Treatment of Coronavirus Disease 2019 (COVID-19): Investigational Drugs and Other Therapies

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

No drugs or biologics have been approved by the FDA for the prevention or treatment of COVID-19. Remdesivir gained emergency use authorization (EUA) from the FDA on May 1, 2020, based on preliminary data showing a faster time to recovery of hospitalized patients with severe disease. ^[5] A new drug application (NDA) for remdesivir was submitted to the FDA in August 2020. An EUA for convalescent plasma was announced on August 23, 2020. ^[6] Numerous other antiviral agents, immunotherapies, and vaccines continue to be investigated and developed as potential therapies. Searching for effective therapies for COVID-19 infection is a complex process. Guidelines and reviews of pharmacotherapy for COVID-19 have been published. ^{[7, 8, 9, 10, 11, 12]}

The urgent need for treatments during a pandemic can confound the interpretation of resulting outcomes of a therapy if data are not carefully collected and controlled. Andre Kalil, MD, MPH, writes of the detriment of drugs used as a single-group intervention without a concurrent control group that ultimately lead to no definitive conclusion of efficacy or safety. ^[13]

Rome and Avorn write about unintended consequences of allowing widening access to experimental therapies. First, efficacy is unknown and may be negligible, but, without appropriate studies, physicians will not have evidence on which to base judgement. Existing drugs with well-documented adverse effects (eg, hydroxychloroquine) subject patients to these risks without proof of clinical benefit. Expanded access of unproven drugs may delay implementation of randomized controlled trials. In addition, demand for unproven therapies can cause shortages of medications that are approved and indicated for other diseases, thereby leaving patients who rely on these drugs for chronic conditions without effective therapies. ^[14]

Drug shortages during the pandemic go beyond off-label prescribing of potential treatments for COVID-19. Drugs that are necessary for ventilated and critically ill patients and widespread use of inhalers used for COPD or asthma are in demand. ^{[15, 16]}

It is difficult to carefully evaluate the onslaught of information that has emerged regarding potential COVID-19 therapies within a few months’ time in early 2020. A brief but detailed approach regarding how to evaluate resulting evidence of a study has been presented by F. Perry Wilson, MD, MSCE. By using the example of a case series of patients given hydroxychloroquine plus azithromycin, he provides clinicians with a quick review of critical analyses. ^[17]

As an example of the number of compounds being evaluated, Gordon et al identified 332 high-confidence SARS-CoV-2 human protein-protein interactions. Among these, they identified 66 human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials, and/or preclinical compounds. As of March 22, 2020, these researchers are in the process of evaluating the potential efficacy of these drugs in live SARS-CoV-2 infection assays. ^[18]

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

The NIH Accelerating Covid-19 Therapeutics Interventions and Vaccines (ACTIV) trials public-private partnership to develop a coordinated research strategy has several ongoing protocols that are adaptive to the progression of standard care. ^[20]

Another adaptive platform trial is the I-SPY COVID-19 Trial for treating critically ill patients. The clinical trial is designed to allow numerous investigational agents to be evaluated in the span of 4-6 months, compared with standard of care (supportive care for ARDS, remdesivir backbone therapy). Depending on the time course of COVID-19 infections across the US. As the trial proceeds and a better understanding of the underlying mechanisms of the COVID-19 illness emerges, expanded biomarker and data collection can be added as needed to further elucidate how agents are or are not working. ^[21]

The WHO has embarked on an ambitious global “megatrial” called SOLIDARITY in which confirmed cases of COVD-19 are randomized to standard care or one of four active treatment arms (remdesivir, chloroquine or hydroxychloroquine, lopinavir/ritonavir, or lopinavir/ritonavir plus interferon beta-1a). As of July 4, 2020, the treatment arms in hospitalized patients that include hydroxychloroquine, chloroquine, or lopinavir/ritonavir have been discontinued owing to the drugs showing little or no reduction in mortality compared with standard of care. ^[22]

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

The broad-spectrum antiviral agent remdesivir (GS-5734; Gilead Sciences, Inc) is a nucleotide analog prodrug. On May 1, 2020, The US FDA issued their EUA of remdesivir to allow prescribing of the agent for severe COVID-19 (confirmed or suspected) in hospitalized adults and children prior to approval. ^{[23, 24]} A new drug application (NDA) for remdesivir was submitted to the FDA in August 2020. A phase 1b trial of inhaled nebulized remdesivir was initiated in late June 2020 to determine if remdesivir can be used on an outpatient basis and at earlier stages of disease. ^[25]

It was studied in clinical trials for Ebola virus infections but showed limited benefit. ^[26] Remdesivir has been shown to inhibit replication of other human coronaviruses associated with high morbidity in tissue cultures, including severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012. Efficacy in animal models has been demonstrated for SARS-CoV and MERS-CoV. ^[27]

Several phase 3 clinical trials are testing remdesivir for treatment of COVID-19 in the United States, South Korea, and China. Positive results were seen with remdesivir after use by the University of Washington in the first case of COVID-19 documented on US soil in January 2020. ^[28] The drug was prescribed under an open-label compassionate use protocol, but the US FDA later moved to allow expanded access to remdesivir, permitting approved sites to prescribe the investigational product for multiple patients under protocol prior to the EUA without requesting permission for each. ^[29] 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 evidence emerges. The first experience with this study involved passengers of the Diamond Princess cruise ship in quarantine at the University of Nebraska Medical Center in February 2020 after returning to the United States from Japan following an on-board outbreak of COVID-19. ^[30] Trials of remdesivir for moderate and severe COVID-19 compared with standard of care and varying treatment durations are ongoing.

The EUA for remdesivir was based on preliminary data analysis of the Adaptive COVID-19 Treatment Trial (ACTT) was announced April 29, 2020. The analysis included 1,063 hospitalized patients with advanced COVID-19 and lung involvement, showing that patients who received remdesivir recovered faster than similar patients who received placebo. Preliminary results indicated that patients who received remdesivir had a 31% faster time to recovery than those who received placebo (P< 0.001). Specifically, the median time to recovery was 11 days in patients treated with remdesivir compared with 15 days in those who received placebo. Results also suggested a survival benefit by day 14, with a mortality rate of 7.1% in the remdesivir group, compared with 11.9% in the placebo group, but this was not statistically significant. ^[5]

The ACTT results differ from a smaller randomized trial conducted in China and published hours before the press release by the NIH about the study. Results from this other randomized, double-blind, placebo-controlled, multicenter trial (n = 237; 158 to remdesivir and 79 to placebo; 1 patient withdrew) found remdesivir was not associated with statistically significant clinical benefits, measured as time to clinical improvement, in adults hospitalized with severe COVID-19. Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less. The authors concluded that numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. ^[31]

A phase 3, randomized, open-label trial showed remdesivir was associated with significantly greater recovery and reduced odds of death compared with standard of care in patients with severe COVID-19. The recovery rate at day 14 was higher in patients who 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). ^[32]

The open-label phase 3 SIMPLE trial (n = 397) in hospitalized patients with severe COVID-19 disease not requiring mechanical ventilation showed similar improvement in clinical status with the 5-day remdesivir regimen compared with the 10-day regimen on day 14 (OR: 0.75 [95% CI 0.51-1.12]). In this study, 65% of patients who received a 5-day course of remdesivir showed a clinical improvement of at least 2 points on the 7-point ordinal scale at day 14, compared with 54% of patients who received a 10-day course. After adjustment for imbalances in baseline clinical status, patients receiving a 10-day course of remdesivir had a distribution in clinical status at day 14 that was similar to that of patients receiving a 5-day course (P = 0.14). The study demonstrates the potential for some patients to be treated with a 5-day regimen, which could significantly expand the number of patients who could be treated with the current supply of remdesivir. The trial is continuing with an enrollment goal of 6,000 patients. ^[33]

Data presented at the virtual COVID-19 Conference in July 2020 included a comparative analysis of clinical recovery and mortality outcomes from the phase 3 SIMPLE trials versus a real-world cohort of patients with severe COVID-19 receiving standard of care. The analysis showed remdesivir was associated with a 62% reduction in the risk of mortality compared with standard of care. Subgroup analyses found these results were similar across different racial and ethnic groups. While these data are important, they require confirmation in prospective clinical trials. ^[34]

Similarly, the phase 3 SIMPLE II trial in patients with moderate COVID-19 disease (n = 596) showed that 5 days of remdesivir treatment had a statistically significant higher odds of a better clinical status distribution on Day 11 compared with those receiving standard care (odds ratio, 1.65; p = 0.02). Improvement on Day 11 did not differ between the 10-day remdesivir group and standard of care (P = 0.18). ^[35]

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

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

Additional data for compassionate use of remdesivir was released on July 10, 2020, and demonstrated that remdesivir treatment was associated with significantly improved clinical recovery and a 62% reduction in the risk of mortality compared with standard of care. Findings from the comparative analysis showed that 74.4% of remdesivir-treated patients recovered by day 14 versus 59% of patients receiving standard of care. The mortality rate in patients treated with remdesivir in the analysis was 7.6% at day 14 compared with 12.5% among patients not taking remdesivir (adjusted OR, 0.38; 95% CI, 0.22-0.68, P = 0.001). The analyses also found that 83% of pediatric patients (n = 77) and 92% of pregnant and postpartum women (n = 86) with a broad spectrum of COVID-19 severity recovered by day 28. ^[34]

An in vitro study showed that the antiviral activity of remdesivir plus interferon beta (IFNb) for MERS-CoV was superior to that of lopinavir/ritonavir (LPV/RTV; Kaletra, Aluvia; AbbVie Corporation). Prophylactic and therapeutic remdesivir improved pulmonary function and reduced lung viral loads and severe lung pathology in mice, whereas LPV/RTV-IFNb slightly reduced viral loads without affecting other disease parameters. Therapeutic LPV/RTV-IFNb improved pulmonary function but did not reduce virus replication or severe lung pathology in the mice. ^[37]

Remdesivir use in children

Remdesivir emergency use authorization includes pediatric dosing that was derived from pharmacokinetic data in healthy adults. Remdesivir has been available through compassionate use to children with severe COVID-19 since February 2020. A phase 2/3 trial (CARAVAN) of remdesivir was initiated in June 2020 to assess safety, tolerability, pharmacokinetics, and efficacy in children with moderate-to-severe COVID-19. CARAVAN is an open-label, single-arm study of remdesivir in children from birth to age 18 years. ^[38]

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. ^[39]

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

Remdesivir use in pregnant women

Data were presented at the virtual COVID-19 Conference held July 10-11, 2020, on compassionate use of remdesivir in 86 pregnant women (67 while pregnant and 19 on postpartum days 0-3). No new safety signals were observed. Results showed pregnant women had higher rates of recovery than nonpregnant adults treated with compassionate use remdesivir (92% vs 62%), likely owing to the younger age of pregnant women (median age, 33 years vs 64 years). ^[40]

Drug interactions with remdesivir

Coadministration of remdesivir is not recommended with chloroquine or hydroxychloroquine. Based on in vitro data, chloroquine demonstrated an antagonistic effect on the intracellular metabolic activation and antiviral activity of remdesivir. ^[24]

Favipiravir

Favipiravir (Avigan, Avifavir, Coronavir; Fujifilm Pharmaceuticals; Appili Therapeutics) is an oral antiviral approved for treatment of influenza in Japan. It is approved in Russia for 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-19 was conducted in Russia. Both dosing regimens of favipiravir demonstrated similar virologic response. Viral clearance on Day 5 was 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%) in the standard care group (p = 0.155). ^[41]  

In the United States, a phase 2 trial will enroll approximately 50 patients with COVID-19, in collaboration with Brigham and Women’s Hospital, Massachusetts General Hospital, and the University of Massachusetts Medical School. Stanford University launched an outpatient trial in July 2020 to test whether the drug can reduce symptoms and viral shedding in people with COVID-19. ^{[42, 43, 44]}  Additionally, a phase 2 trial in Canada and the US is planned to evaluate favipiravir as prophylaxis for long-term care facilities experiencing a COVID outbreak. ^[45]

Nitazoxanide

Nitazoxanide extended-release tablets (NT-300; Romark Laboratories) inhibit replication of a broad range of respiratory viruses in cell cultures, including SARS-CoV-2. Two phase 3 trials for prevention of COVID-19 are being initiated in high-risk populations, including elderly residents of long-term care facilities and healthcare workers. In addition to the prevention studies, a third trial for early treatment of COVID-19 is planned. ^{[46, 47]}  Another multicenter, randomized, double-blind phase 3 study was initiated in August 2020 for treatment of people aged 12 years and older with fever and respiratory symptoms consistent with COVID-19. Efficacy analyses will examine those participants who have laboratory-confirmed SARS-CoV-2 infection. ^[48]

Ivermectin

Ivermectin, an antiparasitic drug, showed in vitro reduction of viral RNA in Vero-hSLAM cells 2 hours postinfection with SARS-CoV-2 clinical isolate Australia/VIC01/2020. ^[49] The authors note that this preliminary study does not translate to human use and the effective dose is not established at this early stage of discovery. More research is needed to determine if an antiviral effect would be elicited in humans, as the concentrations tested were much higher than what is achieved from the normal oral dose.

