Tocilizumab (humanized monoclonal antibody against the interleukin-6 receptor)

Hermine, 2022

(TOCI-2 and SARI-2 trial, embedded in the CORIMUNO-19 cohort)

Type of study:

Two cohort-embedded, investigator-initiated, multicenter, open-label, Bayesian randomised controlled clinical trials

Setting:

hospital-based, between March 31 to April 18, 2020 (TOCI-2)

and from March 27 to April, 2020
(SARI-2)

Country:

France (12 sites, TOCI-2; 8 sites, SARI-2)

Source of funding:

This trial was publicly funded (Ministry of Health, Programme Hospitalier de Recherche

Clinique [PHRC COVID-19-20-0143, PHRC COVID-19-20-0029], Foundation for Medical

Research (FRM), AP-HP Foundation, and the Reacting program).

Conflicts of interest:

Roche and Sanofi donated TCZ and SARI.

Transparently reported.

Hospital based COVID-19 patients with moderate, severe pneumonia or critical pneumonia

Inclusion criteria:

• Positive on RT-PCR and/or typical chest CT-scan with moderate to severe, or critical pneumonia (O2>3 L−min⁻¹)
• WHO-CPS score >5

Exclusion criteria:

• Exclusion criteria to the CORIMUNO-19 cohort
• Known hypersensitivity to the intervention
• Pregnancy
• Current documented bacterial infection
• Patients with any out of ranges laboratory results on ANC, haemoglobin levels, PLT, SGOT or SGPT

TOCI-2

N total at baseline:

N = 97

Intervention: 51

Control: 46

Important characteristics:

Age, median (IQR):

I: 63.2 y (59.4-70.9)

C: 65.4 y (57.6-70.5)

Sex, n/N (%) male:

I: 33/49 (67%)

C: 33/43 (77%)

Disease severity, n/N (%)

Defined by WHO-CPS score ≥7, n/N (%)

I: 36/49 (74%)
C: 31/43 (71%)

Groups comparable at baseline.

SARI-2

N total at baseline:

N = 91

Intervention: 50

Control: 41

Important characteristics:

Age, median (IQR):

I: 61.9 y (53.8-66.2)

C: 61.2 y (55.3-68.5)

Sex, n/N (%) male:

I: 36/48 (75%)

C: 26/33 (79%)

Disease severity, n/N (%)

Defined by WHO-CPS score ≥7, n/N (%)

I: 32/48 (67%)
C: 24/33 (41%)

Groups comparable at baseline.

TOCI-2

Tocilizumab was administered intravenously (IV) at 8 mg kg⁻¹ on day 1.

+

Usual care

SARI-2

Sarilumab was administrated IV at a fixed dose of 400 mg on day 1

+

Usual care

Usual care:

antibiotic agents, antiviral agents, corticosteroids, vasopressor support, anticoagulants) was provided at the discretion of the clinicians since, at that time, no standard of care (SOC) was defined, including the use of corticosteroids.

Length of follow-up:

90 days

TOCI-2

Loss-to-follow-up or incomplete data:

I: 2/51 (3.9%)

Reason

• withdrew consent (n = 2)

C: 3/46 (6.5%)

Reasons

• withdrew consent (n = 3)

No loss-to-follow up

SARI-2

Loss-to-follow-up or incomplete data:

I: 2/50 (4.0%)

Reason

• withdrew consent (n = 2)
•  

C: 8/41 (19.5%)

Reasons

• withdrew consent (n = 8)

No loss-to-follow up

Clinical outcomes

Mortality

not reported

Overall survival at D14, estimate (95% CI)

TOCI-2

I: 90% (82 to 99)

C: 79% (68 to 92)

HR: 0.37 (0.12 to 1.15)

SARI-2

I: 75% (64 to 88)

C: 73% (59 to 90)

HR: 0.95 (0.40 to 2.25)

Overall survival at D28, estimate (95% CI)

TOCI-2

I: 84% (74 to 95)

C: 77% (65 to 90)

HR: 0.56 (0.22 to 1.46)

SARI-2

I: 71% (59 to 85)

C: 67% (52 to 85)

HR: 0.89 (0.40 to 1.96)

Overall survival at D90, estimate (95% CI)

TOCI-2

I: 76% (64 to 89)

C: 70% (57 to 85)

HR: 0.67 (0.30 to 1.49)

SARI-2

I: 71% (59 to 85)

C: 61% (46 to 80)

HR: 0.74 (0.35 to 1.58)

Duration of hospitalization

not reported

Discharge at D28, estimate (95%CI)

TOCI-2

I: 55% (40 to 68)

C: 42% (27 to 56)

HR: 1.45 (0.80 to 2.63)

SARI-2

I: 35% (22 to 49)

C: 30% (16 to 46)

HR: 1.21 (0.55 to 2.66)

Discharge at D90, estimate (95%CI)

TOCI-2

I: 70% (54 to 82)

C: 60% (44 to 74)

HR: 1.35 (0.84 to 2.17)

SARI-2

I: 65% (48 to 77)

C: 52% (33 to 68)

HR: 1.30 (0.71 to 2.37)

ICU discharge at D28, estimate (95%CI)

TOCI-2

I: 72% (55 to 84)

C: 60% (42 to 74)

HR: 1.28 (0.73 to 2.24)

SARI-2

I: 60% (43 to 74)

C: 71% (50 to 85)

HR: 0.78 (0.42 to 1.44)

ICU discharge at D90, estimate (95%CI)

TOCI-2

I: 84% (66 to 93)

C: 83% (63 to 93)

HR: 1.15 (0.73 to 1.18)

SARI-2

I: 79% (61 to 89)

C: 82% (57 to 93)

HR: 0.84 (0.49 to 1.47)

Time to symptom resolution

not reported

No improvement in WHO score at D4, n/N (90% CI)

TOCI-2

I: 35/49 (71%)

C: 30/43 (70%)

Median posterior absolute risk difference

+1.7% (-13.6+17.1)

SARI-2

I: 34/48 (71%)

C: 26/33 (79%)

Median posterior absolute risk difference

-7.3% (-22.5 to +8.7)

WHO-CPS score, D2-D14 (longitudinal analysis)

TOCI-2

aOR: 0.76 (0.27 to 2.13)

SARI-2

aOR: 0.72 (0.21 to 2.41)

Extubation or removal of HIV at D14 (95%CI)

TOCI-2

I: 47% (32 to 60)

C: 42% (27 to 56)

HR: 1.19 (0.71 to 2.04)

SARI-2

I: 38% (24 to 51)

C: 33% (18 to 50)

HR: 1.05 (0.55 to 2.07)

Oxygen supply independency, estimate at D28 (95% CI)

TOCI-2

I: 59% (44 to 72)

C: 49% (33 to 63)

HR: 1.44 (0.82 to 2.52)

SARI-2

I: 44% (29 to 57)

C: 36% (20 to 53)

HR: 1.20 (0.59 to 2.44)

Oxygen supply independency, estimate at D90 (95% CI)

TOCI-2

I: 69% (53 to 80)

C: 64% (47 to 77)

HR: 1.28 (0.80 to 2.03)

SARI-2

I: 71% (52 to 83)

C: 56% (35 to 68)

HR: 1.29 (0.74 to 2.25)

Invasive respiratory support

not reported

Non-invasive respiratory support

not reported

Safety

Serious adverse events

Patients with at least one AE

TOCI-2

I: 33/49 (67%)

C: 30/43 (70%)

SARI-2

I: 32/48 (68%)

C: 22/33 (68%)

Virological outcomes

Viral clearance

not reported

Primary outcomes:

• No improvement in WHO score at day 4
• Extubation or removal of NIV >48h at day 14

Secondary outcome(s):

• Overall survival, day 14, 28, 90
• WHO-CPS score at day 4, 7 and 14
• Day-28 ventilator-free days
• Oxygen supply independency at day 28 and 90
• Discharge at day 28 and day 90
• ICU discharge at day 28 and day 90

Definitions:

Remarks:

Results on secondary outcomes should be regarded as exploratory (stated by the authors)

Authors conclusion:

In critically ill patients with COVID-19, anti-IL-6 Receptors did not significantly increase the number of patients alive without any NIV, MV by D14.

Declercq (2021)

See evidence table of Declercq (2021) by Anakinra.

Rosas, 2021b

Type of study:

Randomized, double-blind, placebo-controlled, multicenter, phase 3 trial.

Setting:

Hospital, June 2020-March 2021

Country:

Not stated.

Source of funding:

This trial was supported by F. Hofmann-La Roche Ltd.

Conflicts of interest:

IOR Grant from Roche/Genentech related to the submitted work and grant from Genentech and personal fees from Genentech, Boehringer, and Bristol Myers Squibb outside the submitted work. GD: Grants from Gilead Sciences, Regeneron Inc., Roche, Boehringer Ingelheim, and Edasa Biotech outside the submitted work. Gilead Medical Afairs sentinel panel and Scientifc Advisory Board for Safeology Inc. RLG: Personal fees from Eli Lilly, Gilead Sciences Inc., GlaxoSmithKline, Johnson and Johnson, and Roivant Sciences Inc. and non‑ fnancial support from Gilead Sciences Inc. outside the submitted work. SML: Investigator fees from Roche/Genentech during the conduct of the trial. PR: Nothing to disclose. BDH: Personal fees from Kite Pharma and Novartis outside the submitted work. AWC: Nothing to disclose. JSO: Institutional funding from Roche during conduct of the trial. NAH: Grants from GlaxoSmithKline, Sanof, AstraZeneca, Genentech, Boehringer Ingelheim, Novartis, and Gossamer Bio; personal fees from GlaxoSmithKline, Sanof, AstraZeneca, Genentech, Novartis, Regeneron, Teva, and Amgen outside the submitted work. AS: Personal fees from Genentech, AbbVie, Pharmacyclics, Janssen, Kite Pharma, Celgene, Ver‑ astem, BeiGene, Novartis, TG Therapeutics, Seattle Genetics, Morphosys, Jazz Pharmaceuticals, and Gilead Sciences and nonfnancial support from Bristol Myers Squibb outside the submitted work. JG-D: Nothing to disclose. IG: Nothing to disclose. JC: Grant provided to institution from Roche/Genentech during conduct of the trial. Grants and personal fees from Gilead Sciences Inc. outside the submitted work. OG: Employee of Roche and shareholder of Roche Holding AG. EG: Employee of Roche. NL-K: Employee of Roche/Genen‑ tech. LT: Employee of Roche/Genentech and has an unpublished patent pending, “Tocilizumab and Remdesivir Combination Therapy for COVID-19 Pneumonia.” KT: Former employee of Roche/Genentech and owns stock in Roche/Genentech. HC: Employee of Gilead Sciences Inc. DB: Former employee of and holds stock in Gilead Sciences Inc. JKO: Employee of Roche/Genentech.

Hospitalized COVID-19 patients

Inclusion criteria:

• Positive SARS-CoV-2 polymerase chain reactive test result within 7 days of randomization;
• Pneumonia confirmed by chest x-ray or computed tomography;
• Hypoxemia requiring >6 L/min supplemental oxygen.

Exclusion criteria:

• Estimated glomerular filtration rate was <30 mL/min;
• Alanine aminotransferase or aspartate aminotransferase levels were >5 x the upper limit of normal within 24 hours of screening.
• Patients with suspected active bacterial, fungal, viral, or other infection except COVID-19.

N total at baseline:

N = 640     

Intervention: N = 430

Control: N = 210

Important characteristics:

Age, mean (SD):

I: 60.1 y (13.3)

C: 58.2 y (13.3)

Sex, n/N (%) male:

I: 266/434/ (61.9%)

C: 139/210 (66.2%)

Disease severity, mean (SD):

Defined by ordinal scale for clinical status

3 (Non-ICU hospital ward or ready for hospital ward requiring supplemental oxygen

I: 29/434 (6.7%)

C: 13/210 (6.2%)

4 (ICU or non-ICU hospital ward, requiring noninvasive ventilation or high-fow oxygen)

I: 336/434 (78.1%)

C: 175 (210 (83.3%)

5 (ICU, requiring intubation and mechanical ventilation)

I: 30/434 (9.1%)

C: 9/210 (4.3%)

6 ICU, requiring extracorporeal membrane oxygenation or mechanical ventilation and additional organ support)

I: 26/434 (6.0%)

C: 13/210 (6.2%)

Groups comparable at baseline?

Yes.

Remdesivir plus tocilizumab

Remdesivir was administered intravenously, followed by a single intravenous dose of tocilizumab 8 mg/kg (maximum, 800 mg)

Remdesivir plus placebo

Remdesivir was administered intravenously, followed by a single intravenous dose of placebo 9 mg/kg (maximum, 800 mg).

Length of follow-up:

60 days.

Loss-to-follow-up:

Intervention:

N = 9

Control:

N =4

Incomplete outcome data:

Intervention:

N = 98

Control:

N = 50

Clinical outcomes

Mortality at day 28, n/N (%)

I: 78/430 (18.1%) (95% CI 14.5 to 21.8)

C: 41/210 (19.5%) (95% CI 14.2 to 24.9)

Weighted difference: -1.3 (-7.8 to 5.2)

P=0.69

Mortality at day 60, n/N (%)

I: 97/430 (22.6%) (95% CI 18.6 to 26.5)

C: 54/210 (25.7%) (95% CI 19.8 to 31.6)

Weighted difference -3 (-10.1 to 4)

P=0.39

Time to death to day 28, median (IQR)

I: non evaluable

C: non evaluable

P=0.79

HR 0.95 (95% CI 0.65 to 1.39)

Duration of hospitalization

Time to hospital discharge or ready for discharge to day 28, median (IQR)

I: 14 (12-15) days

C: 14 (11-16) days

P=0.74

HR 0.97 (95% CI 0.78 to 1.19)

Time to symptom resolution

Clinical status at day 14 assessed on the 7-category ordinal scale, n/N (%)

1

I: 231/430 (54.0%)

C: 110/210 (52.4%)

2

I: 11/430 (2.6%)

C: 4/210 (1.9%)

3

I: 38/430 (8.9%)

C: 24/210 (11.4%)

4

I: 41/430 (9.6%)

C: 14/210 (6.7%)

5

I: 21/430 (4.9%)

C: 14/210 (6.7%)

6

I: 43/430 (10%)

C: 24/210 (11.4%)

7

I: 43/430 (10%)

C: 20/210 (9.5%)

Respiratory support

Time to mechanical ventilation or death to day 28, median (IQR)

I: non evaluable

C: non evaluable

P=0.9

HR 0.98 (95% CI 0.72 to 1.34)

Safety

Adverse events, N

I: N = 1094

C: N = 530

Patients with 1 or more than 1 event, n/N (%)

I: 320 (429 (74.6%)

C: 147/213 (69.0%)

Patients with 1 or more than 1 serious adverse event, n/N (%)

I: 128/429 (29.8%)

C: 72/213 (33.8%)

Virological outcomes

Viral clearance

Not reported

Definitions:

-

Remarks:

-

Authors conclusion:

In this randomized, double-blind, placebo-controlled trial, tocilizumab plus remdesivir did not shorten time to hospital discharge or “ready for discharge” to day 28 compared with placebo plus remdesivir in patients with severe COVID-19 pneumonia, most of whom received systemic corticosteroids. Serious infections were not more frequent with tocilizumab treatment, and no new safety signals were identified.

Horby, 2021a

Recovery Collaborative Group

Type of study:

RCT (open-label), part of the RECOVERY trial.

Setting:

131 National Health Service Hospitals participating in the RECOVERY trial, enrolment between April 23, 2020 until Jan 24, 2021;

This study was part of the RECOVERY trial, in which patients were randomized to one of the following groups:

Part A: 542 dexamethasone,

557 lopinavir− ritonavir, 383 hydroxy-chloroquine,

2041 azithromycin,

3083 colchicine,

8107 usual care;

Part B:

5285 convalescent plasma, 2416 REGN−COV2, 6301 usual care;

Part C: 4450 aspirin,

4594 usual care;

After 21 days, eligible patients were randomised to either tocilizumab + usual care versus usual care alone.

Country:

United Kingdom

Source of funding:

UK Research and Innovation, National Institute of Health Research, Roche (provision of tocilizumab and reviewed draft publication for factual accuracy on tocilizumab).

