key: cord-0901760-xqlvdziu
authors: Babaei, Fatemeh; Mirzababaei, Mohammadreza; Nassiri‐Asl, Marjan; Hosseinzadeh, Hossein
title: Review of registered clinical trials for the treatment of COVID‐19
date: 2020-11-29
journal: Drug Dev Res
DOI: 10.1002/ddr.21762
sha: 2b4d8d4830fc58ff43a0f3c58a75ba3d4ea7fc28
doc_id: 901760
cord_uid: xqlvdziu

Coronavirus disease 2019 (COVID‐19) is a viral disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). The disease was first reported in December 2019 in Wuhan, China, but now more than 200 countries have been affected and the coronavirus pandemic is still ongoing. The severity of COVID‐19 symptoms can range from mild to severe. FDA approved remdesivir as a treatment of COVID‐19 so far. Various clinical trials are underway to find an effective method to treat patients with COVID‐19. This review aimed at summarizing 219 registered clinical trials in the ClinicalTrials.gov database with possible mechanisms, and novel findings of them, and other recent publications related to COVID‐19. According to our analyses, various treatment approaches and drugs are being investigated to find an effective drug to cure COVID‐19 and among all strategies, three important mechanisms are suggested to be important against COVID‐19 including antiviral, anti‐inflammatory, and immunomodulatory properties. Our review can help future studies get on the way to finding an effective drug for COVID‐19 treatment by providing ideas for similar researches.

. Furthermore, some people have experienced hypogeusia and hyposmia (Bénézit et al., 2020) . A summary of the clinical manifestations of COVID-19 disease is illustrated in Figure 1 .

COVID-19 and severe acute respiratory syndrome (SARS) have similar pathological characterization (Hui & Zumla, 2019) . Organ dysfunctions, including acute respiratory distress syndrome (ARDS), acute kidney injury, acute cardiac injury, liver dysfunction, and secondary inflammation are causes of death in patients with COVID-19 Guan et al., 2020; Wan, Xiang, Fang, et al., 2020; . FDA approved remdesivir as a treatment of COVID-19 so far and common medical therapies include symptomatic treatment or supportive care. Various therapeutic protocols have been used all over the world and some clinical trials are underway to find an effective and safe strategy to treat In this review, we collected some registered clinical trials with all types of treatment approaches that are underway and showed the most widely used treatment protocols and drugs that are being investigated for the treatment of COVID-19. Our study can help future studies get on the way to finding an effective drug for COVID-19 treatment by providing ideas for similar researches in basic and clinical studies.

ClinicalTrials.gov database was searched with the keywords "COVID-19" and "SARS-CoV-2" on April 10, 2020, and found 440 trials. We 

Following the screening of titles and study descriptions, 440 trials were assessed for eligibility. Among them, after applying the exclusion criteria we found 219 relevant trials (Figure 2 ). There are various treatment or prophylactic approaches in extracted COVID-19 clinical trials that are shown in Figure 3a that are including cell therapy (n = 15) ( Table 1) , plasma therapy (n = 9), oxygen support and nitric oxide inhaler (n = 11), vaccines (n = 9) (Table 2), drugs (n = 163), and herbal medicines or supplements or biological agents (n = 15) ( Table 3 ). Three trials are common among the three groups of treatment, then the total of studies is 222. All clinical trials that we have selected with title, intervention, and primary outcome have been shown in a supplemental data file. In this review, treatment or prophylactic regimens by the priority, possible mechanisms, important findings of them, and similar studies against COVID-19 will be explained. (Table 1) .

It seems that MSCs could regulate the inflammatory response by reducing the serum levels of pro-inflammatory cytokines and chemokines and promote tissue repair and regeneration via increasing IL-10 and vascular endothelial growth factor (VEGF). Another important issue in this study is that MSCs are resistant to SARS-CoV-2 due to a lack of ACE2 receptors (Leng et al., 2020) . Similarly, antiinflammatory effects are suggested for MSCs by Saldanha-Araujo et al. Now, several cell therapies are under investigation (Saldanha-Araujo et al., 2020) . However, there several questions about various doses, MSCs sources, and short-term therapy that need to be answered.

