Drug	Status	Indication	Dosing
Dexamethasone	Recommended for use	Severe and critical COVID-19 patients requiring supplemental oxygen, but not recommended for non-severe COVID-19	6 mg orally or IV daily for 7-10 days
Hydrocortisone	Recommended for use	Severe and critical COVID-19 patients, but not recommended for non-severe COVID-19	50 mg IV every 8 hours for 7-10 days
Methylprednisolone	Available with supporting evidence	Severe and critical COVID-19 patients, but not recommended for non-severe COVID-19	2 mg/kg/day
Budesonide	Available with supporting evidence	Outpatients with COVID-19	Two inhalations twice daily, 400 mcg/actuation, until symptom resolution
Ciclesonide	Did not improve symptom resolution compared to placebo
Interferon-beta	Not recommended	Recommended against use in severe and critical COVID-19, unless participating in a clinical trial
Tocilizumab	Recommended with EUA	Hospitalized patient two years of age and older, require supplemental oxygen, mechanical ventilation, or ECMO	In combination with systemic corticosteroid 8 mg/kg (patients ≥30 kg) or 12 mg/kg (patients <30 kg) as a single dose (maximum: 800 mg/dose)
Sarilumab	Recommended for use	Severe and critical COVID-19	400 mg once, administered over 1 hour. Recommended four use as an alternative agent to tocilizumab when tocilizumab is unavailable
Siltuximab	Approved drug being evaluated
Aspirin	Available with supporting evidence	Hospitalized patients with COVID-19	81 mg daily
Baracitinib	Recommended with EUA	Hospitalized patients with COVID-19 aged 2 years and older that require supplemental oxygen, mechanical ventilation, or ECMO NIH: add to corticosteroid in hospitalized patients with progressive hypoxemia	4 mg daily for 14 days or until discharge, whichever is first
Bisindole	Investigational drug being evaluated	Hospitalized COVID-19 patients at high risk for developing ARDS
Canakinumab	Approved drug without supporting evidence
CM4620-IE	Investigational drug being evaluated	ARDS in patients with serious and critical COVID-19
Colchicine	Approved drug without supporting evidence	Should not be used in hospitalized patients, except as part of a trial
Emricasan	Investigational drug being evaluated	Mild symptomatic COVID-19
Fluvoxamine	Available drug being evaluated	Non-hospitalized patients with severe acute respiratory syndrome from COVID-19	100 mg three times daily for 15 days
Icosapent ethyl	Available drug without supporting evidence
Lenzilumab	Investigational drug being evaluated
Mavrilimuma	Investigational drug being evaluated	Non-ventilated patients with COVID-19 pneumonia and systemic hyperinflammation
PB1046	Investigational drug being evaluated	Hospitalized COVID-19 patients at risk for clinical deterioration and ARDS
PTC299	Investigational drug being evaluated	Cytokine storm
Remestemcel-L	Investigational drug being evaluated	ARDS due to COVID-19 infection
Tofacitinib	Available drug with supporting evidence	Hospitalized patients with COVID-19	10 mg twice daily for up to 14 days or until hospital discharge, whichever is earlier
Tradipitant	Investigational drug being evaluated
Clazakizumab	Investigational drug being evaluated	Severe and critical COVID-19

Drugs with mechanisms of action that reduce inflammation and cytokine storm in the lungs are being evaluated in patients with severe COVID-19 pneumonia. 
 
Corticosteroids
 
Three studies evaluating dexamethasone and hydrocortisone in the treatment of COVID-19 with acute respiratory failure were recently published in JAMA. All three studies (CAPE COVID, CoDEX, REMAP-CAP) are likely underpowered, because they were stopped early after results of the British RECOVERY trial (NCT04381936) demonstrated efficacy with dexamethasone in the treatment of hospitalized patients with COVID-19. The data from the three trials suggested a benefit with the use of corticosteroids in patients with COVID-19 and acute respiratory failure. To further examine the role of corticosteroids the World Health Organization (WHO) sponsored a meta-analysis of seven trials involving 1,700 critically ill COVID-19 patients. The analysis found the 28-day mortality rate lower with corticosteroids (32% vs. 40%) compared to not receiving corticosteroids. Based on the results of the trials and the meta-analysis, the WHO now recommends 6 mg of dexamethasone orally or intravenously daily or 50 mg of hydrocortisone intravenously every 8 hours for 7 to 10 days in severe and critical COVID-19 patients. The WHO also recommends that corticosteroids not be used in non-severe COVID-19 patients.
 
