COVID-19 Treatment Research Brief

12/03/21 The section on Disulfiram was added to reflect new findings on the effect of disulfiram on COVID-19 severity (see Disulfiram)

11/17/21 The section on Dexamethasone was updated to reflect new findings on the benefits and harms of dexamethasone use (see Dexamethasone)

11/16/21 The section on Anticoagulants was updated to reflect new findings on the benefits of heparin (see Anticoagulants)

11/10/21 The section on Azithromycin was added to reflect new findings on the efficacy of azithromycin for reducing the need for hospitalization (see Azithromycin)

11/08/21 The section on Fluvoxamine was updated to reflect new findings on early treatment with fluvoxamine (see Fluvoxamine). The section on Molnupiravir was updated to reflect the most recent approval by the the United Kingdom's Medicines and Healthcare products Regulatory Agency (see Molnupiravir). The section on Sotrovimab was added to reflect new findings on the use of sotrovimab for preventing disease progression (see Sotrovimab). The section on Convalescent Plasma was updated to reflect new findings on the use of covalescent plasma for preventing disease progression in certain populations (see Convalescent Plasma)

10/26/21 The section on Ivermectin was updated to reflect the most recent treatment guidelines released by the NIH (see Ivermectin)

10/22/21 The section on Interferons was updated to reflect the most recent treatment guidelines released by the NIH (see Interferons) 

6/09/21 The section on Baricitinib was updated to reflect the most recent treatment guidelines released by the NIH (see Baricitinib)

4/23/21 The sections Colchicine, Outpatient Management, and Fluvoxamine were added to reflect updated treatment guidelines released by the NIH (see Colchicine, Outpatient Management, and Fluvoxamine)

4/20/21 The section on Bamlanivimab was updated to reflect the most recent treatment guidelines released by the FDA (see Bamlanivimab)

The global research and scientific responses to the SARS-CoV-2 virus identified at the beginning of 2020 have been active. They range from preclinical efforts to emergency authorizations, with no clear homeruns at this stage. Researchers are sifting through previous studies to repurpose compounds that may show efficacy in treating issues such as respiratory problems and cytokine storms, so as to shorten the disease course and lower mortality rates. As the medical and scientific communities better understand how the virus affects the body, they can better target treatments. We present some of the most promising and advanced efforts to date to combat SARS-CoV-2 virus.

Navigate this resource by topic:

I. TABLES OF TREATMENTS
     a. Table 1. FDA or NIH Recommended Treatments
     b. Table 2. NIH Treatment Guidelines
     c. Table 3. Experimental Treatments
     d. Table 4. Treatments Determined Ineffective or Not Promising

II. CURRENT TREATMENTS FOR COVID-19
     a. Corticosteroids
           1. Dexamethasone
     b. Remdesivir
     c. REGN-COV2
     d. Bamlanivimab
     e. Baricitinib
     f. Convalescent Plasma
     g. Aviptadil

III. EXPERIMENTAL COVID-19 TREATMENTS
     a. Favipiravir
     b. Vilobelimab
     c. Plitidepsin
     d. Camostat Mesylate
     e. Ruxolitinib
     f. Sarilumab
     g. Tocilizumab
     h. Recombinant Human ACE-2
     i. Molnupiravir
     j. Interferons
     k. Nanobodies
     l. PF-07321332
     m. Fluvoxamine

     n. Sotrovimab

     o. Azithromycin

     p. Disulfiram

IV. PREVIOUSLY INVESTIGATED TREATMENTS DETERMINED INEFFECTIVE OR NOT PROMISING
     a. Hydroxychloroquine and Chloroquine
     b. Ivermectin
     c. Lopinavir/Ritonavir and Other HIV-Protease Inhibitors
     d. Mesenchymal Stem Cells
     e. Immunoglobulins
     f. Colchicine

V. ADJUNCTIVE THERAPY
     a. Anticoagulants
     b. Vitamins and Zinc

VI. PREVENTION AND PROPHYLAXIS

VII. OUTPATIENT TREATMENT

VIII. REFERENCES

TABLES OF TREATMENTS
 

Table 1. US Food and Drug Administration (FDA) or National Institutes of Health (NIH) Recommended COVID-19 Treatments

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Table 2. NIH Treatment Guidelines for COVID-19

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Table 3. Experimental COVID-19 Treatments

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Table 4. Treatments That Are Not Promising or Are Determined Ineffective

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CURRENT TREATMENTS FOR COVID-19

Corticosteroids

Corticosteroids suppress inflammation, and COVID-19 is a disease that affects the respiratory system and can cause severe inflammation. A meta-analysis of studies on corticosteroid use in patients with acute respiratory distress syndrome (ARDS) showed that usage reduced the risk of all-cause mortality and reduced mechanical ventilation duration.¹ Several corticosteroids are in clinical trials alone or in combination with other drugs for COVID-19 treatment.

Dexamethasone

Dexamethasone was the first to show effectiveness in reducing mortality in severely ill patients with COVID-19. The multicenter, open-label RECOVERY trial in hospitalized patients in the United Kingdom with COVID-19 enrolled 2104 patients to receive dexamethasone and 4321 to receive standard care.² Researchers found that the medication lowered mortality by one-third for patients on ventilators and by one-fifth for patients on oxygen. Researchers did not find a benefit of giving dexamethasone to patients needing no respiratory support. Patients in the dexamethasone arm also experienced a shorter hospitalization duration compared with the usual-care group. The findings suggest that corticosteroids may modulate inflammation-mediated lung injury, reducing a patient’s progression to respiratory failure and death. The NIH recommends prescribing dexamethasone to hospitalized patients under these conditions and recommends against prescribing it to patients who are not receiving supplemental oxygen.³ Alternative corticosteroids such as prednisone, methylprednisolone, or hydrocortisone could be given if dexamethasone is unavailable.³ More studies are underway internationally.

Dexamethasone reduced the risk of death and ICU admission in individuals hospitalized with COVID-19 by 56%, according to the results of a recent study. The results indicated that male gender, hypertension, increased frailty, and lower estimated glomerular filtration rates were independently associated with mortality and ICU admission. Further, dexamethasone use was associated with an increased risk of glycaemic complications such as steroid-induced dysglycaemia. However, glycaemic complications did not increase mortality or ICU admissions.¹²³

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Remdesivir

On October 22, 2020, the FDA granted approval to remdesivir for the treatment of hospitalized patients with COVID-19.⁴ This approval makes remdesivir the first medication indicated for the treatment of COVID-19.

The medication that arguably has made the biggest splash is remdesivir (veklury), an intravenous treatment previously developed as a broad-spectrum antiviral. It was tested previously during the outbreaks of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), ebola, and other infectious diseases.⁵ A phase 3 open-label randomized trial compared remdesivir with standard care, with 312 patients receiving the treatment and 818 patients receiving stand of care.⁶ The remdesivir arm was associated with a significantly greater recovery and a 62% reduced risk of mortality compared with standard of care at day 14.⁶ The ACTT-1 trial, which was conducted from mid-February 2020 to mid-April 2020, enrolled 1062 hospitalized patients with varying levels of illness severity.⁷ The trial was conducted at 60 sites in multiple countries, with most sites in the United States. Eligible patients were randomly assigned in equal numbers to remdesivir or placebo for up to 10 days. The median time to recovery (hospital discharge, not needing supplemental oxygen, or not needing ongoing medical care) was 10 days for the remdesivir group and 15 days for the standard-care group. Patients receiving remdesivir had experienced improvement in mortality, but it was not statistically significant.⁷ In the ACTT-1 trial, researchers observed no benefit of remdesivir in patients with mild to moderate COVID-19 (SpO₂ >94% on room air or respiratory rate <24 breaths/min without supplemental oxygen).⁷ Due to these results, the NIH COVID-19 panel does not have enough data to recommend for or against the use of remdesivir for nonhospitalized or hospitalized patients not requiring oxygen therapy for the treatment of COVID-19.  

