key: cord-0827711-7t5ce2hb
authors: Baroutjian, Amanda; Sanchez, Carol; Boneva, Dessy; McKenney, Mark; Elkbuli, Adel
title: SARS-CoV-2 pharmacologic therapies and their safety/effectiveness according to level of evidence
date: 2020-09-01
journal: Am J Emerg Med
DOI: 10.1016/j.ajem.2020.08.091
sha: dd6c3b14e0a46a376125427d8785e6d2621792a5
doc_id: 827711
cord_uid: 7t5ce2hb

INTRODUCTION: There is a pressing need for COVID-19 transmission control and effective treatments. We aim to evaluate the safety and effectiveness of SARS-CoV-2 pharmacologic therapies as of August 2, 2020 according to study level of evidence. METHODS: PubMed, ScienceDirect, Cochrane Library, JAMA Network and PNAS were searched. The following keywords were used: ((COVID-19) OR (SARS-CoV-2)) AND ((((((therapeutics) OR (treatment)) OR (vaccine)) OR (hydroxychloroquine)) OR (antiviral)) OR (prognosis)). Results included peer-reviewed studies published in English. RESULTS: 15 peer-reviewed articles met study inclusion criteria, of which 14 were RCTs and one was a systematic review with meta-analysis. The following pharmacologic therapies were evaluated: chloroquine (CQ), hydroxychloroquine (HCQ), antivirals therapies, plasma therapy, anti-inflammatories, and a vaccine. CONCLUSION: According to level 1 evidence reviewed here, the most effective SARS-Co-V-2 pharmacologic treatments include remdesivir for mild to severe disease, and a triple regimen therapy consisting of lopinavir-ritonavir, ribavirin and interferon beta-1b for mild to moderate disease. Also, dexamethasone significantly reduced mortality in those requiring respiratory support. However, there is still a great need for detailed level 1 evidence on pharmacologic therapies.

Introduction also showed that the high-dose group had a higher incidence of QT prolongation greater than 500ms.

Following an unplanned interim analysis of study findings due to CQ dosages related safety concerns, the study independent data safety and monitoring board (DSMB) recommended the immediate interruption of the trial for patients on high dose CQ from all age groups, unmasking, and converting all to low dose CQ. 13 They concluded that patients with severe COVID-19 should not be given a high dose of CQ especially with azithromycin and oseltamivir due to risk of QT prolongation and associated lethality.

However, findings from patients with prolonged QT showed no clear association between the first day of prolonged QT and day of death, and that cumulative dosages were not higher among prolonged QT associated fatalities. 13 In addition, it is important to be aware that this study had a small sample size, lacked of a placebo control group and used a historical control group. Instead, findings were only adjusted by age, and pre-protocol analysis was not conducted due to inability to register daily untaken or mistaken CQ doses because or renal or liver failures. 13 An open label RCT conducted on patients 18 years and older with mild or moderate ongoing SARS CoV-2 investigated the effects of hydroxychloroquine (HCQ) on negative conversion by 28 days. 14 Patients were administered 1200 mg of HCQ daily for three days followed by a maintenance dose of 800 mg daily (11 days if mild, 18 days if moderate). 14 Results showed that those treated with standard care plus HCQ had an 85.4% probability of negative conversion by day 28 (95% CI 73. 8-93.8) , whereas those treated with standard care alone had an 81.3% chance (95% CI 71. 2-89.6 ). 14 However, this difference was reportedly not significant. Due to the trial ending early and only two patients (out of 150) with severe disease being enrolled, results on clinical improvement were not presented. 14 This study was limited by its underpowered sample size, non-computerized randomization protocol, and open label design. 14 A more recent, multicenter, open-labeled controlled trial was conducted to assess the efficacy of HCQ with and without azithromycin compared to the standard of care. 15 The study was performed on patients with suspected or confirmed mild to moderate COVID-19 with 14 or fewer days since symptom onset.

