|Year : 2021 | Volume
| Issue : 1 | Page : 27-40
COVID-19: A Review of Clinical Trials and Repurposed Drugs
A Ruckmani1, KR Ilamathi1, R Arun Kumar1, PM Umesh Kumar2
1 Department of Pharmacology, Chettinad Hospital & Research Institute, Kelambakkam, Chengalpet Dt., Tamil Nadu, India
2 King Salman Hospital, Riyadh, Ministry of Health, Kingdom of Saudi Arabia
|Date of Submission||12-Sep-2020|
|Date of Decision||30-Sep-2020|
|Date of Acceptance||27-Oct-2020|
|Date of Web Publication||18-Dec-2020|
Associate Professor of Pharmacology, Chettinad Hospital & Research Institute, Kelambakkam, Chengalpet Dt., Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
This review was undertaken to synthesize data from various databases on therapeutic clinical trials conducted on COVID- 19 in order to find out the trial details and outcome of the completed trials as well as the rationale for selecting the different trial drugs. The data were obtained from articles published December 2019 to September 4, 2020. The analysis of the data has shown that Corona Virus Disease-19 (COVID-19) is the only disease for which more than 2100 clinical trials have been registered. In these trials many existing drugs like Hydroxychloroquine (HCQ), Remdesivir, Tocilizumab, Sarilumab, Lopinavir/Ritonavir, Favipiravir, Glucocorticoids, COVID-19 convalescent plasma, Mesenchymal stem cells, Interferons, Azithromycin, Ivermectin, traditional medicines and many others are being tested globally for their efficacy in COVID-19. 225 trials have been completed as of September 4, 2020 and the results are available only for a few trials. Out of these results, two have shown favorable outcome for Favipiravir, one for HCQ alone, and one for HCQ + Azithromycin and one for Meplazumab. Topline data of two trials have resulted in the emergency use authorization (EUA) for Remdesivir on May 1, 2020. The available results of NIAD, WHO’s SOLIDARITY, Gilead and RECOVERY trials have not shown the anticipated outcome. The results of the rest of the completed trials are awaited to draw conclusion regarding the definite therapy of COVID-19. The new drug development for COVID-19 is still in its preliminary stage. Identification of potential drug candidates which could selectively inhibit Severe Acute Respiratory Syndrome-Corona Virus 2 (SARS-CoV2) protease (Mpro) and SARS CoV2 S protein is in progress.
Keywords: Clinical trials, COVID-19, repurposed, review, SARS-COV-2
|How to cite this article:|
Ruckmani A, Ilamathi K, Kumar R A, Kumar PU. COVID-19: A Review of Clinical Trials and Repurposed Drugs. Int J Nutr Pharmacol Neurol Dis 2021;11:27-40
|How to cite this URL:|
Ruckmani A, Ilamathi K, Kumar R A, Kumar PU. COVID-19: A Review of Clinical Trials and Repurposed Drugs. Int J Nutr Pharmacol Neurol Dis [serial online] 2021 [cited 2021 Jul 28];11:27-40. Available from: https://www.ijnpnd.com/text.asp?2021/11/1/27/303908
| Introduction|| |
Corona Virus Disease-19 (COVID-19) has emerged as a massive pandemic with 44 cases in China in December 2019. It has affected more than 200 countries infecting about 26,601,173 million people in nine months (as of September 4, 2020). The morbidity and mortality of COVID-19 vary from country to country with the highest morbidity of about 6 million in the USA and three cases in Anguilla. The global case fatality rate is 3.3%.
The clinical presentation is expanding from the initial triad of symptoms − fever, cough, and breathlessness − to manifestations involving gastrointestinal, cardiac, neurological, ocular, and dermatological systems. Studies have shown that men are at higher risk to develop severe form of the disease and 65% higher mortality compared to women. Age-dependent difference in morbidity has not been reported so far. Until now different groups of currently available drugs are under testing. To mention a few, antiviral drugs such as lopinavir, ritonavir, oseltamivir, remdesivir, favipiravir, anti-inflammatory agents such as glucocorticoids, hydroxychloroquine (HCQ), antimicrobials like azithromycin and antiprotozoals have been used both in clinical trials and outside clinical trials. In spite of taking preventive measures such as physical distancing, frequent hand wash, wearing mask, quarantine, and lockdown, the disease is spreading exponentially.
In this scenario, this study purports to synthesize data from various databases and search engines to review and analyze the available information on COVID-19 clinical trials and the therapeutic status of repurposed drugs.
Literature Search Methodology
A literature search was performed in PubMed, Google Scholar, and WHO databases to identify relevant articles published in English language till September 4, 2020. Search terms included coronavirus, SARS-CoV-2, COVID-19, COVID 19, COVID-19 treatment, drugs used in COVID-19, pharmacotherapy of COVID-19, new drugs in COVID, clinical trials, and COVID trials. We included review articles, case reports and case series, and preprint articles. Completed and ongoing clinical trials were included from <COVID-trials.org> (global database) till September 4, 2020. Additional articles were obtained from the citations of the referenced articles.
| Results|| |
As of September 4, 2020, total 2191 clinical trials have been registered from 100 countries in <covid-trials.org>. The multicentric trials have been counted as single trial. The registered trials are in various stages such as those completed (225), completed with results (12), recruiting (1156), and active not recruiting (802).