In May 2020, remdesivir was the first COVID-19 treatment to receive EUA from the FDA. As of late August 2020, the FDA’s authorized use covered all hospitalized patients receiving COVID-19 treatment, regardless of disease severity.⁸ The medication, while helpful, is not felt to be independently sufficient in treating patients with COVID-19. Researchers recommended trials combining it with other antiviral medications or other treatments.⁷

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REGN-COV2 (casirivimab and imdevimab)

The FDA issued an EUA on November 21, 2020, for casirivimab and imdevimab (regeneron) to be administered to patients with mild to moderate COVID-19 who are at risk for progressing to severe COVID-19.⁹ Monoclonal antibodies (mAb) are produced in the laboratory to mimic those produced by the body’s immune system to neutralize viruses or pathogens. The EUA was granted based on initial data from 275 patients in a phase 1/2/3 trial of the antibody cocktail REGN10933 + REGN10987 (REGN-COV2) compared with placebo.⁹ The investigators found the greatest treatment benefit was among those who had not yet developed their own antibodies. Patients were randomly assigned to receive a placebo or 1 of 2 infusion doses. Patients in this laboratory trial were confirmed positive for COVID-19 and treated in the outpatient setting, with serology tests to see whether they were seropositive or negative. The researchers found that for seronegative patients, the cocktail reduced viral load through the key virologic endpoint at day 7.⁹ It also alleviated symptoms faster (6 to 8 days for treatment arms, 13 days for placebo). In this first cohort, 56% were Hispanic, 13% were Black, and 64% had at least one underlying risk factor. The investigators are recruiting at least 1300 patients into the phase 2/3 portion of the outpatient trial, as well as a trial for hospitalized patients.¹⁰ Another REGN-COV2 trial began recruiting in July 2020 to enroll 2000 asymptomatic adults who are household contacts with someone infected with the virus.¹¹ The combination binds to the virus’s spike protein in 2 spots, preventing it from entering healthy cells. The investigators will evaluate the efficacy 1 month after administration.¹¹ This combination received attention in October 2020 when it was given to US President Donald Trump shortly after he had tested positive for COVID-19.¹²

Roche released new phase IIIa data on March 23, 2021 regarding the use of casirivimab and imdevimab for non-hospitalized patients with COVID-19.¹⁰⁸ The trial assessed the treatment cocktail in non-hospitalized patients (n=4,566). The trial met it's primary endpoint, it demonstrated a reduction in risk of hospitalization or death by 70%.¹⁰⁸ The combination medication also met all key secondary enpoints, including reducing symptom duration from a median of 14 to 10 days.¹⁰⁸ To date, this combination is the only monoclonal antibody that has demonstrated ptoency against new variants.¹⁰⁸

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Bamlanivimab

The FDA issued an EUA for bamlanivimab (LY-CoV555) on November 9, 2020.¹³ The EUA was indicated for treating nonhospitalized patients who are at high risk for progressing to severe COVID-19 and/or requiring hospitalization. The COVID-19 Treatment Guidelines panel determined that, at this time, there is insufficient data to recommend for or against the use of bamlanivimab.¹⁴ The FDA's EUA approval was based on interim results from the BLAZE-1 study, a phase 2, randomized, placebo-controlled trial that demonstrated potential clinical benefit of bamlanivimab for outpatients with mild to moderate COVID-19. Patients who received bamlanivimab had a significantly greater mean decrease in nasopharyngeal SARS-CoV-2 level from baseline to day 11 compared with patients who received placebo. Additionally, COVID-19-related hospitalization, emergency department visits, and death were lower among patients who received bamlanivimab than those who received placebo over the 28-day treatment period.¹⁴ More data are needed to fully assess the use of bamlanivimab in the clinical course of COVID-19.

Another phase 3 trial will evaluate LY-CoV555, an mAb isolated from a recovered person with COVID-19.¹¹ The trial will assess whether the mAb can prevent the virus from infecting individuals at high risk due to living or working in skilled-nursing or assisted-living facilities. Participants will be enrolled within a week of someone at their facility becoming infected. The study will evaluate the prevention efficacy and safety of the mAb compared with placebo over 8 weeks and will evaluate efficacy in preventing symptoms in those already infected. The study will enroll up to 2400 participants.¹¹

On January 22, 2020, Eli Lilly released a news statement regarding the results of the BLAZE-2 trial. The Phase 3 COVID-19 prevention trial was comprised of residents and staff at skilled nursing and assisted living facilities.¹⁵ A total of 965 patients (299 residents and  666 staff) were included in the study and randomized into groups to receive bamlanivimab 4,200mg or placebo for preventative treatment against COVID-19.¹⁵ Residents who received bamlanivimab were 80% less likely to contract COVID-19 when compared to the residents who received placebo.¹⁵ Of the 299 residents 4 died from COVID-19, all which had received the placebo. The BLAZE-2 trial is ongoing and full results will be made available at a later date. 

An ongoing Phase 2/3 clinical trial is analyzing the effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in mild to moderate COVID-19. The primary outcome of the study was the viral load from baseline to day 11, plus or minus 4 days.¹⁶ The group of patients who received bamlanivimab as monotherapy did not have a statistically significant difference in their viral load compared to the placebo group (0.09 [95% CI, -0.35 to 0.52], P=0.69 for 700mg group; -0.27 [95% CI, -0.71 to 0.16], P=0.21 for 2800mg group; and 0.31 [95% CI, -0.13 to 0.76], P=0.16 for 7000mg group).¹⁶ The change between the group who received bamlanivimab and etesevimab compared to placebo was statistically significant (-0.57 [95% CI, -1.00 to -0.14], P=0.01).¹⁶ Additional studies are needed to fully determine the benefit of bamlanivimab. 

On February 9, 2021, the FDA issued an EUA to Eli Lilly's bamlanivimab administered in combination with etesevimab for treatment of mild-moderate COVID-19 in patients who are at high risk of progressing to severe COVID-19.¹⁷ The medication combination, administered via a single intravenous dose, was granted authorization for patients age 12 and older to be administered following a positive coronavirus test and within 10 days of symptom onset.¹⁷ The infusion time is 21 minutes, significantly shorter in duration from the previously authorized 60 minutes.¹⁷ 

The COVID-19 Treatment Guidelines Panel updated their statement on anti-SARS-CoV-2 monoclonal antibodies on February 11, 2021. The panel believes that there is no sufficient data to recommended for or against the use of bamlanivimab or casirivimab plus imdevimab for treatment of non-hospitalized patients with mild to moderate COVID-19.¹⁸ The panel recognized that, given the EUA issued for bamlanivimab, high risk patients who meet the criteria stated in the EUA may benefit from receiving a monoclonal antibody but it should not be considered a standard of care.¹⁸ 

