Summary
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.
Keywords: COVID-19, SARS-CoV-2, coronavirus disease 2019, clinical trial, Japan
Introduction
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 (1). The SARS-CoV-2 belongs to Betacoronavirus which also contains severe acute respiratory syndrome coronavirus (SARS-COV-1) spread in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) spread in 2012 (2). As of April 5, 2020, over 2,845 cases have been confirmed in Japan, including 69 deaths as well as over 1,169,217 confirmed cases including 63,437 deaths all over the world. Such huge numbers of infected and dead people call for an urgent demand of effective, available, and affordable treatments to control and diminish the pandemic SARS-CoV-2 infection. Currently, hundreds of clinical trials on a wide variety of treatments against COVID-19 are being conducted around the world. Here, we summarize major ongoing clinical trials registered to ClinicalTrials.gov database as of April 2, 2020, and describe the trials which are now being conducted or scheduled in Japan.
Methods
A search for ongoing clinical trials for the treatment of COVID-19 was conducted at the clinicaltrials.gov database on April 2, 2020. The search words were "COVID-19", "SARS-CoV-2", "2019-nCoV" and "2019 novel coronavirus", and they were entered to the simple search field "conditions or disease", with "Status" being "All studies" and without any restrictions in other search windows. The subsequent filter conditions for identifying the eligible studies were as follows: recruitment is "Recruiting", "Active, not recruiting", "Enrolling by invitation", or "Completed"; study type is "Interventional"; study phase is "Phase I-IV"; and primary purpose is "treatment". The other conditions including sex, age, study results, funder type, and study documents were not restricted.
The severity of COVID-19 infection was defined according to the previous report as follows (3).
Mild: asymptomatic or symptomatic (i.e., with fever, cough, or myalgia), but might not require hospitalization for treatment.
Severe: tachypnoea (≥ 30 breaths per min) or oxygen saturation 93% or higher at rest, PaO2/FiO2 ratio less than 300 mm Hg, and requiring hospitalization for treatment.
Critical: requiring mechanical ventilation, septic shock, or other organ dysfunction or failure that requires intensive care.
Results And Discussion
Summary of the identified trials
We identified 48 clinical trials in total. Of these, 41 trials adopted drug intervention (Table 1) and the other 7 trials utilized biological intervention (Table 2).
Table 1. Clinical trials identified at Clinicaltrials.gov related to drug intervention for COVID-19 treatment.
| Study | Study Start | Interventions | Severity | Target Number | Phase | Status | Country |
|---|---|---|---|---|---|---|---|
| Safety and Efficacy of Hydroxychloroquine Associated With Azithromycin in SARS-CoV2 Virus (Coalition Covid-19 Brasil II) | 28-Mar-20 | hydroxychloroquine +/- azithromycin | Severe/Critical | 440 | III | Recruiting | Brazil |
| Cohort Multiple Randomized Controlled Trials Open-label of Immune Modulatory Drugs and Other Treatments in COVID-19 Patients - Sarilumab Trial - CORIMUNO-19 - SARI | 27-Mar-20 | sarilumab vs. control | Severe/Critical | 240 | II/III | Recruiting | France |
| Sargramostim in Patients With Acute Hypoxic Respiratory Failure Due to COVID-19 (SARPAC) | 24-Mar-20 | sargramostim vs. control | Severe | 80 | IV | Recruiting | Belgium, Italy |