Available pharmacokinetic data from clinically relevant and excessive dosing studies indicate that the SARS-CoV-2 inhibitory concentrations for ivermectin are not likely attainable in humans. ^[50]

Chaccour et al believe the recent findings regarding ivermectin warrant rapid implementation of controlled clinical trials to assess efficacy against COVID-19. They also raise concerns regarding ivermectin-associated neurotoxicity, particularly in patients with a hyperinflammatory state possible with COVID-19. In addition, drug interactions with potent CYP3A4 inhibitors (eg, ritonavir) warrant careful consideration of coadministered drugs. Finally, evidence suggests that ivermectin plasma levels with meaningful activity against COVID-19 would not be achieved without potentially toxic increases in ivermectin doses in humans. More data are needed to assess pulmonary tissue levels in humans. ^[51]

A retrospective cohort study (n = 280) in hospitalized patients with confirmed SARS-CoV-2 infection at four Florida hospitals showed significantly lower mortality rates in those who received ivermectin compared with usual care (15% vs 25.2%; P = 0.03). The mortality rate was also lower among 75 patients with severe pulmonary disease treated with ivermectin (38.8% vs 80.7%; P = 0.001), although the rate of successful extubation did not differ significantly. ^[52]

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

Oral antiviral in phase 2 trial in combination with remdesivir initiated in June 2020. The mechanism of merimepodib is believed to be inhibition of inosine-5’-monophosphate dehydrogenase (IMPDH), leading to a depletion of guanosine for use by the viral polymerase during replication.

Various methods of immunomodulation are being quickly examined, mostly by repurposing existing drugs, in order to blunt the hyperinflammation caused by cytokine release. Interleukin (IL) inhibitors, Janus kinase inhibitors, and interferons are just a few of the drugs that are in clinical trials. Ingraham et al provide a thorough explanation and diagram of the SARS-CoV-2 inflammatory pathway and potential therapeutic targets. ^[77]

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

Interleukin-6 inhibitors

IL-6 is a pleiotropic proinflammatory cytokine produced by various cell types, including lymphocytes, monocytes, and fibroblasts. SARS-CoV-2 infection induces a dose-dependent production of IL-6 from bronchial epithelial cells. This cascade of events is the rationale for studying IL-6 inhibitors. ^[78] As of June 2020, the NIH guidelines note insufficient data to recommend for or against use of IL-6 inhibitors. ^[79]

On March 16, 2020, Sanofi and Regeneron announced initiation of a phase 2/3 trial of the IL-6 inhibitor sarilumab (Kevzara). The United States–based component of the trial will be initiated in New York. The multicenter, double-blind, phase 2/3 trial has an adaptive design with two parts and is anticipated to enroll up to 400 patients. The first part will recruit patients with severe COVID-19 infection across approximately 16 US sites, and will evaluate the effect of sarilumab on fever and the need for supplemental oxygen. The second, larger, part of the trial will evaluate improvement in longer-term outcomes, including preventing death and reducing the need for mechanical ventilation, supplemental oxygen, and/or hospitalization. ^[80]

Based on the phase 2 trial analysis, the ongoing phase 3 design was modified on April 27, 2020, to include only higher-dose sarilumab (400 mg) or placebo in critical patients (ie, requiring mechanical ventilation or high-flow oxygenation or ICU admission). Minor positive trends were observed in the primary prespecified analysis group (n = 194; critical patients on sarilumab 400 mg who were mechanically ventilated at baseline) that did not reach statistical significance, and these were countered by negative trends in a subgroup of critical patients who were not mechanically ventilated at baseline. ^[81] Based on the results, the US-based trial was stopped, including in a second cohort of patients who received a higher dose (800 mg). ^[82]

Another IL-6 inhibitor, tocilizumab (Actemra), is part of several randomized, double-blind, placebo-controlled phase 3 clinical trials (REMDACTA, COVACTA, EMPACTA) to evaluate the safety and efficacy of tocilizumab plus standard of care in hospitalized adult patients with severe COVID-19 pneumonia compared to placebo plus standard of care. Results from the COVACTA trial were released in July 2020, announcing that the trial did not meet its primary endpoint of improved clinical status in patients with COVID-19–associated pneumonia or the secondary endpoint of reduced patient mortality. The trial did show a positive trend in time to hospital discharge among patients who received tocilizumab. ^[83]

An observational study of consecutive patients (n=239) at Yale (New Haven, CT) with severe COVID-19 disease were treated with a standardized algorithm that included tocilizumab to treat cytokine release syndrome. These early observations showed despite a surge of hospitalizations, tocilizumab-treated patients (n = 153) comprised 90% of those with severe disease, but their survival was similar to that of patients with nonsevere disease (83% vs 91%; p = 0.11). For tocilizumab-treated patients requiring mechanical 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 use study (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 with COVID-19 requiring mechanical ventilation. Tocilizumab was associated with a 45% reduction in hazard of death (hazard ratio 0.55 [95% CI 0.33, 0.90]) and improved status on the ordinal outcome scale (odds ratio per one-level increase: 0.59 [0.36, 0.95]). Tocilizumab was associated with an increased incidence of superinfections (54% vs 26%; P< 0.001); however, there was no difference in 28-day case fatality rate among tocilizumab-treated patients with superinfection versus those without superinfection (22% vs 15%; P = 0.42). ^[86]

An observational study in New Jersey showed an improved survival rate among patients who received tocilizumab. Among 547 ICU patients, including 134 receiving tocilizumab in the ICU, an exploratory analysis found a trend toward an improved survival rate of 56% who received tocilizumab compared with 46% who did not receive the therapy and a propensity adjusted hazard ratio of 0.76. ^[87]

A retrospective, observational cohort study in tertiary care centers in Bologna, Reggio Emilia, and Modena, Italy, between February 21 and March 24, 2020, concluded that tocilizumab may reduce the risk of invasive mechanical ventilation or death in patients with severe COVID-19 pneumonia. Of 1351 patients admitted, 544 (40%) had severe COVID-19 pneumonia and were included in the study. Fifty-seven (16%) of 365 patients in the standard care group needed mechanical ventilation compared with 33 (18%) of 179 patients treated with tocilizumab (P = 0.41; 16 [18%] of 88 patients treated IV and 17 [19%] of 91 patients treated SC). Seventy-three (20%) patients in the standard care group died, compared with 13 (7%; P< 0.0001) patients treated with tocilizumab (6 [7%] treated IV and 7 [8%] treated SC). ^[88]

However, another Italian study was halted after enrolling 126 patients with COVID-19 pneumonia, about one-third of the intended number, because the interim analysis showed it did not reduce severe respiratory symptoms, intensive care, or death compared with standard care. ^[89]

An open label, non-controlled, non–peer reviewed study was conducted in China in 21 patients with severe respiratory symptoms related to COVID-19. All had a confirmatory diagnosis of SARS-CoV-2 infection. The patients in the trial had a mean age of 56.8 years (18 of 21 were male). Although all patients met enrollment criteria of (1) respiratory rate of 30 breaths/min or more, (2) SpO₂ of 93% or less, and (3) PaO₂/FiO₂ of 300 mm Hg or less, only two of the patients required invasive ventilation. The other 19 patients received various forms of oxygen delivery, including nasal cannula, mask, high-flow oxygen, and noninvasive ventilation. All patients received standard of care, including lopinavir and methylprednisolone. Patients received a single dose of 400 mg tocilizumab via intravenous infusion. In general, the patients improved with lower oxygen requirements, lymphocyte counts returned to normal, and 19 patients were discharged with a mean of 15.5 days after tocilizumab treatment. The authors concluded that tocilizumab was an effective treatment in patients with severe COVID-19. ^[90]

A retrospective review of 25 patients with confirmed severe COVID-19 who received tocilizumab plus investigational antivirals showed patients who received tocilizumab experienced a decline in inflammatory markers, radiological improvement, and reduced ventilatory support requirements. The authors acknowledged the study’s limitations and the need for adequately powered randomized controlled trials of tocilizumab. ^[91]

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

Another anti-interleukin-6 receptor monoclonal antibody (TZLS-501; Tiziana Life Sciences and Novimmune) is currently under development. ^[92]

Interleukin-1 inhibitors

Endogenous IL-1 levels are elevated in individuals with COVID-19 and other conditions, such as severe CAR-T-cell–mediated cytokine-release syndrome. Anakinra has been used off-label for this indication. As of June 2020, the NIH guidelines note insufficient data to recommend for or against use of IL-1 inhibitors. ^[93]

Several studies involving the IL-1 inhibitor anakinra (Kineret) have emerged. A retrospective study in Italy looked at patients with COVID-19 and moderate-to-severe ARDS who were managed with noninvasive ventilation outside of the ICU. The study compared outcomes of patients who received anakinra (5 mg/kg IV BID [high-dose] or 100 mg SC BID [low-dose]) plus standard treatment (ie, hydroxychloroquine 200 mg PO BID and lopinavir/ritonavir 400 mg/100 mg PO BID) with standard of care alone. At 21 days, treatment with high-dose anakinra was associated with reductions in serum C-reactive protein levels and progressive improvements in respiratory function in 21 (72%) of 29 patients; 5 (17%) patients were on mechanical ventilation and 3 (10%) died. In the standard treatment group, 8 (50%) of 16 patients showed respiratory improvement at 21 days; 1 (6%) patient was on mechanical ventilation and 7 (44%) died. At 21 days, survival was 90% in the high-dose anakinra group and 56% in the standard treatment group (P = 0.009). ^[94]

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

Drugs that target numb-associated kinase (NAK) may mitigate systemic and alveolar inflammation in patients with COVID-19 pneumonia by inhibiting essential cytokine signaling involved in immune-mediated inflammatory response. In particular, NAK inhibition has been shown to reduce viral infection in vitro. ACE2 receptors are a point of cellular entry by COVID-19, which is then expressed in lung AT2 alveolar epithelial cells. A known regulator of endocytosis is the AP2-associated protein kinase-1 (AAK1). The ability to disrupt AAK1 may interrupt intracellular entry of the virus. Baricitinib (Olumiant; Eli Lilly Co), a Janus kinase (JAK) inhibitor, is also identified as a NAK inhibitor with a particularly high affinity for AAK1. ^{[96, 97, 98]}

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. ^[99]

Other selective JAK inhibitors (ie, fedratinib, ruxolitinib) may be effective against consequences of elevated cytokines, although baricitinib has the highest affinity for AAK1. ^[96]

