key: cord-0957722-hchxei1i
authors: Shah, Syed Muhammad Ali; Rasheed, Tahir; Rizwan, Komal; Bilal, Muhammad; Iqbal, Hafiz M.N.; Rasool, Nasir; Toma, Sebastian; Marceanu, Luigi Geo; Bobescu, Elena
title: Risk management strategies and therapeutic modalities to tackle COVID-19/SARS-CoV-2
date: 2020-12-29
journal: J Infect Public Health
DOI: 10.1016/j.jiph.2020.12.023
sha: 4bd74e2e6455877b58ce31db05131db4d2a31dec
doc_id: 957722
cord_uid: hchxei1i

The recent emergence of novel coronavirus disease (COVID-19) triggered by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has resulted in substantial mortality worldwide. Presently, there is no approved treatment for COVID-19. Consequently, the clinical, scientific, and regulatory authorities have joint efforts to reduce the severe impact of COVID-19. To date, there is minimal arsenal with no definite curative drugs, licensed-vaccines, or therapeutic conducts to combat the COVID-19 infections. Keeping in view the threats of this pandemic, various global organizations, physicians, researchers, and scientists, are trying to recognize the epidemiological characteristics and pathogenic mechanisms of COVID-19 to discover potential treatment regimens, vaccines, and therapeutic modes for future anticipation. Herein, we summarize a contemporary overview of curative invasions and vaccines for COVID-19 based on the earlier information and considerate of similar earlier RNA coronaviruses. The information reviewed here establishes a paramount intellectual basis to promote ongoing research to develop vaccines and curative agents. Thus, this review suggests the furthermost accessible frontiers in the vaccine development to tackle or combat the COVID-19/SARS-CoV-2.

(NF-κB) and interferon regulatory factor 3 (IRF3), are activated to help nuclear translocation. These factors initiate the type I Interferons (IFN-α/β) and proinflammatory cytokines production, especially IL-6 [18] . The dysregulated immune response may lead to a cytokine storm. JAK-STAT pathway is initiated by type I IFN and also suppresses the viral replication, thus modulating the phagocytosis of antigens by macrophage and restriction of infected cells by NK cells [19] . Antigenpresenting cells mediate a cytokine release causing the response of T-cells.

CD4 helper T cells assist cytotoxic T cells in initiating adaptive immunity. CD8 cytotoxic T cells secrete molecules including IFN-γ, granzymes, and perforins, necessary for viral eradication from host cells. B-cell mediated humoral immune response protects by the production of antibodies and thus reinfection [20] .

A comprehensive bibliographic evaluation was performed to justify the work contents 

The COVID-19 can be transmitted to humans by two different routes, such as contact and respiratory. When infected people sneeze or cough, it generates tiny droplets, which can readily travel through the air and enter another person's respiratory system. Likewise, if a healthy person has close contact with a person who has respiratory symptoms (coughing and sneezing) has a greater chance of catching infection through inhaling the respiratory droplets of an infected person [21] . These droplets can quickly drop down on different surfaces, e.g., ground, walls, doors, the railing of stairs, etc. The COVID-19 can easily remain viable for several hours resulting in the immediate contamination of the environment. This, in turn, poses a J o u r n a l P r e -p r o o f severe threat of infection for the persons who may contact these surfaces. This transmission route is termed as contact transmission. On the other hand, the chances of infection from the waste (feces) of an infected person are relatively lower.

There is very little evidence that a person got infected from COVID-19 from intestinal infection and is present in feces. Among the confirmed COVID-19 cases, nearly 2−10% of the patients suffer from diarrhea [22] [23] [24] . Whereas two investigations spotted COVID-19 viral RNA wreckages in the patients' feces [25, 26] . Conversely, only a single study has cultured the COVID-19 from a single sampling [27] . No fecaloral transmissions of the virus have been reported yet.

