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Three Part Question

In [adult patients confirmed with COVID-19] does [monoclonal antibody therapy] lead to [improved clinical outcomes]?

Clinical Scenario

A 66-year-old man came to the emergency department by ambulance for cough and viral illness. His chest X-ray revealed bilateral infiltrates concerning for viral pneumonia. RT-PCR test confirmed the diagnosis of COVID-19 infection. You wonder if monoclonal antibody therapy would provide any benefits to mortality, length of stay, requirement for ventilation.

Search Strategy

Pubmed
EMBASE using OVID interface
Cochrane Library
Further Google Scholar search to ensure no missing relevant material

Studies were limited to those published in English and those that used only human subjects

PubMed:
("monoclonal antibody"[All Fields]) AND ("Covid-19"[All Fields] OR "coronavirus"[All Fields] OR "Severe acute respiratory syndrome coronavirus 2"[All Fields] OR "SARS-CoV-2"[All Fields] OR "2019 novel coronavirus"[All Fields] OR "2019-nCoV"[All Fields] OR "coronavirus disease 2019"[All Fields]) AND (hasabstract[text] AND ("2019/12/01"[PDAT] : "3000/12/31"[PDAT]) AND English[lang])

Embase:
'monoclonal antibody' AND 'coronavirus disease 2019' AND 'randomized controlled trial'/de

Cochrane:
monoclonal antibody in All Text AND covid-19 in All Text

Google Search:
(monoclonal antibody) AND (Covid-19 OR coronavirus OR Severe acute respiratory syndrome coronavirus 2 OR SARS-CoV-2 OR 2019 novel coronavirus OR 2019-nCoV OR coronavirus disease 2019) LIMIT to English AND Human

Search Outcome

PubMed: 632 papers of which 18 relevant
EMBASE: 65 papers no new relevant research found
Cochrane: 13 trials found but no new published research
Google Scholar: no new relevant papers found