Baricitinib is being studied as part of the NIAID Adaptive Covid-19 Treatment Trial, which evaluated the combination of baricitinib and remdesivir compared with remdesivir alone. ^[100]  Another phase 3, placebo-controlled trial is studying baricitinib in hospitalized patients who have an elevated level of at least one inflammation marker but do not require invasive mechanical ventilation at study entry. ^[101]

A small open-labeled study (n = 12) conducted in Italy added baricitinib 4 mg/day to existing therapies (ie, lopinavir/ritonavir 250 mg BID and hydroxychloroquine 400 mg/day). All therapies were given for 2 weeks. Fever, SpO₂, PaO₂/FiO₂, C-reactive protein, and modified early warning scores significantly improved in the baricitinib-treated group compared with controls (P: 0.000; 0.000; 0.017; 0.023; 0.016, respectively). ICU transfer occurred in 33% (4/12) of controls and in none of the baricitinib-treated patients (P = 0.093). Discharge at week 2 occurred in 58% (7/12) of the baricitinib-treated patients compared with 8% (1/12) of controls (P = 0.027). ^[102]

Ruxolitinib (Jakafi; Incyte) is part of the phase 3 RUXCOVID clinical trial. ^[103]

Pacritinib (CTI Biopharma) is a JAK2, interleukin-1 receptor-associated kinase-1 (IRAK-1), and colony stimulating factor-1 receptor (CSF-1R) inhibitor that is pending FDA approval for myelofibrosis. The phase 3 PRE-VENT trial has commenced to compare pacritinib with standard of care. Outcomes assessed include progression to mechanical ventilation, ECMO, or death in hospitalized patients with severe COVID-19, including those with cancer. As a JAK2/IRAK-1 inhibitor, pacritinib may ameliorate the effects of cytokine storm via inhibition of IL-6 and IL-1 signaling. Furthermore, as a CSF-1R inhibitor, pacritinib may mitigate effects of macrophage activation syndrome. ^[104]

The UK RECOVERY trial assessed the mortality rate at day 28 in hospitalized patients with COVID-19 who received low-dose dexamethasone 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 1110 patients (25.7%) in the usual care group died within 28 days after randomization (P< 0.001). In the dexamethasone group, the incidence of death was lower than the usual care group among patients receiving invasive mechanical ventilation (29.3% vs 41.4%) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs 26.2%), but not among those who were receiving no respiratory support at randomization (17.8% vs 14%). ^[105]

Corticosteroids are not generally recommended for treatment of viral pneumonia. ^[106] The benefit of corticosteroids in septic shock results from tempering the host immune response to bacterial toxin release. The incidence of shock in patients with COVID-19 is relatively low (5% of cases). It is more likely to produce cardiogenic shock from increased work of the heart need to distribute oxygenated blood supply and thoracic pressure from ventilation. Corticosteroids can induce harm through immunosuppressant effects during the treatment of infection and have failed to provide a benefit in other viral epidemics, such as respiratory syncytial virus (RSV) infection, influenza infection, SARS, and MERS. ^[107]

Early guidelines for management of critically ill adults with COVID-19 specified when to use low-dose corticosteroids and when to refrain from using corticosteroids. The recommendations depended on the precise clinical situation (eg, refractory shock, mechanically ventilated patients with ARDS); however, these particular recommendations were based on evidence listed as weak. ^[108] The results from the RECOVERY trial in June 2020 provided evidence for clinicians to consider when low-dose corticosteroids would be beneficial. ^[105]

A study describing clinical outcomes of patients diagnosed with COVID-19 was conducted in Wuhan China (N = 201). Eighty-four patients (41.8%) developed ARDS, and of those, 44 (52.4%) died. Among patients with ARDS, treatment with methylprednisolone decreased the risk of death (HR, 0.38; 95% CI, 0.20-0.72). ^[109]

Researchers at Henry Ford Hospital in Detroit implemented a protocol on March 20, 2020, using early, short-course, methylprednisolone 0.5-1 mg/kg/day divided in 2 IV doses for 3 days in patients with moderate-to-severe COVID-19. Outcomes of pre- and post-corticosteroid groups were evaluated. A composite endpoint of escalation of care from ward to ICU, new requirement for mechanical ventilation, or mortality was the primary outcome measure. All patients had at least 14 days of follow-up. They analyzed 213 eligible patients, 81 (38%) and 132 (62%) in pre-and post-corticosteroid groups, respectively. The composite endpoint occurred at a significantly lower rate in the post-corticosteroid group than in the pre-corticosteroid group (34.9% vs 54.3%; P = 0.005). This treatment effect was observed within each individual component of the composite endpoint. A significant reduction in median hospital length of stay was observed in the post-corticosteroid group (8 vs 5 days; P< 0.001). ^[110]

A study in the Netherlands showed a 5-day course of high-dose corticosteroids accelerated respiratory recovery, lowered hospital mortality rates, and reduced the likelihood of mechanical ventilation in patients with severe COVID-19–associated cytokine storm syndrome compared with historical controls. Forty-three percent of patients also received tocilizumab. ^[111]

A retrospective study at Montefiore Hospital in the Bronx borough of New York was conducted to evaluate if early glucocorticoid treatment (ie, within 48 hours of admission) reduced mortality rates or the need for mechanical ventilation in hospitalized patients with COVID-19. Of the 1,806 patients included in the study, 140 (7.7%) were treated with glucocorticoids, and 1,666 patients never received glucocorticoids. A key finding of this analysis is the need to verify which patients should receive glucocorticoid treatment. Glucocorticoid use in patients with initial C-reactive protein (CRP) levels of 20 mg/dL or greater was associated with significantly reduced risk of mortality or mechanical ventilation (OR, 0.23; 95% CI, 0.08-0.70), while use in patients with a CRP level of less than 10 mg/dL was associated with significantly increased risk of mortality or mechanical ventilation (OR, 2.64; 95% CI, 1.39-5.03). ^[112]  For further information regarding administration, see the EUA COVID-19 Convalescent Fact Sheet for Health Care Provider.

The FDA granted emergency use authorization (EUA) on August 23, 2020 for use of convalescent plasma in hospitalized patients with COVID-19. Convalescent plasma contains antibody-rich plasma products collected from eligible donors who have recovered from COVID-19. An expanded access program (EAP) for convalescent plasma was initiated in early April 2020. ^{[6, 113]}  The Mayo Clinic coordinated the open-access COVID-19 expanded access program, but will discontinue enrollment on August 28, as the FDA authorizes emergency use. 

Additionally, the CoVIg-19 Plasma Alliance [link https://www.covig-19plasmaalliance.org/en-us#recruitment] is a partnership of numerous pharmaceutical companies who are collecting, developing, producing, and distributing immunoglobulin from patients with confirmed COVID-19 infection who have recovered.

Preliminary data from an open-label, multicenter, expanded access program in hospitalized adults conducted by the Mayo Clinic observed a gradient mortality in relation to IgG antibody levels in transfused ABO-compatible human COVID-19 convalescent plasma. The study analysis is from 2,807 acute care facilities in the US and territories and 5000 participants. The 35,322 transfused patients had heterogeneous demographic and clinical characteristics. This cohort included a high proportion of critically-ill patients, with 52.3% in the ICU and 27.5% receiving mechanical ventilation at the time of plasma transfusion. The 7-day mortality rate in patients who received a high-antibody product was 8.7% in patients transfused within 3 days of COVID-19 diagnosis compared with 11.9% patients transfused 4 or more days after diagnosis (p < 0.001). Similar findings were observed in 30-day mortality (21.6% vs. 26.7%, p < 0.0001). Importantly, a gradient of mortality was seen in relation to IgG antibody levels in the transfused plasma – the pooled relative risk of mortality among patients transfused with high antibody level plasma units was 0.65 [0.47-0.92] for 7 days and 0.77 [0.63-0.94] for 30 days compared with to low antibody level plasma units. The authors note this information may be informative for the treatment of COVID-19 and design of randomized clinical trials involving convalescent plasma. ^[114]  The incidence of serious adverse events, including mortality rate (0.3%) within the first 4 hours after transfusion was < 1%. ^[115]  

Similar observations were published from a study at Houston Methodist Hospital.  Of the 316 transfused patients, 136 met a 28-day outcome and were matched to 251 nontransfused control patients with COVID-19. Matching criteria included age, sex, BMI, comorbidities, and baseline ventilation requirement 48 hours from admission, and in a second matching analysis, ventilation status at Day 0. Variability in the timing of transfusion relative to admission and titer of antibodies of plasma transfused allowed for analysis in specific matched cohorts. The analysis showed a significant reduction (P = 0.047) in mortality within 28 days in patients transfused within 72 hours of admission with plasma that measured an anti-spike protein receptor binding domain titer of 1:1350 or greater. ^[116]

The use of convalescent plasma has a long history in the treatment of infectious diseases. Writing in the Journal of Clinical Investigation Casadevall and Pirofski ^[117]  proposed using it as a treatment for COVID-19, and Bloch et al ^[118]  laid out a conceptual framework for implementation. Two small case series reported improvement in oxygenation, sequential organ failure assessment (SOFA) scores, and eventual ventilator weaning in some patients. The timelines of improvement varied from days to weeks. Caution is advised, as these were not controlled trials and other pharmacologic methods (antivirals) were used in some patients. ^{[119, 120]}  

A Cochrane review of convalescent plasma use in patients with COVID-19 is perpetually being updated as data emerge. As of July 10, 2020, the review included 20 studies with 5443 participants, of whom 5211 received convalescent plasma. Among these studies was one randomized controlled trial with 103 participants (52 received convalescent plasma). At the time of publication, the authors expressed uncertainty as to the benefits of convalescent plasma in terms of affecting mortality at hospital discharge, prolonging time to death, or improving clinical symptoms at 7 or 28 days. ^[121]

A meta-analysis of 15 controlled studies showed a significantly lower mortality rate in patients with COVID-19 who received convalescent plasma compared with control groups. However, the authors point out that the studies were mostly of low or very low quality with a moderate or high risk of bias. ^[122]

An open-label study (n = 103) of patients with laboratory-confirmed COVID-19 in Wuhan, China, given convalescent plasma did not result in a statistically significant improvement in time to clinical improvement within 28 days compared with standard of care alone. ^[123]

A nonrandomized study transfused patients based on supplemental oxygen needs with convalescent plasma from donors with a SARS-CoV-2 anti-spike antibody titer of at least 1:320 dilution. Matched control patients were retrospectively identified within the electronic health record database. Supplemental oxygen requirements and survival were compared between plasma recipients and controls. Results showed convalescent plasma transfusion improved survival in nonintubated patients (P = 0.015), but not in intubated patients (P = 0.752). ^[124]

Laboratory studies suggest normal interferon response is suppressed in some people infected with SARS-CoV-2. In the laboratory, type 1 interferon can inhibit SARS-CoV-2 and two closely related viruses, SARS-CoV and MERS-CoV. ^[125]

The third iteration of the NIAID’s Adaptive COVID-19 Treatment Trial (ACTT-3) commenced in August 2020 to compare subcutaneous interferon beta-1a (Rebif) plus remdesivir versus remdesivir plus placebo. The ACTT-3 trial anticipates enrolling over 1000 patients in up to 100 sites across the United States. ^[126]

Nitric oxide

Published findings from the 2004 SARS-CoV infection suggest the potential role of inhaled nitric oxide (iNO; Mallinckrodt Pharmaceuticals, plc) as a supportive measure for treating infection in patients with pulmonary complications. Treatment with iNO reversed pulmonary hypertension, improved severe hypoxia, and shortened the length of ventilatory support compared with matched control patients with SARS. ^[127]

A phase 3 study (PULSE-CVD19-001) for iNO (INOpulse; Bellerophon Therapeutics) was accepted by the FDA in mid-March 2020 to evaluate efficacy and safety in patients diagnosed with COVID-19 who require supplemental oxygen before the disease progresses to necessitate mechanical ventilation support. ^[128] The Society of Critical Care Medicine recommends against the routine use of iNO in patients with COVID-19 pneumonia. Instead, they suggest a trial only in mechanically ventilated patients with severe ARDS and hypoxemia despite other rescue strategies. ^[90] 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 inflammatory processes of atherosclerosis. ^[129] Because of this, questions have arisen whether statins may be beneficial to reduce inflammation associated with COVID-19.

