|Year : 2021 | Volume
| Issue : 1 | Page : 26-63
Emerging trends from COVID-19 research registered in the Clinical Trials Registry - India
M Vishnu Vardhana Rao1, Atul Juneja1, Mohua Maulik2, Tulsi Adhikari1, Saurabh Sharma1, Jyotsna Gupta2, Yashmin Panchal2, Neha Yadav2
1 ICMR-National Institute of Medical Statistics, New Delhi, India
2 Clinical Trials Registry-India, ICMR-National Institute of Medical Statistics, New Delhi, India
|Date of Submission||16-Jun-2020|
|Date of Web Publication||26-Mar-2021|
Dr. Mohua Maulik
Clinical Trial Registry - India, ICMR-National Institute of Medical Statistics, New Delhi 110 029
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Since the beginning of the year, the deadly coronavirus pandemic, better known as coronavirus disease 2019 (COVID-19), brought the entire world to an unprecedented halt. In tandem with the global scenario, researchers in India are actively engaged in the conduct of clinical research to counter the pandemic. This review attempts to provide a comprehensive overview of the COVID-19 research in India including design aspects, through the clinical trials registered in the Clinical Trials Registry - India (CTRI) till June 5, 2020. One hundred and twenty two registered trials on COVID-19 were extracted from the CTRI database. These trials were categorized into modern medicine (n=42), traditional medicine (n=67) and miscellaneous (n=13). Of the 42 modern medicine trials, 28 were on repurposed drugs, used singly (n=24) or in combination (n=4). Of these 28 trials, 23 were to evaluate their therapeutic efficacy in different severities of the disease. There were nine registered trials on cell- and plasma-based therapies, two phytopharmaceutical trials and three vaccine trials. The traditional medicine trials category majorly comprised Ayurveda (n=45), followed by homeopathy (n=14) and others (n=8) from Yoga, Siddha and Unani. Among the traditional medicine category, 31 trials were prophylactic and 36 were therapeutic, mostly conducted on asymptomatic or mild-to-moderate COVID-19 patients. This review would showcase the research being conducted on COVID-19 in the country and highlight the research gaps to steer further studies.
Keywords: Ayurveda, Yoga and Naturopathy, Unani, Siddha, Homeopathy - clinical trials - CTRI-India - convalescent plasma therapy - COVID-19 - drug trials - registration - vaccine trials
|How to cite this article:|
Rao M V, Juneja A, Maulik M, Adhikari T, Sharma S, Gupta J, Panchal Y, Yadav N. Emerging trends from COVID-19 research registered in the Clinical Trials Registry - India. Indian J Med Res 2021;153:26-63
|How to cite this URL:|
Rao M V, Juneja A, Maulik M, Adhikari T, Sharma S, Gupta J, Panchal Y, Yadav N. Emerging trends from COVID-19 research registered in the Clinical Trials Registry - India. Indian J Med Res [serial online] 2021 [cited 2021 Jul 26];153:26-63. Available from: https://www.ijmr.org.in/text.asp?2021/153/1/26/298626
The novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first reported from Wuhan, China, in December 2019. Since then, the disease has spread worldwide and as of June 5, 2020, there were 6,824,499 cases and 408,307 deaths globally.
In the absence of any vaccine or definitive therapeutic strategy, medical scientists are working tirelessly to not only save lives but also search for effective treatment modalities against the deadly virus. Drug development is a costly and time-consuming process and is not feasible in the context of the immediate global challenge. Therefore, drug repurposing strategies are being considered to develop safe and effective treatment regimens against the disease. Currently, an array of drugs used for the other health conditions are being studied for the treatment of COVID-19 in several hundred clinical trials around the globe.
Globally, clinical trial registries may be considered the best source to review the ongoing clinical trial scenario as crucial details pertaining to proposed intervention, study type and design, sample size, and outcomes and phase of the trial are publicly available. The Clinical Trials Registry - India (CTRI), one of the primary registries of the World Health Organization's International Clinical Trial Registry Platform (ICTRP), is one such database,.