Conflicts of interest:

The authors have no conflict of interest or financial relationships

relevant to the submitted work.

Hospitalized, adult patients with clinical evidence of progressive COVID-19.

Inclusion criteria:

• Adult patients
• Clinical evidence of progressive COVID-19 (oxygen saturation <92% on room air or receiving oxygen therapy, and CRP ≥75 mg/L)

Exclusion criteria:

• Tocilizumab not available at the hospital/time of enrolment
• Tocilizumab was definitely contra-indicated or definitely indicated
• Patients with known hypersensitivity to tocilizumab, evidence of active tuberculosis infection or clear evidence of active bacterial, fungal, viral, or other infection (besides COVID-19)

N total at baseline:

N = 4116

Intervention: 2022

Control: 2094

Important characteristics:

Age, mean (SD):

I: 63.3 y (13.7)

C: 63.9 y (13.6)

Sex, n/N (%) male:

I: 1337/2022 (66%)

C: 1437/2094 (69%)

Number of days since symptom onset, median (IQR):

I: 9 (7–13)

C: 10 (7–14)

Number of days since hospitalisation, median (IQR):

I: 2 (1–5)

C: 2 (1–5)

Disease severity

Respiratory support at second randomisation

No ventilator support, n/N (%):

Defined as patients not

receiving any oxygen and patients receiving low-flow oxygen

I: 935/2022 (46%)

C: 933/2094 (45%)

Non-invasive ventilation, n/N (%):

Defined as patients receiving high-flow nasal oxygen, continuous positive airway pressure, or other non-invasive ventilation

I: 819/2022 (41%)

C: 867/2094 (41%)

Invasive mechanical ventilation, n/N (%):

Defined as patients receiving invasive mechanical

ventilation or extracorporeal membranous oxygenation

I: 268/2022 (13%)

C: 294/2094 (14%)

Oxygen saturation, median (IQR):

I: 94% (92–96)

C: 94% (91–95)

Groups comparable at baseline?

Yes

Usual care + Tocilizumab

(A single intravenous infusion over

60 min was provided. The dose was established by

bodyweight (800 mg if weight >90 kg; 600 mg if weight >65 and ≤90 kg; 400 mg if weight >40 and ≤65 kg; and 8 mg/kg if weight ≤40 kg). A second dose could be given 12–24 h later if the patient’s condition had not improved.)

Usual care

Length of follow up:

Until discharge, death or at day 28 after randomisation.

Loss to follow-up:

I: 1964/2022 (97%) completed follow-up

Reasons: not reported

C: 2049/2094 (98%) completed follow-up

Reasons: not reported

(for the outcome 28-day mortality 99% completed follow-up)

Clinical outcomes

Mortality (28-30 day), n/N (%)

28-day mortality, n/N (%)

I: 621/2022 (31%)

C: 729/729 (35%)

RR (95%CI): 0.85 (0.76–0.94)

P= 0.0028

Subgroup analyses are available, based on e.g. days since symptom onset, corticosteroid treatment and respiratory support.

Duration of hospitalization

Median time to discharge, days

I: 19

C: >28

Discharged from hospital <28 days, n/N (%)

I: 1150/2022 (57%)

C: 1044/2094 (50%)

RR (95%CI): 1.22 (1.12–1.33)

P<0.0001

Time to symptom resolution

Not reported

Respiratory support

Receipt of invasive mechanical ventilation or death

Invasive mechanical ventilation, n/N (%)

I: 265/1754 (15%)

C: 343/1800 (19%)

RR (95%CI): 0.79 (0.69–0.92)

P= 0.0019

Death, n/N (%)

I: 490/1754 (28%)

C: 580/1800 (32%)

RR (95%CI): 0.87 (0.78–0.96)

P=0.0055

Receipt of ventilation

Non-invasive ventilation, n/N (%)

I: 281/935 (30%

C: 309/933 (33%)

RR (95%CI): 0.91 (0.79–1.04)

P= 0.15

Invasive mechanical ventilation, n/N (%)

I: 67/935 (7%)

C: 86/933 (9%)

RR (95%CI): 0.78 (0.57–1.06)

P= 0.11

Successful cessation of invasive mechanical ventilation, n/N (%)

I: 95/268 (35%)

C: 98/294 (33%)

RR (95%CI): 1.08 (0.81–1.43)

P=0.60

Safety

Adverse events

Any major cardiac arrhythmia

I: 108/2022 (6%)

C: 133/2094 (7%)

Authors stated that there were three reports of serious adverse reactions believed to be related to tocilizumab: one each of otitis externa, Staphylococcus aureus bacteraemia, and lung abscess, all of which resolved with standard treatment.

Virological outcomes

Viral clearance

Not reported

Also reported: Use of haemodialysis or

Hemofiltration

Definitions:

Receipt of invasive mechanical ventilation or death/receipt of ventilation included only those on no ventilator support or non-invasive ventilation at second randomisation (of tocilizumab). Successful cessation of invasive mechanical ventilation included only those on invasive mechanical ventilation at second randomisation

Remarks:

16% of patients in the

tocilizumab group reportedly did not receive treatment and reasons were not recorded. Furthermore, 77 patients in the usual care group did receive tocilizumab.

There is high risk of bias, since participants and local study staff were not blinded.

Roche Products supported the study through the supply of tocilizumab and reviewed the draft publication for factual accuracy relating to tocilizumab.

Authors conclusion:

The RECOVERY trial has shown that for patients

hospitalised with severe COVID-19, treatment with

tocilizumab reduces mortality, increases the chances of successful hospital discharge, and reduces the chances of

requiring invasive mechanical ventilation. These benefits are additional to those previously reported for dexamethasone. These findings require an update to clinical guidelines, which has already begun, and efforts to increase

the global availability and affordability of tocilizumab.

Wang, 2021

Type of study:

open-label multicenter RCT

Setting

hospital-based, between February 13 and March 13, 2020

Country:

6 hospitals in Anhui and Hubei, China

Source of funding:

This work was supported by the Department of Science and Technology of Anhui Province and Health Commission of Anhui Province (No. 202004a07020001) and the China National Center for Biotechnology Development (No. 2020YFC0843800). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Conflicts of interest:

The authors declare that they have no conflicts of interest.

patients with moderate or severe COVID-19

Inclusion criteria:

• PCR confirmed COVID-19
• age 18-85 years
• elevated plasma IL-6 levels
• moderate (with bilateral pulmonary lesions) or severe disease*
• patient or authorized family member voluntarily participated in the study and signed the informed consent form

Exclusion criteria:

• participation in other drug clinical trials
• pregnant or breast-feeding women;
• ALT or AST > 5 ULN (neutropenia < 0.5 x 10⁹/L; platelet < 50 x 10⁹/L)
• rheumatism- and immunity-related diseases, cancer, and other related diseases
• use of antirejection or immunomodulatory drugs
• allergy to tocilizumab or any of the excipients
• active hepatitis and tuberculosis, associated with specific bacterial and fungal infections
• history of organ transplantation
• mental disorders

N total at baseline:

Randomized: N = 65

Intervention: N = 33

Control: N = 32

One patient in the control group, who worsened severely 3 days after randomization, was crossed over to the tocilizumab group in accordance with the study protocol. However, this patient was erroneously included in the intervention group for the ITT analyses.

Important characteristics:

Age, median (IQR):

I: 63.5 y (58-71)

C: 63 y (54-69)

Sex, n/N (%) male:

I: 18/34 (52.94%)

C: 15/31 (48.39%)

Groups were comparable at baseline.

tocilizumab + standard care

(The first dose of tocilizumab was 400 mg, diluted in 100 mL of 0.9% saline, and administered intravenously for more than 1 h. A second dose was given if a patient remained febrile for 24 h after the first dose.)

standard care

Length of follow-up:

Not specified.

Loss-to-follow-up:

None.

Incomplete outcome data:

None.

Subgroup analyses were performed for patients with moderate or severe COVID-19 for primary and secondary outcomes. The primary outcome was the cure rate.

Clinical outcomes

Mortality

Not reported.

Cure rate**

I: 32/34 (94.14%)

C: 27/31 (87.10%)

rate difference 7,02 (95%CI: -7.19-21.23)

Recovery rate of hypoxia at day 14

I: 22/24 (91.67%)

C: 12/20 (60.00%)

rate difference 31.67 (95%CI: 7.52-55.82)

Worsening rate of hypoxia during hospitalization

Not reported.

Duration of hospitalization

Median (IQR)

I: 26 (17-27)

C: 24 (15-28)

median difference 2 (95%CI: -4-2)

Time to symptom resolution

Not reported.

Respiratory support

Not reported.

Safety

Serious adverse events

I: 0/34 (0%)

C: 1/31 (3.23%)

Non-serious adverse events

I: 20/34 (58.82%)

C: 4/31 (12.90%)

Also reported are specific treatment-related adverse events.

Virological outcomes

Viral clearance (i.e. time to negative virus load)

Median (IQR)

I: 17 (12-20)

C: 16 (12-21.5)

median difference 1.5 (95%CI: -4-5)

Definitions:

* The diagnosis of moderate or severe disease was defined according to the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (5th or updated version) as follows: moderate disease, fever or other respiratory symptoms, bilateral pulmonary lesions confirmed by chest imaging; severe disease was defined if any of the following conditions was met: (1) respiratory rate ≥ 30 breaths/min; (2) SpO₂ ≤ 93% while breathing room air; (3) PaO2/FiO₂ ≤ 300 mmHg.

**The definition for cure followed the standard given by the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (5th or updated version): (1) fever attenuated continuously for 7 days, (2) twice negative SARS-CoV-2 nucleic acid detections, (3) CT scan demonstrating chest effusion improved more than 50%.

when the patient is discharged from the hospital.

Remarks:

The authors did not enrol enough eligible patients in accordance with the previously designed protocol. The time between the onset of disease and randomization was relatively long in some patients.

Authors conclusion:

This study showed that tocilizumab treatment is not associated with a significantly higher cure rate among COVID-19 patients. However, it can improve oxygenation, symptoms, and reduce disease worsening with an acceptable side effect profile. Tocilizumab had no significant influence on the time needed for negative viral load. For COVID-19 patients with bilateral pulmonary lesions and elevated IL-6 levels, tocilizumab is recommended for better disease management.

Soin, 2020

COVINTOC trial

Type of study:

RCT; open-label, multicentre

Setting:

Public and private hospitals; recruited between May 30, 2020, and Aug 31, 2020.

Country:

India

Source of funding:

Medanta Institute of Education and Research, Roche India, Cipla India, and Action COVID-19 India; The funder of the study had a role in study design, data collection, data analysis, data interpretation, and writing of the report.

Hospitalized COVID-19 patients with moderate to severe illness

Inclusion criteria:

• Age ≥ 18 years
• admitted to hospital
• SARS-CoV-2 infection confirmed by WHO criteria (positive PCR test on any specimen)
• moderate to severe disease defined according to the Indian MoHFW clinical management protocol for COVID-1920 (moderate: defined as respiratory rate 15–30 per min [revised to 24 per min on June 13, 2020] and blood oxygen saturation [SpO2] 90–94%;

severe: respiratory rate ≥30 per min or SpO2 <90% in ambient air, or ARDS or septic shock)

Exclusion criteria:

• known severe allergic reaction to tocilizumab or other monoclonal antibodies
• active tuberculosis infection
• suspected or active bacterial, fungal, or viral infection (except treated hepatitis C or B), or any other infection except COVID-19
• if death was imminent and inevitable within 24 h
• imminent and inevitable within 24 h
• received any oral anti-rejection or immuno-modulatory drugs in the previous 6 months or treatment with any investigational agent (including antivirals, cell-depleting therapies, biologics, and Janus kinase inhibitors) within five half-lives or 30 days before randomisation, whichever was longer.
• diagnosis of immunerelated rheumatic disease or be receiving corticosteroids equivalent to methylprednisolone at a dose of more than 1 mg/kg per day at screening or baseline.
• absolute neutrophil count < 500 cells per µL, platelet count < 50000 cells per µL, and alanine aminotransferase or aspartate aminotransferase concentrations > 10 x upper limit of normal within 24 h of screening or baseline

N total at baseline:

N = 180

Randomized: 90 vs. 90

Analyzed:

Intervention: 91

Control: 88

Important characteristics:

Age, median (IQR):

I: 56 (47–63) y

C: 54 (43–63) y

Sex, n/N (%) male:

I: 76/91 (84%)

C: 76 (86%)

Disease severity

  Moderate

  I: 41 (45%)

  C: 47 (53%)

  Severe

  I: 50 (55%)

  C: 41 (47%)

Respiratory support

  Supplemental oxygen

  I: 81 (89%)

  C: 80 (91%)

  Non-invasive bilevel positive

  airway pressure ventilation

  I: 28 (31%)

  C: 20 (23%)

  Mechanical ventilation

  I: 5 (5%)

  C: 4 (5%)

  Intensive care unit

  I: 64 (70%)

  C: 54 (61%)

Groups comparable at baseline.

Tocilizumab

Tocilizumab 6 mg/kg plus standard care

Tocilizumab was administered as a single intravenous

infusion at 6 mg/kg up to a maximum dose of 480 mg. An

additional dose of 6 mg/kg (max 480 mg/kg) could be administered if clinical symptoms worsened or did not

show improvement within 12 h to 7 days after administration

of the first dose. The dosing regimen was selected on the

basis of the cost and supply considerations in India and because a single dose between 4 mg/kg and 8 mg/kg plus an additional dose to a maximum of 800 mg, if required, has been recommended on the basis of initial reports on the use of tocilizumab in the treatment of COVID-19 in China [ref 21].

Standard care

Length of follow up:

28 days

Loss to follow-up:

I: 16/91 (17.6%)

(died, n=11; withdrawn consent, n=2; withdrew because of no efficacy, n=2; not willing to visit hospital, n=1)

C: 20/88 (22.7%)

(died, n=15; withdrew consent, n=3, discharged against medical advice, n=1; chose to receive tocilizumab, n=1)

143 (79%) of 180 patients completed

28 days of follow-up, 75 (82%) in the tocilizumab group and 68 (76%) in the standard care group

Clinical outcomes

Mortality

Day 7

I: 2 (2%)

C: 2 (2%)

Diff –0·1 (–4·4 to 4·3), p= 0·97

Day 14

I: 8 (9%)

C: 9 (10%)

Diff –1·4 (–10·0 to 7·2), p= 0·74

Day 21

I: 10 (11%)

C: 14 (16%)

Diff –4·9 (–14·9 to 5·1), p= 0·33

Day 28

I: 11 (12%)

C: 15 (17%)

Diff –5·0 (–15·3 to 5·4), p= 0·35

Duration of hospitalization

ICU admission

I: 71 (78%)

C: 64 (73%)

Diff 5·3 (–7·3 to 17·9), p= 0·41

Duration of ICU stay, days

Mean (SD)

I: 8·2 (6·2)

C: 8·4 (6·5), p= 0·91

Median (IQR)

I: 7·0 (3·0 to 10·0)

C: 6·0 (3·5 to 11·0)

Symptom resolution

Progression of COVID-19, day 14; defined as progression from moderate to severe or from severe to death up to

I: 8 (9%)

C: 11 (13%)
diff –3·7 (–18·2 to 11·2)*

At least a one-grade Improvement in cytokine release syndrome up to day 28 [American Society for Transplantation and Cellular Therapy cytokine release

syndrome grade ref 22]

I: 58 (64%)

C: 59 (67%)

diff –3·3 (–17·9 to 11·3), p= 0·64

Time to clinical improvement (defined

as National Early Warning Score 2 [NEWS2] ≤2 maintained

for 24 h)

Organ failure-free days

Mean (SD)

I: 24·6 (9·2)

C: 23·2 (10·6), p= 0·35

Median (IQR)

I: 28·0 (28·0 to 28·0)

C: 28·0 (28·0 to 28·0)

Time to clinical improvement, median time (days)

based on NEWS2 score

I: 9·0 (95% CI 8·0–21·0)

C: 8·0 (95% CI 6·0–10·0)

Log rank p=0·43

Based on COVID-19 grade

I: 7·0 (95% CI 5·0–8·0)

C: 7·0 (95% CI 5·0–9·0)

Log rank p=0·93

Need for respiratory support

Ventilator-free days

Mean (SD)

I: 24·3 (9·2)

C: 23·2 (10·6), p= 0·45

Median (IQR)

I: 28·0 (28·0 to 28·0)

C: 28·0 (28·0 to 28·0)

Duration of supplemental oxygen-free days

Mean (SD)

I: 17·1 (9·4)

C: 18·3 (9·9), p= 0·41

Median (IQR)

I: 20·0 (12·0 to 24·0)

C: 22·0 (16·0 to 25·0)

Incidence of mechanical ventilation up to day 28

I: 14 (15%)

C: 13 (15%)

Diff 0·6 (–9·9 to 11·1), p= 0·91

Safety

Adverse events, 28 days

Adverse events, patients with at least one event

I: 33 (36%) patients, 54 events

C: 22 (25%) patients, 55 events

Infections

I: 6 (7%)

C: 5 (6%)

Serious adverse events*

I: 18 (20%) patients, 23 events

C: 15 (17%) patients, 24 events

Deaths

I: 13 (14%)

C: 15 (17%)

Grade 3 or worse adverse events

I: 2 (2%)

C: 5 (6%)

Virological outcomes

Viral clearance

time to negative result on RT-PCR

Also reported: Serum concentrations of IL-6, ferritin, and C-reactive protein (CRP), requirement for renal

replacement therapy

Authors conclusion:

Routine use of tocilizumab in patients admitted to hospital with moderate to severe COVID-19 is not supported. However, post-hoc evidence from this study suggests tocilizumab might still be effective in patients with severe COVID-19 and so should be investigated further in future studies.

