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4/16/2021 https://emedicine.medscape.com/article/2500116-print

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COVID-19 Treatment:Investigational Drugs and OtherTherapies Updated: Apr 02, 2021Author: Scott J Bergman, PharmD, FCCP, FIDSA, BCPS, BCIDP;

OverviewCoronavirus disease 2019 (COVID-19) is defined as illness caused by a novel coronavirus now called severe acute respiratorysyndrome coronavirus 2 (SARS-CoV-2; formerly called 2019-nCoV), which was first identified amid an outbreak of respiratoryillness cases in Wuhan City, Hubei Province, China.[1] It was initially reported to the World Health Organization (WHO) onDecember 31, 2019. On January 30, 2020, the WHO declared the COVID-19 outbreak a global health emergency.[2, 3] OnMarch 11, 2020, the WHO declared COVID-19 a global pandemic, its first such designation since declaring H1N1 influenza apandemic in 2009.[4]

Utilization of programs established by the FDA to allow clinicians to gain access to investigational therapies during the pandemichas been essential. The expanded access (EA) and emergency use authorization (EUA) programs allowed for rapid deploymentof potential therapies for investigation and investigational therapies with emerging evidence. A review by Rizk et al describes therole for each of these measures and their importance to providing medical countermeasures in the event of infectious diseaseand other threats.[5]

As of October 22, 2020, remdesivir, an antiviral agent, is the only drug fully approved for treatment of COVID-19. It is indicatedfor treatment of COVID-19 disease in hospitalized adults and children aged 12 years and older who weigh at least 40 kg.[6] Anemergency use authorization (EUA) remains in place for treat pediatric patients weighing 3.5 kg to less than 40 kg or childrenyounger than 12 years who weigh at least 3.5 kg.[7] An EUA for convalescent plasma was announced on August 23, 2020.[8]

The FDA issued an emergency use authorization (EUA) for bamlanivimab, a monoclonal antibody directed against the spikeprotein of SARS-CoV-2 on November 9, 2020. The EUA permits bamlanivimab to be administered for treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients with positive results of direct SARS-CoV-2 viraltesting who are age 12 years and older weighing at least 40 kg, and at high risk for progressing to severe COVID-19 and/orhospitalization.[9] An EUA for bamlanivimab plus etesevimab was issue on February 9, 2021.[10]

Another EUA for the antibody mixture, casirivimab and imdevimab, was issued by the FDA on November 21, 2020.[11]

Baricitinib was issued an EUA on November 19, 2020 for use, in combination with remdesivir, for treatment of suspected orlaboratory confirmed coronavirus disease 2019 (COVID-19) in hospitalized patients aged 2 years and older who requiresupplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).[12]

The FDA has granted EUAs for 3 SARS CoV-2 vaccines since December 2020. Two are mRNA vaccines – BNT-162b2 (Pfizer)and mRNA-1273 (Moderna), whereas the third is a viral vector vaccine – Ad26.COV2.S (Johnson & Johnson).

Information, including allocation, for COVID-19 therapies granted emergency use authorization is located at the United StatesPublic Health Emergency webpage.

Numerous other antiviral agents, immunotherapies, and vaccines continue to be investigated and developed as potentialtherapies. Searching for effective therapies for COVID-19 infection is a complex process. Guidelines and reviews ofpharmacotherapy for COVID-19 have been published.[13, 14, 15, 16, 17, 18, 19] The Milken Institute maintains a detailedCOVID-19 Treatment and Vaccine Tracker of research and development progress.

Information, including allocation, for COVID-19 therapies granted emergency use authorization is located at the United StatesPublic Health Emergency [link https://www.phe.gov/emergency/events/COVID19/investigation-MCM/Pages/default.aspx]webpage.

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The urgent need for treatments during a pandemic can confound the interpretation of resulting outcomes of a therapy if data arenot carefully collected and controlled. Andre Kalil, MD, MPH, writes of the detriment of drugs used as a single-group interventionwithout a concurrent control group that ultimately lead to no definitive conclusion of efficacy or safety.[20]

Rome and Avorn write about unintended consequences of allowing widening access to experimental therapies. First, efficacy isunknown and may be negligible, but, without appropriate studies, physicians will not have evidence on which to basejudgement. Existing drugs with well-documented adverse effects (eg, hydroxychloroquine) subject patients to these risks withoutproof of clinical benefit. Expanded access of unproven drugs may delay implementation of randomized controlled trials. Inaddition, demand for unproven therapies can cause shortages of medications that are approved and indicated for otherdiseases, thereby leaving patients who rely on these drugs for chronic conditions without effective therapies.[21]

Drug shortages during the pandemic go beyond off-label prescribing of potential treatments for COVID-19. Drugs that arenecessary for ventilated and critically ill patients and widespread use of inhalers used for COPD or asthma are in demand.[22,23]

It is difficult to carefully evaluate the onslaught of information that has emerged regarding potential COVID-19 therapies within afew months’ time in early 2020. A brief but detailed approach regarding how to evaluate resulting evidence of a study has beenpresented by F. Perry Wilson, MD, MSCE. By using the example of a case series of patients given hydroxychloroquine plusazithromycin, he provides clinicians with a quick review of critical analyses.[24]

As an example of the number of compounds being evaluated, Gordon et al identified 332 high-confidence SARS-CoV-2 humanprotein-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 theprocess of evaluating the potential efficacy of these drugs in live SARS-CoV-2 infection assays.[25]

How these potential COVID-19 treatments will translate to human use and efficacy is not easily or quickly understood. Thequestion of whether some existing drugs that have shown in vitro antiviral activity might achieve adequate plasmapharmacokinetics 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. EC90values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug afteradministration of the approved dose to humans (Cmax/EC90 ratio). The researchers also calculated the unbound drug to tissuepartition coefficient to predict lung concentrations that would exceed their reported EC50 levels.[26]

The NIH Accelerating Covid-19 Therapeutics Interventions and Vaccines (ACTIV) trials public-private partnership to develop acoordinated research strategy has several ongoing protocols that are adaptive to the progression of standard care.[27]

Another adaptive platform trial is the I-SPY COVID-19 Trial for treating critically ill patients. The clinical trial is designed to allownumerous investigational agents to be evaluated in the span of 4-6 months, compared with standard of care (supportive care forARDS, remdesivir backbone therapy). Depending on the time course of COVID-19 infections across the US. As the trialproceeds and a better understanding of the underlying mechanisms of the COVID-19 illness emerges, expanded biomarker anddata collection can be added as needed to further elucidate how agents are or are not working.[28]

The WHO developed a blueprint of potential therapeutic candidates in January 2020. WHO has embarked on an ambitiousglobal "megatrial" called SOLIDARITY in which confirmed cases of COVD-19 are randomized to standard care or one of fouractive treatment arms (remdesivir, chloroquine or hydroxychloroquine, lopinavir/ritonavir, or lopinavir/ritonavir plus interferonbeta-1a). In early July 2020, the treatment arms in hospitalized patients that included hydroxychloroquine, chloroquine, orlopinavir/ritonavir were discontinued owing to the drugs showed little or no reduction in mortality compared with standard ofcare.[29] Interim results released mid-October 2020 found the 4 aforementioned repurposed antiviral agents appeared to havelittle or no effect on hospitalized patients with COVID-19, as indicated by overall mortality, initiation of ventilation, and duration ofhospital stay. The 28-day mortality was 12% (39% if already ventilated at randomization, 10% otherwise).[30]

Antiviral Agents

Remdesivir

Remdesivir (Veklury) was the first drug approved by the FDA for treating the SARS-CoV-2 virus. It is indicated for treatment ofCOVID-19 disease in hospitalized adults and children aged 12 years and older who weigh at least 40 kg. The broad-spectrumantiviral is a nucleotide analog prodrug. Full approval was preceded by the US FDA issued an EUA (emergency useauthorization) on May 1, 2020 to allow prescribing of remdesivir for severe COVID-19 (confirmed or suspected) in hospitalizedadults and children prior to approval.[31] Upon approval of remdesivir in adults and adolescents, the EUA was updated tomaintain the ability for prescribers to treat pediatric patients weighing 3.5 kg to less than 40 kg or children younger than 12 yearswho weigh at least 3.5 kg.[7] As of October 1, 2020, remdesivir is available from the distributor (ie, AmerisourceBergen).Wholesale acquisition cost is approximately $520/100-mg vial, totaling $3,120 for a 5-day treatment course.



It was studied in clinical trials for Ebola virus infections but showed limited benefit.[32] Remdesivir has been shown to inhibitreplication of other human coronaviruses associated with high morbidity in tissue cultures, including severe acute respiratorysyndrome coronavirus (SARS-CoV) in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012. Efficacy inanimal models has been demonstrated for SARS-CoV and MERS-CoV.[33]

Several phase 3 clinical trials have tested 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 documentedon US soil in January 2020.[34] An adaptive randomized trial of remdesivir coordinated by the National Institute of Health(NCT04280705) was started first against placebo, but additional therapies have been added to the protocol as evidenceemerges. The first experience with this study involved passengers of the Diamond Princess cruise ship in quarantine at theUniversity of Nebraska Medical Center in February 2020 after returning to the United States from Japan following an on-boardoutbreak of COVID-19.[35] Trials of remdesivir for moderate and severe COVID-19 compared with standard of care and varyingtreatment durations are ongoing.

The EUA for remdesivir was based on preliminary data analysis of the Adaptive COVID-19 Treatment Trial (ACTT) wasannounced April 29, 2020. The final analysis included 1,062 hospitalized patients with advanced COVID-19 and lunginvolvement, showing that patients treated with 10-days of remdesivir recovered faster than similar patients who receivedplacebo. Results showed that patients who received remdesivir had a 31% faster time to recovery compared with those whoreceived placebo (P < 0.001). Specifically, the median time to recovery was 10 days in patients treated with remdesivircompared with 15 days in those who received placebo (P < 0.001). Patients with severe disease (n = 957) had a median time torecovery of 11 days compared with 18 days for placebo. A statistically significant difference was not reached for mortality by day15 (remdesivir 6.7% vs placebo 11.9%) or by day 29 (remdesivir 11.4% vs placebo 15.2%).[36]

The final ACTT-1 results for shortening the time to recovery differed from interim results from the WHO SOLIDARITY trial forremdesivir. These discordant conclusions are complicated and confusing as the SOLIDARITY trial included patients from ACTT-1. In SOLIDARITY, over 11,000 hospitalized patients with COVID-19 (from 405 hospitals and 30 countries) were randomizedbetween whichever study drugs (up to 4 options) were locally available and open control.[30] An analysis by Sax describesvariables to consider when interpreting the results. The ACTT-1 trial included a placebo arm and was blinded, providing strongerevidence of remdesivir efficacy. Also, remdesivir worked for patients with shorter duration of symptoms and in those requiringoxygen. When the SOLIDARITY trial began in March 2020, it was a time during much of the enrollment period where patientstried to avoid hospitalization. The issue of when the drug was initiate in relationship to the stage of infection is an importantfactor. Duration of symptoms is not reported in the preliminary SOLIDARITY trial, a critical piece of information.[37] An editorialby Harrington et al, notes the complexity of the SOLIDARITY trial and the variation within and between countries in the standardof care and in the burden of disease in patients who arrive at hospitals. The editorial also mentions that trials solely focused onremdesivir were able to observe nuanced outcomes (ie, ability to change the course of hospitalization), whereas the larger,simple randomized SOLIDARITY trial focused on more easily defined outcomes.[38]

The ACTT results also differed from a smaller randomized trial conducted in China and published hours before the press releaseby the NIH about the study. Results from this other randomized, double-blind, placebo-controlled, multicenter trial (n = 237; 158to remdesivir and 79 to placebo; 1 patient withdrew) found remdesivir was not associated with statistically significant clinicalbenefits, measured as time to clinical improvement, in adults hospitalized with severe COVID-19. Although not statisticallysignificant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placeboamong patients with symptom duration of 10 days or less. The authors concluded that numerical reduction in time to clinicalimprovement in those treated earlier requires confirmation in larger studies. This study was underpowered owing to droppingcase numbers in China as the study was starting.[39]

A phase 3, randomized, open-label trial showed remdesivir was associated with significantly greater recovery and reduced oddsof death compared with standard of care in patients with severe COVID-19. The recovery rate at day 14 was higher in patientswho received remdesivir (n = 312) compared with those who received standard of care (n = 818) (74.4% vs 59%; P< 0.001).The mortality rate at day 14 was also lower in the remdesivir group (7.6% vs 12.5%; P = 0.001).[40]

The open-label phase 3 SIMPLE trial (n = 397) in hospitalized patients with severe COVID-19 disease not requiring mechanicalventilation showed similar improvement in clinical status with the 5-day remdesivir regimen compared with the 10-day regimenon 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 aclinical improvement of at least 2 points on the 7-point ordinal scale at day 14, compared with 54% of patients who received a10-day course. After adjustment for imbalances in baseline clinical status, patients receiving a 10-day course of remdesivir hada distribution in clinical status at day 14 that was similar to that of patients receiving a 5-day course (P = 0.14). The studydemonstrates the potential for some patients to be treated with a 5-day regimen, which could significantly expand the number ofpatients who could be treated with the current supply of remdesivir. The trial is continuing with an enrollment goal of 6,000patients.[41]

Data presented at the virtual COVID-19 Conference in July 2020 included a comparative analysis of clinical recovery andmortality outcomes from the phase 3 SIMPLE trials versus a real-world cohort of patients with severe COVID-19 receivingstandard of care. The analysis showed remdesivir was associated with a 62% reduction in the risk of mortality compared withstandard of care. Subgroup analyses found these results were similar across different racial and ethnic groups. While these dataare important, they require confirmation in prospective clinical trials.[42]



Similarly, the phase 3 SIMPLE II trial in patients with moderate COVID-19 disease (n = 596) showed that 5 days of remdesivirtreatment had a statistically significant higher odds of a better clinical status distribution on Day 11 compared with thosereceiving standard care (odds ratio, 1.65; p = 0.02). Improvement on Day 11 did not differ between the 10-day remdesivir groupand standard of care (P = 0.18).[43]

The first published report with a group of patients receiving remdesivir compassionate use described clinical improvement in 36of 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.[44]

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 ventilationwho 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 notreceiving invasive ventilation.

Additional data for compassionate use of remdesivir was released on July 10, 2020, and demonstrated that remdesivir treatmentwas associated with significantly improved clinical recovery and a 62% reduction in the risk of mortality compared with standardof care. Findings from the comparative analysis showed that 74.4% of remdesivir-treated patients recovered by day 14 versus59% of patients receiving standard of care. The mortality rate in patients treated with remdesivir in the analysis was 7.6% at day14 compared with 12.5% among patients not taking remdesivir (adjusted OR, 0.38; 95% CI, 0.22-0.68, P = 0.001). The analysesalso found that 83% of pediatric patients (n = 77) and 92% of pregnant and postpartum women (n = 86) with a broad spectrumof COVID-19 severity recovered by day 28.[42]

An in vitro study showed that the antiviral activity of remdesivir plus interferon beta (IFNb) for MERS-CoV was superior to that oflopinavir/ritonavir (LPV/RTV; Kaletra, Aluvia; AbbVie Corporation). Prophylactic and therapeutic remdesivir improved pulmonaryfunction and reduced lung viral loads and severe lung pathology in mice, whereas LPV/RTV-IFNb slightly reduced viral loadswithout affecting other disease parameters. Therapeutic LPV/RTV-IFNb improved pulmonary function but did not reduce virusreplication or severe lung pathology in the mice.[45]

Remdesivir use in children

Remdesivir emergency use authorization includes pediatric dosing that was derived from pharmacokinetic data in healthyadults. Remdesivir has been available through compassionate use to children with severe COVID-19 since February 2020. Aphase 2/3 trial (CARAVAN) of remdesivir was initiated in June 2020 to assess safety, tolerability, pharmacokinetics, and efficacyin children with moderate-to-severe COVID-19. CARAVAN is an open-label, single-arm study of remdesivir in children from birthto age 18 years.[46]

Data were presented on compassionate use of remdesivir in children at the virtual COVID-19 Conference held July 10-11, 2020.Results showed most of the 77 children with severe COVID-19 improved with remdesivir. Clinical recovery was observed in 80%of children on ventilators or ECMO and in 87% of those not on invasive oxygen support.[47]

For additional information, see Coronavirus Disease 2019 (COVID-19) in Children.

Remdesivir use in pregnant women

Outcomes in the first 86 pregnant women who were treated with remdesivir (March 21 to June 16, 2020) have been published.Recovery rates were high among women who received remdesivir (67 while pregnant and 19 on postpartum days 0-3). No newsafety signals were observed. At baseline, 40% of pregnant women (median gestational age 28 weeks) required invasiveventilation compared with 95% of postpartum women (median gestational age at delivery 30 weeks). Among pregnant women,93% of those on mechanical ventilation were extubated, 93% recovered, and 90% were discharged. Among postpartum women,89% were extubated, 89% recovered, and 84% were discharged. There was 1 maternal death attributed to underlying diseaseand no neonatal deaths.[48]

Data continue to emerge. A case series of 5 patients describe successful treatment and monitoring throughout treatment withremdesivir in pregnant women with COVID-19.[49]

Drug interactions with remdesivir

Coadministration of remdesivir is not recommended with chloroquine or hydroxychloroquine. Based on in vitro data, chloroquinedemonstrated an antagonistic effect on the intracellular metabolic activation and antiviral activity of remdesivir.[7]

Investigational antivirals

Molnupiravir



Molnupiravir (MK-4482 [previously EIDD-2801]; Merck) is an oral antiviral agent that is a prodrug of the nucleoside derivativeN4-hydroxycytidine. It elicits antiviral effects by introducing copying errors during viral RNA replication of the SARS-CoV-2 virus.Preliminary results from the phase 2a dose-ranging study showed at an average of 10 days after symptom onset, 24% ofpatients in the placebo group remained culture positive for SARS-CoV-2; whereas, no infectious virus could be recovered atstudy day 5 in any molnupiravir-treated patients. The drug is entering phase 3 trials in Q4 2020 for hospitalized andnonhospitalized patients with COVID-19.[50, 51]

Favipiravir

Favipiravir (Avigan; Appili Therapeutics) is an oral antiviral approved for treatment of influenza in Japan. It is approved in Russiafor treatment of COVID-19.

Favipiravir selectively inhibits RNA polymerase, which is necessary for viral replication. An adaptive, multicenter, open label,randomized, phase 2/3 clinical trial of favipiravir compared with standard of care I hospitalized patients with moderate COVID-19was conducted in Russia. Both dosing regimens of favipiravir demonstrated similar virologic response. Viral clearance on Day 5was achieved in 25/40 (62.5%) patients on in the favipiravir group compared with 6/20 (30%) patients in the standard care group(p = 0.018). Viral clearance on Day 10 was achieved in 37/40 (92.5%) patients taking favipiravir compared with 16/20 (80%) inthe standard care group (p = 0.155).[52]

In the United States, the phase 3 PRESECO (Preventing Severe COVID Disease) study is evaluating use in patients with mild-to-moderate symptoms to prevent disease progression and hospitalization. The phase 3 PEPCO (Post Exposure Prophylaxis forCOVID-19) study will look at asymptomatic individuals with direct exposure (within 72 hours) to an infected individual. A study inhospitalized patients is also underway.[53, 54] Additionally, the phase 2 CONTROL study is evaluating use to control outbreaksof COVID-19 in Canadian long-term care facilities.[55]

Clinical trials of existing drugs with antiviral properties

Nitazoxanide

Nitazoxanide extended-release tablets (NT-300; Romark Laboratories) inhibit replication of a broad range of respiratory virusesin cell cultures, including SARS-CoV-2. Two phase 3 trials for prevention of COVID-19 are being initiated in high-riskpopulations, 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.[56, 57] Another multicenter, randomized, double-blind phase 3 studywas initiated in August 2020 for treatment of people aged 12 years and older with fever and respiratory symptoms consistentwith COVID-19. Efficacy analyses will examine those participants who have laboratory-confirmed SARS-CoV-2 infection.[58]

Niclosamide

Niclosamide (FW-1002 [FirstWave Bio]; ANA001 [ ANA Therapeutics]) is an anthelmintic agent used primarily for tapeworms fornearly 50 years. Niclosamide is thought to disrupt SARS-CoV-2 replication through S-phase kinase-associated protein 2(SKP2)-inhibition, by preventing autophagy and blocking endocytosis.

A proprietary formulation that targets the viral reservoir in the gut to decrease prolonged infection and transmission has beendeveloped, specifically to decrease gut viral load. It is being tested in a phase 2 trial.[59] A phase 2/3 trial is testing safety andthe potential to improved outcomes and reduce hospital stay by reducing viral load.[60]

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

Antiviral Agent Description

Rintatolimod(Poly I:PolyC12U; Ampligen;AIMImmunoTech) [61]

Toll-like receptor 3 (TLR-3) agonist that is being tested as a potential treatment for COVID-19 by theNational Institute of Infectious Diseases (NIID) in Japan and the University of Tokyo. A clinical trial formyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), also call ‘Long Haulers’ syndrome,was announced in December 2020. It is a broad-spectrum antiviral agent with immunologicproperties.

Bemcentinib(BerGenBioASA) [62]

Selective oral AXL kinase inhibitor, has previously been reported to exhibit potent antiviral activity inpreclinical models against several enveloped viruses, including Ebola and Zika virus. Recent datahave expanded this to SARS-CoV-2. A phase 2 study of bemcentinib in hospitalized patients withCOVID-19 is planned as part of the UK’s Accelerating COVID-19 Research and Development(ACCORD) initiative.

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Plitidepsin(Aplidin;PharmaMar)

Member of the compound class known as didemnins. In vitro studies from Spain report plitidepsinpotentially targets EF1A, which is key to multiplication and spread of the virus. [63]

VIR-2703 (ALN-COV; VirBiotechnologyInc and AlnylamPharmaceuticals,Inc) [64]

In vitro data shows the drug targets small interfering RNA (siRNA). RNA interference (RNAi) is anatural cellular process of gene silencing. The siRNA molecules mediate RNAi function by silencingmessenger 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.

Emetinehydrochloride(AcerTherapeutics)[65]

Active ingredient of syrup of ipecac (given orally to induce emesis), has been formulated as aninjection to treat amebiasis. Clinical trials have been conducted for viral hepatitis and varicella-zostervirus infection. Several in vitro studies have demonstrated potency against DNA and RNA-replicatingviruses, including Zika, Ebola, Rabies Lyssavirus, CMV, HIV, influenza A, echovirus,metapneumovirus, and HSV2. It is also a potent inhibitor of multiple genetically distinctcoronaviruses. Plans are underway to evaluate the safety and antiviral activity of emetine with anadaptive design phase 2/3 randomized, blinded, placebo-controlled multicenter trial in high-risksymptomatic adults with confirmed COVID-19 not requiring hospitalization.

AT-527 (AteaPharmaceuticals)[66]

Oral purine nucleotide prodrug designed to inhibit RNA polymerase enzyme. It has demonstrated invitro and in vivo antiviral activity against several enveloped single-stranded RNA viruses, includinghuman flaviviruses and coronaviruses. IND for phase 2 study accepted by FDA for patientshospitalized with moderate COVID-19.

Trabedersen(OT-101; MateonTherapeutics,Oncotelic) [67]

Antisense oligonucleotide that inhibits transforming growth factor (TGF)-beta2 expression. Viralreplication requires cell cycle arrest that is mediated by viral induction of TBF-beta. Phase 2 trialsinitiated in India and Peru.

Stannousprotoporphyrin(SnPP; RBT-9;RenibusTherapeutics)[68]

Antiviral agent in phase 2 trial for treatment of COVID-19 in patients who are at high risk ofdeteriorating health owing to age or comorbid conditions (eg, kidney or cardiovascular disease).

Antroquinonol(Hocena; GoldenBiotechnologyCorp) [69]

Antiviral/anti-inflammatory agent. Reduces viral nucleic acid replication and viral protein synthesis inboth cell and animal experiments. Prevention of organ and tissue damage was also observed withantroquinonol when treating mice with excessive inflammation. The FDA has accepted the IND for aphase 2 clinical trial in patients with mild-to-moderate COVID-19 pneumonia.

Apilimoddimesylate(LAM-002A; AITherapeutics)[70]

Inhibits the lipid kinase enzyme PIKfyve. It disrupts lysosome dysfunction and interferes with theentry and trafficking of the SARS-CoV-2 virus in cells. Phase 2 trial is starting at Yale University inlate July 2020.

Remdesivirinhaled (GileadScience) [71]

A phase 1b trial of inhaled nebulized remdesivir initiated in late June 2020 to determine if remdesivircan be used on an outpatient basis and at earlier stages of disease.

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Brequinar (ClearCreek Bio, Inc)[72]

Orally available dihydroorotate dehydrogenase (DHODH) inhibitor. Shown in vitro to inhibit of viralSARS-CoV-2 viral replication, as well as a broad spectrum of RNA viruses. Inhibition of the DHODHenzyme causes pyrimidine depletion and reduces mitochondrial electron transport needed for viralreplication. The phase 2 study (CRISIS2) in hospitalized patients was initiated in November 2020.

Brilacidin(InnovationPharmaceuticals)[73] [74]

Host defense protein mimetic with antiviral, anti-inflammatory and antibacterial properties. It’s anti-inflammatory effects are attributed to inhibition of of IL-6, IL-1beta, TNF-alpha, and otherproinflammatory cytokines. Potent in vitro antiviral activity against SARS-CoV-2 has beendemonstrated.

