are there any clinical trials available for the coronavirus

So far, there is a lack of effective drugs for the new coronavirus pneumonia. With more and more patients diagnosed, China has carried out more than 100 clinical studies of new coronavirus infection, including antiviral drugs, antimalarial drugs, glucocorticoids, plasma therapy, virus vaccine, and other Western drugs, while Chinese medicine research accounted for half of the studies. Most of the trials were initiated by investigators and the study period would last for 1 to 11 months. The primary endpoints included symptom improvement and virus nucleic acid turning negative, but the optimal endpoint has not been determined. Although the final results of studies will take a long time to complete, the interim research data may provide some help for the current urgent demand for drug treatment. Compared with that of during SARS period in 2003, China has the stronger capability to carry out clinical trials of new drugs in emergency period.

Clinical trial analysis of 2019-nCoV therapy registered in China

Since the report of the first case of coronavirus disease 2019 (COVID-19) in China in late December 2019, there have been 204 610 cases worldwide as of 18 March, 2020. As part of the response to this outbreak, there has been an impressive amount of research undertaken to better characterize the disease and to evaluate therapeutic options. By March 12, 2020, there are more than 382 studies registered in the clinical trials databases addressing COVID-19 including more than 80 randomized controlled trials.

Clinical trials for coronavirus disease 2019: What is being evaluated and what is not

Clinical trial analysis of 2019‐nCoV therapy registered in China

More than 80 clinical trials launch to test coronavirus treatments.

Coronavirus vaccine trials have delivered their first results - but their promise is still unclear

Coronavirus vaccine trials have delivered their first results - but their promise is still unclear.

The World Health Organization (WHO) was informed on December 2019 about a coronavirus pneumonia outbreak in Wuhan, Hubei province (China). Subsequently, on March 12, 2020, 125,048 cases and 4,614 deaths were reported. Coronavirus is an enveloped RNA virus, from the genus Betacoronavirus, that is distributed in birds, humans, and other mammals. WHO has named the novel coronavirus disease as COVID-19. More than 80 clinical trials have been launched to test coronavirus treatment, including some drug repurposing or repositioning for COVID-19. Hence, we performed a search in March 2020 of the clinicaltrials.gov database. The eligibility criteria for the retrieved studies were: contain a clinicaltrials.gov base identifier number; describe the number of participants and the period for the study; describe the participants’ clinical conditions; and utilize interventions with medicines already studied or approved for any other disease in patients infected with the novel coronavirus SARS-CoV-2 (2019-nCoV). It is essential to emphasize that this article only captured trials listed in the clinicaltrials.gov database. We identified 24 clinical trials, involving more than 20 medicines, such as human immunoglobulin, interferons, chloroquine, hydroxychloroquine, arbidol, remdesivir, favipiravir, lopinavir, ritonavir, oseltamivir, methylprednisolone, bevacizumab, and traditional Chinese medicines (TCM). Although drug repurposing has some limitations, repositioning clinical trials may represent an attractive strategy because they facilitate the discovery of new classes of medicines; they have lower costs and take less time to reach the market; and there are existing pharmaceutical supply chains for formulation and distribution.

Clinical trials on drug repositioning for COVID-19 treatment

Rapid diagnostics, vaccines and therapeutics are important interventions for the management of the 2019 novel coronavirus (2019-nCoV) outbreak. It is timely to systematically review the potential of these interventions, including those for Middle East respiratory syndrome-Coronavirus (MERS-CoV) and severe acute respiratory syndrome (SARS)-CoV, to guide policymakers globally on their prioritization of resources for research and development. A systematic search was carried out in three major electronic databases (PubMed, Embase and Cochrane Library) to identify published studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Supplementary strategies through Google Search and personal communications were used. A total of 27 studies fulfilled the criteria for review. Several laboratory protocols for confirmation of suspected 2019-nCoV cases using real-time reverse transcription polymerase chain reaction (RT-PCR) have been published. A commercial RT-PCR kit developed by the Beijing Genomic Institute is currently widely used in China and likely in Asia. However, serological assays as well as point-of-care testing kits have not been developed but are likely in the near future. Several vaccine candidates are in the pipeline. The likely earliest Phase 1 vaccine trial is a synthetic DNA-based candidate. A number of novel compounds as well as therapeutics licensed for other conditions appear to have in vitro efficacy against the 2019-nCoV. Some are being tested in clinical trials against MERS-CoV and SARS-CoV, while others have been listed for clinical trials against 2019-nCoV. However, there are currently no effective specific antivirals or drug combinations supported by high-level evidence.

Potential Rapid Diagnostics, Vaccine and Therapeutics for 2019 Novel Coronavirus (2019-nCoV): A Systematic Review

Since coronavirus disease 2019 (COVID-19) emerged in Wuhan, China in December 2019 and spread around the world, over 1100 clinical studies have been registered globally on clinical trials registries, including over 500 randomised controlled trials. Such rapid development and launch of clinical trials is impressive but presents challenges, including the potential for duplication and competition. There is currently no known effective treatment for COVID-19. In order to focus on those studies most likely to influence clinical practice, we summarise the 31 currently registered randomised trials with a target sample size of at least 1000 participants. We have grouped these trials into four categories: prophylaxis; treatment of outpatients with mild COVID-19; treatment of hospitalised patients with moderate COVID-19; and treatment of hospitalised patients with moderate or severe disease. The most common therapeutic agent being trialled currently is hydroxychloroquine (24 trials with potential sample size of over 25 000 participants), followed by lopinavir-ritonavir (seven trials) and remdesevir (five trials) There are many candidate drugs in pre-clinical and early phase development, and these form a pipeline for future large clinical trials if current candidate therapies prove ineffective or unsafe.

Clinical trials for the prevention and treatment of COVID-19: current state of play

Here, we present an overview of the clinical trials that are currently being conducted or have concluded to date on COVID-19 globally. A comprehensive search was conducted to present 16 trial registries from around the world. Collectively, there are 1,528 trials reported for COVID-19 to date. Out of them, 50 studies included paediatric age group from day 0 to less than or equal to 18 years of age. A few 18 studies involve only females and 20 only males. There are 2 trials currently underway in Bangladesh, 4 in Pakistan and 13 in India. Overall, 940 trials are related to medicines and/or interventions. They include standard of care for any viral illness, antivirals, anti-inflammatory and immune altering medications. Two out of 10 vaccine trials are novel vaccines. It is knowledgeable and resourceful to reach out to the concerned sponsor if a physician thinks his patient can benefit from the trials in the region.

Comprehensive overview of COVID-19 clinical trials.

The first rumblings about a new coronavirus spreading in China were heard in January 2020. By the end of that month, the World Health Organization, recognizing the severity of the disease and the potential for global spread, had declared a public health emergency. By February 2020, cases had been identified in multiple countries, clinical trials of treatments with some biological plausibility had begun in China, and the initial steps of vaccine development were underway. In mid-March, by which time countries around the world were experiencing rapidly increasing numbers of cases and deaths, the World Health Organization categorized the outbreak as a pandemic. This new coronavirus was designated SARS-COV-2 in recognition of its similarity to the coronavirus responsible for the severe acute respiratory syndrome outbreak in 2002-2003. The race is on to develop treatments that can mitigate the severe consequences of infection and vaccines that can prevent infection and/or diminish the severity of disease in those who do get infected. Many challenges face these development efforts. Some are similar to those faced in the past; others are new. The urgency of finding ways to treat, and ultimately prevent, the consequences of this new and potentially deadly infection has led to unprecedented focus on clinical trials.

Clinical trials in the time of a pandemic.

Clinical trials in the time of a pandemic

During the recent global outbreak of severe acute respiratory syndrome (SARS), thousands of patients received treatments of uncertain efficacy and known toxicity such as ribavirin and corticosteroids. Despite this, no controlled clinical trials assessing the efficacy of these agents were conducted. If a second global SARS outbreak occurred, clinicians would not have controlled data on which to base therapeutic decisions. We discuss the unique methodologic and logistical challenges faced by researchers who attempt to conduct controlled trials of therapeutic agents during an outbreak of a novel or unknown infectious pathogen. We draw upon our own experience in attempting to conduct a randomized controlled trial (trial) of ribavirin therapy for SARS and discuss the lessons learned. Strategies to facilitate future clinical trials during outbreaks of unknown or novel pathogens are also presented.

Clinical Trials and Novel Pathogens: Lessons Learned from SARS

Background and objective: Despite medical advances, we are facing the unprecedented disaster of the coronavirus disease 2019 (COVID-19) pandemic without available treatments and effective vaccines. As the COVID-19 pandemic has approached its culmination, desperate efforts have been made to seek proper treatments and response strategies, and the number of clinical trials has been rapidly increasing. In this time of the pandemic, it is believed that learning lessons from it would be meaningful in preparing for future pandemics. Thus, this study aims at providing a comprehensive landscape of COVID-19 related clinical trials based on the ClinicalTrials.gov database. Materials and methods: Up to 30 March 2020, we identified a total of 147 eligible clinical trials and reviewed the overview of the studies. Results: Until then, the most clinical trials were set up in China. Treatment approaches are the most frequent purpose of the registered studies. Chloroquine, interferon, and antiviral agents such as remdesivir, lopinavir, and ritonavir are agents under investigation in these trials. Conclusions: In this study, we introduced the promising therapeutic options that many researchers and clinicians are interested in, and to address the hidden issues behind clinical trials in this COVID-19 pandemic.

A Comprehensive Analysis of Clinical Trials in the COVID-19 Pandemic Era.

More than 80 clinical trials launch to test coronavirus treatments

Comprehensive overview of COVID-19 clinical trials

Since coronavirus disease 2019 (COVID‐19) emerged in Wuhan, China in December 2019 and spread around the world, over 1100 clinical studies have been registered globally on clinical trials registries, including over 500 randomised controlled trials. Such rapid development and launch of clinical trials is impressive but presents challenges, including the potential for duplication and competition. There is currently no known effective treatment for COVID‐19. In order to focus on those studies most likely to influence clinical practice, we summarise the 31 currently registered randomised trials with a target sample size of at least 1000 participants. We have grouped these trials into four categories: prophylaxis; treatment of outpatients with mild COVID‐19; treatment of hospitalised patients with moderate COVID‐19; and treatment of hospitalised patients with moderate or severe disease. The most common therapeutic agent being trialled currently is hydroxychloroquine (24 trials with potential sample size of over 25 000 participants), followed by lopinavir–ritonavir (seven trials) and remdesevir (five trials). There are many candidate drugs in pre‐clinical and early phase development, and these form a pipeline for future large clinical trials if current candidate therapies prove ineffective or unsafe.

Clinical trials for the prevention and treatment of COVID‐19: current state of play

There are few published data on the protection of masks or respirators against coronavirus infections. This is an important research question to inform the response to the COVID-19 epidemic. The transmission modes of human coronaviruses are similar, thought to be by droplet, contact and sometimes airborne routes. There are several randomised clinical trials of masks and respirators, but most used clinical endpoints or tested only for influenza. In four trials which we conducted, we tested for human coronaviruses, but only composite viral endpoints were reported in the trials. We reviewed and analysed the coronavirus data from four of our trials. Laboratory-confirmed coronavirus infections were identified in our community household trial (1 case), health worker trials (8 cases) and trial of mask use by sick patients (19 cases). No coronavirus infections were transmitted in households to parents who wore P2 or surgical masks, but one child with coronavirus infection transmitted infection to a parent in the control arm. No transmissions to close contacts occurred when worn by sick patients with coronavirus infections. There was a higher risk of coronavirus infection in HCWs who wore a mask compared to a respirator, but the difference was not statistically significant. These are the only available data on coronavirus infections associated with mask or respirator use. More clinical trials are needed to assess the efficacy of respiratory protection against coronavirus infections.