It is not evident that the human coronaviruses are present in surface or groundwater. For example, the existence of human coronavirus in dechlorinated water has been documented. It can only survive for two days at 20 °C in hospital wastewater [28] . 

Based on the present studies, COVID-19 in drinkable water bodies is out of the question; therefore, the risk of transmission from water supplies is low [32] .

Correspondingly, the investigations are carried out in a well-controlled environment such as a laboratory reveals that the COVID-19 might persist contagious in water bodies polluted with feces for several days to weeks [30] . Water safety can easily be improved by observing various measures such as protection of water source, water treatment at distribution points, and storage of water with great care at homes in covered and frequently cleaned containers. Typically, integrated water treatment procedures, which use disinfection and filtration, should deactivate the COVID-19.

The disinfection of other human coronaviruses can quickly be done with UV-light and chlorination [33] .

The enveloped viruses have a fragile lipid-based cell membrane. Therefore, the coronavirus is more profound to oxidants and chlorine. The concentration and contact time for the disinfection of viruses should be in the range of ≥0.5 mg/L and 30 minutes, respectively, at pH < 8.0 [32] . The chlorine should be continuously maintained through the water distribution system. In the places or communities where central distribution systems are not available, different domestic treatment technologies such as ultra-filtration membranes, boiling, solar irradiation, UV irradiation, and nano-membrane filters, etc., prove best in destroying or removing viruses [21] .

The transmission of COVID-19 has not been reported through sewerage systems with or without treatment. Moreover, there are no reports that wastewater or sewage treatment workers acquire acute respiratory syndrome (SARS). This type of illness has been caused by another class of coronavirus that triggered a massive outbreak of severe respiratory infection in 2003. The wastewater or sewage systems should J o u r n a l P r e -p r o o f be treated in well-managed, and well-designed consolidated wastewater treatment approaches for the better safety of public health. The potential contamination can quickly be decreased by carefully observing the treatment platforms. A large wastewater stabilization pool is usually considered to be a practical and straightforward wastewater treatment methodology. This type of pool is predominantly well appropriate to abolishing pathogens, as comparatively long retaining time combined with sunlight, high pH values, biological activity, and added factors assist the acceleration of pathogen demolition. Protective outwears such as masks, gloves, face shields, boots, goggles, etc., should be provided to the workers.

Further, precautionary measures, such as hand hygiene, should also be observed to maintain sanitation workers' health. One should not touch his mouth, nose, eyes, etc., with unwashed hands. 

Hand hygiene at regular intervals using various methods such as washing with soap, alcohol-based hand sanitizers, or pads is of extreme importance. This should be 

Adequate sanitation facilities such as toilets, flush, or latrine should be provided to the confirmed or suspected patients of COVID-19. Toilets, flush should be operated well and have operative drain set-ups. After using the bathrooms, the lid should be properly drop down to reduce the spreading of droplet splash and aerosol clouds. If the availability of individual toilets is not feasible, then cleaning the toilets should be carried out by specialist cleaners wearing all safety gadgets. This task should be performed twice a day using a disinfectant.

Moreover, systematic with current regulation, health care workers, and staff should have separate toilet facilities from the patients. The WHO commends the use of wellmaintained and standard plumbing, including closed bathroom pipes, and backflow stopcocks on atomizers to avoid aerosolized fecal material from arriving the ventilation or plumbing system, accompanied by the standard wastewater treatment As the health care facilities are associated with sanitation systems, one should have carried out the risk assessment to assure the confinement of wastewater within the sanitation system such as pipes (no leak) before its appearance at a disposal site or functioning treatment. Risks concerning the storage or disposal and treatment systems' suitability should be evaluated, ensuring a safety development methodology [44], accompanied by major controlling points highlighted for mitigation.