Immunomodulators and Other Investigational TherapiesVarious methods of immunomodulation are being quickly examined, mostly by repurposing existing drugs, in order to blunt thehyperinflammation caused by cytokine release. Interleukin (IL) inhibitors, Janus kinase inhibitors, and interferons are just a fewof the drugs that are in clinical trials. Ingraham et al provide a thorough explanation and diagram of the SARS-CoV-2inflammatory pathway and potential therapeutic targets.[75] A review of pharmaco-immunotherapy by Rizk et al summarizes theroles and relationships of innate immunity and adaptive immunity, along with immunomodulators (eg, interleukins, convalescentplasma, JAK inhibitors) prevent and control infection.[76]

NIH immune modulators trial

In October 2020, the NIH launched an adaptive phase 3 trial (ACTIV-Immune Modulators [IM]) to assess safety and efficacy of 3immune modulator agents in hospitalized patients with Covid-19. The three drugs are infliximab (Remicade), abatacept(Orencia), and cenicriviroc, a late-stage investigational drug for hepatic fibrosis associated with nonalcoholic steatohepatitis.[27]

Infliximab

Monoclonal antibody that inhibits TNF, a proinflammatory cytokine that may cause excess inflammation during advanced stagesof COVID-19. Initially approved in 1998 to treat various chronic autoimmune inflammatory diseases (eg, rheumatoid arthritis,psoriasis, inflammatory bowel diseases).

Abatacept

Selective T-cell costimulatory immunomodulator. The drug consists of the extracellular domain of human cytotoxic T cell-associated antigen 4 fused to a modified immunoglobulin. It works by preventing full activation of T cells, resulting in inhibition ofthe downstream inflammatory cascade.

Cenicriviroc

An immunomodulator that blocks 2 chemokine receptors, CCR2 and CCR5, shown to be closely involved with the respiratorysequelae of COVID-19 and of related viral infections. It is also part of the I-SPY COVID-19 clinical trial.[28]

Interleukin inhibitors

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

Tocilizumab and other 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 therationale for studying IL-6 inhibitors.[77]

Tocilizumab has been studied in several randomized, double-blind, placebo-controlled phase 3 clinical trials to evaluate thesafety and efficacy plus standard of care in hospitalized adults with COVID-19 pneumonia compared with placebo plus standard

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of care. Average whole sale price of tocilizumab is approximately $5000 for an 800-mg dose. Preliminary results for sarilumabhave also been reported.

The Infectious Diseases Society of America guidelines recommend tocilizumab in addition to standard of care (ie, steroids)among hospitalized adults with COVID-19 who have elevated markers of systemic inflammation.[17] The NIH guidelines TheNIH guidelines recommend use of tocilizumab (single IV dose of 8 mg/kg, up to 800 mg) in combination with dexamethasone inrecently hospitalized patients who are exhibiting rapid respiratory decompensation caused by COVID-19.[78] Theserecommendations are based on the paucity of evidence from randomized clinical trials to show certainty of mortality reduction.

The EMPACTA trial found nonventilated hospitalized patients who received tocilizumab (n = 249) in the first 2 days of ICUadmission had a lower risk of progression to mechanical ventilation or death by day 28 compared with those not treated withtocilizumab (n = 128) (12% vs 19.3% respectively; p = 0.04). The data cutoff for this study was September 30, 2020. In the 7days before the trial or during the trial, 200 patients in the tocilizumab group (80.3%) and 112 patients in the placebo group(87.5%) received systemic glucocorticoids and 55.4% and 67.2% of the patients received dexamethasone. Antiviral treatmentwas administered in 196 (78.7%) and 101 (78.9%), respectively, and 52.6% and 58.6% received remdesivir. However, there wasno difference in incidence of death from any cause between the 2 groups.[79]

Preliminary results from the REMAP-CAP international adaptive trial evaluated efficacy of tocilizumab 8 mg/kg (n = 353),sarilumab 400 mg (n = 48), or control (n = 402) in critically ill hospitalized adults receiving organ support in intensive care.Hospital mortality at day 21 was 28% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab, and 35.8% (142/397) for control. Ofnote, corticosteroids became part of the standard of care midway through the trial. Estimates of the treatment effect for patientstreated with either tocilizumab or sarilumab and corticosteroids in combination were greater than for any single intervention.[80]

The US-based trial (n = 194) for sarilumab was stopped in July 2020 after observing positive trends in the primary prespecifiedanalysis group (critical patients on 400 mg who were mechanically ventilated at baseline) did 48), not reach statisticalsignificance and these were countered by negative trends in a subgroup of critical patients who were not mechanically ventilatedat baseline.

The RECOVERY trial assessed use of 4,116 hospitalized adults with COVID-19 infection who received either tocilizumab (n =2,022) compared with standard of care (n = 2,094) in the UK from April 23, 2020 to January 24, 2021. Among participants, 562(14%) received invasive mechanical ventilation, 1686 (41%) received non-invasive respiratory support, and 1868 (45%)received no respiratory support other than oxygen. Median C-reactive protein was 143 mg/L and 3385 (82%) patients werereceiving systemic corticosteroids at randomization. Preliminary results show 596 (29%) of patients allocated to tocilizumab and694 (33%) allocated to usual care died within 28 days (p = 0.007). Tocilizumab mortality benefits were clearly seen among thosewho also received systemic corticosteroids. Patients in the tocilizumab group were more likely to be discharged from thehospital within 28 days (54% vs 47; p < 0.0001). Among those not receiving invasive mechanical ventilation at baseline, patientswho received tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (33% vs38%; p = 0.0005).[81]

Results from early trials produced conflicting results. The dynamic changes and knowledge of treatment that took place duringthese trials (eg, ventilatory support, medications) and varying degrees of diseases severity causes added dimensions toconsider. Several of these initial studies are discussed.

Results from the BACC Bay randomized, double-blind trial (n = 243; conducted between April 20 to June 15, 2020) foundtocilizumab was not effective in preventing intubation or death in nonventilated hospitalized patients with moderate COVID-19disease. The researchers point out that the confidence interval for efficacy comparisons were wide, so some benefit or harm isuncertain. Additionally, results of the ACTT-1 trial for remdesivir were release during the trial, so some patients receivedremdesivir. The RECOVERY trial results for dexamethasone had not been released, so no patients received dexamethasone.Other antiviral or glucocorticoid therapies were permitted.[82]

Results from the COVACTA randomized, controlled phase 3 trial included approximately 38% mechanically ventilated patients.The trial did not meet its primary endpoint of improved clinical status in patients with COVID-19–associated pneumonia or thesecondary endpoint of reduced patient mortality. The trial did show a positive trend in time to hospital discharge among patientswho received tocilizumab.[83]

An observational study of consecutive patients (n=239) at Yale (New Haven, CT) with severe COVID-19 disease were treatedwith a standardized algorithm that included tocilizumab to treat cytokine release syndrome. These early observations showeddespite a surge of hospitalizations, tocilizumab-treated patients (n = 153) comprised 90% of those with severe disease, but theirsurvival was similar to that of patients with nonsevere disease (83% vs 91%; p = 0.11). For tocilizumab-treated patients requiringmechanical ventilation, survival 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.[84] Similarly, a small compassionate usestudy (n = 27) found a single 400-mg IV dose of tocilizumab reduced inflammation, oxygen requirements, vasopressor support,and mortality.[85]

A study compared outcomes of patients who received tocilizumab (n = 78) with tocilizumab-untreated controls in patients withCOVID-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 wasno difference in 28-day case fatality rate among tocilizumab-treated patients with superinfection versus those withoutsuperinfection (22% vs 15%; P = 0.42).[86]

Interleukin-1 inhibitors

Endogenous IL-1 levels are elevated in individuals with COVID-19 and other conditions, such as severe CAR-T-cell–mediatedcytokine-release syndrome. Anakinra has been used off-label for this indication. As of June 2020, the NIH guidelines noteinsufficient data to recommend for or against use of IL-1 inhibitors.[87]

Several studies involving the IL-1 inhibitor anakinra (Kineret) have emerged. A retrospective study in Italy looked at patients withCOVID-19 and moderate-to-severe ARDS who were managed with noninvasive ventilation outside of the ICU. The studycompared outcomes of patients who received anakinra (5 mg/kg IV BID [high-dose] or 100 mg SC BID [low-dose]) plus standardtreatment (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 andprogressive improvements in respiratory function in 21 (72%) of 29 patients; 5 (17%) patients were on mechanical ventilationand 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).[88]

A study in Paris from March 24 to April 6, 2020, compared outcomes of 52 consecutive patients with COVID-19 who were givenanakinra 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 invasivemechanical ventilation alone (0.22 [0.09-0.56]; P = 0.0015).[89]

The phase 3 CAN-COVID investigating canakinumab plus standard of care did not meet its primary endpoint of a greaterchance of patient survival without the need for invasive mechanical ventilation, or its key secondary endpoint of reduced COVID-19 mortality, compared with standard of care.[90]

Interleukin-7 inhibitors

The recombinant interleukin-7 inhibitor, CYT107 (RevImmune), increases T-cell production and corrects immune exhaustion.Several phase 2 clinical trials have been completed in France, Belgium, and the UK to assess immune reconstitution inlymphopenic patients with COVID-19.[91, 92, 93] Phase 2 trials were initiated in November 2020 in the US.

JAK and NAK inhibitors

Drugs that target numb-associated kinase (NAK) may mitigate systemic and alveolar inflammation in patients with COVID-19pneumonia by inhibiting essential cytokine signaling involved in immune-mediated inflammatory response. In particular, NAKinhibition has been shown to reduce viral infection in vitro. ACE2 receptors are a point of cellular entry by COVID-19, which isthen 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 Januskinase (JAK) inhibitor, is also identified as a NAK inhibitor with a particularly high affinity for AAK1.[94, 95, 96]

Emergency use authorization EUA was issued by the FDA for baricitinib on November 19, 2020. The EUA is for use, incombination with remdesivir, for treatment of suspected or laboratory confirmed coronavirus disease 2019 (COVID-19) inhospitalized patients aged 2 years and older who require supplemental oxygen, invasive mechanical ventilation, orextracorporeal membrane oxygenation (ECMO).[12]

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.[97]

Other selective JAK inhibitors may be effective against consequences of elevated cytokines, although baricitinib has the highestaffinity for AAK1.[94]

The NIAID Adaptive Covid-19 Treatment Trial (ACTT-2) evaluated the combination of baricitinib (4 mg PO daily up to 14 days)and remdesivir (100 mg IV daily up to 10 days) compared with remdesivir alone. The multinational trial included 1033 patients(515 received baricitinib plus remdesivir and 518 received control [remdesivir plus placebo]). Results demonstrated patients whoreceived baricitinib had a median time to recovery of 7 days compared with 8 days with control (P = 0.03), and a 30% higherodds of improvement in clinical status at day 15. Additionally, those receiving high-flow oxygen or noninvasive ventilation atenrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51;95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio fordeath, 0.65; 95% CI, 0.39 to 1.09). Incidence of serious adverse events were less frequent in the combination group than in the



control group (16.0% vs. 21.0%; P = 0.03) There were also fewer new infections in patients who received baricitinib (5.9% vs.11.2%; P =0 .003).[98]

Another phase 3, placebo-controlled trial (COV-BARRIER) is studying baricitinib in hospitalized patients who have an elevatedlevel of at least one inflammation marker but do not require invasive mechanical ventilation at study entry.[99]

A prospective observational study at a single hospital in Spain from March 15 to April 26, 2020 compared addition of baricitinibor baricitinib plus corticosteroids to standard treatment regimens of patients admitted with moderate-to-severe SARS-CoV-2pneumonia. Patients received lopinavir/ritonavir and hydroxychloroquine as part of their standard therapy during the time of thisstudy. Among 876 patients admitted during the time period, 558 had respiratory insufficiency (SpO2 92% or less breathing roomair). Of these, 387 patients were enrolled. After excluding patients with major comorbidities, treatment with otherimmunomodulators, or nonevaluable cases, a total of 112 patients were analyzed. A greater improvement in SpO2/FiO2 fromhospitalization to discharge was observed in the baricitinib plus corticosteroid group (n = 62) compared with the corticosteroidgroup (n = 50) (p < 0.001).[100]

A small open-labeled study (n = 12) conducted in Italy added baricitinib 4 mg/day to existing therapies (ie, lopinavir/ritonavir 250mg BID and hydroxychloroquine 400 mg/day). All therapies were given for 2 weeks. Fever, SpO2, PaO2/FiO2, C-reactiveprotein, 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).[101]

Pacritinib (CTI Biopharma) is a JAK2, interleukin-1 receptor-associated kinase-1 (IRAK-1), and colony stimulating factor-1receptor (CSF-1R) inhibitor that is pending FDA approval for myelofibrosis. The phase 3 PRE-VENT trial has commenced tocompare pacritinib with standard of care. Outcomes assessed include progression to mechanical ventilation, ECMO, or death inhospitalized patients with severe COVID-19, including those with cancer. As a JAK2/IRAK-1 inhibitor, pacritinib may amelioratethe effects of cytokine storm via inhibition of IL-6 and IL-1 signaling. Furthermore, as a CSF-1R inhibitor, pacritinib may mitigateeffects of macrophage activation syndrome.[102]

A phase 2 trial is underway in the UK for a nebulized JAK inhibitor (TD-0903; Theravance Biopharma) to treat hospitalizedpatients with acute lung injury caused by COVID-19. Preclinical studies suggest that TD-0903 has a very high lung:plasma ratioand rapid metabolic clearance resulting in low systemic exposure, compatible with its lung selectivity.[103]

Corticosteroids

The UK RECOVERY trial assessed the mortality rate at day 28 in hospitalized patients with COVID-19 who received low-dosedexamethasone 6 mg PO or IV daily for 10 days added to usual care. Patients were assigned to receive dexamethasone (n =2104) plus usual care or usual care alone (n = 4321). Overall, 482 patients (22.9%) in the dexamethasone group and 1110patients (25.7%) in the usual care group died within 28 days after randomization (P< 0.001). In the dexamethasone group, theincidence of death was lower than the usual care group among patients receiving invasive mechanical ventilation (29.3% vs41.4%) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs 26.2%), but not among those whowere receiving no respiratory support at randomization (17.8% vs 14%).[104]

Corticosteroids are not generally recommended for treatment of viral pneumonia.[105] The benefit of corticosteroids in septicshock results from tempering the host immune response to bacterial toxin release. The incidence of shock in patients withCOVID-19 is relatively low (5% of cases). It is more likely to produce cardiogenic shock from increased work of the heart need todistribute oxygenated blood supply and thoracic pressure from ventilation. Corticosteroids can induce harm throughimmunosuppressant effects during the treatment of infection and have failed to provide a benefit in other viral epidemics, suchas respiratory syncytial virus (RSV) infection, influenza infection, SARS, and MERS.[106]

Early guidelines for management of critically ill adults with COVID-19 specified when to use low-dose corticosteroids and whento 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 asweak.[107] The results from the RECOVERY trial in June 2020 provided evidence for clinicians to consider when low-dosecorticosteroids would be beneficial.[104]

Several trials examining use of corticosteroids for COVID-19 were halted following publication of the RECOVERY trial results.However, a prospective meta-analysis from the WHO rapid evidence appraisal for COVID-19 therapies (REACT) pooled datafrom 7 trials (eg, RECOVERY, REMAP-CAP, CoDEX, CAP COVID) that totaled 1703 patients (678 received corticosteroids and1025 received usual care or placebo). An association between corticosteroids and reduced mortality was similar fordexamethasone and hydrocortisone, suggesting the benefit is a general class effect of glucocorticoids. The 28-day mortalityrate, the primary outcome, was significantly lower among corticosteroid users (32% absolute mortality for corticosteroids vs 40%assumed mortality for controls).[108] An accompanying editorial addresses the unanswered questions regarding these studies.[109]



WHO guidelines for use of dexamethasone (6 mg IV or oral) or hydrocortisone (50 mg IV every 8 hours) for 7-10 days in themost seriously ill patients coincides with publication of the meta-analysis.[110]

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 withmethylprednisolone decreased the risk of death (HR, 0.38; 95% CI, 0.20-0.72).[111]

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. Outcomesof pre- and post-corticosteroid groups were evaluated. A composite endpoint of escalation of care from ward to ICU, newrequirement for mechanical ventilation, or mortality was the primary outcome measure. All patients had at least 14 days offollow-up. They analyzed 213 eligible patients, 81 (38%) and 132 (62%) in pre-and post-corticosteroid groups, respectively. Thecomposite 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).[112]

A study in the Netherlands showed a 5-day course of high-dose corticosteroids accelerated respiratory recovery, loweredhospital mortality rates, and reduced the likelihood of mechanical ventilation in patients with severe COVID-19–associatedcytokine storm syndrome compared with historical controls. Forty-three percent of patients also received tocilizumab.[113]

A retrospective study at Montefiore Hospital in the Bronx borough of New York was conducted to evaluate if early glucocorticoidtreatment (ie, within 48 hours of admission) reduced mortality rates or the need for mechanical ventilation in hospitalizedpatients with COVID-19. Of the 1,806 patients included in the study, 140 (7.7%) were treated with glucocorticoids, and 1,666patients never received glucocorticoids. A key finding of this analysis is the need to verify which patients should receiveglucocorticoid treatment. Glucocorticoid use in patients with initial C-reactive protein (CRP) levels of 20 mg/dL or greater wasassociated with significantly reduced risk of mortality or mechanical ventilation (OR, 0.23; 95% CI, 0.08-0.70), while use inpatients with a CRP level of less than 10 mg/dL was associated with significantly increased risk of mortality or mechanicalventilation (OR, 2.64; 95% CI, 1.39-5.03).[114] For further information regarding administration, see the EUA COVID-19Convalescent Fact Sheet for Health Care Provider.

An investigational suprapharmacologic dexamethasone sodium phosphate formulation (AVM0703; Seattle AVM Biotechnology)is starting in phase 1 and 2 trials to determine how it quickly it mobilizes natural killer T- (NKT), cytotoxic T-, and dendritic cells totreat ARDS.[115]

Convalescent plasma

The FDA granted emergency use authorization (EUA) on August 23, 2020 for use of convalescent plasma in hospitalizedpatients with COVID-19. Convalescent plasma contains antibody-rich plasma products collected from eligible donors who haverecovered from COVID-19. An expanded access (EA) program for convalescent plasma was initiated in early April 2020.[8, 116] The Mayo Clinic coordinated the open-access COVID-19 expanded access program, but will discontinued enrollment on August28, as the FDA authorized emergency use.

A retrospective analysis of a US national registry determined the anti–SARS-CoV-2 IgG antibody levels in convalescent plasmaused to treat hospitalized adults with Covid-19. The primary outcome was death within 30 days after plasma transfusion. Amongpatients hospitalized with COVID-19 who were not receiving mechanical ventilation, transfusion of plasma with higher anti–SARS-CoV-2 IgG antibody titers was associated with a lower risk of death than transfusion of plasma with lower antibody levels.Among 3082 patients in the analysis, death within 30 days occurred in 115 of 515 patients (22.3%) in the high-titer group, 549 of2006 patients (27.4%) in the medium-titer group, and 166 of 561 patients (29.6%) in the low-titer group. High plasma titerdefined as 250 or greater in the Broad Institute’s neutralizing antibody assay or an S/C cutoff of 12 or higher in the OrthoVITROS IgG assay.[117]

NIH guidelines

The NIH COVID-19 Guidelines Panel further evaluated the Mayo Clinic’s EAP data and further reviewed subgroups. Amongpatients who were not intubated, 11% of those who received convalescent plasma with high antibody titers died within 7 days oftransfusion compared with 14% of those who received convalescent plasma with low antibody titers. Among those who wereintubated, there was no difference in 7-day survival.[118]

The NIH halted its trial of convalescent plasma in emergency departments for treatment of patients with mild symptoms as ofMarch 2021. The second planned interim analysis of the trial data determined that while the convalescent plasma interventioncaused no harm, it was unlikely to benefit this group of patients.

IDSA guidelines



IDSA recommends limiting use of convalescent plasma for hospitalized patients with COVID-19 to the context of a clinical trial.Convalescent plasma transfusion failed to show or to exclude a beneficial or detrimental effect on mortality based on the body ofevidence.[17]

Interferons

Laboratory studies suggest normal interferon response is suppressed in some people infected with SARS-CoV-2. In thelaboratory, type 1 interferon can inhibit SARS-CoV-2 and two closely related viruses, SARS-CoV and MERS-CoV.[119]

The third iteration of the NIAID’s Adaptive COVID-19 Treatment Trial (ACTT-3) commenced in August 2020 to comparesubcutaneous interferon beta-1a (Rebif) plus remdesivir versus remdesivir plus placebo. The ACTT-3 trial anticipates enrollingover 1000 patients in up to 100 sites across the United States.[120]

Miscellaneous Therapies

Nitric oxide

Published findings from the 2004 SARS-CoV infection suggest the potential role of inhaled nitric oxide (iNO; MallinckrodtPharmaceuticals, plc) as a supportive measure for treating infection in patients with pulmonary complications. Treatment withiNO reversed pulmonary hypertension, improved severe hypoxia, and shortened the length of ventilatory support compared withmatched control patients with SARS.[121]

The phase 3 study (COViNOX) for iNO (INOpulse; Bellerophon Therapeutics) for patients with mild-to-moderate COVID-19 whoare hospitalized and require supplemental oxygen has been put on hold after interim analysis from the first 100 patients. Thestudy has recruited nearly 200 patients as of November 2020.[122] The Society of Critical Care Medicine recommends againstthe routine use of iNO in patients with COVID-19 pneumonia. Instead, they suggest a trial only in mechanically ventilatedpatients with severe ARDS and hypoxemia despite other rescue strategies. The cost of iNO is reported as exceeding $100/hour.

Statins

In addition to the cholesterol-lowering abilities of HMG-CoA reductase inhibitors (statins), they also decrease the inflammatoryprocesses of atherosclerosis.[123] Because of this, questions have arisen whether statins may be beneficial to reduceinflammation associated with COVID-19.

This question has been posed before with studies of patients taking statins who have acute viral infections. Virani[124] providesa 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 werehospitalized with influenza and/or pneumonia. RCTs of statins as anti-inflammatory agents for viral infections are limited, andresults have been mixed. An important factor that Virani points out regarding COVID-19 is that no harm was associated withstatin therapy in previous trials of statins and viral infections, emphasizing that patients should adhere to their statin regimen.

Two meta-analyses have shown opposing conclusions regarding outcomes of patients who were taking statins at the time ofCOVID-19 diagnosis.[125, 126] Randomized controlled trials are needed to examine the ability of statins to attenuateinflammation, presumably by inhibiting expression of the MYD88 gene, which is known to trigger inflammatory pathways.[127]

Adjunctive Nutritional Therapies

Vitamin and mineral supplements have been promoted for the treatment and prevention of respiratory viral infections; however,there is insufficient evidence to suggest a therapeutic role in treating COVID-19.[128]

Zinc

A retrospective analysis showed lack of a causal association between zinc and survival in hospitalized patients with COVID-19.[129]

Vitamin D

A study found individuals with untreated vitamin D deficiency were nearly twice as likely to test positive for COVID-19 comparedwith peers with adequate vitamin D levels. Among 489 individuals, vitamin D status was categorized as likely deficient for 124participants (25%), likely sufficient for 287 (59%), and uncertain for 78 (16%). Seventy-one participants (15%) tested positive forCOVID-19. In a multivariate analysis, a positive COVID-19 test was significantly more likely in those with likely vitamin Ddeficiency than in those with likely sufficient vitamin D levels (relative risk [RR], 1.77; 95% CI, 1.12 - 2.81; P = .02). Testingpositive for COVID-19 was also associated with increasing age up to age 50 years (RR, 1.06; P = .02) and race other thanWhite (RR, 2.54; P = .009).[130]



Additional Investigational Drugs for ARDS/Cytokine ReleaseHuman Vasoactive Intestinal Polypeptides

Aviptadil (Zyesami; RLF-100; NeuroRx) is a synthetic vasoactive intestinal peptide (VIP) that prevents NMDA-induced caspase-3 activation in lungs and inhibits IL-6 and TNF-alpha production. Results from a phase 2b/3 trial of IV aviptadil for treatment ofrespiratory failure in critically ill patients with COVID-19 demonstrated meaningful recovery at days 28 (p = 0.014) and 60 (p =0.013) and survival (P < 0.001).[131, 132]

Additionally, it is being studied as an inhaled treatment. [133]

Colony-stimulating factors

In COVID-19, high levels of granulocyte macrophage-colony stimulating factor (GM-CSF) and inflammatory myeloid cellscorrelate with disease severity, cytokine storm, and respiratory failure.

Lenzilumab

Lenzilumab (Humanigen) is a monoclonal antibody directed against GM-CSF. Results from a phase 3 trial in hospitalizedpatients who had not yet progressed to requiring invasive medical ventilation showed a 54% greater relative likelihood ofventilator-free survival compared with patients who did not receive lenzilumab.[134]

Additionally, lenzilumab is part of the NIH ACTIV-5/BET trial that is ongoing as of April 2021.