Rosas, 2021a

Type of study:

A phase 3, international, randomized, double-blind placebo-controlled trial

Setting:

62 hospitals

Country:

Nine countries in Europe and North America (Canada, Denmark, France, Germany, Italy, the Netherlands, the United Kingdom, and the United States).

Source of funding:

Supported F. Hoffmann–La Roche and by a grant (HHSO100201800036C) from the Biomedical Advanced Research and Development Authority of the Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services. Drs. Cooper and Youngstein were supported in part by the Biomedical Research Centre of the United Kingdom National Institute for Health Research. Dr. Malhotra is supported by the National Institutes of Health.

hospitalized patients with severe COVID-19 pneumonia.

Inclusion criteria:

• Patients with confirmed positive polymerase-chain-reaction (PCR) assay of any body fluid and evidenced by bilateral chest infiltrates on chest radiography or computed tomography;
• Patients with blood oxygen saturation of 93% or less or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen of less than 300 mm Hg.

Exclusion criteria:

• Patients were the treating physician determined that death was imminent and inevitable within 24 hours;
• Patients with tuberculosis or a bacterial, fungal, or viral infection other than SARS-CoV-2.

N total at baseline:

N = 438

Intervention: 294

Control: 144

Important characteristics:

Age, mean (SD):

I: 60.9 y (14.6)

C: 60.6 y (13.7)

Distribution (age) n/N (%):

18-64:

I: 163/297 (55.4%)

C: 81/144 (56.2%)

65-84:

I: 117/294 (39.8%)

C: 60/144 (41.7%)

>84:

I: 14/294 (4.8%)

C: 3/144 (2.1%)

Sex, n/N (%) male:

I: 205/294 (69.7%)

C: 101/144 (70.1%)

Illness severity on National Early Warming Score 2, mean (SD):

I: 7.1 (3.0)

C: 7.0 (3.0)

Ordinal scale for clinical status, n/N (%):

2

I: 9/294 (3.1%)

C: 6/144 (4.2%)

3

I: 78/297 (26.5%)

C: 44/144 (30.6%)

4

I: 94/294 (32.0%)

C: 39/144 (27.1%)

5:

I: 45/294 (15.3%)

C: 15/144 (10.4%)

6

I: 68/294 (23.1%)

C: 40/144 (27.8%)

Groups comparable at baseline?

Single intravenous infusion of tociluzumab at a dose of 8 mg per kilogram of bodyweight, with a maximum dose of 800 mg plus standard care.

Placebo plus standard care

Length of follow up:

The primary analysis was performed at day 28, and the final trial visit occurred at day 60.

Loss to follow-up:

Intervention group:

- N= 70 (24%) discontinued trial on or before day 28;

- N=57 (19%) died;

- N=7 (2%) were lost to follow-up;

- N=6 (2%) withdrew)

The 28 day follow-up evaluation completed in 224/294 (76.2%) patients.

Control group:

- N=36 discontinued trial on or before day 28;

- N=27 (19%) died;

- N=5 (3%) were lost to follow-up;

- N=2 (1%) withdrew;

- N=2 (1%) were withdrawn by physician.

The 28 day follow-up evaluation completed in 108/144 (75%) patients.

Clinical outcomes

Mortality at day 28, n/N (%):

I: 58/294 (19.7%)

C: 28/144 (19.4%)

Difference: 0.3 (95% CI= -7.6 to 8.2)

P=0.94

Clinical status on 7-category ordinal scale at day 28, median value (95% CI)

I: 1.0 (95% CI= 1.0 to 1.0)

C: 2.0 (95% CI= 1.0 to 4.0)

Difference: -1.0 (95% CI= -2.5 to 0.00)

P=0.31

Clinical status on 7-category ordinal scale at day 14, median value (95% CI)

I: 3.0 (95% CI= 2.0 to 4.0)

C: 4.0 (95% CI=. 3.0 to 5.0)

Difference: -1.0 (95% CI= -2.0 to 0.5)

Days until hospital discharge or readiness for discharge, median number (95% C)

I: 20.0 (95% CI= 17.0 to 27.0)

C: 28.0 (95% CI= 20.0 to ‘not evaluable’)

Symptom resolution – days until improvement by ≥2 categories on 7-category ordinal scale in clinical status, median number of days (95% CI)

I: 14.0 (95% CI= 12.0 to 17.0)

C: 18.0 (95% CI= 15.0 to 28.0)

HR= 1.26 (95% CI= 0.97 to 1.64)

Day in ICU, median number of days (95% CI)

I: 9.8 (95% CI= 7.0 to 15.7)

C: 15.5 (95% CI= 8.7 to 25.5)

Difference: -5.8 (95% CI= -15.0 to 2.9)

Incidence of ICU stay among patients not in ICU at baseline, n/N (%)

I: 27/127 (21.3%)

C: 23/64 (35.9%)

Difference: -14.8 (95% CI= -28.6 to -1.0)

Ventilator-free days at day 28, median number (95% CI)

I: 22.0 (95% CI= 18.0 to 28.0)

C: 16.5 (95% CI= 11.0 to 26.0)

Difference: 5.5 (95% CI= -2.8 to 13.0)

Subgroup analysis

Incidence of mechanical ventilation among patients not receiving mechanical ventilation at randomization, n/N (%)

I: 51/183 (27.9%)

C: 33/90 (36.7%)

Difference: -8.9% (95% CI= -20.7 to 3.0)

Clinical failure among patients not receiving mechanical ventilation at randomization, n/N (%)

I: 53/183 (29.0%)

C: 38/90 (42.2%)

HR= 0.61 (95% CI= 0.40 to 0.94)

Clinical status on the ordinal scale at day 28 among patients who were receiving mechanical ventilation at randomization, median value (95% CI)

I: 5.0 (95% CI= 3.0 to 5.0)

C: 5.0 (95% CI= 4.0 to 6.0)

Clinical status on the ordinal scale at day 28 among patients who were not receiving mechanical ventilation at randomization, median value (95% CI)

I: 1.0 (95% CI= 1.0 to 1.0)

C: 1.0 (95% CI= 1.0 to 1.0)

Safety population

I: N = 295

C: N = 143

Any adverse event

Patients with ≥1 event, N (%)

I: 228/295 (77.3%)

C: 116 (81.1)

Total number of events, N

I: N = 778

C: N = 360

Any serious adverse event

Patients with ≥1 event, N (%)

I: 103/295 (34.9%)

C: 55/143 (38.5%)

Total number of events, N

I: N = 160

C: N = 101

Death N (%)

I: 58/295 (19.7%)

C: 28/143 (19.6)

Patients with adverse events of special interest, n/N (%)

Infection

I: 113/295 (38.3%)

C: 58/143 (40.6%)

Serious infection

I: 62/295 (21.0%)

C: 37/143 (25.9%)

Opportunistic infection

I: 1/295 (0..3%)

C: 1/143 (0.7%)

Virological outcomes

Not reported

Definitions:

- National Early Warning Score 2: a standardized assessment for identifying acutely ill patients on the basis of respiration rage, oxygen saturation, systolic blood pressure, pulse rate, level of consciousness, and temperature. Values on this instrument range from 0 to 20, with higher scores indicating greater clinical risk.

- Standard of care: according to local practice (anti-viral treatment, low-dose glucocorticoids, convalescent plasma, and supportive care).

- Opportunistic infections were reported in one patient with candida sepsis in the intervention group and in one patient with respiratory moniliasis in the control group.

Remarks:

-

Authors conclusion:

Results of this trial must be interpreted in the context of therapies for severe Covid-19 pneumonia. Among the treatments for hospitalized patients with Covid-19 that have been investigated in randomized, controlled trials, dexamethasone was found to reduce mortality only among patients who were receiving mechanical ventilation or supplemental oxygen at randomization.28 Remdesivir shortened the time until recovery but did not have a significant effect on 14-day mortality.27 Clinical trials are under way to investigate many potential treatments, including other antiviral and antiinflammatory drugs, other targeted immunomodulators (e.g., sarilumab, anakinra, baricitinib, and canakinumab), anticoagulants, and antifibrotics (tyrosine kinase inhibitors).29 However, the need for effective treatments for patients with severe Covid-19 pneumonia continues to be a major challenge at this point in the pandemic

The REMAP-CAP Investigators, 2020

See the evidence table of the REMAP-CAP Investigators (2020) by sarilumab.

Veiga, 2021

Type of study:

RCT (open label trial)

Setting:

Nine hospitals in Brazil, 8 May to 17 July 2020. Follow-up for the last patient was completed on August 11, 2020.

Country:

Brazil

Source of funding:

Trial was funded by the hospitals and research institutes participating in the Coalition covid-19 Brazil. Exploratory laboratory analysis was conducted and funded by Fleury Laboratory in São Paulo, Brazil. Instituto Votorantim provided a donation for tocilizumab. It has no role in the design of the trial, the conduct, the analysis, or the decision to submit the manuscript for publication.

Inclusion criteria:

• Hospital in-patients (aged 18 years or older) with confirmed severe or critical covid-19 and symptoms for more than three days;
• receiving supplemental oxygen or mechanical ventilation;
• and abnormal levels of at least two serum biomarkers (D dimer, C reactive protein, ferritin or lactate dehydrogenase).

Exclusion criteria:

• Active uncontrolled infection;
• raised aspartate aminotransferase or alanine aminotransferase levels greater than five times the upper limit of normal;
• renal disease with an estimated glomerular filtration of <30 mL/min/1.72 m².

N total at baseline:

N = 129 patients

Intervention: 65 patients

Control: 64 patients (two patients received tocilizumab at discretion of the doctor)

Important characteristics:

Age, mean (SD):

I: 57.4 years (15.7)

C: 57.3 years (13.5)

Sex, n/N (%) male:

I: 44/65 (68%)

C: 44/64 (69%)

Disease severity, n/N (%):

Based on a seven level ordinal clinical status scale (see comments)

I:
4: 39/65 (60%)
5: 15/65 (23%)
6: 11/65 (17%)

C:
4: 28 (44%)
5: 26 (41%)
6: 10 (16%)

Groups comparable at baseline? Not for respiratory support, baseline clinical status and use of azithromycin.

Post hoc analysis adjusted for baseline levels of respiratory support were consistent with the main analysis.

Post hoc sensitivity analysis for the primary outcome adjusted for baseline clinical status on the seven level ordinal scale was also not indicative of treatment benefit.

Azithromycin has proven to be ineffective for patients admitted to hospital with covid-19.  

Tocilizumab (a single intravenous infusion at a dose of 8 mg/kg (maximum 800 mg) plus standard care. The concomitant use of hydroxychloroquine, azithromycin, corticosteroids, and antibiotics was allowed according to standard care per local institutional guidelines for patients with covid-19. Remdesivir was not available in Brazil.

Standard care

The concomitant use of hydroxychloroquine, azithromycin, corticosteroids, and antibiotics was allowed according to standard care per local institutional guidelines for patients with covid-19. Remdesivir was not available in Brazil.

Length of follow up:

15 day follow-up

Loss to follow-up:

“The 15 day follow-up was completed for all patients.” However, it is unclear if the 28/29 days follow-up also was completed for all patients.

Clinical outcomes

Mortality at day 15:
I: 11 / 65 (17)
C: 2 / 64 (3)

Mortality up to 28 days (n/N (%)):
I: 14 / 65 (21)
C: 6 / 64 (9)
Effect size (OR, 95% CI): 2.70 (0.97 to 8.35)
P-value = 0.07

Duration of hospitalization (days, mean (SD)):
I: 11.3 (8.0)
C: 14.7 (8.2)
Effect size (RR, 95% CI): 0.70 (0.55 to 0.87)
P-value = 0.001

Clinical status (6 level ordinal scale) at day 8:
1:
I: 23/65 (35)
C: 16/64 (25)

2:
I: 7/65 (11)
C: 7/64 (11)

3:
I: 10/65 (5)
C: 12/64 (19)

4:
I: 1/65 (1)
C: 4/64 (6)

5:
I: 19/65 (29)
C: 24/64 (37)

6:
I: 5/65 (8)
C: 1/64 (2)

Effect measure (OR, 95% CI; 1-4 vs 5-6): 0.91 (0.44 to 1.89)
p-value = 0.79

Clinical status (7 level ordinal scale) at day 15:
1:
I: 32/65 (49)
C: 26/64 (41)

2:
I: 3/65 (5)
C: 5/64 (8)

3:
I: 6/65 (9)
C: 6/64 (9)

4:
I: 6/65 (9)
C: 10/64 (16)

5:
I: 0/65 (0)
C: 4/64 (6)

6:
I: 7/65 (11)
C: 11/64 (17)

7:
I: 11/65 (17)
C: 2/64 (3)

Effect measure (OR, 95% CI; 1-5 vs 6-7): 1.54 (0.66 to 3.66)
p-value = 0.32

Any adverse events
I: 29 / 67 (43)
C: 21 / 62 (34)
P-value = 0.26

Reported severe adverse event, according to classification:
Any severe adverse event
I: 11/ 67 (16)
C: 7 / 62 (11)
P-value: 0.45

Raised ALT, AST, or bilirubin level
I: 7/67 (10)
C: 3/62 (5)
P-value: 0.33

Anaemia
I:3/67 (4)
C: 3/62 (5)
P-value: 1.00

Pneumothorax:
I:0/67 (0)
C: 1/62 (2)
P-value: 0.48

Neutropenia
I:1/67 (1)
C: 0/62 (0)
P-value: 1.00

Bleeding
I: 1/67 (1)
C: 0/62 (0)
P-value: 1.00

Intracranial bleeding
I: 0/67 (0)
C: 1/62 (2)
P-value: 1.00

Sudden cardiorespiratory collapse
I: 4/67 (6)
C: 1/62 (2)
P-value: 0.37

Definitions:

Seven level ordinal clinical status scale:
1 – not admitted to hospital and with no limitation in activities

2 – not admitted to hospital but with limitation in activities
3 – admitted to hospital and not receiving supplemental oxygen
4 – admitted to hospital and receiving supplemental oxygen
5 – admitted to hospital and receiving non-invasive positive pressure ventilation or high flow oxygen through a nasal cannula
6 – admitted to hospital and receiving mechanical ventilation
7 – death

Six level ordinal clinical status scale:
1: admitted to hospital
2: admitted to hospital, not receiving supplemental oxygen
3: admitted to hospital, receiving supplemental oxygen
4: admitted to hospital, receiving non-invasive ventilation or high flow oxygen through nasal cannula
5: admitted to hospital, receiving mechanical ventilation
6: death

Clinical status (7 level ordinal scale) at day 29, in-hospital mortality, SOFA score at day 8 and day 15,ventilator-free days within 29 days, time to supplemental oxygen independence within 29 days, duration of hospital stay, secondary infections, thromboembolic events and non-severe adverse events were also reported in the article. In the appendix also additional characteristics of the population at baseline, use of other medications in the first 15 days, cumulative proportions of 7-level ordinal scale at day 15 to the primary outcome, main analysis and sensitivity analysis for the primary outcome, subgroup analysis for the primary outcome, adjudicated causes of in-hospital deaths, adjudicated causes of death at day 28 compared with treatment group, age and clinical status on 7-level ordinal scale, biomarker measurements analyses, effect of tocilizumab on the primary outcome, length of hospital stay and 15-day death according to duration of symptoms at randomization, relative distribution of patient status at day 15 (stratified by group), and serum-inflammatory markers and cytokines at baseline, D5 and D8 in the tocilizumab and control group published.