On April 8th, 2021, the FDA updated the COVID-19 Treatment Guidelines with the new recommendation that bamlanivimab should not be used as monotherapy.¹⁰⁹ The panel recommends the monoclonal antibody combination of bamlanivimab plus etesevimab or casirivimab plus imdevimab for outpatients with mild to moderate COVID-19 at risk of developing severe COVID-19.¹⁰⁹ The next week, on April 16th, the FDA revoked the EUA issued to bamlanivimab, when administered alone as monotherapy.¹¹⁰ This decision was based upon increasing evidence that most variants of SARS-CoV-2 have developed resistance to bamlanivimab when administered as monotherapy, which increases the risk of treatment failure.¹¹⁰

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Baricitinib

The FDA issued an EUA for baricitinib, an oral Janus-kinase (JAK) inhibitor selective for JAK1 and JAK2, on November 19, 2020.¹⁹ The EUA was granted in combination with remdesivir in hospitalized patients aged 2 years or older who have COVID-19 and require supplemental oxygen invasive ventilation, or extracorporeal membrane oxygenation.²⁰ Olumiant, manufactured by Eli Lilly and Company, is approved for the treatment of moderate to severe rheumatoid arthritis. Researchers believe that baricitinib, which targets inflammation, might be useful for regulating the inflammatory response of COVID-19.²¹ The ACTT-2 trial, a phase 3, randomized, double-blind, placebo-controlled trial, is currently in process. The researchers are comparing the combination of baricitinib and remdesivir with remdesivir alone.²² Initial results have demonstrated a reduced mean time to recovery of hospitalized patients with COVID-19. The reduction decreased from 8 to 7 days.²³ Additionally, patients who required high-flow oxygen or noninvasive ventilation had shortened mean time to recovery, from 18 days to 10 days.²³

A study published on October 18, 2020, presented information collected from the largest dataset of drug-induced transcriptomic perturbations, public SARS-CoV-2 transcriptomic datasets, and expression profiles from lung transcriptiomes.²⁴ This data collection system presented 50 possible drug candidates that could be repurposed for treatment in COVID-19.²⁴ Baricitinib, along with fostamitinib, may have potential in preventing excess inflammation of the lungs in patients with COVID-19.²⁴ Researchers from the study hope that the scientific community will utilize the list of 50 drugs that could be quickly repurposed to treat COVID-19 as they could significantly impact acute treatment of the virus.

The updated NIH COVID-19 treatment guidelines, were updated on February 11, 2021 and now include the statement released by the panel on December 14, 2020. The COVID-19 Treatment Guidelines panel states that there is insufficient evidence to recommend for or against the use of barcitinib in combination with remdesevir in hospitalized patients who are eligible for corticosteroids.²⁵ In rare cases, non-intubated hospitalized patients who require supplemental oxygen are recommended to receive barcitinib in combination with remdesevir.²⁵ The panel recommends against: bacritinib use when not combined with remdesivir and the use of other JAK inhbitiors (not barcitinib) for the treatment of COVID-19.²⁵ 

On May 27, 2021, the NIH updated their COVID-19 treatment guidelines to reflect the preliminary results of a trial examining the use of baricitinib. In patients with COVID-19 who are hospitalized and on high-flow oxygen or noninvasive ventilation who have evidence of clinical progression or increased markers of inflammation, the Panel now recommends the use of either baricitinib or tocilizumab, in combination with dexamethasone alone or dexamethasone and remdesivir.¹¹⁴ Baricitinib is also recommended to be used in combination with remdesivir in rare cases where corticosteroids cannot be used in hospitalized, nonintubated patients who require oxygen supplementation.¹¹⁴ In addition, the Panel recommends against the use of baricitinib in combination with tocilizumab.¹¹⁴ There is insufficient evidence to recommend for or against the use of baricinitib in children, as well as to identify patients who would benefit from the addition of baricitinib or tocilizumab to dexamethasone.¹¹⁴ 

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Convalescent plasma

Convalescent plasma has been known as a treatment, starting even before the 1918 influenza pandemic.²⁶ The idea is to collect antibody-rich plasma from those who have recovered from COVID-19, then administer it to those who are currently infected to boost their infection-fighting ability with antibodies that can more easily recognize and neutralize the virus. The first study, from China, included 103 patients.²⁷ Published in June 2020, the findings showed that convalescent plasma did not result in significant clinical improvement within 28 days, though there were study limitations that could be addressed in other trials.²⁸

Researchers from the Mayo Clinic led an Expanded Access Program (EAP) partly to determine the safety of these transfusions. The program included 35,322 patients who received a transfusion, with 52.3% in the intensive care unit and 27.5% receiving mechanical ventilation at transfer time.²⁹ The results of the EAP showed a lower mortality rate for those receiving plasma, with a better result for those receiving plasma earlier. Several convalescent plasma trials are underway, including one led by NYU Langone Health, with a goal of enrolling 1000 hospitalized adult patients with respiratory symptoms.³⁰ Another trial led by researchers from Vanderbilt University Medical Center will also enroll 1000 participants.³⁰ The FDA gave an EUA to convalescent plasma in August 2020 for hospitalized patients with COVID-19.³¹ 

A singular study on early high-titer plasma therapy demonstrated a decreased progression of COVID-19 in older adults demonstrating mild symptoms.³² The randomized, double-blind, placebo-controlled study treated a total of 160 patients with mild COVID-19 symptoms upon onset of infection. Of the 80 patients who received convalescent plasma, 16% developed severe respiratory disease compared to 31% of patients who received placebo.³² Older adults who were administered convalescent plasma within 72 hours of their onset of symptoms experienced a 48% decrease in their chance of developing severe COVID-19 symptoms.³²

Currently, there is insufficient data for the COVID-19 Treatment Guidelines panel to recommend for or against the use of convalescent plasma in the treatment of COVID-19.³³

On August 18, 2021, the results from a randomized, multi-center trial were published on the efficacy of convalescent plasma as an early treatment for COVID-19. The results indicated that early administration of convalescent plasma with a high level of antibodies to high-risk patients did not prevent disease progression. Included were 511 adults with COVID-19 who presented to the emergency department within 7 days of symptom indication. Disease progression occurred in 30.0% (n = 77 of 257 patients) of the convalescent plasma group, and 30.1% (n = 81 of 254 patients) of the placebo group.¹²⁰

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RLF-100 (aviptadil)

RLF-100 (aviptadil) is in phase 2/3 trials as a synthetic human vasoactive intestinal peptide targeting the VPAC1 receptor of the alveolar type II cells in the lungs. RLF-100 binds to cells in the alveoli, blocking cytokine actions and upregulating surfactant production.³⁴ The drug has shown dramatic effect in a small number of patients with the critical disease.³⁵ The medication received Orphan Drug Designation for ARDS, as well as Emergency Use Investigational New Drug (IND) authorization and Fast Track designation this year for COVID-19.³⁴ The manufacturer submitted a request for EUA in September 2020 based on a study comparing RLF-100 with placebo in 51 patients. The researchers reported that the treatment arm demonstrated a survival advantage, improved recovery time, and other clinical improvements.³⁶

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EXPERIMENTAL COVID-19 TREATMENTS