Sargramostim

Sargramostim (Leukine, rhuGM-CSF; Partner Therapeutics, Inc) is an inhaled colony-stimulating factor. A phase 2 trial(iLeukPulm) in 120 hospitalized patients in the US with COVID-19 was completed and the results are expected mid-2021. GM-CSF may reduce the risk of secondary infection, accelerate removal of debris caused by pathogens, and stimulate alveolarepithelial cell healing during lung injury.[135]

Gimsilumab

Gimsilumab (Riovant Sciences) is being studied in the phase 2 BREATHE clinical trial at Mt Sinai and Temple University isanalyzing this monoclonal antibody that targets granulocyte macrophage-colony stimulating factor (GM-CSF) in patients withARDS.[136]

Mavrilimumab

Mavrilimumab (Kiniksa Pharmaceuticals) is a fully humanized monoclonal antibody that targets granulocyte macrophage colony-stimulating factor (GM-CSF) receptor alpha. An open-label study of mavrilimumab in Italy treated patients with severe COVID-19pneumonia and hyperinflammation. Over the 14-day follow-up period, mavrilimumab-treated patients experienced greater andearlier clinical improvements than control-group patients, including earlier weaning from supplemental oxygen, shorterhospitalizations, and no deaths. Phase 2 trials are ongoing in the US.[137, 138]

Otilimab

Otilimab (GlaxoSmithKline) is a humanized monoclonal anti-GM-CSF antibody under development for rheumatoid arthritis.Clinical trial initiating May 2020 for severe pulmonary COVID-19.[139]

Neurokinin-1 (NK-1) receptor antagonists

Tradipitant

Tradipitant (Vanda Pharmaceuticals) is an NK-1 receptor antagonist. The NK-1 receptor is genetically coded by TACR1 and it isthe main receptor for substance P. The substance P NK-1 receptor system is involved in neuroinflammatory processes that leadto serious lung injury following numerous insults, including viral infections. ODYSSEY phase 3 trial in severe or critical COVID-19 infection reported an interim analysis on August 18, 2020. Patients who received tradipitant recovered earlier than thosereceiving placebo.[140, 141]

Aprepitant

Aprepitant (Cinvanti; Heron Therapeutics) is a substance P/neurokinin-1 (NK1) receptor antagonist. Substance P and itsreceptor, NK1, are distributed throughout the body in the cells of many tissues and organs, including the lungs. Phase 2 clinicalstudy (GUARDS-1) initiated mid-July 2020 in early-hospitalized patients with COVID-19. Administration to these patients isexpected to decrease production and release of inflammatory cytokines mediated by the binding of substance P to NK1receptors, which could prevent the progression of lung injury to ARDS.[142]



Mesenchymal stem cells

Remestemcel-L

Remestemcel-L (Ryoncil; Mesoblast Ltd) is an allogeneic mesenchymal stem cell (MSC) product currently pending FDAapproval for graft versus host disease (GVHD). On December 1, 2020, the FDA granted Fast Track designation forremestemcel-L in the treatment of ARDS due to COVID-19 infection. Fast Track designation is granted if a therapydemonstrates the potential to address unmet medical needs for a serious or life-threatening disease.[143]

As of December 2020, the phase 3 trial for COVID-19 ARDS has enrolled about 200 of the goal of 300 ventilator-dependentpatients with moderate-to-severe ARDS. The trial’s primary endpoint is overall mortality at Day 30, and the key secondaryendpoint is days alive off ventilatory support through Day 60. Two interim analyses by the independent Data Safety MonitoringBoard (DSMB) were completed after 90 and 135 patients were enrolled, with recommendations to continue the trial as planned.A third and final interim analysis is planned when 180 patients have completed 30 days of follow-up. A pilot study underemergency compassionate use at New York’s Mt Sinai Hospital in March-April this year showed 9 of 12 ventilator-dependentpatients with moderate-to-severe COVID-19 ARDS were successfully discharged from hospital a median of 10 days afterreceiving 2 intravenous doses of remestemcel-L. Theorized mechanism is down-regulation of proinflammatory cytokines.[144,143]

PLX-PAD

PLX-PAD (Pluristem Therapeutics) contains allogeneic mesenchymal-like cells with immunomodulatory properties that inducethe immune system’s natural regulatory T cells and M2 macrophages. Initiating phase 2 study in mechanically ventilatedpatients with severe COVID-19.[145]

BM-Allo.MSC

BM-Allo.MSC (NantKwest, Inc) is a bone marrow-derived allogeneic mesenchymal stem cell product. IND for phase 1b trialinitiating Q2 2020 in Los Angeles area hospitals.[146]

HB-adMSC

Autologous, adipose-derived mesenchymal stem cells (HB-adMSCs; Hope Biosciences) has been shown to attenuate systemicinflammation in phase 1/2 clinical trial for rheumatoid arthritis. Three phase 2 trials are in progress that include patients aged 50years and older with preexisting health conditions or at high exposure risk, frontline healthcare workers or first responders, anda placebo-controlled study.[147]

hCT-MSCs

A multicenter trial using human cord tissue mesenchymal stromal cells (hCT-MSC) for children with multisystem inflammatorysyndrome (MIS) was initiated in September 2020. The study will assess if infusion of hCT-MSCs are safe and can suppress thehyperinflammatory response associated with MIS. Duke University is coordinating the study, and is manufacturing the cells atthe Robertson GMP cell laboratory.[148]

ExoFlo

ExoFlo (Direct Biologics) is a paracrine signaling exosome product isolated from human bone marrow MSCs. The EXIT COVID-19 phase 2 study is enrolling patients and was granted expanded access by the FDA to be provided to patients with ARDS.[149]

Phosphodiesterase inhibitors

Ibudilast

Ibudilast (MN-166; MediciNova) is a first-in-class, orally bioavailable, small molecule phosphodiesterases (PDE) 4 and 10inhibitor and a macrophage migration inhibitory factor (MIF) inhibitor that suppresses proinflammatory cytokines and promotesneurotrophic factors. The drug has been approved in Japan and South Korea since 1989 to treat post-stroke complications andbronchial asthma. An IND for a phase 2 trial in the United States to prevent ARDS has been accepted by the FDA.[150]

Apremilast

Apremilast (Otezla; Amgen Inc) is a small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosinemonophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels, which may indirectly modulate theproduction of inflammatory mediators. Part of the I-SPY COVID-19 clinical trial.

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

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Drug DescriptionDrug Description

Ifenprodil (NP-120;AlgernonPharmaceuticals) [151]

N-methyl-d-aspartate (NDMA) receptor glutamate receptor antagonist. NMDA is linked toinflammation and lung injury. An injectable and long-acting oral product are under production tobegin clinical trials for COVID-19 and acute lung injury. The phase 2b part of the 2b/3 studycompleted enrollment mid-December 2020.

Eculizumab (Soliris;Alexion) [152]

Modulates activity of terminal complement to prevent the formation of the membrane attackcomplex; 10-patient proof of concept completed; if 100-patient single-arm trial in the UnitedStates and Europe for 2 weeks shows a positive risk/benefit ratio, a 300-patient randomizedcontrolled trial will proceed.

Ravulizumab(Ultomiris; Alexion)[153]

Monoclonal antibody that is a C5 complement inhibitor. Phase 3 randomized controlled trial inhospitalized adults with severe pneumonia or acute ARDS requiring mechanical ventilation wasinitiated in April 2020, but was paused in January 2021 owing to initial outcomes not showingefficacy. Another phase 3 trial (TACTIC-R) in the UK is studying use of earlier immunemodulation in preventing disease progression.

ATYR1923 (aTyrPharma, Inc) [154]

Phase 2 randomized, double-blind, placebo-controlled trial at up to 10 centers in the UnitedStates. In preclinical studies, ATYR1923 (a selective modulator of neuropilin-2) has been shownto down-regulate T-cell responses responsible for cytokine release.

BIO-11006 (BiomarkPharmaceuticals) [155]

Results of a phase 2a study for 38 ventilated patients with ARDS showed 43% reduction at day28 in the all-cause mortality rate. This study was initiated in 2017. The company is in discussionwith the FDA to proceed with a phase 3 trial.

Dociparstat sodium(DSTAT; Chimerix)[156]

Glycosaminoglycan derivative of heparin with anti-inflammatory properties, including thepotential to address underlying causes of coagulation disorders. Phase 2/3 trial starting May2020.

Opaganib (Yeliva;RedHill BiopharmaLtd) [157, 158]

Orally administered sphingosine kinase-2 (SK2) inhibitor that may inhibit viral replication andreduce levels of IL-6 and TNF-alpha. Nonclinical data indicate both antiviral and anti-inflammatory effects. As of December 2020, the phase 2/3 trial has enrolled more than 60% ofparticipants, who are hospitalized patients with severe COVID-19 who have developedpneumonia and require supplemental oxygen.

Tranexamic acid(LB1148; LeadingBioSciences, Inc) [159]

Oral/enteral protease inhibitor designed to preserve GI tract integrity and protect organs fromproteases leaking from compromised mucosal barrier that can lead to ARDS. Phase 2 studyannounced May 15, 2020.

DAS181 (AnsunBiopharma) [160]

Recombinant sialidase drug is a fusion protein that cleaves sialic receptors. Phase 3 substudyfor COVID-19 added to existing study for parainfluenza infection.

AT-001 (AppliedTherapeutics) [161]

Aldose reductase inhibitor shown to prevent oxidative damage to cardiomyocytes and todecrease oxidative-induced damage.

CM4620-IE (Auxora;CalciMedica, Inc) [162]

Calcium release-activated calcium (CRAC) channel inhibitor that prevents CRAC channeloveractivation, which can cause pulmonary endothelial damage and cytokine storm. Results inmid-July 2020 from a small randomized, controlled, open-label study showed CM4620-IE (n =20) combined with standard of care therapy (n = 10) improved outcomes in patients with severeCOVID-19 pneumonia, showing faster recovery (5 days vs 12 days), reduced use of invasivemechanical ventilation (18% vs 50%), and improved mortality rate (10% vs 20%) compared withstandard of care alone. Part 2 of this trial will start late summer and will be a placebo-controlledtrial, possibly including both remdesivir and dexamethasone.

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Drug Description

Intranasal vazegepant(BiohavenPharmaceuticals) [163]

Calcitonin gene-related peptide (CGRP) receptor antagonist. Received FDA may proceed letterto 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 (pulmonaryedema with acute-phase cytokine/mediator release, with immunologic milieu shift toward TH17cytokines). A CGRP receptor antagonist may blunt the severe inflammatory response at thealveolar level, delaying or reversing the path toward oxygen desaturation, ARDS, requirementfor supplemental oxygenation, artificial ventilation, or death.

Selinexor (Xpovio;KaryopharmaTherapeutics) [164]

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 thevirus. An interim analysis indicated that the trial was unlikely to meet its prespecified primaryendpoint across the entire patient population studied, and has since been discontinued.However, the results demonstrated encouraging antiviral and anti-inflammatory activity for asubset of treated patients with low baseline LDH or D-dimer.

EDP1815 (EveloBiosciences; RutgersUniversity; RobertWood JohnsonUniversity Hospital)[165, 166]

Phase 2/3 trials underway in the United States and United Kingdom to determine if earlyintervention with oral EDP1815 (under development for psoriasis) prevents progression ofCOVID-19 symptoms and complications in hospitalized patients ≥15 years with COVID-19 whopresented at the ER within the preceding 36 hours. The drug showed marked activity oninflammatory markers (eg, IL-6, IL-8, TNF, IL-1b) in a phase 1b study.

VERU-111 (Veru, Inc)[167, 168]

Microtubule depolymerization agent that has broad antiviral activity and has strong anti-inflammatory effects. As of August 2020, a phase 2 trial is underway for hospitalized patientswith COVID-19 at high risk for ARDS.

Vascular leakagetherapy (Q BioMed;Mannin Research)[169]

Targets the angiopoietin-Tie2 signaling pathway to reduce endothelial dysfunction.

Trans sodiumcrocetinate (TSC;DiffusionPharmaceuticals) [170,171]

TSC increases the diffusion rate of oxygen in aqueous solutions. Guidance has been receivedfrom the FDA for a phase 1b/2b clinical trial.

Rayaldee (calcifediol;OPKO Health) [172]

Extended-release formulation of calcifediol (25-hydroxyvitamin D3), a prohormone of the activeform 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 toenable macrophages.

Deupirfenidone (LYT-100; PureTech Bio)[173]

Deuterated form of pirfenidone, an approved anti-inflammatory and anti-fibrotic drug. InhibitsTGF-beta and TNF-alpha. Phase 2 trial initiated in December 2020 for long COVID syndrome toevaluate use for serious respiratory complications, including inflammation and fibrosis, thatpersist following resolution of SARS-CoV-2 infection.

OP-101 (AshvatthaTherapeutics) [174] Selectively targets reactive macrophages to reduce inflammation and oxidative stress.

Vidofludimus calcium(IMU-838; ImmunicTherapeutics) [175,176]

Oral dihydroorotate dehydrogenase (DHODH) inhibitor. DHODH is located on the outer surfaceof the inner mitochondrial membrane. Inhibitors of this enzyme are used to treat autoimmunediseases. Phase 2 CALVID-1 clinical trial for hospitalized patients with moderate COVID-19.Another phase 2 trial (IONIC) in the UK combines vidofludimus with oseltamivir for moderate-to-severe COVID-19.

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Drug Description

Vafidemstat (ORY-2001; Oryzon) [177]

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)[178]

Randomized, open-label study (CardioLink-9; n = 100) focuses on reduction of circulatingproinflammatory biomarkers (eg, high-sensitivity C-reactive protein [hsCRP, D-dimer) in COVID-infected outpatients. Patients in the icosapent ethyl group received a loading dose of 8 g/day for3 days followed by 4 g/day for 11 days plus usual care. Icosapent ethyl showed a 25% reductionin hsCRP (p = 0.011) and a reduction in D-dimer (p = 0.048). Additionally, icosapent ethylresulted in a significant 52% reduction of the total FLU-PRO prevalence score (flulike symptoms)compared with 24% reduction in the usual care group (p = 0.003).

Prazosin (JohnsHopkins) [179, 180]

Cytokine storm syndrome is accompanied by increased catecholamine release. This amplifiesinflammation by enhancing IL-6 production through a signaling loop that requires the alpha1adrenergic receptor. A clinical trial at Johns Hopkins University is using prazosin, an alpha1receptor antagonist, to evaluate its effects to prevent cytokine storm.

Aspartyl-alanyldiketopiperazine (DA-DKP; AmpionTM;AmpioPharmaceuticals) [181]

Low-molecular weight fraction of human serum albumin (developed for inflammation associatedwith osteoarthritis). Theorized to reduce inflammation by suppressing pro-inflammatory cytokineproduction in T-cells. Phase 1 trial results of IV Ampion or standard of care (eg, remdesivirand/or convalescent plasma) were evaluated in September 2020. IND granted for phase 1 trialof inhaled Ampion in September 2020.

Losmapimod (FulcrumTherapeutics) [182]

Selective inhibitor of p38alpha/beta mitogen activated protein kinase (MAPK), which is known tomediate 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 evaluatedin phase 2 clinical trials for facioscapulohumeral muscular dystrophy (FSHD).

DUR-928 (DurectCorp) [183]

Endogenous epigenetic regulator. Preclinical trials have shown the drug regulates lipidmetabolism, inflammation, and cell survival. The FDA accepted the IND application. A phase 2study is planned for approximately 80 hospitalized patients with COVID-19 who have acute liveror kidney injury.

ATI-450 (AclarisTherapeutics, Inc)[184]

IND approved mid-June 2020 for use in hospitalized patients with COVID-19. ATI-450 is an oralmitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2, or MK2) inhibitor thattargets inflammatory cytokine expression. In a phase 1 clinical trial in healthy volunteers at theUniversity of Kansas Medical Center, researchers used a first-in-human study using an ex vivolipopolysaccharide (LPS) stimulation model that demonstrated a dose-dependent reduction ofTNF-alpha, IL-1-beta, IL-6, and IL-8.

Leronlimab (Vyrologix;CytoDyn) [185, 186]

CCR5 antagonist. A phase 2 trial for mild-to-moderate COVID-19 is ongoing. The phase 3 trial insevere-to-critical patients is fully enrolled (n = 390) as of December 2020 and an open-labelextension trial has been added to the protocol. Laboratory data following leronlimabadministration in 15 patients showed increased CD8 T-lymphocyte percentages by day 3,normalization of CD4/CD8 ratios, and resolving cytokine production, including reduced IL-6levels correlating with patient improvement.

Sarconeos (BIO101;Biophytis SA) [187]

Activates MAS, a component of the protective arm of the renin angiotensin system. Phase 2/3trial (COVA) international trial assessing potential treatment for ARDS.

Abivertinib (SorrentoTherapeutics) [188]

Tyrosine kinase inhibitor with dual selective targeting of mutant forms of EGFR and BTK. Phase2 trial starting late July 2020 in hospitalized patients with moderate-to-severe COVID-19 whohave developing cytokine storm in the lungs.

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Drug Description

Nangibotide (LR12;Inotrem S.A.) [189]

Immunotherapy that targets the triggering receptor expressed on myeloid cells-1 (TREM-1)protein pathway, a factor causing unbalanced inflammatory responses. Phase 2a clinical trial(ASTONISH) authorized in the United States, France, and Belgium for mechanically ventilatedpatients with COVID-19 who have systemic inflammation. Previous clinical studies demonstratedsafety and tolerability in patients with septic shock.

Piclidenoson (Can-Fite BioPharma) [190]

A3 adenosine receptor (A3AR) agonist that elicits anti-inflammatory effects. Phase 2 trialplanned in the United States to start late July 2020 involving hospitalized patients with moderateCOVID-19.

LSALT peptide(MetaBlokTM; ArchBiopartners) [191]

LSALT peptide that targets dipeptidase-1 (DPEP1), which is a vascular adhesion receptor forneutrophil recruitment in the lungs, liver, and kidney. The first US phase 2 trial will be at BrowardHealth Medical Center in Florida to treat complications in patients with COVID-19, includingprevention of acute lung and/or kidney injury.

RLS-0071 (ReAltaLife Sciences) [192]

Animal model shows RLS-0071 decreases inflammatory cytokines IL-1b, IL-6, and TNF-alpha. Aphase 1 randomized, double-blind, placebo-controlled trial is planned to begin Q3 2020 in adultswith COVID-19 pneumonia and early respiratory failure.

BLD-2660 (BladeTherapeutics) [193]

Antifibrotic agent. Targets a specific group of cysteine proteases called dimeric calpains(calpains 1, 2 and 9). Overactivity of dimeric calpains leads to inflammation and fibrosis. Phase2 trial (CONQUER) in hospitalized patients (n = 120) with COVID pneumonia completed inSeptember 2020.

EC-18 (EnzychemLifesciences) [194]

Preclinical studies observed EC-18 to control neutrophil infiltration, thereby modulating theinflammatory cytokine and chemokine signaling. A phase 2 multicenter, randomized, double-blind, placebo-controlled study is being initiated in the US to evaluate the safety and efficacy ofEC-18 in preventing the progression of COVID-19 infection to severe pneumonia or ARD.

SBI-101 (SentienBiotechnologies) [195]

Biologic/device combination product designed to regulate inflammation and promote repair ofinjured tissue using allogeneic human mesenchymal stromal cells. The phase 1/2 studyintegrates SBI-101 into the renal replacement circuit for treatment up to 24 hours in patients withARDS and acute kidney injury requiring renal replacement therapy (RRT).

Bacille Calmette-Guérin (BCG) vaccine(Baylor, Texas A&M,and HarvardUniversities; MDAnderson andCedars-Sinai MedicalCenters) [196]

Areas with existing BCG vaccination programs appear to have lower incidence and mortalityfrom COVID19. Study administers BCG vaccine to healthcare workers to see if reduces infectionand disease severity during SARS-CoV-2 epidemic.

ARDS-003 (Tetra Bio-Pharma) [197]

Cannabinoid that specifically targets CB2 receptor. Phase 1 clinical trial planned to evaluateanti-inflammatory properties and reduce cytokine release to prevent ARDS.

CAP-1002 (CapricorTherapeutics) [198]

CAP-1002 consists of allogeneic cardiosphere-derived cells (CDCs), a type of cardiac celltherapy that has been shown in preclinical and clinical studies to exert potentimmunomodulatory activity. CDCs releasing exosomes that are taken up largely bymacrophages and T-cells and begin a cycle of repair. A phase 2 trial (INSPIRE) in hospitalizedpatients with severe or critical COVID-19 was initiated in late 2020.

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Drug Description

Icatibant (Firazyr;TakedaPharmaceuticals) [28]

Competitive antagonist selective for bradykinin B2 receptor. Bradykinin formation results invascular leakage and edema. Part of the I-SPY COVID-19 clinical trial.

Razuprotafib (AKB-9778; AerpioPharmaceuticals) [28]

Tie2 activator that enhances endothelial function and stabilizes blood vessels, includingpulmonary and renal vasculature. SC razuprotafib restores Tie2 activation and improvesvascular stability in multiple animal models of vascular injury and inflammation, includinglipopolysaccharide-induced pulmonary and renal injury, polymicrobial sepsis, and IL-2 inducedcytokine storm. Part of the I-SPY COVID-19 clinical trial.

Fenretinide (LAU-7b;LaurentPharmaceuticals) [199]

Synthetic retinoid shown to address the complex links between fatty acids metabolism andinflammatory signaling, which is distinct from the retinoid class MOA. Believed to work bymodulating key membrane lipids in conjunction with proinflammatory pathways (eg, ERK1/2, NF-kappa-B, and cPLA2) needed for coronavirus entry, replication, and host defense evasion. Itmay also have antiviral properties. The phase 2 RESOLUTION trial in Canada has also gainedFDA approval in August 2020 for an IND in the US.

Ebselen (SPI-1005;SoundPharmaceuticals) [200]

Anti-inflammatory molecule that mimics and induces glutathione peroxidase. It reduces reactiveoxygen and nitrogen species by first binding them to selenocysteine, and then reducing theselenic acid intermediate through a reduction with glutathione. May also inhibit viral replication.Phase 2 studies for moderate and severe COVID-19 infection initiated in Fall 2020.

Fostamatinib(Tavalisse; RigelPharmaceuticals) [201]

Spleen tyrosine kinase (SYK) inhibitor that reduces signaling by Fc gamma receptor (FcγR) andc-type lectin receptor (CLR), which are drivers of proinflammatory cytokine release. It alsoreduces mucin-1 protein abundance, which is a biomarker used to predict ARDS development.Clinical trial initiated at the NIH clinical center.

Vadadustat (AkebiaTherapeutics) [202]

Oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor designed to mimic thephysiologic effect of altitude on oxygen availability and increased RBC production. Approved inJapan for anemia owing to chronic kidney disease (in phase 3 trials in US). Phase 2 trial initiatedat U of Texas Health Center in Houston for prevention and treatment of ARDS in hospitalizedpatients with COVID-19.

Ultramicronizedpalmitoylethanolamide(PEA; FSD201; FSDPharma) [203]

Fatty acid amide studied for its anti-inflammatory and analgesic actions. Phase 2a trial expectedto begin in October 2020 for hospitalized patients with documented COVID-19 disease.

EB05 (Edesa Biotech)[204]

Toll-like receptor 4 (TLR4) inhibitor. TLR4 is a key component of the innate immune systemwhich functions to detect molecules generated by pathogens, acting upstream of cytokine stormand IL-6-mediated acute lung injury.

Fluvoxamine (Luvox)[205]

Preliminary double, randomized study of nonhospitalized adults with COVID-19 in communityliving environment showed no clinical deterioration at Day 15 compared with those takingplacebo. Limited sample size with short follow-up. Clinical efficacy would require largerrandomized trial. Theorized mechanisms include fluvoxamine effects on the S1R agonism (anendoplasmic reticulum chaperone protein), anti-inflammatory actions, and SSRI inhibition ofplatelet activation.

Lanadelumab(Takeda) [206]

mAb that targets kallikrein. Inhibits kallikrein proteolytic activity to control excess bradykinin. Partof the COVID R&D alliance (Amgen, UCB SA, Takeda) to identify drugs that can reduce severityof COVID-19 in hospitalized patients by moderating the immune system.

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Drug Description

Zilucoplan (UCB SA)[206]

Macrocyclic peptide inhibitor of complement C5. Part of the COVID R&D alliance (Amgen, UCBSA, Takeda) to identify drugs that can reduce severity of COVID-19 in hospitalized patients bymoderating the immune system.

CRV431 (Hepion)[207]

Binds cyclophilin A, which blocks the binding of cyclophilin A to specific receptors oninflammatory cells. This decreases infiltration of the cells into the tissue and production ofharmful inflammatory molecules, resulting in reduced lung inflammation. Phase 2 trial startinglate 2020.

Ensifentrine (VeronaPharma) [208]

Phosphodiesterase (PDE) 3 and 4 inhibitor. Elicits both bronchodilator and anti-inflammatoryactivities. Delivered via pressurized metered-dose inhaler. Phase 2 trial in 45 patients completedJanuary 2021.

TZLS-501 (TizianaLife Sciences) [209] Anti-interleukin-6 receptor monoclonal antibody in early development.

Investigational ImmunotherapiesBucillamine

Bucillamine (Revive Therapeutics) is an antirheumatic agent derived from tiopronin. It has been available in Japan and SouthKorea for over 30 years. N-acetyl-cysteine (NAC) has been shown to significantly attenuate clinical symptoms in respiratory viralinfections in animals and humans, primarily via donation of thiols to increase antioxidant activity of cellular glutathione.Bucillamine has 2 thiol groups and its ability as a thiol donor is estimated to be 16 times that of NAC. A phase 3 confirmatorytrial for treatment of outpatients with mild-to-moderate COVID-19 at 10 sites in the US planned for Q1 2021 with enrollment goalof 1000 participants.[210]

MK-7110

MK-7110 (formerly CD24Fc; Merck) is a biological immunomodulator in Phase II/III clinical trial stage. It is a fusion proteincomprised of the nonpolymorphic regions of CD24 attached to the Fc region of human IgG1. An interim analysis in September2020 of data from the Phase 3 trial (SAC-COVID) in 243 participants (full enrollment) indicated that hospitalized patients withCOVID-19 treated with a single dose of MK-7110 showed a 60% higher probability of improvement in clinical status compared toplacebo, as defined by the protocol. The risk of death or respiratory failure was reduced by more than 50%.[211]

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

Immunotherapy Description

Allogeneic naturalkiller (NK) cells(CYNK-001;Celularity, Inc) [212]

Phase 1/2 clinical trial results assessed by data monitoring committee in December 2020 andconfirmed absence of dose-limiting toxicities. Demonstrates a range of biological activitiesexpected of NK cells, including expression of activating receptors (eg, NKG2D, DNAM-1, and thenatural cytotoxicity receptors NKp30, NKp44, and NKp46), which bind to stress ligands and viralantigens on infected cells.

ADX-629 (AldeyraTherapeutics) [213]

Oral reactive aldehyde species (RASP) inhibitor. RASP inhibitors have the potential to representupstream immunological switches that modulate immune systems from pro-inflammatory states toanti-inflammatory states. Phase 2 placebo-controlled trial in hospitalized patients with COVID-19initiated December 2020.

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Immunotherapy Description

MultiStem celltherapy (Athersys)[214]

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 thephase 2/3 trial—MultiStem Administration for COVID-19 Induced Acute Respiratory DistressSyndrome (MACOVIA) at University Hospital’s Cleveland Medical Center.