The CTRI, set up under the aegis of the Indian Council of Medical Research (ICMR), is managed by the ICMR-National Institute of Medical Statistics, New Delhi. The CTRI is a free online registry that prospectively registers clinical trials being conducted in India and also in countries which do not have a primary registry of their own. With the emergence of the pandemic in India, there has been a steady increase in the registration of clinical trials on COVID-19 in the CTRI. Here, we present a comprehensive overview of the COVID-19 trials registered in the CTRI [Table 1],[Table 2],[Table 3],[Table 4]. While the results of these trials will decide whether or not any of these proposed therapies are likely to be of use, information about these would help to identify lacunae as well as plan and guide future clinical research.
|Table 1: An overview of 122 COVID-19 trials registered in the Clinical Trials Registry - India#|
Click here to view
|Table 2: Details of modern medicine trials (n=42) on COVID-19 registered in the Clinical Trials Registry - India#|
Click here to view
|Table 3: Details of AYUSH trials (n=67) on coronavirus disease 2019 registered in the Clinical Trials Registry - India#|
Click here to view
|Table 4: Details of miscellaneous trials (n=13) on coronavirus disease 2019 registered in the Clinical Trials Registry - India#|
Click here to view
| Trial data extraction|| |
One hundred and twenty three registered COVID-19 trials were extracted from the CTRI database using the term %covid% in the different fields of the CTRI data set. These trials were manually screened and analyzed. One trial was excluded because COVID-19 was in the exclusion criteria in that trial. The remaining 122 trials were tabulated into three categories: modern medicine (including drug trials as well as phytopharmaceuticals, cell- and plasma-based therapies and biological products trials); traditional medicine covering Ayurveda, Yoga and Naturopathy, Unani, Siddha, Homeopathy (AYUSH) trials and miscellaneous trials.
| COVID-19 trial scenario in India|| |
Multiple therapeutic and preventive trials including those in the traditional systems of medicine are being conducted in India with the common global objective of demonstrating efficacy as well as safety for all in need. Of the 122 clinical trials on COVID-19 registered in the CTRI (as on June 5, 2020), 42 were on the modern system of medicine, 67 on the traditional system of medicine and 13 miscellaneous [Table 1]. Overall, there were 23 single-armed trials, 68 randomized trials and six cluster randomized trials, while there were
17 non-randomized and eight other (unspecified study design) trials. Most of these trials were either Phase 2 (n=31) or Phase 2/3 (n=13) trials or Phase 3 (n=23) or Phase 3/4 (n=7) trials. Phase was not applicable for 34 trials, and there were only two Phase 1 and five Phase 1/2 trials [Table 2],[Table 3],[Table 4]. Of the remaining trials, four trials were marked as Phase 4 trials and two as post-marketing surveillance studies. There was a wide variation in sample size in the registered trials ranging from 6 to 50,000.
| Modern medicine|| |
Trials registered in this category (n=42) are subdivided into drug trials (n=28), of which 24 trials are on individual drugs which primarily evaluate their therapeutic efficacy (n=19) as do all of the four combination of drug trials (such as the global Solidarity trial). These trials are being conducted in patients with varying severity of COVID-19 ranging from mild to moderate to severe. The severity of COVID-19 has not been specified in seven of these drug trials [Table 1]. Others include trials on phytopharmaceuticals (n=2) cell- and plasma-based therapies (n=9) and biological products (n=3). Only one of these is a prophylactic trial on healthy volunteers and all cell- and plasma-based therapy trials are on either moderate/moderate to severe or severe (n=5) COVID-19 patients. While the key features of these registered trials are presented in [Table 2], these are briefly discussed below.
| Drug trials|| |
Solidarity trial: The Solidarity trial is an international clinical trial initiated by the WHO to help find an effective treatment for COVID-19. The trial compares four treatment options remdesivir; lopinavir/ritonavir; lopinavir/ritonavir with interferon beta-1a and chloroquine or hydroxychloroquine (HCQ) against standard of care, to assess their relative effectiveness against COVID-19. The Solidarity trial has been planned as an open-labelled, randomized, parallel-group, multiple-arm trial with a total sample size of 7000 participants, of whom 1500 participants are to be enrolled from India from 24 sites. The trial is being conducted in India with the support of ICMR.
In addition, a single-centre trial is also underway to assess the safety and efficacy of antiviral combination therapy such as lopinavir–ritonavir combination and HCQ with ribavirin in severe COVID-19-infected patients (CTRI/2020/06/025575).
Favipiravir: A nucleoside precursor, favipiravir, inhibits the influenza virus as well as a number of other RNA viruses. In keeping with global trends, a randomized, open-label, multicentre study to evaluate the efficacy and safety of favipiravir in addition to standard supportive care in patients with mild-to-moderate COVID-19 is currently underway at 12 sites across India (CTRI/2020/05/025114).
During this pandemic time, chloroquine and HCQ have generated much interest in the global community as potential therapeutic agents against COVID-19. An open-label non-randomized trial showed that HCQ - azithromycin was associated with viral load reduction in COVID-19 patients.
Chloroquine: Two open-labelled, randomized controlled trials are being conducted to determine the efficacy of chloroquine in COVID-19 patients who present with severe acute respiratory illness (CTRI/2020/04/024479, CTRI/2020/04/024729).