Most of the trials (1740) are randomized control trials, nonrandomized 150, single-arm 266, and the rest unspecified trials 35. Two trials have been registered for evaluation of COVID-19 in pregnancy and nine trials for children with COVID-19. Total 225 trials have been completed and results are available for a few trials. The number of clinical trials country-wise registered for treatment of COVID-19 (only countries with more than 30 registered trials are included) is shown in [Figure 1] and the details of therapeutic interventions are shown in [Figure 2].
|Figure 1 Number of COVID trials country wise. Source: <COVID-trials.org>|
Click here to view
Among the drugs taken up for trials, HCQ (alone and in combination) tops with 321 trials and angiotensin receptor blockers (ARBs) the lowest [Figure 2]. The outcome assessments include mortality (927 trials), invasive ventilation need (324), adverse events (622), clinical improvement (448), and viral clearance (543). Most trials proposed multiple outcomes. Twenty-six trials involve more than 10,000 patients while 552 less than 50 patients. Among the 26 trials, four on HCQ with standard of care (SOC), one on HCQ + azithromycin, one five-arm trial with HCQ, interferon, lopinavir/ritonavir, remdesivir, SOC in each arm in Argentina and another seven-arm trial in Nigeria with ARB, ARB + statin, non steroidal anti inflammatory drugs (NSAID), NSAID + ARB, NSAID + ARB + statin, statins, and NSAID + statins are ongoing. Another trial involving one lakh patients with five arms, HCQ, interferon, lopinavir/ritonavir, remdesivir, and SOC is in progress in Czechoslovakia. One lakh participants will be involved in meningococcal vaccine trial in Cuba and another 130,000 participants for OPV in Iran. Many nondrug trials have also been registered in <COVID-trials.org>.
The drugs registered for COVID-19 clinical trials are listed in [Table 1],[Table 2],[Table 3]. Among all these trials, 225 trials have been completed and the results are available only for 12 trials. The findings from completed trials are as follows:
1. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial (EUCTR2020-000890-25)
The Méditerranée Infection University Hospital Institute, Marseille in France coordinated the above trial. Patients assigned to HCQ were recruited and treated in the Marseille Centre. Controls were recruited in centers located in southern France. The trial involved 36 COVID-19 confirmed patients based on two criteria: (i) age above 12 years and (ii) polymerase chain reaction (PCR) positive SARS-CoV-2 in nasopharyngeal sample, irrespective of their clinical status.
Twenty patients were treated with HCQ 200 mg thrice daily for 10 days. Sixteen received standard care. Six of the 20 in HCQ group were given azithromycin 500 mg on day 1 and 250 mg per day for the next 4 days.
Virological cure was observed in 100% of patients treated with HCQ + azithromycin (six patients) compared to 57% with HCQ and 12.5% in the control group (P < 0.001) on day 6 after inclusion in study.
2. A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19 (NCT04261517)
This trial was conducted in Shanghai Public Health Clinical Center. Thirty COVID-19 confirmed patients were randomized to either HCQ group or the control. Fifteen received HCQ 400 mg/daily and 15 received SOC. There was no significant difference between the two groups on day 7 in viral negativity and clinical features.
3. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial (chiCTR2000029559)
Sixty-two mild to moderate COVID-19 patients at Renmin Hospital of Wuhan University were equally randomized either to standard or standard care + HCQ (200 mg bd × 5 days). Time to clinical recovery (TTCR) was significantly reduced with HCQ. Pneumonia improved in 80.6% of patients in HCQ group compared to 54.8% in control group. It was concluded that HCQ could significantly shorten TTCR and promote recovery from pneumonia.
4. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19 (chiCTR2000029308)
The above study was conducted at Jin Yin-Tan Hospital, Wuhan, Hubei Province, China with 199 COVID-19 confirmed severely ill patients. Ninety-nine received lopinavir/ritonavir (lpv/r) 400 mg and 100 mg, respectively, twice a day for 14 days and 100 received standard care. Clinical improvement and mortality on day 28 including viral clearance were monitored. Lpv/r was not found to hasten clinical improvement, reduce mortality, or improve viral clearance.
5. Experimental treatment with favipiravir for COVID-19: an open-label control study (chiCTR2000029600)
The national clinical research center for infectious diseases conducted this study (The Third People’s Hospital of Shenzhen, China) from January 30 to February 14, 2020. Eighty patients were allocated to two groups; 35 received favipiravir (fpv) (day 1: 1600 mg twice daily; day 2–14: 600 mg twice daily) plus interferon (IFN)-α aerosol inhalation (5 million U twice daily); and 45 on lpv/r (day 1–14: 400 mg/100 mg twice daily) plus IFN-α aerosol inhalation. Disease progression and viral clearance were better with fewer side effects in fpv group than lpv/r. Time to viral clearance was 4 days in fpv versus 11 days in lpv/r group, (P < 0.001) and improvement in chest imaging was 91.4% versus 62.2%, (P = 0.0045).