Dexamethasone

• The 15,000 patient RECOVERY trial (NCT04381936) has several arms testing lopinavir-ritonavir, dexamethasone, hydroxychloroquine, azithromycin, tocilizumab, convalescent plasma, immunoglobulin (IVIG) and a monoclonal antibody combination REGN-COV2. A final version of the preliminary report of the dexamethasone arm of the RECOVERY trial was published in the New England Journal of Medicine. The results included 2,104 patients that received dexamethasone (6 mg for 10 days) compared to 4,321 patients that received supportive care only. Overall 28-day mortality was 22.9% with dexamethasone compared to 25.7% with placebo. The mortality rate for patients on ventilators was 29.3% with dexamethasone compared to 41.4% with supportive care only. Dexamethasone also had a lower mortality rate in patients requiring oxygen, but not on a ventilator (23.3% vs. 26.2%) but did not reduce mortality in patients not receiving respiratory support at enrollment (17.8% vs. 14.0%).
• In a 28-day, 299 patient, Phase III, open-label, Brazilian CoDEX trial (NCT04327401), patients treated with dexamethasone had 2.6 fewer days requiring a ventilator compared to placebo in patients with COVID-19 and moderate to severe acute respiratory failure. Use of dexamethasone did not decrease mortality or ICU days. The CoDEX trial was stopped early, at the recommendation of the data and safety monitoring board (299 of the planned 350 patients), when the British RECOVERY trial (NCT04381936) demonstrated efficacy with dexamethasone. As part of standard of care, patients in CoDEX received hydroxychloroquine (24% in the dexamethasone group and 19% in the control group), azithromycin (69%, 74%), other antibiotics (88%, 86%) and oseltamivir (29%, 35%).
• Based on the RECOVERY trial, the National Institute of Health recommends use of dexamethasone 6 mg daily for up to ten days in COVID-19 patients the require supplemental oxygen with or without mechanical ventilation. NIH recommends against using dexamethasone in patients that do not require supplemental oxygen.
• The WHO recommends that dexamethasone only be used in patients with severe or critical disease.
• Researchers at Montefiore Medical Center retrospectively reviewed the medical records of 1,806 hospitalized COVID-19 patients and found that glucocorticoids administered within 48 hours of admission was not associated with a decrease in mortality or mechanical ventilation. However, patients with a CRP of 20 mg/dL or greater had a reduced risk of mortality and mechanical ventilation, while use in patients with a CRP < 10 mg/dL was associated with an increased risk of mortality or mechanical ventilation.
• In the 28-day, 982 patient, Phase III, COVID STEROID trial (NCT04509973), treatment with IV dexamethasone 12 mg did not increase days alive without life support compared to a 6 mg dose (22 vs 20.5 days) in  patients with COVID-19 and severe hypoxemia.
• In an 11-day, 200 patient, open-label, Phase III trial ( NCT04726098), 31.4% of patients treated with dexamethasone 6 mg once daily for 10 days had clinical worsening compared to 16.3% with dexamethasone 20 mg once daily for 5 days, followed by 10 mg once daily for additional 5 days in hospitalized Spanish patients with confirmed COVID-19 pneumonia requiring oxygen therapy.
• In a retrospective analysis or data for 1,164 patients, who had been hospitalized for COVID-19 and received less than 10 days of dexamethasone, continuation of dexamethasone after discharge did not reduce mortality or readmission compared to discontinuing dexamethasone at discharge.

Hydrocortisone

• In a 21-day, 148 patient, Phase III French, CAPE COVID trial (NCT02517489), treatment with hydrocortisone did not reduce mortality or the persistent need for ventilators/high flow oxygen compared to placebo (42.1% vs 50.7%) in critically ill patients with COVID-19 and acute respiratory failure. However, the trial was stopped early, due to the recommendation of the data and safety monitoring board (DSMB), so the trial was likely underpowered (149 patients of the planned 290). The DSMB recommended stopping the trial due to slowing in patient recruitment and the British RECOVERY trial (NCT04381936) demonstrating efficacy with dexamethasone. Patients in the trial were also treated with hydroxychloroquine (58% in the dexamethasone group and 64% in the control group), hydroxychloroquine plus azithromycin (30%, 38%), ritonavir plus lopinavir (13%, 15%), eculizimab (4%, 3%), remdesivir (3%, 4%) and toclizumab (1%, 3%).
• The 21-day, 379 patient, Phase IV, open-label, international, REMAP-CAP trial (NCT02735707), found a 93% probability that a fixed 7-day course of hydrocortisone and an 80% probability that a shock-dependent course would reduce ICU-based respiratory or cardiovascular support compared placebo in critically ill patients with COVID-19 requiring ICU-based respiratory or cardiovascular support. The trial was stopped early, due to the recommendation of the blinded international trial steering committee, so the trial was likely underpowered (379 patients of the British RECOVERY trial (NCT04381936) RECOVERY trial demonstrating efficacy with dexamethasone. Data on concomitant drugs were not included in the published description of REMAP-CAP.

Methylprednisolone

• In a 10-day, 86 patient, Iranian study, treatment with methylprednisolone 2 mg/kg/day improved the 9-point WHO ordinal scale (0 - uninfected to death 8) compared to dexamethasone 6 mg/day at five days (4.02 vs. 5.21) and 10 days (2.90 vs. 4.71) in hospitalized COVID-19 patients. Methylprednisolone also decreased the length of hospital stay (7.43 vs 10.52 days) and the need for mechanical ventilation (18.2% vs 38.1%). It should be noted the relative dose of methylprednisolone was higher than dexamethasone.