Hydroxychloroquine (HCQ): In India, the ICMR has proposed a prophylactic dosing schedule of HCQ for healthcare workers. In this regard, a principal investigator (PI)-initiated trial on 500 participants is currently underway wherein the recommended prophylactic dosing regimen is being compared with an alternative dosing pattern for the prevention of new infection and adverse outcomes in those at high risk of infection (CTRI/2020/03/024402). A double-blind, Phase 3 clinical trial, sponsored by the Armed Forces Medical Services, aims to evaluate the efficacy of two different doses of HCQ and also to compare the efficacy of HCQ with or without azithromycin in mild, moderate and severe COVID-19-infected patients. This trial is being conducted at six sites across the country with 300 participants.
In view of the large-scale use of HCQ in India, a study to document the pharmacokinetics of HCQ in the Indian population has also been registered (CTRI/2020/05/025242). In addition, with respect to the growing body of scientific data, regarding risks associated with the use of HCQ, particularly QTc prolongation and cardiac arrhythmias, a Phase 2 trial is underway to assess the effect of topical i.e., nasal application of chloroquine in early-stage COVID-19 on viral load and cure rates (CTRI/2020/04/024729).
Ciclesonide: A Phase 2 trial being conducted at a government medical college in New Delhi plans to evaluate not only the effects of HCQ but also that of ciclesonide, a glucocorticoid, and ivermectin, an anthelmintic drug, in 120 patients with moderate COVID-19 infection (CTRI/2020/04/024948).
Imatinib: Imatinib, which inhibits BCR - ABL tyrosine kinase, revolutionized the treatment of chronic myelogenous leukaemia. Imatinib has been reported to significantly reduce titres of SARS-CoV and Middle East respiratory syndrome (MERS)-CoV, which depend on ABL kinase activity to fuse and enter into the cells,. An open-label, randomized, parallel-group Phase 2 trial with imatinib in 100 patients with mild COVID-19 has been registered in the CTRI (CTRI/2020/04/024806).
Itolizumab: This is an anti-CD6 humanized monoclonal IgG1 antibody which acts upstream by inhibiting the co-stimulation of T cells, resulting in decreased release of signature cytokines of Th1 and Th17 cells,. Sponsored by an Indian pharmaceutical company, this open-label, Phase 2, randomized, parallel-group, active controlled multicenter trial is being conducted on
30 patients with moderate-to-severe COVID-19 to assess mortality rates and possible effects on the dreaded cytokine release syndrome (CTRI/2020/05/024959).
Tocilizumab: Interleukin-6 (IL-6) is believed to play an important role in this syndrome, and an IL-6 receptor blocker, tocilizumab, has generated global interest as a potential agent for patients with severe COVID-19. A multicentric, randomized, Phase 3 trial to evaluate the clinical outcomes and safety of tocilizumab along with standard of care in patients with cytokine release syndrome associated with moderate-to-severe COVID-19 infection has been registered in the CTRI (CTRI/2020/05/025369).
Mycobacterium w: It is a saprophytic cultivable mycobacterium which is a potent immunomodulator. When used as an adjuvant to multidrug therapy, it has been reported to have significant benefits in patients with tuberculosis, leprosy and HIV-AIDS,. Three industry-sponsored trials are proposed to be undertaken with this agent in 40 critically ill COVID-19 patients, 480 hospitalized but not critically ill patients as well as 4000 individuals at high risk of contracting the disease. In addition, a Phase 2 observational study with heat killed Mycobacterium w as add-on therapy is also underway on 50 hospitalized COVID-19 patients at a private medical college (CTRI/2020/05/025350).
Melatonin: Melatonin is a remarkably safe and established anti-inflammatory and anti-oxidative molecule with significant evidence suggesting its potential for limiting virus-related diseases, which may extend to COVID-19 as well. Melatonin has also been reported to possess significant immunomodulatory effects in cancer. A clinical trial on melatonin is underway to evaluate its role on COVID-19 infection rate along with immune response in high-risk groups after eight weeks of treatment (CTRI/2020/06/025613).
Ivermectin: This broad-spectrum antiparasitic agent has been shown to have potent in vitro antiviral activity against a variety of viruses. In in vitro studies, a single dose has been shown to bring a significant reduction in the replication of SARS-CoV-2. This has generated interest in the possibility of repurposing the drug for the management of COVID-19. A total of four clinical trials (CTRI/2020/04/024858, CTRI/2020/05/025068, CTRI/2020/05/025224, CTRI/2020/05/025333) with ivermectin are underway, three of which aim to establish the therapeutic efficacy of ivermectin in COVID-19 patients. The fourth trial is investigating the prophylactic effect of ivermectin on 2000 healthcare workers or healthy contacts (including children) of COVID-19 patients. The primary outcome for this study is resolution of signs and symptoms of COVID-19 and negative reverse transcription-polymerase chain reaction (RT-PCR) done 48 h after drug administration.