6. Favipiravir versus arbidol for COVID-19: a randomized clinical trial (chiCTR2000030254)
Three hospitals, namely, Zhonghan Hospital of Wuhan University, Leishenshan Hospital, and the Third Hospital of Hubei Province of Wuhan, China, conducted this study from February 20 to March 1, 2020. Among 236 patients recruited, 116 were assigned to favipiravir (1600 mg * 2/first day, 600 mg *2/day) and 120 to arbidol (200 mg*3/day) for 10 days. Efficacy and safety of favipiravir and arbidol (umifenovir) were assessed on day 7. The clinical recovery rate was better with favipiravir than arbidol (P = 0.0199). Favipiravir improved the latency to pyrexia and cough relief with mild adverse effects.
7. An exploratory randomized, controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol in adult patients hospitalized with mild/moderate COVID-19 (chiCTR2000030254)
This study was conducted at Guangzhou Eighth People’s Hospital, China. Out of 86 patients recruited for the study, 34 received LPV/r (200 mg LPV boosted by r 50 mg orally twice a day, 500 mg each time) and 35 arbidol (200 mg three times daily) for 7 to 14 days and 17 received control treatment without antiviral therapy.
The results indicated that LPV/r and arbidol did not reduce either the time to negative conversion of viral nucleic acid in respiratory specimens (9.0 vs. 9.1 vs. 9.3 days) or improve the symptoms of COVID-19 and pneumonia in CT lung on day 7 and 14. In addition, more patients in LPV/r group progressed to severe status than patients in arbidol and control groups.
8. Meplazumab treats COVID-19 pneumonia: an open-label, concurrent controlled add-on clinical trial (NCT04275245)
Twenty-eight patients were included for this study at Tangdu Hospital of Fourth Military Medical University in Xi’an, China. Seventeen were on meplazumab and 11 on standard treatment. 10 mg meplazumab was given on day 1, 2, and 5 by IV infusion. Efficacy and safety assessment were done at baseline and daily for 14 days and then weekly till day 28 or discharge.
Meplazumab significantly improved the recovery from pneumonia and reduced the time to viral negativity with better safety profile than the control group.
9. NIAID (National Institute of Allergy and Infectious Diseases) clinical trial on remdesivir (adaptive COID-19 treatment trial, ACTT)
This is the first trial initiated in the USA for COVID-19 at the University of Nebraska Medical Center Omaha. The trial sponsored by NIAID began on February 21, 2020. Totally 1063 participants were enrolled in 10 countries; 538 patients were randomly allocated to local standard care with a 10-day course of remdesivir and 521 patients to local standard care with a placebo.
The findings of 1059 participants were statistically significant.
- Patients who received remdesivir recovered faster by 31% than patients who received placebo (P < 0.001).
- Median recovery time was 11 days with remdesivir compared to 15 days with placebo.
- Results suggested a survival benefit with a mortality rate of 8.0% for remdesivir versus 11.9% for placebo (P = 0.059).
NIAID has begun a clinical trial (ACTT 2) for evaluating remdesivir in combination with baricitinib in comparison with remdesivir alone to improve the clinical outcome on May 8, 2020 (NCT04401579).
10. Gilead trials
Gilead Sciences, Inc., an American Biopharmaceutical Company in Foster City, California, is primarily involved in antiviral drug research for the treatment of HIV, hepatitis B, hepatitis C, and influenza. Gilead has currently focused on evaluation of remdesivir to treat patients with COVID-19. The results of the trials conducted by Gilead are detailed below:
Two randomized, open-label, multicenter Phase 3 clinical trials were started by Gilead to study remdesivir (the SIMPLE studies) in countries with high prevalence of COVID-19. In the first SIMPLE trial, the safety and efficacy of 5-day and 10-day dose regimens of remdesivir were evaluated in hospitalized patients with severe COVID-19. The patients were recruited at 55 hospitals in the United States, Spain, Germany, Italy, South Korea, Hong Kong, Singapore, and Taiwan between March 6 and March 26, 2020. Initially, 397 patients were randomized (1:1 ratio) to receive remdesivir in addition to standard care as per the following protocol.
- Group 1–day 1–Remdesivir 200 mg IV, 100 mg daily next 5 days.
- Group 2–day 1–Remdesivir 200 mg IV, 100 mg daily next 10 days.
The findings did not show a significant difference in both the treatment groups in the safety of remdesivir, time to clinical improvement, clinical recovery, and mortality rate.
This trial on adult patients with severe COVID-19 was conducted in 10 hospitals in Hubei, China. A total of 158 patients were randomly assigned to treatment with remdesivir and 79 to placebo; patients who received remdesivir had a faster time to clinical improvement than the placebo group among patients with symptom duration of 10 days or less (hazard ratio 1.52). Adverse events were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. “Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early”.
The emergency use authorization issued for remdesivir by the United States Food and Drug Administration (U.S. FDA) is based on the review of the topline data of the trial by NIAID (NCT04280705) and from the Gilead-sponsored trial (NCT04292899) detailed above.
11. Solidarity trial
WHO’s global multinational trials in COVID-19 confirmed patients have been conducted in more than 100 countries. The patients got randomized to one of the four treatment arms: chloroquine or HCQ, remdesivir, lopinavir/ritonavir, and lopinavir/ritonavir plus IFN beta-1a. However, WHO temporarily suspended the HCQ trials on May 25, 2020 due to the reports of cardiac complications and death. Later trial was resumed on June 3, 2020 based on the report of the trials data safety monitoring board.