| Chloroquine Diphosphate for the Treatment of Severe Acute Respiratory Syndrome Secondary to SARS-CoV2 | 23-Mar-20 | chloroquine diphosphate (high dose vs. low dose) | Severe/Critical | 440 | II | Recruiting | Brazil |
| Efficacy of Methylprednisolone for Patients With COVID-19 Severe Acute Respiratory Syndrome | 23-Mar-20 | methylprednisolone | Severe/Critical | 104 | II/III | Recruiting | Italy |
| Colchicine Coronavirus SARS-CoV2 Trial (COLCORONA) | 23-Mar-20 | colchicine vs. control | Mild | 6,000 | III | Recruiting | Canada |
| Trial of Treatments for COVID-19 in Hospitalized Adults | 22-Mar-20 | remdesivir vs. lopinavir/ritonavir +/- interferon β-1A vs. hydroxychloroquine vs. control | Severe/Critical | 3,100 | III | Recruiting | France |
| Nitric Oxide Gas Inhalation Therapy for Mild/Moderate COVID-19 | 21-Mar-20 | nitric oxide gas vs. control | Mild | 240 | II | Recruiting | United States |
| Nitric Oxide Gas Inhalation in Severe Acute Respiratory Syndrome in COVID-19 | 21-Mar-20 | nitric oxide gas vs. control | Severe/Critical | 200 | II | Recruiting | United States |
| Tocilizumab in COVID-19 Pneumonia (TOCIVID-19) | 19-Mar-20 | tocilizumab | Critical | 330 | II | Recruiting | Italy |
| Treatments for COVID-19: Canadian Arm of the SOLIDARITY Trial | 18-Mar-20 | lopinavir/ritonavir vs. control | Severe/Critical | 440 | II | Active not recruiting | Canada |
| Post-exposure Prophylaxis / Preemptive Therapy for SARS-Coronavirus-2 | 17-Mar-20 | hydroxychloroquine vs. control | Mild | 3,000 | III | Recruiting | United States |
| Evaluation of the Efficacy and Safety of Sarilumab in Hospitalized Patients With COVID-19 | 16-Mar-20 | sarilumab vs. control | Severe/Critical | 400 | II/III | Recruiting | United states |
| Baricitinib in Symptomatic Patients Infected by COVID-19: an Open-label, Pilot Study. | 16-Mar-20 | baricitinib vs. control | Mild | 60 | III | Recruiting | Italy |
| Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS- 5734™) in Participants With Moderate Coronavirus Disease (COVID-19) Compared to Standard of Care Treatment | 15-Mar-20 | remdesivir vs. control | Mild | 600 | III | Recruiting | Multinational* |
| Comparison of Lopinavir/Ritonavir or Hydroxychloroquine in Patients With Mild Coronavirus Disease (COVID-19) | 11-Mar-20 | lopinavir/ritonavir vs. hydroxychloroquine sulfate vs. control | Mild | 150 | II | Recruiting | Korea |
| Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS- 5734™) in Participants With Severe Coronavirus Disease (COVID-19) | 6-Mar-20 | remdesivir vs. control | Severe | 400 | III | Recruiting | Multinational† |
| Tetrandrine Tablets Used in the Treatment of COVID-19 | 5-Mar-20 | tetrandrine vs. control | Mild/Severe | 60 | IV | Enrolling by invitation | China |
| Yinhu Qingwen Decoction for the Treatment of Mild / Common CoVID-19 | 27-Feb-20 | YinHu QingWen Decoction vs. Chinese medicine treatment vs. standard western medicine treatment | Mild | 300 | II/III | Active not recruiting | China |
| Fingolimod in COVID-19 | 22-Feb-20 | fingolimod vs. control | Mild/Severe | 30 | II | Recruiting | China |
| Adaptive COVID-19 Treatment Trial (ACTT) | 21-Feb-20 | remdesivir vs. control | Severe/Critical | 440 | III | Recruiting | Multinational‡ |
| Evaluation of Ganovo (Danoprevir) Combined With Ritonavir in the Treatment of Novel Coronavirus Infection | 17-Feb-20 | danoprevir + ritonavir +/- interferon nebulization | Mild | 11 | IV | Completed | China |
| Treatment of Pulmonary Fibrosis Due to 2019-nCoV Pneumonia With Fuzheng Huayu | 15-Feb-20 | N-acetylcysteine +/- Fuzheng Huayu Tablet | Mild/Severe | 136 | II | Recruiting | China |
