Coronavirus Disease 2019 (COVID-19) Treatment & Management

Updated: Jul 08, 2020
  • Author: David J Cennimo, MD, FAAP, FACP, AAHIVS; Chief Editor: Michael Stuart Bronze, MD  more...
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Treatment

Approach Considerations

The antiviral drug remdesivir gained emergency use authorization (EUA) from the FDA on May 1, 2020, based on preliminary data showing a faster time to recovery of hospitalized patients with severe disease. [24, 25, 26] Numerous other antiviral agents, immunotherapies, and vaccines continue to be investigated and developed as potential therapies.

All infected patients should receive supportive care to help alleviate symptoms. Vital organ function should be supported in severe cases. [28]

Early in the outbreak, concerns emerged about nonsteroidal anti-inflammatory drugs (NSAIDs) potentially increasing the risk of adverse effects in individuals with COVID-19. However, in late April, the WHO took the position that NSAIDS do not increase the risk of adverse events or affect acute healthcare utilization, long-term survival, or quality of life. [143]

No vaccine is currently available for SARS-CoV-2. Avoidance is the principal method of deterrence.

Numerous collaborative efforts to discover and evaluate effectiveness of antivirals, immunotherapies, monoclonal antibodies, and vaccines have rapidly emerged. Guidelines and reviews of pharmacotherapy for COVID-19 have been published. [29, 30, 31, 32]

Searching for effective therapies for COVID-19 infection is a complex process. Gordon et al identified 332 high-confidence SARS-CoV-2 human protein-protein interactions. Among these, they identified 66 human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials, and/or preclinical compounds. As of March 22, 2020, these researchers are in the process of evaluating the potential efficacy of these drugs in live SARS-CoV-2 infection assays. [144]

How these potential COVID-19 treatments will translate to human use and efficacy is not easily or quickly understood. The question of whether some existing drugs that have shown in vitro antiviral activity might achieve adequate plasma pharmacokinetics with current approved doses was examined by Arshad et al. The researchers identified in vitro anti–SARS-CoV-2 activity data from all available publications up to April 13, 2020, and recalculated an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). The researchers also calculated the unbound drug to tissue partition coefficient to predict lung concentrations that would exceed their reported EC50 levels. [145]

The WHO has embarked on an ambitious global "megatrial" called SOLIDARITY in which confirmed cases of COVD-19 are randomized to standard care or one of four active treatment arms (remdesivir, chloroquine or hydroxychloroquine, lopinavir/ritonavir, or lopinavir/ritonavir plus interferon beta-1a). As of July 4, 2020, the treatment arms in hospitalized patients that include hydroxychloroquine, chloroquine, or lopinavir/ritonavir have been discontinued owing to the drugs showing little or no reduction in mortality compared with standard of care. [146]

The urgent need for treatments during a pandemic can confound the interpretation of resulting outcomes of a therapy if data are not carefully collected and controlled. Andre Kalil, MD, MPH, writes of the detriment of drugs used as a single-group intervention without a concurrent control group that ultimately lead to no definitive conclusion of efficacy or safety. [147]

Rome and Avorn write about unintended consequences of allowing widening access to experimental therapies. First, efficacy is unknown and may be negligible, but, without appropriate studies, physicians will not have evidence on which to base judgement. Existing drugs with well-documented adverse effects (eg, hydroxychloroquine) subject patients to these risks without proof of clinical benefit. Expanded access of unproven drugs may delay implementation of randomized controlled trials. In addition, demand for unproven therapies can cause shortages of medications that are approved and indicated for other diseases, thereby leaving patients who rely on these drugs for chronic conditions without effective therapies. [148]

Drug shortages during the pandemic go beyond off-label prescribing of potential treatments for COVID-19. Drugs that are necessary for ventilated and critically ill patients and widespread use of inhalers used for COPD or asthma are in demand. [149, 150]

It is difficult to carefully evaluate the onslaught of information that has emerged regarding potential COVID-19 therapies within a few months’ time in early 2020. A brief but detailed approach regarding how to evaluate resulting evidence of a study has been presented by F. Perry Wilson, MD, MSCE. By using the example of a case series of patients given hydroxychloroquine plus azithromycin, he provides clinicians with a quick review of critical analyses. [151]

For more information on investigational drugs and biologics being evaluated for COVID-19, see Treatment of Coronavirus Disease 2019 (COVID-19): Investigational Drugs and Other Therapies.

Additional information for investigational drugs and biologics can be obtained from the following resources:

Related articles

See the article Coronavirus Disease 2019 (COVID-19) in Emergency Medicine.

The Medscape article Acute Respiratory Distress Syndrome (ARDS) includes discussions of fluid management, noninvasive ventilation and high-flow nasal cannula, mechanical ventilation, and extracorporeal membrane oxygenation.

Some have raised concerns over whether patients with respiratory distress have presentations more like those of high-altitude pulmonary edema (HAPE) than ARDS.

See also the articles Viral Pneumonia, Respiratory Failure, Septic Shock, and Multiple Organ Dysfunction Syndrome in Sepsis.

Medscape resources describing relevant procedures are as follows:

Ventilator application techniques

Ventilator management and monitoring

Respiratory conditions assessment and management

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Medical Care

For more information on investigational drugs and biologics being evaluated for COVID-19, see Treatment of Coronavirus Disease 2019 (COVID-19): Investigational Drugs and Other Therapies.

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Prevention

No vaccine is currently available for SARS-CoV-2. Avoidance is the principal method of deterrence.

General measures for prevention of viral respiratory infections include the following: [28]

  • Handwashing with soap and water for at least 20 seconds. An alcohol-based hand sanitizer may be used if soap and water are unavailable.
  • Individuals should avoid touching their eyes, nose, and mouth with unwashed hands.
  • Individuals should avoid close contact with sick people.
  • Sick people should stay at home (eg, from work, school).
  • Coughs and sneezes should be covered with a tissue, followed by disposal of the tissue in the trash.

Frequently touched objects and surfaces should be cleaned and disinfected regularly.

Preventing/minimizing community spread of COVID-19

The CDC has recommended the below measures to mitigate community spread. [152, 153, 9]

All individuals in areas with prevalent COVID-19 should be vigilant for potential symptoms of infection and should stay home as much as possible, practicing social distancing (maintaining a distance of 6 feet from other persons) when leaving home is necessary.

Persons with an increased risk for infection—(1) individuals who have had close contact with a person with known or suspected COVID-19 or (2) international travelers (including travel on a cruise ship)—should observe increased precautions. These include (1) self-quarantine for at least 2 weeks (14 days) from the time of the last exposure and distancing (6 feet) from other persons at all times and (2) self-monitoring for cough, fever, or dyspnea with temperature checks twice a day.

On April 3, 2020, the CDC issued a recommendation that the general public, even those without symptoms, should begin wearing face coverings in public settings where social-distancing measures are difficult to maintain in order to abate the spread of COVID-19. [9]

Facemasks

In a 2020 study on the efficacy of facemasks in preventing acute respiratory infection, surgical masks worn by patients with such infections (rhinovirus, influenza, seasonal coronavirus [although not SARS-CoV-2 specifically]) were found to reduce the detection of viral RNA in exhaled breaths and coughs. Specifically, surgical facemasks were found to significantly decreased detection of coronavirus RNA in aerosols and influenza virus RNA in respiratory droplets. The detection of coronavirus RNA in respiratory droplets also trended downward. Based on this study, the authors concluded that surgical facemasks could prevent the transmission of human coronaviruses and influenza when worn by symptomatic persons and that this may have implications in controlling the spread of COVID-19. [44]

In a 2016 systematic review and meta-analysis, Smith et al found that N95 respirators did not confer a significant advantage over surgical masks in protecting healthcare workers from transmissible acute respiratory infections. [45]

Bae et al, in a letter to Annals of Internal Medicine, reported that surgical and cotton masks were ineffective at containing cough droplets of SARS CoV-2 in a study conducted in two hospitals in Seoul, South Korea. [46] Although the study methods were somewhat questionable in terms of mimicking natural transmission (the patients were asked to cough on culture plates placed 20 cm from their mouths), the results may indicate the value of maintaining social distancing even while a mask is worn. [46]

Investigational agents for postexposure prophylaxis

PUL-042

PUL-042 (Pulmotech, MD Anderson Cancer Center, and Texas A&M) is a solution for nebulization with potential immunostimulating activity. It consists of two toll-like receptor (TLR) ligands: Pam2CSK4 acetate (Pam2), a TLR2/6 agonist, and the TLR9 agonist oligodeoxynucleotide M362.

PUL-042 binds to and activates TLRs on lung epithelial cells. This induces the epithelial cells to produce peptides and reactive oxygen species (ROS) against pathogens in the lungs, including bacteria, fungi, and viruses. M362, through binding of the CpG motifs to TLR9 and subsequent TLR9-mediated signaling, initiates the innate immune system and activates macrophages, natural killer (NK) cells, B cells, and plasmacytoid dendritic cells; stimulates interferon-alpha production; and induces a T-helper 1 cells–mediated immune response. Pam2CSK4, through TLR2/6, activates the production of T-helper 2 cells, leading to the production of specific cytokines. [154]

In May 2020, the FDA approved initiation of two COVID-19 phase 2 clinical trials of PUL-042 at up to 20 US sites. The trials are for the prevention of infection with SARS-CoV-2 and the prevention of disease progression in patients with early COVID-19. In the first study, up to 4 doses of PUL-042 or placebo will be administered to 200 participants via inhalation over a 10-day period to evaluate the prevention of infection and reduction in severity of COVID-19. In the second study, 100 patients with early symptoms of COVID-19 will receive PUL-042 up to 3 times over 6 days. Each trial will monitor participants for 28 days to assess effectiveness and tolerability. [155, 156]

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Investigational Antiviral Agents

Remdesivir

The broad-spectrum antiviral agent remdesivir (GS-5734; Gilead Sciences, Inc) is a nucleotide analog prodrug. On May 1, 2020, The US FDA issued EUA of remdesivir to allow emergency use of the agent for severe COVID-19 (confirmed or suspected) in hospitalized adults and children. [24, 25] Phase 1 trials of an inhaled nebulized version were initiated in late June 2020 to determine if remdesivir can be used on an outpatient basis and at earlier stages of disease. [157]

Remdesivir was studied in clinical trials for Ebola virus infections but showed limited benefit. [158] Remdesivir has been shown to inhibit replication of other human coronaviruses associated with high morbidity in tissue cultures, including severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012. Efficacy in animal models has been demonstrated for SARS-CoV and MERS-CoV. [159]

Several phase 3 clinical trials are testing remdesivir for treatment of COVID-19 in the United States, South Korea, and China. Positive results were seen with remdesivir after use by the University of Washington in the first case of COVID-19 documented on US soil in January 2020. [160] The drug was prescribed under an open-label compassionate use protocol, but the US FDA has since moved to allow expanded access to remdesivir, permitting approved sites to prescribe the investigational product for multiple patients under protocol without requesting permission for each. [161] An adaptive randomized trial of remdesivir coordinated by the National Institute of Health (NCT04280705) was started first against placebo, but additional therapies can be added to the protocol as evidence emerges. The first experience with this study involved passengers of the Diamond Princess cruise ship in quarantine at the University of Nebraska Medical Center in February 2020 after returning to the United States from Japan following an on-board outbreak of COVID-19. [162] Trials of remdesivir for moderate and severe COVID-19 compared with standard of care and varying treatment durations are ongoing.