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Fakharian et al 2021 Iran	68 patients with RT-PCR COVID(+) and severe illness, aged 18-70. Intervention group: 34 patients assigned to adalimumab, 40 mg, single-dose. Control group: 34 patients assigned to standard care alone.	RCT	Invasive mechanical ventilation requirement	No significant difference (p=1.0)	Small sample size. Lack of evaluating efficacy of adalimumab as monotherapy. Lack of evaluating different dosing regimens or increased number of administrations.
			Length of hospital and ICU stay	No significant difference (p=1.0, 0.27, respectively)
			Mortality rate	No significant difference (p=1.0)
Caricchio et al 2021 United States, Europe, Russia	454 hospitalized patients with Covid-19 pneumonia, hypoxia (not requiring invasive mechanical ventilation), and systemic hyperinflammation. Intervention group: 227 patients assigned to canakinumab (450 mg for body weight of 40-<60 kg, 600 mg for 60-80 kg, and 750 mg for >80 kg; n = 227). Control group: 227 assigned to placebo.	Phase 3 RCT, double blind, placebo controlled	Survival without invasive mechanical ventilation from day 3 to day 29	No significant difference (OR=1.39, p=0.29)	Homogeneous study population. Imbalance in the use of the prohibited medications (tocilizumab and anakinra) after study therapy was initiated; these medications were not defined as rescue therapies per protocol. The standard care for treatment of COVID-19 evolved during the conduct of the trial, leading to the reversed imbalance of glucocorticoids use in the canakinumab vs placebo group.
			COVID19 related mortality	Rate difference of -2.3% (95%CI, -6.7% to 2.2%) and an odds ratio of 0.67 (95%CI, 0.30 to 1.50)
			Serious adverse events	36 of 225 patients (16%) treated with canakinumab vs 46 of 223 (20.6%) who received placebo
Dougan et al. 2021 United States	1035 outpatients diagnosed with mild or moderate COVID-19. Intervention: 518 patients assigned to 2800 mg of bamlanivimab and 2800 mg of etesevimab. Control: 517 patients assigned to placebo.	RCT, double-blind, placebo controlled, ongoing phase 2-3 trial	Covid-19–related hospitalization (defined as acute care for greater than 24 hours) or death from any cause by day 29	By day 29, a total of 11 of 518 patients (2.1%) in the bamlanivimab-etesevimab group had a Covid-19–related hospitalization or death from any cause, as compared with 36 of 517 patients (7.0%) in the placebo group (absolute risk difference, -4.8 percentage points; 95% confidence interval [CI], -7.4 to -2.3; relative risk difference, 70%; P<0.001).	Homogeneous study population. Study population had low rates of pre-existing common chronic diseases and immunologic conditions (such as chronic kidney disease, cardiovascular disease, and chronic obstructive pulmonary disease were 3.5%, 7.4%, and 8.2%, respectively). The current emergency use authorization for bamlanivimab plus etesevimab dictates that patients must receive these drugs within 10 days after symptom onset. However, in this trial, only approximately 5% of the patients had had symptoms for more than 8 days before receiving the infusion. Demographic differences and differences in health system utilization may have influenced the number of patients who were hospitalized as the trial progressed.
			The change from baseline to day 7 in the SARS-CoV-2 viral load and a persistently high SARS-CoV-2 viral load on day 7	Mean 7-day viral load reduction was 16 times greater in intervention group compared to control (p<0.001)
Cremer et al. 2021 United States	40 hospitalized patients with Covid-19 pneumonia, hypoxaemia, CRP < 5 mg/dL, and not on mechanical ventilation. Intervention: 21 patients assigned to single IV infusion of mavrilimumab 6 mg/kg. Control: 19 patients assigned to placebo.	Double-blind, placebo-controlled, multicentered RCT	Proportion of patients alive and off supplemental oxygen therapy at day 14	No significant difference (p=0.76).	Small sample size. Slow recruitment leads to enrollment stopped after 40 of planned 60 patients. Hypothesis-generating study, subject to type II error. Interaction analyses with treatment and outcome were underpowered. Due to infection control, lab tests were restricted to clinical care, and patients did not return to hospital after discharge. Collection of lab test results varied between patients. Imbalance of treatments due to evolving therapeutic approaches to COVID-19.
			Proportion of patients alive at day 28	No significant difference (p=0.22).
			Proportion of patients alive and without respiratory failure at day 28	No significant difference (p=0.43).
Temesgen et al 2021 United States and Brazil	520 patients with severe Covid pneumonia, >18 years, and less than 94% oxygen saturation on room air and/or requiring supplemental oxygen, but not invasive mechanical ventilation. Intervention group: 261 patients assigned to lenzilumab, 600 mg. Control: 259 patients assigned to placebo.	Phase 3, double-blind, placebo-controlled RCT	Composite endpoint of ventilator-free survival by Day 28.	54% relative improvement in the likelihood of subjects treated with lenzilumab achieving SWOV compared to the placebo group (HR: 1.54; 95%CI: 1.02-2.31, p=0.041	The study was not powered to observe a survival benefit, and did not achieve statistical significance on the secondary endpoint in the mITT population. The observations pertaining to benefits in the population with CRP<150 mg/L and age <85 were exploratory.