Patients in the HCQ group received a dose of 400 mg twice daily for seven days. Patients in the HCQ plus J o u r n a l P r e -p r o o f azithromycin additionally received a dose of 500 mg of azithromycin once daily for seven days. Clinical status at 15 days was evaluated using a 7-level ordinal scale. Results showed no significant difference in the 7-level ordinal scale at 15 days between those treated with HCQ and standard care (OR 1.21, 95% CI 0.69-2.11, p=1.00), or between those treated with HCQ + azithromycin and standard care (OR 0.99, 95% CI 0.57-1.73, p=1.00). 15 There were also no significant differences in the number of days free from respiratory support, use of high-flow nasal cannula or non-invasive ventilation, use of mechanical ventilation, duration of hospital stay, in-hospital death, thromboembolic complications, or acute kidney injury between the groups. 15 They also found that prolongation of QT interval was more frequent in the experimental groups (especially the HCQ plus azithromycin group), and elevation of liver enzymes was more frequent in the HCQ plus azithromycin group than the control group. 15 Limitations of this study include lack of blinding, concomitant treatment of patients with other pharmacologic agents, and the fact that some patients were previously treated with HCQ ± azithromycin at other hospitals prior to enrollment in this trial. 15 Another RCT was conducted to assess the efficacy of HCQ as a post-exposure prophylaxis. 16 Participants were adults with household or occupational exposure to someone with laboratory confirmed COVID-19 at a distance of less than 6 ft for more than 10 minutes without a face mask and/or eye shield. Time from exposure to enrollment varied between 1-4 days in all participants. Patients in the HCQ group were administered 800 mg HCQ once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days for a total course of 5 days. Results showed that the incidence of new illness compatible with COVID-19 did not significantly differ between participants receiving HCQ (11.8%) and placebo (14.3%) (p=0.35). 16 Also, there was no meaningful difference in the effectiveness according to the time of starting post-exposure prophylaxis. 16 Side effects were significantly more frequent in the HCQ group by day 5 (p<0.001), with nausea, loose stools and abdominal discomfort being the most commonly reported side effects. 16 No serious adverse reactions or cardiac arrhythmias were reported. This study is limited by its use of an a priori symptomatic case definition in some patients as opposed to diagnostic testing. 16 J o u r n a l P r e -p r o o f ii.

Preliminary results of a double-blind randomized controlled trial by Beigel et al. suggest that a 10-day course of remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) is superior to placebo. This study, which was conducted in 60 sites throughout the world, analyzed 1,059 patients and aimed to assess the effect of remdesivir on time to recovery, clinical improvement, and mortality in patients with varying baseline severity. 17 Those who received remdesivir had a statistically significant different median recovery time than placebo, 11 days vs 15 days (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; p<0.001). 17 The authors additionally stratified these results by disease severity, where the beneficial effects of remdesivir appeared to be more pronounced in the severe disease stratum.