EUA of remdesivir was based on preliminary data analysis of the Adaptive COVID-19 Treatment Trial (ACTT) was announced April 29, 2020. The analysis included 1,063 hospitalized patients with advanced COVID-19 and lung involvement, showing that patients who received remdesivir recovered faster than similar patients who received placebo. Preliminary results indicate that patients who received remdesivir had a 31% faster time to recovery than those who received placebo (P< 0.001). Specifically, the median time to recovery was 11 days in patients treated with remdesivir compared with 15 days in those who received placebo. Results also suggested a survival benefit by day 14, with a mortality rate of 7.1% in the remdesivir group, compared with 11.9% in the placebo group, but this was not statistically significant. [26]

The ACTT results differ from a smaller randomized trial conducted in China and published hours before the press release by the NIH. Results from this randomized, double-blind, placebo-controlled, multicenter trial (n = 237; 158 to remdesivir and 79 to placebo; 1 patient withdrew) found remdesivir was not associated with statistically significant clinical benefits, measured as time to clinical improvement, in adults hospitalized with severe COVID-19. Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less. The authors concluded that numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. [163]

The open-label phase 3 SIMPLE trial (n = 397) in hospitalized patients with severe COVID-19 disease not requiring mechanical ventilation showed similar improvement in clinical status with the 5-day remdesivir regimen compared with the 10-day regimen on day 14 (OR: 0.75 [95% CI 0.51-1.12]). In this study, 65% of patients who received a 5-day course of remdesivir showed a clinical improvement of at least 2 points on the 7-point ordinal scale at day 14, compared with 54% of patients who received a 10-day course. After adjustment for imbalances in baseline clinical status, patients receiving a 10-day course of remdesivir had a distribution in clinical status at day 14 that was similar to that of patients receiving a 5-day course (P = 0.14). The study demonstrates the potential for some patients to be treated with a 5-day regimen, which could significantly expand the number of patients who could be treated with the current supply of remdesivir. The trial is continuing with an enrollment goal of 6,000 patients. [163]

Similarly, the phase 3 SIMPLE II trial in patients with moderate COVID-19 disease showed that 5 days of remdesivir treatment was 65% more likely to yield clinical improvement at day 11 than standard of care (P = 0.18). These data show that early intervention with a 5-day treatment course can significantly improve outcomes. [164]

The first published report concerning remdesivir compassionate use described clinical improvement in 36 of 53 hospitalized patients (68%) with severe COVID-19. At baseline, 30 patients (57%) were receiving ventilation and 4 (8%) extracorporeal membrane oxygenation (ECMO). Measurement of efficacy requires randomized, placebo-controlled trials. [165]

Observations during compassionate use follow-up (median of 18 days) included the following:

  • Oxygen-support class improved in 36 patients (68%), including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated.
  • Twenty-five patients (47%) were discharged.
  • Seven patients (13%) died.
  • The mortality rate was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation.

An in vitro study showed that the antiviral activity of remdesivir plus interferon beta (IFNb) was superior to that of lopinavir/ritonavir (LPV/RTV; Kaletra, Aluvia; AbbVie Corporation). Prophylactic and therapeutic remdesivir improved pulmonary function and reduced lung viral loads and severe lung pathology in mice, whereas LPV/RTV-IFNb slightly reduced viral loads without affecting other disease parameters. Therapeutic LPV/RTV-IFNb improved pulmonary function but did not reduce virus replication or severe lung pathology. [166]

Drug interactions with remdesivir

Coadministration of remdesivir is not recommended with chloroquine or hydroxychloroquine. Based on in vitro data, chloroquine demonstrated an antagonistic effect on the intracellular metabolic activation and antiviral activity of remdesivir. [25]

Other Early-Stage Investigational Antivirals

Nitazoxanide

Nitazoxanide extended-release tablets (NT-300; Romark Laboratories) inhibit replication of a broad range of respiratory viruses in cell cultures, including SARS-CoV-2. Two phase 3 trials for prevention of COVID-19 are being initiated in high-risk populations, including elderly residents of long-term care facilities and healthcare workers. In addition to the prevention studies, a third trial for early treatment of COVID-19 is planned. [167, 168]

Ivermectin

Ivermectin, an antiparasitic drug, showed in vitro reduction of viral RNA in Vero-hSLAM cells 2 hours postinfection with SARS-CoV-2 clinical isolate Australia/VIC01/2020. [169] The authors note that this preliminary study does not translate to human use and the effective dose is not established at this early stage of discovery. More research is needed to determine if an antiviral effect would be elicited in humans, as the concentrations tested were much higher than what is achieved from the normal oral dose.

Available pharmacokinetic data from clinically relevant and excessive dosing studies indicate that the SARS-CoV-2 inhibitory concentrations for ivermectin are not likely attainable in humans. [170]

Chaccour et al believe the recent findings regarding ivermectin warrant rapid implementation of controlled clinical trials to assess efficacy against COVID-19. They also raise concerns regarding ivermectin-associated neurotoxicity, particularly in patients with a hyperinflammatory state possible with COVID-19. In addition, drug interactions with potent CYP3A4 inhibitors (eg, ritonavir) warrant careful consideration of coadministered drugs. Finally, evidence suggests that ivermectin plasma levels with meaningful activity against COVID-19 would not be achieved without potentially toxic increases in ivermectin doses in humans. More data are needed to assess pulmonary tissue levels in humans. [171]

A retrospective cohort study (n = 280) in hospitalized patients with confirmed SARS-CoV-2 infection at four Florida hospitals showed significantly lower mortality rates in those who received ivermectin compared with usual care (15% vs 25.2%; P = 0.03). The mortality rate was also lower among 75 patients with severe pulmonary disease treated with ivermectin (38.8% vs 80.7%; P = 0.001), although the rate of successful extubation did not differ significantly. [172]

Table 1. Other Investigational Antivirals for COVID-19 (Open Table in a new window)

Antiviral Agent Description
Favipiravir (Avigan; Fujifilm Pharmaceuticals, Japan) [173, 174] Oral antiviral approved for the treatment of influenza in Japan. It selectively inhibits RNA polymerase, which is necessary for viral replication. In the United States, a phase 2 trial will enroll approximately 50 patients with COVID-19, in collaboration with Brigham and Women's Hospital, Massachusetts General Hospital, and the University of Massachusetts Medical School.
Merimepodib (VicromaxTM; ViralClear Pharmaceuticals, BioSig Technologies) [175, 176] Oral antiviral in phase 2 trial in combination with remdesivir initiated in June 2020. The mechanism of merimepodib is believed to be inhibition of inosine-5’-monophosphate dehydrogenase (IMPDH), leading to a depletion of guanosine for use by the viral polymerase during replication.
Niclosamide (FW-1002; FirstWave Bio) [177] Anthelmintic agent that has potential use as an antiviral agent. A proprietary formulation that targets the viral reservoir in the gut to decrease prolonged infection and transmission has been developed. Initiation of a phase 2a/2b study is planned for mid-2020.
Rintatolimod (Poly I:Poly C12U; Ampligen; AIM ImmunoTech) [178, 179] Toll-like receptor 3 (TLR-3) agonist that is being tested as a potential treatment for COVID-19 by the National Institute of Infectious Diseases (NIID) in Japan and the University of Tokyo. It is a broad-spectrum antiviral agent.
Beta-D-N4-hydroxycytidine (NHC, EIDD-2801) [180, 181] Orally bioavailable broad-spectrum antiviral. When administered both prophylactically and therapeutically to mice infected with SARS-CoV, NHC improved pulmonary function and reduced virus titer and body weight loss. It was announced that clinical trials will soon move to humans.
Bemcentinib (BerGenBio ASA) [182] Selective oral AXL kinase inhibitor, has previously been reported to exhibit potent antiviral activity in preclinical models against several enveloped viruses, including Ebola and Zika virus. Recent data have expanded this to SARS-CoV-2. A phase 2 study of bemcentinib in hospitalized patients with COVID-19 is planned as part of the UK’s Accelerating COVID-19 Research and Development (ACCORD) initiative.
Umifenovir (Arbidol)

Antiviral drug that binds to hemagglutinin protein; it is used in China and Russia to treat influenza. In a structural and molecular dynamics study, Vankadari corroborated that the drug target for umifenovir is the spike glycoproteins of SARS-CoV-2, similar to that of H3N2. [183] A retrospective study of non-ICU hospitalized patients (n = 81) with COVID-19 conducted in China did not show an improved prognosis or accelerated viral clearance. [184] Another study (n = 86) that compared lopinavir/ritonavir or umifenovir monotherapy with standard care in patients with mild-to-moderate COVID-19 showed no statistical difference between each treatment group. [185] In India, a phase 3 trial combining 2 antiviral agents, favipiravir and umifenovir, started in May 2020. [174]

Plitidepsin (Aplidin; PharmaMar) Member of the compound class known as didemnins. In vitro studies from Spain report plitidepsin potentially targets EF1A, which is key to multiplication and spread of the virus. [186]
VIR-2703 (ALN-COV; Vir Biotechnology Inc and Alnylam Pharmaceuticals, Inc) [187] In vitro data shows the drug targets small interfering RNA (siRNA). RNA interference (RNAi) is a natural cellular process of gene silencing. The siRNA molecules mediate RNAi function by silencing messenger RNA (mRNA). mRNA is the genetic precursor that encodes for disease-causing proteins. The companies plan to advance development of the drug candidate as an inhalational formulation.
EIDD-2801 (Merck, Ridgeback Bio) [188, 189] Oral nucleoside analogue. Phase 1 trials have been completed. Two phase 2 clinical trials were initiated in June 2020 in both inpatient and outpatient settings.
Emetine hydrochloride (Acer Therapeutics) [190] Active ingredient of syrup of ipecac (given orally to induce emesis), has been formulated as an injection to treat amebiasis. Clinical trials have been conducted for viral hepatitis and varicella-zoster virus infection. Several in vitro studies have demonstrated potency against DNA and RNA-replicating viruses, including Zika, Ebola, Rabies Lyssavirus, CMV, HIV, influenza A, echovirus, metapneumovirus, and HSV2. It is also a potent inhibitor of multiple genetically distinct coronaviruses. Plans are underway to evaluate the safety and antiviral activity of emetine with an adaptive design phase 2/3 randomized, blinded, placebo-controlled multicenter trial in high-risk symptomatic adults with confirmed COVID-19 not requiring hospitalization.
AT-527 (Atea Pharmaceuticals) [191] Oral purine nucleotide prodrug designed to inhibit RNA polymerase enzyme. It has demonstrated in vitro and in vivo antiviral activity against several enveloped single-stranded RNA viruses, including human flaviviruses and coronaviruses. IND for phase 2 study accepted by FDA for patients hospitalized with moderate COVID-19.
Trabedersen (OT-101; Mateon Therapeutics, Oncotelic) [192] Antisense oligonucleotide that inhibits transforming growth factor (TGF)-beta2 expression. Viral replication requires cell cycle arrest that is mediated by viral induction of TBF-beta. IND for phase 2 randomized, controlled, multicenter trial submitted to FDA.
Stannous protoporphyrin (SnPP; RBT-9; Renibus Therapeutics) [193] Antiviral agent in phase 2 trial for treatment of COVID-19 in patients who are at high risk of deteriorating health owing to age or comorbid conditions (eg, kidney or cardiovascular disease).
Antroquinonol (Hocena; Golden Biotechnology Corp) [194] Antiviral/anti-inflammatory agent. Reduces viral nucleic acid replication and viral protein synthesis in both cell and animal experiments. Prevention of organ and tissue damage was also observed with antroquinonol when treating mice with excessive inflammation. The FDA has accepted the IND for a phase 2 clinical trial in patients with mild-to-moderate COVID-19 pneumonia.
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Immunomodulators and Other Investigational Therapies

Various methods of immunomodulation are being quickly examined, mostly by repurposing existing drugs, in order blunt the hyperinflammation caused by cytokine release. Interleukin (IL) inhibitors, Janus kinase inhibitors, and interferons are just a few of the drugs that are in clinical trials. Ingraham et al provide a thorough explanation and diagram of the SARS-CoV-2 inflammatory pathway and potential therapeutic targets. [195]

Interleukin Inhibitors

Interleukin (IL) inhibitors may ameliorate severe damage to lung tissue caused by cytokine release in patients with serious COVID-19 infections. Several studies have indicated a “cytokine storm” with release of IL-6, IL-1, IL-12, and IL-18, along with tumor necrosis factor alpha (TNFα) and other inflammatory mediators. The increased pulmonary inflammatory response may result in increased alveolar-capillary gas exchange, making oxygenation difficult in patients with severe illness.