Niclosamide: Used to treat tapeworm infestation, niclosamide inhibits ATP production by uncoupling of oxidative phosphorylation. It has been reported to have in vitro antiviral activity,. A randomized, parallel-group trial which proposes to investigate the virologic cure rates of niclosamide in patients with mild-to-very mild COVID-19 infection has been registered (CTRI/2020/04/024949).
Losartan: Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for SARS-CoV-2 infection and in the process causes internalization and destruction of ACE2. The major complications of COVID-19 are possibly caused by excessive angiotensin II activation due to loss of ACE2 and can be potentially reversed by angiotensin receptor blockers such as losartan. A randomized, parallel-group, placebo-controlled trial of losartan for the prevention of COVID-19 complications has been registered and is being conducted in an academic setting (CTRI/2020/05/025319).
Resveratrol-copper and sodium-copper-chlorophyllin: It has been hypothesized that following microbial infection, cell-free chromatin (cfCh) particles are released from dying cells, causing apoptosis and inflammation in the adjoining host cells. This process triggers a vicious cycle leading to sepsis. The novel pro-oxidant combination of resveratrol and copper has been reported to inactivate cfCh and demonstrated improved survival in animal models of sepsis.
The commonly used food colorant and dietary supplement, sodium copper chlorophyllin (SCC), has been reported to have significant antimutagenic and antioxidant properties. Two trials with resveratrol-copper and SCC as add-on treatment to standard treatment in asymptomatic/mildly symptomatic patients (Phase 3 trial) as well as hospitalized patients (Phase 2 trial) with COVID-19 have been registered (CTRI/2020/05/025336, CTRI/2020/05/025337).
2-deoxy-D-glucose (2-DG): A glucose analogue, 2-deoxy-D-glucose, is believed to have profound effects on a range of diseases such as cancer, viral infection and ageing-related morbidity. Recent in vitro studies suggest the potential benefits of using 2-DG to mitigate COVID-19 infection,. A Phase 2 trial to determine the safety and efficacy of the drug as an adjunctive therapy to standard of care in patients with moderate-to-severe COVID-19 is underway at 12 sites (CTRI/2020/06/025664).
| Phytopharmaceutical products|| |
Purified aqueous extract of Cocculus hirsutus (AQCH)
An industry-sponsored trial has been registered with aqueous extract of Cocculus hirsutus which is a phytopharmaceutical product derived from the tropical, climbing shrub C. hirsutus. This plant has been reported to have significant medicinal properties in a variety of disease conditions including viral infection. The trial is proposed to be conducted at 14 sites across the country on patients with moderate COVID-19 (CTRI/2020/05/025397).
Nigella sativa, commonly known as black cumin, has shown a wide spectrum of biological activities, the most prominent being antioxidant, anti-inflammatory and antimicrobial activities. An open-label, two-arm, parallel study is being conducted to evaluate the efficacy and safety of thymoquinone, a phytopharmaceutical compound extracted from Nigella sativa seeds, compared to best supportive care in patients with COVID-19 (CTRI/2020/05/025167).
| Cell- and plasma-based therapies|| |
Convalescent plasma therapy (CPT)
For immediate short-term immunity, convalescent plasma therapy (CPT) has generated particular interest as it appears to be safe, to be clinically effective and reduces mortality in times of large-scale epidemics,,. The ICMR has developed a protocol, which is approved by the Drugs Controller General of India, for a multicentre trial (PLACID trial) to test the efficacy of convalescent plasma obtained from recovered COVID-19 patients for administration to moderately ill COVID-19 patients. This is a multicentre, randomized, parallel-group, open-label, active controlled Phase 2 trial to be conducted on 452 patients at 39 sites in India (CTRI/2020/04/024775). In addition, two other trials have been registered which are being conducted by private hospitals on 100 patients each (CTRI/2020/04/024915, CTRI/2020/05/025328). Further, five additional small trials have also been registered investigating the role of CPT in hospitalized severely ill COVID-19 patients (CTRI/2020/04/024706, CTRI/2020/04/024804, CTRI/2020/05/025299, CTRI/2020/05/025346, CTRI/2020/05/025209).
Cytokine cocktail therapy
A Phase 1 trial to evaluate the safety and tolerability of cytokine cocktail therapy in healthy volunteers from healthy donors (derived by T cells) has been registered (CTRI/2020/05/025432). This trial is being conducted at Bengaluru, Karnataka.
| Biological products|| |
As per reports, vaccine against COVID-19 is being developed in about 90 institutions worldwide.
