Anakinra

Kyriazopoulou, 2021

Type of study:

Prospective, doubleblind randomized

controlled trial.

Setting:

37 study sites

Country:

29 sites in Greece and

eight in Italy.

Source of funding:

Not reported.

Conflicts of interest:

G.P. has received

independent

educational grants

from Pfizer, MSD,

Angelini and Bio

-Rad. H.M. reports receiving honoraria, consulting fees and non -financial

support from

healthcare companies,

including Amgen,

Angelini, Bayer, Mylan, MSD, Pfizer and Servier. L.D. received consultation honoraria from Sobi. M.B. has received funds for research grants and/or

advisor/consultant

and/or speaker/chairman from Angelini, Astellas,

Bayer, bioMérieux,

Cidara, Cipla, Gilead,

Menarini, MSD, Pfizer,

Roche, Shionogi and

Nabriva. M.G.N. is

supported by an ERC

Advanced Grant (no.

833247) and a Spinoza

grant of the

Netherlands

Organization for

Scientific Research. He

has also received

independent

educational grants

from TTxD, GSK and

ViiV Healthcare. J.E.

-O. is a co-founder,

shareholder and CSO of ViroGates, Denmark, and is a named inventor on patients on

suPAR owned by

Copenhagen University

Hospital Hvidovre,

Denmark. P.P. has

received honoraria

from Gilead, Janssen

and MSD. G.N.D. is an

advisor or lecturer for

Ipsen, Pfizer, Genkyotex, Novartis

and Sobi, has received

research grants from

Abbvie and Gilead and

has served as principal

investigator in studies

for Abbvie, Novartis,

Gilead, Novo Nordisk,

Genkyotex, Regulus

Therapeutics, Tiziana

Life Sciences, Bayer,

Astellas, Pfizer,

Amyndas

Pharmaceuticals,

CymaBay Therapeutics,

Sobi and Intercept

Pharmaceuticals. E.J.G.- B. has received

honoraria from Abbott, bioMérieux, Brahms, GSK, InflaRx, Sobi and XBiotech; independent

educational grants

from Abbott,

AxisShield, bioMérieux,

InflaRx, Johnson &

Johnson, MSD, Sobi

and XBiotech; and

funding from the

Horizon 2020 Marie

- Curie Project European Sepsis Academy (granted to the National and

Kapodistrian University

of Athens) and the

Horizon 2020 European. Grants ImmunoSep and RISKinCOVID (granted to the Hellenic Institute for the Study of Sepsis). The other authors do not have any competing interests to declare.

Patients with COVID-19 at risk of progressing to respiratory failure

Inclusion criteria:

• Adult patients of either sex;

• For women, unwillingness of

remain pregnant during the

study period;

• Confirmed infection by SARSCoV-2 by molecular test;

• Findings in chest X-ray or chest computed tomography

compatible with lower

respiratory tract infection;

• Need for hospitalization;

• Plasma suPAR ≥6 ng ml-1.

Exclusion criteria:

• Any stage IV malignancy;

• Any do-not-resuscitate order;

• Ratio or partial oxygen pressure to fraction of inspired oxygen less than 150 mmHg;

• Need for NIV (CPAP or BPAP) or mechanical ventilation;

• Any primary immunodeficiency; • Fewer than 1500 neutrophils

per mm3;

• Oral or intravenous intake of

corticosteroids at a daily dose

greater than or equal to 0.4

mg/kg-1 or prednisone for a

period longer than the last 15

days;

• Any anti-cytokine biological

treatment including JAK

inhibitors, during the last 1

month;

• Severe hepatic failure; • End-stage renal failure

necessitating hemofiltration or

peritoneal hemodialysis;

• Pregnancy of lactation.

N total at baseline:

N = 594

Intervention: N = 405

Control: N = 189

Important characteristics:

Age, mean (SD):

I: 62.0 y (11.4)

C: 61.5 y (11.3)

Sex, n/N (%)male:
I: 236/405 (58.3%)
C: 108/189 (57.1%)

Disease severity, mean (SD):

Defined by WHO classification for COVID-19 at the time of

screening (%)

Moderate pneumonia

I: 39/405 (9.6%)

C: 11/189 (5.8%)

Severe pneumonia

I: 366/405 (90.4%)

C: 178/189 (94.2%)

Groups comparable at baseline

?

Yes.

Anakinra

Patients allocated to the

active drug were daily injected with 100mg of

anakinra at a final volume

of 0.67ml.

Placebo

Patients

allocated to

placebo

treatment were daily injected with 0.67ml of

0.9% sodium

chloride.

Length of follow up:

Until day 28.

Loss to follow-up:

Intervention:

N = 1

Reasons: not

reported.

Control:

N = 0

Reasons: not

reported.

Clinical outcomes

Mortality day 28

I: 13/405 (3.2%)

C: 13/189 (6.9%)

Duration of hospitalization

Median (IQR) time to

hospital discharge in days

I: 11 (7.8)

C: 12 (8.5)

OR 1.22 (95% CI 1.02 to

1.47)

P=0.033

Time to symptom

resolution

Not reported

Median (IQR) time of ICU

stay in days

I: 10 (21)

C: 14 (22)

OR 2.33 (95% CI 1.11 to

4.92)

P=0.026

Respiratory support

WHO-CPS by day 28

 Fully recovered PCR

-, n/N(%)

I: 204/405 (50.4%)

C: 50/189 (26.5%)

 Asymptomatic PCR

+, n/N(%)

I: 40/405 (9.9%)

C: 6/189 (3.2%)

Symptomatic independent, n/N (%)

I: 93/405 (23.0%)

C: 74/189 (39.2%)

Symptomatic assistance

needed, n/N (%)

I: 25/405 (6.2%)

C: 21/189 (11.1%)

Hospitalized with no

need for oxygen, n/N (%)

I: 9/405 (2.2%)

C: 3/189 (1.6%)

Hospitalized with

nasal/mask oxygen, n/N

(%)

I: 8/405 (2.0%)

C: 10/189 (5.3%)

Need for HFO or NIV, n/N

(%)

I: 1/405 (0.2%)

C: 1/189 (0.5%)

Mechanical ventilation

with P/F >150 mmHg, n/N (%)

I: 1/405 (0.2%)

C: 1/189 (0.5%)

MV with P/F <150 mmHg

or vasopressors, n/N (%)

I: 5/405 (1.2%)

C: 4/189 (2.1%)

MV with P/F <150 mmHg

and vasopressors or

hemodialysis or ECMO,

n/N (%)

I: 6/405 (1.5%)

C: 6/189 (3.2%)

Absolute decrease of

WHO-CPS at day 28 from

baseline day 1, median

(IQR)

I: 4 (2.0)

C: 3 (2.5)

OR 0.40 (95% CI 0.29 to

0.55)

P<0.0001

Absolute decrease of

WHO-CPS at day 14 from

baseline day 1, median

(IQR)

I: 3 (2.0)

C: 2 (3.0)

OR 0.63 (95% CI 0.46 to

0.86)

P=0.003

Absolute decrease of SOFA score at day 7 from

baseline day 1, median

(IQR)

I: 1 (2)

C: 0 (1)

OR 0.64 (0.47 to 088)

P=0.007

Safety

Adverse events

At least one serious

adverse event , n/N (%)

I: 65/405 (16.0%)

C: 41/189 (21.7%)

P=0.107

At least one non-serious

adverse event, n/N (%)

I: 335/405 (82.7%)

C: 156/189 (82.5%)

P=1.00

Virological outcomes

Viral clearance

Not reported.