HUMAN CORONAVIRUS DATA FROM FOUR CLINICAL TRIALS OF MASKS AND RESPIRATORS

Human Coronavirus Data from Four Clinical Trials of Masks and Respirators

A Comprehensive Analysis of Clinical Trials in the COVID-19 Pandemic Era

The outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to global public health and economies Currently, hundreds of clinical trials on a wide variety of treatments against COVID-19 are being conducted around the world Here, we conducted a search for ongoing clinical trials for the treatment of COVID-19 at the clinicaltrials gov database on April 2, 2020 In total, 48 clinical trials were identified, and of these, 41 trials adopted drug intervention and the other 7 trials utilized biological intervention The number of trials stratified by a chief country conducting the investigation were 18 in China, 5 in the United States, 4 in Canada, 3 in Italy, 2 in France and Brazil, and 4 trials are being performed multinationally The drugs utilized in more than one trials were remdesivir (6 trials), lopinavir/ritonavir (6 trials), hydroxychloroquine (6 trials), interferon (5 trials), methylprednisolone (3 trials), nitric oxide gas (3 trials), oseltamivir (2 trials), arbidol (2 trials), and vitamin C (2 trials) We also described the Japanese trials which are now being conducted or scheduled, utilizing lopinavir/ritonavir, remdesivir, favipiravir, ciclesonide and nafamostat

Major ongoing clinical trials for COVID-19 treatment and studies currently being conducted or scheduled in Japan

Objective: To summarize the main characteristics of clinical studies regarding coronavirus disease 2019 (COVID-19) registered on the Chinese and US NIH Official Clinical Trial Registration Websites. Methods: To search all the clinical studies about COVID-19 which were registered on the Chinese and U.S. NIH official clinical trial registration websites until March 9, 2020. The search terms were "new coronavirus pneumonia (COVID-19), 2019-nCoV, novel coronavirus pneumonia". Results: Overall, 360 studies with a total sample size of 268, 773 participants are registered on Chinese clinical trial registration website, and 74 studies with a total sample size of 73, 723 participants in the U.S. NIH clinical trial registration website. According to the information provided by the Chinese Clinical Trial Registration Website, there are 237 interventional studies, 108 observational studies, and 15 diagnostic test studies; and the most commonly studied interventions were Traditional Chinese Medicine in 80 studies, antiviral therapy in 58 studies, stem cells in 19 studies, plasma of recovered patients in 13 studies, glucocorticoid in 7 studies, molecular targeted therapy in 4 studies, and vaccine in 2 studies. According to the information provided by the U.S. NIH Clinical Trial Registration Website, there were 54 interventional studies, 17 observational studies, and 3 diagnostic test studies; and the most commonly studied interventions were antiviral therapy in 16 studies, stem cells in 7 studies, Traditional Chinese Medicine in 6 studies, molecular targeted therapy in 3 studies, and vaccine in 3 studies. Conclusions Numerous clinical studies related to COVID-19 have been registered during a very short period. Among them, Traditional Chinese Medicine is the most commonly studied intervention, which suggests the Chinese characteristics in medical care. However, considering such a large sample size needed for these clinical studies, it is very important to ensure the enrollment of participants effectively and orderly in future.

Current status of clinical trial registration regarding coronavirus disease 2019

The novel coronavirus strain, severe acute respiratory syndrome coronavirus-2, the causative agent of COVID-19 emerged in Wuhan, China, in December 2019 and is skyrocketing throughout the globe and become a global public health emergency. Despite promising preventive measures being taken, there is no vaccine or drug therapy officially approved to prevent or treat the infection. Everybody is waiting the findings of ongoing clinical trials in various chemical and biological products. This review is specifically aimed to summarize the available evidence and ongoing clinical trials of remdesivir as a potential therapeutic option for COVID-19. Remdesivir is an investigational drug having broad spectrum antiviral activity with its target RNA dependent RNA polymerase. It has not yet been officially approved for Ebola and Coronaviruses. Several studies showed that remdesivir had promising in vitro and in vivo antiviral activities against SARS-CoV-1 and MERS-CoV strains. On the top of this, it exhibited a promising in vitro activity against SARS-CoV-2 strains though there are no published studies that substantiate its activity in vivo until the time of this review. There are few phase 3 randomized double-blind placebo controlled trials on the way to investigate the safety and efficacy of remdesivir. Of which, one completed double blind, placebo controlled trial showed that remdesivir showed faster time to clinical improvement in severe COVID-19 patients compared to placebo though not found statistically significant. In addition, two phase 3 randomized open label clinical trials coordinated by Gilead Sciences are being conducted. In addition, WHO Solidarity trial and INSERM DisCoVeRy trials (randomized open labels) were launched recently.

Available Evidence and Ongoing Clinical Trials of Remdesivir: Could It Be a Promising Therapeutic Option for COVID-19?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has reached global epidemic status claiming more than 319K lives and affecting more than 4 81M people and counting worldwide Considering the severity of the situation and low recovery rate many research institutions and pharmaceutical industries are rushing to learn more about this new virus and the morbid physiology of this disease with effective diagnostic methods, therapeutic agents and vaccines Various approaches are highlighted for comparing the possible treatment methods available for COVID-19 some of which are BCG vaccination on COVID-19 and Non-pharmaceutical interventions, drug based clinical trials of Hydroxychloroquine-Azithromycin, chloroquine, lopinavir/ritonavir, ChAdOx1 nCoV-19, Remdesivir, Stem Cell therapy and mesenchymal stromal cell therapy, etc

Current Clinical Trials and Vaccine Development Strategies for Corona Virus Disease (COVID-19)

INTRODUCTION: While the global COVID-19 pandemic has challenged the entire humanity and health systems, it also triggered researchers to urgently perform clinical trials to assess the safety and efficacy of many agents and modalities to combat COVID-19. As of April 22, over 650 clinical studies have been registered both in USA and internationally. Results from these studies are also coming at a brisk pace in this unprecedented emergency. AREAS COVERED: We searched the NCI website and Medline and summarize various national and international clinical trials and summarize few of the pivotal ones in this paper, including those specific to oncology population. Two hundred and eighty four studies are actively recruiting adults and children with confirmed COVID-19, including 25 are early-phase I/phase I, 72 phase II, 58 phase III, 12 phase IV, and 31 other trials. They can be categorized into four groups: drugs that combat SARS-CoV-2, immunomodulatory agents to counteract cytokine storm, convalescence plasma therapies and vaccines trials. EXPERT OPINION: It is hoped that these efforts will results in a successful treatment to COVID-19, especially in a timely fashion before the second pandemic expected in fall. It is essential to acknowledge the devotion and hard work of the clinical research team and clinical research volunteers.

COVID-19 Clinical Research

As of January 22, 2020, a total of 571 cases of the 2019-new coronavirus (2019-nCoV) have been reported in 25 provinces (districts and cities) in China. At present, there is no vaccine or antiviral treatment for human and animal coronavirus, so that identifying the drug treatment options as soon as possible is critical for the response to the 2019-nCoV outbreak. Three general methods, which include existing broad-spectrum antiviral drugs using standard assays, screening of a chemical library containing many existing compounds or databases, and the redevelopment of new specific drugs based on the genome and biophysical understanding of individual coronaviruses, are used to discover the potential antiviral treatment of human pathogen coronavirus. Lopinavir /Ritonavir, Nucleoside analogues, Neuraminidase inhibitors, Remdesivir, peptide (EK1), abidol, RNA synthesis inhibitors (such as TDF, 3TC), anti-inflammatory drugs (such as hormones and other molecules), Chinese traditional medicine, such ShuFengJieDu Capsules and Lianhuaqingwen Capsule, could be the drug treatment options for 2019-nCoV. However, the efficacy and safety of these drugs for 2019- nCoV still need to be further confirmed by clinical experiments.

Drug treatment options for the 2019-new coronavirus (2019-nCoV).

INTRODUCTION Since December 2019, there has been an outbreak of a novel beta-coronavirus (SARS-CoV-2) in Wuhan, China. On March the 11th the World Health Organization (WHO) declared COVID-19 as a pandemic, with over 118,000 cases in more than 110 countries around the world. In response to the global coronavirus disease 2019 (COVID-19) emergency, clinical trial research assessing the efficacy and safety of experimental vaccines to prevent COVID-19 are emerging at an unprecedented rate. The aim of this systematic review is to summarize the preliminary experiences and ongoing clinical trials of the major candidates and challenges of the vaccine strategies in humans. EVIDENCE ACQUISITION After a priori protocol registration with PROSPERO (181483), a systematic research of the published literature was conducted on 24 April 2020 using Medline (via PubMed), Embase (via Ovid), and WHO databases. Moreover, to explore the more recent literature we also searched the preprint server medRxiv. Finally, we scrutinized the Cochrane COVID-19 study register and the COVID-19 section of ClinicalTrials.gov database for identifying relevant ongoing clinical trials. Thereafter we selected the articles according to the PRISMA guidelines. Animal or in-vitro experimental studies were excluded. Moreover editorials, commentaries, abstracts, reviews, book chapters, and articles not in English were not included. EVIDENCE SYNTHESIS Our search identified 1359 published papers, 478 pre-print articles and 367 ongoing clinical trials. Finally, only ten ongoing clinical trials met the inclusion criteria. Specifically, seven developed vaccines for the S protein of SARS-CoV-2 and three clinical trials assessed the protective role of BCG vaccine against COVID-19. The first group included phase I/II trials with different types of molecules (DNA or mRNA vaccine, bacterial plasmid or viral vectors), the latter were phase III/IV trials designed on the basis of a heterologous lymphocyte activation by the BCG vaccine. CONCLUSIONS This new disease is pushing the scientific community to develop swiftly a safe and effective vaccine. Notwithstanding the limitations of our analysis, given by the absence of available results, we try to provide a comprehensive view of the ongoing clinical trials in humans. Our analysis reveals a worldwide effort of both scientists and enterprises to achieve one of the most challenging goals of our century.

The vaccine journey for COVID-19: a comprehensive systematic review of current clinical trials in humans.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has prompted the repurposing of drugs on the basis of promising in vitro and therapeutic results with other human coronavirus diseases such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). These repurposed drugs have mainly included remdesivir, favipiravir, lopinavir/ritonavir, ribavirin, interferons, and hydroxychloroquine. Unfortunately, the first open-label, randomized controlled trials are showing the poor efficacy of these repurposed drugs. These results highlight the necessity of identifying and characterizing specific and potent SARS-CoV-2 antivirals.

Clinical trials of repurposed antivirals for SARS-CoV-2

INTRODUCTION: Since December 2019, there has been an outbreak of a novel beta-coronavirus (SARS-CoV-2) in Wuhan, China. On March the 11th the World Health Organization (WHO) declared COVID-19 as a pandemic, with over 118,000 cases in more than 110 countries around the world. In response to the global coronavirus disease 2019 (COVID-19) emergency, clinical trial research assessing the efficacy and safety of experimental vaccines to prevent COVID-19 are emerging at an unprecedented rate. The aim of this systematic review is to summarize the preliminary experiences and ongoing clinical trials of the major candidates and challenges of the vaccine strategies in humans. EVIDENCE ACQUISITION: After a priori protocol registration with PROSPERO (181483), a systematic research of the published literature was conducted on 24 April 2020 using Medline (via PubMed), Embase (via Ovid), and WHO databases. Moreover, to explore the more recent literature we also searched the preprint server medRxiv. Finally, we scrutinized the Cochrane COVID-19 study register and the COVID-19 section of ClinicalTrials.gov database for identifying relevant ongoing clinical trials. Thereafter we selected the articles according to the PRISMA guidelines. Animal or in-vitro experimental studies were excluded. Moreover editorials, commentaries, abstracts, reviews, book chapters, and articles not in English were not included. EVIDENCE SYNTHESIS: Our search identified 1359 published papers, 478 pre-print articles and 367 ongoing clinical trials. Finally, only ten ongoing clinical trials met the inclusion criteria. Specifically, seven developed vaccines for the S protein of SARS-CoV-2 and three clinical trials assessed the protective role of BCG vaccine against COVID-19. The first group included phase I/II trials with different types of molecules (DNA or mRNA vaccine, bacterial plasmid or viral vectors), the latter were phase III/IV trials designed on the basis of a heterologous lymphocyte activation by the BCG vaccine. CONCLUSIONS: This new disease is pushing the scientific community to develop swiftly a safe and effective vaccine. Notwithstanding the limitations of our analysis, given by the absence of available results, we try to provide a comprehensive view of the ongoing clinical trials in humans. Our analysis reveals a worldwide effort of both scientists and enterprises to achieve one of the most challenging goals of our century.