Budesonide

• Interim data from the 2,422 patients enrolled in the 28-day, Phase III, PRINCIPLE trial, found that inhaled budesonide added to usual care decreased time to recovery by 3-days compared to usual care alone in outpatients with COVID-19.
• In the 28-day, 146 patient, open-label, Phase III, STOIC trial (NCT04416399), 3% of patients treated with inhaled budesonide added to usual care required urgent care or hospitalization compared to 15% with usual care alone in outpatients with COVID-19. Clinical recovery was also one-day less with budesonide.

Ciclesonide

• In the seven-day, 203 patient, Phase II, CONTAIN trial (NCT04435795), treatment with inhaled and intranasal ciclesonide did not improve symptom resolution compared to placebo in low-risk, Canadian outpatients with COVID-19.

Interferon-beta

• NIH currently recommends against the use of interferons for the treatment of severe and critical COVID-19, unless the patient is participating in a clinical trial. NIH does not recommend for or against the use of interferon in the treatment of mild and moderate COVID-19.
• Subcutaneous interferon-beta-1a
  • Interim results from the WHO sponsored, 11,330 patient, Phase II/III SOLIDARITY trial (NCT04315948), did not find an improvement in hospitalized COVID-19 patients treated with remdesivir, hydroxychloroquine, lopinavir or subcutaneous interferon compared to no drug in mortality, initiation of ventilation or duration of hospital stay. But some analysts did not agree with the study’s findings. A physician reviewer speculated that remdesivir may be more effective when given early in the infection to patients at high risk for progression. An editorialist highlighted the benefit of remdesivir“to change the course of hospitalization in some patients”. A second editorialist pointed out that SOLIDARITY was not designed to measure time to recovery or clinical improvement
  • In a 28-day, 81 patient, Israeli trial, adding subcutaneous interferon beta 1a to hydroxychloroquine plus lopinavir/ritonavir or atazanavir/ritonavir did not decrease the time to clinical response, but did increase discharge rate on day 14 and decreased 28-day mortality, compared to not adding interferon in patients with severe COVID-19.
  • In an 89 patient trial in Oman, favipiravir and nebulized interferon beta-1b did not improve time to recovery, decrease in inflammatory markers nor improvement in oxygenations compared to hydroxychloroquine in hospitalized patients with moderate to severe COVID-19 pneumonia. Almost all patients also received antibiotics, one-third received tocilizumab, two-thirds received a corticosteroid and over half received convalescent plasma.
  • In the 28-day, 969 patient, Phase III, ACTT-3 trial (NCT04492475), adding subcutaneous interferon beta-1a to intravenous remdesivir did not decrease time to recovery or mortality compared to remdesivir alone in hospitalized patients with COVID-19.
• SNG001 is a nebulizer formulation of interferon-beta-1a. 
  • SNG001 is being evaluated as a potential treatment for COVID-19 because of data from two trials showing an improvement in lung function in patients with asthma and a respiratory viral infection.
  • In a 28-day, 101 patient, Phase II trial (NCT04385095), patients treated with nebulized interferon beta-1a were twice as likely to have improved their WHO Ordinal Scale for Clinical Improvement by day 15-16 and three times as likely by day 28 in hospitalized British patients with COVID-19.
• Synairgen announced that in a 28-day, 120 patient, Phase II trial (NCT04385095), only two patients in the placebo group advanced to hospitalization compared to none in the nebulized interferon beta-1a group in high risk, British outpatients with COVID-19. Due to the low incidence of hospitalizations, prevention of progression to severe COVID-19 could not be calculated. An analysis of a small group of patients with severe breathlessness suggested that use of nebulized interferon beta-1a may help patients recover more quickly. When combining all patients who were markedly or severely breathless in both the home treatment cohort and hospital treatment cohort, treatment with nebulized interferon beta-1 increased the likelihood of recovery.
• Synairgen announced that in the 623 patient, 28-day, Phase III SPRINTER trial (NCT04732949), treatment with SNG001 did not decrease time to hospital discharge compared to placebo in hospitalized patients with COVID-19.
• Synairgen announced that NIAID had discontinued the Phase II/III ACTIV-2 COVID-19 trial (NCT04518410) in March 2022, due to changes in the pandemic that necessitate a change in how COVID-19 therapies are evaluated. ACTIV-2 was evaluating SNG001 and several other drugs in the treatment of COVID-19.

Interferon-lambda

• Eiger BioPharmaceuticals announced that in the 28-day, 4,669 patient, Phase III TOGETHER trial (NCT04727424), 2.7% of patients treated with peginterferon lambda were hospitalized or had an ER visit compared to 5.6% with placebo in non-hospitalized adult Brazilian patients with COVID-19, who were at high risk of progressing to severe illness.IL-6 Inhibitors

IL-6 inhibitors
A meta-analysis, by the World Health Organization, of 27 trials involving 10,930 patients, evaluated IL-6 inhibitors in the treatment of COVID-19.  At 28-days the mortality risk in tocilizumab or sarilumab patients was 22% compared to 25% with usual care or placebo. The mortality benefit was maintained in patients receiving corticosteroids (21% vs 25%). The data supporting tocilizumab was more robust than sarilumab due to the larger patient population and the trials being conducted later in the pandemic, when use of corticosteroids became more common. There was not enough data (one trial) to estimate the effect of using siltuximab. Based on the data, the WHO now recommends that either tocilizumab or sarilumab be added to corticosteroids for the treatment of severe or critical COVID-19 infections.