The pit-toilets are a better option in the areas where health care facilities are not appropriate. One must take care of the standard safety measures in arranging the pit-flush to avoid environmental contamination due to the excreta. If both precautionary measures are available, then the storage tank for the wastes must be impenetrable. The feces of the patients should not get in contact with the groundwater table. Also, the storage tank must have the ability to reduce the contamination levels before the excreta's disposal. Another option is to adopt the two-tank system, which is parallels connected to facilitate inactivation by increasing the retention time. Furthermore, intensive care should be taken while emptying or cleaning the storage tanks so that droplets' splashing or release must be avoided.

Upon direct or suspected contact to hands with wastage of the COVID-19 patient, the hand hygiene must be carried out with due care by using soaps to wash hands rather than alcohol-based hand rubs (if dirt is visible). Suppose the latrine is not available to the patient. In that case, a diaper or clean bedpan must be used to collect excreta and be deposed in the separate toilet, which is only used by suspected or Suppose all these protective gears (PPE) are not available or have limited supply.

In that case, the other hygienic measures should be observed, which include hand wash, the medical workers should maintain 1 m distance from the patients regularly.

In case of using a bedpan, it must be washed and cleaned with some detergents, followed by using chlorinated water for the disinfection. It should be noticed that the water used for washing and final rinsing must be thrown into the drain or toilet. Some commercially available disinfectants, including cetylpyridinium chloride (quaternary ammonium salt) and peroxyacetic acid (500−2000 mg/L) can also be used for disinfection purposes according to the instructions provided by the manufacturers [46] . Chlorine is futile for disinfection of media that contain vast amounts of dissolved and solid organic matter. For that reason, the use of chlorine solution for disposing of fresh excreta is not suitable as it may create some health risks or possibly splashing.

The holding tanks for waste used by the COVID-19 patients must not be emptied until their capacity. Generally, the best safety measures should be observed in safely managing the excreta. Both media should be prepared according to the patient requirement by considering a potential increase in the number of cases, and a regular timetable should be obeyed for evacuating them centered on the volumes of wastewater generated. The persons dealing with all this must wear PPE to avoid all the possible health risks. After carefully disposing of the waste and making sure that there is no risk of more exposure, persons should carefully take out their PPE and implement hand hygiene afore ingoing to the transport vehicle. A sealed bag should be used to put the dirty PPE for safe laundering afterward. In the areas where no off-J o u r n a l P r e -p r o o f site treatment facility is available, in-situ treatment can be carried out using lime. This treatment includes 10% lime slurry, in which 1-part lime slurry is added per 10 parts of waste. 

The reusable stuff such as plastic aprons, heavy-duty gloves, gowns, etc., should be cleaned with chlorinated water (0.5% sodium hypochlorite) and soap as per WHO recommendations. On the other hand, disposable stuff should be handled with care and dispose of as recommended. If the disinfectant is present in greywater due to prior washing, then the addition of chlorine is not necessary. Correspondingly, this greywater should be drained of in septic tanks or a soak away container or sewer system. In the case of soak away container, the container must follow the health policy to eradicate the chances of exposure and risk of infection.

The healthcare waste must be treated by observing the complete guidelines to 

The maintenance of best washing practices should be observed in the community and home to prevent the transmission of COVID-19. Consistent and precise hand hygiene is of specific significance. In schools, homes, and crowded public places, including markets, worship places, bus or train stations, hand hygiene should be obeyed strictly. Similarly, before cooking food, before and after eating, changing the diapers of the child, touching animals after attending the toilets, etc. the regular J o u r n a l P r e -p r o o f handwashing should have followed. Operative handwashing services with soap and water should be accessible within 5 m vicinities of bathrooms.

For treatment and control of COVID-19, there is an urgent need to develop therapeutic drugs until the development of a vaccine. Viral entry mechanism of SARS-CoV-2 and proposed treatments for COVID-19 targeting ACE2 receptors are illustrated in Figure 2 . Considering available drugs, there is an opportunity to employ them against SARS-CoV-2 by considering their mechanism of action and SAR (structure-activity relationship). Following available medications have been used for the treatment of SARS-CoV-2 ( Figure 3 ). Data of their trials, recommendations, and outcomes have been presented in detail (Table 1) .