Bacille Calmette-Guérin (BCG) is believed to stimulate the general immune response with a consequent faster response to infections that could reduce the severity of disease and lead to quicker recovery rates. In India, mass immunization with BCG has been underway since 1948. The global interest in BCG was recently sparked when Miller et al, reported a negative correlation between BCG immunization status of a country and mortalities due to COVID-19. In the CTRI, currently, there are three BCG vaccine trials registered. One of these is on the BCG-Denmark (Green Signal) vaccine for the prevention of COVID-19 in 1826 healthcare workers, whereas the other is a Phase 3 trial of recombinant BCG VPM1002 vaccine for the reduction in infection incidence and severity of COVID-19 in 5946 high risk individuals. Both these trials are triple-blinded, randomized, parallel-group, placebo-controlled trials (CTRI/2020/04/024833 and CTRI/2020/04/024749, respectively). A single-blind, single-centre Phase 2 trial on 60 patients, is evaluating the therapeutic efficacy of BCG in COVID-I9 (CTRI/2020/05/025013).
| Traditional medicine|| |
During this pandemic, the potential of traditional medicine is being actively explored through the conduct of clinical trials to identify prophylactic as well as therapeutic agents. The AYUSH approach to manage the outbreak broadly comprises: preventive and prophylactic, symptom management of COVID-19-like illnesses and add-on interventions to the conventional care. Trials in the AYUSH system of medicine have been registered in the CTRI (n=67) and include Ayurveda (n=45), Yoga and Naturopathy (n=3), Unani (n=2), Siddha (n=3), Homeopathy (n=14) trials [Table 3].
Ayurveda is a comprehensive system of medicine that has been practiced in India for >5000 years. A total of 45 Ayurveda trials [Table 1] and [Table 3] are currently registered in the CTRI. These are categorized as individual agents (11 trials) or combination preparations (10 trials, of which 3 trials include other systems of AYUSH such as homeopathy and/or yoga) as available under classical interventions. In addition, there are 24 trials registered on patented ayurvedic products. Four major plant products are under investigation, namely Tinospora cordifolia, Withania somnifera, Glycyrrhiza glabra and Curcuma longa (only in combination with other agents).
While the classical interventions, individual and combination trials (n=21), are mostly designed to assess their prophylactic efficacy (n=16) in either healthy human volunteers in the community or those at risk (n=16), the trials with patented products (n=24) are primarily investigating the therapeutic efficacy (n=18) in patients ranging from asymptomatic to moderate to severe COVID-19 patients [Table 1].
Guduchi: Tinospora cordifolia, commonly named as Guduchi, is used in a variety of conditions in the traditional Ayurvedic literature. Guduchi has been reported to possess a range of activities (antipyretic, anti-inflammatory, antioxidant, anti-infective, anti-neoplastic and immuno-modulatory effects) notable in the context of COVID-19. Currently, in the CTRI, there are seven registered trials investigating the role of only Guduchi, in healthy high risk individuals in the community to test its role as a preventive agent against COVID-19. Four of these are large trials with sample size ranging from 5000 to 40,000 (the latter has 20 sites across India). In addition, there are three trials exploring the effects of Guduchi in combination with other agents. One of these is being conducted on 50,000 police personnel in Delhi [Table 3].
Ashwagandha: Withania somnifera (Ashwagandha) is well known for its anti-inflammatory, antitumour, anti-stress, antioxidant, immunomodulatory, hemopoietic and rejuvenating properties. In addition, it has been demonstrated to inhibit certain RNA viruses. The role of Ashwagandha in the prevention of COVID-19 is being investigated in three trials registered in the CTRI, one of which is on 5000 high-risk participants (CTRI/2020/05/025429).
Turmeric: The antiviral effects of curcumin, a plant derivative of turmeric, have been demonstrated in in vitro studies, which makes it an antiviral drug candidate. Evaluation of the effects of curcumin and adjuvants in COVID-19 patients, in terms of changes in acute-phase reactants and clinical outcome, is being evaluated in a randomized, parallel-group trial on 50 patients (CTRI/2020/05/025482). In addition, polyherbal compounds are being investigated for immunomodulatory and antiviral properties and their potential as therapeutic and prophylactic agents.
Currently, there are 24 trials registered on patented products including AYUSH-64 patented by Central Council for Research in Ayurvedic Sciences.