Also, the remdesivir group had higher odds of improvement in the 8-level ordinal scale score at day 15 compared to placebo (OR 1.50, 95% CI 1.18-1.91). 17 Although mortality was numerically lower in the remdesivir group, this difference was not statistically significant. 17 Patients on remdesivir who were receiving high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation did not achieve significant differences compared to placebo. 17 Another double blind, placebo-controlled, multicenter RCT was conducted on the effectiveness of remdesivir in confirmed SARS-CoV-2 positive patients with severe COVID-19. 18 Patients were either assigned to receive intravenous remdesivir or placebo infusions. Remdesivir was administered at 200 mg on day 1 followed by 100 mg on days 2-10. Their primary outcome was time to clinical improvement within 28 days after randomization. Some patients were concomitantly treated with corticosteroids, lopinavir-ritonavir or interferons. Intention to treat analysis revealed a non-significant decrease in the time to clinical improvement for the remdesivir group compared to placebo. Survival at 28 days and clinical improvement at 14 and 28 days were also not statistically significantly different, although numerically higher in the remdesivir group. Serious adverse events occurred in 18% and 26% of the remdesivir and placebo groups respectively. 18 Intravenous remdesivir did not provide significant improvements in J o u r n a l P r e -p r o o f patients with severe COVID-19. This study was limited by insufficient power, the late initiation of therapy and absence of data on viral recovery. 18 Another RCT evaluated the efficacy of remdesivir therapy after a 5-or 10-day regimen in patients with varying baseline clinical status. 19 Clinical status on day 14 as measured by a 7-point ordinal scale was the primary endpoint. Patients were administered 200 mg of remdesivir on day 1, followed by 100 mg once daily for the next 4 or 9 days. Results showed that clinical improvement of 2 points or more occurred in 65% of patients in the 5-day group and 54% of patients in the 10-day group. 19 After correction of imbalance of baseline clinical status, clinical status at day 14 was similar between the 5-day and 10-day groups (p=0.14). It was concluded that there was no significant difference in efficacy between a 5-day or 10-day course. This study is limited by the fact that the patients in the 10-day group had a significantly worse clinical status than those in the 5-day group (p=0.02), however the authors state that results were adjusted for this discrepancy. 19 Other limitations include lack of placebo and the open-label design. 19 One clinical trial was conducted on 14-day triple medication protocols compared to 14-day lopinavirritonavir therapy alone. 20 This open-label, randomized trial tested a triple medication regimen including interferon beta-1b, lopinavir-ritonavir, and ribavirin. Patients enrolled had mild to moderate COVID-19.

The dosage for the experimental group was lopinavir 400 mg and ritonavir 100 mg every 12h, ribavirin 400 mg every 12h, and three doses of 8 million IU of interferon beta-1b on alternate days. The control group received 14 days of lopinavir 400 mg and ritonavir 100 mg every 12h. Patients who were admitted to the clinical trial after the 7th day of experiencing symptoms were not treated with interferon beta-1b due to its proinflammatory properties. Their primary outcome measure was time to a negative RT-PCR assay by nasopharyngeal swab. The combination group had a significantly shorter median time to a negative RT-PCR than the control group. A negative SARS-CoV-2 was achieved in a median time of 7 days in the experimental group vs 12 in the control. Additionally, clinical improvement was significantly better in the experimental group than the control with a median time to alleviation of symptoms of 4 vs 8 days. 20 This study had an open-label design, absence of placebo group, and was also confounded by J o u r n a l P r e -p r o o f subgroup omitting of interferon beta-1b within the combination group, depending on time from symptom onset. 20 Another randomized controlled open-label trial in 199 hospitalized patients with confirmed SARS-CoV-2 with severe COVID-19 was done to compare the clinical effectiveness of lopinavir-ritonavir to standard care alone. 21 Severe COVID-19 was defined as SARS-CoV-2 positivity, pneumonia confirmed by chest imaging, and an oxygen saturation of 94% or less while breathing ambient air or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen at or below 300 mg Hg. Patients in the experimental group were treated with 400 mg/100 mg of lopinavir-ritonavir for 14 days. The time to clinical improvement, mortality at day 28, and detectable viral load were not significantly different between groups. 21 Limitations of this study include a non-blinded protocol, higher baseline throat viral loads in the lopinavir-ritonavir group, and absence of data on lopinavir exposure levels in severe and critically ill patients. 21 A more recent RCT done on patients with mild to moderate COVID-19 aimed to compare the difference in rate of positive-to-negative conversion of SARS-CoV-2 nucleic acid between lopinavir/ritonavir and arbidol (umifenovir). 22 Patients were administered either 400mg/100mg lopinavir/ritonavir PO twice daily for 7-14 days, or 200 mg of umifenovir PO three times daily for 7-14 days. Results showed no significant difference in the rate of positive-to-negative conversion between the lopinavir/ritonavir, arbidol, and control groups (p>0.05). 22 There was also no significant differences between the groups for the rates of antipyresis, cough alleviation, or improvement of CT findings at day 7 or 14 (p>0.05). 22 The lopinavir/ritonavir and arbidol groups experienced adverse effects; whereas the control group did not. 22 Limitations include small sample size, single center design, and lack of blinding to clinicians who recruited patients and research staff. 22 iii.