Chloroquine is an aminoquinoline, which has been widely used in malaria treatment, prophylaxis of malaria, and treatment of extraintestinal amoebiasis. It is an old drug, but its use has been reduced after introducing novel anti-malarial drugs. However, it is associated with a prolonged QT interval, which may be fatal when prescribed with other medications, causing prolonged QT interval. The anti-viral properties of chloroquine are well established, and it has been tested against many viruses In vitro (Table 1) . Currently, the WHO does not recommend Chloroquine Phosphate in prophylaxis or treatment of COVID-19 at any stage. Potential mechanisms of action of chloroquine against coronaviruses/SARC-CoV/SARC-CoV-2 are shown in Figure   4 .

Hydroxychloroquine (HCQ) is an analog of chloroquine. It has been widely used to treat rheumatoid arthritis, systemic lupus erythematosus, porphyria cutanea tarda and malaria prophylaxis and treatment. It is given orally in different doses in different diseases. Its mechanism is unclear in the case of treating rheumatological conditions. However, in the case of COVID-19, HCQ can increase the intracellular pH and impede lysosomal activity in antigen-presenting cells preventing antigen processing and MHC class II-mediated autoantigen presentation to T cells. It reduces activation of T cells, decreases expression and differentiation of costimulatory proteins, and also reduces the production of cytokines by T and B cells [54, 55] . It also disrupts the interaction between DNA in cytosols and the cyclic GMP-AMP synthase [56, 57] .

One recent ongoing French study demonstrated the HCQ use in patients with COVID-19. It revealed a significant decrease in the viral load of patients with COVID-19 who were given HCQ 600mg orally daily. Although only 36 patients were included and divided into three groups of mild disease, respiratory infection of the upper tract (URTI), and respiratory infection of the lower tract (LRTI), 70% of the study population were given HCQ were virologically cured compared to control group.

Furthermore, the response was better in patients with respiratory infection of the upper and lower tract [58] . However, one pilot study conducted in China did not determine any differences using HCQ [59, 60] . There are many trials whose results Table 1 . Despite its promise as a drug for COVID-19 and widespread use, there is no evidence currently for its use in COVID-19. [64] . However, the case report of a patient infected with SARS CoV 2 showed that this combination had decreased viral loads in a patient with COVID-19 [65] . In one case series done in Taiwan, this combination was not found to reduce the viral loads of SARS-CoV-2 [66] . Still, this combination needs to evaluate via randomized controlled trials. Following trials ( 

Remdesivir is a new anti-viral drug that is an adenosine analog and has shown efficacy against many viruses. It was initially launched as treatment of the Ebola virus [67] but was later discovered to work against many other viruses, including Marburg virus, RSV, Lassa fever virus, Junin Virus, Hendra Virus, Nipah virus, MERS , and SARS viruses [68] [69] [70] . Due to its activity against other coronaviruses, it has been considered an option against SARS-CoV-2. It is an adenosine analog and a prodrug that metabolizes to its active component. It masks viral RNA polymerase and is not proofread by viral exonuclease, thus decreasing the production of viral RNA production. Its anti-viral activity is due to a delayed chain cessation of the virus's nascent viral RNA, which incorporates itself in viral RNA and leads to premature termination of viral RNA [71] . Randomized clinical trials have not been conducted in patients with SARS-CoV-2 using Remdesivir. One recent study published showed that Remdesivir, when used compassionately, showed improvement in almost 68% of patients with severe disease [72] . However, many clinical trials are being undertaken for its probable efficacy against this virus (Table 1) . WHO does not currently recommend the use of Remdesivir in the treatment of COVID-19. The potential mechanism of action of Remdesivir against coronaviruses is shown in Figure 5 .