About the role of NK cells against COVID-19, one hypothesis is that NK cells have dual effects against SARS-CoV-2: (a) Healthy NK in low-risk individuals could clear virus infection and prevent lung damage. (b) Abnormality of NK cells in high-risk individuals, inhibits viral clearance, induces inflammatory responses, and consequence severe lung injury will happen (i.e., cytokine storm) (Market et al., 2020; Saldanha-Araujo et al., 2020) . It seems that overexpression of the inhibitory NK group 2 member A (NKG2A) receptors in the exhausted phenotype of NK cells is responsible to suppress T-cell and NK cytotoxic function and result in the progression of proinflammatory events and virus spreading (Masselli et al., 2020) . This hypothesis for the first time has been described by Zheng et al. They observed the NKG2A receptor was upregulated compared with healthy controls, while the ability to produce CD107a, IFNγ, IL-2, granzyme B, and TNF-ɑ was low in COVID-19 patients, and the percentage of NKG2A + cytotoxic lymphocytes was decreased in recovered patients .

There are two ongoing registered clinical trials NCT04280224 and NCT04324996 with NK cells for the treatment of COVID-19 patients ( Table 1 ). The results of these clinical trials will demonstrate the importance of this hypothesis.

F I G U R E 3 (a) Total studies that have been registered, (b) Classification of drugs that will be used in clinical trials, (c) Hydroxychloroquine regimen A randomized controlled trial NCT04338347 is evaluating CAP-1002 versus placebo for the treatment of severe COVID-19 (Table 1) .

Allogeneic cardiosphere-derived cells (CAP-1002) is another strategy in cell therapy. Administration of CAP-1002 to six patients with severe COVID-19 as compassionate therapy indicates that it was safe and effective and improved clinical symptoms. It also reduced inflammatory markers (C-reactive protein, IL-6, and Ferritin) in most patients. All patients received conventional therapy against COVID-19 (Singh, Chakravarty, et al., 2020) . Taken together, further studies need to evaluate the efficacy and safety of cell therapy in COVID-19 patients.

Convalescent plasma therapy from recovered patients is under investigation. Up to now, some studies have reported that convalescent plasma containing neutralizing antibody could potentially improve clinical outcomes (Ahn et al., 2020; Duan et al., 2020; Shen et al., 2020; Ye et al., 2020; Zhang, Liu, et al., 2020) . Convalescent plasma has been administered as a last resort to increase the survival rate of patients with severe acute respiratory syndrome infection in China . Direct neutralization of virus and decrement of viral load are suggested as possible mechanisms to improve COVID-19 patients' symptoms in all of these published papers. However, other possibilities such as the control of overactivity of the immune system (i.e., cytokine storm) and immunomodulation of hypercoagulable state (i.e., thrombosis) have been discussed by Rojas et al., with two ongoing clinical trials NCT04332835, and NCT04332380 on the convalescent plasma in COVID-19 (Details in supplementary data) (Rojas et al., 2020) .

However, patient and donor conditions such as level of plasma antibodies in the donor, administration time of convalescent plasma (early or late stage of disease), and cotherapy with other treatments such as antivirals, steroids, and so forth should be considered as confounding variables in the studies. Further studies in well-designed trials are needed to confirm the efficacy of plasma therapy. I/II study of universal off-the-shelf NKG2D-ACE2 CAR-NK cells for therapy of COVID-19   Biological: NK cells, IL15-NK cells, NKG2D CAR-NK  cells, ACE2 CAR-NK cells, NKG2D-ACE2 CAR-NK  cells   3 

In addition to the treatment of COVID-19, disease prevention is also important especially in healthcare providers and housemates of patients with COVID-19. Some registries of clinical trials are trying to design a specific vaccine against COVID-19. For more details, see Table 2 .