Interleukin-6 inhibitors

IL-6 is a pleiotropic proinflammatory cytokine produced by various cell types, including lymphocytes, monocytes, and fibroblasts. SARS-CoV-2 infection induces a dose-dependent production of IL-6 from bronchial epithelial cells. This cascade of events is the rationale for studying IL-6 inhibitors. As of June 2020, the NIH guidelines note insufficient data to recommend for or against use of IL-6 inhibitors. [196]

On March 16, 2020, Sanofi and Regeneron announced initiation of a phase 2/3 trial of the IL-6 inhibitor sarilumab (Kevzara). The United States–based component of the trial will be initiated in New York. The multicenter, double-blind, phase 2/3 trial has an adaptive design with two parts and is anticipated to enroll up to 400 patients. The first part will recruit patients with severe COVID-19 infection across approximately 16 US sites, and will evaluate the effect of sarilumab on fever and the need for supplemental oxygen. The second, larger, part of the trial will evaluate improvement in longer-term outcomes, including preventing death and reducing the need for mechanical ventilation, supplemental oxygen, and/or hospitalization. [197]

Based on the phase 2 trial analysis, the ongoing phase 3 design was modified on April 27, 2020, to include only higher-dose sarilumab (400 mg) or placebo in critical patients (ie, requiring mechanical ventilation or high-flow oxygenation or ICU admission). In the preliminary phase 2 analysis, sarilumab had no notable benefit on clinical outcomes when combining the severe (ie, required oxygen supplementation) and critical groups versus placebo. However, there were negative trends for most outcomes in the severe group, while there were positive trends for all outcomes in the critical group. [198]

Phase 2 data for critical patients in the 400-mg group (n=145) compared with placebo (n=77), respectively, included the following: [198]

  • Change from baseline C-reactive protein level: -79% versus -21%
  • Died: 23% versus 27%
  • Remained on ventilator: 9% versus 27%
  • Clinical improvement: 59% versus 41%
  • Off oxygenation: 58% versus 41%
  • Discharged: 53% versus 41%

Another IL-6 inhibitor, tocilizumab (Actemra), is part of several randomized, double-blind, placebo-controlled phase 3 clinical trials to evaluate the safety and efficacy of tocilizumab plus standard of care in hospitalized adult patients with severe COVID-19 pneumonia compared to placebo plus standard of care. The REMDACTA study adds tocilizumab to a regimen of remdesivir in hospitalized patients with severe COVID-19 pneumonia. The COVACTA study is nearing enrollment completion to evaluate tocilizumab plus standard of care versus standard of care alone in patients hospitalized with severe COVID-19. In addition, the EMPACTA study will focus on trials in sites known to provide critical care to underserved and minority populations. [199]

An observational study of 239 consecutive patients with severe COVID-19 was conducted at Yale (New Haven, CT). Patients were treated with a standardized algorithm that included tocilizumab to treat cytokine release syndrome. These early observations showed that, despite a surge of hospitalizations, tocilizumab-treated patients (n = 153) comprised 90% of those with severe disease, but their survival rate was similar to that in patients with nonsevere disease (83% vs 91%; P = 0.11). In tocilizumab-treated patients requiring mechanical ventilation, the survival rate was 75%. Oxygenation and inflammatory biomarkers (eg, high-sensitivity C-reactive protein, IL-6) improved; however, D-dimer and soluble IL-2 receptor levels increased significantly. [200] Similarly, a small compassionate use study (n = 27) found that a single 400-mg IV dose of tocilizumab reduced inflammation, oxygen requirements, vasopressor support, and mortality. [201]

A study compared outcomes of patients who received tocilizumab (n = 78) with tocilizumab-untreated controls in patients with COVID-19 requiring mechanical ventilation. Tocilizumab was associated with a 45% reduction in hazard of death (hazard ratio 0.55 [95% CI 0.33, 0.90]) and improved status on the ordinal outcome scale (odds ratio per one-level increase: 0.59 [0.36, 0.95]). Tocilizumab was associated with an increased incidence of superinfections (54% vs 26%; P< 0.001); however, there was no difference in 28-day case fatality rate among tocilizumab-treated patients with superinfection versus those without superinfection (22% vs 15%; P = 0.42). [202]

An observational study in New Jersey showed an improved survival rate among patients who received tocilizumab. Among 547 ICU patients, including 134 receiving tocilizumab in the ICU, an exploratory analysis found a trend toward an improved survival rate of 54% who received tocilizumab compared with 44% who did not receive the therapy and a propensity adjusted hazard ratio of 0.76. [203]

However, an Italian study was halted after enrolling 126 patients with COVID-19 pneumonia, about one-third of the intended number, because the interim analysis showed it did not reduce severe respiratory symptoms, intensive care, or death compared with standard care. [204]

An open label, non-controlled, non–peer reviewed study was conducted in China in 21 patients with severe respiratory symptoms related to COVID-19. All had a confirmatory diagnosis of SARS-CoV-2 infection. The patients in the trial had a mean age of 56.8 years (18 of 21 were male). Although all patients met enrollment criteria of (1) respiratory rate of 30 breaths/min or more, (2) SpO2 of 93% or less, and (3) PaO2/FiO2 of 300 mm Hg or less, only two of the patients required invasive ventilation. The other 19 patients received various forms of oxygen delivery, including nasal cannula, mask, high-flow oxygen, and noninvasive ventilation. All patients received standard of care, including lopinavir and methylprednisolone. Patients received a single dose of 400 mg tocilizumab via intravenous infusion. In general, the patients improved with lower oxygen requirements, lymphocyte counts returned to normal, and 19 patients were discharged with a mean of 15.5 days after tocilizumab treatment. The authors concluded that tocilizumab was an effective treatment in patients with severe COVID-19. [205]

A retrospective review of 25 patients with confirmed severe COVID-19 who received tocilizumab plus investigational antivirals showed patients who received tocilizumab experienced a decline in inflammatory markers, radiological improvement, and reduced ventilatory support requirements. The authors acknowledged the study’s limitations and the need for adequately powered randomized controlled trials of tocilizumab. [206]

Nonetheless, these conclusions should be viewed with extreme caution. No controls were used in this study, and only one patient was receiving invasive mechanical ventilation. In addition, all patients were receiving standard therapy for at least a week before tocilizumab was started. AWP for 400 mg of tocilizumab is $2765.

Another anti-interleukin-6 receptor monoclonal antibody (TZLS-501; Tiziana Life Sciences and Novimmune) is currently under development. [207]

Interleukin-1 inhibitors

Endogenous IL-1 levels are elevated in individuals with COVID-19 and other conditions, such as severe CAR-T-cell–mediated cytokine-release syndrome. Anakinra has been used off-label for this indication. As of June 2020, the NIH guidelines note insufficient data to recommend for or against use of IL-1 inhibitors. [208]

Several studies involving the IL-1 inhibitor anakinra (Kineret) have emerged. A retrospective study in Italy looked at patients with COVID-19 and moderate-to-severe ARDS who were managed with noninvasive ventilation outside of the ICU. The study compared outcomes of patients who received anakinra (5 mg/kg IV BID [high-dose] or 100 mg SC BID [low-dose]) plus standard treatment (ie, hydroxychloroquine 200 mg PO BID and lopinavir/ritonavir 400 mg/100 mg PO BID) with standard of care alone. At 21 days, treatment with high-dose anakinra was associated with reductions in serum C-reactive protein levels and progressive improvements in respiratory function in 21 (72%) of 29 patients; 5 (17%) patients were on mechanical ventilation and 3 (10%) died. In the standard treatment group, 8 (50%) of 16 patients showed respiratory improvement at 21 days; 1 (6%) patient was on mechanical ventilation and 7 (44%) died. At 21 days, survival was 90% in the high-dose anakinra group and 56% in the standard treatment group (P = 0.009). [209]

A study in Paris from March 24 to April 6, 2020, compared outcomes of 52 consecutive patients with COVID-19 who were given anakinra with 44 historical cohort patients. Admission to the ICU for invasive mechanical ventilation or death occurred in 13 (25%) patients in the anakinra group and 32 (73%) patients in the historical group (hazard ratio [HR] 0.22 [95% CI, 0.11-0.41; P< 0.0001). Similar results were observed for death alone (HR 0.30 [95% CI, 0.12-0.71]; P = 0.0063) and need for invasive mechanical ventilation alone (0.22 [0.09-0.56]; P = 0.0015). [210]

Corticosteroids

The UK RECOVERY trial showed that low-dose dexamethasone (6 mg PO or IV daily for 10 days) randomized to 2104 patients reduced deaths by 35% in ventilated patients (P = 0.0003) and by 20% in other patients receiving oxygen only (P = 0.0021) compared with patients who received standard of care (n = 4321). No benefit was seen in patients who did not require respiratory intervention (P = 0.14). [211]

Corticosteroids are not generally recommended for treatment of viral pneumonia. [212] The benefit of corticosteroids in septic shock results from tempering the host immune response to bacterial toxin release. The incidence of shock in patients with COVID-19 is relatively low (5% of cases). It is more likely to produce cardiogenic shock from increased work of the heart need to distribute oxygenated blood supply and thoracic pressure from ventilation. Corticosteroids can induce harm through immunosuppressant effects during the treatment of infection and have failed to provide a benefit in other viral epidemics, such as respiratory syncytial virus (RSV) infection, influenza infection, SARS, and MERS. [213]

Early guidelines for management of critically ill adults with COVID-19 specified when to use low-dose corticosteroids and when to refrain from using corticosteroids. The recommendations depended on the precise clinical situation (eg, refractory shock, mechanically ventilated patients with ARDS); however, these particular recommendations were based on evidence listed as weak. [214] The results from the RECOVERY trial in June 2020 provided evidence for clinicians to consider when low-dose corticosteroids would be beneficial. [211]

A study describing clinical outcomes of patients diagnosed with COVID-19 was conducted in Wuhan, China (N = 201). Eighty-four patients (41.8%) developed ARDS, and of those, 44 (52.4%) died. Among patients with ARDS, treatment with methylprednisolone decreased the risk of death (HR, 0.38; 95% CI, 0.20-0.72). [103]

Researchers at Henry Ford Hospital in Detroit implemented a protocol on March 20, 2020, using early, short-course, methylprednisolone 0.5-1 mg/kg/day divided in 2 IV doses for 3 days in patients with moderate-to-severe COVID-19. Outcomes of pre- and post-corticosteroid groups were evaluated. A composite endpoint of escalation of care from ward to ICU, new requirement for mechanical ventilation, or mortality was the primary outcome measure. All patients had at least 14 days of follow-up. They analyzed 213 eligible patients, 81 (38%) and 132 (62%) in pre-and post-corticosteroid groups, respectively. The composite endpoint occurred at a significantly lower rate in the post-corticosteroid group than in the pre-corticosteroid group (34.9% vs 54.3%; P = 0.005). This treatment effect was observed within each individual component of the composite endpoint. A significant reduction in median hospital length of stay was observed in the post-corticosteroid group (8 vs 5 days; P< 0.001). [215]

Convalescent Plasma

The FDA is facilitating access to convalescent plasma, antibody-rich products that are collected from eligible donors who have recovered from COVID-19. Convalescent plasma has not yet been shown to be effective in COVID-19. The FDA states that it is important to determine its safety and efficacy via clinical trials before routinely administering convalescent plasma to patients with COVID-19.