NIH recommends that baricitinib or tocilizumab be added to a corticosteroid in the treatment of hospitalized patients who are receiving conventional oxygen therapy who may have progressive hypoxemia associated with significant systemic inflammation.

IDSA has updated their COVID-19 guidelines with a conditional recommendation to add tocilizumab to a corticosteroid in patients with severe or critical COVID-19 with elevated systemic inflammation.

Tocilizumab (Actemra, Roche) is an interleukin 6 (IL-6) monoclonal antibody.

• The FDA granted an EUA for tocilizumab (Actemra, Roche) to treat hospitalized adults and pediatric patients two years of age or older, with COVID-19 and who are receiving a systemic corticosteroid and require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).
• Chinese researchers announced that in a 21 patient, open-label trial, patients treated with tocilizumab had a reduction in fever and 15/20 patients had a reduction in their need for supplemental oxygen in hospitalized patients with a COVID-19 infection. 
• Italian researchers announced that in a 123 patient trial, treatment with tocilizumab did not reduce admission to intensive care (28.3% vs. 27.0%) or 30-day mortality (3.3% vs. 3.2%) compared to placebo in patients with early-stage COVID-19 pneumonia.
• In a 544 patient, retrospective Italian study, treatment with tocilizumab reduced the risk of mechanical ventilation or death, but had a higher incidence of new infections compared to standard of care alone after the patient sample was adjusted for sex, age, recruiting center, duration of symptoms, and Sequential Organ Failure Assessment (SOFA) score. Standard of care in Italy at the time of the study (February 21 to April 30, 2020) included treatment with oxygen, hydroxychloroquine, azithromycin, lopinavir–ritonavir or darunavir–cobicistat, and low molecular weight heparin.
• In an observational trial, University of Michigan researchers examined outcomes in 154 mechanically ventilated patients with severe COVID-19 that received tocilizumab to those not receiving tocilizumab. Around a quarter of patients in each group received hydroxychloroquine and/or a corticosteroid and 3% received remdesivir. Patients that received tocilizumab were younger (55 vs. 60), less likely to have chronic pulmonary disease (10% vs. 28%), and lower D-dimer values (2.4 vs. 6.5 mg/dL). During a 47-day follow-up, tocilizumab patients had a higher rate of superinfections (54% vs. 26%), but a lower 28-day mortality rate (18% vs. 36%).
• In the 28-day, 452 patient, Phase III COVACTA trial (NCT04320615), treatment with tocilizumab improved the clinical status (7 point scale ranging from discharge or death) by a non-significant 1 point compared to placebo in hospitalized patients with severe COVID-19-associated pneumonia. There was no difference in mortality between tocilizumab and placebo, but patients treated with tocilizumab were discharged six days sooner, spent 5.8 less days in ICU and needed a ventilator for 5.5 fewer days.
• In the 28-day, 389 patient, Phase III EMPACTA trial (NCT04372186), 12% of patients treated with tocilizumab progressed to mechanical ventilation or death compared to 19.3% of patients treated with placebo in hospitalized patients with COVID-19 who did not require noninvasive or invasive mechanical ventilation. Almost 85% of patients were non-white with the majority being Hispanic, with inclusion of Native American and Black populations.
• In a 126 patient, Phase II, Italian trial (NCT04346355), treatment with tocilizumab did not reduce intensive care admission with invasive mechanical ventilation, death from all causes, or clinical aggravation compared to placebo in patients with early-stage COVID-19 pneumonia.
• In a 131 patient, Phase II, French trial (NCT04331808), treatment with tocilizumab did not improve clinical progression at day 4, but did reduce death or the need for high-flow oxygen or ventilation at day 14 (24% vs. 36%) compared to placebo in patients with moderate-to-severe COVID-19 pneumonia.
• A 3,924 patient retrospective U.S. analysis found a lower risk for death in 433 patients that received tocilizumab compared with those not treated with tocilizumab in critically ill COVID-19 patients.
• In a 243 patient, Phase III, U.S. trial (NCT04356937), treatment with tocilizumab did not reduce intubation or death compared to placebo in patients with severe COVID-19.
• In the 15-day, 129 patient, Phase III, TOCIBRAS trial (NCT04403685), treatment with tocilizumab did not reduce a composite of death or mechanical ventilation (28% vs 20%) compared to placebo in patients with COVID-19 who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers (C reactive protein, D dimer, lactate dehydrogenase, or ferritin). At 15-days, mortality was higher with tocilizumab compared to placebo (17% vs 3%), but the difference was no longer significant at day 29.
• In the 21-day, 803 patient, Phase IV, REMAP-COVID trial (NCT02735707), the number of organ support-free days were 10 for tocilizumab, 11 for sarilumab and none for standard of care in patients with critical COVID-19 receiving organ support in intensive care. In-hospital mortality was 27% with the pooled interleukin-6 receptor antagonist groups (tocilizumab and sarilumab), compared to 36% with standard of care. A third of patients received remdesivir and 80% received a corticosteroid. REMAP-COVID is a sub-study of the REMAP-CAP trial.
• In the 28-day, 4,116 patient, Phase III, DISCOVERY trial (NCT04381936), adding tocilizumab to usual care resulted in 31% mortality compared to 35% with usual care alone in hospitalized adults with COVID-19 with oxygen saturation < 92% or requiring oxygen therapy and C-reactive protein of 75 mg/L or >. Corticosteroids were used in 82% of the study population.
• Roche announced that in the 28-day, 450 patient, Phase III REMDACTA trial (NCT04409262), adding tocilizumab to remdesivir did not decrease time to hospital discharge compared to remdesivir alone in patient with severe COVID-19. The addition of tocilizumab also did not improve clinical status, decrease mortality, or decrease the need for mechanical ventilation.