The vaccine journey for COVID-19: a comprehensive systematic review of current clinical trials in humans

TYPE: Abstract Publication TOPIC: Respiratory Care PURPOSE: 2019 novel coronavirus (2019-nCoV) is attributed for outbreak with first human infection detected in December 2019 in Wuhan, China, which has caused clusters of severe respiratory illness like severe acute respiratory syndrome coronavirus. The latest mortality was 2.07%. Currently, the standard care is supportive care, and no treatment is proven to be effective METHODS: We systematically analysed the contemporary protocols of the seven ongoing trials through the Chinese Clinical Trial Registry (4 trials) and the trials registry (3 trials) database. The latest evaluation was on January 29, 2020 with key word ‘2019-nCoV’, for the trials evaluating the diagnostic and the therapeutic interventions to manage the respiratory infection caused by 2019-nCoV RESULTS: Therapeutic interventions include, lopinavir-ritonavir with aerosolized interferon-alpha compared with the adjunctive IV methylprednisolone, umifenovir (broad-spectrum antiviral), SARI-nCoV trial for role of glucocorticoid, three comparative antiviral therapies utilising ribavirin, interferon alpha-1b, lopinavir -ritonavir, Xue-Bi-Jing injection (only Chinese medicine injection approved for sepsis) and novel isothermal nucleic acid amplification technique is under trial for simple, fast and portable diagnosis. The mean number of patients being enrolled is 193 (SD ± 183, maximum 500, minimum 40, range 460, 95% CI 24 to 362). Cumulatively, 1350 patients are targeted across 7 trials. CONCLUSIONS: Varied novel approaches based on the current scientific understanding of the disease are being evaluated for quick and effective management CLINICAL IMPLICATIONS: As the 2019-nCoV becomes a global threat, the rapidity of the Chinese trials for an evidence-based approach are in direction to provide rational, efficacious and potential solutions to effectively manage the disease DISCLOSURE: No significant relationships. KEYWORDS: Ongoing Trials, Systematic Review, 2019-nCoV

SYSTEMATIC REVIEW OF THE ONGOING CLINICAL TRIALS EVALUATING THE DIAGNOSTIC AND THERAPEUTIC INTERVENTIONS TO MANAGE THE RESPIRATORY INFECTION CAUSED BY 2019 NOVEL CORONAVIRUS (2019-NCOV)

Drug treatment options for the 2019-new coronavirus (2019-nCoV)

The recent, fatal outbreak of the novel coronavirus strain in the Middle East highlights the real threat posed by this unique virus family. Neither pharmaceutical cures nor preventive vaccines are clinically available to fight against coronavirus associated syndromes, not to mention a lack of symptom soothing drugs. Development of treatment options is complicated by the unpredictable, recurring instances of cross-species viral transmission. The vastly distributing virus reservoir and the rapid rate of host-species exchange of coronavirus demands wide spectrum potency in an ideal therapeutic. Through summarizing the available information and progress in coronavirus research, this review provides a systematic assessment of the potential wide-spectrum features on the most popular drug targets including viral proteases, spike protein, RNA polymerases and editing enzymes as well as host-virus interaction pathways associated with coronaviruses.

Drug Targets for Rational Design against Emerging Coronaviruses.

Drug targets for rational design against emerging coronaviruses.

Coronavirus drugs trials must get bigger and more collaborative.

In late December 2019, a group of patients was observed with pneumonia-like symptoms that were linked with a wet market in Wuhan, China. The patients were found to have a novel coronavirus genetically related to a bat coronavirus that was termed SARS-CoV-2. The virus gradually spread worldwide and was declared a pandemic by WHO. Scientists have started trials on potential preventive and treatment options. Currently, there is no specific approved treatment for SARS-CoV-2, and various clinical trials are underway to explore better treatments. Some previously approved antiviral and other drugs have shown some in vitro activity. Here we summarize the fight against this novel coronavirus with particular focus on the different treatment options and clinical trials exploring treatment as well as work done toward development of vaccines.

Emergence of novel coronavirus and progress toward treatment and vaccine

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health crisis since its initial reports in China. Since no effective vaccine or drug has been developed to treat and combat the COVID-19, the current approaches for clinical management focus on supportive care. There is a pressing need for evidence-based interventions to address the devastating clinical and public health effects of the COVID-19 pandemic. The Chinese scientists supported by private and government resources have adopted extensive efforts to identify effective drugs against the virus. To date, a large number of clinical trials addressing various aspects of COVID-19 have been registered in the Chinese Clinical Trial Registry (ChiCTR), including more than 200 interventional studies. Under such an urgent circumstance, the scope and quality of these clinical studies vary significantly. Hence, this review aims to make a comprehensive analysis on the profiles of COVID-19 clinical trials registered in the ChiCTR, including a wide range of characteristics. Our findings will provide a useful summary on these clinical studies, since most of these studies will encounter major challenges from the design to completion. It will be a long road for the outcomes of these studies to be published and international collaboration will help the ultimate goals of developing new vaccines and antiviral drugs. Trial registration: ClinicalTrials.gov identifier: NCT04252664.. Trial registration: ClinicalTrials.gov identifier: NCT04257656..

Profiles of COVID-19 clinical trials in the Chinese Clinical Trial Registry.

We have read the article by Zhang et al. published in the recent issue of the Journal of Medical Virology1 . Zhang and his colleagues have made a cross-sectional survey of currently registered clinical trials concerning 2019-nCoV, including the published literature. As such, they have given a preliminary assessment on the prospects of therapy for 2019-nCoV. This article is protected by copyright. All rights reserved.

Comments on Zhang et al: Clinical trial analysis of 2019‐nCoV therapy registered in China

We thank Dr. Yang and colleagues for their attention to our article1,2 . And we appreciate their meaningful suggestions, which we highly agree with. With the purpose of letting the public know the overall situation of the clinical trials of new coronary pneumonia in China as soon as possible, we completed the data collection and brief analysis in a very short time. This article is protected by copyright. All rights reserved.

Response to "Comments on 'Zhang et al.: Clinical trial analysis of 2019-nCoV therapy registered in China '".

As of March 10, 2020, more than 100,000 novel coronavirus pneumonia cases have been confirmed globally. With the continuous spread of the new coronavirus pneumonia epidemic in even the world, prevention and treatment of the disease have become urgent tasks. The drugs currently being developed are not adequate to deal with this critical situation. In addition to being controlled through effective isolation, we need a rapid response from the healthcare and biotechnology industries to accelerate drug treatment research. By reviewing the currently available literature published at home and abroad, we summarize the current research progress of drug treatment during the epidemic period. At present, the drugs that can be used for treatment mainly include antiviral drugs, antimalarials, glucocorticoids, plasma therapy, biological agents, and traditional Chinese medicine. The effectiveness and safety of drug therapy need to be confirmed by more clinical studies.

Research Progress of Drug Treatment in Novel Coronavirus Pneumonia

Coronaviruses are positive stranded RNA viruses that cause respiratory, enteric and central nervous system diseases in many species, including humans. Until recently, the relatively low burden of disease in humans caused by few of these viruses impeded the development of coronavirus specific therapeutics. However, the emergence of severe acute respiratory syndrome coronavirus (SARS-CoV), and more recently, Middle East respiratory syndrome coronavirus (MERS-CoV), has impelled the development of such drugs. This review focuses on some newly identified SARS-CoV inhibitors, with known mechanisms of action and their potential to inhibit the novel MERS-CoV. The clinical development of optimized versions of such compounds could be beneficial for the treatment and control of SARS-CoV, the current MERS-CoV and other future SARS-like epidemics.

Antiviral Drugs Specific for Coronaviruses in Preclinical Development

Clinical trials of repurposed antivirals for SARS-CoV-2.

Finding efficacious and safe treatments for COVID-19 emerges as a crucial need in order to control the spread of the pandemic. Whereas plasma therapy attracts much interest, the European project Discovery focuses on the potentialities of small molecules like remdesivir, the combination of lopinavir/ritonavir, hydroxychloroquine, and chloroquine. Results recently published on the clinical evaluation of those drugs are compiled in this brief report, although complete data are still impatiently awaited.

COVID-19: An Update about the Discovery Clinical Trial

Profiles of COVID-19 clinical trials in the Chinese Clinical Trial Registry

BACKGROUND: The purpose of the current systematic review is to evaluate the efficacy of antiviral therapies in treatment of COVID-19. In addition, clinical trials on the efficacy of antiviral therapies in the management of Severe Acute Respiratory Syndrome coronavirus (SARS-Cov) or Middle East Respiratory Syndrome coronavirus (MERS-CoV) have also been reviewed, in order to identify potential treatment options for COVID-19. METHOD: An extensive search was performed in Medline, Embase, Scopus, Web of Science and CENTRAL databases until the end of March 15, 2020. Two independent researchers performed the screening, and finally the related studies were included. RESULTS: Only one clinical trial on the efficacy of antiviral therapy in management of COVID-19 was found. The results depicted that adding Lopinavir-Ritonavir to the standard treatment regimen of patients with severe COVID-19 has no benefits. Moreover, 21 case-series and case-report studies reported the prescription of antiviral agents in COVID-19, none of which can be used to determine the efficacy of antiviral therapies in confronting COVID-19. In addition, no clinical trials were found to be performed on the efficacy of antiviral agents in the management of SARS-CoV and MERS-CoV. CONCLUSION: The current evidence impede researchers from proposing an appropriate antiviral therapy against COVID-19, making the current situation a serious concern for international organizations such as World Health Organization (WHO). In the time of the current pandemic and future epidemics, organizations such as WHO should pursue more proactive actions and plan well-designed clinical trials so that their results can be used in managing future epidemics.

Antiviral therapy in management of COVID-19: a systematic review on current evidence

COVID-19 Clinical Trials: A Primer for the Cardiovascular and Cardio-Oncology Communities

Controlled human challenge trials of SARS-CoV-2 vaccine candidates could accelerate the testing and potential rollout of efficacious vaccines. By replacing conventional phase 3 testing of vaccine candidates, such trials may subtract many months from the licensure process, making efficacious vaccines available more quickly. Obviously, challenging volunteers with this live virus risks inducing severe disease and possibly even death. However, we argue that such studies, by accelerating vaccine evaluation, could reduce the global burden of coronavirus-related mortality and morbidity. Volunteers in such studies could autonomously authorize the risks to themselves, and their net risk could be acceptable if participants comprise healthy young adults, who are at relatively low risk of serious disease following natural infection, if they have a high baseline risk of natural infection, and if during the trial they receive frequent monitoring and, following any infection, the best available care.