The FDA has posted information for investigators wishing to study convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 through the process of single-patient emergency Investigational New Drug (IND) applications for individual patients. The FDA is also actively engaging with researchers to discuss the possibility of collaboration on the development of a master protocol for use of convalescent plasma, with the goal of reducing duplicative efforts. [216]

The use of convalescent plasma has a long history in the treatment of infectious diseases. Writing in the Journal of Clinical Investigation Casadevall and Pirofski [217] proposed using it as a treatment for COVID-19, and Bloch et al [218] laid out a conceptual framework for implementation. To date, two small case series have been published. [219, 220] These series reported improvement in oxygenation, sequential organ failure assessment (SOFA) scores, and eventual ventilator weaning in some patients. The timelines of improvement varied from days to weeks. Caution is advised, as these were not controlled trials and other pharmacologic methods (antivirals) were used in some patients. [220]

An open-label study (n = 103) of patients with laboratory-confirmed COVID-19 in Wuhan, China, given convalescent plasma did not result in a statistically significant improvement in time to clinical improvement within 28 days compared with standard of care alone. [221]

A nonrandomized study transfused patients based on supplemental oxygen needs with convalescent plasma from donors with a SARS-CoV-2 anti-spike antibody titer of at least 1:320 dilution. Matched control patients were retrospectively identified within the electronic health record database. Supplemental oxygen requirements and survival were compared between plasma recipients and controls. Results showed convalescent plasma transfusion improved survival in nonintubated patients (P = 0.015), but not in intubated patients (P = 0.752). [222]

Nitric Oxide

Published findings from the 2004 SARS-CoV infection suggest the potential role of inhaled nitric oxide (iNO; Mallinckrodt Pharmaceuticals, plc) as a supportive measure for treating infection in patients with pulmonary complications. Treatment with iNO reversed pulmonary hypertension, improved severe hypoxia, and shortened the length of ventilatory support compared with matched control patients with SARS. [223]

A phase 2 study of iNO is underway in patients with COVID-19 with the goal of preventing disease progression in those with severe ARDS. [224] A phase 3 study (PULSE-CVD19-001) for iNO (INOpulse; Bellerophon Therapeutics) was accepted by the FDA in mid-March 2020 to evaluate efficacy and safety in patients diagnosed with COVID-19 who require supplemental oxygen before the disease progresses to necessitate mechanical ventilation support. [225] The Society of Critical Care Medicine recommends against the routine use of iNO in patients with COVID-19 pneumonia. Instead, they suggest a trial only in mechanically ventilated patients with severe ARDS and hypoxemia despite other rescue strategies. [214] The cost of iNO is reported as exceeding $100/hour.

JAK and NAK Inhibitors

Drugs that target numb-associated kinase (NAK) may mitigate systemic and alveolar inflammation in patients with COVID-19 pneumonia by inhibiting essential cytokine signaling involved in immune-mediated inflammatory response. In particular, NAK inhibition has been shown to reduce viral infection in vitro. ACE2 receptors are a point of cellular entry by COVID-19, which is then expressed in lung AT2 alveolar epithelial cells. A known regulator of endocytosis is the AP2-associated protein kinase-1 (AAK1). The ability to disrupt AAK1 may interrupt intracellular entry of the virus. Baricitinib (Olumiant; Eli Lilly Co), a Janus kinase (JAK) inhibitor, is also identified as a NAK inhibitor with a particularly high affinity for AAK1. [226, 227, 228]

Mehta and colleagues describe the cytokine profile of COVID-19 as being similar to that of hemophagocytic lymphohistiocytosis (sHLH). sHLH is characterized by increased IL-2, IL-7, GCSF, INF-gamma, monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein-1 (MIP-1) alpha, and TNF-alpha. JAK inhibition may be a therapeutic option. [229]

Other selective JAK inhibitors (ie, fedratinib, ruxolitinib) may be effective against consequences of elevated cytokines, although baricitinib has the highest affinity for AAK1. [226]

Baricitinib is being studied as part of the NIAID Adaptive Covid-19 Treatment Trial, which evaluated the combination of baricitinib and remdesivir compared with remdesivir alone. [230] Another phase 3, placebo-controlled trial is studying baricitinib in hospitalized patients who have an elevated level of at least one inflammation marker but do not require invasive mechanical ventilation at study entry. [231]

A small open-labeled study (n = 12) conducted in Italy added baricitinib 4 mg/day to existing therapies (ie, lopinavir/ritonavir 250 mg BID and hydroxychloroquine 400 mg/day). All therapies were given for 2 weeks. Fever, SpO2, PaO2/FiO2, C-reactive protein, and modified early warning scores significantly improved in the baricitinib-treated group compared with controls (P: 0.000; 0.000; 0.017; 0.023; 0.016, respectively). ICU transfer occurred in 33% (4/12) of controls and in none of the baricitinib-treated patients (P = 0.093). Discharge at week 2 occurred in 58% (7/12) of the baricitinib-treated patients compared with 8% (1/12) of controls (P = 0.027). [232]

Ruxolitinib (Jakafi; Incyte) is part of the phase 3 RUXCOVID clinical trial. [233]

Pacritinib (CTI Biopharma) is a JAK2, interleukin-1 receptor-associated kinase-1 (IRAK-1), and colony stimulating factor-1 receptor (CSF-1R) inhibitor that is pending FDA approval for myelofibrosis. The phase 3 trial (PRE-VENT) has commenced to compare pacritinib with standard of care. Outcomes assessed include progression to mechanical ventilation, ECMO, or death in hospitalized patients with severe COVID-19, including those with cancer. As a JAK2/IRAK-1 inhibitor, pacritinib may ameliorate the effects of cytokine storm via inhibition of IL-6 and IL-1 signaling. Furthermore, as a CSF-1R inhibitor, pacritinib may mitigate effects of macrophage activation syndrome. [234]

Statins

In addition to the cholesterol-lowering abilities of HMG-CoA reductase inhibitors (statins), they also decrease the inflammatory processes of atherosclerosis. [235] Because of this, questions have arisen whether statins may be beneficial to reduce inflammation associated with COVID-19.

This question has been posed before with studies of patients taking statins who have acute viral infections. Virani [236] provides a brief summary of information regarding observational and randomized controlled trials (RCTs) of statins and viral infections. Some, but not all, observational studies suggest that cardiovascular outcomes were reduced in patients taking statins who were hospitalized with influenza and/or pneumonia. RCTs of statins as anti-inflammatory agents for viral infections are limited, and results have been mixed. An important factor that Virani points out regarding COVID-19 is that no harm was associated with statin therapy in previous trials of statins and viral infections, emphasizing that patients should adhere to their statin regimen.

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Additional Investigational Drugs for ARDS/Cytokine Release

Table 2. Investigational Drugs for ARDS/Cytokine Release Associated With COVID-19 (Open Table in a new window)