Definitions:

WHO-CPS: World Health Organisation

Clinical Progression Scale

SOFA: Sequential Organ Failure

Assessment Score suPAR: “denotes the presence of dangerassociated molecular patterns (DAMPs), namely calprotectin (S100A8/A9) and IL-1α3, 4, both of which contribute to pathogenic inflammation in COVID-19." Serious adverse events: infections and infestations, ventilator-associated pneumonia, septic shock and multiple organ dysfunction, bloodstream infection, probable hospital-acquired infection, hospital-acquired pneumonia, acute pyelonephritis and pulmonary

embolism.

Adverse events: anemia, neutropenia, thrombocytopenia, rash at the infection site, constipation, diarrhea, increase of liver function tests, bradycardia, headache, anxiety, creatinine increase, hyperglycemia, hyponatremia, hypernatremia, hypokalemia, hyperkalemia and hypocalcemia.

Remarks: -

Authors conclusion:

In conclusion, the SAVE

-MORE trial showed that early start of treatment with anakinra guided by suPAR levels in patients hospitalized with moderate and severe COVID

-19 significantly reduced the risk of worse clinical outcome at day 28.

Mariette,

2021

CORIMUNO-ANA-1 trial

Type of study:

RCT; open-label

Setting: 16 University hospitals; sub-study of

CORIMUNO-trial

Country:

France

Source of funding:

The Ministry of Health, Programme Hospitalier de Recherche Clinique,

Foundation for Medical Research,

and AP-HP Foundation;

The funders of the study had no role in the study design,

data collection, data

analysis, data interpretation, or

writing of the report.

Patients with mild-to-moderate,

RT-PCR confirmed, COVID-19

Pneumonia

Inclusion criteria:

CORIMUNO-trial overall:

• confirmed SARS-CoV-2 infection

(RT-PCR and/or chest CT)

• mild-to-moderate, severe, or

critical pneumonia (ie, receiving

oxygen at a flow of >3 L/min via

mask or nasal cannula and a

score of ≥5 points on the WHO

Clinical Progression Scale

[WHO-CPS] 10-point ordinal

scale, which is described in the

appendix 2 [pp 12–13]).

CORIMUNO-ANA-1 trial:

• C-reactive protein serum

concentration > 25 mg/L not

requiring admission to hospital

ICU at time of admission

• mild-to-moderate COVID-19

pneumonia with a WHO-CPS

score of 5 points, receiving at

least 3 L/min of oxygen but

without ventilation assistance

(eg, high-flow oxygen, noninvasive ventilation, or

mechanical ventilation).

Exclusion criteria:

• known hypersensitivity to

anakinra or any of its excipients

• pregnancy

• current documented bacterial

infection

• absolute neutrophil count of

1·0 × 10⁹ per L or less

• platelet concentration <50 G/L

• serum aspartate

aminotransferase or serum

alanine aminotransferase > 5x

upper limit of normal

• severe renal insufficiency

defined by an estimated

glomerular filtration rate of <

30 mL/min.

See full list of criteria in appendix 2

N total at baseline:

N = 116

Intervention: 59

Control: 57 (55 included in

baseline characteristics and

analysis)

Important characteristics:

Age, median (IQR):

I: 67·0 (55·5–74·3)

C: 64·9 (59·5–78·3)

Sex, n/N (%) male:

I: 43/59 (73%)

C: 37/55 (67%)

Time from symptoms onset to

randomisation, median (IQR)

days

I: 10·0 (8·0–13·0; n=59)

C: 10·0 (7·0–13·0; n=54)

Groups comparable at baseline.

Anakinra + usual care

Anakinra (Sobi, Puteaux,

France); intravenously;

Day 1-3 after randomization:

200 mg twice a day (total

400 mg) Day 4: 100 mg twice a day (total 200 mg) Day 5: 100 mg once

If no improvement was

seen on the morning of

day 4 (improvement was

determined as a reduction in requirement of oxygen of more than 50%, but the decision was left to the treating physician), 3 supplementary days of

treatment at 400 mg per

day were done on days 4–6, followed by a decrease to 200 mg per day on day 7 and 100 mg per day on day 8,

and no treatment

thereafter.

Actual treatment:

• All received 2–15

injections of anakinra

(median 11 [IQR 9–15]).

• Median dose of anakinra by

• Perfusion: 180 mg (IQR

167–186)

• 55 (93%) patients

• received seven

perfusions or more.

• Median cumulative dose of anakinra was 1900 mg (1500–2700).

Usual care

Usual care

(antibiotic

drugs, antiviral

drugs, corticosteroids,

vasopressor

support,

anticoagulants)

was provided at the discretion

of the site

clinicians.

Length of follow up:

90 days

Loss to follow-up:

I: 4/59 (6.8%)

Reasons: lost contact

C: 2/57 (3.5%)

Reasons: withdrew

consent

Also reported: composite

score for non-invasive

ventilation, high-flow

oxygen, mechanical

ventilation, or

death; mechanical

ventilation of death at day 14;

Clinical outcomes

Mortality

Survival with no need for

mechanical or non-invasive ventilation

median posterior HR 0·97

(90% CrI 0·62 to 1·52)

Mortality, incidence, day

90

I: 16/59 patients

C: 15/55 patients died

Overall survival; adjusted

HR (95% CI)

Day 14

0·56 (0·23–1·39)

Day 28

0·77 (0·33–1·77)

Day 90

overall survival 72% (95%

CI 61 to 85)

overall survival 72%, (95%

CI 62 to 85)

adjusted HR 0·97 (95% CI

0·46 to 2·04)

Duration of hospitalization

Discharge from hospital,

day 28

I: 34/59; 58% (95% CI 44–

69)

C: 34/55; 62% (47–73)

Adjusted HR 0·91 (95% CI

0·56 to 1·48)

Symptom resolution

WHO-CPS score ≥ 5, day 4

I: 21/59 (36%)

C: 21/55 (38%)

Absolute risk diff –2·5%

(90% CrI –17·1 to 12·0)

WHO-CPS score (10-point

scale); median (IQR) and

median posterior odds

ratio adjusted for age and

centre.