Human Challenge Studies to Accelerate Coronavirus Vaccine Licensure

Coronavirus drugs trials must get bigger and more collaborative

Since a novel coronavirus pneumonia outbreak in late December 2019, coronavirus disease -19 (COVID-19) epidemic has gradually spread worldwide, becoming a major public health event. No specific antivirals are currently available for COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The treatments for COVID-19 are mainly based on the experiences of similar virus such SARS-CoV, MERS-CoV, HIV and influenza viruses. Scientists have taken great efforts to investigate the effective methods for the treatment of COVID-19. Up to now, there are over 1000 clinical studies for COVID-19 all over the world. In this article, we reviewed the current options for COVID-19 therapy including small molecules such as Remdesivir, Favipiravir, Lopinavir/Ritonavir etc, peptide inhibitors of ACE2, Traditional Chinese Medicines and Biologics such as SARS-CoV-2-specific neutralizing antibodies, mesenchymal stem cells and vaccines etc. Meanwhile, we systematically reviewed their clinical safety, clinical applications and progress of antiviral researches. The therapeutic effect of these antiviral drugs is summarized and compared, hoping to provide some ideas for clinical options of COVID-19 treatment and also provide experiences for the life-threatening virus diseases in the future.

An overview of the safety, clinical application and antiviral research of the COVID-19 therapeutics

Background: As novel coronavirus disease (COVID-19) cases continue to steeply rise globally within an unprecedented short period of time, solid evidence from large randomised controlled trials is still lacking. Currently, numerous trials testing potential treatment and preventative options are undertaken globally. Objectives: We summarised all currently registered clinical trials examining treatment and prevention options for COVID-19 pneumonia. Additionally, we evaluated the quality of the retrieved interventional studies. Data sources: The ClinicalTrials.gov, the Chinese Clinical Trial Registry and the European Union Clinical Trials Register were systematically searched. Study eligibility criteria: Registered clinical trials examining treatment and/or prevention options for COVID-19 were included. No language, country or study design restrictions were applied. Withdrawn, cancelled studies and trials not reporting therapeutic or preventative strategies for COVID-19 were excluded. Participants and interventions: No restrictions in terms of participants' age and medical background or type of intervention were enforced. Methods: The registries were searched using the term "coronavirus" or "COVID-19" from their inception until 26th March 2020. Additional manual search of the registries was also performed. Eligible studies were summarised and tabulated. Interventional trials were methodologically analysed, excluding expanded access studies and trials testing Traditional Chinese Medicine. Results: In total, 309 trials evaluating therapeutic management options, 23 studies assessing preventive strategies and 3 studies examining both were retrieved. Interventional treatment studies were mostly randomised (n=150, 76%) and open-label (n=73, 37%) with a median number of planned inclusions of 90 (IQR 40-200). Major categories of interventions that are currently being investigated are discussed. Conclusion: Numerous clinical trials have been registered since the onset of the COVID-19 pandemic. Summarised data on these trials will assist physicians and researchers to promote patient care and guide future research efforts for COVID-19 pandemic containment. However, up to the end of March, 2020, significant information concerning reported trials was lacking.

Review and methodological analysis of trials currently testing treatment and prevention options for the novel coronavirus disease (COVID-19) globally.

Abstract Coronaviruses may cause respiratory, enteric and central nervous system diseases in many species, including humans. Until recently, the relatively low burden of disease in humans caused by few of these viruses hampered development of coronavirus specific therapeutics. However, the emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) has prompted the discovery of such drugs. Subsequent studies in animal models demonstrated the efficacy of SARS-CoV specific monoclonal antibodies, pegylated-interferon-α and siRNAs against SARS-CoV. Furthermore, several antivirals shown to be effective against other viruses were tested in vitro. Because of availability and shown efficacy, the use of interferons may be considered should SARS-CoV or a related coronavirus (re)-emerge. The more recent design of wide-spectrum inhibitors targeting the coronavirus main proteases may lead to the discovery of new antivirals against multiple coronavirus induced diseases.

Coronaviruses and their therapy

Abstract The COVID-19 pandemic has resulted in a proliferation of clinical trials that are designed to slow the spread of SARS-CoV-2, the virus that causes COVID-19. The overwhelming majority of cardiovascular and cancer patients are at increased risk for SARS-CoV-2 infection; accordingly, the cardiovascular and cardio-oncology communities are playing a major role in caring for COVID-19 patients. Many of the therapeutic agents that are being used to treat patients with COVID-19 are repurposed treatments for influenza, drugs that were not effective in Ebola patients, or treatments for malaria that were developed decades ago, and are unlikely to be familiar to the cardiovascular and cardio-oncology communities. Here we have provided a foundation for cardiovascular and cardio-oncology physicians who are on the frontline providing care to COVID-19 patients, so that they can better understand the emerging cardiovascular epidemiology of COVID-19, as well as the biological rationale for the clinical trials that are ongoing for the treatment of COVID-19 patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), initially termed 2019-new CoV (2019-nCoV), is a novel coronavirus responsible for the severe respiratory illness currently ongoing worldwide from the beginning of December 2019. This beta gene virus, very close to bat coronaviruses (bat-CoV-RaTG13) and bat-SL-CoVZC45, causes a severe disease, similar to those caused by Middle East respiratory syndrome (MERS)-CoV and SARS-CoV viruses, featured by low to moderate mortality rate. Unfortunately, the antiviral drugs commonly used in clinical practice to treat viral infections, are not applicable to SARS-Cov-2 and no vaccine is available. Thus, it is extremely necessary to identify new drugs suitable for the treatment of the 2019-nCoV outbreak. Different preclinical studies conducted on other coronaviruses suggested that promising clinical outcomes for 2019-nCoV should be obtained by using alpha-interferon, chloroquine phosphate, arabinol, remdesivir, lopinavir/ritonavir, and anti-inflammatory drugs. Moreover, clinical trials with these suitable drugs should be performed on patients affected by SARS-Cov-2 to prove their efficacy and safety. Finally, a very promising therapeutic drug, tocilizumab, is discussed; it is currently used to treat patients presenting COVID-19 pneumonia. Herein, we recapitulate these experimental studies to highlight the use of antiviral drugs for the treatment of SARS-Cov-2 disease.

Potential Antiviral Drugs for SARS-Cov-2 Treatment: Preclinical Findings and Ongoing Clinical Research.

Abstract The novel coronavirus disease (COVID-19) is spreading rapidly, a pandemic that has already affected millions of people across the world Currently there are no vaccines or drugs approved for COVID-19 Initial data which are coming from large clinical trials using Hydroxychloroquine, Lopinavir/Ritonavir, Remdesevir, and Favipiravir are not satisfactory against COVID-19 till now and we are in the midst of a worldwide public health threat In this context human convalescent plasma is considered as an option for treatment of COVID-19 disease Convalescent plasma therapy is a classic adaptive immunotherapy which involves the administration of antibodies against COVID-19 to a COVID-19 patient for the purpose of treating the viral disease Over the last two decades, convalescent plasma therapy was used for the treatment of 2003 SARS-CoV-1 epidemic, 2009-2010 H1N1 influenza virus pandemic, the 2012 Middle East Respiratory Syndrome (MERS)-CoV epidemic and 2014-2016 Ebola epidemic

Randomization amid a pandemic - a critical appraisal regarding convalescent plasma therapy clinical trials for COVID-19 patients

In humans, infections with the human coronavirus (HCoV) strains HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1 usually result in mild, self-limiting upper respiratory tract infections, such as the common cold. By contrast, the CoVs responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which were discovered in Hong Kong, China, in 2003, and in Saudi Arabia in 2012, respectively, have received global attention over the past 12 years owing to their ability to cause community and health-care-associated outbreaks of severe infections in human populations. These two viruses pose major challenges to clinical management because there are no specific antiviral drugs available. In this Review, we summarize the epidemiology, virology, clinical features and current treatment strategies of SARS and MERS, and discuss the discovery and development of new virus-based and host-based therapeutic options for CoV infections. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nrd.2015.37) contains supplementary material, which is available to authorized users.

Coronaviruses — drug discovery and therapeutic options

The COVID-19 pandemic represents the greatest global public health crisis since the pandemic influenza outbreak of 1918. We are facing a new virus, so several antiviral agents previously used to treat other coronavirus infections such as SARS and MERS are being considered as the first potential candidates to treat COVID-19. Thus, several agents have been used by the beginning of the current outbreak in China first and all over the word successively, as reported in several different guidelines and therapeutic recommendations. At the same time, a great number of clinical trials have been launched to investigate the potential efficacy therapies for COVID-19 highlighting the urgent need to get as quickly as possible high-quality evidence. Through PubMed, we explored the relevant articles published on treatment of COVID-19 and on trials ongoing up to April 15, 2020.

Update on treatment of COVID-19: ongoing studies between promising and disappointing results.

COVID-19 has rapidly developed into a worldwide pandemic with a significant health and economic burden. There are currently no approved treatments or preventative therapeutic strategies. Hundreds of clinical studies have been registered with the intention of discovering effective treatments. Here, we review currently registered interventional clinical trials for the treatment and prevention of COVID-19 to provide an overall summary and insight into the global response.

Ongoing Clinical Trials for the Management of the COVID-19 Pandemic

Background The purpose of the current systematic review is to evaluate the efficacy of antiviral therapies in treatment of COVID-19. In addition, clinical trials on the efficacy of antiviral therapies in the management of Severe Acute Respiratory Syndrome coronavirus (SARS-Cov) or Middle East Respiratory Syndrome coronavirus (MERS-CoV) have also been reviewed, in order to identify potential treatment options for COVID-19. Method An extensive search was performed in Medline, Embase, Scopus, Web of Science and CENTRAL databases until the end of March 15, 2020. Two independent researchers performed the screening, and finally the related studies were included. Results Only one clinical trial on the efficacy of antiviral therapy in management of COVID-19 was found. The results depicted that adding Lopinavir-Ritonavir to the standard treatment regimen of patients with severe COVID-19 has no benefits. Moreover, 21 case-series and case-report studies reported the prescription of antiviral agents in COVID-19, none of which can be used to determine the efficacy of antiviral therapies in confronting COVID-19. In addition, no clinical trials were found to be performed on the efficacy of antiviral agents in the management of SARS-CoV and MERS-CoV. Conclusion The current evidence impede researchers from proposing an appropriate antiviral therapy against COVID-19, making the current situation a serious concern for international organizations such as World Health Organization (WHO). In the time of the current pandemic and future epidemics, organizations such as WHO should pursue more proactive actions and plan well-designed clinical trials so that their results can be used in managing future epidemics.

Antiviral therapy in management of COVID-19: a systematic review on current evidence.

Potential Antiviral Drugs for SARS-Cov-2 Treatment: Preclinical Findings and Ongoing Clinical Research

INTRODUCTION: In December 2019, an outbreak of pneumonia caused by a novel coronavirus occurred in Wuhan, the capital of Central China's Hubei Province and has been declared a public health emergency of international concern by the World Health Organization since January 2020. MATERIAL AND METHODS: A comprehensive search using the PubMed database was carried out to summarize the latest published information about the epidemiology, definition, pathogenesis, clinical characteristics, treatment options, prognosis and prevention of coronavirus disease 2019. DISCUSSION: This new strain of coronavirus, named severe acute respiratory syndrome coronavirus 2, enters human cells that express angiotensin-converting enzyme II receptors, which exist in the respiratory, gastrointestinal and genitourinary tracts and heart, causing coronavirus disease. Transmission occurs essentially through the respiratory tract and the main symptoms are fever, cough and dyspnea. Diagnosis is based on epidemiological, clinical and imaging features and confirmed by nucleic acid testing. CONCLUSION: Despite intensive research, the exact origin of the virus and pathophysiology of coronavirus disease is not yet completely known, and clinically approved vaccines and drugs that target severe acute respiratory syndrome coronavirus 2 are lacking.