Results of solidarity trial
On July 4, 2020, the Solidarity Trial’s International Steering Committee recommended to WHO to discontinue the trial’s HCQ and lopinavir/ritonavir arms. The interim results showed that HCQ and lopinavir/ritonavir combination did not reduce the mortality of hospitalized COVID-19 patients compared to standard treatment. Hence, the trial has been interrupted immediately. However, this decision applies to the Solidarity trial conducted in hospitalized patients and not to those in nonhospitalized patients or as pre- or postexposure prophylaxis for COVID-19.
12. RECOVERY trial (NCT04381936).
It is another mega national trial carried out in UK in more than 170 sites. The trial design is a dynamic one with four treatments: lopinavir-ritonavir, low-dose dexamethasone, HCQ, and azithromycin. Subsequently, patients will be randomly allocated to tocilizumab based on specific criteria. The results of the recovery trial are as follows:
12.1 Results of dexamethasone study
A total of 2104 patients received dexamethasone 6 mg once a day (oral or IV injection) for 10 days and compared with 4321 patients who received only the usual care. Dexamethasone was found to reduce 28-day mortality among patients on invasive mechanical ventilation or oxygen, but not among those who did not receive respiratory support. Hence, recruitment to the dexamethasone arm was halted on June 8, 2020, as the trial Steering Committee concluded that sufficient patients had been enrolled to establish a meaningful benefit.
12.2 Results of hydroxychloroquine study
Total 1542 patients were allocated to HCQ and compared with 3132 patients who received usual care alone. No significant difference was observed at 28-day mortality and in the duration of hospital stay or other outcomes. It was concluded that there is no beneficial effect of HCQ in COVID-19 hospitalized patients. Hence, it has been decided to stop enrollment of patients to the HCQ arm of the RECOVERY trial.
12.3 Results of lopinavir-ritonavir study
A total of 1596 patients were assigned to lopinavir/ritonavir and compared with 3376 patients who were on usual care. There was no significant difference in 28-day mortality (22.1% lopinavir/ritonavir vs. 21.3% usual care; relative risk 1.04 [95% confidence interval 0.91–1.18]; P = 0.58) and the risk of progression to mechanical ventilation or duration of hospital stay in both arms. On June 29, the trial Steering Committee concluded that there is no beneficial effect of lopinavir/ritonavir in patients hospitalized with COVID-19 and closed randomization to that treatment arm.
13. COVID-19 in pregnancy
Though 14 million cases of COVID-19 in pregnant women have been reported worldwide, pregnant women have been excluded in most of the clinical trials. Hence, limited reports are available. The data of a systematic review reveal that the morbidity and mortality in pregnancy do not significantly differ from the general population. The maternal and neonatal survival rate observed is 98% and 99%, respectively. The various drugs used in pregnancy are HCQ or chloroquine, azithromycin, steroids, oseltamivir, interferon, monoclonal antibodies, and lopinavir/ritonavir. However, some of the drugs such as renin-angiotensin blockers and favipiravir are not recommended because of fetal toxicity.
At present, only two clinical trials have been registered in ClinicalTrials.gov, one in France ongoing with 714 COVID-19 positive pregnant patients and they are tested with HCQ and azithromycin, the other in Spain with HCQ alone. The results are awaited for both the studies.
14. COVID-19 in children
The prevalence of COVID-19 in children is found to be low. Children including neonates and infants present with fever, cough, gastrointestinal symptoms, and other manifestations similar to adults. In a study conducted with 707 neonates born to COVID-19 mothers, 11 were positive for COVID-19 and among them nine had pneumonia and all of them have recovered. Thus, the chance for the vertical transmission appears to be too low.
According to CDC report dated August 14, 2020, the prevalence of COVID-19 in older children is 7.3% and 45% of them are found to be asymptomatic. The transmissibility of the infection through children is not well studied. CDC suggests the possibility of using remdesivir and dexamethasone in COVID-positive children.
Though currently no drug has been approved for treatment of COVID‐19 in adults as well as children, a few drugs are being investigated as potential therapies in children. These include antivirals such as ribavirin, oseltamivir, lopinavir/ritonavir, peramivir, interferon α‐2b, arbidol hydrochloride and antibiotics such as azithromycin + ceftazidime, glucocorticoids, immunoglobulin along with other supportive therapies including oxygen therapy.
There are now nine ongoing clinical trials involving children from birth to <17 years who are positive for COVID-19 and these trials are registered in ClinicalTrials .gov for various treatments, such as Chinese medicine (two trials), convalescent plasma (four trials), bromhexine HCL, Vitamin D, and remdesivir (one trial each).
15. Vaccine trials
Forty-two candidate vaccines are under clinical trials. These vaccines’ platform include inactivated SARS-CoV-2 virus, viral vector based vaccines (adenovirus), lipid nanoparticle (LNP) encapsulated mRNA, adjuvanted recombinant protein (RBD-dimer), RNA, DNA and recombinant spike proteins. Among the 42 vaccines, there is only one oral vaccine, vaxart, (Ad5 adjuvanted Oral vaccine platform) and all others are administered intramuscularly except two of the DNA-based vaccines which are given intradermally. In addition to these clinical vaccine trials, 151 candidate vaccines are under preclinical trials (WHO DRAFT landscape of COVID-19 candidate vaccines −October 2, 2020).