AYUSH 64: A multiplant formulation, AYUSH-64, has been demonstrated to be useful in several research studies carried out over several decades to treat febrile infections including malaria and is considered to possess anti-inflammatory and immunomodulatory effects. One of its components, Glycyrrhiza glabra or Yashtimadhu, has demonstrated potential as a wound-healing, anti-ulcer and anti-inflammatory agent. In addition, recent studies reveal that Yashtimadhu may interfere with viral entry as well as replication, thereby impacting the severity of infection. Further, AYUSH-64 along with standard care has been shown to be effective in influenza-like illnesses with potential for better outcomes. While a community-based clinical study on 1200 healthy but at-risk individuals has been registered in the CTRI to evaluate the preventive role of only Yashtimadhu, there are five trials on the proprietary formulation, AYUSH 64 [Table 3].
Chyawanprash: This is an ancient Indian polyherbal formulation prepared according to a traditional Ayurvedic recipe. It consists of about 50 different medicinal herbs including Emblica officinalis (Indian gooseberry or Amla), a rich source of vitamin C, as well as processed minerals and is considered as an essential health supplement. Currently, four trials are registered which are investigating the preventive role of Chyawanprash in high risk healthcare workers/containment zone population as well as the community [Table 3].
| Yoga and naturopathy|| |
Stress is known to suppress the immune system and is believed to be the harbinger of many diseases including respiratory infections,. Evidence supports the role of meditation in regulating the stress response and impacting virus-specific immune response,. Further, Pranayama has been shown to have a positive impact on lung function. Currently, three yoga trials are registered, of which two randomized, parallel-group trials focus on the role of Pranayama and meditation in the prevention as well as treatment of COVID-19. In addition, in one trial, yoga is being tried in combination with naturopathy and Ayurvedic agents (CTRI/2020/05/025320).
| Unani|| |
The Unani system of medicine, originally from Greece, has been influenced by Ayurveda, Siddha and Chinese systems of medicine. Even though an ancient system, Unani medicine also recommends isolation and quarantine during an epidemic. In addition, it also recommends (i) cleanliness, (ii) health boosting and immune-modulation, and (iii) use of drugs. Two trials investigating the prophylactic role of Unani medicine: one is on 4000 participants and the other on 40,000 participants, have been registered in population at risk of contracting COVID-19 [Table 3].
| Siddha|| |
The Siddha system, one of the six accepted branches of Indian systems of medicine, is particularly popular in southern India. Although it is similar to Ayurveda in certain aspects, these are two distinct streams of medicine. There are three Siddha trials registered investigating the role of Kabasura Kudineer, a Siddha formulation alone and in combination as a preventive agent in the management of asymptomatic COVID-19 patients [Table 3].
| Homeopathy|| |
Homeopathy focuses on patient characteristics rather than disease per se. There has been a call to utilize the benefits of homeopathy as a therapeutic system suitable to cope with this pandemic,. Several homeopathic agents have been recommended by the Ministry of AYUSH, Government of India, for the prevention of COVID-19. Of the 14 homeopathic trials registered in the CTRI, most (n=11) are of Arsenicum album 30 or Bryonia alba [Table 3].
| Miscellaneous trials|| |
Thirteen trials have been categorized as miscellaneous trials as these explore a range of interventions such as nutraceuticals, process-of-care changes (n=9) and critical care-related trials and include management of non-COVID-19 patients in the pandemic [Table 1]. Some of these trials evaluate methods to minimize infection risks, whereas others compare different types of video laryngoscopes for ease of intubation while wearing personal protective equipment [Table 4]. Some of the other registered trials in this category include efficacy of nutraceuticals, feasibility of developing a novel artificial intelligence algorithm to screen COVID-19, telemedicine and ventilatory management training to ramp up capacity.
| Observational studies|| |
Apart from the clinical trials, the CTRI has registered observational studies on COVID-19 as well. Due to the imposition of lockdown and the imperative need for social distancing, observational studies have been undertaken to assess the impact of COVID-19 on mental health, clinical practice in general and in particular for oncology patients. Findings and observations from these studies would likely help develop better guidelines for the care of the most vulnerable in these pandemic times.
| Concluding remarks|| |
Notwithstanding the deadly virulence of the SARS-CoV-2 and the enforcement of widespread physical restrictions, medical researchers in India have risen to the dual challenge of caring for the sick and testing potential therapeutic options. This article culls the data of 122 COVID-19-related trials from the data of over 27,000 trials registered in the CTRI and presents a concise and comprehensive overview of the pharmacological and clinical aspects of the registered trials. This also provides a comprehensive insight into the COVID-19 clinical research underway in the country through CTRI database. This would encourage researchers to critically review CTRI data, identify gaps particularly methodological and design aspects of research and further decide on acceptability of the results. We hope that this information would help researchers to not only understand the clinical research scenario, but also encourage healthy debate, train researchers to avoid obvious errors/oversights, steer clear of repetitive research and indirectly promote the quality of research in the country.