Coronavirus Disease 2019: Clinical Review

SARS-CoV-2/novel coronavirus (2019-nCoV) is a new strain that has recently been confirmed in Wuhan City, Hubei Province of China, and spreads to more than 165 countries of the world including India. The virus infection leads to 245,922 confirmed cases and 10,048 deaths worldwide as of March 20, 2020. Coronaviruses (CoVs) are lethal zoonotic viruses, highly pathogenic in nature, and responsible for diseases ranging from common cold to severe illness such as Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) in humans for the past 15 years. Considering the severity of the current and previous outbreaks, no approved antiviral agent or effective vaccines are present for the prevention and treatment of infection during the epidemics. Although, various molecules have been shown to be effective against coronaviruses both in vitro and in vivo, but the antiviral activities of these molecules are not well established in humans. Therefore, this chapter is planned to provide information about available treatment and preventive measures for the coronavirus infections during outbreaks. This chapter also discusses the possible role of supportive therapy, repurposing drugs, and complementary and alternative medicines for the management of coronaviruses including COVID-19.

Therapeutic Development and Drugs for the Treatment of COVID-19

The severe acute respiratory syndrome virus (SARS-CoV-2), a novel coronavirus first discovered in Wuhan, China in December 2019 causes the Coronavirus Disease 19 (COVID-19), which presents with a wide range of clinical symptoms from mild or moderate to severe and critical illnesses With the continuing transmission of the virus worldwide and the rapidly evolving situation globally, the World Health Organization (WHO) declared the COVID-19 outbreak a pandemic in March Currently, there is no proven specific treatment for this potentially deadly disease beyond supportive care However, a massive effort has been put globally into the investigation of medications and other interventional measures to fight COVID-19 Convalescent plasma therapy from recovered patients has recently drawn considerable interest Several alternative medical treatments, although evidence of their efficacy still lacking, have also gained popularity, especially in countries with such traditions such as India and China Rapid repurposing of drugs for COVID-19 has revealed a few promising candidate antiviral agents, but further research, especially high quality randomized controlled trials, will be needed to prove their efficacy and safety in the clinical use to treat COVID-19 Vaccine development has been the imperative task in the battle against SARS-CoV-2 While clinical trials have been launched for several candidate vaccines, research on COVID-19 vaccines is still at an early stage So far, optimized supportive care remains the best practice against COVID-19

Current Status of Treatment Options, Clinical Trials, and Vaccine Development for SARS-CoV-2 Infection

As this ever-evolving pandemic lays itself, more of its impact is being understood. Until recently, most guidelines were reported to aid in managing and treating suspected or confirmed cases. Research institutions around the world are responding with a sense of confusion. Some are continuing routinely, especially those who are overseeing clinical trials that could offer life-saving therapies, particularly against the novel coronavirus. Since research must continue even in the face of a shutdown, we aim to collate the currently available recommendations from various organizations and provide guidance to head and neck researchers across the world during these trying times.

Clinical trials during COVID-19

As this ever‐evolving pandemic lays itself, more of its impact is being understood. Until recently, most guidelines were reported to aid in managing and treating suspected or confirmed cases. Research institutions around the world are responding with a sense of confusion. Some are continuing routinely, especially those who are overseeing clinical trials that could offer life‐saving therapies, particularly against the novel coronavirus. Since research must continue even in the face of a shutdown, we aim to collate the currently available recommendations from various organizations and provide guidance to head and neck researchers across the world during these trying times.

Clinical trials during COVID‐19

The ongoing novel coronavirus disease 2019 (COVID-19) pandemic has been responsible for millions of infections and hundreds of thousands of deaths. To date, there is no approved targeted treatment, and many investigational therapeutic agents and vaccine candidates are being considered for the treatment of COVID-19. To extract and summarize information on potential vaccines and therapeutic agents against COVID-19 at different stages of clinical trials from January to March 2020, we reviewed major clinical trial databases such as ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP), and other primary registries between January and March 15, 2020. Interventional studies at different phases under the COVID-19 pipeline were included. A total of 249 clinical trials were identified between January to March 15, 2020. After filtering observational studies (194 studies), a total of 56 interventional trials were considered. The majority of clinical trials have been conducted on chloroquine (n=10) and traditional Chinese medications (TCMs; n=10), followed by antivirals (n=8), anti-inflammatory/immunosuppressants (n=9), cellular therapies (n=4), combinations of different antivirals therapies (n=3), antibacterial (n=1), and other therapies (n=5). Five vaccines are under phase I, and there are a couple of phase III trials on the Bacillus Calmette-Guérin (BCG) vaccine under investigation among healthcare workers. Many novel compounds and vaccines against COVID-19 are currently under investigation. Some candidates have been tested for other viral infections and are listed for clinical trials against the COVID-19 pipeline. Currently, there are no effective specific antivirals or drug combinations available for the treatment of COVID-19.

Vaccines and Drug Therapeutics to Lock Down Novel Coronavirus Disease 2019 (COVID-19): A Systematic Review of Clinical Trials

The sudden outbreak of 2019 novel coronavirus (2019-nCoV, later named SARS-CoV-2) in Wuhan, China, which rapidly grew into a global pandemic, marked the third introduction of a virulent coronavirus into the human society, affecting not only the healthcare system, but also the global economy. Although our understanding of coronaviruses has undergone a huge leap after two precedents, the effective approaches to treatment and epidemiological control are still lacking. In this article, we present a succinct overview of the epidemiology, clinical features, and molecular characteristics of SARS-CoV-2. We summarize the current epidemiological and clinical data from the initial Wuhan studies, and emphasize several features of SARS-CoV-2, which differentiate it from SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), such as high variability of disease presentation. We systematize the current clinical trials that have been rapidly initiated after the outbreak of COVID-19 pandemic. Whereas the trials on SARS-CoV-2 genome-based specific vaccines and therapeutic antibodies are currently being tested, this solution is more long-term, as they require thorough testing of their safety. On the other hand, the repurposing of the existing therapeutic agents previously designed for other virus infections and pathologies happens to be the only practical approach as a rapid response measure to the emergent pandemic, as most of these agents have already been tested for their safety. These agents can be divided into two broad categories, those that can directly target the virus replication cycle, and those based on immunotherapy approaches either aimed to boost innate antiviral immune responses or alleviate damage induced by dysregulated inflammatory responses. The initial clinical studies revealed the promising therapeutic potential of several of such drugs, including favipiravir, a broad-spectrum antiviral drug that interferes with the viral replication, and hydroxychloroquine, the repurposed antimalarial drug that interferes with the virus endosomal entry pathway. We speculate that the current pandemic emergency will be a trigger for more systematic drug repurposing design approaches based on big data analysis.

A Review of SARS-CoV-2 and the Ongoing Clinical Trials

Abstract With the recent emergence of Middle East Respiratory Syndrome coronavirus in humans and the outbreak of devastating porcine epidemic diarrhea coronavirus in swine, therapeutic intervention is urgently needed. However, anti-coronavirus drugs currently are not available. In an effort to assist rapid development of anti-coronavirus drugs, here we screened the NIH Clinical Collection in cell culture using a luciferase reporter-expressing recombinant murine coronavirus. Of the 727 compounds screened, 84 were found to have a significant anti-coronavirus effect. Further experiments revealed that 51 compounds blocked virus entry while 19 others inhibited viral replication. Additional validation studies with the top 3 inhibitors (hexachlorophene, nitazoxanide and homoharringtonine) demonstrated robust anti-coronavirus activities (a reduction of 6 to 8log10 in virus titer) with an IC50 ranging from 11nM to 1.2μM. Furthermore, homoharringtonine and hexachlorophene exhibited broad antiviral activity against diverse species of human and animal coronaviruses. Since the NIH Clinical Collection consists of compounds that have already been through clinical trials, these small molecule inhibitors have a great potential for rapid development as anti-coronavirus drugs.

A screen of the NIH Clinical Collection small molecule library identifies potential anti-coronavirus drugs

Abstract Background The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was first described in 2012 and attracted a great international attention due to multiple healthcare associated outbreaks. The disease carries a high case fatality rate of 34.5%, and there is no internationally or nationally recommended therapy. Method We searched MEDLINE, Science Direct, Embase and Scopus databases for relevant papers published till March 2019 describing in vitro, in vivo or human therapy of MERS. Results Initial search identified 62 articles: 52 articles were from Medline, 6 from Embase, and 4 from Science Direct. Based on the inclusions and exclusions criteria, 30 articles were included in the final review and comprised: 22 in vitro studies, 8 studies utilizing animal models, 13 studies in humans, and one study included both in vitro and animal model. There are a few promising therapeutic agents on the horizon. The combination of lopinavir/ritonavir and interferon-beta- 1b showed excellent results in common marmosets and currently is in a randomized control trial. Ribavirin and interferon were the most widely used combination and experience comes from a number of observational studies. Although, the data are heterogenous, this combination might be of potential benefit and deserve further investigation. There were no randomized clinical trials to recommend specific therapy for the treatment of MERS-CoV infection. Only one such study is planned for randomization and is pending completion. The study is based on a combination of lopinavir/ritonavir and interferon-beta- 1b. A fully human polyclonal IgG antibody (SAB-301) was safe and well tolerated in healthy individuals and this agent may deserve further testing for efficacy. Conclusion Despite multiple studies in humans there is no consensus on the optimal therapy for MERS-CoV. Randomized clinical trials are needed and potential therapies should be evaluated only in such clinical trials. In order to further enhance the therapeutic aroma for MERS-CoV infection, repurposing old drugs against MERS-CoV is an interesting strategy and deserves further consideration and use in clinical settings.

A Systematic Review of therapeutic agents for the treatment of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV)

PURPOSE OF REVIEW Severe acute respiratory syndrome is a new, sometimes lethal disease of humans that is caused by a novel coronavirus. To date there have been over 750 related deaths and there is clearly an urgent need to develop specific antiviral drugs to combat this disease. In this review, the authors shall focus on the molecular biology of the coronavirus and suggest how this information can be used to identify possible targets for antiviral drugs. RECENT FINDINGS Within a remarkably short period of time, the severe acute respiratory syndrome coronavirus has been isolated, its genome has been sequenced and the structure of at least one key viral enzyme has been deduced. In addition, bioinformatic analysis has predicted a number of enzymatic activities associated with proteins of the viral replicase-transcriptase complex. In some cases, these functions have been confirmed by biochemical analysis. Thus, there has been significant progress in the rational approach to anti-severe acute respiratory syndrome coronavirus drug design. This approach, combined with the random screening of licensed compounds or existing compound libraries, should result in the identification of novel lead compounds and the expeditious development of antiviral drugs. SUMMARY Although the initial severe acute respiratory syndrome epidemic has been controlled by conventional measures, the animal reservoir for the coronavirus progenitor has not been identified. It is therefore likely that the virus will be reintroduced into the human population in the future. When this happens, the most economical and effective way to contain the virus will be the therapeutic use of antiviral drugs.

Potential for antiviral treatment of severe acute respiratory syndrome.

A survey of 434 clinical trials about coronavirus disease 2019 in China

In late December 2019, a group of patients was observed with pneumonia‐like symptoms that were linked with a wet market in Wuhan, China. The patients were found to have a novel coronavirus genetically related to a bat coronavirus that was termed SARS‐CoV‐2. The virus gradually spread worldwide and was declared a pandemic by WHO. Scientists have started trials on potential preventive and treatment options. Currently, there is no specific approved treatment for SARS‐CoV‐2, and various clinical trials are underway to explore better treatments. Some previously approved antiviral and other drugs have shown some in vitro activity. Here we summarize the fight against this novel coronavirus with particular focus on the different treatment options and clinical trials exploring treatment as well as work done toward development of vaccines.