| Vitamin C Infusion for the Treatment of Severe 2019-nCoV Infected Pneumonia | 14-Feb-20 | vitamine C vs. control | Severe/Critical | 140 | II | Recruiting | China |
| Mild/Moderate 2019-nCoV Remdesivir RCT | 12-Feb-20 | remdesivir vs. control | Mild | 308 | III | Recruiting | China |
| Lopinavir/ Ritonavir, Ribavirin and IFN-beta Combination for nCoV Treatment | 10-Feb-20 | lopinavir/ritonavir + ribavirin + lnterferon β-1B vs. control | Mild/Severe/ Critical | 70 | II | Recruiting | Hong Kong |
| A Pilot Study of Sildenafil in COVID-19 | 9-Feb-20 | sildenafil citrate | Mild/Severe | 10 | III | Recruiting | China |
| Severe 2019-nCoV Remdesivir RCT | 6-Feb-20 | remdesivir vs. control | Severe | 453 | III | Recruiting | China |
| Efficacy and Safety of Hydroxychloroquine for Treatment of Pneumonia Caused by 2019-nCoV (HC-nCoV) | 6-Feb-20 | hydroxychloroquine vs. control | Mild/Severe/ Critical | 30 | III | Completed | China |
| Clinical Study of Anti-CD147 Humanized Meplazumab for Injection to Treat With 2019-nCoV Pneumonia | 3-Feb-20 | meplazumab | Mild/Severe | 20 | I/II | Recruiting | China |
| Bevacizumab in Severe or Critical Patients With COVID-19 Pneumonia | Feb-20 | bevacizumab | Severe/Critical | 20 | II/III | Recruiting | China |
| A Randomized, Open, Controlled Clinical Study to Evaluate the Efficacy of ASC09F and Ritonavir for 2019-nCoV Pneumonia | 1-Feb-20 | ASC09F + oseltamivir vs. ritonavir + oseltamivir vs. oseltamivir | Mild | 60 | III | Recruiting | China |
| A Prospective/Retrospective, Randomized Controlled Clinical Study of Antiviral Therapy in the 2019-nCoV Pneumonia | 1-Feb-20 | arbidol hydrochloride vs. oseltamivir vs. lopinavir/ritonavir vs. control | Mild/Severe/ Critical | 400 | IV | Recruiting | China |
| A Prospective/Retrospective, Randomized Controlled Clinical Study of Interferon Atomization in the 2019-nCoV Pneumonia | 1-Feb-20 | arbidol hydrochloride +/- lnterferon atomization | Mild/Severe/ Critical | 100 | IV | Recruiting | China |
| The Efficacy of Different Hormone Doses in 2019-nCoV Severe Pneumonia | 1-Feb-20 | methylprednisolone (< 40 mg/day vs. 40-80 mg/day) | Severe | 100 | IV | Recruiting | China |
| Efficacy and Safety of Darunavir and Cobicistat for Treatment of Pneumonia Caused by 2019-nCoV | 30-Jan-20 | darunavir + cobicistat vs. control | Mild/Severe/ Critical | 30 | III | Recruiting | China |
| Glucocorticoid Therapy for Novel Coronavirus Critically Ill Patients With Severe Acute Respiratory Failure | 26-Jan-20 | methylprednisolone vs. control | Severe/Critical | 80 | II/III | Recruiting | China |
| STOP PIV - Phase III DAS181 Lower Tract PIV Infection in Immunocompromised Subjects | 23-May-19 | DAS181 | Severe | 250 | III | Recruiting | United States |
| Lessening Organ Dysfunction With Vitamin C | 8-Nov-18 | vitamin C vs. control | Critical | 800 | III | Recruiting | Canada |
| Inhaled Gaseous Nitric Oxide (gNO) Antimicrobial Treatment of Difficult Bacterial and Viral Lung (COVID-19) Infections | 24-Oct-17 | nitric oxide gas | Mild | 20 | II | Active not recruiting | Canada |
| Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia | 11-Apr-16 | lopinavir/ritonavir +/- hydroxychloroquine vs. lnterferon β-1A vs. Anakinra vs. control | Severe/Critical | 6,800 | IV | Recruiting | Multinational§ |
*United States, China, Germany, Hong Kong, Italy, Korea, Singapore, Spain, Switzerland, Taiwan, United Kingdom, †United States, Germany, Hong Kong, Italy, Korea, Singapore, Spain, Switzerland, Taiwan, United Kingdom, ‡United States, Japan, Korea, Singapore.