Remarks:

- Groups were not comparable at baseline for respiratory support, baseline clinical status and use of Azithromycin.
- Open label trial

- “The 15 day follow-up was completed for all patients.” However, it is unclear if the 28/29 days follow-up also was completed for all patients.

Authors conclusion:

In patients with severe or critical covid-19 tocilizumab plus standard care was not superior to standard care alone in improving clinical outcomes at 15 days, and might increase mortality.

Salama, 2020 

EMPACTA trial 

Type of study: 

RCT; double-blind, placebo-controlled, phase 3 trial 

Setting: 

EMPACTA trial; multi-center 

Country: 

International; United States 45 sites, Mexico 2 sites, Kenya 2 sites, South Africa 3 sites, Peru 5 sites, and Brazil 6 sites 

Source of funding: 

Funded by Genentech; EMPACTA ClinicalTrials.gov 

number, NCT04372186. 

“The sponsor designed the trial, conducted it according to the protocol, collected the data, and performed analyses; a contract research organization paid by the sponsor managed and 

monitored the trial under the direction and supervision of the sponsor.” 

Hospitalized patients with COVID-19 pneumonia

Inclusion criteria: 

• Age ≥ 18 years 
• Hospitalized with Covid-19 pneumonia 
• COVID-19 confirmed by a positive polymerase-chain-reaction test and radiographic imaging
• Patients had a blood oxygen saturation < 94% while breathing ambient air 

Exclusion criteria: 

• receiving continuous 

positive airway pressure, bilevel positive airway pressure, or mechanical ventilation 

• progression of illness to death was imminent and inevitable 

within 24 hours, as determined by treating physician 

active tuberculosis or 

• suspected active bacterial, fungal, or viral infection 

(other than SARS-CoV-2 infection or well controlled 

HIV infection) 

• coexisting condition only in case when investigator determined that the condition would preclude safe participation in the trial. 

N total at baseline: 

N = 389 

Modified intention-to-treat: 

Intervention: 249 (259 assigned to this arm; 10 dropped out) 

Control: 128 (129 assigned to this arm, 1 dropped out) 

Important characteristics: 

Age, mean±SD: 

 I: 56.0±14.3 

 C: 55.6±14.9 

Sex, n/N (%) male: 

 I: 150/249 (60.2%) 

 C: 73/128 (57.0%) 

BMI, mean±SD: 

 I: 32.0±7.9 

 C: 33.1±7.2 

Days from first Covid-19 symptom at baseline, median (range)

 I: 8.0 (0.0-31.0; n=248)

 C: 8.0 (0.0-36.0, n=127) 

Disease severity, mean (SD): 

Defined by ordinal scale; see right column for definitions 

I: 2: 24/249 (9.6%) 

  3: 161/249 (64.7%) 

  4: 64/249 (25.7%) 

C: 2: 11/128 (8.6%) 

  3: 81/128 (63.3%) 

  4: 36/128 (28.1%) 

ICU admission at baseline, no. (%)

 I: 36 (14.5%)

C: 22 (17.2%) 

Groups comparable at baseline. 

Other drugs - within 7 days prior to first dose study drug or during study 

Systemic corticosteroid 

 I: 200/249 (80.3%)

 C: 112/128 (87.5%) 

Antiviral

 I: 196/249 (78.7%)

 C: 101/128 (78.9%) 

Dexamethasone

 I: 138/249 (55.4%)

 C: 86/128 (67.2%) 

Remdesivir

 I: 131/249 (52.6%)

 C: 75/128 (58.6%) 

Tocilizumab + standard care 

Tocilizumab:

one or two doses of intravenous tocilizumab (8 mg per kilogram of 

body weight, to a maximum of 800 mg per dose) 

Standard care + placebo 

Standard care: according to local practice, which could include antiviral treatment, the limited use of systemic glucocorticoids (recommended 

dose, ≤1 mg per kilogram of body weight of 

methylprednisolone or equivalent), and supportive care.

Placebo: one or two doses of placebo 

Length of follow up: 

60 days; “Efficacy was evaluated by day 28, and patients 

were followed for a total of 60 days. Patients who were discharged before day 28 were considered to have completed the trial and were followed 

weekly up to day 28, with a safety follow-up visit 

conducted by day 60.” 

Loss to follow-up: 

I: 10/259 (3.9 %) 

Reasons: withdrew, n = 8; withdrawn by physician, n = 1; site unable to confirm administration of study drug, n = 1. 

C: 1/129 (0.8%) 

Reasons: withdraw, n = 1. 

Clinical outcomes 

Mortality, day 28: 

I:  26/ (10.4 [7.2 to 14.9]) 

C: 11 (8.6 [4.9 to 14.7])

HR 1.04 (95% CI 0.51 to 2.12) 

Weighted difference, percentage points: 2.0 (95% CI −5.2 to 7.8) 

Mechanical ventilation (invasive mechanical ventilation or ECMO) or death by day 28: 

I: 12.0% (95% CI 8.5 to 16.9)

C: 19.3% (95% CI 13.3 to 27.4) 

HR 0.56 (0.33 to 0.97) 

Sub group - age ≤60:

 I: 9/151 events 

 C: 7/76 events 

 HR 0.63 (95% CI 0.23 – 1.71) 

Subgroup - age >60:

 I: 20/98 events

 C: 17/52 events 

 HR 0.53 (95% CI 0.28 to 1.03) 

Time to hospital discharge or readiness for discharge, day 28; score of 1 on ordinal scale 

I: 6.0 (6.0 to 7.0) days 
C: 7.5 (7.0 to 9.0) days 

HR 1.16 (0.91 to 1.48) 

Time to clinical improvement, day 28; at least a two-category improvement in clinical status relative to baseline score (for category 2 at baseline, clinical status of category 1 was considered to have met threshold), median: 

I: 6.0 (6.0 to 7.0) days 

C: 7.0 (6.0 to 9.0) days

HR 1.15 (95% CI 0.90 to 1.48) 

Time to clinical failure, day 28; time to death, mechanical ventilation, admission to ICU, or, in patients who were already in ICU at enrollment, worsening by two categories from baseline on the seven-category ordinal scale], or withdrawal [whichever occurred first]); median: 

HR 0.55 (95% CI 0.33 to 0.93) 

Safety 

Incidence and severity of adverse events [according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0] 

Total adverse events 

I: 357 

C: 187

Patients with ≥1 adverse event, no. (%)

I: 127/250 (50.8%) 

C: 67/127 (52.8%) 

Serious event

I: 38/250 (15.2%)

C: 25/127 (19.7%) 

 of which events related to tocilizumab 

 or placebo, as determined by the 

 investigator 

 I: 3/250 (1.2%)

 C: 0/127 (0.0%) 

Definitions: 

Clinical status - 7-category ordinal scale

1 - discharged (or ready for discharge as evidenced by normal body temp. and respiratory rate + stable oxygen saturation while breathing ambient air or ≤2 liters of suppl. oxygen); 

2, hospitalized in non–intensive care unit (ICU) hospital ward (or ready for a hospital ward) and not receiving suppl. oxygen;

3, hospitalized in non–ICU hospital ward (or ready for hospital ward) and receiving suppl. 

oxygen;

4, hospitalized in ICU or non–ICU hospital ward and receiving noninvasive ventilation or high-flow oxygen;

5, hospitalized in ICU and receiving intubation and mechanical ventilation;

6, hospitalized in ICU and receiving ECMO or mechanical ventilation and additional organ support; 

7, died. 

Remarks: 

- 

Authors conclusion: 

In hospitalized patients with Covid-19 pneumonia who were not receiving mechanical ventilation, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival. No new safety signals were identified. 

Stone, 2020

Type of study:

Setting:

Hospital

Country:

Boston, USA

Source of funding:

Not mentioned

Inclusion criteria:

• 19-85 years old;
• Confirmed SARS-CoV-2 infection by either nasopharyngeal swab polymerase chain reaction or serum IgM antibody assay;
• At least two of the following signs: fever (body temp >38 degrees Celsius) within 72 hours before enrolment, pulmonary infiltrates, or a need for supplemental oxygen in order to maintain an oxygen saturation higher than 92%;
• A C-reactive protein level higher than 50 mg liter;
• A ferritin level higher than 500 ng per millilitre;
• A d-dimer level higher than 1000 ng per millilitre;
• A lactate dehydrogenase level higher than 250 U per liter.

Exclusion criteria:

• Receiving supplemental oxygen at a rate that exceeded 10 liters per minute;
• A recent history of treatment with biologic agents or smallmolecule immunosuppressive therapy;
• Receiving other immunosuppressive therapy that the investigator believed placed them at higher risk for an infection;
• Diverticulitis.

N total at baseline:

N =

Intervention:

Control:

Important characteristics:

Age, mean (SD):

I:

C:

P=0

Sex, n/N (%) male:

I:

C:

Groups comparable at baseline?

Standard care plus a single dose of either tocilizumab (8 mg per kilogram of body weight administered intravenously, not to exceed 800 mg)

Placebo

 28 days

TIME-TO-EVENT OUTCOMES IN THE MODIFIED INTENTION-TO-TREAT POPULATION

Mechanical ventilation or death

N patients with event within 28 days

I: N = 17

C: N = 10

Percentage of patients with event (95 CI) at day 14

I: 9.9 (95% CI= 6.2 to 15.7)

C: 10.0 (95% CI= 5.1 to 18.9)

Percentage of patients with event (95 CI) at day 28

I: 10.6 (95% CI= 6.7 to 16.6)

C: 12.5 (95% CI= 6.9 to 22.0)

Hazard ratio (95% CI)

HR= 0.83 (95% CI= 0.38 to 1.81)

Log rank value

0.64

Clinical worsening on ordinal scale

N patients with event within 28 days

I: N = 31

C: N = 14

Percentage of patients with event (95 CI) at day 14

I: 18.0 (95% CI= 12.9 to 24.9)

C: 14.9 (95% CI= 8.7 to 24.7)

Percentage of patients with event (95 CI) at day 28

I: 19.3 (95% CI= 14.0 to 26.2)

C: 17.4 (95% CI= 10.7 to 27.7)

Hazard ratio (95% CI)

HR= 1.11 (95% CI= 0.59 to 2.10)

Log rank value

0.73

Mechanical ventilation

N patients with event within 28 days

I: N = 11

C: N = 8

Percentage of patients with event (95 CI) at day 14

I: 6.8 (95% CI= 3.6 to 11.4)

C: 10.0 (95% CI= 4.6 to 17.7)

Percentage of patients with event (95 CI) at day 28

I: 6.8 (95% CI= 3.6 to 11.4)

C: 10.0 (95% CI= 4.6 to 17.7)

Hazard ratio (95% CI)

HR= 0.65 (95% CI= 0.26 to 1.62)

Death

N patients with event within 28 days

I: N = 9

C: N = 3

Percentage of patients with event (95 CI) at day 14

I: 4.4 (95% CI= 2.1 to 8.9)

C: 1.3 (95% CI= 0.2 to 8.7)

Percentage of patients with event (95 CI) at day 28

I: 5.6 (95% CI= 3.0 to 10.5)

C: 3.8 (95% CI= 1.2 to 11.3)

Hazard ratio (95% CI)

HR= 1.52 (95% CI= 0.41 to 5.61)

Discontinuation of supplemental oxygen among patients receiving it at baseline

N patients with event within 28 days

I: N = 114

C: N = 56

Percentage of patients with event (95 CI) at day 14

I: 75.4 (95% CI= 67.9 to 82.2)

C: 78.8 (95% CI= 68.3 to 87.7)

Percentage of patients with event (95 CI) at day 28

I: 82.6 (95% CI= 75.9 to 88.4)

C: 84.9 (95% CI= 75.2 to 92.2)

Median N of days to event (95% CI)

I: 5.0 (95% CI= 3.8 to 7.6)

C: 4.9 (95% CI= 3.8 to 7.8)

Hazard ratio (95% CI)

HR= 0.94 (95% CI= 0.67 to 1.30)

Log rank value

0.69

Clinical improvement on ordinal scale

N patients with event within 28 days

I: N = 147

C: N = 72

Percentage of patients with event (95 CI) at day 14

I: 86.3 (95% CI= 80.6 to 91.1)

C: 81.5 (95% CI= 72.4 to 89.0)

Percentage of patients with event (95 CI) at day 28

I: 91.3 (95% CI= 86.3 to 95.1)

C: 88.9 (95% CI= 81.0 to 94.5)

Median N of days to event (95% CI)

I: 6.0 (95% CI= 5.0 to 6.0)

C: 5.0 (95% CI= 4.0 to 7.0)

Hazard ratio (95% CI)

HR= 1.06 (95% CI= 0.80 to 1.41)

Initial discharge

N patients with event within 28 days

I: N = 147

C: N = 72

Percentage of patients with event (95 CI) at day 14

I: 86.3 (95% CI= 80.6 to 91.1)

C: 81.5 (95% CI= 72.4 to 89.0)

Percentage of patients with event (95 CI) at day 28

I: 91.3 (95% CI= 86.3 to 95.0)

C: 88.9 (95% CI= 81.0 to 94.5)

Median N of days to event (95% CI)

I: 6.0 (95% CI= 4.0 to 7.0)

C: 6.0 (95% CI= 5.0 to 6.0)

Hazard ratio (95% CI)

HR= 1.08 (95% CI= 0.81 to 1.43)

DURATION OUTCOMES AND ADMISSION TO THE ICU OR DEATH IN THE MODIFIED INTENTION-TO-TREAT POPULATION

Median duration of receipt of supplemental oxygen (IQR) in days

I: 4.0 (1.8 to 11.6)

C: 3.9 (1.1 to 9.2)

Median duration of mechanical ventilation (IQR) in days

I: 15.0 (12.6 to NR)

C: 27.9 (16.3 to NR)

Admission to ICU or death (%)

I: 15.9%

C: 15.8%

Relative risk: 0.97 (0.50 to 1.88)

Remarks:

-

Authors conclusion:

In this randomized, double-blind, placebocontrolled trial, we did not find any efficacy of interleukin-6 receptor blockade for the treatment of hospitalized patients with Covid-19.

Salvarani,

2020

Type of study:

RCT (prospective, open-label, randomized clinical trial)

Setting:

24 hospitals; March 31 - June 11, 2020

Country:

Italy

Source of funding:

“The work at the IRCCS Sacro Cuore Don Calabria Hospital was partly funded by the Italian Ministry of Health “Fondi Ricerca Corrente – Linea 1, progetto 4”. Roche provided the drug and its distribution to the centers.”

Inclusion criteria:

• Age ≥18 years
• Instrumental diagnosis of COVID-19 pneumonia, RT-PCR confirmed respiratory tract specimen.
• Acute respiratory failure with a partial pressure of arterial oxygen to fraction of inspired oxygen (Pao2/Fio2) ratio between 200 and 300 mm/Hg
• inflammatory phenotype defined by a temperature greater than 38 °C during the last 2 days, and/or serum C-reactive protein (CRP) levels of 10 mg/dL or greater and/or CRP level increased to at least twice the admission measurement.
• allowed to receive oxygen therapy with Venturi mask or high-flow nasal cannula with recorded and preset Fio2

Exclusion criteria:

• ICU admission,
• known hypersensitivity to tocilizumab,
• any condition preventing future admission to ICU (e.g. advanced age with multiple comorbidities, will to avoid future intubation)

Patients at enrollment were allowed to receive oxygen therapy with Venturi mask or high-flow nasal cannula with recorded and preset Fio2, but not invasive or noninvasive mechanical ventilation. After randomization, patients were allowed to receive supplemental oxygen therapy, including noninvasive ventilation, according to clinical needs.