Therapy Description
Ifenprodil (NP-120; Algernon Pharmaceuticals) [237] N-methyl-d-aspartate (NDMA) receptor glutamate receptor antagonist. NMDA is linked to inflammation and lung injury. An injectable and long-acting oral product are under production to begin clinical trials for COVID-19 and acute lung injury. Phase 2b/3 multinational study was initiated in May 2020.
Remestemcel-L (Ryoncil; Mesoblast Ltd) [238, 239, 240] Allogeneic mesenchymal stem cell (MSC) product currently pending FDA approval for graft versus host disease (GVHD). Phase 2/3 trial for COVID-19 ARDS started to enroll patients in May 2020. The trial will take place at up to 30 medical centers in North America over 3-4 months in collaboration with the Cardiothoracic Surgical Trials Network. Theorized mechanism is down-regulation of proinflammatory cytokines.
PLX-PAD (Pluristem Therapeutics) [241] Allogeneic mesenchymal-like cells with immunomodulatory properties that induce the immune system’s natural regulatory T cells and M2 macrophages. Initiating phase 2 study in mechanically ventilated patients with severe COVID-19.
BM-Allo.MSC (NantKwest, Inc) [242] Bone marrow-derived allogeneic mesenchymal stem cell product. IND for phase 1b trial initiating Q2 2020 in Los Angeles area hospitals.
Eculizumab (Soliris; Alexion) [243] Modulates activity of terminal complement to prevent the formation of the membrane attack complex; 10-patient proof of concept completed; if 100-patient single-arm trial in the United States and Europe for 2 weeks shows a positive risk/benefit ratio, a 300-patient randomized controlled trial will proceed.
Ravulizumab (Ultomiris; Alexion) [244] Phase 3 randomized controlled trial planned in hospitalized adults with severe pneumonia or acute ARDS to evaluate complement (C5) inhibition for treatment. Trial commencement based on preclinical data of animal models suggesting inhibition of terminal complement may lower cytokine levels and reduce lung inflammation, as well as preliminary evidence from eculizumab compassionate use program.
Aviptadil (RLF-100; NeuroRx and Relief Therapeutics) [245, 246] Synthetic vasoactive intestinal peptide that prevents NMDA-induced caspase-3 activation in lungs and inhibits IL-6 and TNF-alpha production. Phase 2b/3 clinical trial for treatment of ARDS in all patients with severe COVID-19 disease and respiratory failure was initiated June 2020. As part of the drug’s enrollment in the FDA Fast Track program, in late June 2020, the FDA requested NeuroRx to submit a publicly available expanded access for hospitals not participating in the ongoing phase 2/3 clinical trials.
Tradipitant (Vanda Pharmaceuticals) [247] Neurokinin-1 (NK-1) receptor antagonist. The NK-1 receptor is coded by the TACR1 gene and is the main receptor for substance P. The substance P NK-1 receptor system is involved in neuroinflammatory processes that lead to serious lung injury following numerous insults, including viral infections. ODYSSEY phase 3 trial initiated in New York area hospitals has enrolled over 50 of 300 patients as of mid-May 2020.
Gimsilumab (Riovant) [248, 249] Phase 2 BREATHE clinical trial at Mt Sinai and Temple University is analyzing monoclonal antibody that targets granulocyte macrophage-colony stimulating factor (GM-CSF) in patients with ARDS.
Mavrilimumab (Kiniksa Pharmaceuticals [250] Open-label treatment protocol in Italy with mavrilimumab, an investigational fully human monoclonal antibody that targets granulocyte macrophage colony stimulating factor (GM-CSF) receptor alpha in patients with severe COVID-19 pneumonia and hyperinflammation. Over the course of the 14-day follow-up period, mavrilimumab-treated patients experienced greater and earlier clinical improvements than control-group patients, including earlier weaning from supplemental oxygen, shorter hospitalizations, and no deaths.
Otilimab (GlaxoSmithKline; NCT04376684) [251] Human monoclonal anti-GM-CSF antibody under development for rheumatoid arthritis. Clinical trial initiating May 2020 for severe pulmonary COVID-19.
ATYR1923 (aTyr Pharma, Inc) [252] Phase 2 randomized, double-blind, placebo-controlled trial at up to 10 centers in the United States. In preclinical studies, ATYR1923 (a selective modulator of neuropilin-2) has been shown to down-regulate T-cell responses responsible for cytokine release.
BIO-11006 (Biomark Pharmaceuticals) [253] Results of a phase 2a study for 38 ventilated patients with ARDS showed 43% reduction at day 28 in the all-cause mortality rate. This study was initiated in 2017. The company is in discussion with the FDA to proceed with a phase 3 trial.
Ibudilast (MN-166; MediciNova) [254] First-in-class, orally bioavailable, small molecule phosphodiesterases (PDE) 4 and 10 inhibitor and a macrophage migration inhibitory factor (MIF) inhibitor that suppresses proinflammatory cytokines and promotes neurotrophic factors. The drug has been approved in Japan and South Korea since 1989 to treat post-stroke complications and bronchial asthma. An IND for a phase 2 trial in the United States to prevent ARDS has been accepted by the FDA.
Dociparstat sodium (DSTAT; Chimerix) [255] Glycosaminoglycan derivative of heparin with anti-inflammatory properties, including the potential to address underlying causes of coagulation disorders. Phase 2/3 trial starting May 2020.
Trans sodium crocetinate (TSC; Diffusion Pharmaceuticals) [256] TSC was developed to enhance delivery of oxygen to hypoxic tissues, particularly cancerous tumors requiring radiation therapy. Under accelerated review by the FDA to determine if the company can proceed with a clinical trial for COVID-19–related ARDS
Opaganib (Yeliva; RedHill Biopharma Ltd) [257] Oregon Health and Science University is initiating a phase 2a study for patients with moderate-to-severe COVID-19 following a preliminary study in Israel. It has been studied in phase 1 trials in the United States. Sphingosine kinase-2 (SK2) inhibitor that may inhibit viral replication and reduce levels of IL-6 and TNF-alpha. May also elicit antiviral effects.
Tranexamic acid (LB1148; Leading BioSciences, Inc) [258] Oral/enteral protease inhibitor designed to preserve GI tract integrity and protect organs from proteases leaking from compromised mucosal barrier that can lead to ARDS. Phase 2 study announced May 15, 2020.
DAS181 (Ansun Biopharma) [259] Recombinant sialidase drug is a fusion protein that cleaves sialic receptors. Phase 3 substudy for COVID-19 added to existing study for parainfluenza infection.
TJM2 (I-MAB Biopharma) [260] TJM2 is a neutralizing antibody against human granulocyte-macrophage colony stimulating factor (GM-CSF), an important cytokine that plays a critical role in acute and chronic inflammation.
AT-001 (Applied Therapeutics) [261] Aldose reductase inhibitor shown to prevent oxidative damage to cardiomyocytes and to decrease oxidative-induced damage.
CM4620-IE (Auxora; CalciMedica, Inc) [262] Calcium release-activated calcium (CRAC) channel inhibitor that prevents CRAC channel overactivation, which can cause pulmonary endothelial damage and cytokine storm. Received IND from the FDA in April. After an interim analysis of the open-label phase 2 clinical study, the FDA recommended the study move to a blinded, placebo-controlled trial format. The first patients were enrolled at Regions Hospital in St. Paul, and additional patients were enrolled at Henry Ford Hospital in Detroit and additional sites across the United States.
Intranasal vazegepant (Biohaven Pharmaceuticals) [263] Calcitonin gene-related peptide (CGRP) receptor antagonist. Received FDA may proceed letter to initiate phase 2 study. Acute lung injury induces up-regulation of transient receptor potential (TRP) channels, activating CGRP release. CGRP contributes to acute lung injury (pulmonary edema with acute-phase cytokine/mediator release, with immunologic milieu shift toward TH17 cytokines). A CGRP receptor antagonist may blunt the severe inflammatory response at the alveolar level, delaying or reversing the path toward oxygen desaturation, ARDS, requirement for supplemental oxygenation, artificial ventilation, or death.
Selinexor (Xpovio; Karyopharma Therapeutics) [264] Selective inhibitor of nuclear export (SINE) that blocks the cellular protein exportin 1 (XPO1), which is involved in both replication of SARS-CoV-2 and the inflammatory response to the virus.
EDP1815 (Evelo Biosciences; Rutgers University; Robert Wood Johnson University Hospital) [265] Phase 2/3 trials underway in the United States and United Kingdom to determine if early intervention with oral EDP1815 (under development for psoriasis) prevents progression of COVID-19 symptoms and complications in hospitalized patients ≥15 years with COVID-19 who presented at the ER within the preceding 36 hours. The drug showed marked activity on inflammatory markers (eg, IL-6, IL-8, TNF, IL-1b) in a phase 1b study.
Acalabrutinib (Calquence; AstraZeneca; NCT04380688) [266, 267] Findings from an exploratory research project of this Bruton tyrosine kinase inhibitor showed encouraging improvement of excessive inflammation associated with COVID-19. Two phase 2 trials compared with best supportive care in hospitalized patients are underway.
VERU-111 (Veru, Inc) [268] Microtubule depolymerization agent that has broad antiviral activity and has strong anti-inflammatory effects. Phase 2 clinical trial beginning June 2020 for hospitalized patients with COIVD-19 at high risk for ARDS.
Vascular leakage therapy (Q BioMed; Mannin Research) [269] Targets the angiopoietin-Tie2 signaling pathway to reduce endothelial dysfunction.
Trans sodium crocetinate (TSC; Diffusion Pharmaceuticals) [270, 271] June 2020 human trials starting in Europe to study oxygenation-enhancing potential of TSC. Pre-IND meeting with FDA for US study as a component of standard of care for hospitalized patients with severe COVID-19 disease. In human trials to re-oxygenate hypoxic tissue in patients with glioma and stroke. TSC increases the diffusion rate of oxygen in aqueous solutions.
Rayaldee (calcifediol; OPKO Health) [272] Extended-release formulation of calcifediol (25-hydroxyvitamin D3), a prohormone of the active form of vitamin D3. Phase 2 trial (REsCue) objective is to raise and maintain serum total 25-hydroxyvitamin D levels to mitigate COVID-19 severity. Raising serum levels is believed to enable macrophages.
Deupirfenidone (LYT-100; PureTech Bio) [273] Deuterated form of pirfenidone, an approved anti-inflammatory and anti-fibrotic drug. Inhibits TGF-beta and TNF-alpha. Clinical trial starting in summer 2020 to evaluate use for serious respiratory complications, including inflammation and fibrosis, that persist following resolution of SARS-CoV-2 infection.
OP-101 (Ashvattha Therapeutics) [274] Selectively targets reactive macrophages to reduce inflammation and oxidative stress.
Vidofludimus calcium (IMU-838; Immunic Therapeutics) [275] Oral dihydroorotate dehydrogenase (DHODH) inhibitor. DHODH is located on the outer surface of the inner mitochondrial membrane. Inhibitors of this enzyme are used to treat autoimmune diseases. Phase 2 CALVID-1 clinical trial for hospitalized patients with moderate COVID-19.
Vafidemstat (ORY-2001; Oryzon) [276] Oral CNS lysine-specific histone demethylase 1 (LSD1) inhibitor. Phase 2 trial (ESCAPE) initiated in May 2020 to prevent progression to ARDS in severely ill patients with COVID-19.
Icosapent ethyl (Vascepa; Amarin Co) [277] Study focuses on reduction of circulating proinflammatory biomarkers (eg, C-reactive protein).
Prazosin (Johns Hopkins) [278, 279] Cytokine storm syndrome is accompanied by increased catecholamine release. This amplifies inflammation by enhancing IL-6 production through a signaling loop that requires the alpha1 adrenergic receptor. A clinical trial at Johns Hopkins University is using prazosin, an alpha1 receptor antagonist, to evaluate its effects to prevent cytokine storm.
Aspartyl-alanyl diketopiperazine (DA-DKP; AmpionTM; Ampio Pharmaceuticals) [280] Low-molecular weight fraction of human serum albumin (developed for inflammation associated with osteoarthritis). Theorized to reduce inflammation by suppressing pro-inflammatory cytokine production in T-cells. Phase 1 trial in patients starting July 2020.
Losmapimod (Fulcrum Therapeutics) [281] Selective inhibitor of p38alpha/beta mitogen activated protein kinase (MAPK), which is known to mediate acute response to stress, including acute inflammation. FDA authorized a phase 3 trial (LOSVID) for hospitalized patients with COVID-19 at high risk. Losmapimod has been evaluated in phase 2 clinical trials for facioscapulohumeral muscular dystrophy (FSHD).
DUR-928 (Durect Corp) [282] Endogenous epigenetic regulator. Preclinical trials have shown the drug regulates lipid metabolism, inflammation, and cell survival. The FDA accepted the IND application. A phase 2 study is planned for approximately 80 hospitalized patients with COVID-19 who have acute liver or kidney injury.
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Investigational Immunotherapies

Table 3. Investigational Immunotherapies for COVID-19 (Open Table in a new window)

Drug Description
CEL-SCI Corporation [283] Preferentially directed immunotherapy using ligand antigen epitope presentation system (LEAPS) peptide technology to reduce COVID-19 viral load and consequent lung damage.
Brilacidin (Innovation Pharmaceuticals) [284, 285] Defensin-mimetic that mimics the immune system and disrupts the pathogen membrane, leading to cell death. It is undergoing clinical-stage testing at a US regional biocontainment laboratory. Also see Table 5 for potential use as a vaccine adjuvant.
Allogeneic natural killer (NK) cells (CYNK-001; Celularity, Inc) [286] FDA-approved investigational new drug for phase 1/2 clinical trial; demonstrates a range of biological activities expected of NK cells, including expression of activating receptors such as NKG2D, DNAM-1, and the natural cytotoxicity receptors NKp30, NKp44, and NKp46, which bind to stress ligands and viral antigens on infected cells.
Autologous, adipose-derived mesenchymal stem cells (HB-adMSCs; Hope Biosciences) [287, 288, 289] Shown to attenuate systemic inflammation in phase 1/2 clinical trial for rheumatoid arthritis. FDA approves phase 2 single-arm, nonrandomized study for COVID-19 in patients ≥50 years with preexisting health conditions or at high exposure risk. Another phase II trial will enroll 100 frontline healthcare workers and first responders. A third clinical trial placebo-controlled study is planned in collaboration with advanced diagnostics healthcare.
MultiStem cell therapy (Athersys) [290] Potential to produce therapeutic factors in response to signals of inflammation and tissue damage. A previous phase 1-2 study assessed therapy in ARDS. The first patient has been enrolled in the phase 2/3 trial—MultiStem Administration for COVID-19 Induced Acute Respiratory Distress Syndrome (MACOVIA) at University Hospital’s Cleveland Medical Center.
CD24Fc (OncoImmune) [291] Biologic that fortifies an innate immune checkpoint against excessive inflammation caused by tissue injuries. Phase 3 testing was initiated April 20, 2020, at the University of Maryland. As of mid-June 2020, 70 patients have been enrolled.
LY3127804 (Eli Lilly Co) [231] Selective monoclonal antibody against angiopoietin 2 (Ang2), which is known to be elevated in patients with ARDS. Trial initiated at several US medical centers to determine if it reduces progression to ARDS or mechanical ventilation.
Bucillamine (Revive Therapeutics) [292] Bucillamine has been shown to significantly attenuate clinical symptoms in respiratory viral infections in humans, primarily via donation of thiols to restore antioxidant and to reduce the activity of cellular glutathione. A phase 3 trial for treatment of mild-to-moderate COVID-19 was approved by the FDA in late April 2020.
Peginterferon lambda (Eiger Biopharmaceuticals; Stanford University) [293] Phase 2 trial initiated in outpatients with mild COVID-19 to evaluate efficacy of reducing viral shedding. Patients receive a single SC dose and are monitored for 28 days. Interferon lambda is thought to target innate immune response against viral pathogens.
Immune globulin IV (Octagam 10%; Octapharma) [294] IND for phase 3 randomized trial accepted by FDA to assess efficacy and safety in patients with severe COVID-19 disease.
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Investigational Antibody-Directed Therapies

Table 4. Investigational Antibody-Directed Therapy Examples for COVID-19 (Open Table in a new window)