With regard to the similarity between SARS-CoV and SARS- (Bukreyev et al., 2004; Escriou et al., 2014; Netland et al., 2010) .

In some studies, virus inactivation is carried out by using radiation techniques or chemicals such as formalin, and methanol to prepare a vaccine (Stauffer et al., 2006) . Various studies have been designed inactivated SARS-CoV vaccine which stimulated neutralizing antibodies production, proliferated lymph node T-cell, and produced cytokines such as IL-2, IL-4, IL-5, IFN-γ, and TNF-α (Takasuka et al., 2004; Tang et al., 2004; Xiong et al., 2004) . A protein subunit vaccine has been developed against coronavirus that it contains the synthetic or isolated or recombinant or derived highly antigenic protein-based subunits (Vartak & Sucheck, 2016) . The receptor-binding domain is the most widely used protein segment in the coronavirus vaccine (Badgujar et al., 2020) . Several studies have reported that protein subunit coronavirus vaccine induces the generation of neutralizing antibodies, IgA, IgG, Th-1, and Th-2 type of immunogenic responses (du et al., 2016; Tang et al., 2015) . Another type of vaccine is the vector-based vaccine. Various viral vectors such as adenovirus and lentivirus are used as a delivery tool to produce vector-based vaccines (Bouard et al., 2009 ). In addition, an adenovirus vector-based vaccine is designed against SARS-CoV which induces a specific humoral immunogenic response. S gene/spike proteins are often encoded in the adenovirus vector (Ababneh et al., 2019; Folegatti et al., 2020) . and T-cell responses against SARS-CoV-2 . On the other hand, it seems that some researchers have focused on the nucleic acid vaccine against coronaviruses, and various genes are used to design vaccines including N gene, S gene, S1 gene, and S2 gene. The immune response induced by these vaccines includes the production of IL-2, γ-interferon, cytotoxic T lymphocytes, CD4+, CD8+, neutralizing antibodies, and Th-1/Th-2 responses (Badgujar et al., 2020) .

Two registries studies (NCT04336410 and NCT04283461) in our review investigate safety, tolerability, and immunogenicity of DNA and mRNA vaccine for COVID-19 respectively ( Anti-inflammatory and immune regulation effects infections (Arvin et al., 2020; Wan, Shang, Sun, et al., 2020) . Then, it is necessary to determine the ADE in the development of vaccines and antibodies against SARS-CoV-2 in human clinical trials.

Some clinical trials are trying to treat COVID-19 through the prescription of supplements such as vitamin D and C and zinc, herbal medicines, traditional Chinese medicines alone, or in combination with drugs except two of them (For more details, see Table 3 ). The possible mechanisms of the two registries of studies NCT04291053 and NCT04275388 were not available.

An important supplement is vitamin D that has immunomodulatory activity. Recently, a population-based study showed an association between low plasma 25(OH)D level and increased likelihood of COVID-19 infection and hospitalization due to the SARS-CoV-2 (Merzon et al., 2020) .

Recently the inhibitory effects of natural products on coronavirus targets such as S protein and viral replication were reviewed by Boozari & Hosseinzadeh, 2020 . The potential role of natural products in the prevention and treatment of COVID-19 should be considered Boozari & Hosseinzadeh, 2020) .

Overall, it seems that one of the most important mechanisms of these agents is modulatory effects on the immune system that prevents (Table 3) .

Drug studies in clinical trials of treatment of COVID-19 were assessed and categorized into eight groups that have been shown in Figure 3b .

Hydroxychloroquine alone or in combination therapy is the most widely used or being used in clinical trials of treatment of COVID-19. The second most widely treatment is immunotherapy which is explained below. Antivirals, angiotensin system drugs, Nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and tranexamic acid are also being investigated. Some of the trials do not include any of the above groups, which classify as others and include 7.98% of the trials (Figure 3b ).