Favipiravir

Favipiravir is an antiviral that inhibits RNA-dependent RNA polymerase (RdRp), originally approved for influenza in Japan.³⁷ In-vitro studies have so far demonstrated the efficacy of favipiravir against COVID-19 infection.³⁷ Favipiravir is available orally, which would allow for easy outpatient treatment of COVID-19. PRESECO, a double-blinded, placebo-controlled, randomized, phase 3 trial is comparing the use of favipiravir to placebo in adult outpatients with mild to moderate COVID-19.³⁸ The primary endpoint will be the time to sustained clinical recovery. The second trial, PEPCO, was announced on November 24, 2020. The trial aims to determine the safety and efficacy of avian in preventing COVID-19 amongst asymptomatic individuals who have been exposed to COVID-19.³⁹

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Vilobelimab (IFX-1)

High concentrations of C5a and C5b-9 have been found in patients with severe COVID-19.⁴⁰ C5a attracts and activates neutrophils and monocytes at the site of infection. Oxidative radicals and enzymes are released, which cause tissue damage, indicating that C5a may play an important role in the development of acute respiratory distress syndrome in patients with severe COVID-19.⁴⁰  An open-label, phase 2, randomized-controlled trial (part of the adaptive phase 2/3 PANAMO trial) evaluated the monoclonal antibody IFX-1 (vilobelimab) to selectively block the anaphylatoxin and complement protein C5a in patients with severe and diagnosed COVID-19.⁴¹ Targeted patients were adults with severe pneumonia, a history of shortness of breath within 14 days, or those needing noninvasive or invasive ventilation. Researchers defined severe disease as 100 mm Hg to 250 mm Hg, the ratio of the partial pressure of arterial oxygen to fraction of inspired oxygen (Pao2/Fio2) in the supine position. Thirty patients at 3 hospitals in the Netherlands were randomly assigned in equal numbers to receive either up to 7 doses of IFX-1 plus best supportive care or best supportive care alone. The primary outcome was the percentage change in Pao2/Fio2 in the supine position between baseline and day 5, but during the study, the researchers changed to assessing in any position due to severe hypoxemia in some patients. Patients in the treatment arm had a smaller proportion of serious pulmonary embolisms and fewer serious infections than patients in the control group.The researchers found that IFX-1 was safe, and preliminary secondary outcome results favored the treatment arm for further investigation.⁴¹

In patients who received vilobelimab, the Kaplan-Meier estimate of mortality at 28 days was 13% (95% Confidence Interval; 0-31) compared with 27% (95% Confidence Interval; 4-49) in patients who received best supportive care.⁴¹ Additionally, for patients who were intubated, there was a 20% mortality rate (95% Confidence Interval; 0-45) in patients who received IFX-1 and 40% (95% Confidence Interval; 10-70) in patients who only received best supportive care.⁴¹ Of the 30 total patients, 6 (20%) had died by day 28—2 patients from the IFX-1 group and 4 patients from the control group. The 2 patients who had died in the IFX-1 group had died from non-COVID-related complications (ie, tube failure resulting in severe hypoxia and persistent hypoxia related to severe chronic obstructive pulmonary disease). PANAMO is currently in phase 3 with a double-blind, placebo-controlled, randomized trial comparing the standard of care plus vilobelimab to the standard of care plus placebo.⁴²

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Plitidepsin

Aplidin, a medication originally developed for myeloma, may be useful in treating COVID-19. Plitidepsin interferes with the viral cycle by blocking eEF1A, which is required for COVID-19 infection.⁴³ In the APLICOV-PC trial, adult patients who were hospitalized with COVID-19 were divided into 3 cohorts, each receiving a different dose of plitidepsin over 3 consecutive days: 1.5 mg, 2.0 mg, or 2.5 mg. The study demonstrated a reduction in viral load between days 4 and 7. On average, the reduction in viral load at day 7 was 50% and by day 15 was 70%.⁴⁴ Patients were required to be hospitalized for at least 7 days; 80.7% of the patients were discharged before day 15 of hospitalization, and 38.2% were discharged before day 8.⁴⁴ Researchers from PharmaMar, the Spanish company that manufactures Aplidin, plan to begin a phase 3 trial. 

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Camostat Mesylate

Camostat mesylate, a serine protease inhibitor, may work against COVID-19 by limiting viral entry into the cell.⁴⁵ Camostat mesylate is approved to treat pancreatitis and gastroesophageal reflux disease in Japan. There are currently a few phase 2 trials in process of evaluating the use of camostat mesylate. One trial (CAMELOT) is a randomized, double-blind, placebo-controlled trial in ambulatory patients with confirmed COVID-19 with at least 1 risk factor for progressing to severe illness. The study investigators are comparing camostat with placebo.⁴⁶ Researchers conducting another double-blind, randomized controlled phase 2 trial are analyzing the reduction in viral load between camostat and placebo.⁴⁷  

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Ruxolitinib

Ruxolitinib is currently approved in Europe for the treatment of polycythemia vera and primary myelofibrosis. The oral JAK1 and JAK2 tyrosine kinase inhibitor was evaluated in the RUXCOVID trial.⁴⁸ For this phase 3, multicenter, double-blind, randomized, placebo-controlled study, the researchers assessed the efficacy and safety of ruxolitinib and standard of care therapy compared with placebo and standard of care therapy in patients aged 12 years or older with COVID-19 pneumonia.⁴⁹ Representatives from Novartis, the manufacturer of ruxolitinib, released a statement on December 14, 2020, stating that ruxolitinib failed to meet the primary endpoints of the RUXCOVID trial. Novartis reported no significant reduction in severe complications, including death, respiratory failure requiring mechanical ventilation, or admission to the intensive care unit.⁵⁰

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Sarilumab

Sarilumab (kevzara) is an interleukin-6 (IL-6) inhibitor. IL-6 is a pleiotropic proinflammatory cytokine. COVID-19 infections have been shown to induce dose-dependent production of IL-5 in bronchial epithelial cells.⁵¹ On July 2, 2020, representatives from Sanofi, the manufacturer of Kevzara, announced that the phase 3 trial did not meet its primary or secondary endpoints.⁵² The study included 194 patients who were critically ill with COVID-19 and were receiving mechanical ventilation. There was no difference between patients who received sarilumab and those who received a placebo.⁵² 

On January 7, 2021, preliminary data from the REMAP-CAP trial was released. Researchers conducting this study analyzed the effectiveness of sarilumab and tocilizumab in critically ill patients with COVID-19. Patients were randomized to receive either sarilumab, tocilizumab, or the standard of care within 24 hours of the start of organ support in the ICU.⁵³ The primary outcomes of the study were in-hospital mortality and days free of organ support. Both sarilumab and tocilizumab met these endpoints. Of the 803 patients assigned to the different groups, only 48 received sarilumab.⁵³ The median organ support-free days for sarilumab and supportive care were 11 days and 0 days respectively.⁵³ Hospital mortality rates were 22.2% in patients who received sarilumab and 35.8% in patients who received best supportive care.⁵³ This data has not yet been peer reviewed. The National Health Service in the United Kingdom has updated their COVID-19 treatment guidelines to include the use of sarilumab and tocilizumab.⁵⁴

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Tocilizumab

Tocilizumab, an IL-6 inhibitor, is currently under evaluation in several phase 3 clinical trials. Tocilizumab is FDA approved to treat rheumatoid arthritis and several other types of arthritis, as well as cytokine release syndrome.⁵⁵ Investigators conducting the REMDACTA trial—a double-blind, multicenter study—are comparing the efficacy and safety of remdesivir and tocilizumab compared with remdesivir and placebo.⁵⁶ Researchers conducting the COVACTA trial—a randomized, double-blind, placebo-controlled, multicenter study—will analyze the safety and efficacy of tocilizumab in patients with severe COVID-19 pneumonia.⁵⁷ Finally, researchers conducting the EMPACTA trial will evaluate the efficacy and safety of tocilizumab compared with placebo and contain a substudy analyzing the long-term sequelae of COVID-19 pneumonia post-recovery.⁵⁸