Acknowledgment: The CTRI was set up with financial support from the ICMR, Ministry of Health and Family Welfare; Department of Science and Technology, Government of India; and World Health Organization, India Office, New Delhi, India. The CTRI website is hosted by the National Informatics Centre Services Inc., New Delhi, India. Authors acknowledge the support provided by the following: Servshri Anoop Upadhyay, Harish Kumar, and Din Bandhu, and Ms Noori Dua and Ms Deepty Rathi in the initial screening of the trials and typographical work.
Financial support & sponsorship: None.
Conflicts of Interest: None.
| References|| |
World Health Organization. International Clinical Trials Registry Platform (ICTRP)
. Available from: https://www.who.int/ictrp/en,
accessed on June 11, 2020.
Jordan PC, Stevens SK, Deval J. Nucleosides for the treatment of respiratory RNA virus infections. Antivir Chem Chemother
: 1- 19.
Pastick KA, Okafor EC, Wang F, Lofgren SM, Skipper CP, Nicol MR, et al
. Hydroxychloroquine and chloroquine for treatment of SARS-CoV-2 (COVID-19). Open Forum Infect Dis
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
Iqbal N, Iqbal N. Imatinib: a breakthrough of targeted therapy in cancer. Chemother Res Pract
Sisk JM, Frieman MB, Machamer CE. Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors. J Gen Virol
Cherian SS, Agrawal M, Basu A, Abraham P, Gangakhedkar RR, Bhargava B. Perspectives for repurposing drugs for the coronavirus disease 2019. Indian J Med Res
Singh V. Clinical outcome of a novel anti-CD6 biologic itolizumab in patients of psoriasis with comorbid conditions. Dermatol Res Pract
Krupashankar DS, Dogra S, Kura M, Saraswat A, Budamakuntla L, Sumathy TK, et al
. Efficacy and safety of itolizumab, a novel anti-CD6 monoclonal antibody, in patients with moderate to severe chronic plaque psoriasis: results of a double-blind, randomized, placebo-controlled, phase-III study. J Am Acad Dermatol
Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents
Chahar M, Rawat KD, Reddy PVJ, Gupta UD, Natarajan M, Chauhan DS, et al
. Potential of adjunctive Mycobacterium w
(MIP) immunotherapy in reducing the duration of standard chemotherapy against tuberculosis. Indian J Tuberc
Sehgal IS, Bhalla A, Puri GD, Yaddanapudi LN, Singh M, Malhotra P, et al
. Safety of an immunomodulator Mycobacterium w
in COVID-19. Lung India
Zhang R, Wang X, Ni L, Di X, Ma B, Niu S, et al
. COVID-19: Melatonin as a potential adjuvant treatment. Life Sci
Moradkhani F, Moloudizargari M, Fallah M, Asghari N, Heidari Khoei H, et al
. Immunoregulatory role of melatonin in cancer. J Cell Physiol
Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro
. Antiviral Res
Xu J, Shi PY, Li H, Zhou J. Broad spectrum antiviral agent niclosamide and its therapeutic potential. ACS Infect Dis
Guthappa R. Molecular docking studies of N-acetyl cysteine, zinc acetyl cysteine and niclosamide on SARS-CoV-2 protease and its comparison with hydroxychloroquine. ChemRxiv
2020. doi: 10.26434/chemrxiv.12161493.v1.
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al
. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell
Kai H, Kai M. Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19. Hypertens Res
Mittra I, Samant U, Sharma S, Raghuram GV, Saha T, Tidke P, et al
. Cell-free chromatin from dying cancer cells integrate into genomes of bystander healthy cells to induce DNA damage and inflammation. Cell Death Discov
Mittra I, Pal K, Pancholi N, Tidke P, Siddiqui S, Rane B, et al
. Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice. PLoS One
Ferruzzi MG, Failla ML, Schwartz SJ. Sodium copper chlorophyllin: in vitro
digestive stability and accumulation by Caco-2 human intestinal cells. J Agric Food Chem
Xi H, Kurtoglu M, Lampidis TJ. The wonders of 2-deoxy-D-glucose. IUBMB Life
Balkrishna A, Thakur P, Singh S, Dev S, Jain V, Varshney A, et al
. Glucose antimetabolite 2-Deoxy-D-Glucose and its derivative as promising candidates for tackling COVID-19: Insights derived from in silico
docking and molecular simulations. Authorea
2020. doi: 10.22541/au.158567174.40895611.