Sarilumab (Kevzara, Regeneron, Sanofi) is an interleukin 6 (IL-6) monoclonal antibody. 

• Sanofi and Regeneron discontinued a Phase III trial, when an interim analysis of 194 patients revealed that treatment with sarilumab did not improve the percentage of patients who achieved at least a 1-point change from baseline on a 7-point scale (death to hospital discharge) compared to placebo in COVID-19 patients requiring mechanical ventilation.
• In a 28-day, 56-patient, observational study, 28 patients that received sarilumab were compared to 28 that did not receive the drug. Treatment with sarilumab did not improve clinical status or mortality in patients with severe COVID-19 pneumonia and systemic hyperinflammation. The study suggested that sarilumab may speed recovery in patients with minor lung consolidation at baseline. This study used a subset of patients from the Italian, 1,000 patient, COVID-BioB observational study (NCT04318366).
• Sanofi announced that in a non-U.S., 420 patient, Phase III trial (NCT04327388), treatment with sarilumab did not improve symptoms compared to placebo in hospitalized patients with severe or critical COVID-19. 
• BARDA ceased funding IL-6 inhibitor trials evaluating tocilizumab and sarilumab as treatments for severe COVID-19 in August 2020. Tocilizumab and sarilumab have each failed to demonstrate improvements in clinical trials.
• Sanofi and Regeneron ceased evaluation of sarilumab in the treatment of COVID-19 in September 2020.
• In the 21-day, 803 patient, Phase IV, REMAP-COVID trial (NCT02735707), the number of organ support-free days were 10 for tocilizumab, 11 for sarilumab and none for standard of care in patients with critical COVID-19 receiving organ support in intensive care. In-hospital mortality was 27% with the pooled interleukin-6 receptor antagonist groups (tocilizumab and sarilumab), compared to 36% with standard of care. A third of patients received remdesivir and 80% received a corticosteroid. REMAP-COVID is a sub-study of the REMAP-CAP trial.

Siltuximab (Sylvant, EUSA Pharma) is an interleukin 6 (IL-6) monoclonal antibody. The drug is being evaluated in the Italian SISCO trial sponsored by EUSA. 

• Siltuximab has limited efficacy data in patients with COVID-19.

Clazakizumab, an interleukin-6 (IL-6) inhibitor being evaluated by CSL Behring as a treatment for hospitalized patients with severe or critical COVID-19 disease accompanied by hyperinflammation.

• In a 28-day, 152 patient, Phase II trial (NCT04343989), treatment with clazakizumab increased the odds of ventilator-free survival and overall survival compared to placebo in patients with severe COVID-19 disease and hyperinflammation.

Aspirin: In a retrospective review of data from 412 hospitalized patients with COVID-19, 36% of patients receiving aspirin progressed to mechanical ventilation compared to 48% that did not receive aspirin. A multivariable adjustment found a 44% reduced risk for mechanical ventilation with aspirin without an increased risk for major bleeding.

Baricitinib (Olumiant, Lilly), a JAK1 and JAK2 inhibitor. It is theorized that JAK inhibition may reduce cytokine storm associated with COVID-19 infection and decrease viral reproduction. 