Day 4

I: 5 (5 to 6)

C: 5 (5 to 6)

OR 0·80 (95% 0.38 to 1.68

Day 7

I: 5 (5 to 7)

C: 5 (5 to 7)

OR 0·69 (95% CrI 0·33 to

1·43)

Day 14

I: 5 (2 to 8)

C: 5 (3 to 8)

OR 0·70 (95% CrI 0·35 to

1·38)

Day 2 to 14 (longitudinal

analysis)

OR 0·92 (95% CrI 0·32 to

2·65)

Need for respiratory

Support Oxygen independence, day 28

I: 63% (95% CI 49–74)

C: 69% (55–80)

adjusted HR 1·01 (95% CI

0·64 to 1·61)

Safety

Adverse events (I: n=59; C: n=55)

Patients with at least one

AE

I: 29 (49%)

C: 23 (42%)

Patients with multiple AEs

I: 19 (32%)

C: 14 (25%)

Total number of adverse

events

I: 113

C: 60

Serious adverse events

Patients with at least one

SAE

I: 27 (46%)

C: 21 (38%)

Patients with multiple SAEs

I: 8 (14%)

C: 5 (9%)

Total number of SAEs

I: 42

C: 28

Virological outcomes

Viral clearance

not reported

Also reported: C-reactive

protein, neutrophil count,

lymphocyte count,

lymphocyte to neutrophil

ratio

Definitions:

WHO-CPS score

Uninfected

• 0, Uninfected;

Ambulatory: Mild disease

• 1, Asymptomatic; viral RNA detected;

• 2, Symptomatic; independent;

• 3, Symptomatic; assistance needed;

Hospitalised: moderate disease

• 4, hospitalized, not requiring oxygen;

• 5, hospitalized, requiring oxygen by

mask or nasal prongs;

Hospitalised: severe disease

• 6, hospitalized, requiring nasal highflow oxygen therapy, non-invasive mechanical ventilation, or both;

• 7, hospitalized, requiring

• intubation and mechanical ventilation, pO2/FIO2 ≥150 or SpO2/FIO2 ≥ 200;

• 8, hospitalized, requiring

• mechanical ventilation, (pO2/FIO2

<150 OR SpO2/FIO2 < 200) OR

vasopressors (norepinephrine < 0.3

microg/kg/min);

• 9, Mechanical ventilation, pO2/FIO2 <150 AND vasopressors (norepinephrine > 0.3

• microg/kg/min), OR dialysis OR ECMO

Dead

• 10, Dead.

Declercq, 2021

Type of study:

Multicentre, open-label, 2x2 factorial, randomised, controlled phase 3 trial

Setting:

Hospital-based, between April 4 and December 6, 2020

Country:

16 hospitals in Belgium

Source of funding:

Belgian Health Care Knowledge Centre and VIB Grand Challenges program. The funder of the study (Belgian Health Care Knowledge Centre) was involved in purchasing study medication and study design, but was not involved in data collection, data analysis, data interpretation, writing of the manuscript, or the decision to submit. The funder (VIB Grand Challenges) was involved in purchasing reagents for measuring biomarkers.

Conflicts of interest:

Conflicts of interest were transparently and extensively reported.

Hospitalised patients with COVID-19, hypoxia, and signs of a cytokine release syndrome

Inclusion criteria:

• age > 18 y
• laboratory proven diagnosis of COVID-19 with symptoms between 6 and 16 days
• P_aO₂/F_iO₂ < 350 mmHg on room temperature or < 280 mmHg on supplemental oxygen and bilateral pulmonary infiltrates
• COVID-19-associatedcytokine release*
• use of one of the following:
  • invasive mechanical ventilation, OR
  • non-invasive ventilation or continuous use of CPAP for hypoxia, OR
  • oxygen supplementation with an oxygen flow of at least 10 L/min independent of delivery system

Exclusion criteria:

• mechanical ventilation for more than 24 h at randomization
• a clinical frailty score greater than 3 before SARS-CoV-2 infection
• unlikelihood to survive beyond 48 h based on clinical assessment
• an active co-infection defined on clinical grounds (positive blood or sputum cultures)
• thrombocytopenia of less than 50 000/μL or neutropenia of less than 1500/μL
• history of bowel perforation or diverticulitis
• high dose systemic steroid or immunosuppressive drug use for a COVID-19-unrelated disorder

N total at baseline:

Randomized: N = 342

ITT population: N = 342

Intervention 1:: N = 112

Control 1: N = 230

Intervention 2a: N = 113

Intervention 2b: N = 114

Control 2: N = 115

Important characteristics:

Age, median (IQR):

I1: 67 y (56-74)

C1: 64 y (54-72)

I2: 59 y (52-74)

C2: 62 y (55-71)

Sex, n/N (%) male:

I1: 87/112 (78%)

C1: 178/230 (77%)

I2: 175/227 (77%)

C2: 90/115 (78%)

Mechanical ventilation at day of randomisation

Invasive

I1: 17/112 (15%)

C1: 22/230 (10%)

I2: 22/227 (10%)

C2: 17/115 (15%)

Non-invasive or high flow oxygen device

I1: 44/112 (39%)

C1: 84/230 (37%)

I2: 89/227 (39%)

C2: 39/115 (34%)

Groups were comparable at baseline.