This question has been posed before with studies of patients taking statins who have acute viral infections. Virani ^[130] provides a brief summary of information regarding observational and randomized controlled trials (RCTs) of statins and viral infections. Some, but not all, observational studies suggest that cardiovascular outcomes were reduced in patients taking statins who were hospitalized with influenza and/or pneumonia. RCTs of statins as anti-inflammatory agents for viral infections are limited, and results have been mixed. An important factor that Virani points out regarding COVID-19 is that no harm was associated with statin therapy in previous trials of statins and viral infections, emphasizing that patients should adhere to their statin regimen.

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. ^[131]

Zinc

A retrospective analysis showed lack of a causal association between zinc and survival in hospitalized patients with COVID-19. ^[132]

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

Calcium release-activated calcium (CRAC) channel inhibitor that prevents CRAC channel overactivation, which can cause pulmonary endothelial damage and cytokine storm. Results in mid-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 severe COVID-19 pneumonia, showing faster recovery (5 days vs 12 days), reduced use of invasive mechanical ventilation (18% vs 50%), and improved mortality rate (10% vs 20%) compared with standard of care alone. Part 2 of this trial will start late summer and will be a placebo-controlled trial, possibly including both remdesivir and dexamethasone.

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

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

VIR-7831 and VIR-7832 are mAbs that bind to an epitope on SARS-CoV-2. The epitope is also on SARS-CoV-1, indicating the epitope is highly conserved and more difficult to mutate. Each of the monoclonal antibodies are engineered to have an extended half-life.

Antibody treatment from more than 500 unique antibodies isolated from one of the first US patients to recover from COVID-19. Phase 1 study in hospitalized patients initiated in June 2020. A phase 2 study (BLAZE-1) in people recently diagnosed with COVID-19 in the ambulatory setting is ongoing. A phase 3 trial (BLAZE-2) announced in August 2020 by NIAID is planned for prevention of SARS-CoV-2 infection in residents and staff at long-term care facilities in the United States.

The genetic sequence of SARS-CoV-2 was published on January 11, 2020. A rapid emergence of research and collaboration among scientists and biopharmaceutical manufacturers followed. As of late August 2020, The New York Times Coronavirus Vaccine Tracker lists more than 165 vaccines against coronavirus are in development, and 32 vaccines are in human trials. ^[227]  

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

Thanh Le et al describe platforms based on DNA or mRNA that offer flexibility regarding antigen manipulation and speed of development. Recombinant protein-based development may be beneficial owing to existing large-scale production capabilities. Use of an adjuvant can be of particular importance in a pandemic situation. Adjuvants are compounds that potentiate that antigen in the vaccine, thereby reducing the amount of antigen protein required per dose. This method allows more people to be vaccinated and conserves antigen resources. ^[228]

mRNA-1273

mRNA-1273 (Moderna Inc) encodes the S-2P antigen. The phase 1 study, a dose-escalation trial, was initiated in 45 healthy volunteers aged 18-55 years on March 16, 2020 at Kaiser Permanente Washington Health Research Instituted in Seattle and at the Emory University School of Medicine in Atlanta. Three doses—25, 100, and 250 mcg—were administered on a 2-dose schedule given 28 days apart. After the second vaccination, serum-neutralizing activity was detected via 2 methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. 

Phase 2 testing of placebo, 50-mcg, or 100-mcg given as 2 doses 28 days apart in adults aged 18-55 years (n=300) and in adults aged 55 years or older (n=50) was completed in June. US phase 3 trial (COVE) launched July 27, 2020, in cooperation with NIAID and will include about 30,000 participants who will receive two 100-mcg doses on days 1 and 29 or matched placebo. ^{[229, 230]}

mRNA vaccine BNT162b2

Nucleoside-modified messenger RNA (modRNA) vaccine (BioNTech and Pfizer) that encodes an optimized SARS-CoV-2 receptor-binding domain (RBD) antigen. Human testing was initiated in early May 2020. Preliminary results from the phase 1/2 trial showed the vaccine (BNT162b1) could be administered in a 2-dose series that was well tolerated and that generated dose-dependent immunogenicity as measured by RBD-binding IgG concentrations and SARS-CoV-2 neutralizing antibody titers. All subjects in the prime-boost cohorts, except for 2 at the lowest dose level, had CD4+ T-cell responses. The phase 2b/3 trial launched in late July 2020 with BNT162b2 vaccine (one of four mRNA constructs under clinically evaluation). BNT162b2 emerged as the candidate with fewer adverse effects (eg, fevers, fatigue) and it elicited T-cell responses against the RBD, which may generate more a consistent response across diverse populations, including older individuals. ^{[231, 232, 233]}

AZD1222

Following immunization with AZD1222 (ChAdOx1 nCoV-19; AstraZeneca, University of Oxford), production of the surface spiked protein ensues. This primes the immune system to attack the SARS-CoV-2 virus if it later infects the body. Because of testing of a different coronavirus vaccine last year, development for this vaccine has accelerated. Phase 1/2 testing enrolled 1077 participants and showed neutralizing antibody responses in 91% after a single dose and 100% after a booster dose in those tested. T-cell response peaked at Day 14 and were boosted by the second dose. ^[234] As of late August 2020, the vaccine is in Phase 2/3 clinical trials in England and India, and phase 3 trials in Brazil, South Africa, and the US. 

Other examples of vaccines under development are included in Table 5.

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

Adenovirus serotype 26 (Ad26) vector-based vaccine. Preclinical trials showed a single dose elicited neutralizing antibodies and successfully prevented subsequent infection in nonhuman primates. Phase 1/2a testing in healthy volunteers initiating in late July 2020 in Belgium, the United States, Netherlands, Spain, Germany, and Japan. Phase 3 trial expected to commence in September 2020.

Contains an adjuvant that stimulates the entry of antigen-presenting cells into the injection site and enhances antigen presentation in local lymph nodes to boost the immune response. Phase 1/2 trials were initiated in May 2020. Phase 1 data in health adults showed the vaccine induced neutralization titers in 100% of participants. A phase 2 trial began in South Africa mid-August 2020. Phase 3 trials expected to start in October 2020.  

The phase 1 human clinical trial enrolled 40 healthy volunteers was complete late April 2020. Favorable interim results of safety and immunogenicity were reported in June. The phase 1 trial was expanded to include older participants and Phase 2/3 efficacy trials are planned to commence by the end of summer 2020. Inovio has received a grant from the Bill and Melinda Gates Foundation to accelerate testing and scale up a smart device (Cellectra 3PSP) for large-scale intradermal vaccine delivery.

SARS-CoV-2 is known to utilize angiotensin-converting enzyme 2 (ACE2) receptors for entry into target cells. ^[262] Data are limited concerning whether to continue or discontinue drugs that inhibit the renin-angiotensin-aldosterone system (RAAS), namely angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs).

Concern arose regarding appropriateness of continuation of ACEIs and ARBs in patients with COVID-19 after early reports noted an association between disease severity and comorbidities such as hypertension, cardiovascular disease, and diabetes, which are often treated with ACEIs and ARBs. The reason for this association remains unclear. ^{[263, 264]}

The speculated mechanism for detrimental effect of ACEIs and ARBs is related to ACE2. It was therefore hypothesized that any agent that increases expression of ACE2 could potentially increase susceptibility to severe COVID-19 by improving viral cellular entry; ^[263] however, physiologically, ACE2 also converts angiotensin 2 to angiotensin 1-7, which leads to vasodilation and may protect against lung injury by lowering angiotensin 2 receptor binding. ^{[264, 265]} It is therefore uncertain whether an increased expression of ACE2 receptors would worsen or mitigate the effects of SARS-CoV-2 in human lungs.

Vaduganathan et al note that data in humans are limited, so it is difficult to support or negate the opposing theories regarding RAAS inhibitors. They offer an alternate hypothesis that ACE2 may be beneficial rather than harmful in patients with lung injury. As mentioned, ACE2 acts as a counterregulatory enzyme that degrades angiotensin 2 to angiotensin 1-7. SARS-CoV-2 not only appears to gain initial entry through ACE2 but also down-regulates ACE2 expression, possibly mitigating the counterregulatory effects of ACE2. ^[266]

There are also conflicting data regarding whether ACEIs and ARBs increase ACE2 levels. Some studies in animals have suggested that ACEIs and ARBs increase expression of ACE2, ^{[267, 268, 269]} while other studies have not shown this effect. ^{[270, 271]}

As controversy remains regarding whether ACEIs and/or ARBs increase ACE2 expression and how this effect may influence outcomes in patients with COVID-19, cardiology societies have largely recommended against initiating or discontinuing these medications based solely on active SARS-CoV-2 infection. ^{[272, 273]}

Two clinical trials are currently in development at the University of Minnesota evaluating the use of losartan in patients with COVID-19 in inpatient and outpatient settings. ^{[274, 275]} Results from these trials will provide insight into the potential role of ARBs in the treatment of COVID-19.

High plasma glucose levels and diabetes mellitus (DM) are known risk factors for pneumonia. ^{[276, 277]} Potential mechanisms that may increase the susceptibility for COVID-19 in patients with DM include the following: ^[278]

SARS-CoV-2 is known to utilize angiotensin-converting enzyme 2 (ACE2) receptors ^[262] for entry into target cells. Insulin administration attenuates ACE2 expression, while hypoglycemic agents (eg, glucagonlike peptide 1 [GLP-1] agonists, thiazolidinediones) up-regulate ACE2. ^[278] Dipeptidyl peptidase 4 (DPP-4) is highly involved in glucose and insulin metabolism, as well as in immune regulation. This protein was shown to be a functional receptor for Middle East respiratory syndrome coronavirus (MERS-CoV), and protein modeling suggests that it may play a similar role with SARS-CoV-2, the virus responsible for COVID-19. ^[279]

The relationship between diabetes, coronavirus infections, ACE2, and DPP-4 has been reviewed by Drucker. Important clinical conclusions of the review include the following: ^[277]

On June 15, 2020, the FDA revoked the emergency use authorization (EUA) for hydroxychloroquine and chloroquine donated to the Strategic National Stockpile to be used for treating certain hospitalized patients with COVID-19 when a clinical trial was unavailable or participation in a clinical trial was not feasible. ^[280]

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

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

Additionally, the NIH halted the Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease (ORCHID) study on June 20, 2020. After the fourth analysis that included more than 470 participants, the NIH data and safety monitoring board determined that while, there was no harm, the study drug was very unlikely to be beneficial to hospitalized patients with COVID-19. ^[281]

Hydroxychloroquine and chloroquine are widely used antimalarial drugs that elicit immunomodulatory effects and are therefore also used to treat autoimmune conditions (eg, systemic lupus erythematosus, rheumatoid arthritis). As inhibitors of heme polymerase, they are also believed to have additional antiviral activity via alkalinization of the phagolysosome, which inhibits the pH-dependent steps of viral replication. Wang et al reported that chloroquine effectively inhibits SARS-CoV-2 in vitro. ^[282] The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2–infected Vero cells. Physiologically based pharmacokinetic models (PBPK) were conducted for each drug. Hydroxychloroquine was found to be more potent than chloroquine in vitro. Based on PBPK models, the authors recommend a loading dose of hydroxychloroquine 400 mg PO BID, followed by 200 mg BID for 4 days. ^[108]