			The proportion of IMV, ECMO or death, mortality, and Time to Recovery based on the 8 point clinical status scale	Incidence of IMV, ECMO or death was 15.4% in the lenzilumab group and 21.4% in placebo (OR 0.67; 95%CI 0.41-1.10), p=0.111) but was significantly improved in subjects with CRP<150 mg/L and age<85 (OR 0.32; 95%CI, 0.15-0.65, nominal p=0.002). Mortality was significantly improved by 2.17-fold in subjects with CRP<150 mg/L and age<85 (nominal p=0.040). Time to Recovery was not different between groups in the mITT population but was significantly improved by 36% (nominal p=0.012) in the mITT population with CRP<150 mg/L and age<85.
Lescure et al. 2021 Argentina, Brazil, Canada, Europe, Russia, Japan	420 patients aged above 18 years old admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Intervention group: 159 patients assigned to Sarilumab 200 mg IV and 173 assigned to Sarilumab 400 mg IV Control: 84 patients assigned to placebo.	Double-blind, placebo-controlled, multinational phase 3 RCT trial	Time to clinical improvement of two or more points (seven-point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population.	No significant difference.	Homogeneous population. Treatment may have been initiated too late in the disease course Lack of evaluation for biological and clinical markers of inflammation or worsening prognosis (ex. neutrophil counts or uncontrolled fever) during patient selection, which may exclude patients with appropriate immunomodulatory therapy. Unclear timing of administering Sarilumab. More than 60% of patients in the trial received at least one dose of systemic corticosteroids before, during, or after infusion of the study medication, which might have reduced the differences between the investigation between treatment and placebo groups. Also, the frequency of systemic corticosteroid use varied during the study. Limited amount of clinical data available to estimate the efficacy of usual care for patients admitted to hospital with COVID-19 would underpower the study. Efficacy endpoints chosen was insufficiently sensitive for the wide range of disease severity studied. The ordinal clinical status scale based on intensity of respiratory support was crude to measure treatment effects in patients with an acute systemic disease involving multiple organ systems.
			Proportion of patients alive at day 29	No significant difference.
Soin et al. 2021 India	180 patients aged greater than 18 years admitted to hospital with moderate to severe Covid-19 (Indian Ministry of Health grading) confirmed by positive SARS-CoV PCR result Intervention group: 91 patients assigned to tocilizumab 6 mg/kg plus current standard care. Control group: 89 patients assigned to standard care alone.	Open-label, multicenter, phase 3 RCT	Proportion of patients with progression of COVID-19 from moderate to severe or from severe to death up to day 14	No significant difference (p=0.42)	Unmasked study without placebo group. Extensive use of steroids and Remdesivir in both groups may have muted effect of tocilizumab. Unknown number of patients who were initially considered by the investigators but were not screened. Unclear clinical criteria for disease severity (moderate, severe).
			Mortality up to days 7, 14, 21, and 28	No significant difference (p>0.05)
Rosas et al. 2021 United States, Canada, and Europe	438 patients (greater than 18 years of age) with severe Covid-19 pneumonia, a blood oxygen saturation of <=93%, or a Pao2/Fio2 ratio <300 mm Hg. Patients were excluded if the treating physician determined that death was imminent and inevitable within 24 hours or if they had active tuberculosis or a bacterial, fungal, or viral infection other than SARS-CoV-2. Intervention: 294 patients assigned to tocilizumab 8 mg/kg. Control: 144 patients assigned to placebo	Double-blind, placebo-controlled, phase 3 RCT	Clinical status at day 28, as assessed on the ordinal scale ranging from 1 (discharged or ready for discharge) to 7 (death)	No significant difference (p=0.31).	Using ordinal scale for evaluating clinical status can lead to insensitivity to differences in local clinical practice, lack of proportionality between categories, insensitivity to events before the time point of assessment, and lack of an established minimum clinically important difference for therapeutic effect. Lack of standardized treatment across trial sites and countries. Worsening clinical status among patients in the placebo group could have led to increased glucocorticoid use and more frequent administration of a second dose of placebo, which can cause insignificant differences between treatment and placebo groups.
			Mortality at day 28	No significant difference (p=0.94).
Gordon et al. 2021 Canada, US, Europe, Saudi Arabia, Aus, New Zealand	803 patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU). Intervention group: 353 patients on tocilizumab (8 mg/kg), and 48 patients on sarilumab (400 mg). Control group: 402 patients assigned to standard care	Ongoing international, multifactorial, adaptive platform RCT	Respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21	Median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively.	Homogeneous population. Open-label study design without placebo group. Preliminary report with missing data of 11 outcomes. Lack of long-term follow-up. Different standards of care in different ICUs cross country.