Intervention 1:

anakinra 100 mg 1 dd s.c. for 28 days or until hospital discharge + standard care

Intervention 2:

siltuximab 11 mg/kg i.v. (single injection)

(= intervention 2a)

OR

tocilizumab 8 mg/kg i.v. (not exceeding 800 mg; single injection)

(= intervention 2b)

Control 1:

standard care

Control 2:

standard care

Length of follow-up:

28 days

Loss-to-follow-up:

I1: 0/112 (0%)

Reasons: -

C1: 6/230 (3%)

Reasons:

• withdrew consent (n = 4)
• transfer to other hospital (n = 2)

I2a: 2/113 (2%)

Reasons:

• withdrew consent (n = 2)

I2b: 2/114 (2%)

Reasons:

• transfer to other hospital (n = 2)

C2: 2/115 (2%)

Reasons:

withdrew consent (n = 2)

Clinical outcomes

Mortality

Number of deaths

I1: 10/44 (23%)

I1+I2a: 5/32 (16%)

I1+I2b: 6/36 (17%)

I2a: 10/81 (12%)

I2b: 15/75 (20%)

C: 9/74 (12%)

Estimated mortality at day 28

I1: 16% (95%CI: 8-31)

I1+I2a: 13% (95%CI: 5-30)

I1+I2b: 17% (95%CI: 8-33)

I2a: 11% (95%CI: 6-20)

I2b: 13% (95%CI: 7-23)

C: 10% (95%CI: 5-20)

Estimated mortality at day 90

I1: 23% (95%CI: 13-38)

I1+I2a: 16% (95%CI: 7-34)

I1+I2b: 17% (95%CI: 8-33)

I2a: 12% (95%CI: 7-22)

I2b: 19% (95%CI: 12-30)

C: 13% (95%CI: 7-23)

Duration of hospitalization

Time until discharge

Days, median

I1: 14 (95%CI: 11-19)

C1: 12 (95%CI: 11-18)

HR 0.90 (95%CI: 0.70-1.16)

I2: 12 (95%-CI: 11-18)

C2: 13 (95%-CI: 11-19)

HR 1.02 (95%CI: 0.80-1.31)

Number of days in hospital

Mean

I1: 19 (95%CI: 17-22)

C1: 19 (95%CI: 17-21)

expected count ratio 1.01 (95%CI: 0.85-1.21)

I2: 20 (95%-CI: 18-22)

C2: 19 (95%-CI: 16-22)

expected count ratio 1.03 (95%CI: 0.86-1.22)

Number of days in ICU

Mean

I1: 11 (95%CI: 8-15)

C1: 10 (95%CI: 8-13)

expected count ratio 1.05 (95%CI: 0.69-1.59)

I2: 11 (95%-CI: 8-14)

C2: 10 (95%-CI: 7-15)

expected count ratio 1.03 (95%CI: 0.68-1.56)

Number of days in ICU in patients ventilated at day of randomisation

Mean

I1: 20 (95%CI: 15-27)

C1: 22 (95%CI: 17-29)

expected count ratio 0.89 (95%CI: 0.60-1.32)

I2: 20 (95%-CI: 16-27)

C2: 22 (95%-CI: 16-29)

expected count ratio 0.94 (95%CI: 0.64-1.40)

Number of days in ICU relative to the number of days alive the first 28 days after randomisation

Mean

I1: 42% (95%CI: 31-56)

C1: 36% (95%CI: 29-46)

expected count ratio 1.14 (95%CI: 0.79-1.66)

I2: 38% (95%-CI: 30-48)

C2: 40% (95%-CI: 29-54)

expected count ratio 0.96 (95%CI: 0.66-1.39)

Time to symptom resolution

Time to clinical improvement (primary outcome)†

Days, median

I1: 12 (95%CI: 10-16)

C1: 12 (95%CI: 10-15)

HR 0.94 (95%CI: 0.73-1.21)

I2: 11 (95%-CI: 10-16)

C2: 12 (95%-CI: 11-16)

HR 1.00 (95%CI: 0.78-1.29)

Estimated probability of having experienced clinical improvement at day 28

I1: 75% (95%CI: 67-83)

C1: 73% (95%CI: 67-79)

I2: 74% (95%-CI: 68-79)

C2: 74% (95%-CI: 66-82)

Respiratory support

Median time until independence from supplemental O₂ or discharge

Days, median

I1: 12 (95%CI: 10-20)

C1: 12 (95%CI: 10-15)

HR 0.91 (95%CI: 0.71-1.17)

I2: 11 (95%-CI: 10-15)

C2: 12 (95%-CI: 10-15)

HR 1.00 (95%CI: 0.78-1.28)

Median time until independence from invasive ventilation

Days, median

I1: 21 (95%CI: 8-not estimable)

C1: 27 (95%CI: 9-not estimable)

HR 1.21 (95%CI: 0.54-2.71)

I2: 23 (95%-CI: 8-not estimable)

C2: 54 (95%-CI: 9-not estimable)

HR 1.45 (95%CI: 0.63-3.33)

Median time until first use of high-flow oxygen device, ventilation, or death

Days, median

I1: < 50% reached event

C1: < 50% reached event

HR 0.97 (95%CI: 0.52-1.82)

I2: < 50% reached event

C2: < 50% reached event

HR 0.85 (95%CI: 0.47-1.55)

Number of days without supplemental O2 use up to 28 days after randomisation

Mean

I1: 9 (95%CI: 7-12)

C1: 9 (95%CI: 7-12)

expected count ratio 0.97 (95%CI: 0.68-1.38)

I2: 10 (95%-CI: 8-12)

C2: 8 (95%-CI: 6-11)

expected count ratio 1.17 (95%CI: 0.82-1.68)

Number of invasive ventilator days

Mean

I1: 5 (95%CI: 3-9)

C1: 5 (95%CI: 3-7)

expected count ratio 1.05 (95%CI: 0.54-2.03)

I2: 5 (95%-CI: 3-7)

C2: 5 (95%-CI: 3-9)

expected count ratio 0.89 (95%CI: 0.46-1.72)

Number of invasive ventilator days in patients ventilated at day of randomisation

Mean

I1: 15 (95%CI: 11-20)

C1: 16 (95%CI: 13-21)

expected count ratio 0.93 (95%CI: 0.63-1.37)

I2: 15 (95%-CI: 12-20)

C2: 16 (95%-CI: 12-22)

expected count ratio 0.96 (95%CI: 0.65-1.42)

Number of invasive ventilator days relative to the number of days alive the first 28 days after randomisation

Mean

I1: 23% (95%CI: 14-38)

C1: 21% (95%CI: 14-31)

expected count ratio 1.08 (95%CI: 0.57-2.05)

I2: 21% (95%-CI: 14-30)

C2: 23% (95%-CI: 14-38)

expected count ratio 0.89 (95%CI: 0.47-1.70)

Number of invasive ventilator-free days up to 28 days after randomisation

Mean

I1: 18 (95%CI: 15-21)

C1: 18 (95%CI: 16-20)

expected count ratio 1.00 (95%CI: 0.84-1.19)

I2: 18 (95%-CI: 17-20)

C2: 17 (95%-CI: 15-20)

expected count ratio 1.07 (95%CI: 0.90-1.27)

Number of invasive ventilator-free days up to 28 days after randomisation in patients ventilated at day of randomisation

Mean

I1: 6 (95%CI: 3-14)

C1: 6 (95%CI: 3-13)

expected count ratio 1.01 (95%CI: 0.33-3.07)