Antibody Description
Anti-SARS-CoV-2 polyclonal hyperimmune globulin (Takeda) [295] Under development to treat high-risk patients.
Monoclonal antibodies (mAb) (Regeneron) [296, 297] Clinical trials of dual mAb cocktail initiated in June 2020 for prevention and treatment of COVID-19. The 2 antibodies bind noncompetitively to the critical receptor binding domain (RBD) of the virus' spike protein, which diminishes the ability of mutant viruses to escape treatment. The clinical program consists of 4 separate study populations: hospitalized patients, nonhospitalized symptomatic patients, uninfected people in groups that are at high risk of exposure (eg, healthcare workers, first responders), and uninfected people with close exposure to an individual with COVID-19 (eg, patient's housemate).
VIR-7831 & VIR-7832 (Vir Biotechnology collaborating with Biogen and Generation Bio) [298] VIR-7831 and VIR-7832 are mAbs that binds to an epitope on SARS-CoV-2 that is shared with SARS-CoV-1, indicating the epitope is highly conserved and more difficult to mutate. Each are engineered to have an extended half-life.
Polyclonal hyperimmune immunoglobulin (TAK-888; Takeda) [299] Concentrated virus-specific antibodies from plasma collected from people who have already recovered from COVID-19.
LY-CoV555 (Eli Lilly and AbCellera) [300] Antibody treatment from more than 500 unique antibodies isolated from one of the first US patients to recover from COVID-19. Phase 1 initiated late May 2020.
JS-016 (Junshi Bioschiences and Eli Lilly) [301] Neutralizing antibody that binds a different epitope on the COVID spike protein than Lilly’s other antibody (LY-CoV555). Phase 1 trial to be initiated June 2020.
Amgen collaborating with Adaptive Biotechnologies [302] Discovery/development of fully human neutralizing antibodies targeting SARS-CoV-2.
COVI-SHIELD (Sorrento Therapeutics; NCT04376684) [303] mAb cocktail development in conjunction with Mt Sinai Health System in New York City.
Antibody combination (AstraZeneca; Vanderbilt University) [304] Phase 1 trial of a two-antibody combination product planned to start in August 2020. The two antibodies bind to distinct sites on the SARS-CoV-2 spike protein.
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Investigational Vaccines

The genetic sequence of SARS-CoV-2 was published on January 11, 2020. The rapid emergence of research and collaboration among scientists and biopharmaceutical manufacturers that followed has produced nearly 80 confirmed active vaccine candidates as of April 8, 2020. Various methods are used for vaccine discovery and manufacturing.

In addition to the complexity of finding the most effective vaccine candidates, the production process is also important for manufacturing the vaccine to the scale needed globally.

Thanh Le et al describe platforms based on DNA or mRNA that offer flexibility regarding antigen manipulation and speed of development. Recombinant protein-based development may be beneficial owing to existing large-scale production capabilities. Use of an adjuvant can be of particular importance in a pandemic situation. Adjuvants are compounds that potentiate that antigen in the vaccine, thereby reducing the amount of antigen protein required per dose. This method allows more people to be vaccinated and conserves antigen resources. [305]

Examples of vaccines under development in the United States are included in Table 5.

Table 5. Investigational Vaccines for COVID-19 (Open Table in a new window)

Vaccine Comments
mRNA-1273 (Moderna Inc) [306, 307, 308] The phase 1 study was initiated in 45 healthy volunteers March 16, 2020 at Kaiser Permanente Washington Health Research Instituted in Seattle. The phase 1 trial is evaluating 3 doses—25, 100, and 250 mcg—administered on a 2-dose schedule given 28 days apart. Phase 2 testing of placebo, 50-mcg, or 100-mcg given as 2 doses2 8 days apart in adults aged 18-55 years (n=300) and in adults aged 55 years or older (n=300) started in June. Phase 3 trial expected to launch in July 2020.
ChAdOx1 nCoV-19 vaccine (Jenner Institute, Oxford University; AstraZeneca) [309] Phase 2/3 clinical trials starting May 2020. Because of testing of a coronavirus vaccine, development is accelerated.
Two vaccine candidates (Merck in collaboration with nonprofit IAVI) [310] Developing 2 separate single-dose vaccines. After purchasing Themis Bioscience (Austrian vaccine maker), one vaccine will be based on a modified measles virus that delivers portions of SARS-CoV-2 virus. The second vaccine in collaboration with IAVI uses Merck’s Ebola vaccine technology. This vaccine is expected to start human trials in 2020.
mRNA vaccine BNT162 (BioNTech and Pfizer) [311] Joint development of BioNTech’s mRNA-based vaccine candidate is a nucleoside-modified messenger RNA (modRNA), which encodes an optimized SARS-CoV-2 receptor-binding domain (RBD) antigen. Human testing was initiated in early May 2020. Preliminary results showed the vaccine (BNT162b1) could be administered in a dose that was well tolerated and that generated dose-dependent immunogenicity as measured by RBD-binding IgG concentrations and SARS-CoV-2 neutralizing antibody titers. BNT162b1 is one of four mRNA constructs being clinically evaluated.
SARS-CoV-2 vaccine (Johnson & Johnson [J&J]) [312] Partnering with Emergent BioSolutions and Catalent for manufacturing services to utilize Janssen’s AdVac and PER.C6 technologies, which provide rapid upscale production of an optimal vaccine candidate. Initiating testing in healthy volunteers in mid-July 2020.
Saponin-based Matrix-M adjuvant vaccine (NVX-CoV2373; Novavax and Emergent BioSolutions) [313] Stimulates the entry of antigen-presenting cell into the injection site and enhances antigen presentation in local lymph nodes to boost the immune response. Phase 1/2 trials were initiated in May 2020. Funding received by the Department of Defense (DoD). Plans are to deliver 10 million doses to the DoD for phase 2/3 clinical trial contingent on preliminary data from earlier trials.
INO-4800 (Inovio Pharmaceuticals) [314, 315] The phase 1 human clinical trial enrolled 40 healthy volunteers and was completed late April 2020. Favorable interim results of safety and immunogenicity were reported in June 2020. The phase 1 trial was expanded to include older participants, and phase 2/3 efficacy trials are planned to commence in summer 2020. Inovio has received a grant from the Bill and Melinda Gates Foundation to accelerate testing and scale up a smart device (Cellectra 3PSP) for large-scale intradermal vaccine delivery.
mRNA vaccine (CureVac) [316] Vaccine is in development and not yet ready for human testing as of March 16, 2020.
COVID-19 S-Trimer (GlaxoSmithKline [GSK] and Clover Biopharmaceuticals) [317] Preclinical development is underway using GSK’s adjuvants (compounds that enhance vaccine efficacy) and Clover’s proprietary proteins, which stimulate an immune response.
XWG-03 (GlaxoSmithKline and Xiamen Innovax collaboration) [318] GSK will provide Innovax with its adjuvant system for preclinical vaccine evaluation.
CpG 1018 adjuvant (Dynavax) and Sinovac’s inactivated coronavirus vaccine candidate [319] Collaboration for adjuvanted vaccine development.
Vaccine with CpG 1018 adjuvant (Dynavax and Clover Biopharmaceuticals) [320] Dynavax is providing Clover with adjuvant for its protein-based coronavirus vaccine candidate.
CpG 1018 adjuvant (Dynavax and Valneva) [321] Dynavax is providing technical expertise and the toll-like receptor 9 (TLR9) agonist adjuvant CpG 1018. Valneva is leveraging their platform for Japanese encephalitis vaccine, which operates on a highly purified Vero-cell–based, inactivated, whole-virus strategy for vaccine development.
rDNA vaccine (Sanofi) [322] Collaborating with BARDA to develop a vaccine using their recombinant DNA platform.
Adjuvanted vaccine (GlaxoSmithKline and Sanofi) [323] Adjuvanted vaccine will be developed by combining Sanofi’s S-protein COVID-19 antigen and GSK’s pandemic adjuvant technology.
Live-attenuated vaccine (Codagenix) [324] Codagenix, a clinical-stage biotechnology company, is collaborating with the Serum Institute of India to co-develop a live-attenuated vaccine.
PCR-based DNA vaccine (Applied DNA Sciences and Takis Biotech) [325] The collaboration has designed four COVID-19 vaccine candidates utilizing PCR-based DNA manufacturing systems for preclinical testing in animals.
Intranasal COVID-19 vaccine (Altimmune, Inc) [326] Design and synthesis has been completed and is advancing toward animal testing.
Brilacidin adjuvant vaccine (Innovation Pharmaceuticals) [327] Material Transfer Agreement (MTA) signed with a leading public health-focused US university and top coronavirus expert to evaluate the potential antiviral properties as a defensing adjuvant. Also see Table 1.
HaloVax (Hoth Therapeutics; Voltron Therapeutics) [328] Collaboration with the Vaccine and Immunotherapy Center of the Massachusetts General Hospital. Use of VaxCelerate self-assembling vaccine platform offers one fixed immune adjuvant and one variable immune targeting to allow rapid development.
PittCoVax (U of Pittsburgh School of Medicine) [329] Vaccine candidate using microneedle transdermal for COVID-19. Testing in mice produced antibodies over a 2-week period. Microneedles are made of sugar, making it easy to mass-produce and store without refrigeration.
Nanoparticle SARS-CoV-2 vaccine (Ufovax) [330] Vaccine prototype development utilizing self-assembling protein nanoparticle (1c-SapNP) vaccine platform technology.
Vaccine candidate (PDS Biotechnology Corp) [331] Utilizes Versamune T-cell activating platform for vaccine development.
TNX-1800 (Tonix Pharmaceuticals and Fujifilm Diosynth Biotechnologies) [332] Modified horsepox virus that is designed to express a protein from the SARS-CoV-2 virus.
Virus-like protein (VLP) based vaccine (Catalent; Spicona) [333] Catalent will use its proprietary GPEx cell line development technology to develop a cell line expressing the recombinant VLP.
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Renin Angiotensin System Blockade and COVID-19

SARS-CoV-2 is known to utilize angiotensin-converting enzyme 2 (ACE2) receptors for entry into target cells. [334] Data are limited concerning whether to continue or discontinue drugs that inhibit the renin-angiotensin-aldosterone system (RAAS), namely angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs).

Concern arose regarding appropriateness of continuation of ACEIs and ARBs in patients with COVID-19 after early reports noted an association between disease severity and comorbidities such as hypertension, cardiovascular disease, and diabetes, which are often treated with ACEIs and ARBs. The reason for this association remains unclear. [335, 105]

The speculated mechanism for detrimental effect of ACEIs and ARBs is related to ACE2. It was therefore hypothesized that any agent that increases expression of ACE2 could potentially increase susceptibility to severe COVID-19 by improving viral cellular entry; [335] however, physiologically, ACE2 also converts angiotensin 2 to angiotensin 1-7, which leads to vasodilation and may protect against lung injury by lowering angiotensin 2 receptor binding. [105, 336] It is therefore uncertain whether an increased expression of ACE2 receptors would worsen or mitigate the effects of SARS-CoV-2 in human lungs.

Vaduganathan et al note that data in humans are limited, so it is difficult to support or negate the opposing theories regarding RAAS inhibitors. They offer an alternate hypothesis that ACE2 may be beneficial rather than harmful in patients with lung injury. As mentioned, ACE2 acts as a counterregulatory enzyme that degrades angiotensin 2 to angiotensin 1-7. SARS-CoV-2 not only appears to gain initial entry through ACE2 but also down-regulates ACE2 expression, possibly mitigating the counterregulatory effects of ACE2. [337]

There are also conflicting data regarding whether ACEIs and ARBs increase ACE2 levels. Some studies in animals have suggested that ACEIs and ARBs increase expression of ACE2, [338, 339, 340] while other studies have not shown this effect. [341, 342]

As controversy remains regarding whether ACEIs and/or ARBs increase ACE2 expression and how this effect may influence outcomes in patients with COVID-19, cardiology societies have largely recommended against initiating or discontinuing these medications based solely on active SARS-CoV-2 infection. [343, 344]

Two clinical trials are currently in development at the University of Minnesota evaluating the use of losartan in patients with COVID-19 in inpatient and outpatient settings. [345, 346] Results from these trials will provide insight into the potential role of ARBs in the treatment of COVID-19.