Hydroxychloroquine is often prescribing alone in clinical trials of treatment of COVID-19. It is also being used in combination with other drugs such as supplements (Vitamin C, D, zinc), azithromycin, antivirals, monoclonal antibodies. Additional detail is provided in Figure 3c . 

Immunotherapy is the second most widely used group in clinical trials.

Various immunomodulatory drugs are used in COVID-19 clinical trials, including monoclonal antibodies, glucocorticoids, Janus kinase inhibitors, some immunosuppressive drugs (such as anakinra), immunoglobulins, and interferons that are considered as immunotherapy. Table 4 presents a summary of immunotherapy drugs, their mechanism of actions, and the indication that have been mentioned during registration in ClinicalTrials.gov. In this section, we describe the major Table 4 .

Administration of tocilizumab to ICU and non-ICU patients could improve severe COVID-19 pneumonia with the hyperinflammatory syndrome (n = 43, n = 57, respectively) (Toniati et al., 2020) . The IL-6 serum levels were significantly higher in nonsurvivors than in survivors in COVID-19 patients in post-tocilizumab therapy. It is suggested that IL-6 levels can discriminate nonsurvivors from survivors in post tocilizumab treatment in COVID-19 pneumonia (Quartuccio et al., 2020) .

However, it should pay attention to this issue that the initial treatment of tocilizumab is associated with elevation of IL-6 levels. This may be due to the block of the IL-6 receptors by tocilizumab. This point is Table 4 . several cytokines such as IL-6, IL-12, IL-23, and IFN-γ, result in reducing inflammation induced by a cytokine storm in sever COVID-19 . Details of registries of JAK kinase inhibitors including baricitinib (NCT04331808), tofacitinib (NCT04332042), ruxolitinib (NCT04337359, NCT04334044, NCT04331665, NCT04338958) are in Table 4 , and supplementary data.

Other registry studies contain anakinra (NCT04341584, NCT04330638, NCT04339712, NCT04324021), tacrolimus (NCT04341038), sirolimus (NCT04341675), thalidomide (NCT04273529, NCT04273581), PD-1 blocking antibody (NCT04268537), and thymosin combined with other drugs (NCT04268537, NCT04320238) are under investigation due to immunosuppressive activities. For more detail of mechanisms see Table 4 .

Anakinra is an IL-1 antagonist. A retrospective cohort study showed that a high dose of anakinra (5 mg/kg twice per day, IV, for 21 days) was safe and associated with clinical improvement in 72% of COVID-19 and ARDS patients who were out of ICU (n = 29) (Cavalli et al., 2020) . and Stage III (hyper inflammation phase) (Siddiqi & Mehra, 2020) . The rationale for use of IVIG in COVID-19 is that it may provide an immunomodulatory effect in hyper inflammation state and competitively bind Fcγ receptor to prevent ADE triggered by virus-antibody immune complexes (Nguyen et al., 2020) .

to play a key role in SARS-CoV-2 pathogenesis (Sa Ribero et al., 2020) . Chinese guideline recommends administration of inhaler IFN-α (5 million U, 2 times per day, no more than 10 days) as antiviral therapy for new coronavirus . IFNβ1 may be used to treat COVID-19 in the early stages of infection (Sallard et al., 2020) . The administration of immunomodulatory or antiinflammatory drugs that reduce inflammation has been recommended at the late stage of the disease, and in this stage, IFN-I maybe promotes disease severity causes excessive inflammation and direct tissue damage. Therefore, treatment with IFN-I should be with caution (Lee & Shin, 2020; Sa Ribero et al., 2020) .

Overall, as the important role of immunotherapy, these ongoing clinical trials provide us clues about the efficacy and safety of this regimen in the clinical management of COVID-19 infection.