I2: 7 (95%-CI: 4-15)

C2: 5 (95%-CI: 2-12)

expected count ratio 1.39 (95%CI: 0.46-4.20)

Safety

Serious infections

Sepsis

I1: 5/44 (11%)

I1+I2a: 2/32 (6%)

I1+I2b: 3/36 (8%)

I2a: 4/81 (5%)

I2b: 11/75 (15%)

C: 6/74 (8%)

Septic shock

I1: 5/44 (11%)

I1+I2a: 1/32 (3%)

I1+I2b: 3/36 (8%)

I2a: 3/81 (4%)

I2b: 6/75 (8%)

C: 3/74 (4%)

Serious adverse events not leading to mortality

Infectious disorder (not COVID-19)

I1: 1/44 (2%)

I1+I2a: 2/32 (6%)

I1+I2b: 1/36 (3%)

I2a: -

I2b: 4/75 (5%)

C: 1/74 (1%)

Bleeding

I1: 2/44 (5%)

I1+I2a: 1/32 (3%)

I1+I2b: -

I2a: 1/81 (1%)

I2b: -

C: 1/74 (1%)

Thrombosis

I1: 1/44 (2%)

I1+I2a: -

I1+I2b: 1/36 (3%)

I2a: -

I2b: 1/75 (1%)

C: 1/74 (1%)

Acute kidney injury

I1: 1/44 (2%)

I1+I2a: -

I1+I2b: -

I2a: -

I2b: 1/75 (1%)

C: 1/74 (1%)

Cardiac disorder

I1: -

I1+I2a: -

I1+I2b: -

I2a: 1/81 (1%)

I2b: 1/75 (1%)

C: 1/74 (1%)

Other

I1: -

I1+I2a: 2/32 (6%)

I1+I2b: 2/36 (6%)

I2a: 3/81 (4%)

I2b: 1/75 (1%)

C: 1/74 (1%)

Virological outcomes

Viral clearance

Not reported.

Several subgroups were prespecified on the basis of allocated treatment for the other randomisation, invasive ventilation and serum concentrations of CRP, IL-1β, and IL-6 on the day of randomisation. Post-hoc subgroup analyses included serum concentrations of IL-1RA, admission status to ICU or concomitant glucocorticoid use at randomisation.

Definitions:

* Patients needed to have either a single ferritin concentration measurement of more than 2000 μg/L at inclusion when they immediately required high flow oxygen or mechanical ventilation, or a ferritin concentration of more than 1000 μg/L, which had been increasing over the previous 24 h, or lymphopenia below 800/mL with two of the following criteria: an increasing ferritin concentration of more than 700 μg/L; an increasing lactate dehydrogenase concentration of more than 300 international units (IU)/L; an increasing CRP concentration of more than 70 mg/L; or an increasing D-dimers concentration of more than 1000 ng/mL. If the patient had three of the previous criteria at hospital admission with lymphopenia of less than 800/μL, there was no need to document an increase over 24 h.

† Defined as the time in days from randomisation until either an increase of at least two points on a 6-category ordinal scale (compared with the worst status at day of randomisation) or to discharge from the hospital alive, whichever occurred first. The 6-category ordinal scale was defined as 1=death; 2=hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation; 3=hospitalised, on non-invasive ventilation or high-flow oxygen devices; 4=hospitalised, requiring supplemental oxygen; 5=hospitalised, not requiring supplemental oxygen; 6=not hospitalised.

Remarks:

-

Authors conclusion:

Drugs targeting IL-1 or IL-6 did not shorten the time to clinical improvement in this sample of patients with COVID-19, hypoxic respiratory failure, low SOFA score, and low baseline mortality risk.

Kharazmi, 2021

Type of study:

Open-label, randomized controlled trial.

Setting:

Imam Hossein Medical Centre affiliated with Shahid Beheshti University of Medical Sciences

Country:

Iran

Source of funding:

No information.

Conflicts of interest:

The authors declare that there are no conflict of interests.

Patients with severe COVID-19

Inclusion criteria:

• Patients who had an age of 18 years or older;
• Elevated C-reactive protein levels;
• Oxygen saturation less than or equal to 93% measured using a peripheral capillary pulse oximeter;
• Fever (core temperature of 37.8 or more);
• Cough or shortness of breath;
• PaO₂/FiO₂ less than 300.

Exclusion criteria:

• Patients who had positive results for tuberculosis;
• Viral hepatitis B or C;
• Hemoglobin less than 7,5 g/dl;
• Platelet count of fewer than 100.000 cells/uL;
• Serum glutamic-oxaloacetic transaminase;
• Serum glutamic-pyruvic transaminase more than five upper limits of normal;
• Untreated active infection, and previous administration of canakinumab or anakinra.

N total at baseline:

N = 30

Intervention: N= 15

Control: N = 15

Important characteristics:

Age, mean (SD):

I: 49.25 y (19.12)

C: 59.00 y (1.79)

P=0.424

Sex, n/N (%) male:

I: 8/15 (53.3%)

C: 11/15 (73.3%)

Disease severity ordinal scale, n/N (%)

1. death

I: 0/0 (0%)

C: 0/0 (0%)

2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation.

I: 2/15 (13.3%)

C: 3/15 (20.0%)

3. Hospitalized, on noninvasive ventilation or high flow oxygen

I: 10/15 (66.7%)

C: 6/15 (40%)

4. Hospitalized, requiring low flow supplemental oxygen

I: 3/15 (20%)

C: 6/15 (40%)

5. Hospitalized, not requiring supplemental oxygen—requiring ongoing medical care (COVID‐19 related or otherwise).

I: 0/15 (0%)

C: 0/15 (0%)

6. Hospitalized, not requiring supplemental oxygen—no longer required ongoing medical care.

I: 0/15 (0%)

C: 0/15 (0%)

7. Not hospitalized

I: 0/15 (0%)

C: 0/15 (0%)

Groups comparable at baseline?

Yes.

Anakinra group

Patients in the intervention group received 100 mg anakinra as an intravenous (IV) infusion once daily in addition to the standard protocol for COVID‐19 based on the sixth and seventh national COVID‐19 committee guideline, until discharge or a maximum of 14 days.

Control group

In the control group, patients received medication based on the sixth and seventh national protocol released on April 29, 2020 and June 27, 2020, respectively.

Length of follow-up:

14 days.

Loss-to-follow-up:

None.

Incomplete outcome data:

None.

Clinical outcomes

Mortality (28-30 day)

Not reported.