Peginterferonlambda (EigerBiopharmaceuticals;Stanford University)[215]

Type Ill interferon (IFN) that stimulates immune responses critical for the development of hostprotection during viral infections. A phase 2 double-blind, placebo-controlled trial (ILIAD) wasconducted between May 18 and September 4 2020 in outpatients with COVID-19. Patientsreceived a single SC injection of either peginterferon lambda 180 mcg (n=30) or placebo (n=30).The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon lambda thanplacebo from day 3 onwards, with a difference of 2.42 log copies per mL at day 7 (p = 0.0041). Byday 7, 24 (80%) participants in the peginterferon lambda group had an undetectable viral load,compared with 19 (63%) in the placebo group (p = 0.15). After controlling for baseline viral load,patients in the peginterferon lambda group were more likely to have undetectable virus by day 7than were those in the placebo group (p = 0.029). Of those with baseline viral load above 106copies per mL, 15 (79%) of 19 patients in the peginterferon lambda group had undetectable viruson day 7, compared with 6 (38%) of 16 in the placebo group (p = 0.012). Among the 60 patientsfollowed in the study, 5 required emergency room visits due to deteriorating respiratory symptoms(4 in the placebo group, 1 in the peg-IFN-lambda group).

Immune globulin IV(Octagam 10%;Octapharma) [216]

Pilot study showed that IVIG plus IV methylprednisolone significantly improved hypoxia andreduced hospital length of stay and progression to mechanical ventilation in coronavirus disease2019 patients with A-a gradient greater than 200 mm Hg compared with standard of care. A phase3 multicenter randomized double-blinded clinical trial is under way to validate these findings.

Efineptakin alfa(NT-17;NeoImmuneTech,Inc) [217]

A long-acting human interleukin-7 (IL-7), which plays a key role in T-cell development. IL-7 actsthrough IL-7 receptor (IL-7R), which is expressed on naïve and memory CD4+ and CD8+ T cellsand promotes proliferation, maintenance, and functionality of these T-cell subsets that mediateimmune responses. A phase 1 trial initiated late 2020 for adults with mild COVID-19 in conjunctionwith NIAID and the University of Nebraska Medical Center.

Vilobelimab (IFX-1; InflaRx) [218]

First-in-class monoclonal anti-human complement factor C5a antibody. IFX-1 blocks the biologicalactivity of C5a and demonstrates high selectivity toward its target in human blood; therefore, itleaves the formation of the membrane attack complex (C5b-9) intact as an important defensemechanism, which is not the case for molecules blocking C5 cleavage. Phase 3 trial (PANAMO)initiated September 2020 for treatment of COVID-19 related severe pneumonia.

T-COVID(Altimmune) [219]

Intranasal immune modulator in phase 1/2 trial (EPIC) in US for non-hospitalized patients withearly COVID-19 infection.

ALVR109 (AlloVir)[220]

Allogeneic virus-specific T-cell therapy that targets SARS-CoV-2. Comprised almost exclusively ofCD3+ T cells, with a mixture of cytotoxic (CD8+) and helper (CD4+) T cells. Phase 1 trial inhospitalized patients at high risk for mechanical ventilation started Q4 2020.

Inhaled interferonbeta-1a (SNG001;SynairgenResearch Ltd) [221]

IFN-beta is a naturally occurring protein. Deficiency of IFN-beta increases susceptibility to moresevere respiratory symptoms among older and at-risk patients. It is theorized that SNG001 helpsrestore the lung IFN-beta ability to neutralize the virus. Positive results (fewer days to discharge)from a phase 2 study (101 hospitalized patients with COVID-19) in the UK support continuingclinical trials.

Investigational Antibody Therapies

Antibodies Granted Emergency Use Authorization

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Information, including allocation, for COVID-19 therapies granted emergency use authorization is located at the United StatesPublic Health Emergency webpage.

Owing to the increase in variants of concern (VOC) in the United States, monoclonal antibodies that have gained emergencyuse authorization have been tested to evaluate activity against VOCs. As of March 24, 2021, distribution has ceased ofbamlanivimab alone. Consider use of etesevimab plus bamlanivimab, or casirivimab plus imdevimab in outpatients who qualifyfor monoclonal antibodies.

Bamlanivimab

March 24, 2021: No longer recommended as monotherapy owing to viral variants that are resistant to bamlanivimab.

Bamlanivimab (LY-CoV555; Eli Lilly & Co, AbCellera) is neutralizing IgG1 monoclonal antibody (mAb) directed against the spikeprotein of SARS-CoV-2. It is designed to block viral attachment and entry into human cells, thus neutralizing the virus, potentiallypreventing and treating COVID-19.

The FDA issued an emergency use authorization (EUA) for bamlanivimab on November 9, 2020. The EUA permitsbamlanivimab to be administered for treatment of mild-to-moderate coronavirus disease 2019 (COVID19) in adults and pediatricpatients with positive results of direct SARS-CoV-2 viral testing who are age 12 years and older weighing at least 40 kg, and athigh risk for progressing to severe COVID-19 and/or hospitalization.[9]

The NIH COVID-19 Guidelines Panel issued a statement regarding use of bamlanivimab, including that it should not beconsidered standard of care. The Panel emphasizes the possibility of a limited supply of bamlanivimab, as well as challengesdistributing and administering the drug, recommends only patients at highest risk for COVID-19 progression should be prioritizedfor the drug through the EUA. Additionally, communities most affected by COVID-19 should have equitable access tobamlanivimab.[222]

An interim analysis from the Blocking Viral Attachment and Cell Entry with SARS-CoV-2 Neutralizing Antibodies (BLAZE-1)provided the basis of support for the EUA. In this phase 2 trial, bamlanivimab given to people recently diagnosed with COVID-19in the ambulatory setting showed a reduced rate of hospitalization or ER visits compared with placebo. Patients who receivedbamlanivimab monotherapy or placebo were enrolled first (June 17-August 21, 2020) followed by patients who receivedbamlanivimab plus etesevimab or placebo (August 22-September 3). An EUA was granted for this combination in February2021. Bamlanivimab can be used alone or together with etesevimab, but etesevimab can only be used with bamlanivimab.[223]

Etesevimab plus bamlanivimab

The FDA issued an EUA for etesevimab (LY-CoV016; Eli Lilly & Co, AbCellera) on February 9, 2021. The EUA permits use incombination with bamlanivimab or treatment of mild-to-moderate COVID19 in adults and adolescents who are at high risk forprogressing to severe COVID-19 and/or hospitalization.

In this arm of the phase 3 BLAZE-1 trial, the change in log viral load from baseline at day 11 was -3.72 for bamlanivimab 700mg, -4.08 for bamlanivimab 2800 mg, -3.49 for bamlanivimab 7000 mg, -4.37 for combination treatment, and -3.80 for placebo.Among nonhospitalized patients with mild-to-moderate COVID-19 illness, treatment with bamlanivimab plus etesevimab,compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; however, nosignificant difference in viral load reduction was observed for bamlanivimab monotherapy. No difference in hospitalization ratewas observed between bamlanivimab monotherapy or with the combination. Based on an analysis of available data, theauthorized dosage regimen of the combination is bamlanivimab 700 mg plus etesevimab 1400 mg administered together as asingle IV infusion. This regimen is expected to have similar clinical effects as the 2800 mg dosages evaluated in the study.[224]

Other ongoing clinical trials

A Phase 3 study of bamlanivimab monotherapy for prevention of COVID-19 in residents and staff at long-term care facilities(BLAZE-2).[225] Bamlanivimab is also being tested in the National Institutes of Health-led ACTIV-2 studies of ambulatorypatients with COVID-19. Bamlanivimab is no longer part of the NIH ACTIV-3 trial studying patients who are hospitalized withmore advanced COVID-19 disease, as benefit was not observed.[27]

Weekly bamlanivimab allocation to states and territories can be located on the US Government Public Health Emergencywebsite. The Centers for Medicare and Medicaid Services announced they will pay $309 for an infusion, and once thegovernment purchased supply is exhausted, they will pay for the product at 95% of the average wholesale price.

Casirivimab plus imdevimab

An EUA was issued for coadministration of the monoclonal antibodies casirivimab and imdevimab (REGN-COV; Regeneron) onNovember 21, 2020 for treatment of mild-to-moderate COVID-19 in adults and pediatric patients aged 12 years and older whoweigh at least 40 kg and are at high risk for progressing to severe COVID-19 and/or hospitalization.[11] The mixture is designed



to bind to 2 points on the SARS-CoV-2 spike protein. As with bamlanivimab, administration of casirivimab and imdevimab hasnot shown benefit in hospitalized patients with severe COVID-19.

The study in hospitalized patients was changed in late October 2020 to allow enrollment only in hospitalized patients with low orno oxygen requirements.[226, 227] However, casirivimab and imdevimab did show reduced viral levels and improvedsymptoms in nearly 800 non-hospitalized patients with COVID-19 disease in a phase 2/3 trial. Results showed treatment withthe 2 antibodies reduced COVID-19 related medical visits by 57% through day 29 (2.8% combined dose groups; 6.5% placebo;p = 0.024). In high risk patients (1 or more risk factor including age older than 50 years; body mass index greater than 30;cardiovascular, metabolic, lung, liver or kidney disease; or immunocompromised status) COVID-19 related medical visits werereduced by 72% (p = 0.0065).[228, 229]

A phase 3 trial (n = 4,567) in infected outpatients who were at high risk for hospitalization or severe COVID-19 disease foundcasirivimab plus imdevimab significantly reduced the risk of hospitalization or death. Risk was decreased by 70% with the 1200mg IV dose (n = 827) and by 71% with 2400 mg IV (n = 1,849) compared with placebo (n = 1,843).[230]

An ongoing phase 1/2/3 clinical trial of the antibody cocktail in hospitalized patients with COVID-19 disease requiring low-flowoxygen found encouraging results. Patients who had not yet mounted their own immune response to SARS-CoV-2 (ie,seronegative for antibodies at baseline) had a lower risk of death or progression to mechanical ventilation after receivingcasirivimab and imdevimab (HR: 0.78; 80% CI: 0.51-1.2). Risk of death or mechanical ventilation decreased by approximately50% after 1 week following treatment with the antibody cocktail. Seronegative patients (n = 217) had much higher viral loadsthan those who had already developed their own antibodies (seropositive [n = 270]) to SARS-CoV-2 at the time ofrandomization. In seronegative patients, the antibody cocktail reduced the time-weighted average daily viral load through day 7by -0.54 log10 copies/mL, and through day 11 by -0.63 log10 copies/mL (nominal p = 0.002 for combined doses). As expected,the clinical and virologic benefit of the antibody cocktail was limited in seropositive patients.[231] A larger trial will be required toconfirm these initial observations. The ongoing UK-based RECOVERY trial continues to enroll hospitalized patients to receivecasirivimab and imdevimab.

VIR-7831

VIR-7831 (VIR Biotechnology; GlaxoSmithKline) is a mAb that binds to conserved epitope of the spiked protein of SARS-CoV-1and SARS-CoV-2, thereby indicating unlikelihood of mutational escape. This is supported by a preclinical trial showing itretained ability to neutralize SARS-CoV-2 variants (ie, B.1.1.7, B.1.351, P.1).[232] A request for emergency use authorization(EUA) was submitted to the FDA on March 26, 2021.

The EUA submission was based on an interim analysis of the COMET-ICE phase 3 trial. The trial evaluated VIR-7831 asmonotherapy for early treatment of COVID-19 in adults at high risk of hospitalization or death. The interim analysisdemonstrated an 85% reduction in hospitalization or death in those who received a single IV dose of VIR-7831 (n = 291)compared with placebo (n = 292) (p = 0.002).[233]

Results from a phase 2 trial (BLAZE-4) of a single IV dose of VIR-7831 coadministered with bamlanivimab in low-risk adults withmild-to-moderate COVID-19 demonstrated a 70% (p < 0.001) relative reduction in persistently high viral load at day 7 comparedwith placebo.[234]

Additional trials for VIR-7831 include comparison of IM and IV administration in low-risk adults (COMET-PEAK), IM use in high-risk adults (COMET-TAIL), and IM administration in uninfected adults to prevent symptomatic infection (COMET-STAR).

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

Antibody Therapies Description

COVI-SHIELD (SorrentoTherapeutics) [235] mAb Fc cocktail development in conjunction with Mt Sinai Health System in New York City.

STI-1499 (SorrentoTherapeutics) [236] COVID-19 targeting mAb. Phase 1 dose-ranging trial (COVI-GUARD) in hospitalized patients.

STI-2020 (SorrentoTherapeutics) [237]

Phase 1, dose-ranging trial (COVI-AMG) of monoclonal antibody engineered for high potencyto allow for small volume IV administration to outpatients with mild symptoms. Preclinicalstudies showed strong binding affinities to the currently dominant D614G variant and the mink-associated N439K variant of the spike-protein.

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Antibody Therapies Description

AZD7442 (AstraZeneca)[238]

Long-acting combination of 2 mAbs derived from convalescent patients who recovered fromCOVID-19 infection. Two phase 3 trials starting in October 2020 will measure efficacy ofpreventing infection for up to 12 months.

Foralumab intranasal(Tiziana Life Sciences)[239]

Fully human anti-CD3 monoclonal antibody (mAb) found to induce regulatory T-cells, resultingin an IL-10 anti-inflammatory signal. As of September 2020, it is in a phase 2 trial in Brazil.

Ab8 (Abound Bio; U ofPittsburgh MedicalCenter) [240]

Small antibody in preclinical trials with potential for treatment and/or prophylaxis againstSARS-CoV-2.

ABBV-47D11 (AbbVie)[241]

Neutralizing anti-SARS-CoV-2 monoclonal antibody. Phase 1 study started December 2020.

AR-711 and AR-713(Aridis Pharmaceuticals)[242]

Phase 1/2/3 clinical trials for home-administered inhaled mAb cocktail planned for mid-2021.

Investigational VaccinesThe genetic sequence of SARS-CoV-2 was published on January 11, 2020. A rapid emergence of research and collaborationamong scientists and biopharmaceutical manufacturers followed. The FDA has granted EUAs for 3 SARS-CoV-2 vaccines sinceDecember 2020. Two are mRNA vaccines – BNT-162b2 (Pfizer) and mRNA-1273 (Moderna), whereas the third is a viral vectorvaccine – Ad26.COV2.S (Johnson & Johnson). ACIP has published guidelines on the ethical principles for the initial allocationfor this scarce resource.[243] As of March 2, 2021, The New York Times Coronavirus Vaccine Tracker lists 6 vaccines in earlyor limited use. Another 6 vaccines are approved for full use (outside the United States) and 20 vaccines are in phase 3 clinicaltrials.[244]

In addition to the complexity of finding the most effective vaccine candidates, the production process is also important formanufacturing the vaccine to the scale needed globally. Other variable that increase complexity of distribution include storagerequirements (eg, frozen vs refrigerated) and if more than a single injection is required for optimal immunity. Severaltechnological methods (eg, DNA, RNA, inactivated, viral vector, protein subunit) are available for vaccine development. Vaccineattributes (eg, number of doses, speed of development, scalability) depends on the type of technological method employed. Forexample, the mRNA vaccine platforms allow for rapid development.[245, 246]

Antithrombotics

COVID-19 is a systemic illness that adversely affects various organ systems. A review of COVID-19 hypercoagulopathy aptlydescribes both microangiopathy and local thrombus formation, and a systemic coagulation defect leading to large vesselthrombosis and major thromboembolic complications, including pulmonary embolism, in critically ill patients.[247] While sepsisis recognized to activate the coagulation system, the precise mechanism by which COVID-19 inflammation affects coagulopathyis not fully understood.[248]

Several retrospective cohort studies have described use of therapeutic and prophylactic anticoagulant doses in critically illhospitalized patients with COVID-19. No difference in 28-day mortality was observed for 46 patients empirically treated withtherapeutic anticoagulant doses compared with 95 patients who received standard DVT prophylaxis doses, including those withD-dimer levels greater than 2 mcg/mL. In this study, day 0 was the day of intubation, therefore, they did not evaluate all patientswho received empiric therapeutic anticoagulation at the time of diagnosis to see if progression to intubation was improved.[249]

In contrast to the above findings, a retrospective cohort study showed a median 21 day survival for patients requiringmechanical ventilation who received therapeutic anticoagulation compared with 9 days for those who received DVT prophylaxis.

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[250]

NIH trial

Current guidelines include thrombosis prophylaxis (typically with low-molecular-weight heparin [LMWH]) for hospitalizedpatients. As of September 2020, the NIH ACTIV trial includes an arm (ACTIV-4) for use of antithrombotics in the outpatient,inpatient, and convalescent settings.[27]

The 3 adaptive clinical trials within ACTIV-4 include preventing, treating, and addressing COVID-19-associated coagulopathy(CAC). Additionally, a goal to understand the effects of CAC across patient populations – inpatient, outpatient, andconvalescent.[27]

In December 2020, the ACTIV-4 trial enrolling critically ill patients with COVID-19 requiring intensive care unit supports waspaused owing to a potential for harm in this subgroup. Whether the use of full-dose compared to low-dose anticoagulants leadsto better outcomes in hospitalized patients with less COVID-19 severe disease remains a very important question.

Purpose and initial drugs included in ACTIV-4 are:

Outpatient trial

Investigates whether anticoagulants or antithrombotic therapy can reduce life-threatening cardiovascular or pulmonarycomplications in newly diagnosed patients with COVID-19 who do not require hospital admission. Participants will berandomized to take either a placebo, aspirin, or a low or therapeutic dose of apixaban.

Inpatient trial

Investigates an approach aimed at preventing clotting events and improving outcomes in hospitalized patients with COVID-19.Varying doses of unfractionated heparin or LMWH will be evaluated on ability to prevent or reduce blood clot formation.

Convalescent trial

Investigates safety and efficacy anticoagulants and/or antiplatelets administered to patients who have been discharged from thehospital or are convalescing in reducing thrombotic complications (eg, MI, stroke, DVT, PE, death). Patients will be assessed forthese complications within 45 days of being hospitalized for moderate and severe COVID-19.

Investigational antithrombotics

AB201

AB201 (ARCA Biopharma) is a recombinant nematode anticoagulant protein c2 (rNAPc2) that specifically inhibits tissue factor(TF)/factor VIIa complex and has anticoagulant, anti-inflammatory, and potential antiviral properties. TF plays a central role ininflammatory response to viral infections. Phase 2b/3 clinical trial (ASPEN-COVID-19) started in December 2020 in hospitalizedpatients with COVID-19 at the University of Colorado. The phase 2b trial randomizes 2 AB201 dosage regimens compared withheparin. The primary endpoint is change in D-dimer level from baseline to Day 8. The phase 3 trial design is contingent uponphase 2b results.[251]

Renin Angiotensin System Blockade and COVID-19SARS-CoV-2 is known to utilize angiotensin-converting enzyme 2 (ACE2) receptors for entry into target cells.[252] Data arelimited 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).

The first randomized study to compare continuing vs stopping (ACEIs) or ARBs receptor for patients with COVID-19 has shownno difference in key outcomes between the 2 approaches. A similar 30-day mortality rate was observed for patients whocontinued and those who suspended ACE inhibitor/ARB therapy, at 2.8% and 2.7%, respectively (hazard ratio, 0.97).[253]

The BRACE Corona trial design further explains the 2 hypotheses.[253]

One hypothesis suggests that use of these drugs could be harmful by increasing the expression of ACE2 receptors(which the SARS-CoV-2 virus uses to gain entry into cells), thus potentially enhancing viral binding and viral entry.The other suggests that ACE inhibitors and ARBs could be protective by reducing production of angiotensin II andenhancing the generation of angiotensin 1-7, which attenuates inflammation and fibrosis and therefore could attenuatelung injury.

Concern arose regarding appropriateness of continuation of ACEIs and ARBs in patients with COVID-19 after early reportsnoted 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.[254, 255]

The speculated mechanism for detrimental effect of ACEIs and ARBs is related to ACE2. It was therefore hypothesized that anyagent that increases expression of ACE2 could potentially increase susceptibility to severe COVID-19 by improving viral cellularentry;[254] however, physiologically, ACE2 also converts angiotensin 2 to angiotensin 1-7, which leads to vasodilation and mayprotect against lung injury by lowering angiotensin 2 receptor binding.[255, 256] It is therefore uncertain whether an increasedexpression 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 regardingRAAS 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 onlyappears to gain initial entry through ACE2 but also down-regulates ACE2 expression, possibly mitigating the counterregulatoryeffects of ACE2.[257]

There are also conflicting data regarding whether ACEIs and ARBs increase ACE2 levels. Some studies in animals havesuggested that ACEIs and ARBs increase expression of ACE2,[258, 259, 260] while other studies have not shown this effect.[261, 262]

As uncertainty controversy remains regarding whether ACEIs and/or ARBs increase ACE2 expression and how this effect mayinfluence outcomes in patients with COVID-19, cardiology societies have largely recommended against initiating ordiscontinuing these medications based solely on active SARS-CoV-2 infection.[263, 264]

A systematic review and meta-analysis found use of ACEIs or ARBs was not associated with a higher risk of mortality amongpatients with COVID-19 with hypertension or multiple comorbidities, supporting recommendations of medical societies tocontinue use of these agents to control underlying conditions.[265]

Diabetes and COVID-19High plasma glucose levels and diabetes mellitus (DM) are known risk factors for pneumonia.[266, 267] Potential mechanismsthat may increase the susceptibility for COVID-19 in patients with DM include the following:[268]

Higher-affinity cellular binding and efficient virus entryDecreased viral clearanceDiminished T-cell functionIncreased susceptibility to hyperinflammation and cytokine storm syndromePresence of cardiovascular disease

SARS-CoV-2 is known to utilize angiotensin-converting enzyme 2 (ACE2) receptors[252] for entry into target cells. Insulinadministration attenuates ACE2 expression, while hypoglycemic agents (eg, glucagonlike peptide 1 [GLP-1] agonists,thiazolidinediones) up-regulate ACE2.[268] 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 syndromecoronavirus (MERS-CoV), and protein modeling suggests that it may play a similar role with SARS-CoV-2, the virus responsiblefor COVID-19.[269]

The relationship between diabetes, coronavirus infections, ACE2, and DPP-4 has been reviewed by Drucker. Important clinicalconclusions of the review include the following:[267]

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 withdiabetes who are hospitalized with acute COVID-19.

Therapies Determined Ineffective

Hydroxychloroquine and chloroquine

On June 15, 2020, the FDA revoked the emergency use authorization (EUA) for hydroxychloroquine and chloroquine donated tothe Strategic National Stockpile to be used for treating certain hospitalized patients with COVID-19 when a clinical trial wasunavailable or participation in a clinical trial was not feasible.[270]

Based on its ongoing analysis of the EUA and emerging scientific data, the FDA determined that hydroxychloroquine is unlikelyto 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 outweighthe known and potential risks for the EUA.

