  d
through day 28
P values and confidence intervals have not been adjusted for multiple comparisons.
a. Adjusted Hazard Ratio calculated from the Cox proportional model. Variables used for adjustment were: age (≥ or < 60 years old), PaO2/FiO2 ratio at the randomization, and comorbidities
(a composite of arterial hypertension, diabetes, obesity [body mass index > 30], chronic obstructive pulmonary disease, end-stage renal failure, heart failure, cirrhosis Child-Pugh A-B). A
Hazard ratio (HR) for intubation less than 1 indicates benefit with the use of High-Flow Oxygen Therapy.
b. Adjusted Hazard Ratio calculated from the Cox proportional model. Variables used for adjustment were: age (≥ or < 60 years old), PaO2/FiO2 ratio at the randomization, and comorbidities (a
composite of arterial hypertension, diabetes, obesity [body mass index > 30], chronic obstructive pulmonary disease, end-stage renal failure, heart failure, cirrhosis Child-Pugh A-B). A hazard
ratio for clinical recovery greater than 1 indicates benefit with the use of High-Flow Oxygen Therapy.
c. Scores on the Seven-Level Ordinal Scale are as follows: 1, Discharged from the hospital, resuming complete day-life activities; 2, Discharged from the hospital, but limitation of activities, home
oxygen requirement, or both; 3, Hospitalized in general ward (not intensive care unit), not requiring supplemental oxygen and no longer requiring ongoing medical care (used if hospitalization
was extended for infection-control reasons); 4, Hospitalized in general ward (not intensive care unit), requiring supplemental oxygen / requiring ongoing medical care (Covid-19–related or
other medical conditions); 5, Hospitalized in the Intensive Care Unit, requiring any supplemental oxygen; 6, Hospitalized in the Intensive Care Unit, requiring invasive mechanical ventilation or
ECMO; and 7, death.
d. Proportional odds models adjusted for age (≥ or < 60 years old), PaO2/FiO2 ratio at the randomization, and comorbidities (a composite of arterial hypertension, diabetes, obesity [body
mass index > 30], chronic obstructive pulmonary disease, end-stage renal failure, heart failure, cirrhosis Child-Pugh A-B). Odds ratios > 1 indicates benefit with the use of High-Flow Oxygen
Therapy.

eTable 7. Seven-Category Ordinal Scale at day 28
Overall Seven-Category Ordinal Scale at Baseline
4 5
High-Flow Oxygen Conventional High-Flow Conventional High-Flow Conventional

Therapy Oxygen Therapy Oxygen Oxygen Oxygen Oxygen
(n=99) (n=100) Therapy Therapy Therapy Therapy
(n=18) (n=20) (n=81) (n=80)
Seven-Category
Ordinal scale at day
28 – no. (%) a
1 76 (76,8) 69 (69) 13 (72.2) 10 (50.0) 63 (77.8) 59 (73.8)
2 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
3 2 (2,02) 1 (1,0) 1 ( 5.6) 0 ( 0.0) 1 ( 1.2) 1 ( 1.2)
4 8 (8,08) 5 (5) 2 (11.1) 1 ( 5.0) 6 ( 7.4) 4 ( 5.0)
5 0 (0) 4 (4) 0 ( 0.0) 2 (10.0) 0 ( 0.0) 2 ( 2.5)
6 5 (5,05) 5 (5) 0 ( 0.0) 2 (10.0) 5 ( 6.2) 3 ( 3.8)
7 8 (8,08) 16 (16,0) 2 (11.1) 5 (25.0) 6 ( 7.4) 11 (13.8)
Odds ratio (95%CI) 0,59 (0,31-1,11) d 0,32 (0,08 - 1,30) d 0,69 (0,33 - 1,46) d

a Scores on the Seven-Level Ordinal Scale are as follows: 1, Discharged from the hospital, resuming complete day-life activities; 2, Discharged from the hospital, but limitation of activities,
home oxygen requirement, or both; 3, Hospitalized in general ward (not intensive care unit), not requiring supplemental oxygen and no longer requiring ongoing medical care (used if
hospitalization was extended for infection-control reasons); 4, Hospitalized in general ward (not intensive care unit), requiring supplemental oxygen / requiring ongoing medical care (Covid-
19–related or other medical conditions); 5, Hospitalized in the Intensive Care Unit, requiring any supplemental oxygen; 6, Hospitalized in the Intensive Care Unit, requiring invasive
mechanical ventilation or ECMO; and 7, death.