Representatives from Roche, the manufacturer of Actemra/RoActemra, announced on September 18, 2020, that the primary endpoints of EMPACTA were met. Patients who received tocilizumab plus standard of care treatment were 44% less likely to progress to mechanical ventilation or death compared with patients who only received standard of care. Overall, 12.2% of patients who received Actemra/RoActemra progressed to requiring ventilation or death compared with 19.3% of patients receiving only standard of care treatment.⁵⁹

Researchers conducting the COVACTA trial compared placebo with tocilizumab treatment for 450 patients with COVID-19, from April to July 2020.²³ The study findings showed that clinical status at day 28 was not significantly different for the 2 arms, and there was no difference in mortality rates. The tocilizumab arm had a median time to discharge that was 8 days shorter than the placebo arm.⁶⁰ In July 2020, representatives from Roche reported that the COVACTA study did not meet its primary endpoint of improved clinical status or mortality at 4 weeks.⁶¹

The phase 3 REMDACTA trial combines remdesivir with intravenous tocilizumab (actemra/roactemra), an anti-IL-6 receptor antibody. The study includes patients aged 12 years or older who are hospitalized with severe COVID-19 pneumonia.⁶² The investigators are recruiting 450 patients to the randomized, double-blind study comparing the combination with placebo plus remdesivir. Results are not yet available.⁵⁶

On January 7, 2021, preliminary data from the REMAP-CAP trial was released. Researchers conducting this study analyzed the effectiveness of sarilumab and tocilizumab in critically ill patients with COVID-19. Patients were randomized to receive either sarilumab, tocilizumab, or the standard of care within 24 hours of the start of organ support in the ICU.⁵³ The primary outcomes of the study were in-hospital mortality and days free of organ support. Both sarilumab and tocilizumab met these endpoints. Of the 803 patients assigned to the different groups, 353 received tocilizumab.⁵³ The median organ support-free days for sarilumab and supportive care were 10 days and 0 days respectively.⁵³ Hospital mortality rates were 28.0% in patients who received sarilumab and 35.8% in patients who received best supportive care.⁵³ This data has not yet been peer-reviewed. The National Health Service in the United Kingdom has updated their COVID-19 treatment guidelines to include the use of sarilumab and tocilizumab.⁵⁴

An open-label trial of 129 participants in Brazil aimed to determine if tocilizumab can improved outcomes for patients with severe COVID-19. The trial was stopped early and results, published on January 20, 2021, demonstrated that use of tocilizumab was no better than the standard of care.⁶³ The study was stopped early due to an increase in the number of deaths in patients who received tocilizumab. At the 15 day mark 28% of the patients who received tocilizumab were on mechanical ventilation or had died, compared to 20% of patients who were receiving standard of care treatment.⁶² The researchers suggest the results "raise questions about an anti-inflammatory in the treatment of COVID-19 beyond corticosteroids."⁶³

The NIH COVID-19 Treatment Guideline Panel updated their recommendation regarding tocilizumab on February 3, 2021.⁶⁴ Previously the panel recommended against the use of any IL-6 inhibitors (including tocilizumab). However, as research continues and more data becomes available the panel has adjusted their recommendation to reflect this. Currently, the panel does not recommend for or against the use of tocilizumab, citing a lack of data as the reasoning behind this recommendation.⁶⁴ This recommendation is made specifically for patients with COVID who have been admitted to the ICU within 24 hours and who require supplemental oxygen (mechanical ventilation or high-flow oxygen).⁶⁴ Some of the panelists stated they would administered 1 dose of tocilizumab (8mg/kg based on actual body weight, up to 800mg) with dexamethasone to patients meeting the above criteria based upon results of the REMAP-CAP trial.⁶⁴ The panel still recommends against the use of tocilizumab in patients not in the ICU. 

Following the February 3, 2021 guideline update, the NIH COVID-19 Treatment Guideline Panel has further updated their recommendations regarding tocilizumab following the release of full data from the REMAP-CAP trial and preliminary results from the open-label, pragmatic Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial.¹⁰⁶ The panel now recommends for the use tocilizumab (dosed at 8mg/kg - up to 800mg -  and administered via single intravenous infusion) in combination with dexamethasone (6mg daily for up to 10 days) in hospitalized patients with severe COVID-19 who are experiencing rapid respiratory decompensation.¹⁰⁶ This includes:

• Hospitalized patients who have recently been admitted to the ICU (within the past 24 hours) and require mechanical ventilation, noninvasive mechanical ventilation, or high-flow nasal cannula oxygen.¹⁰⁶
   
• Hospitalized patients not in the ICU, but who require noninvasive mechanical ventilation or high-flow nasal cannula oxygen with significantly increased markers of inflammation. ¹⁰⁶

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Recombinant Human ACE-2

Angiotensin-converting enzyme 2 (ACE2) is important to the COVID-19 receptor and protects multiple tissues from injury. The first patient to receive human recombinant soluble ACE2 (hrsACE2) was a 45-year-old woman who had been admitted to the hospital with COVID-19.⁶⁵ The patient received hrsACE2 9 days after symptom onset. In total, the patient received 7 administrations (once daily) of hrsACE2.⁶² APN01-COVID-19, a phase 2 randomized trial is currently in process to analyze the use of hrsACE2 compared with placebo in hospitalized patients with COVID-19.⁶⁶

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Molnupiravir

Molnupiravir (MK-4482) is an antiviral medication originally developed to treat influenza.⁶⁷ It is an oral antiviral agent that is a prodrug of the nucleoside derivative N4-hydroxycytidine and works against COVID-19 by causing copying errors during viral RNA replication.⁶⁸ For the END-COVID trial—a phase 2, randomized, placebo-controlled, double-blinded trial—researchers will analyze the efficacy and safety of molnupiravir in hospitalized patients with COVID-19 and are currently recruiting.⁶⁹ For the MK-4482-001 trial—a phase 2/3, randomized, placebo-controlled, double-blind study—researchers are analyzing the safety, efficacy, and pharmacokinetics of molnupiravir compared with placebo in hospitalized patients with COVID-19.⁷⁰

On November 4, 2021, the United Kingdom became the first country to approve the use of the first oral antiviral pill, molnupiravir, for use in the treatment of COVID-19. The medication works by interfering with the virus' replication and preventing the virus from multiplying. The pill is produced by Ridgeback Biotherapeutics and Merck.¹¹⁸

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Interferons

The COVID-19 Treatment Guidelines panel recommends against the use of antivirals for the treatment of severe or critical COVID-19, and there is insufficient data regarding the use of interferons in the treatment of mild to moderate COVID-19.⁷¹ Interferons are cytokines with antiviral properties. To date, studies have shown no benefit, and the significant toxicities of interferons outweigh the potential benefit.⁷¹ Remdesivir is also combined with interferon β-1a (rebif) in the ACTT-3 trial, which started enrolling in August 2020, to recruit 1000 hospitalized adults with lung involvement, testing the combination against remdesivir alone in a double-blind randomized study.⁷¹ The researchers note that the normal interferon response can be suppressed by the virus. Interferon β-1a has anti-inflammatory and antiviral properties and is FDA approved to treat multiple sclerosis.⁷²