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

The UK RECOVERY Trial randomized 1542 patients to hydroxychloroquine and 3132 patients to usual care alone. Preliminary results found no significant difference in the primary endpoint of 28-day mortality (25.7% hydroxychloroquine vs 23.5% usual care; hazard ratio 1.11 [95% CI, 0.98-1.26]; P = 0.10). There was also no evidence of beneficial effects on hospital stay duration or other outcomes. ^[283]

A multicenter, randomized, open-label trial in Brazil found no improvement in 504 hospitalized patients with mild-to-moderate COVID-19. Use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days compared with standard care. Prolonged QTc interval and elevated liver-enzyme levels were more common in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent. ^[284]

An observational study of 2512 hospitalized patients in New Jersey with confirmed COVID-19 was conducted between March 1, 2020 and April 22, 2020, with follow-up through May 5, 2020. Outcomes included 547 deaths (22%) and 1539 (61%) discharges; 426 (17%) remained hospitalized. Patients who received at least one dose of hydroxychloroquine totaled 1914 (76%), and those who received hydroxychloroquine plus azithromycin totaled 1473 (59%). No significant differences were observed in associated mortality among patients receiving any hydroxychloroquine during the hospitalization (HR, 0.99 [95% CI, 0.80-1.22]), hydroxychloroquine alone (HR, 1.02 [95% CI, 0.83-1.27]), or hydroxychloroquine with azithromycin (HR, 0.98 [95% CI, 0.75-1.28]). The 30-day unadjusted mortality rate in patients receiving hydroxychloroquine alone, azithromycin alone, the combination, or neither drug was 25%, 20%, 18%, and 20%, respectively. ^[87]

Because of findings from the aforementioned studies, the WHO halted the hydroxychloroquine arm of the Solidarity Trial and then removed its use entirely as of July 4, 2020. ^[22] 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. ^{[280, 285]}

An observational study of consecutively hospitalized patients (n = 1446) at a large medical center in the New York City area showed hydroxychloroquine was not associated with either a greatly lowered or an increased risk of the composite endpoint of intubation or death. ^[286]

A retrospective observational study of 2,541 consecutive patients hospitalized with COVID at Henry Ford Health System from March 10, 2020, to May 2, 2020, showed a decreased mortality rate in patients treated with hydroxychloroquine alone or in combination with azithromycin. Overall in-hospital mortality was 18.1%; by treatment: hydroxychloroquine plus azithromycin, 157/783 (20.1%), hydroxychloroquine alone, 162/1202 (13.5%), azithromycin alone, 33/147 (22.4%), and neither drug, 108/409 (26.4%). Therapy with corticosteroids (methylprednisolone and/or prednisone) was administered in 68% of all patients. Corticosteroids were administered to 78.9% of patients who received hydroxychloroquine alone. In addition to adjunctive use of corticosteroids, an accompanying editorial discusses time bias, missing prognostic indicators, and other confounding factors of this observational study. ^{[287, 288]}

A retrospective analysis of data from patients hospitalized with confirmed COVID-19 infection in all US Veterans Health Administration medical centers between March 9, 2020, and April 11, 2020, has been published. Patients who had received hydroxychloroquine (HC) alone or with azithromycin (HC + AZ) as treatment in addition to standard supportive care were identified. A total of 368 patients were evaluated (HC n=97; HC + AZ n=113; no HC n=158). Death rates in the HC, HC + AZ, and no-HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC + AZ, and no-HC groups were 13.3%, 6.9%, 14.1%, respectively. The authors concluded that they found no evidence that hydroxychloroquine, with or without azithromycin, reduced the risk of mechanical ventilation and that the overall mortality rate was increased with hydroxychloroquine treatment. Furthermore, they stressed the importance of waiting for results of ongoing, prospective, randomized controlled trials before wide adoption of these drugs. ^[289]

A retrospective study assessed effects of hydroxychloroquine according to its plasma concentration in patient hospitalized in the ICU. The researchers compared 17 patients with hydroxychloroquine plasma concentrations within the therapeutic target and 12 patients with plasma concentrations below the target. At 15 days of follow-up, no association was found between hydroxychloroquine plasma concentration and viral load evolution (p = 0.77). Additionally, there was no significant difference between the 2 groups for duration of mechanical ventilation, length of ICU stays, in-hospital mortality, and 15-days mortality. ^[290]

According to a consensus statement from a multicenter collaboration group in China, chloroquine phosphate 500 mg (300 mg base) twice daily in tablet form for 10 days may be considered in patients with COVID-19 pneumonia. ^[291] While no peer-reviewed treatment outcomes are available, Gao and colleagues report that 100 patients have demonstrated significant improvement with this regimen without documented toxicity. ^[292] It should be noted this is 14 times the typical dose of chloroquine used per week for malaria prophylaxis and 4 times that used for treatment. Cardiac toxicity should temper enthusiasm for this as a widespread cure for COVID-19. It should also be noted that chloroquine was previously found to be active in vitro against multiple other viruses but has not proven fruitful in clinical trials, even resulting in worse clinical outcomes in human studies of Chikungunya virus infection (a virus unrelated to SARS-CoV-2).

A randomized controlled trial in Wuhan, China, enrolled 62 hospitalized patients (average age, 44.7 years) with confirmed COVID-19. Additional inclusion criteria included age 18 years or older, chest CT scans showing pneumonia, and SaO₂/SPOs ratio of more than 93% (or PaOs/FIOs ratio >300 mm Hg). Patients with severe or critical illness were excluded. All patients enrolled in the study received standard treatment (oxygen therapy, antiviral agents, antibacterial agents, and immunoglobulin, with or without corticosteroids). Thirty-one patients were randomized to receive hydroxychloroquine sulfate (200 mg PO BID for 5 days) in addition to standardized treatment. Changes in time to clinical recovery (TTCR) was evaluated and defined as return of normal body temperature and cough relief, maintained for more than 72 hours. Compared with the control group, TTCR for body temperature and cough were significantly shortened in the hydroxychloroquine group. Four of the 62 patients progressed to severe illness, all of whom were in the control group. ^[293]

The French have embraced hydroxychloroquine as a potentially more potent therapy with an improved safety profile to treat and prevent the spread of COVID-19. ^[294] If it is effective, the optimal regimen of hydroxychloroquine is not yet known, although some experts have recommended higher doses, such as 600-800 mg per day. A study of hydroxychloroquine for postexposure prophylaxis in healthcare workers or household contacts is underway. ^[295]

An open-label multicenter study using high-dose hydroxychloroquine or standard of care did not show a difference at 28 days for seronegative conversion or the rate of symptom alleviation between the two treatment arms. The trial was conducted in 150 patients in China with mild-to-moderate disease. ^[296]

Hydroxychloroquine plus azithromycin

Opposing conclusions by French researchers regarding viral clearance and clinical benefit with the regimen of hydroxychloroquine plus azithromycin have been published. ^{[297, 298, 299]}

A small prospective study found no evidence of a strong antiviral activity or clinical benefit from use of hydroxychloroquine plus azithromycin. Molina et al assessed virologic and clinical outcomes of 11 consecutive patients hospitalized who received hydroxychloroquine (600 mg per day x10 days) and azithromycin (500 mg Day 1, then 250 mg days 2-5). Patient demographics were as follows: 7 men and 4 women; mean age 58.7 years (range: 20-77); 8 had significant comorbidities associated with poor outcomes (ie, obesity 2; solid cancer 3; hematological cancer 2; HIV-infection 1). Ten of the eleven patients had fever and received oxygen via nasal cannula. Within 5 days, 1 patient died, 2 were transferred to the ICU. Hydroxychloroquine and azithromycin were discontinued in 1 patient owing to prolonged QT interval. Nasopharyngeal swabs remained positive for SARS-CoV-2 RNA in 8/10 patients (80%, 95% confidence interval: 49-94) at days 5-6 after treatment initiation. ^[299]

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 the analysis for having incomplete data, the 20 remaining patients receiving hydroxychloroquine (200 mg PO q8h) had improved nasopharyngeal clearance of the virus on day 6 (70% [14/20] vs 12.5% [2/16]). ^[297] This is an unusual approach to reporting results because the clinical correlation with nasopharyngeal clearance on day 6 is unknown and several patients changed status within a few days of that endpoint (converting from negative back to positive). The choice of that particular endpoint was also not explained by the authors, yet 4 of the 6 excluded patients had adverse outcomes (admission to ICU or death) at that time but were not counted in the analysis. Furthermore, patients who refused to consent to the study group were included in the control arm, indicating unorthodox study enrollment.

This small open-label study of hydroxychloroquine in France included azithromycin in 6 patients for potential bacterial superinfection (500 mg once, then 250 mg PO daily for 4 days). These patients were reported to have 100% clearance of SARS-CoV-2. While intriguing, these results warrant further analysis. The patients receiving combination therapy had initially lower viral loads, and, when compared with patients receiving hydroxychloroquine alone with similar viral burden, the results are fairly similar (6/6 vs 7/9). ^[297]

The French researchers continued their practice of using hydroxychloroquine plus azithromycin and accumulated data in 80 patients with at least 6 days of follow-up. They note that the 6 patients on combination therapy enrolled in their first analysis were also included in the present case series, with a longer follow-up. However, it was not clear from the description in their posted methods when patients were assessed. A favorable outcome was defined as not requiring aggressive oxygen therapy or transfer to the ICU after 3 days of treatment. Sixty-five of the 80 patients (81.3%) met this outcome. One patient aged 86 years died, and a 74-year-old patient remained in the ICU. Two others were transferred to the ICU and then back to the infection ward. Results showed a decrease in nasopharyngeal viral load tested via qPCR, with 83% negative at day 7 and 93% at day 8. Virus culture results from patient respiratory samples were negative in 97.5% patients at day 5. ^[298] This is described as a promising method of reducing spread of SARS-CoV-2, but, unfortunately, the study lacked a control group and did not compare treatment with hydroxychloroquine plus azithromycin to a similar group of patients receiving no drug therapy or hydroxychloroquine alone. Overall, the acuity of these patients was low, and 92% had a low score on the national Early Warning System used to assess risk of clinical deterioration. Only 15% were febrile, a common criterion for testing in the United States, and 4 individuals were considered asymptomatic carriers. In addition, the results did not delineate between asymptomatic carriers and those with high viral load or low viral load.