			90-day survival	Improved in the pooled interleukin-6 receptor antagonist groups, HR=1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%.
Lundgren et al. 2020 United States, Denmark, Singapore	314 patients hospitalized with Covid-19 without end-organ failure. Intervention group: 163 patients assigned to LY-CoV555. Control group: 151 patients assigned to placebo.	Platform trial, multigroup, multistage, double-blind RCT	Sustained recovery during a 90-day period, as assessed in a time-to-event analysis.	The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47).	Smaller sample size and shorter duration of follow-up than planned led to wide confidence intervals around major safety outcomes. Unclear definition of patient enrollment (ex. How to define the symptoms attributable to COVID-19).
			Death from any cause during 90 days of follow-up	No significant difference (p=0.22).
Veiga et al. 2021 Brazil	129 patients with confirmed Covid-19 who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers. Intervention group: 65 patients assigned to tocilizumab, single IV infusion of 8 mg/kg. Control group: 64 patients assigned to standard care alone	Open-label, multicentered RCT	Improvement in mechanical ventilation or death at 15 days	No significant difference (P=0.32)	The decision to perform tracheal intubation and its timing depends on the operator. The sample size was relatively small causing the 95% confidence interval to be wide. The distribution of the seven level ordinal scale at 15 days was not compatible with proportional odds assumptions, which led to the reduction in the statistical power to detect a treatment effect on the primary outcome. No record of the number of patients assessed for eligibility. Unable to report on the specific drug use of different treatment classes, including antivirals, corticosteroids, and antibiotics.
Hermine et al. 2020 France	131 patients ages 57-74 with confirmed Covid-19 and moderate, severe, or critical pneumonia. Intervention group: 63 patients assigned to IV tocilizumab, 8 mg/ kg on day one, followed by a second dose of 400 mg on day 3 if oxygen requirement had not decreased by 50%. Control group: 67 patients assigned to standard care alone.	Open-label, investigator-initiated, multicenter RCT	Scores higher than 5 on the World Health Organization 10-point Clinical Progression Scale (WHO-CPS) on day 4	No significant difference in WHO-CPS scores lower than 5 at day 4	Unblinding due to the impossibility at the time of pandemic of setting up a double-blind study quickly, which could lead to measurement bias and performance bias. Usual care could differ among centers and over time. Small sample size and wide credibility intervals could lead to overestimated treatment effects. Not generalized patient population.
			Survival without need of ventilation (including noninvasive ventilation) at day 14.	At day 14, 12% (95% CI -28% to 4%) fewer patients needed noninvasive ventilation (NIV) or mechanical ventilation (MV) or died in the TCZ group than in the UC group (24% vs 36%, median posterior hazard ratio [HR] 0.58; 90% CrI, 0.33-1.00), with a posterior probability of HR less than 1 of 95.0%, achieving the predefined efficacy threshold.
			Overall survival	No significant difference of mortality on day 28.
Salvarani et al. 2021 Italy	126 patients with confirmed Covid-19 pneumonia, Pao2/Fio2 ratio 200 - 300 mm Hg, and an inflammatory phenotype defined by fever and elevated CRP. Intervention group: 60 patients assigned to IV tocilizumab (8 mg/kg up to 800 mg) followed by a second dose 12 hours later. Control: 63 patients assigned to supportive care after initial protocols	Prospective, multicenter, open-label RCT	Clinical worsening within 14 days since randomization, defined by the occurrence of 1 of the following events, whichever occurred first: - 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	No significant difference (P=0.87)	Open label can cause induced bias. Investigators could be more inclined to classify a patient as clinically worsened in the control arm than in the experimental arm. 14 patients in the control group received tocilizumab after they reached the primary end point, subsequent secondary outcomes might be affected.
			ICU admission with invasive mechanical ventilation at 14 and 30 days	The proportion of patients discharged within 14 and 30 days was the same in the 2 groups (rate ratio, 0.99; 95% CI, 0.73-1.35; and 0.98; 95% CI, 0.87-1.09; respectively).
Stone et al. 2020 United States	243 patients ages 19 to 85 with confirmed SARS-CoV-2, hyperinflammatory states, and at least two of the following: fever, pulmonary infiltrates, or the need for supplemental oxygen in order to maintain saturations above 92%. Intervention group: Patients assigned to tocilizumab (8 mg/kg). Control group: patients assigned to placebo.	Double-blind, placebo-controlled RCT	Intubation (or death, for patients who died before intubation) after administration of tocilizumab or placebo	No significant difference (p=0.64)	Primary event rate observed was lower than anticipated, which could be due to evolving standards of care during the trial. Imbalance in the percentage of older patients between the treatment groups, which could affect the estimated treatment effect on the primary outcome, as evidenced by the difference between the unadjusted and adjusted hazard ratios.
			Clinical worsening.	No significant difference (p=0.73).