Anti-inflammatory agents J o u r n a l P r e -p r o o f

A multicenter, single-blind RCT was conducted to assess the time to clinical improvement in patients with severe COVID-19 treated with ruxolitinib, a JAK inhibitor. 23 Time to clinical improvement was measured as time from randomization to an improvement of 2 points on a 7-category ordinal scale, or live discharge from the hospital. Patients in the experimental group received 5 mg twice daily of ruxolitinib.

Results showed that ruxolitinib plus standard-of-care was associated with a non-statistically significant decrease in median time clinical improvement (12 [IQR, [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] days vs. 15 [IQR, 10-18] days). 23 However, 90% of ruxolitinib patients had significant CT improvement at day 14 compared to 61.9% of control patients (p=0.0495), and levels of 7 cytokines (including IL-6, IL-12 and VEGF) were significantly decreased in the experimental group, demonstrating the anti-inflammatory effects of ruxolitinib. 23 Also, the 28-day overall mortality was 0% in the experimental group and 14.3% in the control group. 23 This study is limited by its small sample size, use of an ordinal scale to assess primary end points, concomitantly treatment of some patients with other pharmacologic agents, and lack of inclusion of critically ill patients and patients with invasive ventilator dependence. 23 A preliminary, open-label RCT was conducted to assess the effect of dexamethasone on 28-day mortality in hospitalized patients with clinically suspected or laboratory confirmed SARS-CoV-2 infection. 24 

A randomized, double-blind, placebo-controlled trial was conducted to assess the effectiveness of an Ad5-vectored COVID-19 vaccine. 25 There were two experimental groups, one of which received a higher dose of viral particles (1 x 10 11 particles) and another that received a lower dose of viral particles (5 x 10 10 particles). Participants who received either a low or high dose of viral particles had a significant increase in RBD-specific ELISA antibodies, seroconversion rates, and neutralizing antibody responses compared to the placebo group. 25 The placebo group showed no increase in antibody from baseline, and no IFNγ-ELISpot responses. 25 Severe adverse reactions occurred in 9% of the high dose patients and 1% of the low dose patients, although no serious adverse reactions were documented. 25 It is important to note that 52% of participants had high pre-existing immunity, and 48% of the participants had low pre-existing immunity. 25 The authors also did not calculate sample size based on study power in advance, and only reported data within 28 days of vaccination. 25 Another RCT sought to evaluate the effects of convalescent plasma therapy on the time to clinical improvement within 28 days in patients with severe or life threatening COVID-19. 26 

According to the level 1 evidence reviewed here, the most effective treatments against SARS-CoV-2, measured by time to negative RT-PCR and time to clinical improvement, are remdesivir therapy and a triple medication regimen (lopinavir-ritonavir, ribavirin, and interferon beta-1b). [17] [18] 20 Remdesivir showed beneficial effects in patients with varying baseline severity. It resulted in a decrease in mean recovery time, higher odds of improvement on an 8-level ordinal scale at day 15, and a non-statistically significant decrease in mortality in patients with mild to severe COVID-19. 17 It also resulted in a nonstatistically significant reduction in time to clinical improvement in patients with severe COVID-19 with no effect on mortality. 18 One reason for not finding a significant effect of remdesivir in severe COVID-19