Nonhospitalized patients with early COVID-19

Hydroxychloroquine did not improve outcomes when administered to outpatient adults (n = 423) with early COVID-19. Change in 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) receiving placebo (P = 0.21). Medication adverse effects occurred in 43% (92 of 212) of participants receiving hydroxychloroquine compared with 22% (46 of 211) receiving placebo (P< 0.001). Among patients receiving placebo, 10 were hospitalized (two cases unrelated to COVID-19), one of whom died. Among patients receiving hydroxychloroquine, four were hospitalized and one nonhospitalized patient died (P = 0.29). ^[300]

Clinical trials evaluating prevention

Various clinical trials in the United States were initiated to determine if hydroxychloroquine reduces the rate of infection when used by individuals at high risk for exposure, such as high-risk healthcare workers, first responders, and individuals who share a home with a COVID-19–positive individual. ^{[295, 301, 302, 303, 304, 305, 306]}

Results from a double-blind randomized trial (n = 821) from the University of Minnesota found no benefit of hydroxychloroquine (n = 414) in preventing illness due to COVID-19 compared with placebo (n = 407) when used as postexposure prophylaxis in asymptomatic participants within 4 days following high-risk or moderate-risk exposure. Overall, 87.6% of participants had high-risk exposures without eye shields and surgical masks or respirators. New COVID-19 (either PCR-confirmed or symptomatically compatible) developed in 107 participants (13%) during the 14-day follow-up. Incidence of new illness compatible with COVID-19 did not differ significantly between those receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]) (P = 0.35). ^[307]

QT prolongation with hydroxychloroquine and azithromycin

Chloroquine, hydroxychloroquine, and azithromycin each carry the warning of QT prolongation and can be associated with an increased risk of cardiac death when used in a broader population. ^[308] Because of this risk, the American College of Cardiology, American Heart Association, and the Heart Rhythm Society have published a thorough discussion of the arrhythmogenicity of hydroxychloroquine and azithromycin that includes a suggested protocol for clinical research QT assessment and monitoring when the two drugs are coadministered. ^[309]

A Brazilian study comparing chloroquine high-dose (600 mg PO BID for 10 days) and low-dose (450 mg BID for 1 day, then 450 mg/day for 4 days) observed QT prolongation in 25% of patients in the high-dose group. All patients received other drugs (ie, azithromycin, oseltamivir) that may contribute to prolonged QT. ^[310]

An increased 30-day risk of cardiovascular mortality, chest pain/angina, and heart failure was observed with the addition of azithromycin to hydroxychloroquine from an analysis of pooled data from Japan, Europe, and the United States. The analysis compared use of hydroxychloroquine, sulfamethoxazole, or the combinations of hydroxychloroquine plus amoxicillin or hydroxychloroquine plus azithromycin. ^[311]

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

The NIH Panel for COVID-19 Treatment Guidelines recommend against the use of lopinavir/ritonavir or other HIV protease inhibitors, owing to unfavorable pharmacodynamics and because clinical trials have not demonstrated a clinical benefit in patients with COVID-19. ^[312]

The Infectious Diseases Society of America (IDSA) guidelines recommend use of lopinavir/ritonavir only in the context of a randomized clinical trial. The guidelines also mention the risk for severe cutaneous reactions, QT prolongation, and the potential for drug interactions owing to CYP3A inhibition. ^[11]

On June 29, 2020, analysis of the RECOVERY trial concluded no beneficial effect in hospitalized patients with COVID-19 who were randomized to receive lopinavir/ritonavir (n = 1596) compared with those who received standard care (n = 3376). Of these patients, 4% required invasive mechanical ventilation when they entered the trial, 70% required oxygen alone, and 26% did not require any respiratory intervention. No significant difference was observed in the 28-day mortality rate (22.1% lopinavir/ritonavir vs 21.3% standard care; relative risk 1.04 [95% CI, 0.91-1.18]; P = 0.58), and the results were consistent in different patient subgroups. No evidence was found for beneficial effects on the risk of progression to mechanical ventilation or length of hospital stay. ^[313]

The WHO discontinued use of lopinavir/ritonavir in the SOLIDARITY trial in hospitalized patients on July 4, 2020. ^[22]

In a randomized, controlled, open-label trial of hospitalized adults (n=199) with confirmed SARS-CoV-2 infection, recruited patients had an oxygen saturation of 94% or less on ambient air or PaO₂ of less than 300 mm Hg and were receiving a range of ventilatory support modes (eg, no support, mechanical ventilation, extracorporeal membrane oxygenation [ECMO]). These patients were randomized to receive lopinavir/ritonavir 400 mg/100 mg PO BID for 14 days added to standard care (n=99) or standard care alone (n=100). Results showed that time to clinical improvement did not differ between the two groups (median, 16 days). The mortality rate at 28 days was numerically lower for lopinavir/ritonavir compared with standard care (19.2% vs 25%) but did not reach statistical significance. ^[314] An editorial accompanies this study that is informative in regard to the extraordinary circumstances of conducting such a study in the midst of the outbreak. ^[315]

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. ^[65]

A multicenter study in Hong Kong compared 14 days of triple therapy (n = 86) (lopinavir/ritonavir [400 mg/100 mg q12h], ribavirin [400 mg q12h], interferon beta1b [8 million IU x 3 doses q48h]) with lopinavir/ritonavir alone (n = 41). Results showed that triple therapy significantly shortened the duration of viral shedding and hospital stay in patients with mild-to-moderate COVID-19. ^[316]

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

Chloroquine, hydroxychloroquine, and azithromycin each carry the warning of QT prolongation and can be associated with an increased risk of cardiac death when used in a broader population. ^[308] Because of this risk, the American College of Cardiology, American Heart Association, and the Heart Rhythm Society have published a thorough discussion on the arrhythmogenicity of hydroxychloroquine and azithromycin, including a suggested protocol for clinical research QT assessment and monitoring when the two drugs are coadministered. ^{[309, 317]}

Giudicessi et al have published guidance for evaluating the torsadogenic potential of chloroquine, hydroxychloroquine, lopinavir/ritonavir, and azithromycin. Chloroquine and hydroxychloroquine block the potassium channel, specifically KCNH2-encoded HERG/Kv11.1. Additional modifiable risk factors (eg, treatment duration, other QT-prolonging drugs, hypocalcemia, hypokalemia, hypomagnesemia) and nonmodifiable risk factors (eg, acute coronary syndrome, renal failure, congenital long QT syndrome, hypoglycemia, female sex, age ≥65 years) for QT prolongation may further increase the risk. Some of the modifiable and nonmodifiable risk factors may be caused by or exacerbated by severe illness. ^[318]

A retrospective study was performed by reviewing 84 consecutive adult patients who were hospitalized at NYU Langone Medical Center with COVID-19 and treated with hydroxychloroquine plus azithromycin. QTc increased by greater than 40 ms in 30% of patients. In 11% of patients, QTc increased to more than 500 ms, which is considered a high risk for arrhythmia. The researcher noted that development of acute renal failure, but not baseline QTc, was a strong predictor of extreme QTc prolongation. ^[319]

A cohort study was performed from March 1 through April 7, 2020, at an academic tertiary care center in Boston to characterize the risk and degree of QT prolongation in patients with COVID-19 who received hydroxychloroquine, with or without azithromycin. Among 90 patients given hydroxychloroquine, 53 received concomitant azithromycin. Seven patients (19%) who received hydroxychloroquine monotherapy developed prolonged QTc of 500 milliseconds or more, and 3 patients (3%) had a change in QTc of 60 milliseconds or more. Of those who received concomitant azithromycin, 11 of 53 (21%) had prolonged QTc of 500 milliseconds or more, and 7 of 53 (13 %) had a change in QTc of 60 milliseconds or more. Clinicians should carefully monitor QTc and concomitant medication usage if considering using hydroxychloroquine. ^[320]

A Brazilian study (n=81) compared chloroquine high-dose (600 mg PO BID for 10 days) and low-dose (450 mg BID for 1 day, then 450 mg/day for 4 days). A positive COVID-19 infection was confirmed by RT-PCR in 40 of 81 patients. In addition, all patients received ceftriaxone and azithromycin. Oseltamivir was also prescribed in 89% of patients. Prolonged QT interval (> 500 msec) was observed in 25% of the high-dose group, along with a trend toward higher lethality (17%) compared with lower dose. The high incidence of QT prolongation prompted the investigators to prematurely halt use of the high-dose treatment arm, noting that azithromycin and oseltamivir can also contribute to prolonged QT interval. The fatality rate was 13.5%. In 14 patients with paired samples, respiratory secretions at day 4 showed negative results in only one patient. ^[310]

Although not specific to patients with COVID-19, an increased 30-day risk of cardiovascular mortality, chest pain/angina, and heart 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, United Kingdom, and the United states were analyzed for adverse effects of hydroxychloroquine, sulfasalazine, or the combinations of hydroxychloroquine plus azithromycin or amoxicillin. Overall, 956,374 and 310,350 users of hydroxychloroquine and sulfasalazine, respectively, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin, respectively, were included in the analysis. ^[311]

PUL-042

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

PUL-042 binds to and activates TLRs on lung epithelial cells. This induces the epithelial cells to produce peptides and reactive oxygen species (ROS) against pathogens in the lungs, including bacteria, fungi, and viruses. M362, through binding of the CpG motifs to TLR9 and subsequent TLR9-mediated signaling, initiates the innate immune system and activates macrophages, natural killer (NK) cells, B cells, and plasmacytoid dendritic cells; stimulates interferon-alpha production; and induces a T-helper 1 cells–mediated immune response. Pam2CSK4, through TLR2/6, activates the production of T-helper 2 cells, leading to the production of specific cytokines. ^[321]

In May 2020, the FDA approved initiation of two COVID-19 phase 2 clinical trials of PUL-042 at up to 20 US sites. The trials are for the prevention of infection with SARS-CoV-2 and the prevention of disease progression in patients with early COVID-19. In the first study, up to 4 doses of PUL-042 or placebo will be administered to 200 participants via inhalation over a 10-day period to evaluate the prevention of infection and reduction in severity of COVID-19. In the second study, 100 patients with early symptoms of COVID-19 will receive PUL-042 up to 3 times over 6 days. Each trial will monitor participants for 28 days to assess effectiveness and tolerability. ^{[322, 323]}

Several extracorporeal blood purification filters (eg, CytoSorb, oXiris, Seraph 100 Microbind, Spectra Optia Apheresis) have received emergency use authorization from the FDA for the treatment of severe COVID-19 pneumonia in patients with respiratory failure. The devices have various purposes, including use in continuous renal replacement therapy or in reduction of proinflammatory cytokines levels. ^[324]

Cellular nanosponges made from plasma membranes derived from human lung epithelial type II cells or human macrophages have been evaluated in vitro. The nanosponges display the same protein receptors required by SARS-CoV-2 for cellular entry and act as decoys to bind the virus. In addition, acute toxicity was evaluated in vivo in mice by intratracheal administration. ^[325]

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

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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.

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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 Aug 13; Accessed: August 21, 2020.

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Mesoblast to evaluate anti-inflammatory cell therapy remestemcel-L for treatment of COVID-19 lung disease. Mesoblast. 2020 Mar 10. Available at http://investorsmedia.mesoblast.com/static-files/c1428818-0b9f-44f9-bb4f-79ad518002cc.

FDA clears investigational new drug application for Mesoblast to use remestemcel-L in patients with acute respiratory distress syndrome caused by COVID-19. Mesoblast Ltd. 2020 Apr 06. Available at http://investorsmedia.mesoblast.com/static-files/f9eb8ecd-9c72-4207-8a51-0187607948b6.

First patients dosed in phase 2/3 randomized controlled trial of Mesoblast’s remestemcel-l for COVID-19 acute respiratory distress syndrome. Mesoblast Ltd. 2020 May 6. Available at http://investorsmedia.mesoblast.com/static-files/12fa62d6-49e1-4b1d-8fb7-0c3e184602ab.

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

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/.

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

Alexion Announces Plans to Initiate Phase 3 Study of ULTOMIRIS® (ravulizumab-cwvz) in Hospitalized Patients with Severe COVID-19. Alexion Pharmaceuticals, Inc. 2020 Apr 20. Available at https://alexionpharmaceuticalsinc.gcs-web.com/news-releases/news-release-details/alexion-announces-plans-initiate-phase-3-study-ultomirisr.

Intravenous aviptadil for critical COVID-19 with acute respiratory failure (COVID-AIV). ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04311697. 2020 Jun 04; Accessed: June 9, 2020.

RLF-100 (aviptadil) intermediate population expanded access protocol (SAMICARE). ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04453839. 2020 Jul 29; Accessed: July 29, 2020.

RLF-100 (aviptadil) individual patient expanded access. ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04453839. 2020 Jul 01; Accessed: July 1, 2020.

Inhaled aviptadil for the treatment of moderate and severe COVID-19 (AVICOVID-2). ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04360096. 2020 Jun 29; Accessed: August 7, 2020.

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

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

Study of sargramostim in patients with COVID-19 (iLeukPulm). ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/ct2/show/NCT04411680. 2020 Aug 21; Accessed: August 26, 2020.