			Discontinuation of supplemental oxygen among patients who had been receiving it at baseline.	No significant difference (p=0.69)
Salama et al. 2020 US, Peru, Brazil, Kenya, South Africa, and Mexico	377 patients aged older than 18 hospitalized with Covid-19, a blood oxygen saturation <94% on room air, without CPAP, BPAP, or mechanical ventilation. Patients were excluded if progression of the illness to death was imminent and inevitable within 24 hours, as determined by the treating physician, or if they had active tuberculosis or suspected active bacterial, fungal, or viral infection (other than SARS-CoV-2 infection or well controlled human immunodeficiency virus infection). Intervention group: 249 assigned to tocilizumab group. Control group: 128 patients assigned to placebo.	Double-blind, placebo-controlled, phase 3 RCT	Mechanical ventilation (invasive mechanical ventilation or extracorporeal membrane oxygenation) or death by day 28.	The cumulative percentage of patients who had received mechanical ventilation or who had died by day 28 was significantly lower in the tocilizumab group (12.0%; 95% confidence interval [CI], 8.5 to 16.9) than in the placebo group (19.3%; 95% CI, 13.3 to 27.4) (hazard ratio, 0.56; 95% CI, 0.33 to 0.97; P=0.04 by the log-rank test).	Clinical care could differ among centers in different countries and over time. Homogeneous study population. The timing of administration could differ among centers.
			The median time to hospital discharge or readiness for discharge over the 28-day period	6.0 days (95% CI, 6.0 to 7.0) in the tocilizumab group and 7.5 days (95% CI, 7.0 to 9.0) in the placebo group (hazard ratio, 1.16; 95% CI, 0.91 to 1.48)
			The median time to at least a two-category improvement in clinical status relative to baseline on the seven-category ordinal scale over the 28-day period	6.0 days (95% CI, 6.0 to 7.0) with tocilizumab and 7.0 days (95% CI, 6.0 to 9.0) with placebo (hazard ratio, 1.15; 95% CI, 0.90 to 1.48)
			Mortality over the 28-day period	10.4% (95% CI, 7.2 to 14.9) in the tocilizumab group and 8.6% (95% CI, 4.9 to 14.7) in the placebo group (weighted difference, 2.0 percentage points; 95% CI, –5.2 to 7.8)
Diaz et al. 2020 Cuba	19 patients aged 64-100 with confirmed Covid-19 by RT-PCR. Intervention: Patients assigned to 200 mg of IV itolizumab. Some recieved a second dose of 200 mg after clinical evaluation and physician's criteria. Control: patients assigned to standard care	Open-label, expanded access RCT	IL-6 serum levels before treatment and 24-48 hours after.	No significant changes in IL-6 serum levels were detected.	Lack of a concurrent control group Limited follow-up of the patients, leading to unknown long-term outcomes. Small sample size
			Length of stay in the hospital.	Median hospital stay of 13 days ranging from 3-40 days.
			Requirement for oxygen therapy.	Significant reduction in required oxygen therapy from baseline.
Weinreich et al. 2021 United States	4180 outpatients aged 18 years or older with confirmed Covid-19 test results and at least one risk factor for severe COVID-19. Intervention group: 2091 patients assigned to REGEN-COV2 at 2.4 g (n=1355) or 1.2 g (n=736). Control group: 2089 patients assigned to placebo.	RCT, double blind, placebo controlled	The percentage of patients with at least one Covid-19 related hospitalization or death from any cause through day 29	Covid-19–related hospitalization or death from any cause occurred in 18 of 1355 patients in the REGEN-COV 2400-mg group (1.3%) and in 62 of 1341 patients in the placebo group who underwent randomization concurrently (4.6%) (relative risk reduction [1 minus the relative risk], 71.3%; P<0.001); these outcomes occurred in 7 of 736 patients in the REGEN-COV 1200-mg group (1.0%) and in 24 of 748 patients in the placebo group who underwent randomization concurrently (3.2%) (relative risk reduction, 70.4%; P=0.002).	Lack of power analysis. Unclear definition of primary outcome (ex. What is COVID-19-related hospitalization?) Unclear administration timing of treatment and placebo. Homogeneous study population. Lack of considering comorbidities between groups.
			The time to resolution of Covid-19 symptoms	The median time to resolution of symptoms was 4 days shorter with each REGEN-COV dose than with placebo (10 days vs. 14 days; P<0.001 for both comparisons).
O'Brien et al. 2021 United States	1505 asymptomatic, healthy adult (greater than 18 years of age) and adolescent (from 12 to 18 years) household contacts of the first known household member with SARS-CoV-2 infection (defined as the index case). Individuals with prior SARS-CoV infection were excluded. Intervention group: 753 patients assigned to REGEN-COV2 at 1.2 g. Control group: 752 patients assigned to placebo.	RCT, double-blind, placebo controlled, phase 3 trial	The proportion of individuals with symptomatic, RT-qPCR-confirmed SARS-CoV-2 infection during the 28-day efficacy assessment period (EAP).	Subcutaneous REGEN-COV significantly prevented symptomatic SARS-CoV-2 infection compared with placebo (81.4% risk reduction; 11/753 [1.5%] vs. 59/752 [7.8%], respectively; P<0.0001), with 92.6% risk reduction after the first week (2/753 [0.3%] vs. 27/752 [3.6%], respectively).	Collection skills of test samples could affect SAES-CoV-2 diagnostic results. Unclear protocol of sample collection. Unclear definition of adverse events. Homogeneous study population.

