Coronavirus Disease 2019 (COVID-19) Treatment & Management

Coronavirus Disease 2019 (COVID-19) Treatment & Management

 Immunomodulators and Investigational Therapies

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

Interleukin Inhibitors

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

Interleukin-6 inhibitors

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

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.

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

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

Change from baseline C-reactive protein level: -79% versus -21%

Died: 23% versus 27%

Remained on ventilator: 9% versus 27%

Clinical improvement: 59% versus 41%

Off oxygenation: 58% versus 41%

Discharged: 53% versus 41%

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

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

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).

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

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

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.

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.

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.

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.

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).

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).

Corticosteroids

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

Corticosteroids are not generally recommended for treatment of viral pneumonia.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.

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. The results from the RECOVERY trial in June 2020 provided evidence for clinicians to consider when low-dose corticosteroids would be beneficial.

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).

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).

Convalescent Plasma

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

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

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  proposed using it as a treatment for COVID-19, and Bloch et al  laid out a conceptual framework for implementation. To date, two small case series have been published. These series reported improvement in oxygenation, sequential organ failure assessment (SOFA) scores, and eventual ventilator weaning in some patients. The timelines of improvement varied from days to weeks. Caution is advised, as these were not controlled trials and other pharmacologic methods (antivirals) were used in some patients.

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. 

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).

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. 

A phase 2 study of iNO is underway in patients with COVID-19 with the goal of preventing disease progression in those with severe ARDS. 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. 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. The cost of iNO is reported as exceeding $100/hour.

JAK and NAK Inhibitors

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

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. 

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

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. 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. 

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). 

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

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

Statins

In addition to the cholesterol-lowering abilities of HMG-CoA reductase inhibitors (statins), they also decrease the inflammatory processes of atherosclerosis. 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 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.