A study to assess the efficacy and safety of gimsilumab in subjects with lung injury or acute respiratory distress syndrome secondary to coronavirus disease 2019. ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04351243?term=gimsilumab&draw=2&rank=1. 2020 Apr 17; Accessed: April 17, 2020.

Roivant Announces Development of Anti-GM-CSF Monoclonal Antibody to Prevent and Treat Acute Respiratory Distress Syndrome (ARDS) in Patients with COVID-19. Roivant Sciences. 2020 Mar 18. Available at http://Roivant Announces Development of Anti-GM-CSF Monoclonal Antibody to Prevent and Treat Acute Respiratory Distress Syndrome (ARDS) in Patients with COVID-19.

DeLuca G, Cavalli G, Campochiaro C, Della-Torre E, Angelillo P, Tomelleri A, et al. GM-CSF blockage with mavrilimumab in severe COVID-19 pneumonia and systemic hyperinflammation: a single-centre, prospective cohort study. Lancet Rheum. 2020 Jun 16. [Full Text].

Study of mavrilimumab (KPL-301) in participants hospitalized with severe corona virus disease 2019 (COVID-19) pneumonia and hyper-inflammation. ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/ct2/show/NCT04447469. 2020 Jul 21; Accessed: July 23, 2020.

Investigating otilimab in patients with severe pulmonary COVID-19 related disease (OSCAR). ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/ct2/show/NCT04376684?term=otilimab&cond=COVID&draw=2&rank=1. 2020 May 06; Accessed: May 12, 2020.

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;

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

MediciNova announces opening of investigational new drug application for MN-166 (ibudilast) for prevention of acute respiratory distress 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.

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.

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

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

LB1148 Now Available for Investigational Use to Treat Pulmonary Dysfunction Associated with COVID-19 Pneumonia. Leading BioSciences. 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.

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. 2020 Apr 17;

I-MAB Biopharma Announces Development of TJM2 to Treat Cytokine Release Syndrome Associated with Severe and Critically-Ill Patients with Coronavirus Disease (COVID-19). I-MAB Biopharma. 2020 Mar 18. Available at http://www.i-mabbiopharma.com/en/article-491.aspx.

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

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

Karyopharm announces dosing of first patient in randomized study evaluating low dose selinexor in patients with severe COVID-19. Karyopharm Therapeutics. 2020 Apr 20. Available at https://investors.karyopharm.com/news-releases/news-release-details/karyopharm-announces-dosing-first-patient-randomized-study.

Evelo Biosciences, Rutgers University, and Robert Wood Johnson University Hospital Announce Submission of IND for a Phase 2 Study 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.

Acalabrutinib study with best supportive care versus best supportive care in subjects hospitalized with COVID-19 (CALAVI US). ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/ct2/show/NCT04380688?term=acalabrutinib&cond=COVID&draw=2&rank=1. 2020 May 08; Accessed: May 12, 2020.

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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/.

VERU-111 suppresses key cytokines responsible for severe acute respiratory distress syndrome in COVID-19. Veru, Inc. 2020 Aug 04. Available at https://verupharma.com/news/veru-111-suppresses-key-cytokines-responsible-for-severe-acute-respiratory-distress-syndrome-in-covid-19/.

Q BioMed partner Mannin Research developing potential treatment for patients infected with coronavirus and other infectious diseases. 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.

Diffusion Pharmaceuticals receives FDA guidance for international phase 1b/2b COVID-19 clinical program with TSC. Diffusion Pharmaceuticals. 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.

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

PureTech advances LYT-100 (deupirfenidone) for treatment of serious respiratory complications that persist following resolution of COVID-19 infection. PureTech Bio. 2020 May 28. Available at https://www.puretechhealth.com/news/23-press-releases/1218-puretech-advances-lyt-100-deupirfenidone-for-treatment-of-serious-respiratory-complications-that-persist-following-resolution-of-covid-19-infection.

Ashvattha Therapeutics subsidiary Orpheris announces FDA agreement to initiate phase 2 study evaluating OP-101 in severe COVID-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/.

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

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. Immunic, Inc. 2020 Jul 27. Available at https://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/.

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.

An investigation on the effects of icosapent ethyl (Vascepa) on inflammatory biomarkers in individuals with COVID-19. ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/ct2/show/NCT04412018. 2020 Jun 05;

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

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

Fulcrum Therapeutics. Fulcrum Therapeutics Announces Initiation of Multi-Center Phase 3 (LOSVID) Trial with Losmapimod for Hospitalized 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.

Durect Corporation announces initiation of patient recruitment in phase 2 safety and efficacy study of DUR-928 in COVID-19 patients with 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.

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

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

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.

Biophytis receives FDA IND clearance for COVA, a phase 2/3 clinical trial with sarconeos (BIO101) for the treatment of patients with COVID-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.

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

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

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

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.

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.

ReAlta Life Sciences announces U.S. FDA clearance of first investigational new drug application for RLS-0071. ReAlta Life Sciences. 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/.

Phase 3 study to evaluate efficacy and safety of lenzilumab in patients with COVID-19. ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04351152. 2020 Aug 05; Accessed: August 7, 2020.

Safety and antiviral activity of BLD-2660 in COVID-19 hospitalized subjects. ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04334460. 2020 Aug 05; Accessed: August 13, 2020.

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

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/.

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.

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

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

Capricor Therapeutics announces U.S. FDA acceptance of its IND application for a phase 2 clinical trial of CAP-1002 in patients with COVID-19. Capricor Therapeutics. 2020 Aug 25. Available at https://irdirect.net/prviewer/release/id/4433141.

CEL-SCI Initiates Development of Immunotherapy to Treat COVID-19 Coronavirus Infection. Cel-Sci. 2020 Mar 09. Available at https://www.irdirect.net/prviewer/release_only/id/4254600.

Innovation Pharmaceuticals Brilacidin Received by U.S. Regional Biocontainment Laboratory; Testing Against Coronavirus (COVID-19). Innovation Pharmaceuticals. 2020 Mar 09. Available at http://www.ipharminc.com/press-release/2020/3/9/innovation-pharmaceuticals-brilacidin-received-by-us-regional-biocontainment-laboratory-testing-against-coronavirus-covid-19.

Celularity Announces FDA Clearance of IND Application for CYNK-001 in Coronavirus, First in Cellular Therapy. PRNewswire. 2020 Apr 02. Available at https://www.prnewswire.com/news-releases/celularity-announces-fda-clearance-of-ind-application-for-cynk-001-in-coronavirus-first-in-cellular-therapy-301034141.html.

Hope Biosciences receives FDA approval to commence first stem cell clinical trial for protection against COVID-19. Hope Biosciences. 2020 Apr 06. Available at https://www.hope.bio/post/fda-approval-to-commence-first-stem-cell-clinical-trial-for-protection-against-covid-19.

Hope Biosciences Receives Second FDA Clearance for a Phase II Clinical Trial for COVID-19. Hope Biosciences. 2020 Apr 13. Available at https://www.hope.bio/post/hope-biosciences-receives-second-fda-clearance-for-a-phase-ii-clinical-trial-for-covid-19.

Hope Biosciences Announces Third FDA-approved Clinical Trial for COVID-19. Hope Biosciences. 2020 Apr 20. Available at https://www.hope.bio/post/hope-biosciences-announces-third-fda-approved-clinical-trial-for-covid-19.

Athersys Announces Commencement of Patient Enrollment in the MACOVIA Study, a Pivotal Phase 2/3 Trial Evaluating MultiStem Cell Therapy for COVID-19 Induced ARDS. Athersys, Inc. 2020 May 05. Available at https://www.athersys.com/investors/press-releases/press-release-details/2020/Athersys-Announces-Commencement-of-Patient-Enrollment-in-the-MACOVIA-Study-a-Pivotal-Phase-23-Trial-Evaluating-MultiStem-Cell-Therapy-for-COVID-19-Induced-ARDS/default.aspx.

CD24Fc as a nonantiviral immunomodulator in COVID-19 treatment (SAC-COVID). ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04317040. 2020 Apr 10;

Revive Therapeutics Announces U.S. FDA Recommendation to Proceed Directly into a Phase 3 Confirmatory Clinical Trial. Revive Therapeutics. 2020 Apr 23. Available at https://www.globenewswire.com/news-release/2020/04/23/2020948/0/en/Revive-Therapeutics-Announces-U-S-FDA-Recommendation-to-Proceed-Directly-Into-A-Phase-3-Confirmatory-Clinical-Trial.html.

Bucillamine in treatment of patients with COVID-19. ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04504734. 2020 Aug 07; Accessed: August 7, 2020.

Eiger Biopharmaceuticals provides update on clinical development activities and business operations during COVID-19 pandemic. Eiger Biopharmaceuticals. 2020 Apr 01. Available at http://www.eigerbio.com/eiger-biopharmaceuticals-provides-update-on-clinical-development-activities-and-business-operations-during-covid-19-pandemic/.

FDA approves Octapharma USA investigational new drug application for severe COVID-19 patients. Octapharma USA. 2020 May 20. Available at https://www.octapharmausa.com/en/news-contact/news-single-view.html?tx_ttnews%5Btt_news%5D=1148&cHash=272a8924d90e94efcabf0d2fe596271d.

NeoImmuneTech announces clearance for investigational new drug application of NT-I7 (efineptakin alfa) in adults with mild COVID-19. NeoImmuneTech. 2020 Jul 15. Available at http://neoimmunetech.com/news/page01_view.html?number=48.

InflaRx announces decision to enter phase III development of IFX-1 in severe COVID-19 induced pneumonia. InflaRx. Available at https://www.inflarx.de/Home/Investors/Press-Releases/07-2020-InflaRx-Announces-Decision-to-Enter-Phase-III-Development-of-IFX-1-in-Severe-COVID-19-Induced-Pneumonia.html. 2020 Jul 21;

Safety, tolerability, and efficacy of anti-spike (S) SARS-CoV-2 monoclonal antibodies for the treatment of ambulatory adult patients with COVID-19. ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04425629. 2020 Jun 25; Accessed: July 1, 2020.

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 Jun 26; Accessed: July 1, 2020.

Vir Biotechnology and Biogen execute agreement to manufacture SARS-CoV-2 antibodies for potential COVID-19 treatment. Vir Biotechnology. 2020 May 29. Available at https://investors.vir.bio/news-releases/news-release-details/vir-biotechnology-and-biogen-execute-agreement-manufacture-sars.

A study of LY3819253 (Ly-CoV555) in participants with mild to moderate COVID-19 illness (BLAZE-1). ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04427501. 2020 Aug 04; Accessed: August 7, 2020.

Lilly initiates phase 3 trial of LY-CoV555 for prevention of COVID-19 at long-term care facilities in partnership with the national institute of allergy and infectious diseases (NIAID). Lilly. 2020 Aug 03. Available at https://investor.lilly.com/news-releases/news-release-details/lilly-initiates-phase-3-trial-ly-cov555-prevention-covid-19-long.

Junshi Biosciences announces completion of enrollment in phase 1. GlobeNewswire. 2020 Jul 12. Available at https://www.globenewswire.com/news-release/2020/07/13/2060944/0/en/Junshi-Biosciences-Announces-Completion-of-Enrollment-in-Phase-I-Trial-of-SARS-CoV-2-Neutralizing-Antibody-JS016-in-China.html.

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

Study to evaluate STI-1499 (COVI-GUARD) in hospitalized patients with COVID-19. ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/ct2/show/NCT04454398. 2020 Jul 27; Accessed: August 25, 2020.

Study to Evaluate the Safety, Tolerability and Pharmacokinetics of AZD7442 in Healthy Adults. ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04507256. 2020 Aug 11; Accessed: August 25, 2020.

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A study to evaluate efficacy, safety, and immunogenicity of mRNA-1273 vaccine in adults aged 18 years and older to prevent COVID-19. ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT04470427. 2020 Jul 28; Accessed: July 28, 2020.