Length of hospital stay, mean (SD)

I: 9.50 (4.45)

C: 19.00 (12.04)

ICU length of stay, mean (SD)

I: 5.43 (1.72)

C: 16.60 (9.04)

Disease severity day 7, n/N (%)

1. death

: 4/15 (26.7%)

C: 5/15 (33.3%)

2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation.

I: 1/15 (6.7%)

C: 5/15 (33.3%)

3. Hospitalized, on noninvasive ventilation or high flow oxygen

I: 1/15 (6.7%)

C: 0/15 (0%)

4. Hospitalized, requiring low flow supplemental oxygen

I: 4/15 (26.7%)

C: 4/15 (26.7%)

5. Hospitalized, not requiring supplemental oxygen—requiring ongoing medical care (COVID‐19 related or otherwise).

I: 1/15 (6.7%)

C: 0/15 (0%)

6. Hospitalized, not requiring supplemental oxygen—no longer required ongoing medical care.

I: 0/15 (0%)

C: 0/15 (0%)

7. Not hospitalized

I: 4/15 (26.7%)

C: 1/15 (6.7%)

Disease severity day 14, n/N (%)

1. death

: 5/15 (33.3%)

C: 7/15 (46.7%)

2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation.

I: 0/15 (0%)

C: 2/15 (13.3%)

3. Hospitalized, on noninvasive ventilation or high flow oxygen

I: 0/15 (0%)

C: 2/15 (13.3%)

4. Hospitalized, requiring low flow supplemental oxygen

I: 0/15 (0%)

C: 4/15 (26.7%)

5. Hospitalized, not requiring supplemental oxygen—requiring ongoing medical care (COVID‐19 related or otherwise).

I: 0/15 (0%)

C: 0/15 (0%)

6. Hospitalized, not requiring supplemental oxygen—no longer required ongoing medical care.

I: 0/15 (0%)

C: 0/15 (0%)

7. Not hospitalized

I: 10/15 (66.7%)

C: 5/15 (33.3%)

Time to symptom resolution

Not reported.

Respiratory support

Not reported.

Safety

Adverse events

I: 1/15 (6.7%) (sputum culture)

C: 3/15 (20%) (positive microbiologic culture: one blood culture, two sputum cultures)

Virological outcomes

Viral clearance

Not reported.

Definitions:

-

Remarks:

There are some limitations to our study. First, this is a pilot study with a small sample size. Second, we did not control the trial with a placebo.

Authors conclusion:

According to the study results, in general, anakinra is effective in improving the respiratory condition and significantly reduces the need for invasive mechanical ventilation in patients with severe COVID‐19. And also, the reduction was observed in hospitalization duration, which makes the medication an effective immunomodulatory agent to combat cytokine storm. As an important consideration, the reliable safety of anakinra in patients with critical conditions is one of this medication's most important properties

Canakinumab

Caricchio, 2021

Type of study: RCT (double blind)

Setting: 39 hospitals in Europe and the United States

Country: Europe and the United States

Source of funding: Novartis Pharma AG, Basel, Switzerland.

Conflicts of interest: All authors received funding from Novartis during the conduct of the study. Dr Caricchio reported receiving grants from Janssen and personal fees from Janssen, GlaxoSmithKline, Bristol Myers Squibb, Eli Lilly, and Siemens outside the submitted work. Dr Abbate reported receiving grants from Kiniksa, Janssen, Olatec, and Serpin Pharma; personal fees from Janssen, Kiniksa, Cromos, Olatec, Serpin Pharma, Eli Lilly, and Merck; and nonfinancial support from Swedish Orphan Biovitrum outside the submitted work. Dr Hsue reported receiving honoraria from Gilead and Merck outside the submitted work. Dr Neogi reported receiving personal fees from Novartis outside the submitted work. Drs Chen, Li, Whelan, and Noviello reported being employees of Novartis. Dr Whelan reported having a patent pending through Novartis. Dr Noviello reported being a former/employee/stockholder of Bristol Myers Squibb and stockholder of Johnson & Johnson; in addition, Dr Noviello reported having a patent pending through Novartis.

ClinicalTrials.gov:NCT04362813

Hospitalized patients with severe COVID-19.

Inclusion criteria:

• at least 12 years old (United States) or 18 years old (Europe); • Had hypoxemia but did not require IMV;

• diagnosis of infection with SARSCoV-2 within 7 days prior to randomization;

• diagnosis of pneumonia with pulmonary infiltrates on chest x-ray or computed tomographic scan within 5 days prior to randomization;

• peripheral capillary oxygen saturation of 93%or less on room air or arterial oxygen partial pressure/fraction of inspired oxygen less than 300mmHg;

• blood levels of CRP of 20mg/L or greater or ferritin of 600 μg/L or greater

Exclusion criteria:

 • Had been treated with therapies targeting IL-1 or IL-6

• had a suspected or known untreated active infection due to another pathogen

• or if progression to death was imminent within 24 hours according to the investigator.

N total at baseline: N = 454 Intervention:227 Control: 227

Important characteristics: Age, median (IQR): I: 59 (49-69) C: 57 (50-68)

Sex, n/N (%) male: I:135/227 (59%) C:132/227 (58%)

Disease severity, mean (SD): Defined by WHO ordinal scale I: 0: 0

1:0

2:0

3: 14 (6.2)

4: 161 (70.9)

5: 52 (22.9)

6: 0

7: 0

8: 0

C:

0: 0

1:0

2:0

3: 12 (5.4)

4: 160 (71.4)

5: 52 (23.2)

6: 0

7: 0

8: 0

Groups comparable at baseline? Yes

Canakinumab single dose of canakinumab (450mg for body weight of 40-<60 kg, 600mg for 60-80 kg, and 750 mg for >80 kg) in 250 mL of 5% dextrose infused intravenously over 2 hours

Placebo placebo in 250 mL of 5% dextrose infused intravenously over 2 hours

Length of follow-up: 127 days; Interim analysis reported for 29 days follow up

Loss-to-follow-up: Intervention: 1 Control: 1 (2%)

Incomplete outcome data:

Intervention: 13 Discontinued the study (12 Died; 1 Participant decision (hospitalized)) Control: 16 Discontinued the study (died)

Clinical outcomes

Mortality (28-30 day) Day 29: No. (%)

I: 12 (5.3)

C: 16 (7.1)

OR :0.67 (95% CI, 0.30-1.50).

Survived without requiring IMV (3-29 day) I:198/223 (88.8%)

C: 191/223 (85.7%)

OR: 1.39 (95% CI, 0.76-2.54; P =.29).