N total at baseline: N = 126

Intervention: 60

Control: 66

Important characteristics:

Age, median (IQR):

I: 61.5y (51.5-73.5)

C: 60.0y (54.0-69.0)

Sex, n/N (%) male:

I: 40/60 (66.7%)

C: 37/66 (56.1%)

Control group had lower CRP, IL-6, ferritin, and D-dimer levels and were more frequently treated with antivirals compared to intervention group.

Tocilizumab + supportive care

Tocilizumab intravenously within 8 hours from randomization at a dose of 8 mg/kg up to a maximum of 800 mg, followed by a second dose after 12 hours.

• 58/60 received treatment without prohibited drugs
• 1/60 received tocilizumab + steroids
• 1/60 did not receive tocilizumab due to SAE
• 5/60 patients received steroids after clinical worsening

Supportive care

Supportive care:

following the treatment protocols of each center:

• Not allowed: IL-1 blockers, Jak inhibitors, tumor necrosis factor inhibitors.
• Steroids were allowed if already taken before hospitalization.
• Clinical worsening: patients in both arms could receive any therapy, including steroids, and, for patients randomized in the control arm, tocilizumab.
• 60/66 received standard care and no prohibited drugs
• 6/60 received additional drug treatment (tocilizumab IV + steroids (n=2), tocilizumab subcut. (n=1), steroids (n=2), canakinumab (n=1))

12/66 received 2 doses of tocilizumab IV after clinical worsening

Length of follow-up:

30 days (primary endpoint 14 days)

Loss to follow-up:

3/66 (4.5%) patients in the control group withdrew consent and were excluded from the analysis.

Other patients were all included in the efficacy analysis.

Clinical worsening at 14 days;

Definition: see information at the right column

I: 17/60 (28.3%)

C: 17/63 (27.0%)

Rate ratio 1.05 (0.59 – 1.86) p=.87

Admission to ICU with mechanical ventilation

14 days

 I: 6/60 (10%)

 C: 5/63 (7.9%)

 Rate ratio 1.26 (0.41 – 3.91)

30 days

 I: 6/60 (10%)

 C: 5/63 (7.9%)

 Rate ratio 1.26 (0.41 – 3.91)

Death from any cause

14 days

 I: 1/60 (1.7%)

 C: 1/63 (1.6%)

 Rate ratio 1.05 (0.07 – 16.4)

30 days

 I: 2/60 (3.3%)

 C: 1/63 (1.6%)

 Rate ratio 2.10 (0.20 – 22.6)

Discharge from hospital

14 days

 I: 34/60 (56.7%)

 C: 36/63 (57.1%)

 Rate ratio 0.99 (0.73 – 1.35)

30 days

 I: 54/60 (90%)

 C: 58/63 (92.1%)

 Rate ratio 0.98 (0.87 – 1.09)

Adverse events, No (%)

I: 14/60 (23.3%)

1 patient had 2 events

C: 7/63 (11.1)

1 patient had 3 events

In publication, also data on 6 sub-categories of AE’s

Information:

The primary outcome ‘clinical worsening’ was defined as occurrence of 1 of the 3 following events:

• admission to ICU with mechanical ventilation
• death from any cause
• Pao2/Fio2 ratio less than 150 mm Hg in 1 of the scheduled arterial blood gas measurements or in an emergency measurement, confirmed within 4 hours by a second examination

Remarks:

• This was an open label trial.
• Analyses were performed according to an intention-to-treat protocol.
• See columns of intervention en control treatment for information on the actual treatment that patients received

Authors conclusion:

The administration of tocilizumab in patients with COVID-19 pneumonia and a Pao2/ Fio2 ratio between 200 and 300 mm Hg did not reduce the risk of clinical worsening. Further blinded, placebo-controlled randomized clinical trials are needed to confirm the results and to explore possible applications of tocilizumab in different stages of the disease, such as in patients with a Pao2/Fio2 ratio less than 200 mm Hg.

Hermine, 2020

Type of study:

Cohort-embedded, investigator-initiated multicenter, open-lael, Bayesian randomized clinical trial.

Setting:

Nine university hospitals

Country:

France

Source of funding:

This trial was publicly funded

(Ministry of Health, Programme Hospitalier de Recherche Clinique, Foundation for Medical Research (FRM), AP-HP Foundation and the

Reacting program).

The funding agencies had no access to the trial data and had no role in the design, conduct or reporting of the trial. Roche

donated TCZ in unrestricted grant, and had no role

in the trial design or conduct; the collection, management, analysis, interpretation of the data; or in the preparation, review of the manuscript or

the approval of the manuscript for submission.

Inclusion criteria group 1:

• Confirmed SARS-CoV-2 infection (positive on rRT-PCR and/or typical chest computed tomographic [CT] scan) with moderate, severe, or critical pneumonia (O2 >3 L/min,WHOClinical Progression Scale [WHO-CPS] score ≥5.

Inclusion criteria group 2:

• aWHO-CPS score of 5with O2 levels of 3 L/min or higher but without noninvasive ventilation (NIV) or mechanical ventilation (MV).

Exclusion criteria:

• Known hypersensitivity to TCZ, pregnancy, current documented bacterial infection, patients with any of following laboratory results out of the ranges detailed below at screening: absolute neutrophil count (ANC) 1.0 ×109 /L or less or platelets (PLT) less 50 G /L..

N total at baseline:

N = 131

Intervention: N = 64

Control: N = 67

Important characteristics:

Age, median (IQR):

I: 64.0 (57.1 to 74.3)

C: 63.3 (57.1 to 72.3)

Sex, n/N (%) male:

I: 44/63 (70%) male

C: 44/67 (66%) male

BMI, median (IQR)

I: 27.9 (23.3 to 30.8)

C: 27.4 (24.5 to 31.3)

Tocilizumab in combination with usual care

Intravenously administration of Tocilizumab of 8 mg/kg on day 1. Administration of an additional fixed doze of tocilizumab, 400 mg IV, on day 3 was recommended if oxygen requirement was not decreased by more than 50%, but decision was left to the treating physician.

Usual care alone

Usual care (antibiotic

agents, antiviral agents, corticosteroids, vasopressor

support, anticoagulants) was provided at the discretion of

the clinicians.

 28 days

The 2 primary outcomes were (1) the proportion of patients dead or needing non-invasive or mechanical ventilation on day 4 (>5 on the WHO-CPS); and (2) survival with no need for non-invasive or mechanical ventilation at day 14.

Primary outcome by day 14; N

I: 15/63

C: 24/67

Mechanical ventilation or death by day 14; N (95% CI)

I: 17% (95% CI= 8 to 26)

C: 27% (95% CI= 15 to 37)

Difference -9 (95% CI= -24 to 5)

Deaths day 14; N

I: 7/63

C: 6/67

Survival day 14; % (95% CI)

I: 89% (95% CI= 81 to 97)

C: 91% (95% CI= 84 to 98)

Deaths day 28; N

I: 7/63

C: 8/67

Survival day 28; % (95% CI)

I: 89% (81 to 97)

C: 88% (80 to 96)

Patients with at least 1 adverse event; N (%)

I: 28 (44%)

C: 36 (54%)

Patients with multiple adverse events; N (%)

I: 16 (25%)

C: 19 (28%)

Patients with at least 1 serious adverse event; N (%)

I: 20 (32%)

C: 29 (43%)

P = 0.21

Patients with multiple serious adverse events; N (%)

I: 5 (8%)

C: 10 (15%)

Remarks:

TCZ (group 1): receiving tociluzumab

UC (group 2): receiving usual care

Authors conclusion:

Sarilumab

Lescure,

2021

Type of study:

RCT; double-blind,

placebo-controlled

Setting:

multinational phase 3

trial; 45 hospitals

Country:

Argentina, Brazil,

Canada, Chile, France,

Germany, Israel, Italy,

Japan, Russia, and

Spain

Source of funding:

‘This study was funded

by Sanofi (Paris,

France) and Regeneron

Pharmaceuticals

(Tarrytown, USA).

Medical writing

assistance was

provided by Richard J

Hogan, and Vojislav

Pejović of Eloquent

Scientific Solutions, a division of Envision Pharma Group, and

editorial and graphics

assistance was

provided by Eloquent

Scientific Solutions.

This support was

funded by Sanofi.’

Hospitalized COVID-19 patients

with severe or critical illness.

Inclusion criteria:

• ≥18 years

• admitted to hospital

• laboratory-confirmed SARSCoV-2 infection in any specimen

within 2 weeks before random

assignment

• evidence of pneumonia by

chest imaging or chest

auscultation

• no alternative explanation for

clinical presentation

• severe disease (defined as

administration of supplemental

oxygen by nasal cannula, simple

face mask, or another similar

device)

or critical disease (defined as

need for supplemental oxygen

delivered by non-rebreather

mask or high-flow nasal

cannula, use of invasive or noninvasive ventilation, or

treatment in ICU).

Exclusion criteria

low probability of surviving 48h

or remaining at the

investigational site > 48h,

• dysfunction ≥ 2 organ systems,

need for extracorporeal life

support, or renal replacement

therapy at screening;

• absolute neutrophil count <

2000 cells per mm

3; aspartate

aminotransferase or alanine

aminotransferase (ALT)

exceeding 5x upper limit of

normal at screening;

• < 50 000 platelets per mm

3 at screening;

• known active, incompletely

treated, suspected or known

extrapulmonary tuberculosis;

• previous or concurrent use of

immunosuppressant drugs at

screening, including, but not

limited to, IL-6 inhibitors or

Janus kinase inhibitors within

30 days of baseline;

• anti-CD20 agents without

evidence of B-cell recovery to

baseline concentrations or IL

-1 receptor antagonist within 1

week of baseline;

• abatacept within 8 weeks of

baseline; tumour necrosis

factor α inhibitors within 2

–8 weeks of baseline;

• alkylating agents, including

cyclophosphamide, within 6

months of baseline;

• cyclosporine, azathioprine,

mycophenolate mofetil,

leflunomide, or methotrexate <

4 weeks of baseline;

• or intravenous immunoglobulin

< 5 months of baseline;

• use of systemic chronic (eg,

oral) corticosteroids for a

condition not related to COVID

-19 at doses higher than

prednisone 10 mg/day or

equivalent at screening;

• suspected or known active

systemic bacterial or fungal

infections < 4 weeks of

screening             

N total at baseline:

Randomized:

N = 420

Intervention-I: 161

Intervention-II: 173

Control: 86

Included in mITT analysis:

N = 416

Intervention-I: 159

Intervention-II: 173

Control: 84

Important characteristics:

Age, median (IQR):

I: 58·0 (51·0–67·0)

II: 58·0 (48·0–67·0)

C: 60·0 (53·0–69·5)

Sex, n/N (%) male:

I: 108/159 (68%)

II: 99/173 (57%)

C: 54/84 (64%)

Severity of illness

Severe

I: 92/159 (58%)

II: 105/173 (61%)

C: 55/84 (65%)

Critical

I: 65/159 (41%)

II: 68/173 (39%)

C: 29/84 (35%)

Multisystem organ dysfunction
I: 2/159 (1%)

II: 0/173

C: 0/84

Clinical status, 7-point scale

2

I: 17/159 (11%)

II: 24/173 (14%)

C: 9/84 (11%)

3

I: 28/159 (18%)

II: 21/173 (12%)

C: 11/84 (13%)

4

I: 112/159 (70%)

II: 128/173 (74%)

C: 64/84 (76%)

5

I: 2/159 (1%)

II: 0/173

C: 0/84

Time from dyspnoea onset to

baseline, days

I: 5·0 (2·0–10·0)

II: 4·0 (2·0–9·0)

C: 7·0 (3·0–10·0)

Duration of hospital stay before

dosing, days

I: 3·0 (1·0–4·0)

II: 2·0 (2·0–4·0)

C: 4·0 (2·0–6·0)

Admitted to ICU before dosing

I: 61 (38%)

II: 59 (34%)

C: 28 (33%)

Duration of ICU stay before

dosing, days

I: 2·0 (1·0–3·0)

II: 2·0 (1·0–3·0)

C: 1·0 (1·0

–3·5)

Groups comparable at baseline?

I: sarilumab 200 mg

II: sarilumab 400 mg

The hospital pharmacist

added the contents of

prefilled syringes of

sarilumab 200 mg solution for subcutaneous injection

supplied by the sponsor

into a specified volume of

locally sourced 0·9%

sodium chloride solution

for IV infusion (two

syringes for the 400 mg

dose, one syringe for the

200mg dose).

An option for a second

dose existed (within the

assigned treatment group) within 24–48 h of the first dose, based on the investigator's benefit-risk assessment (amended

protocol 02; April 8, 2020).

Placebo

The hospital

pharmacist

prepared the

volume of

locally sourced

0·9% sodium

chloride

solution for IV

infusion.

An option for a

second dose

existed (within

the assigned

treatment

group) within

24–48 h of the

first dose,

based on the

investigator's

benefit-risk

assessment

(amended

protocol 02;

April 8, 2020).

Number of

doses received

1 dose:

I: 146 (91·8%)

II: 162 (93·6%)

2 doses:

I: 13 (8·2%)

II: 11 (6·4%)

Length of follow up:

60 days

Loss to follow-up:

I: 2/161 (1.2%)

Reasons: 2 did not

start treatment

(randomised twice,

n=1; suspected

bacterial infection,

n=1)

II: 0/173 (0%)

C: 2/86 (2.3%)

Reasons: 2 did not

start treatment

(improved, n=1;

withdrew consent,

n=1)

Number of doses

received

1 dose: 79 (94·0%)

2 doses: 5 (6·0%)

Clinical outcomes

Mortality

Patients alive at day 29

I: 143 (90%)

II: 159 (92%)

C: 77 (92%)

Difference vs placebo

I: −1·7 (−9·3 to 5·8)

II: 0·2 (−6·9 to 7·4)

Patients alive at day 60, n

(%)

I: 142 (89·3)

II: 155 (89·6)

C: 75 (89·3)

Difference vs placebo (95%

CI)

I: 0·0 (−8·2 to 8·2)

II: 0·3 (−7·7 to 8·3)

Results also reported for

severe vs. critically ill patients separately

Duration of hospitalization

Proportion of patients with need for ICU care during study (among patients not in ICU at baseline), n (%)

I: 11 (11·2)

II: 17 (14·9)

C: 7 (12·5)

Difference vs placebo (95%CI)

I: −1·3 (−12·0 to 9·4)

II: 2·4 (−8·4 to 13·3)

Number of days of

hospitalisation among

patients alive at day 60,

least quares mean (SE),

days

I: 15·6 (1·0)

II: 16·1 (0·9)

C: 15·9 (1·3)

Difference vs placebo (95%CI)

I: −0·2 (−3·5 to 3·0)

II: 0·2 (−3·0 to 3·5)

Time from first dose to

discharge due to recovery,

Kaplan-Meier estimates,

days Median (95% CI)

C: 14·0 (11·0–16·0)

I: 11·0 (10·0–15·0)

II: 13·0 (10·0–15·0)

Hazard ratio vs placebo

(95% CI)

I: 1·05 (0·79 to 1·40)

II: 1·00 (0·76 to 1·33)

Time from first dose to

discharge due to recoveTime to ≥2-point

improvement on seven

-point clinical status scale, median Kaplan Meier estimate, days:

I: 10·0 (9·0 to 12·0)

II: 10·0 (9·0 to 13·0)

C: 12·0 (9·0 to 15·0)

Hazard ratio vs placebo

I: 1·03 (0·75 to 1·40)

II: 1·14 (0·84 to 1·54)

Results also reported for

severe vs. critically ill

patients separately

Time to NEWS2 of <2 and

maintained for 24 hours;

Kaplan

-Meier estimates,

days, Median (95% CI)

I: 9·0 (7·0–10·0)

II: 9·0 (8·0–11·0)

C: 11·0 (8·0–14·0)

Hazard ratio vs placebo

(95% CI)

I: 1·05 (0·77–1·44)

II: 1·09 (0·80–1·48)

Analysis of time to

resolution of fever

Kaplan-Meier estimates,

Days Median (95% CI)§

I: 8·0 (7·0–9·0)

II: 9·0 (7·0–10·0)

C: 7·0 (6·0–12·0)