Emergence of novel coronavirus and progress toward treatment and vaccine

INTRODUCTION The Coronavirus disease-19 (COVID-19) caused by the novel beta coronavirus named Severe Acute Respiratory Syndromecoronavirus-2 (SARS-CoV-2) started in late December 2019 in Wuhan, China. Within a short span, COVID-19 was declared a global public health emergency affecting 214 countries with 5,939,234 confirmed cases and 3,67,255 deaths as of 30 May, 2020. With limited knowledge about SARS-CoV-2, no approved treatment or vaccine is available till date. AREAS COVERED We performed a review of literature on PubMed on the SARS-CoV-2 virus and COVID-19 illness including trials of preventive and therapeutic measures. This review presents the basic biology of coronaviruses, epidemiology of COVID-19, clinical presentations, investigational therapies and vaccines, infection prevention and control measures and the lessons from the present pandemic. EXPERT OPINION The scale of the outbreak has brought the governments, healthcare professionals and scientists around the world under tremendous pressure to devise control strategies and develop novel prevention measures. While availability of vaccine for COVID-19 may take time, the disease may be contained through hand hygiene, physical distancing, travel restriction and aggressive steps such as 'lockdown'. Clinical trials at different phases are ongoing across different countries to expedite development of effective drugs and vaccine to overcome the pandemic.

Covid-19: A Comprehensive Review of a Formidable Foe and the Road Ahead.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by a novel corinavirus (later named SARS-CoV-2 virus), was fistly reported in Wuhan, Hubei Province, China towards the end of 2019. Large-scale spread within China and internationally led the World Health Organization to declare a Public Health Emergency of International Concern on 30(th) January 2020. The clinical manifestations of COVID-19 virus infection include asymptomatic infection, mild upper respiratory symptoms, severe viral pneumonia with respiratory failure, and even death. There are no antivirals of proven clinical efficacy in coronavirus infections. Remdesivir (GS-5734), a nucleoside analogue, has inhibitory effects on animal and human highly pathogenic coronaviruses, including MERS-CoV and SARS-CoV, in in vitro and in vivo experiments. It is also inhibitory against the COVID-19 virus in vitro. The aim of this study is to assess the efficacy and safety of remdesivir in adult patients with severe COVID-19. METHODS: The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. This is a phase 3, randomized, double-blind, placebo-controlled, multicentre trial. Adults (≥ 18 years) with laboratory-confirmed COVID-19 virus infection, severe pneumonia signs or symptoms, and radiologically confirmed severe pneumonia are randomly assigned in a 2:1 ratio to intravenously administered remdesivir or placebo for 10 days. The primary endpoint is time to clinical improvement (censored at day 28), defined as the time (in days) from randomization of study treatment (remdesivir or placebo) until a decline of two categories on a six-category ordinal scale of clinical status (1 = discharged; 6 = death) or live discharge from hospital. One interim analysis for efficacy and futility will be conducted once half of the total number of events required has been observed. DISCUSSION: This is the first randomized, placebo-controlled trial in COVID-19. Enrolment began in sites in Wuhan, Hubei Province, China on 6(th) February 2020. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04257656. Registered on 6 February 2020.

Evaluation of the efficacy and safety of intravenous remdesivir in adult patients with severe COVID-19: study protocol for a phase 3 randomized, double-blind, placebo-controlled, multicentre trial

INTRODUCTION: The Coronavirus disease-19 (COVID-19) caused by the novel beta coronavirus named Severe Acute Respiratory Syndromecoronavirus-2 (SARS-CoV-2) started in late December 2019 in Wuhan, China. Within a short span, COVID-19 was declared a global public health emergency affecting 214 countries with 5,939,234 confirmed cases and 3,67,255 deaths as of 30 May, 2020. With limited knowledge about SARS-CoV-2, no approved treatment or vaccine is available till date. AREAS COVERED: We performed a review of literature on PubMed on the SARS-CoV-2 virus and COVID-19 illness including trials of preventive and therapeutic measures. This review presents the basic biology of coronaviruses, epidemiology of COVID-19, clinical presentations, investigational therapies and vaccines, infection prevention and control measures and the lessons from the present pandemic. EXPERT OPINION: The scale of the outbreak has brought the governments, healthcare professionals and scientists around the world under tremendous pressure to devise control strategies and develop novel prevention measures. While availability of vaccine for COVID-19 may take time, the disease may be contained through hand hygiene, physical distancing, travel restriction and aggressive steps such as 'lockdown'. Clinical trials at different phases are ongoing across different countries to expedite development of effective drugs and vaccine to overcome the pandemic.

Covid-19: A Comprehensive Review of a Formidable Foe and the Road Ahead

BACKGROUND: On 31 December, 2019, the World Health Organization China Country Office was informed of cases of pneumonia of unknown aetiology. Since then, there have been over 75 000 cases globally of the 2019 novel coronavirus (COVID-19), 2000 deaths, and over 14 000 cases recovered. Outbreaks of novel agents represent opportunities for clinical research to inform real-time public health action. In 2018, we conducted a systematic review to identify priority research questions for Severe Acute Respiratory Syndrome-related coronavirus (SARS-CoV) and Middle East Respiratory Syndrome-related coronavirus (MERS-CoV). Here, we review information available on COVID-19 and provide an evidenced-based framework for priority clinical research in the current outbreak. METHODS: Three bibliographic databases were searched to identify clinical studies published on SARS-CoV and MERS-CoV in the outbreak setting. Studies were grouped thematically according to clinical research questions addressed. In February 2020, available information on COVID19 was reviewed and compared to the results of the SARS-CoV and MERS-CoV systematic review. RESULTS: From the research objectives for SARS-CoV and MERS-CoV, ten themes in the literature were identified: Clinical characterisation, prognosis, diagnosis, clinical management, viral pathogenesis, epidemiological characterisation, infection prevention and control/transmission, susceptibility, psychosocial, and aetiology. For COVID19, some information on clinical presentation, diagnostic testing, and aetiology is available but many clinical research gaps have yet to be filled. CONCLUSIONS: Based on a systematic review of other severe coronaviruses, we summarise the state of clinical research for COVID-19, highlight the research gaps, and provide recommendations for the implementation of standardised protocols. Data based on internationally standardised protocols will inform clinical practice real-time.

An evidence-based framework for priority clinical research questions for COVID-19

Background: On 31 December, 2019, the World Health Organization China Country Office was informed of cases of pneumonia of unknown aetiology. Since then, there have been over 75 000 cases globally of the 2019 novel coronavirus (COVID-19), 2000 deaths, and over 14 000 cases recovered. Outbreaks of novel agents represent opportunities for clinical research to inform real-time public health action. In 2018, we conducted a systematic review to identify priority research questions for Severe Acute Respiratory Syndrome-related coronavirus (SARS-CoV) and Middle East Respiratory Syndrome-related coronavirus (MERS-CoV). Here, we review information available on COVID-19 and provide an evidenced-based framework for priority clinical research in the current outbreak. Methods: Three bibliographic databases were searched to identify clinical studies published on SARS-CoV and MERS-CoV in the outbreak setting. Studies were grouped thematically according to clinical research questions addressed. In February 2020, available information on COVID19 was reviewed and compared to the results of the SARS-CoV and MERS-CoV systematic review. Results: From the research objectives for SARS-CoV and MERS-CoV, ten themes in the literature were identified: Clinical characterisation, prognosis, diagnosis, clinical management, viral pathogenesis, epidemiological characterisation, infection prevention and control/transmission, susceptibility, psychosocial, and aetiology. For COVID19, some information on clinical presentation, diagnostic testing, and aetiology is available but many clinical research gaps have yet to be filled. Conclusions: Based on a systematic review of other severe coronaviruses, we summarise the state of clinical research for COVID-19, highlight the research gaps, and provide recommendations for the implementation of standardised protocols. Data based on internationally standardised protocols will inform clinical practice real-time.

OBJECTIVE: The primary purpose of the study was to investigate and to summarize the registered trials that listed COVID-19 as the primary condition. METHODS: We performed a search on ClinicalTrials.gov using the independent search terms COVID-19, SARS, and SARS-CoV-2 and then downloaded the data file on March 23, 2020. All trials were downloaded to a csv file and searched for appropriateness. RESULTS: Of 124 registered trials, 56 (45.2%) were listed as recruiting. The majority (85 [68.5%]) were classified as interventional, 37 (29.8%) as observational, and one (0.8%) each as either expanded access: individual patients|treatment investigational new drug/protocol or expanded access: intermediate-size population|treatment investigational new drug/protocol. There were 67 (54.0%) trials that listed drug as the type of study. Immunologic and antiviral trials were the most common, representing approximately 30% and 21%, respectively. When immunologic and antiviral drugs were used alone or in combination, they represented 41.9% and 34.4%, respectively. Antimalarial agents are represented in 7.5% of trials. Approximately 14% of trials involved traditional Chinese medicine. The study agents used solely or in combination represented approximately 80% of therapeutic approaches to COVID-19. CONCLUSIONS: There was a large and quick response on ClinicalTrials.gov to the COVID-19 outbreak. Many of the registered trials are currently recruiting new patients, whereas some will begin in the near future. Specific potential experimental therapies, including dosing and monitoring, might be found by reviewing content. Within ClinicalTrials.gov, patients, family members, health care professionals, and researchers can search and find ongoing and future trials for COVID-19.

Cardiovascular disease due to novel coronavirus and the search for investigational therapies

INTRODUCTION In December 2019, an outbreak of pneumonia caused by a novel coronavirus occurred in Wuhan, the capital of Central China's Hubei Province and has been declared a public health emergency of international concern by the World Health Organization since January 2020. MATERIAL AND METHODS A comprehensive search using the PubMed database was carried out to summarize the latest published information about the epidemiology, definition, pathogenesis, clinical characteristics, treatment options, prognosis and prevention of coronavirus disease 2019. DISCUSSION This new strain of coronavirus, named severe acute respiratory syndrome coronavirus 2, enters human cells that express angiotensin-converting enzyme II receptors, which exist in the respiratory, gastrointestinal and genitourinary tracts and heart, causing coronavirus disease. Transmission occurs essentially through the respiratory tract and the main symptoms are fever, cough and dyspnea. Diagnosis is based on epidemiological, clinical and imaging features and confirmed by nucleic acid testing. CONCLUSION Despite intensive research, the exact origin of the virus and pathophysiology of coronavirus disease is not yet completely known, and clinically approved vaccines and drugs that target severe acute respiratory syndrome coronavirus 2 are lacking.

Coronavirus Disease 2019: Clinical Review.

The scientific community has risen to the coronavirus disease 2019 (COVID-19) challenge, coming up with an impressive list of candidate drugs and vaccines targeting an array of pharmacological and immunological mechanisms. Yet, generating clinical evidence of efficacy and safety of these candidate treatments may be frustrated by the absence of comprehensive trial coordination mechanisms. Many small stand-alone trials and observational studies of single-agent interventions are currently running or in planning; many of these will likely not deliver robust results that could support regulatory and patient-level treatment decisions. In this paper, we discuss actions that all stakeholders in the clinical trial ecosystem need to take to ensure that the window of opportunity during this pandemic will not shut, both for patients in need of treatment and for researchers to conduct decision-relevant clinical trials.

Clinical Trials for COVID-19: Can we Better Use the Short Window of Opportunity?

Despite the ferment aroused in the scientific community by the COVID-19 outbreak and the over 11,000 papers listed in PubMed, published evidence on safe and effective drugs has not progressed yet at the same speed of the pandemic. However, clinical research is rapidly progressing, as shown by the hundreds of registered clinical trials on candidate drugs for COVID-19. Unfortunately, information on protocols of individual studies differs from registry to registry. Furthermore, study designs, criteria for stratification of patients and choice of outcomes are quite heterogeneous. All this makes data sharing and secondary analysis difficult. At last, small single centre studies and the use of drugs on a compassionate basis should be replaced by highly powered, multi-centre, multi-arm clinical trials, in order to provide the required evidence of safety and efficacy of novel or repurposed candidate drugs. Hopefully, the efforts of clinical researchers in the fight against the SARS Cov-2 will result into the identification of effective treatments. To make this possible, clinical research should be oriented by guidelines for more harmonized high-quality studies and by a united commitment of the scientific community to share personal knowledge and data. Allergists and clinical immunologists should have a leading role in this unprecedent challenge.