The final report of SARS-CoV-2 mRNA − 1273 clinical vaccine trial is available and the report concluded that 100 µg dose resulted in higher binding and neutralizing-antibody titers than 25 µg, recommending the use of 100 µg dose for phase 3 vaccine trials [NCT04283461]. As there are no approved drugs for treatment of COVID-19, the prevention of the disease is the best option, and hence the reports of all these vaccine trials are anxiously awaited.
| Discussion|| |
The 1918 Spanish flu is considered the most severe pandemic of the twentieth century. COVID-19 has emerged with a similar severity in the 21st century in December 2019, from China, and it is still spreading. It has affected more than 30 million people within 9 months. When Spanish flu broke out, patients were treated with the antimalarial drug quinine.
Similarly yet another antimalarial drug HCQ has been recommended for the current COVID-19 pandemic and it is under evaluation in more than 300 clinical trials. In any pandemic, due to a new organism, specific therapy is not feasible and the therapeutic option is repurposing of the existing drugs based on the available evidence for their effectiveness in diseases caused by similar pathogens. In this regard, currently more than 2100 clinical trials have been registered globally, for testing the various treatment options, which might offer benefit in COVID-19.
In this background, this review was undertaken to find out the details of registered clinical trials, explore the basis for using the various therapeutic agents in COVID-19 clinical trials, and the outcome of the trials for which the results are available. More than 100 countries have initiated the trial process and the USA tops the list with more than 427 trials, followed by China with nearly 376 trials.
Nearly 100 drugs under different groups have been chosen for trials, which comprise antivirals, antimalarials, anti-inflammatory agents, antibacterials, antifungals, antiparasitic drugs, anticoagulants, immunomodulators, convalescent plasma, monoclonal antibodies, cytokine inhibitors, mesenchymal stem cells, nutraceuticals, native medicines, and many others ([Table 1],[Table 2],[Table 3]). The mechanisms of actions, rationale, and the supporting evidence for choosing the trial drugs are detailed in [Table 4].
From [Table 4], it can be inferred that most of the drugs act by multiple mechanisms, such as inhibiting, in general, viral entry, multiplication, and release of viral particles. The other major actions include immunomodulatory, anti-inflammatory, antibacterial, and anticoagulant activities. HCQ and chloroquine, umifenovir, Janus kinases (JAKs) inhibitors like tofacitinib, barcitinib and TMPRSS2 inhibitors, ambroxol, and aprotinin inhibit viral entry. Meplazumab also inhibits viral entry by inhibiting CD147 receptor recently identified in host cells. By preventing viral protease activity, drugs like lopinavir inhibit the proteolysis of the Gag polyprotein, resulting in the production of immature viral particles, which become noninfectious. Remdesivir and favipiravir are RNA dependent RNA polymerase (RdRp) inhibitors preventing viral RNA synthesis.
The reasons for selecting most of the antiviral drugs include their therapeutic efficacy experienced in previous viral infections caused by SARS-CoV, influenza, and ebola. Favipiravir was the first drug approved in Japan for the treatment of resistant influenza infection. Later it was used in ebola infection Based on this antiviral activity, it has been now evaluated in COVID-19. Glucocorticoids and interleukin-6 (IL-6) inhibitors inhibit the inflammatory cascade as well as suppress the immune response. Convalescent plasma offers passive immunity. The mechanisms of action of other drugs are given in [Table 4].
Though 225 trials have been completed, the results are available for 12 trials only. The limitation of the first eight trials is the smaller sample size and only one trial had more than 200 patients (236). Out of these eight, two have shown favorable outcome for favipiravir, one for HCQ alone, and one for HCQ + azithromycin, and one for meplazumab.
The results of all other trials (more than 2000) are awaited. Lopinavir/ritonavir has not shown any beneficial effect in all the trials. The combination of lopinavir/ritonavir and HCQ tested in WHO SOLIDARITY trial has not shown clinical benefit in hospitalized COVID-19 patients when compared to standard treatment. Similarly, in the RECOVERY trial conducted in UK, the steering committee concluded that there is no beneficial effect of lopinavir/ritonavir as well as HCQ in patients hospitalized with COVID-19. Dexamethasone was found to reduce 28-day mortality among patients on invasive mechanical ventilation or oxygen, but not among those who did not receive respiratory support.
Remdesivir is found to be better than placebo in the trial conducted by NIAID. The GILEAD conducted trials on remdesivir, one comparing 5-day and 10-day course along with standard care and another comparing remdesivir with placebo, reported that there is no significant difference between 5- and 10-day course and the effect of remdesivir is better than placebo in clinical outcome and the adverse effects of remdesivir are not significantly different from placebo.
Favipiravir has shown favorable outcome in the two trials conducted in comparison with lopinavir/ritonavir and arbidol, but with the limitation of smaller sample size. Another potential supplementary therapy is inhaled nitric oxide (INO). Clinical trial of inhaled NO is conducted at the Massachusetts General Hospital in moderate to severe COVID-19 patients who need ventilatory support. The dose of NO is about 100 ppm, which is found to be safe. If INO use is established, it would reduce the need for oxygen therapy, ventilators, and ICU beds [Table 4].