The results of the Adaptive COVID-19 Treatment Trial 3 (ACTT-3) indicate that immunomodulator interferon β-1a plus the antiretroviral remdesivir was not superior to remdesivir alone. No significant differences were observed between the 2 groups in time to recovery for hospitalized adults. However, the study was modified to exclude individuals with severe COVID-19 who required noninvasive or invasive mechanical ventilation following a higher rate of adverse events and outcomes in this patient population.¹¹⁵ 

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Nanobodies

The development of antibody fragments, or "nanobodies", are promising for neutralizing the SARS-CoV-2 virus in vivo. Antibodies have a large complicated structure and therefore have a more difficult time penetrating deeper into the body. Nanobodies, due to their small size, do not carry the same complications as antibodies.⁷³ Antibody product is a lengthy and difficult process. Comparatively, because nanobodies are small fragments, they are easily produced by yeast or bacteria.⁷³ 

Most recently, an international team, lead by the University of Bonn in Germany, identified 4 different nanobodies that target the receptor binding spike protein in the COVID-19 virus.^73,74 When the nanobodies bind to the receptor binding domain of the virus, they change the virus shape such that it cannot enter the host cell.⁷³ Researchers developed the 4 nanobody particles to be multivalent which increases their neutralizing capabilities by 100-fold compared to monovalent nanobodies.⁷⁴

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PF-07321332

On March 23, 2021, Pfizer announced that their oral antiviral clincial candidate (PF-07321332) for treatment of COVID-19 is entering phase 1 studies.¹⁰⁷ The drug, a protease inhibitor which has demonstrated in vitro activity against the SARS-CoV-2 virus, is currently being study to determine safety and tolerability.¹⁰⁷ This would be the first orally administered protease inhibitor desigend specifically for the coronavrus. The drug candidate works by binding to the viral protease and preventing viral replication from occuring inside the cell. The current Phase 1 trial is a randomized, double-blind, sponsor-open, placebo-controlled, single- and multiple-dose escalation study in health adults.¹⁰⁷  

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Fluvoxamine

The COVID-19 Treatment Guidelines Panel does currently have enough data to make a recommendation for or against the use of fluvoxamine in the treatment of COVID-19.¹¹¹ Fluvoxamine is being investigated as a potential treatment because in a murine sepsis model, it was found to bind to the sigma-1 receptor on immune cells, which results in a reduction of inflammatory cytokines.¹¹¹ A further study in human endotherlial cells and macrophages found a reduction in expression of inflammatory genes.¹¹¹ A placebo-controlled randomized trial in nonhospitalized adults with mild COVID-19 administered fluvoxamine up to 100mg three times a day or placebo for 15 days. The primary endpoint - clinical deterioration - was not met in any of the fluvoaxmie patients (n=80) and was only met in 6 of the 72 patients receiving placebo.¹¹¹ A prospective, nonrandomized observational cohort study gave patients the option of receiving fluvoxamine 50mg twice daily for 14 days or no therapy.¹¹¹ Of the 113 patients who tested positive for COVID-19, 65 took fluvoxamine and 48 did not. At day 14, none of the patients who took fluvoxamine and 60% of the patients who did not had persistent symptoms. While studies are ongoing, the current data from studies is limited to small sample sizes and limited collected data.¹¹¹

In October of 2021, findings from the TOGETHER trial indicated that treating high-risk outpatients with COVID-19 with fluvoxamine may reduce the need for hospitalization in these patients. Patients with a known risk factor for severe disease were randomized to receive 100 mg twice daily for 10 days of fluvoxamine or placebo. Of the 741 patients randomized to take fluvoxamine, 17 deaths occurred, compared to 25 of the 756 patients who received placebo. Hospitalization, defined here as being observed for more than 6 hours in a COVID-19 emergency setting or transfer to a tertitary hospital, was observed in 11% (n = 79) of the fluvoxamine group and 16% (n = 119) of the placebo group.¹¹⁷

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Sotrovimab

Sotrovimab may be a promising treatment for reducing the risk of severe disease progression for COVID-19, according to the results of an ongoing phase 3 trial. Included were 583 nonhospitalized patients with symptomatic COVID-19. All participants had at least 1 risk factor for progression to severe disease. Of the 291 patients who received a single dose of 500 mg of sotrovimab, 1% (n = 3) progressed to requiring hospitalization or death, compared with 7% (n = 21) of the placebo group. Adverse events were reported in 17% of the sotrovimab group and 19% of the placebo group, with more serious adverse events being reported within the placebo group.¹¹⁹

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Azithromycin 

The addition of azithromycin to standard treatment for patients with COVID-19 does not improve outcomes or reduce the risk of hospitalization in individuals with mild-to-moderate disease. Included in the prospective, open-label trial were 292 patients aged 18 years or older from the United Kingdom. Participants were randomly assigned to standard care, or standard care plus 500 mg of azithromycin once daily for 14 days. The results indicated that 10% (n = 15 of 145) of participants in the azithromycin group were admitted to the hospital or died, and 12% (n = 17 of 147) of participants in the standard care group were admitted to the hospital or died.¹²¹

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Disulfiram

Disulfiram may lower the incidence and severity of COVID-19, according to the results of a recent observational study. There was a 34% lower risk of SARS-CoV-2 infection among the study participants who used disulfiram. Statistically, 5 to 6 deaths were expected based upon the untreated population but there were no deaths among the 188 patients who tested positive for COVID-19.¹²⁴

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PREVIOUSLY INVESTIGATED TREATMENTS DETERMINED INEFFECTIVE OR NOT PROMISING

The following treatments have been investigated as possible treatments for COVID-19 given their mechanisms. However, the NIH COVID-19 Treatment Guidelines panel does not recommend their use for COVID-19 treatment.

Hydroxychloroquine and Chloroquine

Early in the pandemic, hydroxychloroquine and chloroquine were considered possible treatments for COVID-19, because researchers found that they stopped coronavirus replication in cells. Hydroxychloroquine, approved for use in the 1950s, is a compound related to the antimalarial medication chloroquine, which was first synthesized in the 1930s. Hydroxychloroquine is currently used to treat rheumatoid arthritis and systemic lupus erythematosus.⁷⁵ Approximately 180 clinical trials,⁷⁶ including 1 from the World Health Organization (WHO),⁷⁴ found that hydroxychloroquine and/or chloroquine did not reduce mortality compared with standard care in patients with COVID-19. WHO’s SOLIDARITY trial of remdesivir, hydroxychloroquine, lopinavir (fixed-dose combination with ritonavir), and interferon β-1a included patients from more than 35 countries and 400 hospitals.⁷⁷

The US Food and Drug Administration (FDA) revoked the EUA of hydroxychloroquine and chloroquine in June 2020; in July 2020, the FDA reported safety issues including serious heart rhythm problems.⁷⁸ The COVID-19 Treatment Guidelines panel recommends against the use of chloroquine or hydroxychloroquine with or without azithromycin in both hospitalized and nonhospitalized patients with COVID-19.⁷⁹