patients could be insufficient power. 18 Remdesivir also appears to have some beneficial effects in severe J o u r n a l P r e -p r o o f COVID-19 patients irrespective of the time to initiation of therapy. 18 However, there was no difference in clinical improvement between a 5-day and 10-day course of remdesivir in patients with varying baseline clinical status. 19 In patients with mild to moderate COVID-19, the triple medication regimen appeared to be most beneficial, as it resulted in a significantly shorter median time to negative RT-PCR compared to therapy with just lopinavir-ritonavir. 20 Evidence gathered from other RCTs show several additional findings. First, in patients with severe COVID-19, treatment with lopinavir-ritonavir showed no significant difference in time to clinical improvement, mortality at day 28, or detectable viral load compared to standard care alone. 21 Also, treatment with lopinavir/ritonavir did not significantly affect the rate of positive-to-negative conversion when compared to arbidol in patients with mild to moderate COVID-19. 22 Second, mortality and QT prolongation was worse in severely ill patients taking high doses of CQ compared to low doses. 13 QT prolongation was also significantly higher in patients with mild to moderate COVID-19 treated with HCQ and HCQ plus azithromycin. 15 Additionally, HCQ showed no significant effect on the probability of negative conversion by day 28 or virologic cure compared to standard care alone in patients with mild to moderate COVID-19. 14,27 It also did not reduce the prevalence of unfavorable secondary outcomes such as need for respiratory support, mechanical ventilation, or thromboembolic complications in patients with mild to moderate COVID-19. 15 Moreover, HCQ did not reduce the incidence of new illness when used as a post-exposure prophylaxis. 16 However, meta-analysis did reveal that HCQ treatment resulted in fewer cases of radiological progression of lung damage. 27 Furthermore, treatment of severe COVID-19 patients with ruxolitinib resulted in a non-statistically significant decrease in median time to clinical improvement, and a statistically significant decrease in levels of seven cytokines including IL-6, IL-12 and VEGF, indicating that it may be useful in treating cytokine storm. 23 Convalescent plasma was also efficacious in reducing the time to clinical improvement in severe and life threatening COVID-19. 26 Oral or intravenous dexamethasone was shown to significantly reduce mortality among hospitalized COVID-19 patients J o u r n a l P r e -p r o o f receiving mechanical ventilation or oxygen without mechanical ventilation. 24 Finally, vaccination of healthy individuals using an Ad5-vectored COVID-19 vaccine showed significant increase in immunity to SARS-CoV-2 by 28 days. 25 While we await higher quality evidence from randomized control trials and meta-analyses, these results provide some context on the efficacy of pharmacologic therapy in COVID-19 patients. As of May 20, 2020, the FDA has granted emergency use authorization for intravenous remdesivir for severe COVID-19. 28 However, they have revoked emergency use authorization for use of hydroxychloroquine and chloroquine due to their high risk to benefit ratio. 28

COVID-19 has undoubtedly posed a detrimental health burden worldwide. There is still a great need for detailed evidence on individual pharmacologic therapies. The findings from our review suggest that there is currently inconclusive evidence for one therapy. It is difficult to conduct studies on one category of pharmacologic treatment due to the lack of a universal systematic approach to treating COVID-19. In the absence of a vaccine available to the public, there is a great need for level 1 evidence from randomized controlled trials and meta-analyses to support the development of evidence-based guidelines to treat COVID-19 patients.

Aside from being novel, part of what makes treatment of SARS-CoV-2 difficult is its ability to affect multiple organ systems. 29 The disease is characterized as an acute respiratory failure but may have systemic outcomes such as gastrointestinal, cardiovascular, and nervous system symptoms in addition to multi-organ failure. There has been evidence of high incidence of pulmonary embolism and thrombotic events. These severe cases often present with thrombocytopenia, elevated D-dimer levels, and PT prolongation. The hypercoagulable state often seen in COVID-19 patients can be explained by the J o u r n a l P r e -p r o o f overwhelming production of inflammatory cytokines. This increase in inflammatory markers leads to an activation of the coagulation cascade and inhibits the fibrinolytic pathway. 29 36 Being over 50 years old had a significantly larger impact on mortality than sex at birth and preexisting comorbidities. 36 Another important point to be discussed is the increase of non-evidence-based treatment and the unintended morbidity and mortality that results from it. There has been a large increase in the spread of false information and non-evidence-based remedies, such as consumption of cow urine and high proof alcohol that have resulted in illness and even death. 37

Furthermore, there has been a recent concern for patients who are using ACE-inhibitors. A casepopulation study in Spain on the admission rate of COVID-19 patients on ACE-inhibitors compared to other antihypertensive medications revealed that there was no increased risk of COVID-19 related admission to a hospital, and concluded that ACE-inhibitors not be discontinued. 38 However, there remains a concern, especially among uninformed providers and patients, on whether use of ACE-inhibitors pose a risk to patients during this pandemic.