Antiviral drugs, as other groups are using in COVID-19 clinical trials.

These drugs are lopinavir/ritonavir, favipiravir, remdesivir, oseltamivir, ASC09/ritonavir (ASC09F), umifenovir (arbidol, abidol), ribavirin, darunavir, and cobicistat ( Figure 3b ).

In The main protease of SARS-CoV is a 3-chymotrypsin-like protease (3CL pro ) that has a key role in proteolytic processing of polyproteins and is important for viral replication (Nukoolkarn et al., 2008) . There is a similarity between the genome sequence of SARS-CoV-2 and SARS-CoV (Tahir Ul Qamar et al., 2020) . It is reported that the binding affinities of both lopinavir and ritonavir to SARS-CoV 3CL pro are very similar to each other (Nukoolkarn et al., 2008) . Chu et al. found that lopinavir/ritonavir has anti-SARS-CoV activity in in vitro and improved clinical outcomes (Chu et al., 2004) . Recent researches have proposed lopinavir/ ritonavir as potential drugs for the treatment of COVID-19 Lu, 2020 (Furuta et al., 2017) . It is administrated to Ebola virusinfected patients and approved for influenza type A and B in Japan (Nagata et al., 2015) . Now, favipiravir is being used in clinical trials against COVID-19.

Any data about selected doses and safety is based on previous clinical trials about the treatment of influenza, and Ebola viruses or experimental studies . Recently, it has been reported that the trough concentration of favipiravir in critically ill patients with COVID-19 was much lower than that of healthy individuals in a previous clinical trial (Irie et al., 2020) . It seems that in addition to studying the efficacy and safety of favipiravir, evaluating the pharmacokinetics is also necessary. (Gordon et al., 2020) . It has an inhibitory effect against SARS-CoV-1, MERS-CoV, and SARS-CoV-2 in vitro and in vivo study Wang, Zhou, et al., 2020) . A possible favorable benefitrisk profile is suggested for remdesivir compared with placebo as the preliminary results of a clinical trial in severe COVID-19 infection .

A randomized, double-blind, placebo-controlled clinical trial with registry number NCT04257656 was carried out to evaluate the efficacy and safety of intravenous remdesivir in adult patients with severe COVID-19. In both groups, concomitant use was continued with conventional therapy and the remdesivir group did not show any significant clinical or antiviral effects in patients compared with the placebo group in clinical studies . Recently, the results of the trial "Adaptive COVID-19 Treatment Trial (ACTT)" with registry number NCT04280705 which underwent on 1062 patients, has

shown that remdesivir (n = 541) has superior effects against the placebo group (n = 521) in shortening the time of recovery in adults who were hospitalized with COVID-19. The respiratory infection was also lower compared with the placebo (Beigel et al., 2020 CoV-2 spike protein and inhibits host cell adhesion and entry (Vankadari, 2020) . Arbidol has shown an inhibitory effect on SARS-

CoV-2 at a concentration of 10-30 μM in vitro . It seems that more clinical investigation is still required to judge the efficacy of umifenovir against COVID-19.

Azithromycin is a macrolide antibiotic that inhibits bacterial mRNA translation and protein synthesis (Parnham et al., 2014) . It is prescribed for different types of infections such as respiratory infections, skin infections, and sexually transmitted diseases (Peters et al., 1992) .

It has shown that azithromycin has immunomodulatory and antiinflammatory effects (Parnham et al., 2014) . In our review, many trials are currently investigating the efficacy of combination therapy of azithromycin and hydroxychloroquine on COVID-19 in registries of trials such as NCT04339816, NCT04329832, NCT04334382, and NCT04336332.