Comment(s)

Of the 18 randomized controlled trials included in this review, 5 found a significant difference for at least one of improved clinical outcomes, 12 did not, and 1 study did not perform formal statistical hypothesis testing. 2 studies suggested that monoclonal antibodies could significantly reduce COVID-19 related hospitalization. 4 studies revealed that monoclonal antibody therapy had no significance in reducing COVID-19 related mortality. Early use of REGEN-CoV in COVID-19 outpatients can be promising in reducing COVID-19-related hospitalization. As such, further research is still needed to better understand which patients may receive the highest benefit from monoclonal antibody therapy in the treatment of COVID-19 disease.

Clinical Bottom Line

Monoclonal antibody therapy, given concurrently with standard Covid-19 treatments, may reduce hospitalization in patients with COVID-19 infection, although there is no clear benefit in reducing mortality.

References

1. Fakharian A, Barati S, Mirenayat M, et al Evaluation of adalimumab effects in managing severe cases of Covid-19: A randomized controlled trial.
2. Caricchio R, Abbate A, Gordeev I, et al Effect of Canakinumab vs Placebo on Survival Without Invasive Mechanical Ventilation in Patients Hospitalized With Severe Covid-19: A Randomized Clinical Trial.
3. Dougan M, Nirula A, Azizad M, et al Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19.
4. Cremer PC, Abbate A, Hudock K, et al. Mavrilimumab in patients with severe Covid-19 pneumonia and systemic hyperinflammation (MASH-Covid): an investigator initiated, multicentre, double-blind, randomised, placebo-controlled trial
5. Temesgen Z, Burger CD, Baker J, et al. LENZILUMAB EFFICACY AND SAFETY IN NEWLY HOSPITALIZED Covid-19 SUBJECTS: RESULTS FROM THE LIVE-AIR PHASE 3 RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL
6. Lescure FX, Honda H, Fowler RA, et al Sarilumab in patients admitted to hospital with severe or critical Covid-19: a randomised, double-blind, placebo-controlled, phase 3 trial
7. Soin AS, Kumar K, Choudhary NS, et al Tocilizumab plus standard care versus standard care in patients in India with moderate to severe Covid-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, contr
8. Rosas IO, Bräu N, Waters M, et al. Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia
9. Gordon AC, Mouncey PR, Al-Beidh F, et al Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.
10. Lundgren JD, Grund B, Barkauskas CE, et al A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19
11. Veiga VC, Prats J, Farias DLC, et al Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial
12. Hermine O, Mariette X, Tharaux PL, et al Effect of Tocilizumab vs Usual Care in Adults Hospitalized With Covid-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial.
13. Salvarani C, Dolci G, Massari M, et al. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With Covid-19 Pneumonia: A Randomized Clinical Trial.
14. Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19
15. Salama C, Han J, Yau L, et al Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia
16. Díaz Y, Ramos-Suzarte M, Martín Y, et al Use of a Humanized Anti-CD6 Monoclonal Antibody (Itolizumab) in Elderly Patients with Moderate Covid-19
17. Weinreich, D. M., Sivapalasingam, S., Norton, T., et al. REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19
18. O'Brien, M. P., Forleo-Neto, E., Musser, B. J., et al. Subcutaneous REGEN-COV Antibody Combination for Covid-19 Prevention