• Lilly is evaluating the effect of baricitinib on mortality or the need for ventilation/high flow oxygen in the 28-day, 400 patient, Phase III, COV-BARRIER trial (NCT04421027).
• In the NIAID sponsored 29-day, 1,033 patient, Phase III, ACTT 2 trial (NCT04401579), baricitinib added to remdesivir reduced the time to recovery by one day (7 vs 8 days) compared to remdesivir alone in hospitalized patients with moderate to severe COVID-19. The largest effect was seen in patients receiving high-flow oxygen or non-invasive ventilation (10 vs 18 days).
• In the 1,525 patient, Phase III, COV-BARRIER trial (NCT04421027), adding baricitinib to standard of care did not decrease the proportion of patients who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28. However, treatment with baricitinib did decrease mortality at 28-days (8% vs 13%) and 60-days (10% vs 15%).
• The FDA granted an EUA for the combination of baricitinib (Olumiant. Lilly) plus remdesivir (Veklury, Gilead) to treat hospitalized adults and pediatric patients two years of age or older, with COVID-19 and who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). The FDA expanded the emergency use authorization for baricitinib to allow the drug to be used alone for the treatment of patients aged 2 years and older who are hospitalized with COVID-19 and require supplemental oxygen, mechanical ventilation or extracorporeal membrane oxygenation. Previously, baricitinib had to be administered with remdesivir when treating COVID-19.
• NIH discontinued enrollment in the 29-day, Phase III, ACTT-4 trial (NCT04640168) after 1,000 patients when an interim analysis found it was unlikely that baricitinib plus remdesivir would reduce the need for mechanical ventilation or death compared to dexamethasone plus remdesivir in hospitalized COVID-19 patients on supplemental oxygen.
• NIH recommends that baricitinib or tocilizumab be added to a corticosteroid in the treatment of hospitalized patients who are receiving conventional oxygen therapy who may have progressive hypoxemia associated with significant systemic inflammation.​
• In the 101 patient, Phase III, COV-BARRIER trial (NCT04421027), adding baricitinib to standard of care,  including corticosteroids, reduced mortality at 28 days (39% vs 58%) and at 60 days (45% vs 62%) compared to placebo in critically ill hospitalized adults with COVID-19 requiring invasive mechanical ventilation or extracorporeal membrane oxygenation.
• In the 29-day, 1,047 patient, Phase III, ACTT 4 trial (NCT04640168), mechanical ventilation-free survival was similar between baricitinib plus remdesivir and dexamethasone plus remdesivir (87% vs 87.6%) in hospitalized patients with COVID-19. There were more treatment related adverse events and severe or life-threatening adverse events with dexamethasone plus remdesivir.
  

Bisindole (VERU-111) binds to and crosslinks the alpha and beta tubulin subunits of microtubules and intermediate filaments of cells resulting in disruption of the cytoskeleton. Veru is developing bisindole for the treatment of castration resistant prostate cancer and triple negative breast cancer. Veru is evaluating bisindole as a treatment for COVID-19 because of antiviral and anti-inflammatory effects.

• Due to its direct effects on S protein-microtubule trafficking, bisindole may decrease viron production and virus replication. Bisindole is also an anti-inflammatory agent and may reduce virally induced severe inflammation and cytokine storm. 
• Veru announced that in a 38 patient, Phase II trial (NCT04388826), a 21-day treatment with bisindole resulted in 94.4% of patients being alive without respiratory failure at Day 29 compared to 70% with placebo in hospitalized COVID-19 patients at high risk for developing Acute Respiratory Distress Syndrome (ARDS).

Canakinumab (Ilaris,Novartis) is an interleukin-1 beta monoclonal antibody approved as a treatment for  auto-inflammatory periodic fever syndromes. systemic juvenile idiopathic arthritis and Still's disease. 

• Novartis announced interim data from the 29-day, 454 patient, CAN-COVID trial (NCT04362813), where treatment with canakinumab did not decrease mortality without the need for invasive mechanical ventilation, compared with placebo in hospitalized patients with COVID-19 pneumonia and cytokine release syndrome.

CM4620-IE is a CRAC channel inhibitor that may prevent cytokine storm in severe COVID-19 pneumonia is being developed by CalciMedica and evaluated in a Phase II trial.

• MediciNova is evaluating ibudilast as a treatment for acute respiratory distress syndrome (ARDS) in patients with serious and critical COVID-19 infection.

Colchicine: The 15,000 patient RECOVERY trial (NCT04381936) has several arms testing lopinavir-ritonavir, dexamethasone, hydroxychloroquine, azithromycin, tocilizumab, convalescent plasma, immunoglobulin (IVIG), the monoclonal antibody combination REGN-COV2, aspirin, baricitinib, and colchicine. British researchers discontinued enrollment in the colchicine arm of the trial, when the independent Data Monitoring Committee did not find a reduction in 28-day mortality (20% colchicine vs 19% usual care alone).

• NIH has determined there is not enough evidence to recommend for or against the use of colchicine to treat COVID-19 in non-hospitalized patients and colchicine should not be used in hospitalized patients, except as part of a trial.
• In the 30-day, 4,488 patient, Phase III, COLCORONA trial (NCT04322682), treatment with colchicine did not reduce hospitalizations or mortality compared to placebo in outpatients with COVID-19 diagnosed by PCR testing or clinical criteria, who were at least 40 years old and had at least one risk factor for more severe disease. Among the 4,159 patients with PCR confirmed infection there was a small benefit with colchicine with 4.6% of patients requiring hospitalization or dying compared to 6% with placebo.