Balkrishna A, Pokhrel S, Singh J, Varshney A. Withanone from Withania Somnifera
may inhibit novel coronavirus (COVID-19) entry by disrupting interactions between viral s-protein receptor binding domain and host ACE2 receptor; 2020. doi: 10.21203/rs.3.rs-17806/v1
Meena MK, Singh N, Meena R, Patni V. Quantitative determination of gallic acid from methanolic extract of Cocculus hirsutus
using HTPLC. Int J Pharm Bio Arch
Khader M, Eckl PM. Thymoquinone: an emerging natural drug with a wide range of medical applications. Iran J Basic Med Sci
Marano G, Vaglio S, Pupella S, Facco G, Catalano L, Liumbruno GM, et al
. Convalescent plasma: new evidence for an old therapeutic tool? Blood Transfus
Rajendran K, Krishnasamy N, Rangarajan J, Rathinam J, Natarajan M, Ramachandran A. Convalescent plasma transfusion for the treatment of COVID-19: Systematic review. J Med Virol
Yang L, Tian D, Liu W. Strategies for vaccine development of COVID-19. Sheng Wu Gong Cheng Xue Bao
Tanner R, Villarreal-Ramos B, Vordermeier HM, McShane H. The humoral immune response to BCG vaccination. Front Immunol
Neelakantan V. Tuberculosis control in postcolonial South India and beyond: Fractured sovereignties in international health, 1948-1960. Wellcome Open Res
Miller A, Reandelar MJ, Fasciglione K, Roumenova V, Li Y, Otazu GH. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. medRxiv
2020. doi: 10.1101/2020.03.24.20042937.
Advisory from Ministry of AYUSH for meeting the challenge arising out of spread of coronavirus (COVID-19) in India. Available from: https://www.ayush.gov.in/docs/125.pdf
, accessed on June 11, 2020.
Mishra L, Singh BB, Dagenais S. Ayurveda: a historical perspective and principles of the traditional healthcare system in India. Altern Ther Health Med
Saha S, Ghosh S. Tinospora cordifolia
: One plant, many roles. Anc Sci Life
Upadhyay AK, Kumar K, Kumar A, Mishra HS. Tinospora cordifolia
(Willd.) Hook. f. and Thoms. (Guduchi
) - validation of the Ayurvedic pharmacology through experimental and clinical studies. Int J Ayurveda Res
Mishra LC, Singh BB, Dagenais S. Scientific basis for the therapeutic use of Withania somnifera
(ashwagandha): A review. Altern Med Rev
Ganguly B, Umapathi V, Rastogi SK. Nitric oxide induced by Indian ginseng root extract inhibits infectious Bursal Disease virus in chicken embryo fibroblasts in vitro
. J Anim Sci Technol
Moghadamtousi SZ, Kadir HA, Hassandarvish P, Tajik H, Abubakar S, Zandi K. A review on antibacterial, antiviral, and antifungal activity of curcumin. Biomed Res Int
Das D, Agarwal SK, Chandola HM. Protective effect of Yashtimadhu
) against side effects of radiation/chemotherapy in head and neck malignancies. Ayu
Maurya DK. Evaluation of Yashtimadhu
) active phytochemicals against novel coronavirus (SARS-CoV-2). Research Square
Gundeti MS, Bhurke LW, Mundada PS, Murudkar S, Surve A, Sharma R, et al
. AYUSH 64, a polyherbal Ayurvedic formulation in Influenza like Illness: Results of a pilot study. J Ayurveda Integr Med
Sharma R, Martins N, Kuca K, Chaudhary A, Kabra A, Rao MM, et al
. Chyawanprash: A traditional Indian bioactive health supplement. Biomolecules
Salleh MR. Life event, stress and illness. Malays J Med Sci
Maxwell L, Barrett B, Chase J, Brown R, Ewers T. Self-reported mental health predicts acute respiratory infection. WMJ
Househam AM, Peterson CT, Mills PJ, Chopra D. The effects of stress and meditation on the immune system, human microbiota, and epigenetics. Adv Mind Body Med
Morgan N, Irwin MR, Chung M, Wang C. The effects of mind-body therapies on the immune system: Meta-analysis. PLoS One
Budhi RB, Payghan S, Deepeshwar S. Changes in lung function measures following Bhastrika Pranayama
(Bellows Breath) and running in healthy individuals. Int J Yoga
Nikhat S, Fazil M. Overview of Covid-19; its prevention and management in the light of Unani medicine. Sci Total Environ
Muthiah K, Ganesan K, Ponnaiah M, Parameswaran S. Concepts of body constitution in traditional Siddha texts: A literature review. J Ayurveda Integr Med
Poitevin B. Integrating homoeopathy in health systems. Bull World Health Organ
Kalliantas D, Kallianta M, Karagianni CS. Homeopathy combat against coronavirus disease (Covid-19). Z Gesundh Wiss
[Table 1], [Table 2], [Table 3], [Table 4]