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Diabetes and COVID-19

High plasma glucose levels and diabetes mellitus (DM) are known risk factors for pneumonia. [347, 348] Potential mechanisms that may increase the susceptibility for COVID-19 in patients with DM include the following: [349]

  • Higher-affinity cellular binding and efficient virus entry
  • Decreased viral clearance
  • Diminished T-cell function
  • Increased susceptibility to hyperinflammation and cytokine storm syndrome
  • Presence of cardiovascular disease

SARS-CoV-2 is known to utilize angiotensin-converting enzyme 2 (ACE2) receptors for entry into target cells. Insulin administration attenuates ACE2 expression, while hypoglycemic agents (eg, glucagonlike peptide 1 [GLP-1] agonists, thiazolidinediones) up-regulate ACE2. [349] Dipeptidyl peptidase 4 (DPP-4) is highly involved in glucose and insulin metabolism, as well as in immune regulation. This protein was shown to be a functional receptor for Middle East respiratory syndrome coronavirus (MERS-CoV), and protein modeling suggests that it may play a similar role with SARS-CoV-2, the virus responsible for COVID-19. [350]

The relationship between diabetes, coronavirus infections, ACE2, and DPP-4 has been reviewed by Drucker. Important clinical conclusions of the review include the following: [348]

  • Hospitalization is more common for acute COVID-19 among patients with diabetes and obesity.
  • Diabetic medications need to be reevaluated upon admission.
  • Insulin is the glucose-lowering therapy of choice, not DPP-4 inhibitors or GLP-1 receptor agonists, in patients with diabetes who are hospitalized with acute COVID-19.
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Hydroxychloroquine, Chloroquine, and Lopinavir/Ritonavir

Hydroxychloroquine and chloroquine

On June 15, 2020, the FDA revoked the emergency use authorization (EUA) for hydroxychloroquine and chloroquine donated to the Strategic National Stockpile to be used for treating certain hospitalized patients with COVID-19 when a clinical trial was unavailable or participation in a clinical trial was not feasible. [351]

Based on its ongoing analysis of the EUA and emerging scientific data, the FDA determined that hydroxychloroquine is unlikely to be effective in treating COVID-19 for the authorized uses in the EUA. Additionally, in light of ongoing serious cardiac adverse events and other potential serious adverse effects, the known and potential benefits of hydroxychloroquine no longer outweigh the known and potential risks for the EUA.

While additional clinical trials may continue to evaluate potential benefit, the FDA determined the EUA was no longer appropriate.

Additionally, the NIH halted the Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease (ORCHID) study on June 20, 2020. After the fourth analysis that included more than 470 participants, the NIH data and safety monitoring board determined that, while there was no harm, the study drug was very unlikely to be beneficial to hospitalized patients with COVID-19. [352]

Hydroxychloroquine and chloroquine are widely used antimalarial drugs that elicit immunomodulatory effects and are therefore also used to treat autoimmune conditions (eg, systemic lupus erythematosus, rheumatoid arthritis). As inhibitors of heme polymerase, they are also believed to have additional antiviral activity via alkalinization of the phagolysosome, which inhibits the pH-dependent steps of viral replication. Wang et al reported that chloroquine effectively inhibits SARS-CoV-2 in vitro. [353] The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2–infected Vero cells. Physiologically based pharmacokinetic models (PBPK) were conducted for each drug. Hydroxychloroquine was found to be more potent than chloroquine in vitro. Based on PBPK models, the authors recommend a loading dose of hydroxychloroquine 400 mg PO BID, followed by 200 mg BID for 4 days. [354]

Published reports stemming from the worldwide outbreak of COVID-19 have evaluated the potential usefulness of these drugs in controlling cytokine release syndrome in critically ill patients. Owing to widely varying dosage regimens, disease severity, measured outcomes, and lack of control groups, efficacy data have been largely inconclusive.

The UK RECOVERY Trial randomized 1542 patients to hydroxychloroquine and 3132 patients to usual care alone. Preliminary results found no significant difference in the primary endpoint of 28-day mortality (25.7% hydroxychloroquine vs 23.5% usual care; hazard ratio 1.11 [95% CI, 0.98-1.26]; P = 0.10). There was also no evidence of beneficial effects on hospital stay duration or other outcomes. [355]

An observational study of 2512 hospitalized patients in New Jersey with confirmed COVID-19 was conducted between March 1, 2020 and April 22, 2020, with follow-up through May 5, 2020. Outcomes included 547 deaths (22%) and 1539 (61%) discharges; 426 (17%) remained hospitalized. Patients who received at least one dose of hydroxychloroquine totaled 1914 (76%), and those who received hydroxychloroquine plus azithromycin totaled 1473 (59%). No significant differences were observed in associated mortality among patients receiving any hydroxychloroquine during the hospitalization (HR, 0.99 [95% CI, 0.80-1.22]), hydroxychloroquine alone (HR, 1.02 [95% CI, 0.83-1.27]), or hydroxychloroquine with azithromycin (HR, 0.98 [95% CI, 0.75-1.28]). The 30-day unadjusted mortality rate in patients receiving hydroxychloroquine alone, azithromycin alone, the combination, or neither drug was 25%, 20%, 18%, and 20%, respectively. [203]

Because of these findings, the WHO paused the hydroxychloroquine arm of the Solidarity Trial and then removed its use entirely as of July 4, 2020. [146] The FDA issued a safety alert for hydroxychloroquine or chloroquine use in COVID-19 on April 24, 2020. [356]

An observational study of consecutively hospitalized patients (n = 1446) at a large medical center in the New York City area showed hydroxychloroquine was not associated with either a greatly lowered or an increased risk of the composite endpoint of intubation or death. [357]

A retrospective observational study of 2,541 consecutive patients hospitalized with COVID at Henry Ford Health System from March 10, 2020, to May 2, 2020, showed a decreased mortality rate in patients treated with hydroxychloroquine alone or in combination with azithromycin. Overall in-hospital mortality was 18.1%; by treatment: hydroxychloroquine plus azithromycin, 157/783 (20.1%), hydroxychloroquine alone, 162/1202 (13.5%), azithromycin alone, 33/147 (22.4%), and neither drug, 108/409 (26.4%). Therapy with corticosteroids (methylprednisolone and/or prednisone) was administered in 68% of all patients. Corticosteroids were administered to 78.9% of patients who received hydroxychloroquine alone. In addition to adjunctive use of corticosteroids, an accompanying editorial discusses time bias, missing prognostic indicators, and other confounding factors of this observational study. [358, 359]

A retrospective analysis of data from patients hospitalized with confirmed COVID-19 infection in all US Veterans Health Administration medical centers between March 9, 2020, and April 11, 2020, has been published. Patients who had received hydroxychloroquine (HC) alone or with azithromycin (HC + AZ) as treatment in addition to standard supportive care were identified. A total of 368 patients were evaluated (HC n=97; HC + AZ n=113; no HC n=158). Death rates in the HC, HC + AZ, and no-HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC + AZ, and no-HC groups were 13.3%, 6.9%, 14.1%, respectively. The authors concluded that they found no evidence that hydroxychloroquine, with or without azithromycin, reduced the risk of mechanical ventilation and that the overall mortality rate was increased with hydroxychloroquine treatment. Furthermore, they stressed the importance of waiting for results of ongoing, prospective, randomized controlled trials before wide adoption of these drugs. [360]

According to a consensus statement from a multicenter collaboration group in China, chloroquine phosphate 500 mg (300 mg base) twice daily in tablet form for 10 days may be considered in patients with COVID-19 pneumonia. [361] While no peer-reviewed treatment outcomes are available, Gao and colleagues report that 100 patients have demonstrated significant improvement with this regimen without documented toxicity. [362] It should be noted this is 14 times the typical dose of chloroquine used per week for malaria prophylaxis and 4 times that used for treatment. Cardiac toxicity should temper enthusiasm for this as a widespread cure for COVID-19. It should also be noted that chloroquine was previously found to be active in vitro against multiple other viruses but has not proven fruitful in clinical trials, even resulting in worse clinical outcomes in human studies of Chikungunya virus infection (a virus unrelated to SARS-CoV-2).

A randomized controlled trial in Wuhan, China, enrolled 62 hospitalized patients (average age, 44.7 years) with confirmed COVID-19. Additional inclusion criteria included age 18 years or older, chest CT scans showing pneumonia, and SaO2/SPOs ratio of more than 93% (or PaOs/FIOs ratio >300 mm Hg). Patients with severe or critical illness were excluded. All patients enrolled in the study received standard treatment (oxygen therapy, antiviral agents, antibacterial agents, and immunoglobulin, with or without corticosteroids). Thirty-one patients were randomized to receive hydroxychloroquine sulfate (200 mg PO BID for 5 days) in addition to standardized treatment. Changes in time to clinical recovery (TTCR) was evaluated and defined as return of normal body temperature and cough relief, maintained for more than 72 hours. Compared with the control group, TTCR for body temperature and cough were significantly shortened in the hydroxychloroquine group. Four of the 62 patients progressed to severe illness, all of whom were in the control group. [363]

The French have embraced hydroxychloroquine as a potentially more potent therapy with an improved safety profile to treat and prevent the spread of COVID-19. [364] If it is effective, the optimal regimen of hydroxychloroquine is unknown, although some experts have recommended higher doses, such as 600-800 mg per day. A study of hydroxychloroquine for postexposure prophylaxis in healthcare workers or household contacts is underway. [365]

An open-label multicenter study using high-dose hydroxychloroquine or standard of care did not show a difference at 28 days for seronegative conversion or the rate of symptom alleviation between the two treatment arms. The trial was conducted in 150 patients in China with mild-to-moderate disease. [366]

Hydroxychloroquine plus azithromycin

Opposing conclusions by French researchers regarding viral clearance and clinical benefit with the regimen of hydroxychloroquine plus azithromycin have been published. [367, 368, 369]

A small prospective study found no evidence of a strong antiviral activity or clinical benefit conferred by hydroxychloroquine plus azithromycin. Molina et al assessed virologic and clinical outcomes of 11 consecutive hospitalized patients who received hydroxychloroquine (600 mg/day for 10 days) and azithromycin (500 mg on day 1, then 250 mg days 2-5). The study group included 7 men and 4 women with a mean age of 58.7 years (range, 20-77 years); 8 had significant comorbidities associated with poor outcomes (ie, obesity in 2, solid cancer in 3, hematological cancer in 2, and HIV infection in 1). Ten of the eleven patients had fever and received oxygen via nasal cannula. Within 5 days, one patient died and two were transferred to the ICU. Hydroxychloroquine and azithromycin were discontinued in one patient owing to prolonged QT interval. Nasopharyngeal swabs remained positive for SARS-CoV-2 RNA in 8 of 10 patients (80%; 95% confidence interval, 49-94) at days 5-6 after treatment initiation. [369]

In direct contrast to the aforementioned results, another study in France evaluated patients treated with hydroxychloroquine (n=26) against a control group (n=16) who received standard of care. After dropping 6 patients from the analysis for having incomplete data, the 20 remaining patients receiving hydroxychloroquine (200 mg PO q8h) had improved nasopharyngeal clearance of the virus on day 6 (70% [14/20] vs 12.5% [2/16]). [367] This is an unusual approach to reporting results because the clinical correlation with nasopharyngeal clearance on day 6 is unknown and several patients changed status within a few days of that endpoint (converting from negative back to positive). The choice of that particular endpoint was also not explained by the authors, yet 4 of the 6 excluded patients had adverse outcomes (admission to ICU or death) at that time but were not counted in the analysis. Furthermore, patients who refused to consent to the study group were included in the control arm, indicating unorthodox study enrollment.