A similar review done by Sanders et al. on pharmacologic treatment for COVID-19 report similar findings regarding the available pharmacologic options and the inconclusive nature of the available data on these drugs. 39 They additionally offer useful resources for clinical treatment guidance. In contrast, we have tailored our review to provide a more up to date, in-depth and systematic analysis using only level 1 evidence. Additionally, our discussion touches on the multisystem effects of SARS-CoV-2.

Undoubtedly, it is of utmost importance to discuss the safety profile of all the medications included.

Many of these pharmacologic agents result in side effects ranging from mild to severe. First, HCQ and CQ have both been shown to cause cardiac electrical disturbances and cardiomyopathy. 40 One clinical trial using a dose of 600 mg twice daily for ten days was terminated early due to the death of 11 patients as a result of arrhythmias by the 6th day. 13 Other adverse effects associated with HCQ include retinopathy, gastrointestinal disturbances, and suicidal behavior. 41 Additionally, agents like HCQ and CQ can cause QT prolongation and their toxicity may be exacerbated when combined with other agents that also prolong the QT interval, such as Azithromycin. 42 Patients who develop QT prolongation without torsades de pointes should be treated immediately by correcting oxygen, potassium, calcium, and magnesium concentrations. Magnesium sulphate is recommended as the first-line therapy for torsades de pointes. 43 Cardiotoxicity has not been reported with remdesivir use. However, side effects of remdesivir include allergic reactions and increased liver enzymes. 44 Adverse effects associated with triple therapy J o u r n a l P r e -p r o o f using interferon beta 1b, lopinavir-ritonavir and ribavirin include diarrhea, nausea, and increased alanine transaminase levels, all of which stopped in one trial upon discontinuation of the drugs. 20 Additional side effect concerns with lopinavir-ritonavir include haptic injury, pancreatitis, acute gastritis, and QT prolongation. 21 Use of ruxolitinib in COVID-19 patients showed a favorable side-effect profile of the drug according to the RCT reviewed in this study. 23 Some of the adverse reactions included mild anemias, neutrocytopenia, thrombocytopenia, elevated liver enzyme levels, dizziness, rash, and nausea. 23 There were no serious adverse events such as acute heart failure, shock, and sepsis. 23 Adverse reactions of dexamethasone were not evaluated in the RCT included in this study; however, clinicians treating COVID-19 patients with dexamethasone should monitor their patients for hyperglycemia, secondary infections, psychiatric effects and avascular necrosis. 45 The Ad5-vectored vaccine also showed a favorable side-effect profile with most side effects being a result of the injection itself such as skin induration, redness, and swelling. 25 The systemic side effects reported were headache, vomiting, diarrhea, joint pain, muscle pain, fatigue, headache, and cough. 25 Lastly, adverse effects associated with the convalescent plasma trial included dyspnea, fever, and an allergic reaction caused by transfusion. 26 These findings lead us to recommend that physicians follow updated guidelines from reputable sources.