Hazard ratio vs placebo

(95% CI)

I: 0·91 (0·59–1·40)

II: 0·92 (0·60–1·40)

Need for respiratory

support

Time to improvement in

oxygenation (defined as

increase in SpO2/FiO2 of

≥50 compared with the

nadir SpO2/FiO2 for ≥48

hours), Kaplan-Meier

estimates, days, median

(95% CI)§

I: 6·0 (5·0–7·0)

II: 6·0 (5·0–7·0)

C: 7·0 (5·0–8·0)

Hazard ratio vs placebo

(95% CI)

I: 1·17 (0·86–1·58)

II: 1·11 (0·83–1·50)

Initiation of mechanical

ventilation, non-invasive

ventilation, or use of high

-flow nasal cannula, n (%)

C: 13 (19·1)

I: 26 (20·5)

II: 33 (23·4)

Difference vs placebo (95%CI)

I: 1·4 (−10·3 to 13·0)

II: 4·3 (−7·4 to 16·0)

Patients alive off

supplemental oxygen at

day 29, n (%)

I: 135/159 (84·9%)

II: 145/173 (83·8%)

C: 73/84 (86·9%)

Difference vs placebo (95%CI

I: −2·0 (−11·1 to 7·1)

II −3·1 (−12·2 to 6·0)

Percent of ventilator

-free days in the first 28 days, least squares mean (SE)

I: 74·8 (2·2)

II: 75·7 (2·1)

C: 77·3 (3·0)

Difference vs placebo (95%CI)

I: −2·4 (−10·2 to 5·3)

II: −1·6 (−9·2 to 6·1)

Also reported: Percent of

days with hypoxaemia / supplemental oxygen /

resting respiratory rate

>24 breaths/min, time to

saturation ≥94% on room

air

Safety

Adverse events

Any treatment-emergent

adverse event I: 103 (65%)

II: 121 (70%)

C: 55 (65%)

Any serious treatment emergent adverse event

I: 42 (26%)

II: 51 (29%)

C: 20 (24%)

of which:

 Any serious infection

 I: 18 (11%)

 II: 22 (13%)

 C: 10 (12%)

 Pneumonia

 I: 1 (1%)

 II: 6 (3%)

 C: 0

 COVID-19 pneumonia

 I: 11 (7%)

 II: 4 (2%)

 C: 2 (2%)

 Bacterial pneumonia

 I: 1 (1%)

 II: 3 (2%)

 C: 1 (1%)

Any treatment-emergent

adverse event leading to

death

I: 17 (11%)

II: 18 (10%

C: 9 (11%)

Any adverse event of

special interest

I: 53 (33%)

II: 76 (44%)

C: 18 (21%)

Of which

 Alanine

aminotransferase increase

 I: 48 (30%)

 II: 55 (32%)

 C: 16 (19%)

 Invasive bacterial or

fungal infection

 I: 8 (5%)

 II: 15 (9%)

 C: 3 (4%)

 Grade ≥2 hypersensitivity

reaction

 I: 1 (1%)

 II: 7 (4%)

 C: 0

 Grade 4 neutropenia

 I: 3 (2%)

 II: 6 (3%)

 C: 0

 Grade ≥2 infusionrelated reaction

 I: 1 (1%)

 II: 6 (3%)

 C: 0

Virological outcomes

Viral clearance

not reported

Also reported: Sarilumab

concentration,

pharmacodynamic

markers, and laboratory

findings potentially related to COVID-19 severity, over time.

Definitions:

7-point ordinal scale:

(1) death; (2) admitted to hospital, on

invasive mechanical ventilation or

extracorporeal membrane oxygenation;

(3) admitted to hospital, on noninvasive ventilation or high-flow oxygen

devices; (4) admitted to hospital,

requiring supplemental oxygen; (5)

admitted to hospital, not requiring

supplemental oxygen, requiring

ongoing medical care (COVID-19-

related or otherwise); (6) admitted to

hospital, not requiring supplemental

oxygen, no longer requiring ongoing

medical care; and (7) discharged from

hospital.

Merchante, 2021

Type of study:

Phase II, open-label, multicentre randomized clinical trial

Setting:

hospital-based, between 13 July 2020 and 5 March 2021

Country:

10 clinical sites in Andalusia, Spain

Source of funding:

This study was funded by the COVID-19 Research Program of the Regional Government of Andalusia.

Conflicts of interest:

The authors declare no competing interest.

hospitalized patients

Inclusion criteria:

• age ≥ 18 y
• confirmed SARS-CoV-2 infection (positive on RT-PCR) no later than 4 days prior inclusion
• interstitial pneumonia confirmed by the presence of infiltrates on chest radiograph or a computer tomograph
• IL-6 levels ≥ 40 pg/mL and/or D-dimer>1500 ng/mL or ≥ 1000 if progressive increments were documented in at least two determination after admission

Exclusion criteria:

• ARDS requiring HFNO
• Mechanical ventilation

N total at baseline:

Randomized: N = 115

Intervention I (200 mg Sarilumab): N = 37

Intervention II (400 mg Sarilumab): N = 39

Control: N = 39

Important characteristics:

Age, median (IQR):

I(I) (200 mg): 65 y (53-72)

I (II) (400 mg): 57 y (49-67)

C: 57 y (51-71)

Sex, n/N (%) male:

I (I) (200 mg): 23/37 (65%)

I (II) (400 mg): 29/39 (74%)

C: 26/39 (66%)

Diabetes mellitus

I (I) (200 mg): 9/37 (24%)

I (II) (400 mg): 2/39 (5%)

C: 6/39 (15%)

Groups were comparable at baseline. Slightly more patients with DM in de Sarilumab 200 mg group (p=0.06)

Intervention I

single subcutaneous dose of 200 mg sarilumab (Sarilumab-200)

+ Usual care

Intervention II

single subcutaneous dose of 400 mg sarilumab (Sarilumab-400)

+ Usual care

Usual care up to 14 days according to local practice as listed in the protocol of the Spanish Ministry of Health and the Spanish Agency of Medicines and Medical products.

Dexamethasone was the preferred therapy.

Length of follow-up:

28 days

Loss-to-follow-up or incomplete data:

One patient withdrew informed consent (intervention I group) and there was a protocol violation (n=1)

One patient withdrew informed consent (intervention II group) and one patient did not receive the allocated intervention.

Clinical outcomes

Progression to HFNO, NIMV, IMV (event within 28 days)

Events, n (%)

I(I): 10/37 (27%)

I (II): 10/39 (26%)

C: 5/39 (13%)

I(I) compared to C

HR 0.87 (95%CI: 0.37-2.06), p=0.76

I(II) compared to C

HR 0.41 (95%CI: 0.14-1.18), p=0.09

Need for mechanical ventilation

Events, n (%)

I(I): 6/37 (16%)

I (II): 3/39 (8%)

C: 4/39 (10%)

I(I) compared to C

HR 1.68 (95%CI: 0.47-5.98), p=0.41

I(II) compared to C

HR 0.78 (95%CI: 0.17-3.48), p=0.74

Death

Events, n (%)

I(I): 4/37 (8%)

I (II): 0/39 (0%)

C: 3/39 (8%)

I(I) compared to C

HR 1.41 (95%CI: 0.31-6.31), p=0.64

I(II) compared to C

HR 0.01 (95%CI: 0.00-160.68), p=0.07

Also clinical improvement on an ordinal scale, discontinuation of supplemental oxygen in patients receiving it at baseline and discharge alive from hospital were reported as well as a detailed overview of the occurred adverse events.

Definitions:

The primary outcome variable was the development of ARDS requiring HFNO, NIMV

259 or IMV during the first 28 days after randomization.

Remarks:

-

Authors conclusion:

In patients recently hospitalised with COVID-19 pneumonia and features of systemic inflammation, early IL-6 blockade with a single dose of sarilumab 400 mg

was safe and associated with a trend for better outcomes.

The

REMAPCAP

Investigato

rs, 2020

Type of study:

RCT

Open-label design

Setting:

Hospitals

up to November 19,

2020

Country:

International trial.

Source of funding:

The trial has multiple

international funders.

Roche Products and

Sanofi supported the

Trial through provision of

tocilizumab and

sarilumab in the United Kingdom. The funders as well as Roche and Sanofi had no role in designing the trial, analyzing the

data, writing the

manuscript, or making the decision to submit the manuscript

for publication.

Critically ill patients with COVID19 admitted to ICU and receiving respiratory or cardiovascular organ support

Inclusion criteria:

• 18 years of age or older

• either clinically suspected or

microbiologically confirmed

Covid-19

• severe disease state: admitted to ICU and receiving respiratory or cardiovascular organ support*

• enrolled within 24 hours after

starting organ support in the

ICU

Exclusion criteria:

• presumption that death was

imminent with a lack of

commitment to full support

previously participated in

REMAP-CAP within 90 days

• Additional exclusion criteria,

specific to the Immune

Modulation Therapy domain,

are listed in a Supplementary

Appendix.

N total at baseline:

N = 803

Tocilizumab: 353

Sarilumab: 48

Control: 402

Important characteristics:

Age, mean±SD:

I_toci: 61.5±12.5

I_sari: 63.4±13.4

C: 61.1±12.8

Sex, n/N (%) male:

I_toci: 261/353 (74)

I_sari: 39/48 (81)

C: 283/402 (70)

Acute respiratory support:

None or supplemental oxygen

only, n/N (%)

I_toci: 1/353 (<1)

I_sari: 0/48

C:2/402 (<1)

High-flow nasal cannulae

I_toci: 101/353 (29)

I_sari: 17/48 (35)

C: 110/402 (27)

Noninvasive ventilation only

I_toci: 147/353 (42)

I_sari: 23/48 (48)

C: 169/402 (42)

Invasive mechanical ventilation

I_toci: 104/353 (29)

I_sari: 8/48 (17)

C: 121/402 (30)

Groups comparable at baseline?

Baseline characteristics were

balanced across intervention

groups and typical of a critically

ill population with Covid

-19.

1) tocilizumab or

2) sarilumab

Tocilizumab, at a dose of 8

mg per kilogram of actual

body weight (up to a

maximum of 800 mg), was

administered as an

intravenous infusion over

a period of 1 hour; this

dose could be repeated 12 to 24 hours later at the discretion of the treating clinician if clinical

improvement was judged

insufficient.

Sarilumab, at a dose of

400 mg, was administered as an

intravenous infusion once

only. All investigational

drugs were dispensed by

local pharmacies and were open label.

standard care

(no immune

modulation)

Length of follow up:

90 days

Loss to follow-up:

Tocilizumab: 16/366

(4.4%)

Reasons:

-13 Withdrew consent

-3 Had outcome that

was

not available

Sarilumab: 3/48

(6.3%)

Reasons:

-3 Had outcome that

was not available

C: 15/412 (3.6%)

Reasons:

-10 Withdrew consent

-5 Had outcome that

Was not available

Clinical outcomes

In-hospital death, n/N (%)

I_toci: 98/350 (28)

I_sari: 10/45 (22)

C: 142/397 (36)

Primary in-hospital survival

Adjusted odds ratio

Mean

I_toci: 1.66±0.31

I_sari: 2.25±0.96

C: 1

Median (95% credible

interval)

I_toci: 1.64 (1.14 to 2.35)

I_sari: 2.01 (1.18 to 4.71)

C: 1

Probability of superiority

to control — %

I_toci: 99.6

I_sari: 99.5

C: -

Time to ICU discharge

Adjusted HR - mean (SD)

I_toci: 1.43 (0.13)

I_sari: 1.69 (0.32)

C: 1

median (95% CrI)

I_toci: 1.42 (1.18 to 1.70)

I_sari: 1.64 (1.21 to 2.45)

C: 1

Probability of superiority

to control, %

I_toci: >99.9

I_sari: 99.9

C: -

Time to hospital discharge

Adjusted HR - mean (SD)

I_toci: 1.42 (0.13)

I_sari: 1.65 (0.31)

C: 1

median (95% CrI)

I_toci: 1.41 (1.18 to 1.70)

I_sari: 1.60 (1.17 to 2.40)

C: 1

Probability of superiority

to control, %

I_toci: >99.9

I_sari: 99.8

C:-

Symptom resolution

Not reported.

Number of respiratory and cardiovascular organ

support*–free days up to

day 21 (primary outcome

)

Median (IQR)

I_toci: 10 (−1 to 16)

I_sari: 11 (0 to 16)

C: 0 (−1 to 15)

Adjusted odds ratio

Mean

I_toci: 1.65±0.23

I_sari: 1.83±0.44

C: 1

Median (95% credible

interval)

I_toci: 1.64 (1.25 to 2.14)

I_sari: 1.76 (1.17 to 2.91)

C: 1

Probability of superiority

to control

—

%

I_toci: >99.9

I_sari: 99.5

C:

-

Safety

Serious adverse events

Patients with >1 serious

adverse event, n (%)

I_toci: 9/353 (2.5)

I_sari: 0/48 (0.0)

C: 11/402 (2.7)

Adjusted OR - mean (SD)

I_toci: 1.22 (0.55)

I_sari: 2.99 (2.95)

C: 1

median (95% CrI)

I_toci: 1.10 (0.48 to 2.58)

I_sari: 2.10 (0.51 to 10.77)

C: 1

Probability of superiority

to control, %

I_toci: 59.3

I_sari: 84.0

C: -

Virological outcomes

Viral clearance

Not reported.

Also reported (secondary

outcomes): 90-day Survival (time to event);

Respiratory support-free

days; Cardiovascular

support-free days; WHO

scale at day 14;

Progression to invasive

mechanical ventilation,

ECMO or death,

restricted to those not

intubated at baseline

.

Definitions:

Respiratory organ support was defined as invasive or noninvasive mechanical ventilation, including through high-flow nasal cannulae if the flow rate was more than 30 liters per minute and the fraction of inspired oxygen was more

than 0.4.

Cardiovascular

organ support was defined as the

intravenous infusion of any vasopressor or inotrope.

The primary outcome was respiratory

and cardiovascular organ support– free days, on an ordinal scale combining inhospital death (assigned a value of −1) and days free of organ support to day 21.

Remarks:

-The trial uses an open-label design.

-Because this is an early, preliminary

report, some data are missing, including 11 outcomes.

Authors conclusion:

In critically ill patients with Covid-19

receiving organ support in ICUs, were

both effective as compared with the current standard of care,

which included glucocorticoids in the

majority of patients (>80%). The benefit was consistent across

primary and secondary outcomes and

across subgroups and secondary

analyses, including survival.

Sancho-López, 2021 [SARTRE-trial]

Type of study: RCT, open-label

Setting: Eight tertiary hospitals

Country: Spain

Source of funding: Biomedical Research Foundation of the Puerta de Hierro Majadahonda University Hospital and Sanofi (provided sarilumab free of charge). None of the funders had any role in the study’s design, collection, management, analysis and interpretation of data, writing of the report and the decision to submit the report for publication.

Conflicts of interest: Authors declared that they have nothing to disclose.

Hospitalized patients with COVID-19, requiring supplemental oxygen by mask or nasal prongs

Inclusion criteria:
• ≥ 18 years;
• Hospitalized, due to COVID-19 confirmed by RT-PCR or antigen test;
• Pneumonia (radiographic evidence of pulmonary infiltrates or rales/crackles);
• Standard oxygen supplementation due to SpO2 ≤94%; • ≥7 days between time from symptom onset and inclusion;
• IL-6>40 pg/mL or d-dimer>1.0mcg/ml or ≥ two of the following inflammatory parameters elevated (CRP, LDH, serum ferritin or lymphopenia).

Exclusion criteria:
• High oxygen requirements;
• Previous treatment with corticosteroids (CS) > 1 day;

• Admission to the ICU;
• Pregnant or lactating;
• Allergy or hypersensitivity to sarilumab or CS;
• Received immunosuppressive monoclonal antibody therapy within past 5 months;
• AST/ALT values >10 x ULN;
• Neutropenia (<0.5 x 109/L);
• Severe thrombocytopenia (<50 x 109/L);
• Sepsis caused by an alternative pathogen;
• Diverticulitis with risk of perforation;
• Ongoing infectious dermatitis.