eTable 8. Post-hoc sensitivity analysis considering all randomized patients who provided consent to use data (N=212)
Outcome High-Flow Oxygen Conventional Effect estimate P-

Therapy oxygen therapy (95% CI) value
(n=105) (n=107) (Hazard ratio a)
Primary Outcomes
Intubation within 28 days, n (%)
Number of intubated (%) 34 (32.4) 53 (49.5) c

0.59 (0.38 – 0.92) d .02
Time to intubation, days (IQR) b 1 (0 – 3) 1 (1 – 3)
Clinical recovery up to day 28, days (IQR)
Number of recoveries (%) 77 (77.8) 71 (71.0)

1.39 (1.00 – 1.92) e .047
Time to recovery, days (IQR) b 11 (9 – 14) 14 (11 – 19)
This analysis includes all randomized patients providing consent to use data (i.e., including patients tranferred to other
hospitals within the 72 hours from randomization by administrative reasons). N=212
a Adjusted Hazard Ratio calculated from the Cox proportional model. Variables used for adjustment were: age (≥ or < 60 years old), PaO2/FiO2 ratio at the
randomization, and comorbidities (a composite of arterial hypertension, diabetes, obesity [body mass index > 30], chronic obstructive pulmonary disease, end-stage
renal failure, heart failure, cirrhosis Child-Pugh A-B).

b Kaplan-Meier median time to clinical recovery estimative
c Two patients in the conventional oxygen therapy group were intubated at the moment they were tranferred
d A Hazard ratio (HR) for intubation or mortality less than 1 indicates benefit with the use of High-Flow Oxygen Therapy.
e A hazard ratio (HR) for clinical recovery greater than 1 indicates benefit with the use of High-Flow Oxygen Therapy.

eTable 9. Post-hoc sensitivity analysis considering the site-by-treatment effects
(N=109)
Mixed Effects Cox Models

End Point Effect estimate (95% CI) p
(Hazard ratio a)
Intubation within 28 days 0.62 (0.40 – 0.96) b 0.031
Clinical recovery up to day 28, days 1.42 (1.03 – 1.97) c 0.035
Analysis was performed to evaluate the site-by-treatment effects, by using a mixed effects
model taking the site (participant hospital) as random effect
a Adjusted Hazard Ratio calculated from the Cox proportional model. Variables used for adjustment were: age (≥ or
< 60 years old), PaO2/FiO2 ratio at the randomization, and comorbidities (a composite of arterial hypertension,
diabetes, obesity [body mass index > 30], chronic obstructive pulmonary disease, end-stage renal failure, heart
failure, cirrhosis Child-Pugh A-B).
b A Hazard ratio (HR) for intubation or mortality less than 1 indicates benefit with the use of High-Flow Oxygen
Therapy.
c A hazard ratio (HR) for clinical recovery greater than 1 indicates benefit with the use of High-Flow Oxygen
Therapy.
eTable 10. Proportional hazard asssumption test *
Cox Regression
End Point Mixed Effects Cox Models
Model
Intubation within 28 days ! ! = 4.6; ' = 0.33 ! ! = 4.6; ' = 0.86
Clinical recovery up to day 28, days ! ! = 9.2; ' = 0.56 ! ! = 8.7; ' = 0.54
The proportional hazard assumption was tested with the Grambsch and Therneau method *
* Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted
residuals. Biometrika. 1994;81(3):515-526.