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

Additionally, the NIH halted the Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients withsymptomatic Disease (ORCHID) study on June 20, 2020. After the fourth analysis that included more than 470 participants, theNIH data and safety monitoring board determined that while, there was no harm, the study drug was very unlikely to bebeneficial to hospitalized patients with COVID-19.[271]

Hydroxychloroquine and chloroquine are widely used antimalarial drugs that elicit immunomodulatory effects and are thereforealso used to treat autoimmune conditions (eg, systemic lupus erythematosus, rheumatoid arthritis). As inhibitors of hemepolymerase, they are also believed to have additional antiviral activity via alkalinization of the phagolysosome, which inhibits thepH-dependent steps of viral replication. Wang et al reported that chloroquine effectively inhibits SARS-CoV-2 in vitro.[272] Thepharmacological 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 bemore potent than chloroquine in vitro. Based on PBPK models, the authors recommend a loading dose of hydroxychloroquine400 mg PO BID, followed by 200 mg BID for 4 days.[107]

Published reports stemming from the worldwide outbreak of COVID-19 have evaluated the potential usefulness of these drugsin 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 1561 patients to hydroxychloroquine and 3155 patients to usual care alone. Resultsfound no significant difference in the primary endpoint of 28-day mortality (27% hydroxychloroquine vs 25% usual care; hazardratio 1.09 [95% CI, 0.97-1.23]; P = 0.15). Secondary outcomes showed patients in the hydroxychloroquine group had a longerduration of hospitalization than those in the usual-care group (median, 16 days vs. 13 days) and a lower probability of dischargealive within 28 days (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98).[273]

A multicenter, randomized, open-label trial in Brazil found no improvement in 504 hospitalized patients with mild-to-moderateCOVID-19. Use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days compared withstandard care. Prolonged QTc interval and elevated liver-enzyme levels were more common in patients receivinghydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent.[274]

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 wereobserved 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, thecombination, or neither drug was 25%, 20%, 18%, and 20%, respectively.[275]

Because of findings from the aforementioned studies, the WHO halted the hydroxychloroquine arm of the Solidarity Trial andthen removed its use entirely as of July 4, 2020.[29] Interim results released mid-October 2020 found hydroxychloroquine andchloroquine appeared to have little or no effect on hospitalized patients with COVID-19, as indicated by overall mortality,initiation of ventilation, and duration of hospital stay. Death rate ratio for hydroxychloroquine was 1.19 (0.89-1.59, p = 0.23;104/947 vs 84/906).[30] The FDA issued a safety alert for hydroxychloroquine or chloroquine use in COVID-19 on April 24,2020, and revoked the EUA on June 15, 2020.[270, 276]

A multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US showed hydroxychloroquine didnot significantly improved clinical status at day 14 in adults who were hospitalized with COVID-19 respiratory illness. Patientswere randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242)or placebo (n = 237).[277]

An observational study of consecutively hospitalized patients (n = 1446) at a large medical center in the New York City areashowed hydroxychloroquine was not associated with either a greatly lowered or an increased risk of the composite endpoint ofintubation or death.[278]

A nationwide, observational cohort study in The Netherlands showed early treatment with hydroxychloroquine (but notchloroquine) on the first day of hospital admission was associated with a 53% reduced risk of transfer to the ICU for mechanicalventilation. Hospitals were given the opportunity to decide independently on the use of 3 different treatment strategies:hydroxychloroquine (n = 189), chloroquine (n = 377), or no treatment (n =498). The authors concluded that additionalprospective data on early hydroxychloroquine use is still needed.[279]



A retrospective observational study of 2,541 consecutive patients hospitalized with COVID at Henry Ford Health System fromMarch 10, 2020, to May 2, 2020, showed a decreased mortality rate in patients treated with hydroxychloroquine alone or incombination 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 ofcorticosteroids, an accompanying editorial discusses time bias, missing prognostic indicators, and other confounding factors ofthis observational study.[280, 281]

A retrospective analysis of data from patients hospitalized with confirmed COVID-19 infection in all US Veterans HealthAdministration medical centers between March 9, 2020, and April 11, 2020, has been published. Patients who had receivedhydroxychloroquine (HC) alone or with azithromycin (HC + AZ) as treatment in addition to standard supportive care wereidentified. 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 were13.3%, 6.9%, 14.1%, respectively. The authors concluded that they found no evidence that hydroxychloroquine, with or withoutazithromycin, reduced the risk of mechanical ventilation and that the overall mortality rate was increased withhydroxychloroquine treatment. Furthermore, they stressed the importance of waiting for results of ongoing, prospective,randomized controlled trials before wide adoption of these drugs.[282]

A retrospective study assessed effects of hydroxychloroquine according to its plasma concentration in patient hospitalized in theICU. The researchers compared 17 patients with hydroxychloroquine plasma concentrations within the therapeutic target and 12patients with plasma concentrations below the target. At 15 days of follow-up, no association was found betweenhydroxychloroquine plasma concentration and viral load evolution (p = 0.77). Additionally, there was no significant differencebetween the 2 groups for duration of mechanical ventilation, length of ICU stays, in-hospital mortality, and 15-days mortality.[283]

According to a consensus statement from a multicenter collaboration group in China, chloroquine phosphate 500 mg (300 mgbase) twice daily in tablet form for 10 days may be considered in patients with COVID-19 pneumonia.[284] While no peer-reviewed treatment outcomes are available, Gao and colleagues report that 100 patients have demonstrated significantimprovement with this regimen without documented toxicity.[285] It should be noted this is 14 times the typical dose ofchloroquine used per week for malaria prophylaxis and 4 times that used for treatment. Cardiac toxicity should temperenthusiasm for this as a widespread cure for COVID-19. It should also be noted that chloroquine was previously found to beactive in vitro against multiple other viruses but has not proven fruitful in clinical trials, even resulting in worse clinical outcomesin 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 confirmedCOVID-19. Additional inclusion criteria included age 18 years or older, chest CT scans showing pneumonia, and SaO2/SPOsratio of more than 93% (or PaOs/FIOs ratio >300 mm Hg). Patients with severe or critical illness were excluded. All patientsenrolled 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 for5 days) in addition to standardized treatment. Changes in time to clinical recovery (TTCR) was evaluated and defined as returnof normal body temperature and cough relief, maintained for more than 72 hours. Compared with the control group, TTCR forbody temperature and cough were significantly shortened in the hydroxychloroquine group. Four of the 62 patients progressedto severe illness, all of whom were in the control group.[286]

An open-label multicenter study using high-dose hydroxychloroquine or standard of care did not show a difference at 28 days forseronegative conversion or the rate of symptom alleviation between the two treatment arms. The trial was conducted in 150patients in China with mild-to-moderate disease.[287]

Hydroxychloroquine plus azithromycin

Opposing conclusions by French researchers regarding viral clearance and clinical benefit with the regimen ofhydroxychloroquine plus azithromycin have been published.[288, 289, 290]

A small prospective study found no evidence of a strong antiviral activity or clinical benefit from use of hydroxychloroquine plusazithromycin. Molina et al assessed virologic and clinical outcomes of 11 consecutive patients hospitalized who receivedhydroxychloroquine (600 mg per day x10 days) and azithromycin (500 mg Day 1, then 250 mg days 2-5). Patient demographicswere as follows: 7 men and 4 women; mean age 58.7 years (range: 20-77); 8 had significant comorbidities associated with pooroutcomes (ie, obesity 2; solid cancer 3; hematological cancer 2; HIV-infection 1). Ten of the eleven patients had fever andreceived oxygen via nasal cannula. Within 5 days, 1 patient died, 2 were transferred to the ICU. Hydroxychloroquine andazithromycin were discontinued in 1 patient owing to prolonged QT interval. Nasopharyngeal swabs remained positive forSARS-CoV-2 RNA in 8/10 patients (80%, 95% confidence interval: 49-94) at days 5-6 after treatment initiation.[290]

In direct contrast to 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 who received treatment from theanalysis 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]).[288] This is an unusual approach to reportingresults because the clinical correlation with nasopharyngeal clearance on day 6 is unknown and several patients changed statuswithin a few days of that endpoint (converting from negative back to positive). The choice of that particular endpoint was also notexplained by the authors, yet 4 of the 6 excluded patients had adverse outcomes (admission to ICU or death) at that time butwere not counted in the analysis. Furthermore, patients who refused to consent to the study group were included in the controlarm, indicating unorthodox study enrollment.

This small open-label study of hydroxychloroquine in France included azithromycin in 6 patients for potential bacterialsuperinfection (500 mg once, then 250 mg PO daily for 4 days). These patients were reported to have 100% clearance ofSARS-CoV-2. While intriguing, these results warrant further analysis. The patients receiving combination therapy had initiallylower viral loads, and, when compared with patients receiving hydroxychloroquine alone with similar viral burden, the results arefairly similar (6/6 vs 7/9).[288]

The French researchers continued their practice of using hydroxychloroquine plus azithromycin and accumulated data in 80patients with at least 6 days of follow-up. They note that the 6 patients on combination therapy enrolled in their first analysiswere also included in the present case series, with a longer follow-up. However, it was not clear from the description in theirposted methods when patients were assessed. A favorable outcome was defined as not requiring aggressive oxygen therapy ortransfer to the ICU after 3 days of treatment. Sixty-five of the 80 patients (81.3%) met this outcome. One patient aged 86 yearsdied, 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. Virusculture results from patient respiratory samples were negative in 97.5% patients at day 5.[289] This is described as a promisingmethod of reducing spread of SARS-CoV-2, but, unfortunately, the study lacked a control group and did not compare treatmentwith 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 assessrisk of clinical deterioration. Only 15% were febrile, a common criterion for testing in the United States, and 4 individuals wereconsidered asymptomatic carriers. In addition, the results did not delineate between asymptomatic carriers and those with highviral load or low viral load.

Nonhospitalized patients with early COVID-19

Hydroxychloroquine did not improve outcomes when administered to outpatient adults (n = 423) with early COVID-19. Changein symptom severity over 14 days did not differ between the hydroxychloroquine and placebo groups (P = 0.117). At 14 days,24% (49 of 201) of participants receiving hydroxychloroquine had ongoing symptoms compared with 30% (59 of 194) receivingplacebo (P = 0.21). Medication adverse effects occurred in 43% (92 of 212) of participants receiving hydroxychloroquinecompared with 22% (46 of 211) receiving placebo (P< 0.001). Among patients receiving placebo, 10 were hospitalized (twocases unrelated to COVID-19), one of whom died. Among patients receiving hydroxychloroquine, four were hospitalized andone nonhospitalized patient died (P = 0.29).[291]

Clinical trials evaluating prevention

Various clinical trials in the United States were initiated to determine if hydroxychloroquine reduces the rate of infection whenused by individuals at high risk for exposure, such as high-risk healthcare workers, first responders, and individuals who share ahome with a COVID-19–positive individual.[292, 293, 294, 295, 296, 297]

Results from the PATCH trial (n=125) did not show any benefit of hydroxychloroquine to reduce infection among healthcareworkers compared with placebo.[294]

Another study rerolled 1483 healthcare workers, of which 79% performed aerosol-generating procedures did not show adifference in preventing infection with once or twice weekly hydroxychloroquine compared with placebo. The incidence of SARS-CoV-2 laboratory-confirmed or symptomatic compatible illness was 0.27 events per person-year with once-weekly and 0.28events per person-year with twice-weekly hydroxychloroquine compared with 0.38 events per person-year with placebo (p =0.18 and 0.22 respectively).[298]

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 inasymptomatic 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 symptomaticallycompatible) 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 of407 [14.3%]) (P = 0.35).[299]

QT prolongation with hydroxychloroquine and azithromycin

Chloroquine, hydroxychloroquine, and azithromycin each carry the warning of QT prolongation and can be associated with anincreased risk of cardiac death when used in a broader population.[300] Because of this risk, the American College ofCardiology, 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 QTassessment and monitoring when the two drugs are coadministered.[301]

A Brazilian study comparing chloroquine high-dose (600 mg PO BID for 10 days) and low-dose (450 mg BID for 1 day, then 450mg/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.[302]

An increased 30-day risk of cardiovascular mortality, chest pain/angina, and heart failure was observed with the addition ofazithromycin to hydroxychloroquine from an analysis of pooled data from Japan, Europe, and the United States. The analysiscompared use of hydroxychloroquine, sulfamethoxazole, or the combinations of hydroxychloroquine plus amoxicillin orhydroxychloroquine plus azithromycin.[303]

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

Doxycycline

A few case reports and small case series have speculated on a use for doxycycline in COVID-19. Most seem to have beensearching for an antibacterial to replace azithromycin for use in combination with hydroxychloroquine. In general, the use ofHCQ has been abandoned. The anti-inflammatory effects of doxycycline were also postulated to moderate the cytokine surge ofCOVID-19 and provide some benefits. However, the data on corticosteroid use has returned, and is convincing and stronglysuggests their use. It is unclear that doxycycline would provide further benefits. Finally, concomitant bacterial infection duringacute COVID-19 is proving to be rare decreasing the utility of antibacterial drugs. Overall, there does not appear to be a routinerole for doxycycline.

Lopinavir/ritonavir

The NIH Panel for COVID-19 Treatment Guidelines recommend against the use of lopinavir/ritonavir or other HIV proteaseinhibitors, owing to unfavorable pharmacodynamics and because clinical trials have not demonstrated a clinical benefit inpatients with COVID-19.[304]

The Infectious Diseases Society of America (IDSA) guidelines recommend against use of lopinavir/ritonavir. The guidelines alsomention the risk for severe cutaneous reactions, QT prolongation, and the potential for drug interactions owing to CYP3Ainhibition.[17]

The RECOVERY trial concluded no beneficial effect was observed in hospitalized patients with COVID-19 who wererandomized to receive lopinavir/ritonavir (n = 1616) compared with those who received standard care (n = 3424). No significantdifference for 28-day mortality was shown. Overall, 374 (23%) patients allocated to lopinavir/ritonavir and 767 (22%) patientsallocated to usual care died within 28 days (p = 0.60). No evidence was found for beneficial effects on the risk of progression tomechanical ventilation or length of hospital stay.[305]

The WHO discontinued use of lopinavir/ritonavir in the SOLIDARITY trial in hospitalized patients on July 4, 2020.[29] Interimresults released mid-October 2020 found lopinavir/ritonavir (with or without interferon) appeared to have little or no effect onhospitalized patients with COVID-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.Death rate ratios were: lopinavir RR = 1.00 (0.79-1.25, p = 0.97; 148/1399 vs 146/1372) and lopinavir plus interferon RR=1.16(0.96-1.39, p = 0.11; 243/2050 vs 216/2050).[30]

In a randomized, controlled, open-label trial of hospitalized adults (n=199) with confirmed SARS-CoV-2 infection, recruitedpatients had an oxygen saturation of 94% or less on ambient air or PaO2 of less than 300 mm Hg and were receiving a range ofventilatory support modes (eg, no support, mechanical ventilation, extracorporeal membrane oxygenation [ECMO]). Thesepatients were randomized to receive lopinavir/ritonavir 400 mg/100 mg PO BID for 14 days added to standard care (n=99) orstandard 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% vs25%) but did not reach statistical significance.[306] An editorial accompanies this study that is informative in regard to theextraordinary circumstances of conducting such a study in the midst of the outbreak.[307]

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.[308]

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 showedthat triple therapy significantly shortened the duration of viral shedding and hospital stay in patients with mild-to-moderateCOVID-19.[309]

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

Ivermectin



NIH COVID-19 guidelines for ivermectin provide analysis of several randomized trials and retrospective cohort studies ofivermectin use in patients with COVID-19. The guidelines concluded most of these studies had incomplete information andsignificant methodological limitations, which make it difficult to exclude common causes of bias. Ivermectin has been shown toinhibit SAR-COV-2 in cell cultures; however, available pharmacokinetic data from clinically relevant and excessive dosingstudies indicate that the SARS-CoV-2 inhibitory concentrations for ivermectin are not likely attainable in humans.[310]

Chaccour and colleagues raised concerns regarding ivermectin-associated neurotoxicity, particularly in patients with ahyperinflammatory 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 meaningfulactivity against COVID-19 would not be achieved without potentially toxic increases in ivermectin doses in humans. More dataare needed to assess pulmonary tissue levels in humans.[311]

A prospective study (n = 400) of adults with mild COVID-19 were randomized 1:1 to receive ivermectin 300 mcg/kg/day for 5days or placebo. Use of ivermectin did not show a significantly shorten duration of symptoms compared with placebo (p = 0.53).[312]

Table 5. Other therapies determined ineffective (Open Table in a new window)

Therapy Comment

Merimepodib(antiviral;BioSigTechnologies)[313]

Phase 2 trial in combination with remdesivir in advanced disease (NCT04410354).

Acalabrutinib(Calquence;AstraZeneca)[314]

Phase 2 trial (CALAVI US) of Bruton kinase inhibitor in hospitalized patients to ameliorate excessiveinflammation (NCT04380688).

Ruxolitinib(Jakafi) [315]

Data from the RUXCOVID study (n = 432) showed treatment with ruxolitinib plus standard-of-care did notprevent complications in patients with COVID-19 associated cytokine storm.

Umifenovir(Arbidol)

Antiviral drug that binds to hemagglutinin protein; it is used in China and Russia to treat influenza. In astructural and molecular dynamics study, Vankadari corroborated that the drug target for umifenovir is thespike glycoproteins of SARS-CoV-2, similar to that of H3N2. [316] A retrospective study of non-ICUhospitalized patients (n = 81) with COVID-19 conducted in China did not show an improved prognosis oraccelerated viral clearance. [317] Another study (n = 86) that compared lopinavir/ritonavir or umifenovirmonotherapy with standard care in patients with mild-to-moderate COVID-19 showed no statisticaldifference between each treatment group. [308]

Colchicine UK RECOVERY trial stopped the colchicine arm upon advice from its independent data monitoringcommittee for lack of efficacy in hospitalized patients with COVID-19.

QT Prolongation with Potential COVID-19 PharmacotherapiesChloroquine, hydroxychloroquine, and azithromycin each carry the warning of QT prolongation and can be associated with anincreased risk of cardiac death when used in a broader population.[300] Because of this risk, the American College ofCardiology, American Heart Association, and the Heart Rhythm Society have published a thorough discussion on thearrhythmogenicity of hydroxychloroquine and azithromycin, including a suggested protocol for clinical research QT assessmentand monitoring when the two drugs are coadministered.[301, 318]

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,

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hypokalemia, hypomagnesemia) and nonmodifiable risk factors (eg, acute coronary syndrome, renal failure, congenital long QTsyndrome, hypoglycemia, female sex, age ≥65 years) for QT prolongation may further increase the risk. Some of the modifiableand nonmodifiable risk factors may be caused by or exacerbated by severe illness.[319]

A retrospective study was performed by reviewing 84 consecutive adult patients who were hospitalized at NYU LangoneMedical Center with COVID-19 and treated with hydroxychloroquine plus azithromycin. QTc increased by greater than 40 ms in30% of patients. In 11% of patients, QTc increased to more than 500 ms, which is considered a high risk for arrhythmia. Theresearcher noted that development of acute renal failure, but not baseline QTc, was a strong predictor of extreme QTcprolongation.[320]

A cohort study was performed from March 1 through April 7, 2020, at an academic tertiary care center in Boston to characterizethe risk and degree of QT prolongation in patients with COVID-19 who received hydroxychloroquine, with or withoutazithromycin. Among 90 patients given hydroxychloroquine, 53 received concomitant azithromycin. Seven patients (19%) whoreceived hydroxychloroquine monotherapy developed prolonged QTc of 500 milliseconds or more, and 3 patients (3%) had achange in QTc of 60 milliseconds or more. Of those who received concomitant azithromycin, 11 of 53 (21%) had prolonged QTcof 500 milliseconds or more, and 7 of 53 (13 %) had a change in QTc of 60 milliseconds or more. Clinicians should carefullymonitor QTc and concomitant medication usage if considering using hydroxychloroquine.[321]

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, allpatients 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 lowerdose. 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 patientswith paired samples, respiratory secretions at day 4 showed negative results in only one patient.[302]

Although not specific to patients with COVID-19, an increased 30-day risk of cardiovascular mortality, chest pain/angina, andheart failure was observed with the addition of azithromycin to hydroxychloroquine in a large study of administrative claims.Pooled data from 14 sources of claims data or electronic medical records from Germany, Japan, Netherlands, Spain, UnitedKingdom, and the United states were analyzed for adverse effects of hydroxychloroquine, sulfasalazine, or the combinations ofhydroxychloroquine plus azithromycin or amoxicillin. Overall, 956,374 and 310,350 users of hydroxychloroquine andsulfasalazine, respectively, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin, respectively, were included in the analysis.[303]

Investigational Agents for Postexposure ProphylaxisPUL-042

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

PUL-042 binds to and activates TLRs on lung epithelial cells. This induces the epithelial cells to produce peptides and reactiveoxygen species (ROS) against pathogens in the lungs, including bacteria, fungi, and viruses. M362, through binding of the CpGmotifs 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-helper1 cells–mediated immune response. Pam2CSK4, through TLR2/6, activates the production of T-helper 2 cells, leading to theproduction of specific cytokines.[322]

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 arefor the prevention of infection with SARS-CoV-2 and the prevention of disease progression in patients with early COVID-19. Inthe first study, up to 4 doses of PUL-042 or placebo will be administered to 200 participants via inhalation over a 10-day periodto evaluate the prevention of infection and reduction in severity of COVID-19. In the second study, 100 patients with earlysymptoms of COVID-19 will receive PUL-042 up to 3 times over 6 days. Each trial will monitor participants for 28 days to assesseffectiveness and tolerability.[323, 324]

Investigational Devices

Blood purification devices

Several extracorporeal blood purification filters (eg, CytoSorb, oXiris, Seraph 100 Microbind, Spectra Optia Apheresis) havereceived 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 ofproinflammatory cytokines levels.[325]

Nanosponges

Cellular nanosponges made from plasma membranes derived from human lung epithelial type II cells or human macrophageshave been evaluated in vitro. The nanosponges display the same protein receptors required by SARS-CoV-2 for cellular entryand act as decoys to bind the virus. In addition, acute toxicity was evaluated in vivo in mice by intratracheal administration.[326]

References

1. CDC. 2019 Novel Coronavirus, Wuhan, China. Centers for Disease Control and Prevention. Available athttps://www.cdc.gov/coronavirus/2019-ncov/about/index.html. 2020 Jan 26; Accessed: March 25, 2020.

2. Gallegos A. WHO Declares Public Health Emergency for Novel Coronavirus. Medscape Medical News. Available athttps://www.medscape.com/viewarticle/924596. 2020 Jan 30; Accessed: March 25, 2020.

3. Ramzy A, McNeil DG. W.H.O. Declares Global Emergency as Wuhan Coronavirus Spreads. The New York Times. Available athttps://nyti.ms/2RER70M. 2020 Jan 30; Accessed: March 25, 2020.

Contributor Information and Disclosures

Author

Scott J Bergman, PharmD, FCCP, FIDSA, BCPS, BCIDP Antimicrobial Stewardship Program Coordinator, Infectious DiseasesPharmacy Residency Program Director, Department of Pharmaceutical and Nutrition Care, Division of Infectious Diseases,Nebraska Medicine; Clinical Associate Professor, Department of Pharmacy Practice, College of Pharmacy, University ofNebraska Medical Center

Scott J Bergman, PharmD, FCCP, FIDSA, BCPS, BCIDP is a member of the following medical societies: American Associationof Colleges of Pharmacy, American College of Clinical Pharmacy, American Pharmacists Association, American Society forMicrobiology, American Society of Health-System Pharmacists, Infectious Diseases Society of America, Society of InfectiousDiseases Pharmacists

Disclosure: Received research grant from: Merck & Co., Inc.

Coauthor(s)

David J Cennimo, MD, FAAP, FACP, AAHIVS Assistant Professor of Medicine and Pediatrics, Adult and Pediatric InfectiousDiseases, Rutgers New Jersey Medical School

David J Cennimo, MD, FAAP, FACP, AAHIVS is a member of the following medical societies: American Academy of HIVMedicine, American Academy of Pediatrics, American College of Physicians, American Medical Association, HIV MedicineAssociation, Infectious Diseases Society of America, Medical Society of New Jersey, Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

Molly Marie Miller, PharmD Pharmacy Resident, Nebraska Medicine

Molly Marie Miller, PharmD is a member of the following medical societies: American College of Clinical Pharmacy, AmericanPharmacists Association, American Society of Health-System Pharmacists, Nebraska Pharmacists Association, Society ofInfectious Diseases Pharmacists


Keith M Olsen, PharmD, FCCP, FCCM Dean and Professor, College of Pharmacy, University of Nebraska Medical Center


Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference




4. The New York Times. Coronavirus Live Updates: W.H.O. Declares Pandemic as Number of Infected Countries Grows. The New YorkTimes. Available at https://www.nytimes.com/2020/03/11/world/coronavirus-news.html#link-682e5b06. 2020 Mar 11; Accessed:March 24, 2020.

5. Rizk JG, Forthal DN, Kalantar-Zadeh K, Mehra MR, Lavie CJ, Rizk Y, et al. Expanded Access Programs, compassionate drug use,and Emergency Use Authorizations during the COVID-19 pandemic. Drug Discov Today. 2020 Nov 27. [Medline]. [Full Text].

6. FDA. FDA Approves First Treatment for COVID-19. FDA.gov. 2020 Oct 22. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19.

7. FDA. Fact sheet for healthcare providers emergency use authorization (EUA) of Veklury (remdesivir) for hospitalized pediatricpatients weighing 3.5 kg to less than 40 kg or hospitalized pediatric patients less than 12 years of age weight at least 3.5 kg. fda.gov.Available at https://www.fda.gov/media/137566/download. October, 2020 (revised); Accessed: June 22, 2020.

8. FDA News Release. FDA Issues Emergency Use Authorization for Convalescent Plasma as Potential Promising COVID–19Treatment, Another Achievement in Administration’s Fight Against Pandemic. US Food and Drug Administration. Available athttps://www.fda.gov/news-events/press-announcements/fda-issues-emergency-use-authorization-convalescent-plasma-potential-promising-covid-19-treatment?utm_campaign=082320_PR_Issues%20EUA%20for%20Convalescent%20Plasm&utm_medium=email&utm_source=Eloqua. 2020Aug 23; Accessed: August 23, 2020.

9. Fact sheet for health care providers emergency use authorization (EUA) of bamlanivimab. United States Food and DrugAdministration. Available at https://www.fda.gov/media/143603/download. 2021 Feb 09 (revised); Accessed: February 10, 2021.

10. Fact sheet for health care providers emergency use authorization (EUA) of bamlanivimab and etesevimab. United States Food andDrug Administration. Available at https://www.fda.gov/media/145802/download. 2021 Feb 09; Accessed: February 10, 2021.

11. FDA. Fact sheet for health care providers emergency use authorization (EUA) of casirivimab and imdevimab. United States Foodand Drug Administration. Available at https://www.fda.gov/media/143892/download. 2020 Nov 21; Accessed: November 21, 2020.

12. FDA. Fact sheet for healthcare providers emergency use authorization (EUA) of baricitinib. fda.gov. Available athttps://www.fda.gov/media/143823/download. November 2020; Accessed: November 19, 2020.

13. McCreary EK, Pogue JM. COVID-19 Treatment: A Review of Early and Emerging Options. Open Forum Infectious Diseases (OFID).2020 Mar 23. [Full Text].

14. [Guideline] Alhazzani W, Møller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving Sepsis Campaign: Guidelines on theManagement of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19). Crit Care Med. 2020 Jun. 48 (6):e440-e469.[Medline]. [Full Text].

15. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): AReview. JAMA. 2020 Apr 13. [Medline]. [Full Text].

16. Barlow A, Landolf KM, Barlow B, Yeung SYA, Heavner JJ, Claassen CW, et al. Review of Emerging Pharmacotherapy for theTreatment of Coronavirus Disease 2019. Pharmacotherapy. 2020 Apr 7. [Medline]. [Full Text].

17. [Guideline] Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America Guidelines on the Treatment andManagement of Patients with COVID-19. IDSA. IDSA. Available at https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/. 2021 Mar 05; Accessed: March 12, 2021.

18. Jomah S, Asdaq SMB, Al-Yamani MJ. Clinical efficacy of antivirals against novel coronavirus (COVID-19): A review. J Infect PublicHealth. 2020 Aug 3. [Medline]. [Full Text].

19. [Guideline] COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutesof Health. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/. 2020 Dec 03; Accessed:December 4, 2020.

20. Kalil AC. Treating COVID-19-Off-Label Drug Use, Compassionate Use, and Randomized Clinical Trials During Pandemics. JAMA.2020 Mar 24. [Medline]. [Full Text].

21. Rome BN, Avorn J. Drug Evaluation during the Covid-19 Pandemic. N Engl J Med. 2020 Apr 14. [Medline]. [Full Text].

22. Marcia Frellick. Key Drugs Join PPEs on List of Front-Line Shortages. Medscape Medical News. 2020 Apr 02. Available athttps://www.medscape.com/viewarticle/928039.

23. Live Updates: Which Drugs Are In Shortage Because of COVID-19?. GoodRx. Available at https://www.goodrx.com/blog/covid-19-drug-shortages-updates/. Accessed: April 15, 2020.