COVID-19 Clinical trials: Quality matters more than quantity

PURPOSE: The primary purpose of the current study was to investigate and summarize the registered trials that listed COVID-19 as the primary condition. METHODS: We performed a search on ClinicalTrials.gov using the independent search terms COVID-19, SARS, and SARS COV2, and then downloaded the data file on March 23, 2020. All trials were downloaded to a csv file and searched for appropriateness. RESULTS: Fifty-six of 124 (45.2%) registered trials were listed as recruiting. The majority (85, 68.5%) classified their study as interventional, 37 (29.8%) classified as observational and one (0.8%) each classified their study as either expanded access:individual patients | treatment IND/Protocol or expanded access:intermediate-size population | treatment IND/Protocol. There were 67 (54.0%) of the trials that listed drug as the type of study. Immunological and antiviral trials were the greatest, representing approximately 30% and 21%, respectively. When immunological and antiviral drugs were used alone or in combination, they represented 41.9% and 34.4%, respectively. Anti-malarial agents are represented in 7.5% of trials. Approximately 14% of trials involved Traditional Chinese Medicine. The aforementioned study agents used solely or in combination represented approximately 80% of therapeutic approaches to COVID19. CONCLUSION: There was a large and quick response on ClinicalTrials.gov to the COVID-19 outbreak. Many of the registered trials are currently recruiting new patients, while some will begin in the near future. Specific potential experimental therapies, including dosing and monitoring, might be found by reviewing content. Within clinicaltrials.gov, patients, family members, health care professionals and researchers can search and find ongoing and future trials for COVID-19.

Cardiovascular Disease Novel Coronavirus and the Search for Investigational Therapies

Statins in coronavirus outbreak: It's time for experimental and clinical studies

SARS-CoV-2 continues to spread rapidly outside of mainland China. As of April 6, there are over 300,000 cases and 10,000 deaths in the US. Effective therapies for the novel Coronavirus are urgently needed and over 200 clinical trials are now underway across the globe. Recognizing the need for robust randomized control trials, the World Health Organization (WHO) recently organized a multinational randomized trial-the SOLIDARITY trial-to study the effect of drugs that have been identified as promising based on in-vitro data and the early clinical experience with COVID-19: Remdesivir, lopinavir and ritonavir; lopinavir and ritonavir + interferon; and chloroquine or hydroxychloroquine.

Off‐Label Therapies for COVID‐19—Are We All In This Together?

The current coronavirus (SARS-COV-2) pandemic and phenomenal spread to every nook and cranny of the world has raised major apprehensions about the modern public health care system. So far as a result of this epidemic, 4,434,653 confirmed cases and 302,169 deaths are reported. The growing infection rate and death toll demand the use of all possible approaches to design novel drugs and vaccines to curb this disease. In this study, we combined drugs repurposing and virtual drug screening strategies to target 3CLpro, which has an essential role in viral maturation and replication. A total of 31 FDA approved anti-HIV drugs, and Traditional Chinese medicines (TCM) database were screened to find potential inhibitors. As a result, Saquinavir, and five drugs (TCM5280805, TCM5280445, TCM5280343, TCM5280863, and TCM5458190) from the TCM database were found as promising hits. Furthermore, results from molecular dynamics simulation and total binding free energy revealed that Saquinavir and TCM5280805 target the catalytic dyad (His41 and Cys145) and possess stable dynamics behavior. Thus, we suggest that these compounds should be tested experimentally against the SARS-COV-2 as Saquinavir has been reported to inhibit HIV protease experimentally. Considering the intensity of coronavirus dissemination, the present research is in line with the idea of discovering the latest inhibitors against the coronavirus essential pathways to accelerate the drug development cycle.Communicated by Ramaswamy H. Sarma.

Combined drug repurposing and virtual screening strategies with molecular dynamics simulation identified potent inhibitors for SARS-CoV-2 main protease (3CLpro)

The current coronavirus (SARS-COV-2) pandemic and phenomenal spread to every nook and cranny of the world has raised major apprehensions about the modern public health care system. So far as a result of this epidemic, 4,434,653 confirmed cases and 302,169 deaths are reported. The growing infection rate and death toll demand the use of all possible approaches to design novel drugs and vaccines to curb this disease. In this study, we combined drugs repurposing and virtual drug screening strategies to target 3CLpro, which has an essential role in viral maturation and replication. A total of 31 FDA approved anti-HIV drugs, and Traditional Chinese medicines (TCM) database were screened to find potential inhibitors. As a result, Saquinavir, and five drugs (TCM5280805, TCM5280445, TCM5280343, TCM5280863, and TCM5458190) from the TCM database were found as promising hits. Furthermore, results from molecular dynamics simulation and total binding free energy revealed that Saquinavir and TCM5280805 target the catalytic dyad (His41 and Cys145) and possess stable dynamics behavior. Thus, we suggest that these compounds should be tested experimentally against the SARS-COV-2 as Saquinavir has been reported to inhibit HIV protease experimentally. Considering the intensity of coronavirus dissemination, the present research is in line with the idea of discovering the latest inhibitors against the coronavirus essential pathways to accelerate the drug development cycle. Communicated by Ramaswamy H. Sarma.

The coronavirus outbreak could make it quicker and easier to trial drugs.

BACKGROUND: The Middle East Respiratory Syndrome coronavirus (MERS-CoV) is an emerging respiratory pathogen with a high mortality rate and no specific treatments available to date. The purpose of this study was to determine the feasibility of conducting a randomized controlled trial (RCT) of convalescent plasma therapy for MERS-CoV-infected patients by using MERS-CoV-specific convalescent plasma obtained from previously recovered patients. METHODS: A survey was adapted from validated questionnaire originally aimed to measure network capacities and capabilities within the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC). The questionnaire was modified for this study to include 26 items that were divided into three main domains of interest: (1) the ability to care for critically ill MERS-CoV patients; (2) laboratory capacity to diagnose MERS-CoV and blood bank ability to prepare convalescent plasma; and (3), research capacity to conduct randomized controlled trials. The questionnaire was emailed to physicians. RESULTS: Of 582 physicians who were invited to the survey, 327 responded (56.2 %). The professional focus of the majority of respondents was critical care (106/249 (43 %)), pediatrics (59/249, (24 %)) or internal medicine (52/249 (21 %)) but none was blood banking. Nearly all respondents (251/263 (95 %)) reported to have access to ICU facilities within their institutions. Most respondents (219/270 (81 %)) reported that intensivists were the most physician group responsible for treatment decisions about critically ill SARI patients. While 125/165 respondents (76 %) reported that they conduct research in ICUs, and 80/161 (49.7 %) had been involved in the conduct of RCTs, including using a placebo comparison (60/161 (37 %)), only 49/226 (21 %) of respondents regularly participated in research networks. CONCLUSIONS: Our survey indicated that in the Kingdom of Saudi Arabia (KSA), ICUs are the most likely clinical locations for conducting a clinical trial of convalescent plasma therapy for MERS-CoV, and that most ICUs have experience with such research designs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12871-016-0198-x) contains supplementary material, which is available to authorized users.

Feasibility of a randomized controlled trial to assess treatment of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection in Saudi Arabia: a survey of physicians

OBJECTIVES: The emergence of SARS-CoV-2 has presented clinicians with a difficult therapeutic dilemma. With supportive care as the current mainstay of treatment, the fatality rate of COVID-19 is 6.9%. There are currently several trials assessing the efficacy of different antivirals as treatment. Of these, chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) have garnered the most attention. METHODS: In this study, the literature currently available on CQ and HCQ as treatment of COVID-19 was surveyed using EMBASE, PubMed, Cochrane Library, MedRxiv, and one clinical trial registry. Upon gathering published and preprint trials, risk of bias was assessed using Cochrane Risk of Bias Tool 2.0. RESULTS: There are currently seven completed clinical trials and 29 registered clinical trials focusing on HCQ or CQ as a therapeutic avenue for COVID-19. Of these, five of seven trials have shown favorable outcomes for patients using CQ or HCQ and two of seven have shown no change compared to control. However, all seven trials carried varying degrees of bias and poor study design. CONCLUSION: There are currently not enough data available to support the routine use of HCQ and CQ as therapies for COVID-19. Pending further results from more extensive studies with more stringent study parameters, clinicians should defer from routine use of HCQ and CQ. There are several clinical trials currently under way with results expected soon.

A Rapid Systematic Review of Clinical Trials Utilizing Chloroquine and Hydroxychloroquine as a Treatment for COVID-19

Considering the massive amount of clinical trial registers aimed to find effective drugs for the prevention and treatment of COVID-19, it is challenging to have a comprehensive view of which drugs are being studied more extensively and when is expected that we will have consistent results regarding their effectiveness. This systematic review included all clinical trials on pharmacological therapy related to COVID-19 and SARS-CoV-2 registered at the International Clinical Trials Registry Platform (WHO-ICTRP) up to April 22, 2020. Clinical trials characteristics (country, design, sample size, main outcomes, expected completion data, type of participants, length of the interventions, main outcomes). How many trials and he accumulated sample size by drug or combination of drugs, and by month in 2020 was depicted. We identified 412 clinical trials registers addressing the effect of pharmacological treatments on COVID-19, predominantly from Asia and Europe (42.2% and 31.1% of clinical trials registers, respectively). The most main outcomes studied were clinical recovery (54.4% of the clinical trials registers, respiratory recovery (28.2%) mortality (27.4%), viral load/negativity (20.4%). During 2020, a huge amount of clinical trials are expected to be completed: 41 trials (60,366 participants) using hydroxychloroquine, 20 trials (1,588 participants) using plasma, 18 trials (6,830 participants) using chloroquine, 12 trials (9,938 participants using lopinavir/ritonavir, 11 trials (1,250 participants) using favipiravir, 10 trials ( 2,175 participants) using tocilizumab and 6 trials (13,540 participants) using Remdesivir. The distribution of the number of registered clinical trials among the different therapeutic options leads to an excess of sample size for some and a lack for others. Our data allow us to conclude that by the end of June we will have results of almost 20 trials involving 40000 patients for hydroxychloroquine and 5 trials with 4500 patients for remdesivir; however, low statistical power is expected from the 9 clinical trials testing the efficacy of favipiravir or the 5 testing tocilizumab, since they will recruit less than 1000 patients each one.

The race to find a SARS-CoV-2 drug can only be won by a few chosen drugs: a systematic review of registers of clinical trials of drugs aimed at preventing or treating COVID-19

SARS-coronavirus-2 (SARS-CoV-2), the etiologic agent of the new lung disease COVID-19 is closely related to SARS-CoV, and together with MERS-CoV are three new human coronaviruses that emerged in the last 20 years. The COVID-19 outbreak is a rapidly evolving situation with higher transmissibility and infectivity compared with SARS and MERS. Clinical presentations range from asymptomatic or mild symptoms to severe illness. The prevalent cause of mortality is pneumonia that progresses to ARDS. The ongoing pandemic has already resulted in more than 135,000 deaths and an unprecedented burden on national health systems worldwide. Pending the availability of a vaccine, there is a critical need to identify effective treatments and a number of clinical trials have been implemented worldwide. Trials are based on repurposed drugs that are already approved for other infections, have acceptable safety profiles or have performed well in animal studies against the other two deadly coronaviruses. Supportive care remains the mainstay of therapy at present, as it is still unclear how well these data can be extrapolated to SARS-CoV-2. Most of those emerging re-introduced drugs are administered to patients in the context of clinical trials. In this review, we summarize the strategies currently employed in the treatment of COVID-19.