e Figures
eFigure 1. Time course of PaO2/FiO2 ratio for study groups
Mixed linear regression considering patient as random effect and adjusting for baseline value
of the variable. Interaction Therapy Group*Time, 0.36 (-2.19 – 2.92); p=0.78; Effect
modification by therapy:: 17.71 (3.34 – 32.08); p=0.02

eFigure 2. Time course of oxygen flow (L/min) for study groups
of the variable. Interaction Therapy Group*Time, -6.33 (-7.06 – -5.61); p<0.001; Effect
modification by therapy: 47.36 (43.73 - 51.00); p<0.001
eFigure 3. Time course of multiple organ dysfunction according to SOFA score

for study groups
of the variable. Interaction Therapy Group*Time, -0.03 ( -0.12 – 0.06); p=0.55; Effect
modification by therapy: -0.41 ( -1.12 – 0.29); p=0.25

eFigure 4. Time course of extra-pulmonary organ dysfunction according to SOFA
score for study groups
modification by therapy: - 0.13 ( -0.83 – 0.56); p=0.71

eFigure 5. Kaplan Meier estimates of cumulative intubation events according to
initial PaO2/FiO2 < or ≥ 100
Kaplan Meier estimates of cumulative intubation events according to PaO2/FiO2 ratio < 100
(Panel A) or > 100 (Panel B). The P values were calculated with a log-rank test

age < or ≥ 60 years old
Kaplan Meier estimates of cumulative intubation events according to age < 60 years (Panel A)
or ≥ 60 years old (Panel B). The P values were calculated with a log-rank test

initial IL-6 < or ≥ 100 pg/mL
Kaplan Meier estimates of cumulative intubation events according to IL-6 < 100 (Panel A) or ≥
100 pg/mL (Panel B). The P values were calculated with a log-rank test

eFigure 8. Kaplan Meier estimates of clinical recovery according to initial
PaO2/FiO2 < or ≥ 100
Kaplan Meier estimates for Clinical Recovery according to PaO2/FiO2 ratio < 100 (Panel A) or ≥
100 (Panel B). The P values were calculated with a log-rank test

eFigure 9. Kaplan Meier estimates of clinical recovery according to age < or ≥ 60
years old
Kaplan Meier estimates for Clinical Recovery according to age < 60 years (Panel A) or ≥ 60 years
old (Panel B). The P values were calculated with a log-rank test

eFigure 10. Kaplan Meier estimates of clinical recovery according to initial IL-6
< or ≥ 100 pg/mL
Kaplan Meier estimates for Clinical Recovery according to IL-6 < 100 (Panel A) or ≥ 100 pg/mL
(Panel B). The P values were calculated with a log-rank test

eFigure 11. Time course of total leucocyte count for study groups
modification by therapy: -854.81 ( -2,099.04 – 389.41); p=0.18
eFigure 12. Time course of neutrophil:lymphocyte ratio for study groups
of the variable. Interaction Therapy Group*Time, 0.03 (-0.45 – 0.51); p=0.90; Effect
modification by therapy: -2.21 (-5.2 – 0.77); p=0.15

eFigure 13. Time course of Ferritin levels for study groups
of the variable. Interaction Therapy Group*Time, -105.83 (-227.16 – 15.49); p=0.09; Effect
modification by therapy: 51.09 (-496.5 – 598.68); p=0.85
eFigure 14. Time course of D-Dimer for study groups
of the variable. Interaction Therapy Group*Time, -1.21 (-2.16 – -0.25); p=0.01; Effect
modification by therapy: 5.87 (1.49 – 10.26); p=0.01

eFigure 15. Time course of Lactate dehydrogenase levels for study groups
of the variable. Interaction Therapy Group*Time, -10.17 (-19.32 – -1.02); p=0.03; Effect
modification by therapy: 16.26 (-30.36 – 62.89); p=0.49
eFigure 16. Time course of Platelets count for study groups
of the variable. Interaction Therapy Group*Time, 372.38 ( -3,057.08 – 3,801.84); p=0.83; Effect
modification by therapy: -14,498.22 ( -36,842.3 – 7,845.86); p=0.20