24. Wilson FP. Hydroxychloroquine for COVID-19: What’s the Evidence? (Commentary). Medscape Medical News and Perspectives.2020 Mar 25. Available at https://www.medscape.com/viewarticle/927342.

25. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, O’Mera MJ, et al. A SARS-CoV-2-Human Protein-Protein Interaction MapReveals Drug Targets and Potential Drug-Repurposing. bioRxiv. Available at



https://www.biorxiv.org/content/10.1101/2020.03.22.002386v1. 2020 Mar 22; Accessed: March 23, 2020.

26. Arshad U, Pertinez H, Box H, Tatham L, Rajoki RKR, Curley P, et al. Prioritisation of potential anti-SARS-CoV-2 drug repurposingopportunities based on ability to achieve adequate target site concentrations derived from their established humanpharmacokinetics. medRxiv. 2020 Apr 22. [Full Text].

27. Lundgren JD, Brund B, Barkauskas CE, and the ACTIV-3/TICO Ly-CoV555 Study Group. A Neutralizing Monoclonal Antibody forHospitalized Patients with Covid-19. N Engl J Med. 2020 Dec 22. [Medline]. [Full Text].

28. I-SPY COVID-19 TRIAL: An Adaptive Platform Trial for Critically Ill Patients (I-SPY_COVID). ClinicalTrials.gov. Available athttps://clinicaltrials.gov/ct2/show/NCT04488081. 2020 Aug 12; Accessed: August 25, 2020.

29. Solidarity clinical trial for COVID-19 treatments. World Health Organization. Available athttps://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments. 2020 Oct 06; Accessed: October 16, 2020.

30. WHO Solidarity Trial Consortium. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med.2020 Dec 2. [Medline]. [Full Text].

31. FDA. Coronavirus (COVID-19) Update: FDA Issues Emergency Use Authorization for Potential COVID-19 Treatment. fda.gov.Available at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment. May 1, 2020; Accessed: May 1, 2020.

32. Mulangu S, Dodd LE, Davey RT Jr, Tshiani Mbaya O, Proschan M, and the PALM Consortium Study Team, et al. A Randomized,Controlled Trial of Ebola Virus Disease Therapeutics. N Engl J Med. 2019 Dec 12. 381 (24):2293-2303. [Medline].

33. Martinez MA. Compounds with therapeutic potential against novel respiratory 2019 coronavirus. Antimicrob Agents Chemother. 2020Mar 9. [Medline]. [Full Text].

34. Holshue ML, DeBolt C, Lindquist S, and the Washington State 2019-nCoV Case Investigation Team, et al. First Case of 2019 NovelCoronavirus in the United States. N Engl J Med. 2020 Mar 5. 382 (10):929-936. [Medline]. [Full Text].

35. National Institutes of Health. NIH clinical trial of remdesivir to treat COVID-19 begins. Department of Health and Human Services.Available at https://www.nih.gov/news-events/news-releases/nih-clinical-trial-remdesivir-treat-covid-19-begins. 2020 Feb 25;Accessed: March 24, 2020.

36. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the Treatment of Covid-19 - Final Report.N Engl J Med. 2020 Oct 8. [Medline]. [Full Text].

37. Sax PE. Does Remdesivir Actually Work?. NEJM Journal Watch. Available at https://blogs.jwatch.org/hiv-id-observations/index.php/does-remdesivir-actually-work/2020/10/18/. 2020 Oct 18; Accessed: October 19, 2020.

38. Harrington DP, Baden LR, Hogan JW. A Large, Simple Trial Leading to Complex Questions. N Engl J Med. 2020 Dec 2. [Medline].[Full Text].

39. Wang Y, Zhang D, Du G, Du R, Zhao J, Yang J, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind,placebo-controlled, multicentre trial. Lancet. 2020 Apr 29. [Full Text].

40. Olender SA, Perez KK, Go AS, Balani B, Price-Haywood EG, Shah NS, et al. Remdesivir for Severe COVID-19 versus a CohortReceiving Standard of Care. Clin Infect Dis. 2020 Jul 24. [Medline]. [Full Text].

41. Goldman JD, Lye DCB, Hui DS, Marks KM, Bruno R, Montejano R, et al. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. N Engl J Med. November 5, 2020. 383:1827-1837. [Medline]. [Full Text].

42. Gilead presents additional data on investigational antiviral remdesivir for the treatment of COVID-19. Gilead Sciences. 2020 Jul 10.Available at https://www.gilead.com/news-and-press/press-room/press-releases/2020/7/gilead-presents-additional-data-on-investigational-antiviral-remdesivir-for-the-treatment-of-covid-19.

43. Spinner CD, Gottlieb RL, Criner GJ, and the, GS-US-540-5774 Investigators. Effect of Remdesivir vs Standard Care on ClinicalStatus at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2020 Aug 21. [Medline]. [Full Text].

44. Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate Use of Remdesivir for Patients with SevereCovid-19. N Engl J Med. 2020 Apr 10. [Medline]. [Full Text].

45. Sheahan TP, Sims AC, Leist SR, Schäfer A, Won J, Brown AJ, et al. Comparative therapeutic efficacy of remdesivir and combinationlopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020 Jan 10. 11 (1):222. [Medline]. [Full Text].

46. Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of Remdesivir (GS-5734) in Participants From Birth to < 18Years of Age With Coronavirus Disease 2019 (COVID-19) (CARAVAN). ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04431453. 2020 Jun 01; Accessed: : Jul 14, 2020.

47. Chiotos K, Hayes M, Kimberlin DW, et al. Multicenter interim guidance on use of antivirals for children with COVID-19/SARS-CoV-2.J Pediatric Infect Dis Soc. 2020 Sep 12. [Medline]. [Full Text].



48. Burwick RM, Yawetz S, Stephenson KE, Collier AY, Sen P, Blackburn BG, et al. Compassionate Use of Remdesivir in PregnantWomen with Severe Covid-19. Clin Infect Dis. 2020 Oct 8. [Medline]. [Full Text].

49. McCoy JA, Short WR, Srinivas SK, Levine LD, Hirshberg A. Compassionate use of remdesivir for treatment of severe coronavirusdisease 2019 in pregnant women at a United States academic center. Am J Obstet Gynecol MFM. 2020 Aug. 2 (3):100164.[Medline]. [Full Text].

50. Efficacy and Safety of Molnupiravir (MK-4482) in Hospitalized Adult Participants With COVID-19. ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04575584. 2021 Mar 12; Accessed: March 12, 2021.

51. Efficacy and Safety of Molnupiravir (MK-4482) in Non-Hospitalized Adult Participants With COVID-19. ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04575597. 2021 Mar 12; Accessed: March 12, 2021.

52. Ivashchenko AA, Dmitriev KA, Vostokova NV, Azarova VN, Blinow AA, Egorova AN, et al. AVIFAVIR for Treatment of Patients withModerate COVID-19: Interim Results of a Phase II/III Multicenter Randomized Clinical Trial. Clin Infect Dis. 2020 Aug 9. [Medline].[Full Text].

53. Oral favipiravir compared to placebo in subjects with mild COVID-19. ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04346628. 2020 Oct 05; Accessed: December 3, 2020.

54. Russian firm gets approval for drug said to block coronavirus replication. The New York Times. 2020 Jul 08. Available athttps://www.nytimes.com/reuters/2020/07/08/world/europe/08reuters-health-coronavirus-russia-drug.html.

55. Control of COVID-19 outbreaks in long term care. ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04448119.2020 Jun 25; Accessed: August 11, 2020.

56. Trial to Evaluate the Efficacy and Safety of Nitazoxanide (NTZ) for Post-Exposure Prophylaxis of COVID-19 and Other ViralRespiratory Illnesses in Elderly Residents of Long-Term Care Facilities (LTCF). ClinicalTrials.gov. Available athttps://clinicaltrials.gov/ct2/show/NCT04343248?term=nitazoxanide&recrs=ab&cond=COVID&draw=2&rank=6. 2020 Apr 16;Accessed: April 28, 2020.

57. Trial to Evaluate the Efficacy and Safety of Nitazoxanide (NTZ) for Pre- or Post Exposure Prophylaxis of COVID-19 and Other ViralRespiratory Illnesses (VRI) in Healthcare Workers. ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04359680?term=nitazoxanide&recrs=ab&cond=COVID&draw=2&rank=5. 2020 Apr 24; Accessed: April 28, 2020.

58. Romark initiates new phase 3 clinical trial of NT-300 for the treatment of COVID-19. Romark Pharmaceuticals. 2020 Aug 11.Available at https://www.romark.com/romark-initiates-new-phase-3-clinical-trial-of-nt-300-for-the-treatment-of-covid-19/.

59. Niclosamide in moderate COVID-19. ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04436458. 2020 Jun 18;Accessed: August 7, 2020.

60. ANA Therapeutics begins phase 2/3 clinical trial of proprietary oral niclosamide formulation to treat COVID-19. Businesswire. 2020Oct 26. Available at https://www.businesswire.com/news/home/20201026005569/en/ANA-Therapeutics-Begins-Phase-23-Clinical-Trial-of-Proprietary-Oral-Niclosamide-Formulation-to-Treat-COVID-19.

61. AIM ImmunoTech announces availability of the ME/CFS clinical trial of its drug Ampligen for enrollment to COVID-19 ‘long haulers’.AIM ImmunoTech. 2020 Dec 24. Available at https://aimimmuno.com/press-release/aim-immunotech-announces-availability-of-the-me-cfs-clinical-trial-of-its-drug-ampligen-for-enrollment-to-covid-19-long-haulers/.

62. BerGenBio’s bemcentinib selected to be fast-tracked as potential treatment for COVID-19 through new national UK governmentclinical trial initiative. BerGenBio. 2020 Apr 28. Available at https://www.bergenbio.com/bergenbios-bemcentinib-selected-to-be-fast-tracked-as-potential-treatment-for-covid-19-through-new-national-uk-government-clinical-trial-initiative/.

63. PharmaMar reports positive results for Aplidin against coronavirus HCoV-229E. PharmaMar. 2020 Mar 13. Available athttp://pharmamar.com/wp-content/uploads/2020/03/PR_Results_Aplidin_coronavirus.pdf.

64. Vir and Alnylam Identify RNAi Therapeutic Development Candidate, VIR-2703 (ALN-COV), Targeting SARS-CoV-2 for the Treatmentof COVID-19. Vir Biotechnology. 2020 May 05. Available at https://investors.vir.bio/news-releases/news-release-details/vir-and-alnylam-identify-rnai-therapeutic-development-candidate.

65. Acer Therapeutics to develop emetine as potential COVID-19 treatment in collaboration with National center for AdvancingTranslational Sciences, one of the National Institutes of Health. Acer Therapeutics. 2020 May 11. Available athttps://www.acertx.com/2020/05/11/acer-therapeutics-to-develop-emetine-as-potential-covid-19-treatment-in-collaboration-with-national-center-for-advancing-translational-sciences-one-of-the-national-institutes-of-health/.

66. Safety and Efficacy of AT-527 in subjects with moderate coronavirus disease (COVID-19) (NCT04396106). ClinicalTrials.gov.Available at https://www.clinicaltrials.gov/ct2/show/NCT04396106. 2020 May 20;

67. Mateon’s global study for OT-101/TGF-beta inhibitor against COVID-19 enrolls and treats its first patient. Mateon Therapeutics. 2020Dec 30. Available at http://investor.mateon.com/news-releases/news-release-details/mateons-global-study-ot-101-tgf-b-inhibitor-against-covid-19.



68. A study to evaluate the effect of RBT-9 on progression of COVID-19 in high-risk individuals (the PREVENT study). ClinicalTrials.gov.Available at https://www.clinicaltrials.gov/ct2/show/NCT04364763. 2020 Sep 28; Accessed: January 6, 2021.

69. Double-blind study to evaluate the safety and efficacy of antroquinonol in mild-moderate COVID-19 hospitalized patients.ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/ct2/show/NCT04523181. 2020 Dec 08; Accessed: January 6, 2020.

70. A study of LAM-002A for the prevention of progression of COVID-19. ClinicalTrials.gov. Available athttps://clinicaltrials.gov/ct2/show/NCT04446377. 2020 Jul 17; Accessed: July 28, 2020.

71. Study in participants with early stage coronavirus disease 2019 (COVID-19) to evaluate the safety, efficacy, and pharmacokinetics ofremdesivir administered by inhalation. ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/ct2/show/NCT04539262. 2020Dec 09; Accessed: January 6, 2021.

72. CRISIS2: A phase 2 study of the safety and antiviral activity of brequinar in non-hospitalized patients with COVID-19.ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/ct2/show/NCT04575038. 2020 Nov 24; Accessed: November 25, 2020.

73. Innovation Pharmaceuticals' brilacidin for the treatment of COVID-19 receives FDA fast track designation. InnovationPharmaceuticals. 2020 Jan 14. Available at http://www.ipharminc.com/press-release/2021/1/14/innovation-pharmaceuticals-brilacidin-for-the-treatment-of-covid-19-receives-fda-fast-track-designation.

74. Bakovic A, Risner K, Bhalla N, Alem F, Chang TL, Weston W, et al. Brilacidin, a COVID-19 drug candidate, exhibits potent in vitroantiviral activity against SARS-CoV-2. bioRxiv. 2020 Oct 30. [Full Text].

75. Ingraham NE, Lotfi-Emran S, Thielen BK, Techar K, Morris RS, Holtan SG, et al. Immunomodulation in COVID-19. Lancet RespirMed. 2020 May 4. [Medline]. [Full Text].

76. Rizk JG, Kalantar-Zadeh K, Mehra MR, Lavie CJ, Rizk Y, Forthal DN. Pharmaco-Immunomodulatory Therapy in COVID-19. Drugs.2020 Sep. 80 (13):1267-1292. [Medline]. [Full Text].

77. Wagner JL, Veve MP, Barber KE. Using IL-6 inhibitors to treat COVID-19. ContagionLive. Available athttps://www.contagionlive.com/publications/contagion/2020/august/using-il6-inhibitors-to-treat-covid19?ekey=c2NiZXJnbWFuQG5lYnJhc2thbWVkLmNvbQ. 2020 Aug 17; Accessed: August 18, 2020.

78. [Guideline] NIH. Interleukin-6 Inhibitors. COVID-19 Treatment Guidelines. Available athttps://www.covid19treatmentguidelines.nih.gov/immune-based-therapy/interleukin-6-inhibitors/. 2021 Mar 05; Accessed: March 12,2021.

79. Salama C, Han J, Yau L, Reiss WG, Kramer B, Neidhart JD, et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. NEngl J Med. 2021 Jan 7. 384 (1):20-30. [Medline]. [Full Text].

80. Gordon AC, Mouncey PR, Al-Beidh F, and the, REMAP-CAP Investigators. Interleukin-6 receptor antagonists in critically ill patientswith Covid-19 – Preliminary report. medRxiv. 2021 Jan 07. [Full Text].

81. Horby PW, Pessoa-Amorim G, Peto L, and the, RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital withCOVID-19 (RECOVERY): preliminary results of a randomized, controlled, open-label, platform trial. medRxiv. 2021 Feb 11. [FullText].

82. Stone JH, Frigault MJ, Serling-Boyd NJ, and the, BACC Bay Tocilizumab Trial Investigators. Efficacy of Tocilizumab in PatientsHospitalized with Covid-19. N Engl J Med. 2020 Oct 21. [Medline]. [Full Text].

83. Genentech provides an update on the phase III COVACTA trial of Actemra in hospitalized patients with severe COVID-19 associatedpneumonia. Genentech. 2020 Jul 28. Available at https://www.gene.com/media/press-releases/14867/2020-07-28/genentech-provides-an-update-on-the-phas.

84. Price CC, Altice FL, Shyr Y, Koff A, Pischel L, Goshua G, et al. Tocilizumab treatment for Cytokine Release Syndrome in hospitalizedCOVID-19 patients: survival and clinical outcomes. Chest. 2020 Jun 15. [Medline]. [Full Text].

85. Jordan SC, Zakowski P, Tran HP, Smith EA, Gaultier C, Marks G, et al. Compassionate Use of Tocilizumab for Treatment of SARS-CoV-2 Pneumonia. Clin Infect Dis. 2020 Jun 23. [Medline]. [Full Text].

86. Somers EC, Eschenauer GA, Troost JP, Golob JL, Gandhi TN, Wang L, et al. Tocilizumab for treatment of mechanically ventilatedpatients with COVID-19. Clin Infect Dis. 2020 Jul 11. [Medline]. [Full Text].

87. [Guideline] NIH. Interleukin-1 Inhibitors. COVID-19 Treatment Guidelines. Available athttps://www.covid19treatmentguidelines.nih.gov/immune-based-therapy/interleukin-1-inhibitors/. 2020 Jun 11; Accessed: June 16,2020.

88. Cavalli G, DeLuca G, Campochiraro C, Della-Torre E, Ripa M, Canetti D, et al. Interleukin-1 blockade with high-dose anakinra inpatients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. LancetRheumatol. 2020 May 07. [Full Text].

89. Huet T, Beaussier H, Voisin O, Jouveshomme S, Daurait Gaelle, Lazareth I, et al. Anakinra for severe forms of COVID-19: a cohortstudy. Lancet Rheumatol. 2020 May 29. [Full Text].



90. Novartis provides update on CAN-COVID trial in hospitalized patients with COVID-19 pneumonia and cytokine release syndrome(CRS). Novartis. 2020 Nov 06. Available at https://www.novartis.com/news/media-releases/novartis-provides-update-can-covid-trial-hospitalized-patients-covid-19-pneumonia-and-cytokine-release-syndrome-crs.

91. Intereukin-7 to improve clinical outcomes in lymphopenic patients with COVID-19 infection FR BL Cohort (ILIAD-7-FR).ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04407689. 2020 Jun 22; Accessed: November 16, 2020.

92. Interleukin-7 (CYT107 to improve clinical outcomes in lymphopenic patients with COVID-19 infection UK cohort (ILIAD-7-UK).ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04379076. 2020 May 15; Accessed: November 16, 2020.

93. Laterre PF, François B, Collienne C, Hantson P, Jeannet R, Remy KE, et al. Association of Interleukin 7 Immunotherapy WithLymphocyte Counts Among Patients With Severe Coronavirus Disease 2019 (COVID-19). JAMA Netw Open. 2020 Jul 1. 3(7):e2016485. [Medline]. [Full Text].

94. Stebbing J, Phelan A, Griffin I, Tucker C, Oechsle O, Smith D, et al. COVID-19: combining antiviral and anti-inflammatorytreatments. Lancet Infect Dis. 2020 Apr. 20 (4):400-402. [Medline]. [Full Text].

95. Richardson P, Griffin I, Tucker C, Smith D, Oechsle O, Phelan A, et al. Baricitinib as potential treatment for 2019-nCoV acuterespiratory disease. Lancet. 2020 Feb 15. 395 (10223):e30-e31. [Medline]. [Full Text].

96. Stebbing J, Krishnan V, de Bono S, Ottaviani S, Casalini G, Richarson PJ, et al. Mechanism of baricitinib supports artificialintelligence-predicted testing in COVID-19 patients. Nature Research. 2020 Apr 15. [Full Text].

97. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: consider cytokine storm syndromes andimmunosuppression. Lancet. 2020 Mar 28. 395 (10229):1033-1034. [Medline]. [Full Text].

98. Kalil AC, Patterson TF, Mehta AK, Tomashek KM, Wolfe CR, Ghazaryan V, et al. Baricitinib plus Remdesivir for Hospitalized Adultswith Covid-19. N Engl J Med. 2020 Dec 11. [Medline]. [Full Text].

99. A study of baricitinib (LY3009104) in participants with COVID-19 (COV-BARRIER). ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04421027. 2020 Jun 09;

100. Rodriguez-Garcia JL, Sanchez-Nievas G, Arevalo-Serrano J, Garcia-Gomez C, Jimenez-Vizuete JM, Martinez-Alfaro E. Baricitinibimproves respiratory function in patients treated with corticosteroids for SARS-CoV-2 pneumonia: an observational cohort study.Rheumatology (Oxford). 2020 Oct 6. [Medline]. [Full Text].

101. Cantini F, Niccoli L, Matarrese D, Nicastri E, Stobbione P, Goletti D. Baricitinib therapy in COVID-19: A pilot study on safety andclinical impact. J Infect. 2020 Apr 23. [Medline]. [Full Text].

102. CTI BioPharma Announces Enrollment of First Patient in COVID-19 PRE-VENT Phase 3 Clinical Trial. CTI Biopharma. 2020 Jun 01.Available at https://cbc.gcs-web.com/news-releases/news-release-details/cti-biopharma-announces-enrollment-first-patient-covid-19-pre.

103. TD-0903 for ALI associated with COVID-19. ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04402866. 2020Jun 26; Accessed: August 11, 2020.

104. RECOVERY Collaborative Group., Horby P, Lim WS, Emberson JR, et al. Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report. N Engl J Med. 2020 Jul 17. [Medline]. [Full Text].

105. [Guideline] Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected. WorldHealth Organization. Available at https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected.. 2020 Mar 13; Accessed: March 24, 2020.

106. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020Feb 15. 395 (10223):473-475. [Medline].

107. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design ofHydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020Mar 9. [Medline]. [Full Text].

108. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association Between Administration of SystemicCorticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA. 2020 Sep 2. [Medline]. [Full Text].

109. Prescott HC, Rice TW. Corticosteroids in COVID-19 ARDS: Evidence and Hope During the Pandemic. JAMA. 2020 Sep 2. [Medline].[Full Text].

110. [Guideline] WHO. Corticosteroids for COVID-19 – Living Guidance. World Health Organization. Available athttps://www.who.int/publications/i/item/WHO-2019-nCoV-Corticosteroids-2020.1. 2020 Sep 02; Accessed: September 3, 2020.

111. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death inPatients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020 Mar 13. [Medline].



112. Fadel R, Morrison AR, Vahia A, Smith ZR, Chaudhry Z, Bhargava P, et al. Early Short Course Corticosteroids in HospitalizedPatients with COVID-19. medRxiv. 2020 May 05. [Full Text].

113. Ramiro S, Mostard RLM, Magro-Checa C, van Dongen CMP, Dormans T, Buijs J, et al. Historically controlled comparison ofglucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19-associated cytokine stormsyndrome: results of the CHIC study. Ann Rheum Dis. 2020 Jul 20. [Medline]. [Full Text].

114. Keller MJ, Kitsis EA, Arora S, Chen JT, Agarwal S, Ross MJ, et al. Effect of systemic glucocorticoids on mortality or mechanicalventilation in patients with COVID-19. J Hosp Med. 2020 Aug. 15(8):489-493. [Full Text].

115. Evaluating AVM0703 for treatment of COVID-19 or influenza-mediated ARDS. AVM Biotechnology LCC. Available athttps://clinicaltrials.gov/ct2/show/NCT04366115. 2020 Sep 18; Accessed: September 22, 2020.

116. Fact Sheet for Health Care Providers - Emergency Use Authorization (EUA) of COVID-19 Convalescent Plasma for Treatment ofCOVID-19 in Hospitalized Patients. US Food and Drug Administration. Available at https://www.fda.gov/media/141478/download.2020 Aug 23; Accessed: August 23, 2020.

117. Joyner MJ, Carter RE, Senefeld JW, Klassen SA, Mills JR, Johnson PW, et al. Convalescent plasma antibody levels and the risk ofdeath from Covid-19. N Engl J Med. 2021 Jan 13. [Full Text].

118. NIH COVID-19 Treatment Guidelines Panel. Statement on the emergency use authorization of convalescent plasma for thetreatment of COVID-19. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/statement-on-convalescent-plasma-eua/. 2020 Oct 09; Accessed: January 9, 2021.

119. NIAID. NIH clinical trial testing remdesivir plus interferon beta-1a for COVID-19 treatment begins. National Institutes of Health. 2020Aug 05. Available at https://www.niaid.nih.gov/news-events/nih-clinical-trial-testing-remdesivir-plus-interferon-beta-1a-covid-19-treatment-begins.

120. Adaptive COVID-19 Treatment Trial 3 (ACTT-3). ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04492475.2020 Aug 07; Accessed: August 7, 2020.

121. Chen L, Liu P, Gao H, Sun B, Chao D, Wang F, et al. Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome:a rescue trial in Beijing. Clin Infect Dis. 2004 Nov 15. 39 (10):1531-5. [Medline].

122. A study to assess pulsed inhaled nitric oxide vs placebo in subjects with mild or moderate COVID-19 (COViNOX). ClinicalTrials.gov.Available at https://www.clinicaltrials.gov/ct2/show/NCT04421508. 2020 Sep 09; Accessed: November 25, 2020.

123. Schönbeck U, Libby P. Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as antiinflammatory agents?. Circulation.2004 Jun 1. 109 (21 Suppl 1):II18-26. [Medline]. [Full Text].

124. Virani SS. Is There a Role For Statin Therapy in Acute Viral Infections?. Cardiology Magazine – American College of Cardiology.2020 Mar 18. Available at https://www.acc.org/latest-in-cardiology/articles/2020/03/18/15/09/is-there-a-role-for-statin-therapy-in-acute-viral-infections-covid-19.

125. Hariyanto TI, Kurniawan A. Statin therapy did not improve the in-hospital outcome of coronavirus disease 2019 (COVID-19)infection. Diabetes Metab Syndr. 2020 Aug 26. 14 (6):1613-1615. [Medline]. [Full Text].

126. Kow CS, Hasan SS. Meta-analysis of Effect of Statins in Patients with COVID-19. Am J Cardiol. 2020 Aug 12. [Medline]. [Full Text].

127. Castiglione V, Chiriacò M, Emdin M, Taddei S, Vergaro G. Statin therapy in COVID-19 infection. Eur Heart J CardiovascPharmacother. 2020 Jul 1. 6 (4):258-259. [Medline]. [Full Text].

128. [Guideline] NIH. COVID-19 Treatment Guidelines - Adjunctive Therapy. National Institutes of Health. Available athttps://www.covid19treatmentguidelines.nih.gov/adjunctive-therapy/. 2020 Jul 17; Accessed: July 31, 2020.