Duration of hospitalization Discharged at day 29

I: 199/211

C: 187/206

Time to symptom resolution Not reported

Respiratory support

Intubation and mechanical ventilation

I: 5 (2.2)

C: 2 (0.9)

Ventilation plus additional organ support (pressors, KRT, ECMO):

I: 2 (0.9)

C: 8 (3.6)

Safety

Adverse events Any AE: No. (%)

I: 122 (54.2)

C: 120 (53.8)

SAEs: No. (%)

I: 36 (16.0)

C: 46 (20.6)

Virological outcomes Viral load > day 22: ≥ 500 I: 1/15 (6.7)

C: 5/17 (29.4)

<500

I: 14/ 15 (93.3)

C: 12/ 17 (70.6)

Definitions: World Health Organization’s 9-point ordinal scale: 0 No clinical or virological evidence of infection

1 No limitation of activities

2 Limitation of activities

3 Hospitalized, no oxygen therapy

4 Oxygen by mask or nasal prongs

5 Noninvasive ventilation or high-flow oxygen

6 Intubation and mechanical ventilation

7 Ventilation plus additional organ support (pressors, KRT, ECMO)

8 Death.

Primary end point: the proportion of patients who survived without ever requiring IMV from day 3 to day 29 (inclusive).

The key secondary outcome: the proportion of patients who died of COVID-19 (causality assessed by investigators) between days 1 and 29.

Remarks: The sponsor, in consultation with investigators, designed and conducted the study. Collection of data and management of trial sites were conducted by the sponsor. An independent data monitoring committee reviewed trial safety data weekly. All authors contributed to the interpretation of the data, including sponsor co-authors. A preliminary draft of the manuscript was prepared by a writer contracted by Novartis.

Authors conclusion: Among patients hospitalized with severe COVID-19, treatment with canakinumab, compared with placebo, did not significantly increase the likelihood of survival without IMV at day 29.

Cremer, 2021

Type of study: RCT (double blind)

Setting: 5 hospitals in Cleveland Clinics

Country: the United States

Source of funding: This study was funded by an investigator-initiated grant fromNovartis.

Conflicts of interest:

Paul Cremer has served on scientific advisory committees for Sobi and Kiniksa pharmaceuticals and has received investigator-initiated grants from Kiniksa andNovartis pharmaceuticals.

Hospitalized patients with severe COVID-19.

Inclusion criteria:

- Written informed consent must be obtained before any assessment is performed.

- Hospitalized due to COVID-19 infection

- Documented SARS-CoV2 acute myocardial injury: Defined as upper respiratory tract specimen positive for COVID-19 AND troponin greater than 99th percentile upper reference range without signs or symptoms of acute myocardial ischemia

- NT-proBNP or BNP greater than upper reference limit

- Receiving current standard therapy

- C-reactive protein (CRP) > 50 mg/L

Exclusion criteria:

- Alternative explanation for acute cardiac injury (Type I or Type II MI according to 4th Universal Definition of Myocardial Infarction, which in addition to a rise and fall of tropnonin above the 99th percentile upper reference limit, includes symptoms of acute myocardial ischemia, new ischemic ECG changes, development of pathologic Q waves, and imaging evidence of damage in a pattern consistent with an ischemic etiology)

- Chronic Systolic Heart Failure with EF<35%

- Age < 18 years-old

- Uncontrolled systemic bacterial or fungal infection

- Concomitant viral infection (e.g., Influenza or other respiratory virus)

- Pregnant. Breast-feeding women are eligible with the decision to continue or discontinue breast-feeding during therapy taking into account the risk of infant exposure, the benefits of breast-feeding to the infant, and benefits of treatment to the mother.

- On mechanical circulatory support

- On mechanical ventilation for greater than 48 hours

- Resuscitated cardiac arrest

- Has a known hypersensitivity to canakinumab or any of its excipients

- Neutrophil count <1000/mm3

- Has a history of myeloproliferative disorder or active malignancy receiving chemotherapy

- Known active tuberculosis or history of incompletely treated tuberculosis

- Current treatment with immunosuppressive agents

- Chronic prednisone use >10 mg/daily (for more than 3 weeks prior to admission)

- Has a history of solid-organ or bone marrow transplant

- Severe pre-existing liver disease with clinically significant portal hypertension

- End-stage renal disease on chronic renal replacement therapy

- Enrollment in another investigational study using immunosuppressive therapy

- In the opinion of the investigator and clinical team, should not participate in the study

- If male and sexually active, must have documented vasectomy or must practice birth control and not donate sperm during the study and for 3 months after study drug administration.

- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of investigational drug.

N total at baseline: N = 45 Intervention1: 14

Intervention 2: 15

Control: 16

Important characteristics: Age, median (IQR): 68.8 (61.1-74.3)

Sex, n/N (%) male: 33/48 (73.3%)

a single infusion of canakinumab

600 mg intravenous (IV), canakinumab 300 mg IV

Intervention 1 = 600mg

Intervention 2 = 300mg

Equal volume (250mL) of 5% dextrose for

placebo infusion

Length of follow-up:

28 days

Loss-to-follow-up: None.

Incomplete outcome data:

None.

Clinical outcomes

Mortality (28-30 day) Day 28: No. (%)

I-1: 1 (6.7)

I-2: 3 (21.4)

C: 3 (18.3)

HR-1: 0.20 (95%CI 0.02 to 1.98)

HR-2: 1.21 (95%CI 0.23 to 5.59)

Respiratory support:

Requiring invasive respiratory support (high flow nasal cannula (HFNC)/Optiflow, continuous positive airway pressure (CPAP), non-invasive ventilation (NIV), mechanical ventilation, extracorporeal membrane oxygenation (ECMO or ECLS))

At day 14:

I1: 5/16

I2:1/11*

C:2/14*

At day 28:

I1: 1/18*

I2:1/11*

C:1/13*

Requiring non-invasive respiratory support (supplemental oxygen low flow oxygen, non-rebreathing mask)

At day 14:

I1: 1/16

I2: 3/11*

C:4/14*

At day 28:

I1: 0/15*

I2:1/11*

C:1/13*

duration of hospitalization:

not reported.

time to symptom resolution:
clinical improvement or discharge at day 14, n (%)
I1: 9 (60)
I2: 7 (58.1)
C: 9 (58.3)
RR1: 1.15 (95%CI 0.46 to 2.91)
RR2: 0.61 (95% CI 0.23 to 1.64)

clinical improvement or discharge at day 28, n (%)
I1: 14 (93.5)
I2: 11 (78.6)
C: 11 (68.8)
RR1: 2.10 (95%CI 0.89 to 1.98)
RR2: 1.44 (95% CI 0.57 to 3.62)

Safety:
not reported.