§Australia, Belgium, Canada, Croatia, Germany, Hungary, Ireland, Netherlands, New Zealand, Portugal, Romania, Spain, United Kingdom
Table 2. Clinical trials identified at Clinicaltrials.gov related to biological intervention for COVID-19 treatment.
| Study | Study Start | Interventions | Severity | Target Number | Phase | Status | Country |
|---|---|---|---|---|---|---|---|
| Immunity and Safety of Covid-19 Synthetic Minigene Vaccine | 24-Mar-20 | LV-SMENP-DC vaccine + antigen-specific CTLs | Mild/Severe | 100 | I/II | Recruiting | China |
| A Phase I/II Study of Universal Off-the-shelf NKG2D-ACE2 CAR-NK Cells for Therapy of COVID-19 | 21-Mar-20 | NK cells vs. IL15-NK cells vs. NKG2D CAR-NK cells vs. ACE2 CAR-NK cells vs. NKG2D-ACE2 CAR-NK cells | Mild/Severe | 90 | I/II | Recruiting | China |
| Treatment of COVID-19 Patients Using Wharton's Jelly-Mesenchymal Stem Cells | 16-Mar-20 | WJ-MSCs | Mild/Severe/ Critical | 5 | I | Recruiting | Jordan |
| Treatment With Mesenchymal Stem Cells for Severe Corona Virus Disease 2019 (COVID-19) | 5-Mar-20 | MSCs vs. control | Severe | 90 | 1I/II | Recruiting | China |
| NK Cells Treatment for Novel Coronavirus Pneumonia | 20-Feb-20 | NK Cells vs. control | Mild/Severe/ Critical | 30 | I | Recruiting | China |
| Safety and Immunity of Covid-19 aAPC Vaccine | 15-Feb-20 | Pathogen-specific aAPC | Mild/Severe | 100 | I | Recruiting | China |
| Mesenchymal Stem Cell Treatment for Pneumonia Patients Infected With 2019 Novel Coronavirus | 27-Jan-20 | MSCs vs. control | Mild/Severe/ Critical | 20 | I | Recruiting | China |
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 performed multinationally. The drugs utilized in more than one trial 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). The other pharmaceutical interventions included danoprevir, darunavir, ritonavir, ribavirin, cobicistat, chloroquine, bevacizumab, sarilumab, meplazumab, baricitinib, tocilizumab, anakinra, sargramostim, fingolimod, corchicine, sildenafil citrate, tetrandrine, DAS181, ASC09F, and traditional Chinese medicines.
As for the 7 clinical trials utilizing biological intervention, almost all the trials were conducted in China except one in Jordan. The biological interventions included MSCs, NK cells, aAPC vaccine and synthetic minigene vaccine. All the trials are clinical phase I or II with a relatively small target number of patients.
Clinical trials conducted or scheduled in Japan
The clinical trials which are now being conducted or scheduled in Japan for the treatment of COVID-19 are as follows, and the details of the drugs utilized in the trials are briefly summarized.
Lopinavir/ritonavir
Lopinavir is a human immunodeficiency virus (HIV) type 1 aspartate protease inhibitor, and ritonavir is combined with lopinavir to increase its plasma half-life through the inhibition of cytochrome P450. Because lopinavir/ritonavir has been reported to have a benefit treating both SARS-CoV-1 (4) and MERS-CoV infection (5), similar effectiveness for COVID-19 is expected and several clinical studies using lopinavir/ritonavir are currently being conducted for COVID-19 around the world as mentioned above. However, a latest report published from China on March 18, 2020 reported no benefit of lopinavir/ritonavir treatment beyond standard care in hospitalized adult patients with severe COVID-19 (6). In Japan, lopinavir/ritonavir was administered to patients with COVID-19 from February 21, 2020 as part of an observational study. To confirm or exclude the treatment benefit of lopinavir/ritonavir, the results of the ongoing studies should be carefully observed in the future.
Remdesivir
Remdesivir is a broad-spectrum antiviral agent and was developed by Gilead Sciences in 2017 as a treatment for Ebola virus infection (7). The antiviral mechanism of remdesivir is a delayed chain cessation of nascent viral RNA by obscuring viral RNA polymerase and evading proofreading by viral exonuclease (7). Remdesivir has been recently recognized as a promising antiviral drug against a wide array of RNA viruses including SARS-CoV-1 and MERS-CoV infection in cultured cells, mice and non-human primate models (8-10). Based on the broad-spectrum anti-corona virus activity of remdesivir that were demonstrated in pre-clinical studies, several multinational, randomized, placebo controlled, double-blind clinical trials are currently being conducted. Of these, Japan is participating in Adaptive COVID-19 Treatment Trial, in which remdesivir (200 mg on day 1, then 100 mg/day up to 10 days) or placebo was administered to patients with severe or critical COVID-19 infection. Remdesivir is one of the most expectant and frequently investigated treatment for COVID-19 around the world, and accumulation of cases and analysis of results are awaited.