On March 2, 2021, the World Health Organization (WHO) strongly recommended against the use of hydroxychloroquine for the treatment of COVID-19.⁸⁰ The recommendation, made as part of their living guidelines published in the British Medical Journal, is based upon a meta-analysis of 6 trials. Hydroxychloroquine was found to have little or no effect on hospital admission or mortality.⁸⁰ Additionally, there was an increased risk for adverse effects leading to discontinuation of hydroxychloroquine.⁸⁰ The panel creating the WHO guidelines considers hydroxychloroquine to not be worthwhile and recommend it is no longer researched or administered.⁸⁰ 

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Ivermectin

The COVID-19 Treatment Guidelines panel currently recommends against the use of ivermectin for COVID-19.⁸¹ Ivermectin inhibits host importin α/β-1 nuclear transport proteins. In cell cultures, ivermectin has demonstrated the ability to inhibit replication of SARS-CoV-2.⁸² In order to achieve the necessary plasma concentrations to effectively target the virus in vivo, the administration would need to be up to 100-fold higher than the currently approved dose.^83,84 In a small retrospective analysis of 276 patients with COVID-19 at 4 Florida hospitals, researchers compared patients who received at least 1 dose of ivermectin (n = 173 patients), and the rest (n = 103 patients) received usual care. Of the patients who received ivermectin, all-cause mortality was lower (Odds Ratio, 0.27; P = 0.003).⁸⁵ This study is not peer-reviewed. It did not include any information on oxygen saturation, and the timing of therapeutic interventions was not standardized.

Interest in ivermectin as a treatment for COVID-19 renewed upon a publication by the Front Line COVID-19 Critical Care Alliance (FLCCC) on December 18, 2020. The FLCCC conducted an extensive review of the currently available data on ivermectin in the treatment of COVID-19.⁸⁶ The review contained 7,3000 persons from a total of 24 controlled studies, 12 of which have been peer-reviewed and published. The FLCCC argues that, given the current pandemic and available efficacy and safety data, ivermectin should be used as exposure prophylaxis for and treatment of COVID-19.⁸⁶ The FLCCC suggested that the NIH change their recommendation to support the use of ivermectin at a level of AII.⁸⁶ The NIH has not updated the recommendations regarding ivermectin since August 2020.⁷⁷ On January 6, 2021 the FLCCC was invited to present their findings regarding ivermectin to the NIH as the panel is currently reviewing the use ivermection in COVID-19.⁸⁷

On January 14, 2021, the COVID-19 Treatment Guidelines Panel updated their recommendation regarding the their recommendation of ivermectin.⁸⁸ Previously, the Panel had recommended against the use of ivermect but they have since changed their statement. The Panel has now determined that their is insufficient data to recommend either for or against the use of ivermectin to treat COVID-19.⁸⁸ Data gathered from well-designed and well-conducted trials are needed in order for the panel to make an evidence-based ruling on the use of ivermectin. 

On October 19, 2021, the Clinical Spectrum of SARS-CoV-2 Infection Guidelines were updated to include the reactivation of several dormant infections as an infectious complication of COVID-19. The update was based upon case reports of individuals with COVID-19 who received immunomodulators as treatment, and had reactivated hepatitis B virus, tuberculosis, herpes simplex virus, varicella zoster virus, and strongyloidiasis infections. For individuals in areas where Strongyloides is endemic, empiric treatment with ivermectin may be used, with or without serologic testing.¹¹⁶

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Lopinavir/Ritonavir and Other HIV-Protease Inhibitors

Both lopinavir + ritonavir and darunavir + cobicistat have been evaluated in patients with COVID-19. The COVID-19 Treatment Guidelines panel recommends against the use of HIV-protease inhibitors. COVID-19 replication is dependent upon polyprotein cleavage, which is driven by 2 proteases.⁸⁹ Lopinavir + ritonavir has activity against 1 of these proteases (3CLpro) in vitro. HIV-protease inhibitor use is recommended against due to lack of data and concerns about drug concentrations needed to inhibit the proteases. A moderately sized, randomized trial of 199 patients demonstrated that patients receiving lopinavir + ritonavir did not have a shorter time to clinical improvement. There was no difference in median hospital stay duration or median viral RNA clearance.⁹⁰

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Mesenchymal Stem Cells

The FDA has issued several warnings regarding the treatment of mesenchymal stem cells. At this time, no mesenchymal stem cells are approved by the FDA for the treatment of COVID-19.⁹¹ The FDA issued a statement regarding vulnerable patients receiving illegal and potentially harmful stem cell treatments. It is theorized that mesenchymal stem cells could reduce acute lung injury and inhibit cell-mediated inflammatory response caused by COVID-19. Current data regarding mesenchymal stem cells is limited to case reports and small, open-label studies. A pilot study of 10 patients in China found that all of the 7 patients who received stem cells had recovered. Of the 3 patients who received the placebo, 1 had died, 1 had developed acute respiratory distress syndrome, and 1 had remained stable.⁹² In a small study, 12 patients received human umbilical cord mesenchymal stem cells, and 29 patients received standard care. All the patients who received hUC-MSC had recovered without requiring mechanical ventilation. Four patients who received standard care required mechanical ventilation, 3 of whom had died.⁹³

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Immunoglobulins

The COVID-19 Treatment Guidelines panel recommends against the use of non-SARS-CoV-2-specific intravenous immunoglobulin (IVIG) and does not have enough data to make a recommendation for the use of SARS-CoV-2-specific immunoglobulins.⁹⁴ To date, no clinical data regarding the use of SARS-CoV-2 IVIG are available. The proposed mechanism for use of SARS-CoV-2 IVIG relies on concentrated antibody preparations from individuals who have recovered from COVID-19, which could then be administered to a patient with COVID-19 to suppress the virus and modify the inflammatory response.⁹⁵ The use of non-SARS-CoV-2-specific IVIG is not recommended, as it is unknown whether plasma from donors without COVD-19 would possess enough SARS-CoV-2 antibodies.⁹⁶

A nonpeer-reviewed, retrospective, nonrandomized cohort study was conducted between December 2019 and March 2020 at 8 treatment centers in China. The study demonstrated no difference in 28- or 60-day mortality between patients who received IVIG and patients who did not receive IVIG.⁹⁷

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Colchicine

The NIH COVID-19 Treatment Guidelines Panel has insufficient data to recommend for or against the use of colchicine in non-hospitalized patients.¹¹² The COLCORONA trial, a large, randomized outpatient trial, did not reach its primary efficacy endpoint of reducing hospitalizations and death.¹¹² There was a slight reduction in hospitalizations in patients who tested positive for COVID-19 via a positive nasopharyngeal swab but more data are needed.¹¹² 

The Panel recommends against the use of colchicine in hospitalized patients.¹¹² Data from the RECOVERY trial found no significant difference in mortality between colchicine and placebo, 27% of patients who received colchicine and 19% receiving placebo died during the course of the study.¹¹² Data from the GRECCO-19 trial demonstrated that fewer patients receiving colchicine than those receiving standard of care treatment had deterioration in clinical status from baseline. This study however was very small and open-label.¹¹² 

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ADJUNCTIVE THERAPY

Anticoagulants

COVID-19-induced coagulopathy (CID) can cause venous thromboembolism (VTE) in some patients. Guidelines for anticoagulant administration during and after hospitalization for prophylaxis and treatment have been published.⁹⁸ The COVID-19 Treatment Guidelines panel recommends that hospitalized patients should receive VTE prophylaxis per the standard of care and that a diagnosis of COVID-19 should not influence this treatment. These guidelines note that one study⁹⁹ showed that without VTE prophylaxis, 25% of patients with COVID-19 had developed lower-extremity deep vein thrombosis (DVT), a figure higher than in medically ill hospitalized patients, who had a 5% to 15% incidence in earlier studies.