Primary endpoint: Time to clinical improvement up to Day 14, defined as the time in days from randomization to either an improvement

of two points on seven category ordinal scale or discharge

from the hospital, whichever occurred first.

Remarks:

The funder of the study provided the study drug and assisted with the

study design. The funder was not involved in data collection or analysis.

The corresponding author (P.C.C.) had full access to all of the data and

the final responsibility to submit for publication.

Authors conclusion:

There was no difference in time to clinical improvement at Day 14 in patients treated with canakinumab, and no safety concerns were identified. Future studies could focus on high dose canakinumab in the treatment arm and assess

efficacy outcomes at Day 28.

Anakinra

Kyriazopoulou,

2021

“Patients were

electronically 1:2

randomized into

treatment with placebo

or anakinra using four

randomization strata:

classification into

moderate or severe

disease using the WHO

definition based on the

need for oxygen support

(https://www.who.int/p

ublications/i/item/

clinical-management-ofcovid-19); need for

dexamethasone intake;

body mass index (BMI)

higher than 30kg m−2 ;

and country.”)

Unlikely

Patients were randomized using for

randomization strata:

• classification into

moderate or severe

disease using the

WHO definition based on the need for oxygen support (https://www.who.

int/publications/i/i

tem/ clinicalmanagement-ofcovid-19);

• need for Dexamethasone intake;

• body mass index

(BMI) higher than 30kg m−2;

• country.

Unlikely

Double-blind study.

Unlikely

The study drug was

prepared by an

unblinded pharmacist

with access to the

electronic study

system using a

separate username

and password.

Administration was

done by a blinded

study nurse

Unlikely

Data were captured

after review of all

medical and nursing

charts by a physician

team blinded to the

allocation group

Unlikely

All predefined

outcome measures

were reported.

Unlikely

Only one patient was

lost to follow-up in the

study. The patient was

initially allocated to

the intervention

group.

Unlikely

Participants included

in the analysis are

exactly those who

were randomized into

the trial

.

Mariette, 2020

Computerized

randomization

Participants were

assigned by means of a

centralized computer

program to each

intervention, starting

with balanced

assignment for

tocilizumab, sarilumab,

or control, with actual

proportions dependent

on the number of

interventions available

at each site

Unclear

Centralized

randomization was used

that was remote from

study sites.

Likely

(mortality: unlikely)

‘Patients and

investigators were not

masked to treatment

assignment due to the

nature of the

intervention.’

Likely

(mortality: unlikely)

‘Patients and

investigators were not

masked to treatment

assignment due to the

nature of the

intervention.’

Likely

(mortality: unlikely)

‘Patients and

investigators were not

masked to treatment

assignment due to the

nature of the

intervention.’

Unlikely

Not all outcomes that

are reported in trial

registration are

reported in

publication.

Registered

ClinicalTrials.gov:

NCT04341584.

Unlikely

4 patients (6.8%) in

the intervention group

en 2 patients (3.5%) in

the control group

were lost to FU or

withdrew consent.

This is not expected to

induce a bias in the

results.

Mariette, 2020

Declercq, 2021

Computerised

Included patients were randomly assigned by means of permuted block randomization with varying block size and stratification by center. Patients were allocated in a 1:2 ratio to anakinra or no IL-1 blockade. Simultaneously, patients were randomly assigned in a 1:1:1 ratio to siltuximab, tocilizumab, or no IL-6 blockade. Randomization and subsequent data collection were done by means of the web based system REDCap.

Unlikely

Randomization and subsequent data collection were done by means of the web based system REDCap.

Likely

open-label trial

Likely

open-label trial

Unclear

not described

Unlikely

All outcome measures described in the methods are reported in the results.

Unlikely

The percentage of patients lost to follow-up is less than 10% and is similar between treatment groups.

Unlikely

The primary and supportive efficacy endpoints were assessed in the intention-to-treat population. Safety was assessed in the safety population.

Kharazmi, 2021

The sample size of 30 patients was divided into parallel groups of intervention and control considered.

Unlikely

Permuted block randomization with the sample size of four patients in each block which was stratified based on receiving invasive mechanical ventilation at baseline was performed

Likely

Open-label study

Likely

Open-label study

Likely

Open-label study

Unlikely

All predefined outcome measures were reported.

Unlikely

No loss to follow-up reported.

Unlikely

Participants included in the analysis are exactly those who were randomized into the trial.

Canakinumab

Caricchio, 2021

Block randomisation The randomization was stratified by country, with a block size of 4 within each stratum. It was implemented using an interactive response technology system in which a new patient meeting the inclusion and exclusion criteria was randomly assigned to a treatment group based on a random allocation sequence. This sequence was created by a separate randomization office of the sponsor and kept blinded to the study team until the scheduled unblinding for data analysis.

Unlikely

It was implemented using an interactive response technology system in which a new patient meeting the inclusion and exclusion criteria was randomly assigned to a treatment group based on a random allocation sequence.

Unlikely

It was implemented using an interactive response technology system in which a new patient meeting the inclusion and exclusion criteria was randomly assigned to a treatment group based on a random allocation sequence.

Unlikely

Double blinded

Unlikely

Double blinded

Unlikely

All outcomes mentioned in Methods were reported. ClinicalTrials.gov Identifier: NCT04362813

Unclear

Reason for loss to follow up was not reported

Unlikely

Patients randomized in the study were the same patients who were analysed.

Cremer, 2021

Computerised

Randomization was centralized through REDCap Cloud,

Unlikely

Randomization will be centralized through REDcap Cloud. Randomization will be stratified on whether or not the patient is intubated at the time of enrollment (in addition to site).

Unlikely

Randomization will be centralized through REDcap Cloud. Randomization will be stratified on whether or not the patient is intubated at the time of enrollment (in addition to site).

Unlikely

Subjects, investigator staff, persons performing the assessments, and the clinical trial team will be blinded to treatment. Only the Research Pharmacist and members of the Data Safety Monitoring Board will have access to the treatment assignments. If the clinical team decides that unblinding the patient is essential for subsequent significant clinical management, then the patient may be unblinded after discussion between the clinical team and the Principal Investigator, Paul Cremer.

Unlikely

Subjects, investigator staff, persons performing the assessments, and the clinical trial team will be blinded to treatment. Only the Research Pharmacist and members of the Data Safety Monitoring Board will have access to the treatment assignments. If the clinical team decides that unblinding the patient is essential for subsequent significant clinical management, then the patient may be unblinded after discussion between the clinical team and the Principal Investigator, Paul Cremer.

Unlikely

Reported in study protocol. This is included in the supplementary file.

Unlikely

None of the participants were lost to follow up

Unlikely.