This small open-label study of hydroxychloroquine in France included azithromycin in 6 patients for potential bacterial superinfection (500 mg once, then 250 mg PO daily for 4 days). These patients were reported to have 100% clearance of SARS-CoV-2. While intriguing, these results warrant further analysis. The patients receiving combination therapy had initially lower viral loads, and, when compared with patients receiving hydroxychloroquine alone with similar viral burden, the results are fairly similar (6/6 vs 7/9). [367]

The French researchers continued their practice of using hydroxychloroquine plus azithromycin and accumulated data in 80 patients with at least 6 days of follow-up. They note that the 6 patients enrolled in their first analysis were also included in the present case series, with a longer follow-up. However, it was not clear from the description in their posted methods when patients were assessed. A favorable outcome was defined as not requiring aggressive oxygen therapy or transfer to the ICU after 3 days of treatment. Sixty-five of the 80 patients (81.3%) met this outcome. One patient aged 86 years died, and a 74-year-old patient remained in the ICU. Two others were transferred to the ICU and then back to the infection ward. Results showed a decrease in nasopharyngeal viral load tested via qPCR, with 83% negative at day 7 and 93% at day 8. Virus culture results from patient respiratory samples were negative in 97.5% patients at day 5. [368] This is described as a promising method of reducing spread of SARS-CoV-2, but, unfortunately, the study lacked a control group and did not compare treatment with hydroxychloroquine plus azithromycin to a similar group of patients receiving no drug therapy or hydroxychloroquine alone. Overall, the acuity of these patients was low, and 92% had a low score on the national Early Warning System used to assess risk of clinical deterioration. Only 15% were febrile, a common criterion for testing in the United States, and 4 individuals were considered asymptomatic carriers. In addition, the results did not delineate between asymptomatic carriers and those with high viral load or low viral load.

Preventing hospitalization and death in outpatients with COVID-19

An NIH randomized, placebo-controlled, phase 2b clinical trial has begun to evaluate whether short-term outpatient treatment with hydroxychloroquine plus azithromycin can prevent hospitalization and death due to COVID-19. Study participants must have confirmed infection using a specimen collected within 96 hours before the first dose and experience fever, cough, or shortness of breath within 24 hours. [370, 371]

Prevention trials in high-risk individuals

Several clinical trials in the United States have been conducted to determine if hydroxychloroquine reduces the rate of infection when used by individuals at high risk for exposure, such as high-risk healthcare workers, first responders, and individuals who share a home with a COVID-19–positive individual. [365, 372, 373, 374, 375]

Results from a double-blind randomized trial (n = 821) from the University of Minnesota found no benefit of hydroxychloroquine (n = 414) in preventing illness due to COVID-19 compared with placebo (n = 407) when used as postexposure prophylaxis in asymptomatic participants within 4 days following high-risk or moderate-risk exposure. Overall, 87.6% of participants had high-risk exposures without eye shields and surgical masks or respirators. New COVID-19 (either PCR-confirmed or symptomatically compatible) developed in 107 participants (13%) during the 14-day follow-up. Incidence of new illness compatible with COVID-19 did not differ significantly between those receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]) (P = 0.35). [376]

QT prolongation with hydroxychloroquine and azithromycin

Chloroquine, hydroxychloroquine, and azithromycin each carry the warning of QT prolongation and can be associated with an increased risk of cardiac death when used in a broader population. [377] Because of this risk, the American College of Cardiology, American Heart Association, and the Heart Rhythm Society have published a thorough discussion of the arrhythmogenicity of hydroxychloroquine and azithromycin that includes a suggested protocol for clinical research QT assessment and monitoring when the two drugs are coadministered. [378, 379]

A Brazilian study comparing chloroquine high-dose (600 mg PO BID for 10 days) and low-dose (450 mg BID for 1 day, then 450 mg/day for 4 days) observed QT prolongation in 25% of patients in the high-dose group. All patients received other drugs (ie, azithromycin, oseltamivir) that may contribute to prolonged QT. [380]

An increased 30-day risk of cardiovascular mortality, chest pain/angina, and heart failure was observed with the addition of azithromycin to hydroxychloroquine from an analysis of pooled data from Japan, Europe, and the United States. The analysis compared use of hydroxychloroquine, sulfamethoxazole, or the combinations of hydroxychloroquine plus amoxicillin or hydroxychloroquine plus azithromycin. [288]

For more information, see QT Prolongation with Potential COVID-19 Pharmacotherapies.

Lopinavir/ritonavir

The NIH Panel for COVID-19 Treatment Guidelines recommend against the use of lopinavir/ritonavir or other HIV protease inhibitors, owing to unfavorable pharmacodynamics and because clinical trials have not demonstrated a clinical benefit in patients with COVID-19. [381]

The Infectious Diseases Society of America (IDSA) guidelines recommend use of lopinavir/ritonavir only in the context of a randomized clinical trial. The guidelines also mention the risk for severe cutaneous reactions, QT prolongation, and the potential for drug interactions owing to CYP3A inhibition. [30]

On June 29, 2020, analysis of the RECOVERY trial concluded no beneficial effect in hospitalized patients with COVID-19 who were randomized to receive lopinavir/ritonavir (n = 1596) compared with those who received standard care (n = 3376). Of these patients, 4% required invasive mechanical ventilation when they entered the trial, 70% required oxygen alone, and 26% did not require any respiratory intervention. No significant difference was observed in the 28-day mortality rate (22.1% lopinavir/ritonavir vs 21.3% standard care; relative risk 1.04 [95% CI, 0.91-1.18]; P = 0.58), and the results were consistent in different patient subgroups. No evidence was found for beneficial effects on the risk of progression to mechanical ventilation or length of hospital stay. [382]

The WHO discontinued use of lopinavir/ritonavir in the SOLIDARITY trial in hospitalized patients on July 4, 2020. [146]

In a randomized, controlled, open-label trial of hospitalized adults (n=199) with confirmed SARS-CoV-2 infection, recruited patients had an oxygen saturation of 94% or less on ambient air or PaO2 of less than 300 mm Hg and were receiving a range of ventilatory support modes (eg, no support, mechanical ventilation, extracorporeal membrane oxygenation [ECMO]). These patients were randomized to receive lopinavir/ritonavir 400 mg/100 mg PO BID for 14 days added to standard care (n=99) or standard care alone (n=100). Results showed that time to clinical improvement did not differ between the two groups (median, 16 days). The mortality rate at 28 days was numerically lower for lopinavir/ritonavir compared with standard care (19.2% vs 25%) but did not reach statistical significance. [383] An editorial accompanies this study that is informative in regard to the extraordinary circumstances of conducting such a study in the midst of the outbreak. [384]

Another study (n = 86) that compared lopinavir/ritonavir or umifenovir monotherapy with standard care in patients with mild-to-moderate COVID-19 showed no statistical difference between each treatment group. [185]

A multicenter study in Hong Kong compared 14 days of triple therapy (n = 86) (lopinavir/ritonavir [400 mg/100 mg q12h], ribavirin [400 mg q12h], interferon beta1b [8 million IU x 3 doses q48h]) with lopinavir/ritonavir alone (n = 41). Results showed that triple therapy significantly shortened the duration of viral shedding and hospital stay in patients with mild-to-moderate COVID-19. [385]

Average wholesale price (AWP) for a course of lopinavir/ritonavir at this dose is $575.

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QT Prolongation with Potential COVID-19 Pharmacotherapies

Chloroquine, hydroxychloroquine, and azithromycin each carry the warning of QT prolongation and can be associated with an increased risk of cardiac death when used in a broader population. [377] Because of this risk, the American College of Cardiology, American Heart Association, and the Heart Rhythm Society have published a thorough discussion on the arrhythmogenicity of hydroxychloroquine and azithromycin, including a suggested protocol for clinical research QT assessment and monitoring when the two drugs are coadministered. [378, 379]

Giudicessi et al have published guidance for evaluating the torsadogenic potential of chloroquine, hydroxychloroquine, lopinavir/ritonavir, and azithromycin. Chloroquine and hydroxychloroquine block the potassium channel, specifically KCNH2-encoded HERG/Kv11.1. Additional modifiable risk factors (eg, treatment duration, other QT-prolonging drugs, hypocalcemia, hypokalemia, hypomagnesemia) and nonmodifiable risk factors (eg, acute coronary syndrome, renal failure, congenital long QT syndrome, hypoglycemia, female sex, age ≥65 years) for QT prolongation may further increase the risk. Some of the modifiable and nonmodifiable risk factors may be caused by or exacerbated by severe illness. [386]

A cohort study was performed from March 1 through April 7, 2020, at an academic tertiary care center in Boston to characterize the risk and degree of QT prolongation in patients with COVID-19 who received hydroxychloroquine, with or without azithromycin. Among 90 patients given hydroxychloroquine, 53 received concomitant azithromycin. Seven patients (19%) who received hydroxychloroquine monotherapy developed prolonged QTc of 500 milliseconds or more, and 3 patients (3%) had a change in QTc of 60 milliseconds or more. Of those who received concomitant azithromycin, 11 of 53 (21%) had prolonged QTc of 500 milliseconds or more, and 7 of 53 (13 %) had a change in QTc of 60 milliseconds or more. Clinicians should carefully monitor QTc and concomitant medication usage if considering using hydroxychloroquine. [387]

A retrospective study was performed by reviewing 84 consecutive adult patients who were hospitalized at NYU Langone Medical Center with COVID-19 and treated with hydroxychloroquine plus azithromycin. QTc increased by greater than 40 ms in 30% of patients. In 11% of patients, QTc increased to more than 500 ms, which is considered a high risk for arrhythmia. The researcher noted that development of acute renal failure, but not baseline QTc, was a strong predictor of extreme QTc prolongation. [388]

A Brazilian study (n=81) compared chloroquine high-dose (600 mg PO BID for 10 days) and low-dose (450 mg BID for 1 day, then 450 mg/day for 4 days). A positive COVID-19 infection was confirmed by RT-PCR in 40 of 81 patients. In addition, all patients received ceftriaxone and azithromycin. Oseltamivir was also prescribed in 89% of patients. Prolonged QT interval (> 500 msec) was observed in 25% of the high-dose group, along with a trend toward higher lethality (17%) compared with lower dose. The high incidence of QT prolongation prompted the investigators to prematurely halt use of the high-dose treatment arm, noting that azithromycin and oseltamivir can also contribute to prolonged QT interval. The fatality rate was 13.5%. In 14 patients with paired samples, respiratory secretions at day 4 showed negative results in only one patient. [380]

An increased 30-day risk of cardiovascular mortality, chest pain/angina, and heart failure was observed with the addition of azithromycin to hydroxychloroquine. Pooled data from 14 sources of claims data or electronic medical records from Germany, Japan, Netherlands, Spain, United Kingdom, and the United states were analyzed for adverse effects of hydroxychloroquine, sulfasalazine, or the combinations of hydroxychloroquine plus azithromycin or amoxicillin. Overall, 956,374 and 310,350 users of hydroxychloroquine and sulfasalazine, respectively, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin, respectively, were included in the analysis. [288]

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Investigational Devices

Blood purification devices

Several extracorporeal blood purification filters (eg, CytoSorb, oXiris, Seraph 100 Microbind, Spectra Optia Apheresis) have received emergency use authorization from the FDA for the treatment of severe COVID-19 pneumonia in patients with respiratory failure. The devices have various purposes, including use in continuous renal replacement therapy or in reduction of proinflammatory cytokines levels. [389]

Nanosponges

Cellular nanosponges made from plasma membranes derived from human lung epithelial type II cells or human macrophages have been evaluated in vitro. The nanosponges display the same protein receptors required by SARS-CoV-2 for cellular entry and act as decoys to bind the virus. In addition, acute toxicity was evaluated in vivo in mice by intratracheal administration. [390]

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