Favipiravir is a purine nucleic acid analog and was developed for the treatment of severe influenza infection. It is effective against RNA viruses but not against DNA viruses. Due to its anti-viral activity against RNA viruses, it was used against SARS- It has a broad spectrum of activity against other RNA viruses. The drug is currently J o u r n a l P r e -p r o o f approved for influenza infection in Japan but is not approved in the US [75] . Due to its efficacy against RNA viruses, it has been considered for SARS CoV 2 infections.

One recent RCT was conducted in China, which compared favipiravir versus arbidol in moderate COVID-19 infections. The trial showed that favipiravir had better efficacy in treating moderate COVID-19 infections as compared to arbidol. Multiple trials are being conducted and are tabulated in Table 1 . It is currently not recommended in treatment for COVID-19 until the results of the above trials are available.

This drug has been widely used in several indications. It is being used for chronic Hepatitis C treatment, HIV treatment, and in cases of several viral hemorrhagic fevers. However, the data for use in viral hemorrhagic fevers is lacking, and it may be only effective in early disease stages [76] . It is a prodrug, and when converted to activate form, it resembles purine nucleotide. It inhibits viral mRNA capping and RNA synthesis in the virus. More than five mechanisms have been postulated for its exact mechanism of action [77]. This drug has been recommended for repurposing in SARS-CoV-2 infection [78]. Although its efficacy has been shown along interferons in inhibiting replication of coronavirus in human and animal cell lines [79] , there are no trials that have been conducted to prove its efficacy in humans against COVID 19. However, the following trails are being shown (Table 1) .

Umefenovir (arbidol) is an anti-viral drug with a broad spectrum and is used to treat influenza in China and Russia [80] . It is, however, not recommended for this use in other countries. Arbidol inhibits the fusion of membranes [68] . It inhibits the contact of viral and host cell membranes, thus inhibiting their fusion. It prevents the entry of the virus into target cells; therefore, protecting it from viral infection. Few studies suggest that it is also more effective against RNA viruses as compared to DNA viruses [81] . Multiple studies have been conducted regarding the use of arbidol in COVID-19. One retrospective cohort study determined that it speeds up the clearance of virus, improves radiologic images, and decreases the oxygen demand, J o u r n a l P r e -p r o o f particularly in those with a mild disease on admission. [64] One comparative study of arbidol against favipiravir showed that favipiravir is superior to arbidol in combating SARS-CoV-2 [82] . Another retrospective cohort study showed that the combination of lopinavir/ritonavir with arbidol is more effective in treating SARS CoV 2 than arbidol alone [83] . One randomized control trial showed no arbidol or lopinavir/ritonavir efficacy in patients with mild to moderate COVID 19 [84] . Tests that are being conducted to evaluate its efficacy are presented in Table 1 . Arbidol is currently not recommended for the treatment of COVID 19.

It is an immunosuppressant that is used to treat rheumatoid arthritis and systemic sclerosis. It is a monoclonal antibody that is directed against interleukine-6 receptor (IL-6R), thus blocking the cytokine related inflammatory process. Cytokine Response is an inflammatory response that leads to a sudden increase in the levels of multiple pro-inflammatory cytokines [85, 86] . It is common among diseases related to the immune system and therapy associated with the immune system, such as sepsisassociated transplantation of organs [87] and viral infections. The SARS-CoV-2 binds epithelial cells of alveoli in the lungs via ACE2, and activates the adaptive and innate immune system. It leads to the release of cytokines, including interleukin 6 (IL-6). Usually, the signal of IL-6 is only limited to the cells that express the IL-6 receptor (IL-6R). This combination leads to gp130 homologous dimerization and initiates the downstream pathway. However, when the levels of IL-6 increase, its signal is expressed because gp130 is present everywhere. Tocilizumab binds cellrelated IL-6R and soluble IL-6R, thus inhibiting their signals and cytokine response [88] . The efficacy of tocilizumab in randomized clinical trials is being investigated [89] . No trial has been completed yet. However, one clinical study was conducted in patients with severe disease, and it is found to be effective in patients with severe COVID-19 [90] . Thus, several studies are under investigation for its possible role in severe SARS-CoV-2 infection (Table 1) . It is being investigated for use in severe COVID 19 disease. There are no current recommendations for its use in patients.