The guidelines also report that early studies showed that pharmacologic VTE prophylaxis was associated with up to 60% reduction in VTE incidence without a major bleed increase.¹⁰⁰ The guidelines note that a study from Italy reported a 21% cumulative rate of VTE and arterial thromboembolic events in hospitalized patients with COVID-19.¹⁰⁰ The guidelines recommend pharmacologic VTE prophylaxis with anticoagulants such as enoxaparin or heparin for hospitalized nonpregnant patients diagnosed with or highly suspected of having COVID-19.⁹⁸

On January 22, 2021, the National Institutes of Health published a news release regarding several large clinical trials studying the use of full-dose blood thinners in COVID-19 patients.¹⁰¹ The 3 large clinical trials are colaborating internationally to study the effects of blood thinners in patients with COVID-19. The 3 studies include: the Randomized, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REM-CAP) Therapeutic Anticoagulation; Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 (ACTIV-4) Antithrombotics Inpatient; and Antithrombotic Therapy to Ameliorate Complication of COVID-19 (ATTACC).¹⁰¹ When patients hospitalized with moderate COVID-19 are administered full dose heparin, the need for vital organ support decreases.¹⁰¹ Full results are not yet available. 

Low molecular weight heparin (LMWH) may reduce mortality and the duration of infection for patients with COVID-19. LMWH may also improve markers of cell death. Included in this retrospective observational study were 586 adults in Austria who were hospitalized with COVID-19. Of these participants, 71.5% (n = 419) of patients received LMWH and 10.5% (n = 62) received non-vitamin-K antagonist oral anticoagulants. In patients with and without LMWH, time courses of hemostatic and thromboinflammatory biomarkers were similar. However, LMWH had no impact on hemostasis or hypercoagulability.¹²²

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Vitamins and Zinc

Vitamins C and D, as well as zinc, have been proposed as adjunctive therapy for COVID-19. Currently, there is insufficient data to recommend for or against the use of any of these supplements.^102,103,104 The NIH COVID-19 panel updated their recommendations on February 11, 20201; the panel now recommends against the use of zinc supplementation above the recommended daily dietry allowance for prevention of COVID-19.¹⁰⁴

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PREVENTION AND PROPHYLAXIS

In updated guidelines, released February 11, 2021, the NIH COVID-19 Treatment Guidelines Panel made specific recommendations regarding medications used for prevention and prophylaxis. The panel recomended against the use of any drugs for COVID-19 pre-exposure prophylaxis (PREP) and the use of hydroxychloroquine (specifically mentioned) and all other drugs for post-exposure prophylaxis (PEP).¹⁰⁵ Several studies analyzing the use of hydroxychloroquine as PREP and PEP found that persons who received hydroxychloroquine did not experience reduced rates of COVID-19 infection.¹⁰⁵ Unless in clinical trials, there are no medications recommended for use for pre- or post-exposure prophylaxis.¹⁰⁵

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OUTPATIENT MANAGEMENT

When managing outpatients with COVID-19, the NIH Treatment Guidelines panel recommends providing supportive care, reducing the risk of SARS-CoV-2 transmission via isolation, and seeking treatment from a healthcare provider when needed.¹¹³ When possible, patients with suspected or confirmed COVID-19 infection should receive health via telehealth visits to reduce the risk of transmission.¹¹³ However, if the patient is experiencing dyspnea they should receive care in person. Patients should be monitored for symptoms indicative of progression to severe COVID-19.¹¹³

In patient with mild to moderate COVID-19 who are at high risk for progressing to severe COVID-19, the should be treated with either: (1) bamlanivimab 700mg + etesevimab 1,400mg or (2) casirivimab 1,200mg + imdevimab 1,200mg.¹¹³ 

The Panel recommends against outpatient treatment with chloroquine or hydroxychloroquine (with or without azithromycin), dexamethasone or other systemic glucocorticoids, and antibacterial therapy.¹¹³ 

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REFERENCES

1. Mammen MJ, Aryal K, Alhazzani W, Alexander PE. Corticosteroids for patients with acute respiratory distress syndrome: a systematic review and meta-analysis of randomized trials. Pol Arch Intern Med. 2020;130(4):276-286. doi:10.20452/pamw.15239
2. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with Covid-19 - preliminary report. N Engl J Med. 2020;NEJMoa2021436. doi:10.1056/NEJMoa2021436
3. COVID-19 treatment guidelines: corticosteroids. National Institutes of Health. Updated August 27, 2020. Accessed October 27, 2020. https://www.covid19treatmentguidelines.nih.gov/immune-based-therapy/immunomodulators/corticosteroids/
4. What’s new in the guidelines. National Health Institution COVID-19 Treatment Guidelines. Updated November 18, 2020. Accessed December 2, 2020. https://www.covid19treatmentguidelines.nih.gov/whats-new/
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10. Regeneron's REGN-COV2 antibody cocktail reduced viral levels and improved symptoms in non-hospitalized COVID-19 patients. News release. Regeneron. September 29, 2020. Accessed October 27, 2020. https://investor.regeneron.com/news-releases/news-release-details/regenerons-regn-cov2-antibody-cocktail-reduced-viral-levels-and
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14. The COVID-19 treatment guidelines panel statement on the emergency use authorization of bamlanivimab for the treatment of COVID-19. National Health Institute COVID-19 Treatment Guidelines. Updated November 18, 2020. Accessed December 2, 2020. https://www.covid19treatmentguidelines.nih.gov/statement-on-bamlanivimab-eua
15. Lilly's neutralizing antibody bamlanivimab (LY-CoV555) prevented COVID-19 at nursing homes in BLAZE-2 trial, reducing risk by up to 80% for residents. Eli Lilly. News Release. January 21, 2020. Accessed January 25, 2020. https://investor.lilly.com/news-releases/news-release-details/lillys-neutralizing-antibody-bamlanivimab-ly-cov555-prevented 
16. Gottlieb RL, Nirula A, Chen P, et al. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19. JAMA. Published online. January 21, 2021. doi: 10.1001/jama.2021.0202 
17. Lilly's bamlanivimab (LY-CoV555) administered with etesevimab (LY-CoV016) receives FDA emergency use authorization for COVID-19. Lilly. News Release. February 9, 2021. Accessed February 12, 2021. https://investor.lilly.com/news-releases/news-release-details/lillys-bamlanivimab-ly-cov555-administered-etesevimab-ly-cov016 
18. Anti-SARS-CoV-2 Monoclonal Antibodies. National Institutes of Health COVID-19 Treatment Guidelines. Updated February 11, 2021. Accessed February 12, 2021. https://www.covid19treatmentguidelines.nih.gov/anti-sars-cov-2-antibody-products/anti-sars-cov-2-monoclonal-antibodies/ 
19. The COVID-19 treatment guidelines panel’s statement on the emergency use authorization of baricitinib for the treatment of COVID-19. Updated December 14, 2020. Accessed December 16, 2020. https://www.covid19treatmentguidelines.nih.gov/statement-on-baricitinib-eua/
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21. Baricitinib plus remdesivir shows promise for treating COVID-19. National Institutes of Health. News Release. December 11, 2020. Accessed December 16, 2020. https://www.nih.gov/news-events/news-releases/baricitinib-plus-remdesivir-shows-promise-treating-covid-19
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