129. Yao JS, Paguio JA, Dee EC, Tan HC, Moulick A, Milazzo C, et al. The minimal effect of zinc on the survival of hospitalized patientswith Covid-19: an observational study. Chest. 2020 Jul 22. [Medline]. [Full Text].

130. Meltzer DO, Best TJ, Zhang H, Vokes T, Arora V, Solway J. Association of Vitamin D Status and Other Clinical Characteristics WithCOVID-19 Test Results. JAMA Netw Open. 2020 Sep 1. 3 (9):e2019722. [Medline]. [Full Text].

131. Intravenous aviptadil for critical COVID-19 with acute respiratory failure (COVID-AIV). ClinicalTrials.gov. Available athttps://clinicaltrials.gov/ct2/show/NCT04311697. 2021 Feb 26; Accessed: March 30, 2021.

132. NeuroRx announces Zyesami (aviptadil, RLF-100) met the primary endpoint of its phase 2b/3 clinical trial and also demonstrated ameaningful benefit in survival from critical COVID-19. NeuroRx. 2021 Mar 29. Available at https://www.neurorxpharma.com/press-releases/neurorx-announces-zyesami-aviptadil-rlf-100-met-the-primary-endpoint-of-its-phase-2b-3-clinical-trial-and-also-demonstrated-a-meaningful-benefit-in-survival-from-critical-covid-19/.

133. Inhaled aviptadil for the treatment of moderate and severe COVID-19 (AVICOVID-2). ClinicalTrials.gov. Available athttps://clinicaltrials.gov/ct2/show/NCT04360096. 2021 Mar 11; Accessed: March 30, 2021.



134. Phase 3 study to evaluate efficacy and safety of lenzilumab in patients with COVID-19. ClinicalTrials.gov. Available athttps://clinicaltrials.gov/ct2/show/NCT04351152. 2021 Mar 03; Accessed: March 30, 2021.

135. Study of sargramostim in patients with COVID-19 (iLeukPulm). ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04411680. 2021 Mar 02; Accessed: March 30, 2021.

136. A study to assess the efficacy and safety of gimsilumab in subjects with lung injury or acute respiratory distress syndrome secondaryto coronavirus disease 2019. ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04351243. 2020 Dec 03;Accessed: March 31, 2021.

137. De Luca G, Cavalli G, Campochiaro C, Della-Torre E, Angelillo P, Tomelleri A, et al. GM-CSF blockade with mavrilimumab in severeCOVID-19 pneumonia and systemic hyperinflammation: a single-centre, prospective cohort study. Lancet Rheumatol. 2020 Aug. 2(8):e465-e473. [Medline]. [Full Text].

138. Study of mavrilimumab (KPL-301) in participants hospitalized with severe corona virus disease 2019 (COVID-19) pneumonia andhyper-inflammation. ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/ct2/show/NCT04447469. 2021 Mar 09; Accessed:March 31, 2021.

139. Investigating otilimab in patients with severe pulmonary COVID-19 related disease (OSCAR). ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04376684. 2021 Mar 08; Accessed: March 31, 2021.

140. A Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy of Tradipitant in Treating Inflammatory Lung Injuryand Improving Clinical Outcomes Associated With Severe or Critical COVID-19. (NCT04326426). ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04326426?term=tradipitant&cond=COVID&draw=2&rank=1. 2020 Mar 30;

141. Vanda Pharmaceuticals’ interim analysis from ODYSSEY study shows tradipitant may accelerate clinical improvement in patientswith COVID-19 pneumonia. Vanda Pharmaceuticals. 2020 Aug 18. Available at https://vandapharmaceuticalsinc.gcs-web.com/node/14256/pdf.

142. Aprepitant injectable emulsion in patients with COVID-19 (GUARDS-1). ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04470622. 2020 Jul 17; Accessed: July 23, 2020.

143. FDA grants fast track designation for remestemcel-L in the treatment of acute respiratory distress syndrome due to COVID-19.Mesoblast. 2020 Dec 01. Available at http://investorsmedia.mesoblast.com/static-files/046bf826-c5bf-4606-a0b2-0420f8c7a933.

144. MSCs in COVID-19 ARDS. ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/ct2/show/NCT04371393. 2020 Nov 06;Accessed: December 3, 2020.

145. U.S. FDA clears Pluristem’s IND application for phase II COVID-19 study. Pluristem Therapeutics, Inc. 2020 May 08. Available athttps://www.pluristem.com/wp-content/uploads/2020/05/FDA-Clearance-COVID-19-FINAL.pdf.

146. NantKwest announces FDA authorization of IND application for mesenchymal stem cell product for the treatment of severe COVID-19 patients. NantKwest. 2020 May 18. Available at https://nantkwest.com/nantkwest-announces-fda-authorization-of-ind-application-for-mesenchymal-stem-cell-product-for-the-treatment-of-severe-covid-19-patients/.

147. Efficacy and safety study of allogeneic HB-adMSCs for the treatment of COVID-19. ClinicalTrials.gov. 2020 Aug 12. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04362189.

148. FDA approves study to investigate the use of cell therapy to treat COVID-19 related multisystem inflammatory syndrome in children(MIS-C). PR Newswire. 2020 Sep 16. Available at https://www.prnewswire.com/news-releases/fda-approves-study-to-investigate-the-use-of-cell-therapy-to-treat-covid-19-related-multisystem-inflammatory-syndrome-in-children-mis-c-301131904.html.

149. Extracellular vesicle infusion therapy for severe COVID-19 (EXIT COVID-19). ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04493242. 2020 Jul 30; Accessed: October 19, 2020.

150. MediciNova announces opening of investigational new drug application for MN-166 (ibudilast) for prevention of acute respiratorydistress syndrome in patients with COVID-19. MediciNova. 2020 Jul 01. Available at https://investors.medicinova.com/news-releases/news-release-details/medicinova-announces-opening-investigational-new-drug-1.

151. Safety and efficacy of NP-120 (ifenprodil) for the treatment of hospitalized patient with confirmed COVID-19 disease.ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/ct2/show/NCT04382924. 2020 Jul 09; Accessed: July 21, 2020.

152. Eculizumab (Soliris) in Covid-19 Infected Patients (SOLID-C19). ClinicialTrials.gov. Available athttps://clinicaltrials.gov/ct2/show/NCT04288713. 2020 Mar 30; Accessed: 2020 Apr 06.

153. Alexion provides update on phase 3 study of Ultomiris (ravulizumab-cwvz) in hospitalized patients with severe COVID-19. AlexionPharmaceuticals, Inc. 2021 Jan 13. Available at https://ir.alexion.com/news-releases/news-release-details/alexion-provides-update-phase-3-study-ultomirisr-ravulizumab.

154. Study to evaluate the safety and efficacy of ATYR1923 in patients with severe pneumonia related to COVID-19. ClinicalTrials.gov.Available at https://www.clinicaltrials.gov/ct2/show/NCT04412668. 2020 Jun 04;



155. Evaluation of Safety & Efficacy of BIO-11006 Inhalation Solution in Patients with ARDS. ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT03202394?term=NCT03202394&draw=2&rank=1. 2018 Dec 06; Accessed: Apr 24, 2020.

156. Chimerix Announces Initiation of a Phase 2/3 Study of DSTAT in Acute Lung Injury for Patients with Severe COVID-19. Chimerix.2020 Apr 29. Available at https://ir.chimerix.com/news-releases/news-release-details/chimerix-announces-initiation-phase-23-study-dstat-acute-lung.

157. A study of opaganib in coronavirus disease 2019 pneumonia (COVID-19). ClinicalTrials.gov. Available athttps://clinicaltrials.gov/ct2/show/NCT04414618. 2020 Jul 31; Accessed: July 31, 2020.

158. Opaganib, a sphingosine kinase-2 (SK2) inhibitor in COVID-19 pneumonia. ClinicalTrials.gov. Available athttps://clinicaltrials.gov/ct2/show/NCT04467840. 2020 Jul 17; Accessed: July 31, 2020.

159. LB1148 Now Available for Investigational Use to Treat Pulmonary Dysfunction Associated with COVID-19 Pneumonia. LeadingBioSciences. 2020 May 15. Available at https://www.globenewswire.com/news-release/2020/05/15/2034269/0/en/Leading-BioSciences-Receives-IND-Clearance-for-Phase-2-COVID-19-Study.html.

160. Phase III DAS181 Lower Tract PIV Infection in Immunocompromised Subjects (Substudy: DAS181 for COVID-19): RCT Study.ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT03808922?term=DAS181&cond=COVID&draw=2&rank=4. 2020Apr 17;

161. Applied Therapeutics Announces IND and Investigator-Initiated Studies of AT-001 in Critical COVID-19 Patients. AppliedTherapeutics. 2020 Apr 02. Available at https://ir.appliedtherapeutics.com/news-releases/news-release-details/applied-therapeutics-announces-ind-and-investigator-initiated.

162. Miller J, Bruen C, Schnaus M, Zhang J, Ali S, Lind A, et al. Auxora versus standard of care for the treatment of severe or criticalCOVID-19 pneumonia: Results from a randomized controlled trial. Research Square. 2020 Jul 15. [Full Text].

163. Biohaven receives FDA may proceed letter to begin phase 2 trial of intranasal vazegepant to treat lung inflammation after COVID-19infection. Biohaven Pharmaceuticals. 2020 Apr 09. Available at https://www.biohavenpharma.com/investors/news-events/press-releases/04-09-2020.

164. ClinicalTrials.gov. Evaluation of activity and safety of oral selinexor in participants with severe COVID-19 infection (coronavirus).Available at https://www.clinicaltrials.gov/ct2/show/NCT04349098. 2020 May 08; Accessed: October 7, 2020.

165. Evelo Biosciences, Rutgers University, and Robert Wood Johnson University Hospital Announce Submission of IND for a Phase 2Study of EDP1815 in COVID-19 Patients. Evelo Biosciences. 2020 May 07. Available at http://ir.evelobio.com/news-releases/news-release-details/evelo-biosciences-rutgers-university-and-robert-wood-johnson.

166. Evelo Biosciences announces EDP1815 to advance into phase 2/3 TACTIC-E COVID-19 trial. Evelo Biosciences. 2020 Jun 22.Available at http://ir.evelobio.com/news-releases/news-release-details/evelo-biosciences-announces-edp1815-advance-phase-23-tactic-e.

167. Veru Secures FDA Agreement to Initiate Phase 2 Study of VERU-111, Novel Microtubule Depolymerization Drug to Combat COVID-19. Veru, Inc. 2020 May 12. Available at https://verupharma.com/news/veru-secures-fda-agreement-to-initiate-phase-2-study-of-veru-111-novel-microtubule-depolymerization-drug-to-combat-covid-19/.

168. VERU-111 suppresses key cytokines responsible for severe acute respiratory distress syndrome in COVID-19. Veru, Inc. 2020 Aug04. Available at https://verupharma.com/news/veru-111-suppresses-key-cytokines-responsible-for-severe-acute-respiratory-distress-syndrome-in-covid-19/.

169. Q BioMed partner Mannin Research developing potential treatment for patients infected with coronavirus and other infectiousdiseases. Q BioMed. 2020 Feb 04. Available at https://qbiomed.com/news-and-media/news-2020/180-q-biomed-partner-mannin-research-developing-potential-treatment-for-patients-infected-with-coronavirus-and-other-infectious-diseases.

170. Diffusion Pharmaceuticals receives FDA guidance for international phase 1b/2b COVID-19 clinical program with TSC. DiffusionPharmaceuticals. 2020 Jul 27. Available at https://investors.diffusionpharma.com/News/news-details/2020/Diffusion-Pharmaceuticals-Receives-FDA-Guidance-for-International-Phase-1b2b-COVID-19-Clinical-Program-with-TSC/default.aspx.

171. NCI drug Dictionary. Trans sodium crocetinate. NIH, National Cancer Institute. Available athttps://www.cancer.gov/publications/dictionaries/cancer-drug/def/trans-sodium-crocetinate. Accessed: 2020 May 28.

172. FDA authorizes OPKO Health clinical trial evaluating Rayaldee in COVID-19 patients. OPKO Health. 2020 Jun 01. Available athttps://www.opko.com/news-media/press-releases/detail/394/fda-authorizes-opko-health-clinical-trial-evaluating.

173. LYT-100 in Post-acute COVID-19 Respiratory Disease. ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04652518. 2020 Dec 07; Accessed: December 11, 2020.

174. Ashvattha Therapeutics subsidiary Orpheris announces FDA agreement to initiate phase 2 study evaluating OP-101 in severeCOVID-19 patients. Ashvattha Therapeutics. 2020 May 28. Available at http://avttx.com/ashvattha-therapeutics-subsidiary-orpheris-announces-fda-agreement-to-initiate-phase-2-study-evaluating-op-101-in-severe-covid-19-patients/.



175. A Study to Evaluate the Efficacy, Safety and Tolerability of IMU-838 as Addition to Investigator's Choice of Standard of CareTherapy, in Patients With Coronavirus Disease 19 (COVID-19). ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04379271. 2020 May 11;

176. Immunic, Inc. announces first patients enrolled in investigator-sponsored phase 2 clinical trial of IMU-838 in combination withoseltamivir for the treatment of patients with moderate-to-severe COVID-19. Immunic, Inc. 2020 Jul 27. Available athttps://www.immunic-therapeutics.com/2020/07/27/immunic-inc-announces-first-patients-enrolled-in-investigator-sponsored-phase-2-clinical-trial-of-imu-838-in-combination-with-oseltamivir-for-the-treatment-of-patients-with-moderate-to-severe-covid-19/.

177. Oryzon announces enrollment of first patient in ESCAPE: a Phase II clinical trial with vafidemstat in severely ill COVID-19 patients.Oryzon Genomics. 2020 May 18. Available at https://www.oryzon.com/sites/default/files/PRESS_RELEASE_13-2020.pdf.

178. Bhatt DL. First Human Trial of a Loading Dose of Icosapent Ethyl in Patients with COVID-19: Primary Results of the VascepaCOVID-19 CardioLink-9 Randomized Trial. Presented at the National Lipid Association Scientific Sessions December 12, 2020. [FullText].

179. Prazosin to prevent COVID-19 (PREVENT-COVID Trial). ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04365257. 2020 May 15; Accessed: June 16, 2020.

180. Konig MF, Powell M, Staedtke V, Bai RY, Thomas DL, Fischer N, et al. Preventing cytokine storm syndrome in COVID-19 using α-1adrenergic receptor antagonists. J Clin Invest. 2020 May 26. [Medline]. [Full Text].

181. Study of Ampion for the treatment of adult COVID-19 patients requiring oxygen supplementation. ClinicalTrials.gov. Available athttps://clinicaltrials.gov/ct2/show/NCT04456452. 2020 Jul 24; Accessed: July 28, 2020.

182. Fulcrum Therapeutics. Fulcrum Therapeutics Announces Initiation of Multi-Center Phase 3 (LOSVID) Trial with Losmapimod forHospitalized COVID-19 Patients. 2020 Jun 24. Available at https://ir.fulcrumtx.com/news-releases/news-release-details/fulcrum-therapeutics-announces-initiation-multi-center-phase-3.

183. Durect Corporation announces initiation of patient recruitment in phase 2 safety and efficacy study of DUR-928 in COVID-19 patientswith acute liver or kidney injury. Durect Corporation. 2020 Jul 01. Available at https://investors.durect.com/news-releases/news-release-details/durect-corporation-announces-initiation-patient-recruitment?field_nir_news_date_value[min]=2020.

184. Aclaris Therapeutics Supports Investigator-Initiated Clinical Trial of ATI-450 for Cytokine Release Syndrome in Hospitalized Patientswith COVID-19. Aclaris Therapeutics. 2020 Jun 17. Available at https://investor.aclaristx.com/news-releases/news-release-details/aclaris-therapeutics-supports-investigator-initiated-clinical.

185. Study to evaluate the efficacy and safety of leronlimab for mild to moderate COVID-19. ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04343651. 2020 Jun 11; Accessed: July 13, 2020.

186. Study to evaluate the efficacy and safety of leronlimab for patients with severe or critical coronavirus disease 2019 (COVID-19).ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/ct2/show/NCT04347239. 2020 Jun 11; Accessed: July 13, 2020.

187. Biophytis receives FDA IND clearance for COVA, a phase 2/3 clinical trial with sarconeos (BIO101) for the treatment of patients withCOVID-19 related respiratory failure. Biophytis. 2020 Jul 01. Available at https://www.biophytis.com/wp-content/uploads/2020/07/Biophytis-COVA-FDA-IND-Clearance-PR-EN-vF-.pdf.

188. FDA clears abivertinib for Phase 2 safety and efficacy study in hospitalized patients with moderate to severe COVID-19. SorrentoTherapeutics. 2020 July 20. Available at https://investors.sorrentotherapeutics.com/news-releases/news-release-details/fda-clears-abivertinib-phase-2-safety-and-efficacy-study.

189. Safety, tolerability and efficacy of nangibotide in mechanically ventilated patients with COVID-19 and features of systemicinflammation. ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/ct2/show/NCT04429334. 2020 Jun 12; Accessed: July 23,2020.

190. Can-Fite Submits Investigational New Drug Application to U.S. FDA for COVID-19 Phase II Study. Can-Fite BioPharma. 2020 Jul 27.Available at https://ir.canfite.com/press-releases/detail/917/can-fite-submits-investigational-new-drug-application-to-u-s-fda-for-covid-19-phase-ii-study.

191. LSALT peptide vs placebo to prevent ARDS and acute kidney injury in patients infected with SARS-CoV-2 (COVID-19).ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/ct2/show/NCT04402957. 2020 Jun 16; Accessed: July 28, 2020.

192. ReAlta Life Sciences announces U.S. FDA clearance of first investigational new drug application for RLS-0071. ReAlta LifeSciences. 2020 Jul 28. Available at https://realtalifesciences.com/realta-life-sciences-announces-u-s-fda-clearance-of-first-investigational-new-drug-application-for-rls-0071/.

193. Safety and antiviral activity of BLD-2660 in COVID-19 hospitalized subjects. ClinicalTrials.gov. Available athttps://clinicaltrials.gov/ct2/show/NCT04334460. 2020 Sep 03; Accessed: September 15, 2020.

194. Enzychem Lifesciences announces FDA acceptance of phase 2 study of EC-18 in preventing acute respiratory distress Syndrome(ARDS) due to COVID-19 pneumonia. Enzychem Lifesciences. 2020 Aug 14. Available at https://www.enzychem.com/enzychem-



lifesciences-announces-fda-acceptance-of-phase-2-study-of-ec-18-in-preventing-acute-respiratory-distress-syndrome-ards-due-to-covid-19-pneumonia/.

195. A study of cell therapy in COVID-19 subjects with acute kidney injury who are receiving renal replacement therapy. ClinicalTrials.gov.Available at https://clinicaltrials.gov/ct2/show/NCT04445220. 2020 Aug 13; Accessed: August 19, 2020.

196. BCG Vaccine for Health Care Workers as Defense Against COVID 19 (BADAS). ClinicalTrials.gov. Available athttps://clinicaltrials.gov/ct2/show/NCT04348370. 2020 May 27; Accessed: August 19, 2020.

197. Synthetic cannabinoid drug for COVID-19 approved for phase 1 clinical trials. Forbes. 2020 Aug 20. Available athttps://www.forbes.com/sites/emilyearlenbaugh/2020/08/20/synthetic-cannabinoid-drug-for-covid-19-approved-for-phase-1-clinical-trials/#7b9374223329.

198. Intravenous infusion of CAP-1002 in patients with COVID-19 (INSPIRE). ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04623671. 2020 Nov 24; Accessed: November 25, 2020.

199. Study of LAU-7b for the treatment of COVID-19 disease in adults (RESOLUTION). ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04417257. 2020 Jul 17; Accessed: August 26, 2020.

200. SPI-1005 treatment in severe COVID-19 patients. ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04483973. 2020 Jul 23; Accessed: September 14, 2020.

201. Rigel Announces NIH/NHLBI-sponsored trial of fostamatinib in hospitalized COVID-19 patients in collaboration with Inova. RigelPharmaceuticals. 2020 Sep 17. Available at https://ir.rigel.com/news-events/press-releases/detail/296/rigel-announces-nihnhlbi-sponsored-trial-of-fostamatinib.

202. Vadadustat for the prevention and treatment of acute respiratory distress syndrome (ARDS) in hospitalized patients with coronavirusdisease 2019 (COVID-19). ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/ct2/show/NCT04478071. 2020 Sep 10;Accessed: September 22, 2020.

203. FSD Pharma begins Phase 2 clinical trial to evaluate FSD201 for the treatment of hospitalized COVID-19 patients. FSD Pharma Inc.2020 Sep 28. Available at https://www.fsdpharma.com/news/fsd-pharma-begins-phase-2-clinical-trial-to-evaluate-fsd201-for-the-treatment-of-hospitalized-covid-19-patients/.

204. A randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of EB05 + SOC vs. placebo + SOC in adulthospitalized patients with moderate to severe COVID-19. ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04401475. 2020 Jul 01; Accessed: October 26, 2020.

205. Lenze EJ, Mattar C, Zorumski CF, Stevens A, Schweiger J, Nicol GE, et al. Fluvoxamine vs Placebo and Clinical Deterioration inOutpatients With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA. 2020 Nov 12. [Medline]. [Full Text].

206. COVID R&D Alliance launches trial of Amgen, UCB, Takeda drugs. Reuters. 2020 Nov 30. Available athttps://www.reuters.com/article/health-coronavirus-treatment-trial/covid-rd-alliance-launches-trial-of-amgen-ucb-takeda-drugs-idUSL1N2I31W4.

207. Hepion Pharmaceuticals announces FDA clearance of IND application for CRV431 for COVID-19. Hepion Pharmaceuticals. 2020Dec 22. Available at https://hepionpharma.com/news/hepion-pharmaceuticals-announces-fda-clearance-of-ind-application-for-crv431-for-covi/4573734.

208. Study of ensifentrine or placebo delivered via pMDI in hospitalized patients with COVID-19. ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04527471. 2020 Dec 14; Accessed: January 14, 2021.

209. Tiziana Life Sciences Announces an Expedited Clinical Development Plan for Its Anti-Interleukin-6-Receptor, a Fully HumanMonoclonal Antibody, for the Treatment of COVID-19 Patients. Tiziana Life Sciences. 2020 Aug 04. Available athttps://ir.tizianalifesciences.com/news-releases/news-release-details/tiziana-life-sci-plc-expedited-clinical-development-plan.

210. Bucillamine in treatment of patients with COVID-19. ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04504734.2021 Feb 24; Accessed: February 25, 2021.

211. CD24Fc as a nonantiviral immunomodulator in COVID-19 treatment (SAC-COVID). ClinicalTrials.gov. Available athttps://clinicaltrials.gov/ct2/show/NCT04317040. 2021 Feb 11; Accessed: February 25, 2021.

212. Natural killer cell (CYNK-001) infusions in adults with COVID-19 (CYNKCOVID). ClinicalTrials.gov. Available athttps://clinicaltrials.gov/ct2/show/NCT04365101. 2020 Nov 23; Accessed: February 25, 2021.

213. Aldeyra Therapeutics announces initiation of phase 2 clinical trials of ADX-629, a first-in-class orally administered RASP inhibitor, forthe treatment of COVID-19, atopic asthma, and psoriasis. Businesswire. 2020 Dec 17. Available athttps://www.businesswire.com/news/home/20201217005223/en/Aldeyra-Therapeutics-Announces-Initiation-of-Phase-2-Clinical-Trials-of-ADX-629-a-First-in-Class-Orally-Administered-RASP-Inhibitor-for-the-Treatment-of-COVID-19-Atopic-Asthma-and-Psoriasis.



214. MultiStem administration for COVID-19 induced ARDS (MACoVIA). ClinicalTrials.gov. Available athttps://clinicaltrials.gov/ct2/show/NCT04367077. 2021 Jan 25; Accessed: February 25, 2021.

215. Feld JJ, Kandel C, Biondi MJ, Kozak RA, Zahoor MA, Lemieux C, et al. Peginterferon lambda for the treatment of outpatients withCOVID-19: a phase 2, placebo-controlled randomised trial. Lancet Respir Med. 2021 Feb 5. [Medline]. [Full Text].

216. Sakoulas G, Geriak M, Kullar R, Greenwood KL, Habib M, Vyas A, et al. Intravenous Immunoglobulin Plus MethylprednisoloneMitigate Respiratory Morbidity in Coronavirus Disease 2019. Crit Care Explor. 2020 Nov. 2 (11):e0280. [Medline]. [Full Text].

217. NeoImmuneTech announces first patient dosed in phase 1 study of NT-17 (efineptakin alfa) in adults with mild COVID-19.NeoImmuneTech. 2020 Nov 30. Available at http://neoimmunetech.com/news/page01_view.html?number=64.

218. Randomized, controlled study of IFX-1 in patients with severe COVID-19 pneumonia (PANAMO). ClinicalTrials.gov. Available athttps://clinicaltrials.gov/ct2/show/NCT04333420. 2020 Dec 07; Accessed: March 1, 2021.

219. Altimmune presents highlights of intranasal COVID-19 vaccine and therapeutics programs – AdCOVID and T-COVID – at the WorldVaccine Congress. Altimmune. 2020 Sep 28. Available at https://ir.altimmune.com/news-releases/news-release-details/altimmune-presents-highlights-intranasal-covid-19-vaccine-and.

220. Anti-SARS Cov-2 T cell infusions for COVID-19 (BATIT). ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04401410. 2021 Jan 29; Accessed: March 2, 2021.

221. Monk PD, Marsden RJ, Tear VJ, Brookes J, Batten TN, Mankowski M, et al. Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet RespirMed. 2021 Feb. 9 (2):196-206. [Medline]. [Full Text].

222. NIH News Releases. The COVID-19 treatment guidelines panel’s statement on the emergency use authorization of bamlanivimabfor the treatment of COVID-19. NIH.gov. Available at https://www.covid19treatmentguidelines.nih.gov/statement-on-bamlanivimab-eua/. 2020 Nov 18; Accessed: November 19, 2020.