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

Interferons (IFN-α/β) have broad-spectrum anti-viral activity against RNA viruses, inducing an anti-viral response across several cell types and mediating adaptive immune response. Humans produce 13 kinds of IFN-α and a singular IFN-β [91] .

Clinically, type 1 interferons have been approved to treat certain cancers, viral infections, and autoimmune disorders. One recent study also demonstrated the in vitro effects of interferons on SARS-CoV-2. It showed that it inhibits the viral replication at the same doses used for chronic hepatitis B and C treatment [92] .

Another study also showed a significant effect of interferon on replication of SARS-CoV-2 [93] . No trials have been completed regarding the role of interferons in COVID-19 management. However, many attempts are under process to look for their potential as treatment or prophylaxis (Table 1) . Interferons are currently not suggested for COVID-19 treatment.

Baricitinib is a drug primarily approved for use in rheumatoid arthritis. It is an immunosuppressant drug. Cytokine storm has been postulated in patients with COVID 19 [94] . Thus, baricitanib has been considered a potential treatment for COVID 19 ( Figure 6 ) [95] . However, some researchers suggest that it may not be an ideal drug to treat COVID 19 [96] . As cytokine storm is considered in the pathology of COVID 19, baricitinib inhibits the activity of Janus Kinase 1 and 2 enzymes, which interfere with the JAK-STAT signaling pathway, thus reducing disease severity.

There are no trials conducted in this regard; however, one study is being conducted in Italy, recruiting the patients ( Moreover, another phase 1/2 trial was conducted in the UK using a viral vectored vaccine expressing the spike protein of SARS-CoV-2 induced both cellular and humoral immunity among its participants [102] . Another phase 1 trial conducted in the USA using RNA-based vaccines (BNT162b1 and BNT162b2) showed effective immunogenicity [103] . Although these are preliminary results of different vaccine trials that have been conducted throughout the world, the vaccines have shown promise. There are hundreds of trials ongoing for other vaccines for COVID-19 all over the world. Maybe it is just a matter of time until phase 3/4 studies are conducted, and the world will be free from this deadly pandemic.

In conclusion, the details provided in this review are based on the literature and 

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Randomized, placebo-Controlled, double-blind, MultIcenter, parallel group Study to assess the Efficacy and safety of hydroxychloroquine in chinese patients with primary Sjogren's Syndrome

Single-Dose, Parallel Study of Generic and Branded Hydroxychloroquine Sulfate Tablet in Healthy Chinese Male Volunteers

Recruiting USA NCT04315948 Trial of Treatments for COVID-19 in Hospitalized Adults

Recruiting France NCT04276688

Ribavirin and IFN-beta Combination for nCoV Treatment

Randomised Evaluation Of Covid-19 Therapy (Recovery)

Recruiting UK ChiCTR2000030187 Clinical study for Lopinavir and Ritonavir in the treatment of novel coronavirus pneumonia

Recruiting China ChiCTR2000029741 Efficacy of Chloroquine and Lopinavir/Ritonavir in mild/general novel coronavirus (CoVID-19) infections: a prospective, open-label

Recruiting China ChiCTR2000029603 A Randomized, Open-Label, Multi-Centre Clinical Trial Evaluating and Comparing the Safety and Efficiency of ASC09/Ritonavir and Lopinavir/Ritonavir for Confirmed Cases of Novel Coronavirus Pneumonia

open-label, controlled trial for evaluating of the efficacy and safety of Baloxavir Marboxil, Favipiravir, and Lopinavir-Ritonavir in the treatment of novel coronavirus pneumonia