Azithromycin has shown antiviral effects and for this effect, it has been added to hydroxychloroquine to enhance clearance of COVID-19 (Rameshrad et al., 2020 4.6.5 | Clinical trials related to the reninangiotensin system Some drugs such as losartan (n = 5), valsartan (n = 1), angiotensin 1-7 (n = 1), and recombinant human angiotensin-converting enzyme 2 (rhACE2) (n = 1) are under investigation (Figure 3b) For this reason, we refer to recently published studies as follow:

The result of a retrospective cohort study on 4480 patients with COVID-19 showed that prior use of ACEI/ARBs in 895 patients was not significantly associated with a higher incidence rate of COVID-19 diagnosis among patients with hypertension or with mortality or severe disease compared with ACEI/ARB nonusers (Fosbøl et al., 2020) . According to the results of a meta-analysis, there was no significant association between the use of ACEI/ARB and the severity and mortality of COVID-19 (Grover & Oberoi, 2020) . Furthermore, the results have shown that in COVID-19 patients with hypertension who received ACEI/ARB have a lower rate of severe disease compared with the non-ACEI/ARB group. Also, the viral load and level of IL-6 are decreased and the number of CD3 and CD8 T cells in peripheral blood was increased . The results of a recent retrospective single-center study on 614 hospitalized hypertensive COVID-19 patients showed that continued use of ACEI/ARB reduced mortality rate, and intensive care unit admission (ICU) compared with the non-ACEI/ARB group. Also, the percentages of developed hypotension and acute kidney injury in these hospitalized patients were higher in the discontinued ACEI/ARB group (Lam et al., 2020) . Overall, it seems that further clinical trial studies on a large population need to confirm these two mentioned hypotheses.

NSAIDs are being studied against COVID-19. In the LIBERATE study (NCT04334629), three doses of lipid ibuprofen will be administrated to patients with acute hypoxemic respiratory failure due to COVID-19. The antiviral effects of naproxen have been reported in several experimental studies. Naproxen inhibited influenza A virus nucleoprotein (NP) and result in inhibiting replication of the virus in the mouse model of intranasal infection (Lejal et al., 2013) . Also, the binding affinity influenza B virus NP to naproxen was higher than the influenza A virus. Naproxen has anti-influenza B properties both in vivo and in vitro studies. It is suggested that naproxen acts as an anti-influenza drug with broad, and multi-mechanistic potential (Zheng et al., 2019) .

In our review, aspirin as another NSAID is being used as an antithrombotic and cardioprotective agent in two registries of trials 

A few clinical trials are also underway on some other drugs with a different mechanism of effects against COVID-19 such as sildenafil citrate, deferoxamine, piclidenoson, sargramostim, tetrandrine, tradipitant, eicosapentaenoic acid gastro-resistant capsules, aviptadil, PUL-042 (Pam2-ODN) (TLR 2/6/9 agonist), BLD-2660 (inhibitor of calpains 1, 2, and 9), camostat mesilate (serine protease inhibitor) ( Figure 3b ).

This review aimed at summarizing some of the registries of clinical trials in ClinicalTrials.gov database with possible mechanisms, and novel findings of them related to COVID-19. Various treatment or prophylactic approaches are underway to treat COVID-19, including cell therapy, oxygen therapy, and ventilator support, using plasma of the convalescent patient, herbal medicines, traditional Chinese medicine, supplements, vaccine, and drugs. Hydroxychloroquine, antivirals, monoclonal antibodies, or other immunomodulatory drugs, reninangiotensin system drugs are the most commonly registered drugs in COVID-19 clinical trials. It seems that among the various proposed therapeutic mechanisms, antiviral, anti-inflammatory, and immunomodulatory properties, have pivotal roles to combat COVID-19 disease. Our study can help future studies get on the path to finding an effective drug for COVID-19 treatment by providing ideas for similar researches. However, terminating the clinical trials and performing meta-analysis for each treatment approach is necessary.

The authors declare no potential conflict of interest.

The data that supports the findings of this study are available in the supplementary material of this article ORCID Marjan Nassiri-Asl https://orcid.org/0000-0003-3701-0758

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