Emricasan is a pan-caspase inhibitor being developed by Histogen for the treatment of nonalcoholic steatohepatitis. Because of emricasan ability to reduce inflammation, Histogen is evaluating the drug for the treatment of COVID-19. 

• Histogen announced that in a 45-day, 13 patient, Phase I trial (NCT04803227), treatment with emricasan resulted in complete resolution of symptoms by day seven compared to no resolution in the placebo arm in patients with mild symptomatic COVID-19.

Fluvoxamine, a selective serotonin reuptake inhibitor and sigma-1 receptor (S1R) agonist, approved for the treatment of obsessive-compulsive disorder, is being evaluated for the treatment of COVID-19. Inhibiting S1R decreases cytokine production through its interaction with the endoplasmic reticulum stress sensor inositol-requiring enzyme 1alpha (IRE1). The decrease in cytokines reduces the inflammatory response, which diminishes progression of COVID-19.

• NIH has determined there is not enough evidence to recommend for or against the use of fluvoxamine to treat COVID-19.​ Based on the review of available scientific evidence the FDA declined to approve an emergency use authorization (EUA) for fluvoxamine for the treatment of COVID-19 because the data was insufficient to support use of the drug in the treatment for COVID-19.
• In a 15-day, 152 patient, Phase II trial (NCT04342663), no patient treated with fluvoxamine experienced clinical deterioration (shortness of breath or oxygen saturation of 92% or less) compared to 8.7% with placebo in nonhospitalized patients with severe acute respiratory syndrome from COVID-19. Patients were mostly white and over half were female with a median age of 45 to 46.
• In a 14-day, 113 patient, non-randomized, Phase III trial (NCT04668950), no patient treated with fluvoxamine required hospitalization compared to 12.5% of observation patients with COVID-19. At day 14, no fluvoxamine patient continued to have symptoms compared to 60% of observation patients. The patient population was mostly male Latinos with a median age of 42 recruited from an occupational setting with congregate living at a horse racing track in California. Fewer patients that chose to receive fluvoxamine were asymptomatic (38% vs 58%) at the beginning of the study.​
• In the 28-day, 1,497 patient, Brazilian Phase III, TOGETHER trial (NCT04727424), 11% of patients treated with fluvoxamine required prolonged emergency treatment or were admitted to a hospital for worsening COVID-19 compared to 16% with placebo in outpatients with COVID-19 at high risk to progress to severe disease.

Icosapent ethyl: In the 28-day, 2,052 patient, Phase III, PREPARE-IT 2 trial (NCT04460651), treatment with icosapent ethyl did not reduce hospitalization or death compared to placebo (13.69% vs 11.16%) in nonhospitalized Argentinian COVID-19 patients.

Lenzilumab is a GM-CSF inhibitor being developed to suppress the cytokine storm seen in graft-versus-host disease and with CAR-T cancer therapies. Because of lenzilumab effect on decreasing cytokine storm, Humanigen is evaluating the drug as a treatment for severe COVID-19 pneumonia. 

• NIH has not found the evidence for use of GM-CSF inhibitors strong enough to recommend either for or against their use for the treatment of hospitalized patients with COVID-19.
• An unpublished, unedited article described 12 patients with severe COVID-19 pneumonia treated under an FDA emergency IND with lenzilumab. Treatment with lenzilumab resulted in at least a 2-point improvement in an 8-point scale (death to discharged) in 11/12 of patients. 
• NIAID is comparing lenzilumab plus remdesivir to remdesivir monotherapy on the need for mechanical ventilation in hospitalized patients with COVID-19, in the 28-day, 200 patient, BIG EFFECT trial (NCT04583969).
• In the 28-day, 479 patient, Phase III, LIVE-AIR trial (NCT04351152), 84% of patients treated with lenzilumab were alive and did not require invasive mechanical ventilation compared to 78% with placebo in hospitalized patients with COVID-19, not requiring ventilation. 94% of patients received a corticosteroid, 72% received remdesivir and 69% received both.
• The FDA declined Humanigen’s request for an emergency use authorization for lenzilumab to treat newly hospitalized COVID-19 patients due to inadequate safety and efficacy data.

Mavrilimumab is a GM-CSF inhibitor and is being developed by MedImmune as a treatment for rheumatoid arthritis. By inhibiting GM-CSF, mavrilimumab is thought to prevent the activation or amplification of several pro-inflammatory cytokine pathways leading to a reduction in inflammation caused by cytokine storm in severe COVID-19 pneumonia.