A randomised, open, controlled trial for darunavir/cobicistat or Lopinavir/ritonavir combined with thymosin a1 in the treatment of novel coronavirus pneumonia

A randomized, open-label study to evaluate the efficacy and safety of Lopinavir-Ritonavir in patients with mild novel coronavirus pneumonia

Recruiting China ChiCTR2000029468 A real-world study for lopinavir/ritonavir (LPV/r) and emtritabine (FTC) / Tenofovir alafenamide Fumarate tablets (TAF) regimen in the treatment of novel coronavirus pneumonia

Recruiting China ChiCTR2000029387 Comparative effectiveness and safety of ribavirin plus interferon-alpha, lopinavir/ritonavir plus interferon-alpha and ribavirin plus lopinavir/ritonavir plus interferon-alphain in patients with mild to moderate novel coronavirus pneumonia

Recruiting China ChiCTR2000029308 A randomized, controlled open-label trial to evaluate the efficacy and safety of lopinavirritonavir in hospitalized patients with novel coronavirus pneumonia

Clinical study for safety and efficacy of Favipiravir in the treatment of novel coronavirus pneumonia

Randomized controlled trial for safety and efficacy of Favipiravir in the treatment of novel coronavirus pneumonia (COVID-19) with poorly responsive

Recruiting China ChiCTR2000030894 Favipiravir Combined With Tocilizumab in the Treatment of novel coronavirus pneumonia (COVID-19)-A Multicenter

A Randomized Controlled Trial for Favipiravir Tablets Combine With Chloroquine Phosphate in the Treatment of Novel Coronavirus Pneumonia

Recruiting China JPRN-jRCTs031190226 Favipiravir in patients infected with

Recruiting Japan JPRN-jRCTs041190120 Favipiravir for SARS

Recruiting Japan NCT04310228 Favipiravir Combined With Tocilizumab in the Treatment of Corona Virus Disease

Clinical Trial of Favipiravir Tablets Combine With Chloroquine Phosphate in the Treatment of Novel Coronavirus Pneumonia

Recruiting China Ribavirin ChiCTR2000030922 Prospective, open-label, controlled, multicenter cohort study of long-acting interferon plus ribavirin in patients with novel coronavirus pneumonia

Ribavirin and IFN-beta Combination for nCoV Treatment

Recruiting Hong Kong ChiCTR2000029387 Comparative effectiveness and safety of ribavirin plus interferon-alpha, lopinavir/ritonavir plus interferon-alpha and ribavirin plus lopinavir/ritonavir plus interferon-alphain in patients with mild to moderate novel coronavirus pneumonia

Recruiting China Umefenovir ChiCTR2000029621 Clinical study of arbidol hydrochloride tablets in the treatment of novel coronavirus pneumonia

Recruiting China NCT04273763 Evaluating the Efficacy and Safety of Bromhexine Hydrochloride Tablets Combined With Standard Treatment/ Standard Treatment in Patients With Suspected and Mild Novel Coronavirus Pneumonia

Controlled trial for Recombinant Super-Compound Interferon (rSIFN-co

Recruiting China ChiCTR2000030262 Clinical study for combination of anti-viral drugs and type I interferon and inflammation inhibitor TFF2 in the treatment of novel coronavirus pneumonia

Randomized, open, blank controlled trial for the efficacy and safety of recombinant human interferon alpha 1beta in the treatment of Wuhan patients with novel coronavirus pneumonia

Prospective, open-label, controlled, multicenter cohort study of long-acting interferon plus ribavirin in patients with novel coronavirus pneumonia

Recruiting China ChiCTR2000031196 Efficacy and optimization of anti-viral therapy for novel coronavirus pneumonia

The listed author(s) are thankful to their representative universities for providing the facilities for the literature survey.

The authors declare no conflict of interest.J o u r n a l P r e -p r o o f