eFigure 17. Time course of IL-6 for study groups
of the variable. Interaction Therapy Group*Time, -58.82 (-153.22 - 35.58); p=0.22; Effect
modification by therapy: 141.78 (-254.66 - 548.23); p=0.49

eREFERENCES
1. Vincent JL, de Mendonça A, Cantraine F, Moreno R, Takala J, Suter PM, et al. Use of the
SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results
of a multicenter, prospective study. Working group on "sepsis-related problems" of the
European Society of Intensive Care Medicine. Crit Care Med. 1998;26(11):1793-800.
2. Frat JP, Thille AW, Mercat A, Girault C, Ragot S, Perbet S, et al. High-flow oxygen through
nasal cannula in acute hypoxemic respiratory failure. N Engl J Med. 2015;372(23):2185-96.
3. Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on
weighted residuals. Biometrika. 1994;81(3):515-26.
4. Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J

Radiol. 1971;44(526):793-7.

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eAppendix. Supplemental Methods

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Members Of Boards And Committees

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- Age 18 years or older;

SARS-CoV-2 infection was confirmed by a positive reverse transcription polymerase-chain-

Definition of Failure to Respiratory Support

Failure to respiratory support (high-flow or conventional oxygen therapy) was considered if at

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Intubation Criteria (for Patients included in the study)

• Signs of persistent respiratory distress

• Signs of hemodynamic derangement

• Signs of neurological derangement

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© 2021 American Medical Association. All rights reserved.

Nevertheless, due to the particular situation during pandemic, an important number of

Continuous variables were described as medians (interquartile ranges) and categorical

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Additional Details for Interim Analysis

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eTable 1. Seven-Point Ordinal Scale

1 Discharged from the hospital, resuming complete day-life

2 Discharged from the hospital, but limitation of activities,

3 Hospitalized in general ward (not intensive care unit), not

requiring supplemental oxygen and no longer requiring

4 Hospitalized in General Ward (not intensive care unit),

5 Hospitalized in the Intensive Care Unit, requiring

6 Hospitalized in the Intensive Care Unit, requiring invasive

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Characteristic High-Flow Oxygen Conventional Oxygen P

Fever - no. (%) 66 (66.7) 73 (73.0) .41

Vital signs at admission, median (IQR)

Laboratory, median (IQR)

pH 7.46 (7.43 – 7.48) 7.45 (7.43 – 7-48) .69

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© 2021 American Medical Association. All rights reserved.

High-Flow Oxygen Conventional Oxygen P

Respiratory support 2-Hours post

Respiratory support 4-Hours post

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© 2021 American Medical Association. All rights reserved.

High-Flow Oxygen Conventional Oxygen P value

No. of intubations by day 28, (%) .026 (a)

Time elapsed from randomization to

Time elapsed with FiO2 > 0.70 from

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(a) P value obtained by X2 test

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High-Flow Oxygen Conventional Oxygen P value

Cause of intubation – no. / total of intubated at day-7 – No. (%)

Persistent signs of respiratory distress 31 / 31 (100) 47 / 47 (100) > .99

Hemodynamic derangement 0 / 31 (0) 1 / 47 (2.1) > .99

Neurologic derangement 3 / 31(9.7) 1 / 47 (2.1) .30

Other 0 / 31 (0) 2 / 47 (4.3) .51

Cause of death – No. / total of deceased at day-28 – No. (%)

Refractory hypoxemia 1 / 8 (12.5) 2 /16 (12.5) .99

Refractory shock 4 / 8 (50.0) 13 / 16 (81.3) .41

Cardiac arrest 1 / 8 (12.5) 2 / 16 (12.5) 1.00

Multiorgan failure 6 / 8 (75.0) 13 / 16 (81.3) 1.00

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Overall Seven-Category Ordinal Scale at Baseline