The Society of Surgical Oncology also offers frequently updated resources to assist physicians in treating particularly vulnerable patients with cancer. 46 Currently, there is also a great deal of randomized clinical trials that are ongoing and should provide the medical community with more conclusive evidence in the near future. According to the NIH, there are 2,962 active studies on COVID-19 as of August 2, 2020. 47 The studies included in this review had several limitations. First, there was an issue of small sample size for several studies. 13, [22] [23] 26 Another limitation to the findings is the inability to generalize them to all patients as a result of specific exclusion criteria such as individuals with mild or severe disease. [13] [14] [15] 18, [20] [21] [22] [23] 26 Also, several studies reviewed above aimed to focus on the efficacy and safety of one drug, but employed multiple drugs in the treatment of patients. 15, 18, 23 These limitations make it difficult to compare J o u r n a l P r e -p r o o f Journal Pre-proof the efficacy and safety profiles of the drugs being used. The findings listed are dependent on the accuracy and validity of data used to assess SARS-CoV-2 pharmacological therapies. Lastly, given the rapidly evolving nature of this pandemic, it is difficult to ensure that all the existing evidence has been included up until this article's publication date and new information and trials will arriving.

There remains uncertainty regarding the safest and most effective pharmacologic therapy for COVID-19

disease. However, the findings from this review conclude that, according to level 1 evidence, remdesivir therapy in mild to severe disease, and the triple medication regimen (lopinavir-ritonavir, ribavirin and interferon beta-1b) in mild to moderate disease are the most efficacious against SARS-CoV-2 in terms of symptom improvement and time to a negative RT-PCR. Also, dexamethasone was significantly able to reduce mortality in patients receiving respiratory support. We recommend that physicians remain informed on up to date evidence such as preliminary data from RCTs, and work with their institution and scientific societies in developing evidence-based systematic guidelines in the treatment of COVID-19

patients.

J o u r n a l P r e -p r o o f Hospitalized patients with clinical suspicion of COVID-19, aged 18 years or older, with respiratory rate higher than 24 rpm and/or heart rate higher than 125 bpm (in the absence of fever) and/or peripheral oxygen saturation lower than 90% in ambient air and/or shock. Participants who received either a low or high viral particles dose had a significant increase in RBD-specific ELISA antibodies, seroconversion rates and neutralizing antibody responses compared to the placebo group.

Placebo group showed no antibody increase from baseline.

No IFNγ-ELISpot responses in placebo group. points on a 6-point disease severity scale, or discharge.

Clinical improvement occurred at a higher rate in those with severe disease compared to those with life threatening disease (91.3% vs 68.2%).

There was no significant difference in 28day mortality (OR 0.65, 95% CI 0.29-1.46) or time to discharge (HR 1.61, 95% CI 0.88-2.93).

Use of convalescent plasma resulted in an 87.2% negative conversion rate of viral PCR at 72 hours compared to 37.5% in the control group.

Zoonotic origins of human coronaviruses

Epidemiology, Pathogenesis, and Control of COVID-19

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Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial

Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19

A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19

Remdesivir for the Treatment of Covid-19 -Preliminary Report

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19

Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Efficacy and Safety of Lopinavir/Ritonavir or Arbidol in Adult Patients with Mild/Moderate COVID-19: An Exploratory Randomized Controlled Trial

Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial

Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report

Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebocontrolled, phase 2 trial

Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in 28

COVID-19 -toward a comprehensive understanding of the disease

Identification of a potential mechanism of acute kidney injury during the COVID-19 outbreak: a study based on single-cell transcriptome analysis

Imaging & other potential predictors of deterioration in COVID-19

Assessment of QT Intervals in a Case Series of Patients With Coronavirus Disease 2019 (COVID-19) Infection Treated With Hydroxychloroquine Alone or in Combination With Azithromycin in an Intensive Care Unit

Gastrointestinal Complications in Critically Ill Patients With COVID-19

Patients with Cancer Appear More Vulnerable to SARS-COV-2: A Multicenter Study during the COVID-19 Outbreak

Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study

Non-evidenced based treatment: An unintended cause of morbidity and mortality related to COVID-19

Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study

Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review

Cardiac complications attributed to chloroquine and hydroxychloroquine: A systematic review of the literature

Risk of using hydroxychloroquine as a treatment of COVID-19

Safety considerations for chloroquine and hydroxychloroquine in the treatment of COVID-19

Pharmacological treatment of acquired QT prolongation and torsades de pointes

US Food and Drug Administration