The available reports indicate that the results are to some extent favorable for remdesivir and favipiravir. However, the results cannot be considered conclusive. Reports of trials on larger populations with varying severity of COVID-19 as well as with other comorbidities are needed to establish the efficacy and safety of the repurposed drugs tested and recommend a definite therapy for COVID-19.
The drugs so far repurposed can be of two groups. One group that inhibits the various stages in viral life cycle and the other which can handle the consequence of viral infection, such as cytokine storm, coagulopathy, secondary infections, and organ failure. As these drugs are not specific for SARS-CoV-2, their efficacy is not certain and unpredictable. This could be a reason for the failure of positive outcome with drugs like lopinavir/ritonavir and HCQ in clinical trials. Hence, it is essential to discover drugs that can act specifically on SARS-CoV-2. The spike protein (S protein) in SARS-CoV-2 has been identified as the potential target for drug discovery. The fusion inhibitor EK1C4 is found to have higher affinity for S protein in SARS-CoV-2 than SARS-CoV. EK1C4 when administered intranasally in mice challenged with HCoV-OC43, it protected the mice from infection. However further research is needed to establish its use in SARS-CoV-2 infection. Meplazumab, an anti-CD147, is also found to be useful in clinical trials.
The viral protease Mpro, otherwise known as 3-chymotrypsin-like pro cysteine protease, is another target to arrest viral replication. The two lead compounds 11a and 11b that target Mpro are found to have inhibitory activity against SARS-CoV-2. Further research with such lead compounds targeting SARS-CoV-2 proteins is needed to find out specific drugs for COVID-19.
| Conclusion|| |
COVID-19 is the only disease for which the maximum number of therapeutic trials have been registered in a short span of 9 months. The results available till date have shown favorable outcome to a limited extent for remdesivir and favipiravir but with the limitation of small study population. Dexamethasone is found to be useful in severe COVID patients in reducing mortality. Viral protease inhibitors, which are under development, may emerge as promising drugs for COVID-19.
The results of all the completed trials should be made available to get additional information on the drugs tested in order to decide the most appropriate therapy for COVID-19. Lead compounds targeting SARS-CoV-2 Spike protein (EK1C4) and 3CL protease/Mpro (11a,11b) and other target proteins should be further researched in order to find out effective therapy for COVID-19. Only when the vaccine trials are completed and approved for clinical use, prevention of the pandemic is possible.
| Acknowledgement|| |
The authors thank Dr Abinaya, Department of Pharmacology, for helping in the organization of the manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
Compliance with ethical standards
| References|| |
Maleki Dana P, Sadoughi F, Hallajzadeh J et al.
An insight into the sex differences in COVID-19 patients: what are the possible causes? Prehosp Disaster Med 2020;35:438-41.
Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M et al.
Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020;56:105949. doi: 10.1016/j.ijantimicag.2020.105949. Epub 2020 Mar 20. PMID: 32205204; PMCID: PMC7102549.
Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L et al.
A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19. Zhejiang Da XueXueBao Yi XueBan 2020;49:215‐9. Chinese. doi: 10.3785/j.issn.1008-9292.2020.03.03. PMID: 32391667.
Chen Z, Hu J, Zhang Z, Jiang S et al.
Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. MedRxiv 2020. https://doi.org/10.1101/2020.03.22.20040758
. doi: 10.1101/2020.03.22.20040758.
Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G et al.
A trial of Lopinavir-Ritonavir in adults hospitalized with severe Covid-19. N England J Med 2020;382:1787-99. https://doi.org/10.1056/NEJMoa2001282
Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J et al.
Experimental treatment with favipiravir for COVID-19: an open-label control study. Engineering (Beijing) 2020. doi: 10.1016/j.eng.2020.03.007. Epub ahead of print. PMID: 32346491; PMCID: PMC7185795.
Chen C, Zhang Y, Huang J, Zhang Y, Cheng Z, Wu J et al.
Favipiravir versus arbidol for COVID-19: a randomized clinical trial. medRxiv 2020. doi: 10.1101/2020.03.17.20037432. PPR:PPR118169.
Li Y, Xie Z, Lin W, Cai W, Wen C, Guan Y et al.
An exploratory randomized, controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI). MedRxiv. 2020. doi: https://doi.org/10.1101/2020.03.19.20038984
Bian H, Zheng ZH, Wei D, Zhang Z, Kang W, Hao C et al.
Meplazumab treats COVID-19 pneumonia: an open- labelled, concurrent controlled add-on clinical trial. medRxiv 2020. doi: 10.1101/2020.03.21.20040691. PPR:PPR118681.
Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC et al.
ACTT-1 Study Group Members. Remdesivir for the treatment of Covid-19-preliminary report. N Engl J Med 2020;383:1813-26. doi: 10.1056/NEJMoa2007764. Epub 2020 Oct 8. PMID: 32445440; PMCID: PMC7262788.
Goldman JD, Lye DCB, Hui DS, Marks KM, Bruno R, Montejano R et al.
GS-US-540-5773 Investigators. Remdesivir for 5 or 10 days in patients with severe Covid-19. N Engl J Med 2020;383:1827-37. doi: 10.1056/NEJMoa2015301. Epub 2020 May 27. PMID: 32459919; PMCID: PMC7377062.
Wang Y, Zhang D, Du G et al.
Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020;395:1569-78.