[Comment] Treatment strategies to fight the new coronavirus SARS-CoV-2: A challenge for a Rubik's Cube solver

Background: The purpose of the current systematic review is to evaluate the efficacy of antiviral therapies in treatment of COVID-19 In addition, clinical trials on the efficacy of antiviral therapies in the management of Severe Acute Respiratory Syndrome coronavirus (SARS-Cov) or Middle East Respiratory Syndrome coronavirus (MERS-CoV) have also been reviewed, in order to identify potential treatment options for COVID-19 Method: An extensive search was performed in Medline, Embase, Scopus, Web of Science and CENTRAL databases until the end of March 15, 2020 Two independent researchers performed the screening, and finally the related studies were included Results: Only one clinical trial on the efficacy of antiviral therapy in management of COVID-19 was found The results depicted that adding Lopinavir-Ritonavir to the standard treatment regimen of patients with severe COVID-19 has no benefits Moreover, 21 case-series and case-report studies reported the prescription of antiviral agents in COVID-19, none of which can be used to determine the efficacy of antiviral therapies in confronting COVID-19 In addition, no clinical trials were found to be performed on the efficacy of antiviral agents in the management of SARS-CoV and MERS-CoV Conclusion: The current evidence impede researchers from proposing an appropriate antiviral therapy against COVID-19, making the current situation a serious concern for international organizations such as World Health Organization (WHO) In the time of the current pandemic and future epidemics, organizations such as WHO should pursue more proactive actions and plan well-designed clinical trials so that their results can be used in managing future epidemics

Antiviral therapy in management of COVID-19: a systematic review on current evidence

No specific antivirals are currently available for two emerging infectious diseases, Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). A literature search covering pathogenesis, clinical features and therapeutics, clinically developed drugs for repurposing and novel drug targets was performed. This review presents current knowledge on the epidemiology, pathogenesis and clinical features of the SARS and MERS coronaviruses. The rationale for and outcomes with treatments used for SARS and MERS is discussed. The main focus of the review is on drug development and the potential that drugs approved for other indications provide for repurposing. The drugs we discuss belong to a wide range of different drug classes, such as cancer therapeutics, antipsychotics, and antimalarials. In addition to their activity against MERS and SARS coronaviruses, many of these approved drugs have broad-spectrum potential and have already been in clinical use for treating other viral infections. A wealth of knowledge is available for these drugs. However, the information in this review is not meant to guide clinical decisions, and any therapeutic described here should only be used in context of a clinical trial. Potential targets for novel antivirals and antibodies are discussed as well as lessons learned from treatment development for other RNA viruses. The article concludes with a discussion of the gaps in our knowledge and areas for future research on emerging coronaviruses.

Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies

INTRODUCTION: The Coronavirus disease-19 (COVID-19) caused by the novel beta coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) started in late December 2019 in Wuhan, China. Within a short span, COVID-19 was declared a global public health emergency affecting 214 countries with 5,939,234 confirmed cases and 3,67,255 deaths as of 30 May 2020. With limited knowledge about SARS-CoV-2, no approved treatment or vaccine is available till date. AREAS COVERED: We performed a review of literature on PubMed on the SARS-CoV-2 virus and COVID-19 illness including trials of preventive and therapeutic measures. This review presents the basic biology of coronaviruses, epidemiology of COVID-19, clinical presentations, investigational therapies and vaccines, infection prevention and control measures and the lessons from the present pandemic. EXPERT OPINION: The scale of the outbreak has brought the governments, health-care professionals, and scientists around the world under tremendous pressure to devise control strategies and develop novel prevention measures. While availability of vaccine for COVID-19 may take time, the disease may be contained through hand hygiene, physical distancing, travel restriction, and aggressive steps such as 'lockdown.' Clinical trials at different phases are ongoing across different countries to expedite the development of effective drugs and vaccine to overcome the pandemic.

Covid-19: a comprehensive review of a formidable foe and the road ahead

BACKGROUND Severe acute respiratory syndrome (SARS) coronavirus emerged from an animal reservoir in 2002 and has the potential to reemerge, as shown by the occurrence of non-laboratory-associated new cases in the winter of 2003. In the absence of a vaccine, broad spectrum anticoronaviral medications are needed. OBJECTIVE Anticoronavirals targeting viral entry were reviewed in part I. Here we review anticoronaviral therapies directed against the intracellular life cycle, with an emphasis on allowed patents and pending patents. METHOD The published literature, in particular, patent publications is searched for relevant documents. The information is organized and critiqued. RESULTS/CONCLUSION Many promising anticoronaviral strategies are identified. Monoclonal antibodies, protease inhibitors, interferon-based drugs and nucleic-acid based antivirals are most advanced, each having its own advantages and disadvantages. A multi-pronged approach, keeping all venues open, is advocated.

Therapies for coronaviruses. Part 2: Inhibitors of intracellular life cycle.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by a novel corinavirus (later named SARS-CoV-2 virus), was fistly reported in Wuhan, Hubei Province, China towards the end of 2019. Large-scale spread within China and internationally led the World Health Organization to declare a Public Health Emergency of International Concern on 30th January 2020. The clinical manifestations of COVID-19 virus infection include asymptomatic infection, mild upper respiratory symptoms, severe viral pneumonia with respiratory failure, and even death. There are no antivirals of proven clinical efficacy in coronavirus infections. Remdesivir (GS-5734), a nucleoside analogue, has inhibitory effects on animal and human highly pathogenic coronaviruses, including MERS-CoV and SARS-CoV, in in vitro and in vivo experiments. It is also inhibitory against the COVID-19 virus in vitro. The aim of this study is to assess the efficacy and safety of remdesivir in adult patients with severe COVID-19. METHODS: The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. This is a phase 3, randomized, double-blind, placebo-controlled, multicentre trial. Adults (≥ 18 years) with laboratory-confirmed COVID-19 virus infection, severe pneumonia signs or symptoms, and radiologically confirmed severe pneumonia are randomly assigned in a 2:1 ratio to intravenously administered remdesivir or placebo for 10 days. The primary endpoint is time to clinical improvement (censored at day 28), defined as the time (in days) from randomization of study treatment (remdesivir or placebo) until a decline of two categories on a six-category ordinal scale of clinical status (1 = discharged; 6 = death) or live discharge from hospital. One interim analysis for efficacy and futility will be conducted once half of the total number of events required has been observed. DISCUSSION: This is the first randomized, placebo-controlled trial in COVID-19. Enrolment began in sites in Wuhan, Hubei Province, China on 6th February 2020. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04257656. Registered on 6 February 2020.

Evaluation of the efficacy and safety of intravenous remdesivir in adult patients with severe COVID-19: study protocol for a phase 3 randomized, double-blind, placebo-controlled, multicentre trial

Importance The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected by SARS-CoV-2, clinicians need accurate evidence regarding effective medical treatments for this infection. Observations No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomized trials. Oseltamivir has not been shown to have efficacy, and corticosteroids are currently not recommended. Current clinical evidence does not support stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with COVID-19. Conclusions and Relevance The COVID-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918. The speed and volume of clinical trials launched to investigate potential therapies for COVID-19 highlight both the need and capability to produce high-quality evidence even in the middle of a pandemic. No therapies have been shown effective to date.

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

Mysterious Virus: A Review on Behavior and Treatment Approaches of the Novel Coronavirus, 2019-nCoV

SARS-CoV-2 is a severe respiratory infection that infects humans. Its outburst entitled it as a pandemic emergence. To get a grip on this, outbreak specific preventive and therapeutic interventions are urgently needed. It must be said that, until now, there are no existing vaccines for coronaviruses. To promptly and rapidly respond to pandemic events, the application of in silico trials can be used for designing and testing medicines against SARS-CoV-2 and speed-up the vaccine discovery pipeline, predicting any therapeutic failure and minimizing undesired effects. Here, we present an in silico platform that showed to be in very good agreement with the latest literature in predicting SARS- CoV-2 dynamics and related immune system host response. Moreover, it has been used to predict the outcome of one of the latest suggested approach to design an effective vaccine, based on monoclonal antibody. UISS is then potentially ready to be used as an in silico trial platform to predict the outcome of vaccination strategy against SARS-CoV-2.

In Silico Trial to test COVID-19 candidate vaccines: a case study with UISS platform

Background: Although a number of antiviral agents have been evaluated for coronaviruses there are no approved drugs available. To provide an overview of the landscape of therapeutic research for COVID-19, we conducted a review of registered clinical trials. Methods: A review of currently registered clinical trials was performed on registries, including the Chinese (chictr.org.cn) and US (clinicaltrials.gov) databases to identify relevant studies up to March, 7th 2020. The search was conducted using the search terms “2019-nCoV”, “COVID-19”, “SARS-CoV-2”, “Hcov-19”, “new coronavirus”, “novel coronavirus”. We included interventional clinical trials focusing on patients with COVID-19 and assessing antiviral drugs or agents. Findings: Out of the 353 studies identified, 115 clinical trials were selected for data extraction. Phase IV trials were the most commonly reported study type (n=27, 23%). However, 62 trials (54%) did not describe the phase of the study. Eighty percent (n=92) of the trials were randomized with parallel assignment and the median number of planned inclusions was 63 (IQR, 36-120). Open-label studies were the most frequent (46%) followed by double-blind (13%) and single blind studies (10%). The most frequently assessed therapies were: stem cells therapy (n=23 trials), lopinavir/ritonavir (n=15), chloroquine (n=11), umifenovir (n=9), hydroxychloroquine (n=7), plasma treatment (n=7), favipiravir (n=7), methylprednisolone (n=5), and remdesivir (n=5). Remdesivir was tested in 5 trials with a median of 400 (IQR, 394-453) planned inclusions per trial, while stem cells therapy was tested in 23 trials, but had a median of 40 (IQR, 23-60) planned inclusions per trial. Lopinavir/ritonavir was associated with the highest total number of planned inclusions (2606) followed by remdesivir (2155). Only 52% of the clinical trials reported the treatment dose (n=60) and only 34% (n=39) the duration. The primary outcome was clinical in 76 studies (66%), virological in 27 (23%); radiological in 9 (8%) or immunological in three studies (3%). Interpretation: Numerous clinical trials have been registered since the beginning of the COVID-19 outbreak, however, a number of information regarding drugs or trial design were lacking. Funding: None

A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19

Here, we explore the dynamics of the response of the scientific community to several epidemics, including Coronavirus 2019 (COVID-19), as assessed by the numbers of clinical trials, publications, and level of research funding over time. All six prior epidemics studied [bird flu, severe acute respiratory syndrome (SARS), swine flu, Middle East Respiratory Syndrome (MERS), Ebola, and Zika] were characterized by an initial spike of research response that flattened shortly thereafter. Unfortunately, no antiviral medications have been discovered to date as treatments for any of these diseases. By contrast, the HIV/AIDS pandemic has garnered consistent research investment since it began and resulted in drugs being developed within 7 years of its start date, with many more to follow. We argue that, to develop effective treatments for COVID-19 and be prepared for future epidemics, long-term, consistent investment in antiviral research is needed.

Learning from history: do not flatten the curve of antiviral research!

Abstract At the end of the year 2019, the novel coronavirus (2019-nCoV) was spreading in Wuhan, China, and the outbreak process has a high speed. It was recognized as a pandemic by the World Health Organization (WHO) on 11 March 2020. Coronaviruses are enveloped and single-stranded RNA that have several families including Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). The pathogenesis mechanism and disease outcomes of SARS and MERS are now clear to some extent, but little information is available for 2019-nCoV. This newly identified corona virus infection represents flu-like symptoms, but usually the first symptoms are fever and dry cough. There has been no specific treatment against 2019-nCoV up to now, and physicians only apply supportive therapy. In the present article, we made an attempt to review the behavior of the virus around the world, epidemiology, a pathway for influx into the host cells, clinical presentation, as well as the treatments currently in use and future approaches; nitazoxanide may be our dream drug. We hope that this review has a positive impact on public knowledge for helping to deal with the 2019-nCoV and move one step forward toward its treatment in the near future.