223. Chen P, Nirula A, Heller B, Gottlieb RL, Boscia J, Morris J, et al. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients withCovid-19. N Engl J Med. 2020 Oct 28. [Medline]. [Full Text].

224. Gottlieb RL, Nirula A, Chen P, Boscia J, Heller B, Morris J, et al. Effect of Bamlanivimab as Monotherapy or in Combination WithEtesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2021 Jan 21. [Medline].[Full Text].

225. A Study of LY3819253 (LY-CoV555) in Preventing SARS-CoV-2 Infection and COVID-19 in Nursing Home Residents and Staff(BLAZE-2). ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/ct2/show/NCT04497987. 2020 Oct 30; Accessed: October30, 2020.

226. Safety, tolerability, and efficacy of anti-spike (S) SARS-CoV-2 monoclonal antibodies for hospitalized adult patients with COVID-19.ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04426695. 2020 Oct 01; Accessed: October 2, 2020.

227. REGN-COV2 independent data monitoring committee recommends holding enrollment in hospitalized patients with high oxygenrequirements and continuing enrollment in patients with low or no oxygen requirements. Regeneron. 2020 Oct 30. Available athttps://investor.regeneron.com/news-releases/news-release-details/regn-cov2-independent-data-monitoring-committee-recommends.

228. Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, et al. REGN-COV2, a Neutralizing Antibody Cocktail, inOutpatients with Covid-19. N Engl J Med. 2020 Dec 17. [Medline]. [Full Text].

229. Regeneron’s COVID-19 outpatient trial prospectively demonstrates that REGN-COV2 antibody cocktail significantly reduced viruslevels and need for further medical attention. Regeneron. 2020 Oct 28. Available at https://investor.regeneron.com/news-releases/news-release-details/regenerons-covid-19-outpatient-trial-prospectively-demonstrates.

230. Phase 3 trial shows REGEN-COV (casirivimab with imdevimab) antibody cocktail reduced hospitalization or death by 70% in non-hospitalized COVID-19 patients. Regeneron. 2021 Mar 23. Available at https://investor.regeneron.com/news-releases/news-release-details/phase-3-trial-shows-regen-covtm-casirivimab-imdevimab-antibody.

231. Regeneron announces encouraging initial data from COVID-19 antibody cocktail trial in hospitalized patients on low-flow oxygen.PRNewswire. 2020 Dec 29. Available at https://investor.regeneron.com/news-releases/news-release-details/regeneron-announces-encouraging-initial-data-covid-19-antibody.

232. Cathcart AL, Havenar-Daughton C, Lempp FA, Ma D, Schmid M, Agostini ML, et al. The dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2. bioRxiv. 2021 Mar 10. [Full Text].

233. GSK and Vir Biotechnology announce submission of emergency use authorization request to FDA for VIR-7831 for the earlytreatment of COVID-19. VIR Biotechnology. 2021 Mar 26. Available at https://investors.vir.bio/news-releases/news-release-details/gsk-and-vir-biotechnology-announce-submission-emergency-use.



234. Lilly, VIR Biotechnology and GSK announce positive topline data from the phase 2 BLAZE-4 trial evaluating bamlanivimab with VIR-7831 in low-risk adults with COVID-19. VIR Biotechnology. 2021 Mar 29. Available at https://investors.vir.bio/news-releases/news-release-details/lilly-vir-biotechnology-and-gsk-announce-positive-topline-data.

235. Sorrento and Mount Sinai team up for antibody cocktail COVI-Shield project. Biospace. 2020 May 08. Available athttps://www.biospace.com/article/sorrento-and-mount-sinai-team-to-develop-antibody-therapy-against-covid-19/?keywords=covi-shield.

236. Study to evaluate STI-1499 (COVI-GUARD) in hospitalized patients with COVID-19. ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04454398. 2020 Nov 20; Accessed: December 11, 2020.

237. Study to evaluate the safety, pharmacokinetics and efficacy of STI-2020 (COVI-AMG) in outpatients with COVID-19.ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/ct2/show/NCT04584697. 2020 Nov 05; Accessed: December 11, 2020.

238. COVID-19 long-acting antibody (LAAB) combination AZD7442 rapidly advances into phase III clinical trials. AstraZeneca. 2020 Oct09. Available at https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/covid-19-long-acting-antibody-laab-combination-azd7442-rapidly-advances-into-phase-iii-clinical-trials.html.

239. Tiziana to conduct a clinical study with nasally administered foralumab, a fully human anti-CD3 monoclonal antibody, for treatment ofCOVID-19 patients in Brazil. Tiziana Life Sciences. 2020 Sep 17. Available at https://www.tizianalifesciences.com/news-item?s=2020-09-17-tiziana-to-conduct-a-clinical-study-with-nasally-administered-foralumab-a-fully-human-anti-cd3-monoclonal-antibody-for-treatment-of-covid-19-patients-in-brazil.

240. Pitt Scientists discover tiny antibody component that is highly effective in preventing and treating SARS-CoV-2 infection in animalmodels. Pittwire. 2020 Sep 14. Available at https://www.pittwire.pitt.edu/news/pitt-scientists-discover-tiny-antibody-component-highly-effective-preventing-and-treating-sars.

241. Study to Assess Adverse Events and How Intravenous (IV) ABBV-47D11 Moves Through the Body of Adult Participants HospitalizedWith Coronavirus Disease 2019 (COVID-19). ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/ct2/show/NCT04644120.2020 Nov 25; Accessed: December 15, 2020.

242. Aridis Pharmaceuticals provides multiple program updates including the addition of a second inhaled antibody to neutralize newlyemerging COVID-19 mutated variants. Aridis Pharmaceuticals, Inc. 2021 Feb 23. Available athttps://investors.aridispharma.com/2021-02-23-Aridis-Pharmaceuticals-Provides-Multiple-Program-Updates-Including-the-Addition-of-a-Second-Inhaled-Antibody-to-Neutralize-Newly-Emerging-COVID-19-Mutated-Variants.

243. McClung N, Chamberland M, Kinlaw K, Bowen Matthew D, Wallace M, Bell BP, et al. The Advisory Committee on ImmunizationPractices' Ethical Principles for Allocating Initial Supplies of COVID-19 Vaccine - United States, 2020. MMWR Morb Mortal WklyRep. 2020 Nov 27. 69 (47):1782-1786. [Medline]. [Full Text].

244. Coronavirus Vaccine Tracker. The New York Times. Available at https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html. 2020 Nov 19; Accessed: November 19, 2020.

245. Lurie N, Saville M, Hatchett R, Halton J. Developing Covid-19 Vaccines at Pandemic Speed. N Engl J Med. 2020 May 21. 382(21):1969-1973. [Medline]. [Full Text].

246. Koirala A, Joo YJ, Khatami A, Chiu C, Britton PN. Vaccines for COVID-19: The current state of play. Paediatr Respir Rev. 2020 Sep.35:43-49. [Medline]. [Full Text].

247. Iba T, Levy JH, Levi M, Connors JM, Thachil J. Coagulopathy of Coronavirus Disease 2019. Crit Care Med. 2020 Sep. 48 (9):1358-1364. [Medline]. [Full Text].

248. Katneni UK, Alexaki A, Hunt RC, Schiller T, DiCuccio M, Buehler PW, et al. Coagulopathy and Thrombosis as a Result of SevereCOVID-19 Infection: A Microvascular Focus. Thromb Haemost. 2020 Aug 24. [Medline]. [Full Text].

249. Ferguson J, Volk S, Vondracek T, Flanigan J, Chernaik A. Empiric therapeutic anticoagulation and mortality in critically ill patientswith respiratory failure from SARS-CoV-2: A retrospective cohort study. J Clin Pharmacol. 2020 Sep 3. [Medline]. [Full Text].

250. Paranjpe I, Fuster V, Lala A, Russak AJ, Glicksberg BS, Levin MA, et al. Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19. J Am Coll Cardiol. 2020 Jul 7. 76 (1):122-124. [Medline]. [Full Text].

251. Assessing Safety, Hospitalization and Efficacy of rNAPc2 in COVID-19 (ASPEN). ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT0465558. 2020 Dec 15; Accessed: December 16, 2020.

252. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probablebat origin. Nature. 2020 Mar. 579 (7798):270-273. [Medline]. [Full Text].

253. Lopes RD, Macedo AVS, de Barros E Silva PGM, and the, BRACE CORONA investigators. Continuing versus suspendingangiotensin-converting enzyme inhibitors and angiotensin receptor blockers: Impact on adverse outcomes in hospitalized patientswith severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)--The BRACE CORONA Trial. Am Heart J. 2020 Aug. 226:49-59. [Medline]. [Full Text].



254. Fang L, Karakiulakis G, Roth M. Correction to Lancet Respir Med 2020; 8: e21. Lancet Respir Med. 2020 Jun. 8 (6):e54. [Medline].[Full Text].

255. Clerkin KJ, Fried JA, Raikhelkar J, Sayer G, Griffin JM, Masoumi A, et al. Coronavirus Disease 2019 (COVID-19) andCardiovascular Disease. Circulation. 2020 Mar 21. [Medline]. [Full Text].

256. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARScoronavirus-induced lung injury. Nat Med. 2005 Aug. 11 (8):875-9. [Medline]. [Full Text].

257. Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-Angiotensin-Aldosterone System Inhibitorsin Patients with Covid-19. N Engl J Med. 2020 Mar 30. [Medline]. [Full Text].

258. Ishiyama Y, Gallagher PE, Averill DB, Tallant EA, Brosnihan KB, Ferrario CM. Upregulation of angiotensin-converting enzyme 2 aftermyocardial infarction by blockade of angiotensin II receptors. Hypertension. 2004 May. 43 (5):970-6. [Medline]. [Full Text].

259. Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA, et al. Effect of angiotensin-converting enzyme inhibitionand angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005 May 24. 111 (20):2605-10.[Medline]. [Full Text].

260. Klimas J, Olvedy M, Ochodnicka-Mackovicova K, Kruzliak P, Cacanyiova S, Kristek F, et al. Perinatally administered losartanaugments renal ACE2 expression but not cardiac or renal Mas receptor in spontaneously hypertensive rats. J Cell Mol Med. 2015Aug. 19 (8):1965-74. [Medline]. [Full Text].

261. Walters TE, Kalman JM, Patel SK, Mearns M, Velkoska E, Burrell LM. Angiotensin converting enzyme 2 activity and human atrialfibrillation: increased plasma angiotensin converting enzyme 2 activity is associated with atrial fibrillation and more advanced leftatrial structural remodelling. Europace. 2017 Aug 1. 19 (8):1280-1287. [Medline]. [Full Text].

262. Burchill LJ, Velkoska E, Dean RG, Griggs K, Patel SK, Burrell LM. Combination renin-angiotensin system blockade and angiotensin-converting enzyme 2 in experimental myocardial infarction: implications for future therapeutic directions. Clin Sci (Lond). 2012 Dec.123 (11):649-58. [Medline].

263. Bozkurt B, Kovacs R, Harrington B. Joint HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19. J Card Fail. 2020 May. 26 (5):370. [Medline]. [Full Text].

264. Sama IE, Ravera A, Santema BT, van Goor H, Ter Maaten JM, Cleland JGF, et al. Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors. Eur Heart J. 2020May 14. 41 (19):1810-1817. [Medline]. [Full Text].

265. Baral R, Tsampasian V, Debski M, Moran B, Garg P, Clark A, et al. Association Between Renin-Angiotensin-Aldosterone SystemInhibitors and Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis. JAMA Netw Open. 2021 Mar1. 4 (3):e213594. [Medline]. [Full Text].

266. Torres A, Blasi F, Dartois N, Akova M. Which individuals are at increased risk of pneumococcal disease and why? Impact of COPD,asthma, smoking, diabetes, and/or chronic heart disease on community-acquired pneumonia and invasive pneumococcal disease.Thorax. 2015 Oct. 70 (10):984-9. [Medline]. [Full Text].

267. Drucker DJ. Coronavirus infections and type 2 diabetes-shared pathways with therapeutic implications. Endocr Rev. 2020 Apr 15.[Medline]. [Full Text].

268. Muniyappa R, Gubbi S. COVID-19 Pandemic, Corona Viruses, and Diabetes Mellitus. Am J Physiol Endocrinol Metab. 2020 Mar 31.[Medline]. [Full Text].

269. DPP4 dipeptidyl peptidase 4. National Center for Biotechnology Information (NCBI). Available athttps://www.ncbi.nlm.nih.gov/gene/1803. 2020 Apr 20; Accessed: April 21, 2020.

270. FDA. Coronavirus (COVID-19) Update: FDA Revokes Emergency Use Authorization for Chloroquine and Hydroxychloroquine. USFood and Drug Administration. 2020 Jun 15. Available at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-chloroquine-and.

271. NIH halts clinical trial of hydroxychloroquine. NIH Media Advisory. 2020 Jun 20. Available at https://www.nih.gov/news-events/news-releases/nih-halts-clinical-trial-hydroxychloroquine.

272. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novelcoronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar. 30 (3):269-271. [Medline]. [Full Text].

273. RECOVERY Collaborative Group., Horby P, Mafham M, Linsell L, et al. Effect of Hydroxychloroquine in Hospitalized Patients withCovid-19. N Engl J Med. 2020 Oct 8. [Medline]. [Full Text].

274. Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LCP, Veiga VC, Avezum A, et al. Hydroxychloroquine with or without Azithromycinin Mild-to-Moderate Covid-19. N Engl J Med. 2020 Jul 23. [Medline]. [Full Text].

275. Ip A, Berry DA, Hansen E, Goy AH, Pecora AL, Sinclaire BA, et al. Hydroxychloroquine and tocilizumab therapy in COVID-19patients – An observational study. medRxiv. 2020 May 25. [Full Text].



276. FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due torisk of heart rhythm problems. US Food & Drug Administration. 2020 Apr 24. Available at https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or.

277. Self WH, Semler MW, Leither LM, Casey JD, Angus DC, Brower RG, et al. Effect of Hydroxychloroquine on Clinical Status at 14Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2020 Nov 9. [Medline]. [Full Text].

278. Geleris J, Sun Y, Platt J, Zucker J, Baldwin M, Hripcsak G, et al. Observational Study of Hydroxychloroquine in Hospitalized Patientswith Covid-19. N Engl J Med. 2020 May 7. [Medline]. [Full Text].

279. Lammers AJJ, Brohet RM, Theunissen REP, Koster C, Rood R, Verhagen DWM, et al. Early Hydroxychloroquine but notChloroquine use reduces ICU admission in COVID-19 patients. Int J Infect Dis. 2020 Sep 29. [Medline]. [Full Text].

280. Arshad S, Kilgore P, Chaudhry ZS, and the, Henry Ford COVID-19 Task Force. Treatment with Hydroxychloroquine, Azithromycin,and Combination in Patients Hospitalized with COVID-19. Int J Infect Dis. 2020 Jul 2. [Medline]. [Full Text].

281. Lee TC, MacKenzie LJ, McDonald EG, Tong SYC. An Observational Cohort Study of Hydroxychloroquine and Azithromycin forCOVID-19: (Can't Get No) Satisfaction. Int J Infect Dis. 2020 Jul 2. [Medline]. [Full Text].

282. Magagnoli J, Narendran S, Pereira F, Cummings T, Hardin JW, Sutton SS, et al. Outcomes of hydroxychloroquine usage in UnitedStates veterans hospitalized with Covid-19. medRxiv. 2020 Apr 21. [Full Text].

283. Lopez A, Duclos G, Pastene B, Bezulier K, Guilhaumou R, Solas C, et al. Effects of Hydroxychloroquine on Covid-19 in IntensiveCare Unit Patients: Preliminary Results. Int J Antimicrob Agents. 2020 Aug 7. 106136. [Medline]. [Full Text].

284. multicenter collaboration group of Department of Science and Technology of Guangdong Province and Health Commission ofGuangdong Province for chloroquine in the treatment of novel coronavirus pneumonia. [Expert consensus on chloroquine phosphatefor the treatment of novel coronavirus pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi. 2020 Mar 12. 43 (3):185-188. [Medline].

285. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associatedpneumonia in clinical studies. Biosci Trends. 2020 Mar 16. 14 (1):72-73. [Medline]. [Full Text].

286. Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of arandomized clinical trial (preprint). MedRxIV. Available at https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v2.full.pdf.2020 Mar 31; Accessed: April 1, 2020.

287. Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in patients with COVID-19: an open-label, randomized,controlled trial. medRxiv. 2020 Apr 14. [Full Text].

288. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment ofCOVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Mar 20. 105949. [Medline]. [FullText].

289. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb, Sevestre J, et al. Hydroxychloroquine-Azithromycin and COVID-19. Available athttps://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf. 2020 Mar 30;

290. Molina JM, Delaugerre C, Goff JL, Mela-Lima B, Ponscarme D, Goldwirt L, et al. No Evidence of Rapid Antiviral Clearance orClinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection. Med MalInfect. 2020 Mar 30. [Medline]. [Full Text].

291. Skipper CP, Pastick KA, Engen NW, Bangdiwala AS, Abassi M, Lofgren SM, et al. Hydroxychloroquine in Nonhospitalized AdultsWith Early COVID-19: A Randomized Trial. Ann Intern Med. 2020 Jul 16. [Medline]. [Full Text].

292. NIH begins clinical trial of hydroxychloroquine and azithromycin to treat COVID-19. National Institutes of Health. Available athttps://www.nih.gov/news-events/news-releases/nih-begins-clinical-trial-hydroxychloroquine-azithromycin-treat-covid-19. Accessed:2020 May 14.

293. A5395: A randomized, double-blind, placebo-controlled trial to evaluate the efficacy of hydroxychloroquine and azithromycin toprevent hospitalization or death in persons with COVID-19. AIDS Clinical Trials Group. Available athttps://actgnetwork.org/studies/a5395/. Accessed: 2020 May 15.

294. Abella, BS, Jolkovsky EL, Biney BT, and the Prevention and Treatment of COVID-19 With Hydroxychloroquine (PATCH)Investigators. Efficacy and safety of hydroxychloroquine vs placebo for pre-exposure SARS-CoV-2 prophylaxis among health careworkers – A randomized clinical trial. JAMA Int Med. 2020 Sep 30. [Full Text].

295. Hydroxychloroquine Post Exposure Prophylaxis for Coronavirus Disease (COVID-19) NCT04318444. ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04318444. 2020 Apr 27;

296. Hydroxychloroquine as Prophylaxis for COVID-19 in Healthcare Workers (HCQPreP) NCT04363450. ClinicalTrials.gov. Available athttps://www.clinicaltrials.gov/ct2/show/NCT04363450. 2020 Apr 29;

297. Healthcare Worker Exposure Response and Outcomes of Hydroxychloroquine (HERO-HCQ) NCT04334148. ClinicalTrials.gov.Available at https://clinicaltrials.gov/ct2/show/NCT04334148. 2020 May 14;



298. Rajasingham R, Bangdiwala AS, Nicol MR, Skipper CP, Pastick KA, Axelrod ML, et al. Hydroxychloroquine as pre-exposureprophylaxis for COVID-19 in healthcare workers: a randomized trial. Clin Infect Dis. 2020 Oct 17. [Medline]. [Full Text].

299. Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, et al. A Randomized Trial of Hydroxychloroquine asPostexposure Prophylaxis for Covid-19. N Engl J Med. 2020 Jun 3. [Medline]. [Full Text].

300. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012 May 17.366 (20):1881-90. [Medline]. [Full Text].

301. Simpson TF, Kovacs RJ, Stecker EC. Ventricular Arrhythmia Risk Due to Hydroxychloroquine-Azithromycin Treatment For COVID-19. American College of Cardiology; Cardiology Magazine. Available at https://www.acc.org/latest-in-cardiology/articles/2020/03/27/14/00/ventricular-arrhythmia-risk-due-to-hydroxychloroquine-azithromycin-treatment-for-covid-19.2020 Mar 29; Accessed: April 1, 2020.

302. Borba M, de Almeida Val F, Sampaio VS, Alexandre MA, Melo GC, Brito M, et al. Chloroquine diphosphate in two different dosagesas adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2)infection: Preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study). MedRxiv. 2020Apr 11. [Full Text].

303. Lane JCE, Weaver J, Kostka K, Duarte-Salles T, Abrahao MTF, Alghoul H, et al. Safety of hydroxychloroquine, alone and incombination with azithromycin, in light of rapid wide-spread use for COVID-19: a multinational, network cohort and self-controlledcase series study. MedRxiv. 2020 Apr 10. [Full Text].

304. [Guideline] NIH. Potential Antiviral Drugs Under Evaluation for the treatment of COVID-19. COVID-19 Treatment Guidelines.Available at https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/. 2020 Jun 11; Accessed: June 16, 2020.

305. OVERY Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomized,controlled, open-label, platform trial. The Lancet. 2020 Oct 05. [Full Text].

306. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. NEngl J Med. 2020 Mar 18. [Medline]. [Full Text].

307. Baden LR, Rubin EJ. Covid-19 - The Search for Effective Therapy. N Engl J Med. 2020 Mar 18. [Medline]. [Full Text].

308. Li Y, Xie Z, Lin W, Cai W, Wen C, Guan Y, et al. Efficacy and safety of lopinavir/ritonavir or Arbidol in adult patients withmild/moderate COVID-19: an exploratory randomized controlled trial. Med (from Cell Press). 2020 Apr 17. [Full Text].

309. Hung IFN, Lung KC, Tso EYK, Liu R, Chung TWH, Chu MY, et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, andribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020 May08. [Full Text].

310. Momekov G, Momekova D. Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view: antiviral levels arenot likely attainable with known dosing regimens. Biotechnology & Biotechnological Equipment. 2020. 34(1):469-474. [Full Text].

311. Chaccour C, Hammann F, Ramón-García S, Rabinovich NR. Ivermectin and Novel Coronavirus Disease (COVID-19): Keeping Rigorin Times of Urgency. Am J Trop Med Hyg. 2020 Apr 16. [Medline]. [Full Text].

312. López-Medina E, López P, Hurtado IC, Dávalos DM, Ramirez O, Martínez E, et al. Effect of Ivermectin on Time to Resolution ofSymptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial. JAMA. 2021 Mar 4. [Medline]. [Full Text].

313. ViralClear halts its phase 2 hospitalized COVID-19 trial. BioSig Technologies. 2020 Oct 26. Available athttps://www.biosig.com/news-media/press-releases/detail/234/viralclear-halts-its-phase-2-hospitalized-covid-19-trial.

314. Update on CALAVI phase II trials for Calquence in patients hospitalized with respiratory symptoms of COVID-19. AstraZeneca. 2020Nov 12. Available at https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/update-on-calavi-phase-ii-trials-for-calquence-in-patients-hospitalised-with-respiratory-symptoms-of-covid-19.html.

315. Incyte Announces Results of Phase 3 RUXCOVID Study of Ruxolitinib (Jakafi) as a Treatment for Patients with COVID-19Associated Cytokine Storm. Incyte Corp. 2020 Dec 14. Available at https://investor.incyte.com/press-releases/press-releases/2020/Incyte-Announces-Results-of-Phase-3-RUXCOVID-Study-of-Ruxolitinib-Jakafi-as-a-Treatment-for-Patients-with-COVID-19-Associated-Cytokine-Storm/default.aspx.

316. Vankadari N. Arbidol: A potential antiviral drug for the treatment of SARS-CoV-2 by blocking the trimerization of viral spikeglycoprotein?. Int J Antimicrob Agents. 2020 Apr 28. [Full Text].

317. Lian N, Xie H, Lin S, Huang J, Zhao J, Lin Q. Umifenovir treatment is not associated with improved outcomes in patients withcoronavirus disease 2019: A retrospective study. Clin Microbiol Infect. 2020 Apr 25. [Medline]. [Full Text].

318. [Guideline] Roden DM, Harrington RA, Poppas A, Russo AM. Considerations for Drug Interactions on QTc in Exploratory COVID-19(Coronavirus Disease 2019) Treatment. Circulation. 2020 Apr 8. [Medline]. [Full Text].

319. [Guideline] Giudicessi JR, Noseworthy PA, Friedman PA, Ackerman MJ. Urgent guidance for navigating and circumventing the QTcprolonging and torsadogenic potential of possible pharmacotherapies for COVID-19. Mayo Clin Proc. 2020 Apr 07. [Full Text].



320. Chorin E, Dai M, Shulman E, Wadhwani L, et al. The QT Interval in Patients with SARS-CoV-2 Infection Treated withHydroxychloroquine/Azithromycin. medRxiv. 2020 Apr 03. [Full Text].

321. Mercuro NJ, Yen CF, Shim DJ, Maher TR, McCoy CM, Zimetbaum PJ, et al. Risk of QT Interval Prolongation Associated With Use ofHydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for CoronavirusDisease 2019 (COVID-19). JAMA Cardiol. 2020 May 1. [Medline]. [Full Text].

322. TLR 2/6/9 agonist PUL-042. NCI Drug Dictionary. Available at https://www.cancer.gov/publications/dictionaries/cancer-drug/def/tlr-2-6-9-agonist-pul-042. Accessed: 2020 Apr 13.

323. The Use PUL-042 Inhalation Solution to Prevent COVID-19 in Adults Exposed to SARS-CoV-2. ClinicalTrials.gov. Available athttps://clinicaltrials.gov/ct2/show/NCT04313023. 2020 Mar 24;

324. The Use of PUL-042 Inhalation Solution to Reduce the Severity of COVID-19 in Adults Positive for SARS-CoV-2 Infection.ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04312997?term=PUL-042&cond=COVID&cntry=US&draw=2&rank=2. 2020 May 07;

325. FDA Combating COVID-19 with Medical Devices. US Food and Drug Administration. Available athttps://www.fda.gov/media/136702/download. 2020 Jun 15; Accessed: June 19, 2020.

326. Zhang Q, et al. Cellular nanosponges inhibit SARS-CoV-2 infectivity. Nano Lett. 2020 Jun 17. [Medline]. [Full Text].

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