• NIH has not found the evidence for use of GM-CSF inhibitors strong enough to recommend either for or against their use for the treatment of hospitalized patients with COVID-19.
• In a 28-day, 39 patient trial, all patients treated with mavrilimumab (n=13) plus hydroxychloroquine, azithromycin and lopinavir–ritonavir improved by two or more points (7-point scale of death to discharge) compared to 65% treated with hydroxychloroquine, azithromycin and lopinavir–ritonavir without mavrilimumab (n=26) in non-ventilated patients COVID-19 pneumonia and systemic hyperinflammation.
• Kiniksa Pharmaceuticals is evaluating mavrilimumab in the treatment of severe COVID-19 pneumonia and systemic hyperinflammation in a 15-day, 573 patient, Phase II/III trial (NCT04447469).​
• In a 14-day, 39 patient, Phase II trial (NCT04399980, NCT04463004, and NCT04492514), treatment with mavrilimumab (n=21) did not decrease morbidity or the need for supplemental oxygen compared to placebo (n=19) in non-ventilated hospitalized COVID-19 patients with hypoxemia, and a C-reactive protein concentration of 5 mg/dL or greater.
• Kiniksa Pharmaceuticals announced that in a 29-day, 582 patient, Phase II/III trial (NCT0444746), treatment with mavrilimumab did not decrease the percentage of patients that required mechanical ventilation or died compared to placebo in patients with severe COVID-19 pneumonia and systemic hyperinflammation.

PhaseBio is evaluating PB1046 as a treatment for hospitalized COVID-19 patients at risk for clinical deterioration and acute respiratory distress syndrome (ARDS) in the 210 patient, Phase II, VANGARD trial. The trial is expected to begin at the end of June with results from the trial expected by the end of 2020. PB1046 is an investigational vasoactive intestinal peptide (VPAC2) receptor-selective agonist being developed by PhaseBio as a treatment of pulmonary arterial hypertension.

PTC299, a dihydroorotate dehydrogenase (DHODH) inhibitor that is being developed by PTC Therapeutics as a treatment for acute myeloid leukemia. PTC299 has been shown in vitro to inhibit replication of the SARS-CoV-2 virus and modulate the immune response by attenuating the stress-induced inflammatory cytokine storm.

• The effect of PTC299 on respiratory symptoms is being evaluated in a 40 patient Phase II trial, followed by a 340 patient Phase III trial.

Remestemcel-L is a Mesenchymal Precursor Cell (Stem cell therapy) being developed by Mesoblast for the treatment of Acute Graft Versus Host Disease following allogeneic bone marrow transplantation. Remestemcel-L decreases pro-inflammatory cytokines, increases anti-inflammatory cytokines, and increases recruitment of naturally occurring anti- inflammatory cells to involved tissues. Due to these properties, Mesoblast is evaluating remestemcel-L to reduce cytokine storm in acute respiratory distress syndrome (ARDS) due to COVID-19 infection. 

• The FDA granted remestemcel-L, a Fast Track designation for the treatment of acute respiratory distress syndrome (ARDS) due to COVID-19 infection.
• Mesoblast announced that in a 60-day, 222 patient, Phase III trial (NCT04371393), treatment with remestemcel-L added to standard of care (SOC) did not reduce all-cause mortality compared to SOC in ventilator-dependent patients with moderate to severe acute respiratory distress syndrome (ARDS) due to COVID-19. In a pre-specified analysis of 123 patients under age 65, remestemcel-L reduced mortality by 46% by day 60, but not in 94 patients 65 or older. The Data Safety Monitoring Board (DSMB) recommended the trial be stopped when an interim analysis of 30-day data for 180 patients found it unlikely the trial would achieve a 43% reduction in mortality at the target enrollment of 300 patients. The DSMB recommended the trial be completed with the 222 patients already enrolled.
• The FDA has requested an additional study to evaluate treatment with remestemcel-L in ventilator-dependent patients with moderate to severe acute respiratory distress syndrome (ARDS) due to COVID-19 in order to be considered for an EUA, if the study demonstrates a benefit with remestemcel-L treatment.

Tofacitinib (Xeljanz, Pfizer) is a JAK1 and JAK3 inhibitor with partial JAK2 inhibition. It is theorized that JAK inhibition may reduce cytokine storm associated with COVID-19 infection and decrease viral reproduction. 

• In the 28-day, 289 patient, Phase III, STOP-COVID trial (NCT04469114), 18.1% of patients treated with tofacitinib plus standard of care required ventilation or died compared to 29% with standard of care alone in hospitalized Brazilian patients with COVID-19. Mortality was 2.8% with tofacitinib and 5.5% with placebo.

Tradipitant is a neurokinin-1 receptor (NK-1R) antagonist being developed by Vanda Pharmaceuticals for the treatment of diabetic gastroparesis, motion sickness, and atopic dermatitis. By inhibiting NK-1R, tradipitant is thought to decrease inflammatory lung injury associated with severe or critical COVID-19 pneumonia.

• Vanda Pharmaceuticals reported that interim results from 60 COVID-19 patients enrolled in the 28-day, 300 patient, Phase III, ODYSSEY trial (NCT04326426), where a 14-day treatment with tradipitant reduced the time to improvement after 7-days compared to placebo. Despite a numerical advantage, the improvement was not significant at 28 days (10 days vs 28 days), likely due to the small number of patients. There was also no statistical difference between tradipitant and placebo in the overall percentage of patients improving (57% vs 50%) or mortality (14.2% vs 16.6%).​