Favipiravir
Favipiravir is an antiviral compound that selectively and potently inhibits the RNA-dependent RNA polymerase of influenza and many other RNA viruses (11). Wan et al. revealed the antiviral effect of favipiravir to COVID-19 in vitro although a high concentration was required to reduce the viral infection (12). A randomized clinical trial from Wuhan, although the report has not been evaluated critically, reported that favipiravir has a higher 7 day's clinical recovery rate and more effectively reduced incidence of fever and cough compared with arbidol in ordinary COVID-19 patients untreated with antiviral previously (13). Although another clinical study comparing favipiravir with lopinavir/ritonavir for COVID-19 was published from Shenzhen on Engineering, it was thereafter withdrawn for some unknown reason. In Japan, Fujita Health University launched a multi-institutional, open-label, phase II study using favipiravir for asymptomatic or mild COVID-19 patients on March 2, 2020. The patients are assigned into immediate and delayed favipiravir arm, and favipiravir is administered orally for 10 days. The administration of favipiravir is scheduled as follows: immediate favipiravir arm, 1,800 mg twice a day on Day 1 followed by 800 mg twice a day from Day 2; delayed favipiravir arm, 1,800 mg twice a day on Day 6 followed by 800 mg twice a day from Day 7 to Day 15. Primary outcome is a proportion of subjects with clearance of COVID-19 virus in nasopharyngeal swab on Day 6. The collection of cases is going to be initiated in the near future.
Ciclesonide
Ciclesonide is an inhaled corticosteroid originally used in the continuous treatment of mild-to-severe asthma (14). A recent report from National Institute of Infectious Diseases (Tokyo, Japan) revealed that ciclesonide blocks coronavirus RNA replication by targeting viral NSP15, and therefore, has an antiviral effect on COVID-19 (15). Thereafter, the efficacy of ciclesonide on three cases with early to middle-stage COVID-19 pneumonia has been reported from Kanagawa Prefectual Ashigarakami Hospital (Kanagawa, Japan). Based on these findings, a clinical trial to investigate the efficacy of ciclesonide for patients with COVID -19 pneumonia commenced on March 2, 2020 in National Center for Global Health and Medicine (Tokyo, Japan) and Fujita Health University (Aichi, Japan). After arrangement of the details, collection of the cases is going to be initiated in the near future.
Nafamostat
Nafamostat mesylate is a low molecular weight (539.6 kD) protease inhibitor that has been shown to inhibit serine proteases, such as trypsin, kallikrein, C1r and C1s, thrombin, and plasmin (16). Based on this inhibitory profile, nafamostat mesylate has been widely used in Asia to treat acute pancreatitis, disseminated intravascular coagulation, and extracorporeal circulation (17). In 2016, Yamamoto et al. revealed that nafamostat mesylate also blocked MERS-CoV infection in vitro by inhibiting the activity of TMPRSS2 and subsequent membrane fusion to the attached cell (18). In addition, Hoffmann et al. recently reported a similar effect on COVID-19 by camostat mesylate, an analogous drug to nafamostat mesylate (19). According to these reports, the effectiveness of nafamostat mesylate on COVID-19 was evaluated in Institute of Medical Science, The University of Tokyo (Tokyo, Japan), and they reported successful inhibition of COVID-19 infection in cultured human airway epithelial cells (Calu-3) at a lower concentration, which was around 10% compared with camostat (not published). Based on the results, a clinical trial for COVID-19 using nafamostat mesylate is scheduled in Institute of Medical Science, The University of Tokyo (Tokyo, Japan), The University of Tokyo Hospital (Tokyo, Japan) and National Center for Global Health and Medicine (Tokyo, Japan).
In conclusion, we summarized 48 major ongoing clinical trials registered to ClinicalTrials.gov database as of April 2, 2020, and presented the trials which are now being conducted or scheduled in Japan. Special attention must be paid to the results of these clinical trials to prevent further disease spread and fatal outcomes of COVID-19.
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