N total at baseline: N = 201 Intervention: 99

Control: 102

Important characteristics: Age, mean (SD):
I: 60.12 y (11.54)
C: 59.85 y (11.77)

Sex, n/N (%) male:
I: 71/99 (71.72%)
C: 70/102 (68.63%)

Disease severity, mean (SD):
I: NR
C: NR

Days from symptom onset to randomization, median (IQR)
I: 9.0 (8.0-11.0)
C: 10.0 (8.0-12.0)

Ferritin, ng/mL
I: 680.5 (405–1284)
C: 908.5 (480-1717)

IL-6, pg/mL
I: 19.20 (6.0-46.0)
C: 13.25 (3.85-43.35)

Also available: coexisting conditions and other laboratory values Groups comparable at baseline?
Unclear, patients in the control group had higher ferritin levels and higher serum IL-6 levels.

Sarilumab + usual care

Sarilumab (IV) at a single dose of 200 mg for patients <75 kg body weight, or 400 mg for patients weighing > 75 kg.

Usual care

CS were given to all patients at a 1 mg/ kg/day of methylprednisolone for at least 3 days (background medication). Standard of care also included antibiotic agents, antiviral agents, steroid boluses, vasopressor support, and anticoagulants that were provided at the discretion of the investigators.

Length of follow-up: 28 days

Loss-to-follow-up: Intervention: 5 (5.1%)
Reasons: loss of FU after discharge (n=4) or after admission at ICU in another hospital (n=1) Another patient did not receive the allocated intervention, due to withdrawing consent to participate.

Control: 5 (4.9%) Reasons: loss of FU after discharge (n=4) or after admission at ICU in another hospital (n=1) Another patient did not receive the allocated intervention, due to withdrawing consent to participate.

Incomplete outcome data:

Intervention: NR Reasons NA

Control: NR Reasons NA

Clinical outcomes Mortality (28 day)
I: 2/99 (2.02)
C: 2/102 (1.96)
RR (95%CI): 1.03 (0.14-7.46)
P= 1

Mortality (15 day), n/N (%)
I:0/0 (0)
C: 2/102 (1.96)
 RR (95%CI): 0.98 (0.95-1.01)

P= 0.4976

Duration of hospitalization
Time to hospital discharge, days (95%CI)
I: 7 (6-8)
C: 7 (6-8)
HR (95%CI): 0.903 (0.68-1.21)
P= 0.4623

ICU admission Day 15
I: 7/99 (7.1)
C: 10/102 (9.8)

RR (95%CI): 0.70 (0.25-1.91)

 P=0.4863

Day 28
I: 7/99 (7.07)
C: 10/102 (9.8)
RR (95%CI): 0.70 (0.25-1.91)
P=0.4863

Time to symptom resolution
Not reported

Respiratory support Progression to IMV or death, n/N (%)
I: 4/99 (4)
C: 9/102 (8.8)
HR (95%CI): 0.4481 (0.14-1.46)
P=0.1673

Brescia-COVID score ≥3, day 15, n/N (%)
I: 16/99 (16.16)

C: 16/102 (15.69)

RR (95%CI): 1.03 (0.48-2.20)

P=0.8874

Brescia-COVID score ≥3, day 28, n/N (%)

I: 16/99 (16.16)

C: 16/102 (15.69)

RR (95%CI): 1.03 (0.48-2.20)

P=0.8874

Time to BRESCIA COVID score = 0
I: 86/99 (86.9)
C: 88/102 (86.3)
HR (95%CI): 0.9488 (0.70-1.28)
P= 0.6381

Time to respiratory failure
I: 16/99 (16.2)
C: 16/102 (15.7)
HR (95%CI): 1.059 (0.51-2.03)
P= 0.9638

Time to reduction of supplemental oxygen requirements
I: 91/99 (91.9)

C: 96/102 (94.1)

HR (95%CI): 0.9742 (0.73-1.30)

P=0.7975

Safety Treatment Emergent Adverse events, n/N (%)
I: 4/99 (4.04)
C: 6/102 (5.88)
Effect (95%CI): NR
P=NR

Adverse events, n/N (%)

I: 18/99 (18.2)

C: 16/102 (15.7)

Effect (95%CI): NR

P=NR

Virological outcomes Viral clearance Not reported

Also available: (other) Brescia-COVID scores at other days than 15 and 28, subgroup analyses for the group BRESCIA COVID score ≥ 3 by age, sex, sarilumab dose

Definitions:

• Treatment Emergent Adverse Events were defined as CTCAE grade 3 or higher;

 • Adverse events included following disorders: blood and lymphatic system, Gastro-intestinal, Hepatobiliary, infections, injury, investigations, metabolism and nutrition, musculoskeletal and connective tissue, nervous system, psychiatric, renal and urinary, respiratory, thoracic and mediastinal, skin and subcutaneous tissue and vascular.

Remarks:

• The largest part of the participants was recruited in one tertiary centre (n=132).

• Study was funded by Sanofi, which had however no role in study’s design, data collection, management, analysis and interpretation nor in writing the report.

• Study might have been underpowered.

• Patients in the control group progressing to

• Brescia-COVID ≥ 2 plus inflammatory parameters were given the option to be rescued with sarilumab at the same weight-adjusted doses (n=18). Patients randomly assigned to sarilumab therapy at baseline progressing to Brescia- COVID ≥ 2 were rescued according to local clinical practice protocol (n=27).

Authors conclusion: Our clinical trial failed to demonstrate any benefits of an early therapeutic intervention with sarilumab when added to an optimized SOC regimen that includes CS in the treatment of hospitalized patients with COVID-19 pneumonia with inflammatory parameters, who were under standard oxygen therapy. No new safety issues were identified.

CORIMUNO-19 Collaborative Group, 2021

(CORIMUNO-SARI-1 trial)

Type of study:

multicentre, open-label, randomized controlled phase 2/3 clinical trial, nested within the CORIMUNO-19 cohort

Setting:

hospital-based, between March 27 and April 6, 2020

Country:

6 centres in France

Source of funding:

This trial was publicly funded by the Ministry of Health, Programme Hospitalier de Recherche Clinique, and Assistance Publique – Hôpitaux de Paris Foundation and Foundation for Medical Research. Sanofi donated sarilumab as an unrestricted grant and had no role in the study design, no role in the collection, analysis, or interpretation of the data, and no role in the writing of the report.

Conflicts of interest:

None to declare.

hospitalized patients with moderate-to-severe COVID-19 pneumonia

Inclusion criteria:

• age ≥ 18 y
• confirmed SARS-CoV-2 infection (positive on RT-PCR or typical chest CT scan)
• moderate-to-severe pneumonia not requiring ICU at admission with WHO CPS score of 5
• receiving ≥ 3L/min of O₂ without ventilation assistance that included high-flow O2, non-invasive ventilation, or mechanical ventilation

Exclusion criteria:

• known hypersensitivity to sarilumab or any of its excipients
• pregnancy
• current documented bacterial infection
• any of following laboratory results out of the ranges detailed below at screening:
• absolute neutrophil count ≤ 1.0 ×10⁹/L
• platelets < 50 G/L
• serum glutamicoxaloacetic transaminase or serum glutamic-pyruvic transaminase > 5N.

N total at baseline:

Randomized: N = 148

ITT population: N = 144*

Intervention: N = 68

Control: N = 76

Important characteristics:

Age, median (IQR):

I: 61.7 y (53.0-71.1)

C: 62.8 y (26.0-71.7)

Sex, n/N (%) male:

I: 49/68 (72%)

C: 59/76 (78%)

Coexisting conditions

Chronic cardiac disease

I: 17/67 (25%)

C: 19/76 (25%)

Diabetes

I: 22/68 (32%)

C: 22/76 (29%)

Chronic kidney disease (stage 1-3) or dialysis

I: 10/67 (15%)

C: 7/76 (9%)

Asthma

I: 3/67 (4%)

C: 8/76 (11%)

Chronic pulmonary disease (not asthma)

I: 6/67 (9%)

C: 3/76 (4%)

Active malignant neoplasm

I: 3/67 (4%)

C: 1/76 (1%)

Groups were comparable at baseline.

sarilumab (fixed dose of 400 mg i.v. on day; additional fixed dose of 400 mg i.v. on day 3 was recommended if O₂ requirement had not decreased by more than 50%, but the decision was left to the treating physician) + usual care (antibiotic agents, antiviral agents, corticosteroids, vasopressor support, anticoagulants)

usual care alone(antibiotic agents, antiviral agents, corticosteroids, vasopressor support, anticoagulants)

Length of follow-up:

90 days

Loss-to-follow-up or incomplete data:

none

A subgroup analysis according to antiviral drug use at baseline was prespecified in the protocol. Analyses according to the use of corticosteroids and particularly dexamethasone were added post-hoc considering recent

publications.

Clinical outcomes

Mortality

Mortality at day 14

I: 6/68 (9%)

C: 8/76 (11%)

Adjusted HR 0.68 (95%CI: 0.23-2.03)

Mortality at day 28

I: 8/68 (12%)

C: 14/76 (18%)

aHR 0.65 (95%CI: 0.27-1.59)

Mortality at day 90

I: 10/68 (15%)

C: 16/76 (21%)

aHR 0.70 (95%CI: 0.31-1.58)

Duration of hospitalisation

Discharged at day 28

I: 51/68 (75%)

C: 53/76 (70%)

aHR 1.19 (95%CI: 0.81-1.75)

Time to symptom resolution

Not reported

Respiratory support

Independent from O₂ at day 28

I: 50/68 (74%)

C: 54/76 (71%)

aHR 1.06 (95%CI: 0.72-1.57)

Other

Dead or needing non-invasive ventilation or mechanical ventilation on

day 4 (i.e. WHO-CPS score > 5; coprimary outcome)

I: 18/68 (26%)

C: 20/76 (26%)

Median posterior ARD 0.2% (90%CrI: -11.7-12.2)

Median posterior aOR 1.02 (90%CrI: 0.54-1.94)

Posterior probability of any benefit 48.9%

Posterior probability of moderate or greater benefit than usual care† 21.6%

Survival with no need for non-invasive ventilation (including high-flow O₂) or mechanical ventilation at day 14 (coprimary outcome)

I: 25/68 (37%)

C: 26/76 (34%)

Median posterior aOR 1.10 (90%CrI: 0.69-1.74)

Posterior probability of any benefit 37.4%

Posterior probability of moderate or greater benefit than usual care† 18.6%

Safety

Adverse events

Patients with at least one adverse event

I: 37/68 (54%)

C: 33/76 (43%)

p = 0.24

Patients with multiple adverse events

I: 17/68 (25%)

C: 11/76 (14%)

Number of adverse events

I: 77

C: 58

Incidence rate per 1000 patient-day

I: 14.6 (95%CI: 11.7-18.2)

C: 10.3 (95%CI: 8.0-13.4)

IRR 1.41 (95%CI: 1.00-1.98); control group is reference group

p = 0.048

Serious adverse events

Patients with at least one serious adverse event

I: 27/68 (40%)

C: 28/76 (37%)

p = 0.73

Patients with multiple serious adverse events

I: 10/68 (15%)

C: 9/76 (12%)

Number of serious adverse events

I: 44

C: 40

Incidence rate per 1000 patient-day

I: 8.3 (95%CI: 6.2-11.2)

C: 7.1 (95%CI: 5.2-9.7)

IRR 1.16 (95%CI: 0.76-1.79); control group is reference group

p = 0.47

Deaths

I: 10/68 (15%)

C: 16/76 (21%)

Virological outcomes

Not reported

Definitions:

† Moderate or greater benefit was defined as an ARD <-5·5% for the day 4 outcome and a HR <·0.85 for the day 14 outcome.

Remarks:

* Four patients in the control group withdrew consent after randomization, and asked their personal data to be erased.

Authors conclusion:

Sarilumab treatment did not improve early outcomes in patients with moderate-to-severe COVID-19 pneumonia. Further studies are warranted to evaluate the effect of sarilumab on long-term survival.

Levilimab (Monoclonal antibody- IL-6 inhibitor- BCD-089; Ilsira)

Lomakin, 2021

Type of study: multicenter double-blind, placebo-controlled phase III trial

Setting:
hospital-based, between April 2020 and August 2020

Country: 12 investigational sites in the Russian Federation Source of funding: This study was funded by JSC BIOCAD grant no. BCD-089-4/CORONA. Conflicts of interest: Several authors are JSC BIOCAD employees. The sponsor designed the trial, was responsible for the monitoring, collected the data, and performed the data analysis. Sponsor’s representatives were not IDMC members, had no access to the blinded data, and did not participate in voting.

hospitalized patients with severe COVID-19 not requiring mechanical ventilation

Inclusion criteria:

 • age ≥ 18 y

• positive for SARS-CoV-2 RNA

• hospitalized with radiologically confirmed pneumonia with at least 1 criteria of disease severity:

• respiratory rate > 30/min

• SpO2 ≤ 93 • PaO2/FiO2 < 300 mmHg

• increase of the lung involvement > 50% after 24-48 h

• decreased consciousness level • agitation • unstable hemodynamics

• arterial blood lactate > 2 mmol/L

• qSOFA > 2, defined by the presence of any 2 symptoms (SBP ≤ 100 mmHg, respiratory rate ≥ 22/min, GCS ≤ 14)

Exclusion criteria:

• critical form of COVID-19, defined by the presence of respiratory failure and need of the invasive mechanical ventilation, septic shock or multiple organ failure

• suspected active bacterial, fungal, viral, or other infection (besides COVID-19)

• confirmed active tuberculosis • life expectancy < 24 h, in the opinion of the investigator or who were unlikely to remain at the investigational site beyond 48 h

• treated with other monoclonal antibodies, immunosuppressive agents or participating in a clinical trials of other drug

• history of allergic reaction to monoclonal antibodies

• any illness or laboratory findings that, in the opinion of the study investigator, might pose an additional risk to the patient by their participation in the study

• pregnant or breastfeeding
• ALT and/or AST levels > 10 x ULN • platelet count < 50 x 109/L

• absolute neutrophil count < 1.0 × 109/L

N total at baseline: Randomized: N = 206

ITT population: N = 206 Intervention: N = 103

Control: N = 103

Important characteristics:

Age, mean (SD):

I: 58.5 y (12.9)

C: 58.2 y (10.8)

Sex, n/N (%) male:

I: 58/103 (56.3%)

C: 51/103 (49.5%)

The proportion of patients aged ≥ 75 y was higher in the intervention group than in the control group (11.7 vs. 3.9%).

Patients in the intervention group more often had cardiac disorders(19.4 vs. 11.7%).