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Pfizer and BioNTech announce early positive updated from German phase 1/2 COVID-19 vaccine study, including first T-cell response data. Pfizer. 2020 Jul 20. Available at https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-early-positive-update-german.

Pfizer and BioNTech choose lead mRNA vaccine candidate against COVID-19 and commence pivotal phase 2/3 global study. BioNTech. 2020 Jul 27. Available at https://investors.biontech.de/news-releases/news-release-details/pfizer-and-biontech-choose-lead-mrna-vaccine-candidate-against.

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Single dose of Johnson & Johnson COVID-19 vaccine candidate demonstrates robust protection in preclinical studies. Johnson & Johnson. 2020 Jul 30. Available at https://www.jnj.com/single-dose-of-johnson-johnson-covid-19-vaccine-candidate-demonstrates-robust-protection-in-pre-clinical-studies.

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Novavax announces positive phase 1 data for its COVID-19 vaccine candidate. Novavax. 2020 Aug 04. Available at https://ir.novavax.com/news-releases/news-release-details/novavax-announces-positive-phase-1-data-its-covid-19-vaccine.

INOVIO Receives New $5 Million Grant to Accelerate Scale Up of Smart Delivery Device for Its COVID-19 Vaccine. Inovio Pharmaceuticals. 2020 Mar 12. Available at http://ir.inovio.com/news-and-media/news/press-release-details/2020/INOVIO-Receives-New-5-Million-Grant-to-Accelerate-Scale-Up-of-Smart-Delivery-Device-for-Its-COVID-19-Vaccine/default.aspx.

Inovio announces positive interim phase 1 data for INO-4800 vaccine for COVID-19. Inovio Pharmaceuticals. 2020 Jun 30. Available at http://ir.inovio.com/news-releases/news-releases-details/2020/INOVIO-Announces-Positive-Interim-Phase-1-Data-For-INO-4800-Vaccine-for-COVID-19/default.aspx.

CureVac CEO Daniel Menichella Discusses Coronavirus Vaccine Development with U.S. President Donald Trump and Members of Coronavirus Task Force. CureVac. 2020 Mar 03. Available at https://www.curevac.com/news/curevac-ceo-daniel-menichella-ber%C3%A4t-mit-us-pr%C3%A4sident-donald-trump-und-mitgliedern-der-corona-task-force-entwicklungsm%C3%B6glichkeiten-eines-coronavirus-impfstoffes.

IAVI and Merck Collaborate to Develop Vaccine Against SARS-CoV-2. Merck. 2020 May 26. Available at https://www.mrknewsroom.com/news-release/research-and-development-news/iavi-and-merck-collaborate-develop-vaccine-against-sars-c.

Clover and GSK announce research collaboration to evaluate coronavirus (COVID-19) vaccine candidate with pandemic adjuvant system. GlaxoSmithKline and Clover Biopharmaceuticals. 2020 Feb 24. Available at https://www.gsk.com/en-gb/media/press-releases/clover-and-gsk-announce-research-collaboration-to-evaluate-coronavirus-covid-19-vaccine-candidate-with-pandemic-adjuvant-system/.

GSK Strikes Deals with Vir Biotechnology and China’s Innovax Biotech Against COVID-19. GlaxoSmithKline. 2020 Apr 06. Available at https://www.gsk.com/en-gb/media/resource-centre/our-contribution-to-the-fight-against-2019-ncov/.

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Dynavax and Clover Biopharmaceuticals Announce Research Collaboration to Evaluate Coronavirus (COVID-19) Vaccine Candidate with CpG 1018 Adjuvant. Dynavax. 2020 Mar 24. Available at http://investors.dynavax.com/news-releases/news-release-details/dynavax-and-clover-biopharmaceuticals-announce-research.

Vaneva and Dynavax announce collaboration to advance vaccine development for COVID-19. Dynavax. 2020 Apr 22. Available at http://investors.dynavax.com/news-releases/news-release-details/valneva-and-dynavax-announce-collaboration-advance-vaccine.

Sanofi Announces It Will Work with HHS to Develop Coronavirus Vaccine. Scientific America. Available at https://www.scientificamerican.com/article/sanofi-announces-it-will-work-with-hhs-to-develop-coronavirus-vaccine/. 2020 Feb 18; Accessed: 2020 Mar 13.

Sanofi and GSK to join forces in unprecedented vaccine collaboration to fight COVID-19. GlaxoSmithKline. 2020 Apr 14. Available at https://www.gsk.com/en-gb/media/press-releases/sanofi-and-gsk-to-join-forces-in-unprecedented-vaccine-collaboration-to-fight-covid-19/.

Codagenix and Serum Institute of India Initiate Co-Development of a Scalable, Live-Attenuated Vaccine Against the 2019 Novel Coronavirus, COVID-19. Codagenix, Inc. 2020 Feb 13. Available at https://www.prnewswire.com/news-releases/codagenix-and-serum-institute-of-india-initiate-co-development-of-a-scalable-live-attenuated-vaccine-against-the-2019-novel-coronavirus-covid-19-301004654.html?tc=eml_cleartime..

Applied DNA, Takis Biotech design four Covid-19 vaccine candidates. Applied DNA Sciences. 2020 Mar 02. Available at https://adnas.com/pharmaceutical-technology-applied-dna-and-takis-biotech-covid-29-vaccine-candidates/.

Altimmune Completes First Development Milestone Toward A Single-Dose Intranasal COVID-19 Vaccine. Altimmune. 2020 Feb 28. Available at https://ir.altimmune.com/news-releases/news-release-details/altimmune-completes-first-development-milestone-toward-single.

Innovation Pharmaceuticals Brilacidin to be Researched as Possible Novel Coronavirus (COVID-19) Vaccine; Brilacidin Now Being Tested as Drug and Vaccine at Different Institutions. Innovation Pharmaceuticals. 2020 Mar 17. Available at http://www.ipharminc.com/press-release/2020/3/17/innovation-pharmaceuticals-brilacidin-to-be-researched-as-possible-novel-coronavirus-covid-19-vaccine-brilacidin-now-being-tested-as-drug-and-vaccine-at-different-institutions.

Hoth Update on HaloVax Partnership Vaccine to Fight COVID-19 with Sponsored Research Agreement with the Vaccine and Immunotherapy Center (VIC) of the Massachusetts General Hospital (MGH). PRNewswire. 2020 Apr 02. Available at https://www.prnewswire.com/news-releases/hoth-update-on-halovax-partnership-vaccine-to-fight-covid-19-with-sponsored-research-agreement-with-the-vaccine-and-immunotherapy-center-vic-of-the-massachusetts-general-hospital-mgh-301034214.html.

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Ufovax successfully extended its nanoparticle vaccine technology to SARS-CoV-2. Ufovax. 2020 Mar 23. Available at https://www.ufovax.com/ufovax-successfully-extended-its-nanoparticle-vaccine-technology-to-sars-cov-2/.

PDS Biotechnology Initiates Novel Vaccine Development Programs for COVID-19 and Universal Influenza. PDS Biotechnology. 2020 Apr 16. Available at https://www.pdsbiotech.com/investors/news-center/press-releases/press-releases1/56-2020-news/377-iotechnologynitiatesovelaccineevelopmentrogr20200416.

Tonix Pharmaceuticals Announces Fujifilm Diosynth Biotechnologies to be manufacturing partner for COVID-19 vaccine candidate TNX-1800. 2020 Jun 01. Tonix Pharmaceuticals. Available at https://www.tonixpharma.com/news-events/press-releases/detail/1202/tonix-pharmaceuticals-announces-fujifilm-diosynth.

Catalent partners with Spicona to develop COVID-19 vaccine candidate using GPEx cell line development platform. Catalent. 2020 Jun 10. Available at https://www.catalent.com/catalent-news/catalent-partners-with-spicona-to-develop-covid-19-vaccine-candidate-using-gpex-cell-line-development-platform/.

GSK and Medicago announce collaboration to develop a novel adjuvanted COVID-19 candidate vaccine. GlaxoSmithKline. 2020 Jul 07. Available at https://us.gsk.com/en-us/media/press-releases/gsk-and-medicago-announce-collaboration-to-develop-a-novel-adjuvanted-covid-19-candidate-vaccine/.

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Oral antiviral in phase 2 trial in combination with remdesivir initiated in June 2020. The mechanism of merimepodib is believed to be inhibition of inosine-5’-monophosphate dehydrogenase (IMPDH), leading to a depletion of guanosine for use by the viral polymerase during replication.

Calcium release-activated calcium (CRAC) channel inhibitor that prevents CRAC channel overactivation, which can cause pulmonary endothelial damage and cytokine storm. Results in mid-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 severe COVID-19 pneumonia, showing faster recovery (5 days vs 12 days), reduced use of invasive mechanical ventilation (18% vs 50%), and improved mortality rate (10% vs 20%) compared with standard of care alone. Part 2 of this trial will start late summer and will be a placebo-controlled trial, possibly including both remdesivir and dexamethasone.

VIR-7831 and VIR-7832 are mAbs that bind to an epitope on SARS-CoV-2. The epitope is also on SARS-CoV-1, indicating the epitope is highly conserved and more difficult to mutate. Each of the monoclonal antibodies are engineered to have an extended half-life.

Antibody treatment from more than 500 unique antibodies isolated from one of the first US patients to recover from COVID-19. Phase 1 study in hospitalized patients initiated in June 2020. A phase 2 study (BLAZE-1) in people recently diagnosed with COVID-19 in the ambulatory setting is ongoing. A phase 3 trial (BLAZE-2) announced in August 2020 by NIAID is planned for prevention of SARS-CoV-2 infection in residents and staff at long-term care facilities in the United States.

Adenovirus serotype 26 (Ad26) vector-based vaccine. Preclinical trials showed a single dose elicited neutralizing antibodies and successfully prevented subsequent infection in nonhuman primates. Phase 1/2a testing in healthy volunteers initiating in late July 2020 in Belgium, the United States, Netherlands, Spain, Germany, and Japan. Phase 3 trial expected to commence in September 2020.

Contains an adjuvant that stimulates the entry of antigen-presenting cells into the injection site and enhances antigen presentation in local lymph nodes to boost the immune response. Phase 1/2 trials were initiated in May 2020. Phase 1 data in health adults showed the vaccine induced neutralization titers in 100% of participants. A phase 2 trial began in South Africa mid-August 2020. Phase 3 trials expected to start in October 2020.  

The phase 1 human clinical trial enrolled 40 healthy volunteers was complete late April 2020. Favorable interim results of safety and immunogenicity were reported in June. The phase 1 trial was expanded to include older participants and Phase 2/3 efficacy trials are planned to commence by the end of summer 2020. Inovio has received a grant from the Bill and Melinda Gates Foundation to accelerate testing and scale up a smart device (Cellectra 3PSP) for large-scale intradermal vaccine delivery.

Scott J Bergman, PharmD, FCCP, FIDSA, BCPS, BCIDP Antimicrobial Stewardship Program Coordinator, Infectious Diseases Pharmacy 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 of Nebraska Medical Center

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

Disclosure: Nothing to disclose.

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

David J Cennimo, MD, FAAP, FACP, AAHIVS is a member of the following medical societies: American Academy of HIV Medicine, American Academy of Pediatrics, American College of Physicians, American Medical Association, HIV Medicine Association, 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, American Pharmacists Association, American Society of Health-System Pharmacists, Nebraska Pharmacists Association

Disclosure: Nothing to disclose.

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

Disclosure: Nothing to disclose.

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

Disclosure: Nothing to disclose.

Treatment of Coronavirus Disease 2019 (COVID-19): Investigational Drugs and Other Therapies

Research & References of Treatment of Coronavirus Disease 2019 (COVID-19): Investigational Drugs and Other Therapies|A&C Accounting And Tax Services
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