RECOVERY Collaborative Group. Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. 2020;396:1345-52. doi: https://doi.org/10.1016/S0140-6736(20)32013-4
Pastick KA, Nicol MR, Smyth E, Zash R, Boulware DR, Rajasingham R, McDonald EG. A systematic review of treatment and outcomes of pregnant women with COVID-19-a call for clinical trials. Open Forum Infect Dis 2020;7:ofaa350. doi:10.1093/ofid/ofaa350. PMID: 32929403; PMCID: PMC7454907.
Louchet M, Sibiude J, Peytavin G, Picone O, Tréluyer JM, Mandelbrot L. Placental transfer and safety in pregnancy of medications under investigation to treat coronavirus disease 2019. Am J Obstet Gynecol MFM 2020;2:100159. doi: 10.1016/j.ajogmf.2020.100159.
Chawla D, Chirla D, Dalwai S et al.
Perinatal-neonatal management of COVID-19 infection − Guidelines of the Federation of Obstetric and Gynaecological Societies of India (FOGSI), National Neonatology Forum of India (NNF), and Indian Academy of Pediatrics (IAP). Indian Pediatr 2020;57:536-48.
Zhang L, Peres TG, Silva MVF, Camargos P. What we know so far about coronavirus disease 2019 in children: a meta-analysis of 551 laboratory-confirmed cases. Pediatr Pulmonol 2020;55:2115-27.
Shors T, McFadden SH. 1918 influenza: a Winnebago County, Wisconsin perspective. Clin Med Res 2009;7:147-56.
Shiraki K, Daikoku T. Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacol Ther 2020;209:107512. doi: 10.1016/j.pharmthera.2020.107512. Epub 2020 Feb 22. PMID: 32097670; PMCID: PMC7102570.
Jacobs M, Aarons E, Bhagani S, Buchanan R, Cropley I, Hopkins S et al.
Post-exposure prophylaxis against Ebola virus disease with experimental antiviral agents: a case-series of health-care workers. Lancet Infect Dis 2015;15:1300-4.
Xia S, Liu M, Wang C et al.
Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion. Cell Res 2020;30:343-55.
Chang GG. Quaternary structure of the SARS coronavirus main protease. Molecular Biology of the SARS-Coronavirus 2009;115-28. doi: 10.1007/978-3-642-03683-5_8.
Dai W, Zhang B, Jiang XM, Su H, Li J, Zhao Y et al.
Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science 2020;368:1331-5. doi: 10.1126/science.abb4489. Epub 2020 Apr 22. PMID: 32321856; PMCID: PMC7179937.
Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;30:269-71.
Savarino A, Di Trani L, Donatelli I, Cauda R, Cassone A. New insights into the antiviral effects of chloroquine. Lancet Infect Dis 2006;6:67-9.
Vincent MJ, Bergeron E, Benjannet S et al.
Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J 2005;2:69. doi: 10.1186/1743-422X- 2-69.
Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P et al.
In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020;71:732-9. doi: 10.1093/cid/ciaa237. PMID: 32150618; PMCID: PMC7108130.
Borba MGS, Val FFA, Sampaio VS, Alexandre MAA, Melo GC, Brito M et al.
CloroCovid-19 Team. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw Open 2020;3:e208857. doi: 10.1001/jamanetworkopen.2020.8857. PMID: 32330277.
Magagnoli J, Narendran S, Pereira F et al.
Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. Pre-print. medRxiv. 2020;2020.04.16.20065920. Published 2020 Apr 21. doi: 10.1101/2020.04.16.20065920.
Rojas M, Rodríguez Y, Monsalve DM, Acosta-Ampudia Y, Camacho B, Gallo JE et al.
Convalescent plasma in COVID-19: possible mechanisms of action. Autoimmun Rev 2020;19:102554. PMID: 32380316; PMCID: PMC7198427.
Mair-Jenkins J, Saavedra-Campos M, Baillie JK et al.
The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis. 2015 211:80‐90.
Mair-Jenkins J, Saavedra-Campos M, Kenneth Baillie J, Cleary P, Khaw FM, Lim WS et al.
The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis 2015;211:80-90. https://doi.org/10.1093/infdis/jiu396
Agostini ML, Andres EL, Sims AC et al.
Coronavirus susceptibility to the antiviral remdesivir (GS5734) is mediated by the viral polymerase and the proofreading exoribonuclease. MBio 2018;9:1-15.
Singh AK, Singh A, Singh R, Misra A. Remdesivir in COVID-19: a critical review of pharmacology, pre-clinical and clinical studies. Diabetes Metab Syndr. 2020;14:641-8.
Costanzo M, De Giglio MAR, Roviello GN. SARS-CoV-2: Recent Reports on Antiviral Therapies Based on Lopinavir/Ritonavir, Darunavir/Umifenovir, Hydroxychloroquine, Remdesivir, Favipiravir and Other Drugs for the Treatment of the New Coronavirus. Curr Med Chem 2020;27:4536-41. doi: 10.2174/0929867327666200416131117. PMID: 32297571.
Yao TT, Qian JD, Zhu WY, Wang Y, Wang GQ. A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus-a possible reference for coronavirus disease-19 treatment option. J Med Virol 2020;92:556-63.
Chan KS, Lai ST, Chu CM et al.
Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J 2003;9:399-406.
Zhu Z, Lu Z, Xu T, Chen C, Yang G, Zha T et al.
Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19. J Infect 2020;81:e21-3. doi: 10.1016/j.jinf.2020.03.060. Epub 2020 Apr 10. PMID: 32283143; PMCID: PMC7195393.
Du YX, Chen XP. Favipiravir: pharmacokinetics and concerns about clinical trials for 2019-nCoV Infection. Clin Pharmacol Ther 2020;108:242-7. doi: 10.1002/cpt.1844.doi:10.1002/cpt.1844. Epub 2020 Apr 21. PMID: 32246834.
Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 2014;6:a016295. doi: 10.1101/cshperspect.a016295. PMID: 25190079; PMCID: PMC4176007.
Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 2011;1813:878-88.
Ingraham NE, Lotfi-Emran S, Thielen BK, Techar K, Morris RS, Holtan SG et al.
Immunomodulation in COVID-19. Lancet Respir Med 2020;8:544-6. doi: 10.1016/S2213-2600(20)30226-5. Epub 2020 May 4. PMID: 32380023; PMCID: PMC7198187.
Gosain R, Abdou Y, Singh A, Rana N, Puzanov I, Ernstoff MS. COVID-19 and cancer: a comprehensive review. Curr Oncol Rep 2020;22:53. doi: 10.1007/s11912-020-00934-7. PMID: 32385672; PMCID: PMC7206576.
Xu X, Han M, Li T et al.
Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci USA 2020;117:10970-5. doi: 10.1073/pnas.2005615117.
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin Risk Manag 2019;15:323-35.
Gritti G, Raimondi F, Ripamonti D, Riva I, Landi F, Alborghetti L et al.
Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support. medRxiv, 2020: p.2020.04.01.20048561. doi: 10.1101/2020.04.01.20048561. PPR:PPR138675.
Cavalli G, De Luca G, Campochiaro C, Della-Torre E, Ripa M, Canetti D et al.
Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol 2020;2:e325-e331.
Richardson P, Griffin I, Tucker C et al.
Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet 2020;395:e30-e31.
Fragoulis GE, McInnes IB, Siebert S. JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis. Rheumatology 2019;58:i43-i54.
Seif F, Khoshmirsafa M, Aazami H, Mohsenzadegan M, Sedighi G, Bahar M. The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun Signal 2017;15:23.
Li SF, Gong MJ, Zhao FR, Shao JJ, Xie YL, Zhang YG, Chang HY. Type I interferons: distinct biological activities and current applications for viral infection. Cell Physiol Biochem 2018;51:2377-96.
Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med 2006;3:e343. doi: 10.1371/journal.pmed.0030343. PMID: 16968120; PMCID: PMC1564166.
Morra ME, Van Thanh L, Kamel MG, Ghazy AA, Altibi AMA, Dat LM et al.
Clinical outcomes of current medical approaches for Middle East respiratory syndrome: a systematic review and meta-analysis. Rev Med Virol 2018;28:e1977. doi: 10.1002/rmv.1977. Epub 2018 Apr 17. PMID: 29664167; PMCID: PMC7169085.
Amsden GW. Anti-inflammatory effects of macrolides − an underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions? J Antimicrob Chemother 2005;55:10-21.
Kanoh S, Rubin BK. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev 2010;23:590-615.
Molina JM, Delaugerre C, Le Goff L, Mela-Lima B, Ponscarme D, Goldwirt L, de Castro N. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19. Med Mal Infect 2020;50:384. doi: 10.1016/j.medmal.2020.03.006. Epub 2020 Mar 30. PMID: 32240719; PMCID: PMC7195369.
Li H, Chen C, Hu F, Wang J, Zhao Q, Gale RP, Liang Y. Impact of corticosteroid therapy on outcomes of persons with SARS-CoV-2, SARS-CoV, or MERS-CoV infection: a systematic review and meta-analysis. Leukemia 2020;34:1503-11.
Mahase E. Covid-19: low dose steroid cuts death in ventilated patients by one third, trial finds. BMJ 2020;369:m2422. doi: 10.1136/bmj.m2422. PMID: 32546467.
Selvaraj V, Dapaah-Afriyie K, Finn A, Flanigan TP. Short-term dexamethasone in Sars-CoV-2 patients. R I Med J (2013) 2020;103:39-43.
Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020;18:844-7.
Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020;18:1094-9.
Thachil J, Tang N, Gando S et al.
ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost 2020;18:1023-6.
Golchin A, Seyedjafari E, Ardeshirylajimi A. Mesenchymal stem cell therapy for COVID-19: present or future. Stem Cell Rev Rep 2020;16:427-33.
Hoffmann M, Kleine-Weber H, Schroeder S et al.
SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271‐80.
McKee DL, Sternberg A, Stange U, Laufer S, Naujokat C. Candidate drugs against SARS-CoV-2 and COVID-19. Pharmacol Res 2020;157:104859. doi: 10.1016/j.phrs.2020.104859. PMID: 32360480; PMCID: PMC7189851.
Ulrich H, Pillat MM. CD147 as a target for COVID-19 treatment: suggested effects of azithromycin and stem cell engagement. Stem Cell Rev Rep 2020;16:434-40.
Ignarro LJ. Inhaled NO and COVID-19. Br J Pharmacol 2020;177:3848-9.
Dai W, Zhang B, Jiang XM et al.
Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science 2020;368:1331-5.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]