More patients in the control group received corticosteroids (4.9 vs. 8.7%)

levilimab 324 mg s.c.

placebo

Length of follow-up: 60 days

Loss-to-follow-up or incomplete data: Intervention: N =1 (1.0%)

Reason • early withdrawal (n = 1) Control: N = 4 (3.9%) Reason • withdrawal before study medication was administered (n = 2)• early withdrawal (n = 1) lost to follow-up (n = 1)

Clinical outcomes Mortality
Not reported; initial primary endpoint was overall mortality, but because the mortality was significantly lower than assumed, the study did not have enough power to detect a meaningful difference

Duration of hospitalisation

Duration of hospital stay Days, median (IQR)
I: 11 (8-16)
C: 11 (7-18)
p=0.4852

Time to symptom resolution
Not reported

Respiratory support
Not reported

Other
Sustained clinical improvement on 7-category ordinal scale on day 14 (primary outcome)*

Day 7
I: 6/103 (5.8%)
C: 6/103 (5.8%)

p = 1.0000

Day 14

I: 65/103 (63.1%)

C: 44/103 (42.7%)

p = 0.0017

Day 21

I: 79/103 (76.7%)

C: 49/103 (47.6%)

p < 0.0001

Day 28

I: 87/103 (84.5%)

C: 57/103 (55.3%)

p < 0.0001

Day 30

I: 87/103 (84.5%)

C: 57/103 (55.3%)

p < 0.0001

Transfer to ICU

I: 3/103 (2.9%)

C: 10/103 (9.7%)

p = 0.0449

Duration of fever Days, median (IQR)

I: 1 (1-3)

C: 2 (1-3)

p = 0.1065

Change in ESR from baseline mm/h, median (IQR)

Day 3

I: 30 (18-44.5)

C: 38 (23-56)

p = 0.0035

Day 5

I: 25 (15-41)

C: 40 (24-55)

p = 0.0002

Day 7

I: 23 (15-36)

C: 31 (21-45)

p = 0.0009

Change in CRP from baseline mg/L, median (IQR)

Day 3

I: 14.6 (5.1-29.8)

C: 31.7 (12-62.6) p < 0.0001

Day 5

I: 5.3 (1.5-15)

C: 17.7 (6.9-44)

p < 0.0001

Day 7

I: 3.9 (1.3-8.4)

C: 9.2 (4.1-19)

p < 0.0001

Change in IL-6 from baseline pg/mL, median (IQR)

Day 3

I: 65.9 (16.5-20.1)

C: 16.4 (3.9-80.4)

p = 0.0017

Day 4

I: 64.2 (18.3-247.1)

C: 20.1 (1.5-119.1)

p = 0.0121

Day 14

I: 25.4 (12.6-77.8)

C: 108.7 (22.1-10.5)

p = 0.1000

Safety

Adverse drug reactions

I: 28/103 (27.2%)

C: 24/101 (9.3%)

p = 0.5750

Grade ≥ 3 adverse drug reactions

I: 10/103 (9.7%)

C: 7/101 (6.9%)

p = 0.4279

Serious adverse events

I: N = 1

C: N = 2

Grade 4 neutropenia

I: N = 0

C: N = 0

Hypersensitivity

I: N = 0

C: N = 0

Injection site reactions

I: N = 0

C: N = 0

Virological outcomes

Not reported

Definitions:
- qSOFA = quick sequential organ failure assessment score
- SBP = systolic blood pressure
- GCS = Glasgow Coma Scale
- ESR = erythrocyte sedimentation rate

* The 7-category ordinal scale includes the following categories: 1 not hospitalized/discharged; 2 hospitalized, not requiring O2 therapy or other medical care; 3 hospitalized, not requiring O2 therapy, requiring other medical care; 4 hospitalized, requiring O2 therapy; 5 hospitalized, requiring high-flow O2 therapy or non-invasive ventilation; 6 hospitalized, requiring mechanical ventilation or ECMO; 7 death.

Remarks: -

Authors conclusion: In patients with radiologically confirmed SARS-CoV-2 pneumonia, requiring or not oxygen therapy (but not ventilation) with no signs of other active infection administration of LVL + SOC results in an increase of sustained clinical improvement rate.

siltuximab

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.

Declercq (2021)

See RoB assessment of the Declercq (2021) by Anakinra.

Rosas, 2021b

Eligible patients were randomly assigned in a 2:1 ratio using an interactive web-based response system and a permuted block method to receive blinded treatment with tocilizumab plus remdesivir or placebo plus remdesivir. Randomization was stratified by geographic region (North America, Europe, other) and by a 2-level factor based on clinical status at screening (ordinal scale categories 4–5, category 6) on a 7-category ordinal scale (additional details are in the Online Resource).

Unlikely

Unlikely

Double-blind study.

Unlikely

Double-blind study

Unlikely

Double-blind study

Unlikely

All predefined outcome measures were reported.

Unlikely

A slightly higher proportion of patients in the placebo plus remdesivir arm than the tocilizumab plus remdesivir arm discontinued remdesivir before completing 10 days of treatment (44.2% vs 39.4%); however, most of these early discontinuations were the result of hospital discharge, consistent with remdesivir use in other trials [17] and in clinical practice

Unlikely

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

Horby, 2021a

Recovery Collaborative group, 2021

Computerized

Patients were assigned to either usual standard of care or usual standard of care plus tocilizumab in a 1:1 ratio by means of web-based simple (unstratified) randomisation.

Unlikely

Allocation was concealed until after randomisation.

Likely

It was an open-label trial; participants were not masked to the allocated treatment

Likely

Local study staff was not masked to the allocated treatment.

(except for mortality)

Unclear

Local study staff was not masked to the allocated treatment. However, the steering committee, investigators, and all others involved in the trial were masked to the outcome data during the trial.

Unlikely

Outcome measures described in the protocol were also reported.

Unlikely

 97% versus 98% completed the trial.

Unlikely

Intention to treat analysis was performed.

Wang, 2021

Computerized

Randomization numbers were generated using SAS statistical software package. Each consecutively coded patient was randomly enrolled by the sub-site investigators until the total number of cases allocated to the site was reached. The patients were randomly assigned in a 1:1 ratio.

Unclear

Not described.

Likely

open-label RCT

Likely

open-label RCT

Unclear

Not described.

Unlikely

However, the worsening rate of hypoxia during hospitalization was only reported for subgroups of patients with moderate or severe COVID-19.

Unlikely

No participants were lost to follow-up.

Unlikely

However, one patient in the control group, who worsened severely 3 days after randomization, was crossed over to the tocilizumab group in accordance with the study protocol. However, this patient was erroneously included in the intervention group for the ITT analyses.

Soin, 2021

Computerized

“Eligible patients were randomly assigned using block

randomisation in a 1:1 ratio to receive open-label tocilizumab plus current standard care (tocilizumab group) or current standard care alone (standard care

group). The randomisation sequence was generated using SAS, version 9.4 and an interactive web response system.”

Unclear

Concealment not described

“Randomisation numbers were assigned in sequential order to the study sites according to the

pregenerated sequence provided by the investigational

medicinal product team at the Medanta Institute of

Education and Research.”

Likely

“After randomisation, none of the study personnel or patients were masked to treatment assignment in this open-label trial.“

Likely

“After randomisation, none of the study personnel or patients were masked to treatment assignment in this open-label trial.“

Likely

“After randomisation, none of the study personnel or patients were masked to treatment assignment in this open-label trial.“

Unlikely

Relevant and announced outcomes reported; registered with the Clinical Trials Registry India (CTRI/2020/05/025369

Unlikely

1 cross-over from control to intervention group, 1 withdrawn consent in standard care group; not expected to induce bias in results

Unlikely

Analysis not performed according to ITT-protocol; small number of patients not included in the analysis, 1 cross-over; not expected to induce bias in results

Rosas, 2021a

Web-based response system and permuted block randomization / Stratification according to use of mechanical ventilation (yes or no).

Eligible patients were randomly assigned in a 2:1 ratio to receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight, with a maximum dose of 800 mg) or placebo plus standard care by means of an interactive voice or Web-based response system and permuted-block randomization. Randomization was stratified according to geographic region (North America or Europe) and the use of mechanical ventilation (yes or no).

Likely

Patients were stratified according to geographic region and use of mechanical ventilation (yes or no).

Unlikely

The study was a double-blinded, placebo-controlled study.

Unlikely

The study was a double-blinded, placebo-controlled study.

Unlikely

The study was a double-blinded, placebo-controlled study.

Unlikely

All predefined outcomes were reported.

Unlikely

Lost to follow-up did not significantly differ between the two groups.

Unlikely

Participants included in the analysis are exactly those who were randomized into the trial and analysed by intention-to-treat analysis.

The REMAP-CAP Investigators, 2020

See RoB assessment of the REMAP-CAP Investigators (2020) by sarilumab.

Veiga, 2021

Patients were randomised in a 1:1 ratio to receive either standard care or tocilizumab plus standard care, with random blocks of sizes 2, 4, 6, and 8, and stratified by age (<60 and ≥60 years) and sex, according to a computer-generated schedule using the sample function of software R 3.6.3 (R Foundation).

Unlikely

Allocation

concealment was ensured by a central automated web

accessed system (REDCap), developed by CZO.

Likely

Open label trial

Likely

Open label trial

Likely

Open label trial + “Hospital researchers, unblinded to treatment assignment, collected outcome data during the patients’ hospital stay”.

Unlikely

Results of all predefined outcome measures were reported.

Unclear

“The 15 day follow-up was completed for all patients.” However, it is unclear if the 28/29 days follow-up also was completed for all patients.

Unlikely

“The primary analysis followed the intention-to-treat principle, except for adverse events, which were analysed in a safety population that included patients according to the drug received, regardless of assigned group.”

Two patients in the placebo group received tocilizumab at discretion of the doctor

Salama, 2020 

Computerized 

“Using permuted-block randomization and an 

interactive voice- or Web-response system, we randomly 

assigned the patients, in a 2:1 ratio, to receive 

standard care plus one or two doses of either 

intravenous tocilizumab (8 mg per kilogram of body weight, to a maximum of 800 mg per dose) 

or placebo. The randomization was stratified according 

to country (the United States, Mexico, Kenya, South Africa, Peru, or Brazil) and age (≤60 or >60 years).” 

Unlikely 

“After initial written 

informed consent has been obtained, all screening procedures and assessments have 

been completed, and eligibility has been established for a patient, the study site will obtain the patient's identification number and treatment assignment from an interactive voice or web-based response system (IxRS).” 

Unlikely 

“Study site personnel and patients will be blinded to treatment assignment during the 

study, with the exception of the study pharmacist.” 

Unlikely 

“Study site personnel and patients will be blinded to treatment assignment during the 

study, with the exception of the study pharmacist.” 

Unlikely 

“Study site personnel and patients will be blinded to treatment assignment during the 

study, with the exception of the study pharmacist.” 

Unlikely 

ClinicalTrials.gov 

number, NCT04372186. 

Primary outcome slightly different (protocol: proportion of patients requiring mechanical ventilation at day 28; publication: proportion of patients who had received mechanical ventilation or who had died 

by day 28. 

Likely 

Percentage of loss to follow-up differs between groups (intervention group 3.9%, control group 0.8%). Unclear why more participants of the intervention group withdrew from study participation. 

Unlikely 

Analysis performed according to (modified) intention-to-treat protocol; as indicated by randomized participants minus participants that withdrew or were withdrawn. 

Stone, 2020

Block randomization

Unlikely

Randomization was performed with randomly permuted blocks of sizes 3 and 6. Randomization was stratified according to site.

Unlikely

It was a randomized, double-blind, placebo-controlled trial.

Unlikely

It was a randomized, double-blind, placebo-controlled trial.

Unlikely

A blinded interim analysis for safety was performed.

]

Unlikely

Unlikely

Unlikely

Intension-to-treat analysis was performed.

Salvarani, 2020

Computerized

“Patients were randomized using a web-based system with a 1:1 allocation ratio. Randomization was stratified by center”

Unlikely

“allocation concealment was based on a centralized randomization list that was not available to clinicians”

Unclear

It was an open label study.

Likely

It was an open label study, which might have led to differences in patient care.

Unclear

It was an open label study, which might have led to differences in reporting the results.

Unlikely

Outcomes reported in accordance with study protocol / trial register

Trial Registration:  ClinicalTrials.gov Identifier NCT04346355;

EudraCT Identifier: 2020-001386-37

Unclear

3 patients withdrew consent in control group.

Unlikely

3 patients withdrew consent in control group. Other patients were included in the analysis according to randomization; adherence to ITT analysis protocol.

Hermine, 2020

Participants were randomly assigned in a 1:1 ratio to receive

TCZ plus usual care (TCZ group) or usual care alone (UCgroup)

via a web-based secure centralized system.

Unlikely

An independent statistician provided a computer-generated assignment randomization

list stratified by center and blocked with varying block sizes unknown to the investigators

Likely

The trial was not blinded because it was logistically impossible at the time of the pandemic to set up a double-blind study quickly

Likely

Likely

Unlikely

Likely

8 patients were lost to follow-up at day 28 in the TCZ group versus 3 in the UC group

Unlikely

Analyses were performed on an intention-to-treat basis with no correction for multiplicity for secondary outcomes. Thus, these results are exploratory and reported as point estimates and

95% confidence intervals (CIs)

Sarilumab

Lescure, 2020

Computerized

Eligible patients were

randomly assigned

(2:2:1) to one dose of

intravenous sarilumab

400 mg, sarilumab 200

mg, or placebo according to a central

randomisation scheme

using permuted blocks of five and implemented

through an interactive

response technology.

Unclear

Concealment was not

described

Unlikely

“Patients, care

providers, outcome

assessors, and investigators remained masked to

assigned intervention throughout the course

of the study. An

unmasked pharmacist

was responsible for

the preparation and

dispensation of all

study interventions.”

Unlikely

“Patients, care

providers, outcome

assessors, and

investigators

remained masked to

assigned intervention throughout the course

of the study. An

unmasked pharmacist

was responsible for

the preparation and

dispensation of all

study interventions.”

Unlikely

“Patients, care

providers, outcome

assessors, and

investigators

remained masked to

assigned intervention throughout the course

of the study. An

unmasked pharmacist

was responsible for

the preparation and

dispensation of all

study interventions.”

Unlikely

Elaborate description

of outcomes in

register; not all FU’s

included in the publication

Register:

ClinicalTrials.gov,

NCT04327388;

EudraCT, 2020-

001162-12; and WHO,

U1111-1249-6021.

Unlikely

Unlikely

Merchante, 2021

Unclear

Patients were randomized in a 1:1:1 ratio, further details are not reported.

Unclear

Not reported

Likely

Open-label trial

Likely

Open-label trial

Unclear

Not described

Likely

Not all outcome measures described in the trial protocol are reported in the results

Unlikely

No participants were lost to follow-up.

Unlikely

Efficacy analyses of the primary outcome were performed both in the intention-to-treat population and per protocol population.

The REMAP-CAP

Investigators,

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

Unlikely

Centralized

randomization was used

that was remote from

study sites.

Likely

Open-label trial.

Likely

Open-label trial.

Clinical staff were

aware of the

intervention

assignment of

individual patients

Unclear

Not reported.

Unlikely

Secondary outcomes

were all prespecified,

and details are

provided in the

Supplementary

Appendix.

Unclear

Because this is an

early, preliminary

report, some data are

missing, including 11

outcomes.

Unclear

Not reported.

Sancho-López, 2021

Computerized

Participants were randomly assigned in a 1:1 ratio to receive either sarilumab plus SOC or SOC alone. Randomization codes were produced by means of the RERAND system integrated within the eCRF system based on Oracle, stratified by center and using blocks multiple of 2 elements.

Unlikely

The randomization schedule was managed through the eCRF in a concealed manner.

Likely

It is an open label study, which mainly will have an impact on the subjective outcomes.

Likely

It is an open label study. However, medical decisions to increase oxygen support were taken by different physicians, many of them not investigators of the trial.

Likely

It is an open label study, which mainly will have an impact on the subjective outcomes.

Unclear

Some of the outcome measures mentioned in the study protocol were not reported in the study (e.g. duration of hospitalization, non-invasive ventilation)

Unlikely

Number of lost to follow-up and reasons were not different between the treatment groups.

Unlikely

ITT-analysis was performed.

CORIMUNO-19 Collaborative Group, 2021

Computerized

Participants were randomly assigned in a 1:1 ratio via a web-based secure centralised system. An independent statistician provided a computer-generated randomisation list stratified by centre and blocked with random block size (randomly selected among 2 and 4); the block size was unknown to the investigators and statisticians analysing the data.

Unlikely

Participants were randomly assigned via a web-based secure centralised system. An independent statistician provided a computer-generated randomisation list.

Likely

Open-label trial

Likely

Open-label trial

Unlikely

Analyses were done

by the study statisticians who were blinded to the actual randomisation groups.

Unlikely

All outcome measures described in the trial protocol are reported in the results.

Unlikely

No patients were lost to follow-up

Unlikely

Analyses were done on an intention-to-treat basis with no correction for multiplicity for prespecified secondary outcomes

Levilimab (Monoclonal antibody- IL-6 inhibitor- BCD-089; Ilsira)

Lomakin, 2021

Computerized Randomization was performed centrally. After the investigator entered the eligibility screening data, the central electronic system generated a unique subject identifier and a unique investigational product lot number.

Unlikely

Randomization was performed centrally

Unlikely

Patients were blinded to the treatment allocation.

Unclear

Not reported. However, levilimab and placebo were provided in identical primary and secondary packages with identical labels.

Unlikely

The investigator was blinded to the treatment allocation.

Unlikely

All outcome measures described in the methods are reported in the results, except for duration of hospital stay. Noteworthy, the initial primary endpoint was overall mortality, but because the mortality was significantly lower than assumed, the study did not have enough power to detect a meaningful difference.

Unlikely

The percentage of patients lost to follow-up is less than 10%, but higher in the control group.

Unlikely

All randomized patients who received levilimab or placebo were included in the ITT (‘as randomized’) analysis.

siltuximab

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.