|Year : 2022 | Volume
| Issue : 4 | Page : 258-269
In search for a panacea for coronavirus disease-19: Analysis of ongoing clinical trials for the management of coronavirus disease-19 pandemic in India
Nidhi Maheshwari1, Vandana Roy2
1 Department of Pharmacology, School of Medical Science and Research, Sharda University, Greater Noida, Uttar Pradesh, India
2 Department of Pharmacology, Maulana Azad Medical College and Associated Hospitals, New Delhi, India
|Date of Submission||01-Sep-2021|
|Date of Decision||07-Aug-2022|
|Date of Acceptance||10-Aug-2022|
|Date of Web Publication||04-Oct-2022|
Dr. Vandana Roy
Department of Pharmacology, Maulana Azad Medical College and Associated Hospitals, New Delhi-02
Source of Support: None, Conflict of Interest: None
OBJECTIVE: To analyze the clinical trials that are registered on the Clinical Trial Registry of India (CTRI) portal for a year, for the treatment, prevention, and supportive therapy of coronavirus disease-19 (COVID-19).
MATERIALS AND METHODS: All the trials registered on CTRI (since January 2020 till January 2021) for therapeutic, preventive, and supportive interventions for COVID-19 were searched with the keywords “Coronavirus,” “COVID-19,” “SARS-COV-2,” and “2019-nCoV”. These registered studies were analyzed as follows: Trials under different systems of Medicine-Allopathy/Homeopathy/Ayurveda/Unani/Yoga/Naturopathy. The Allopathy trials were further analyzed in detail: Intervention, design, comparator, number of subjects, duration, and approvals taken.
RESULTS: A total of 1597 records were found. After excluding the overlaps, behavioral and other studies conducted to understand the diagnosis, epidemiology, a total of 419 registered studies were included for further analysis. Out of these 419 studies, 166 (39.6%) were in Ayurveda, 154 (36.7%) in Allopathy, 33 (7.8%) in Homeopathy, 30 (7%) in Unani/Siddha, 18 (4.3%) in Yoga and Naturopathy and 18 (4.3%) in Nutraceuticals. A total of 264 interventions had been registered in 419 clinical trials. Sixty-seven interventions were being studied under allopathy in 154 studies. Same product was being evaluated in differently designed protocols with different endpoints. Maximum number of trials and subjects were for Hydroxychloroquine 25 (17,998), Ivermectin 11 (2820), Convalescent Plasma 11 (3982), Remdesivir 8 (3725), Tocilizumab 6 (884), and Azithromycin 6 (582).
CONCLUSIONS: In response to the COVID-19 pandemic, Indian researchers came forward from all the systems of medicine to evaluate interventions for prophylaxis or treatment of the disease. The involvement of AYUSH systems of medicine was specifically more in this regard. A wide variation and heterogeneity in doses and outcomes were observed in trial designs which might make it difficult to generalize the study results when they are made available. Urgent analyses of studies involving interventions on the treatment advisory of the Government may help the healthcare providers take more informed decisions for managing COVID-19 patients in India.
Keywords: Clinical trials, coronavirus, design, India, outcomes
|How to cite this article:|
Maheshwari N, Roy V. In search for a panacea for coronavirus disease-19: Analysis of ongoing clinical trials for the management of coronavirus disease-19 pandemic in India. Indian J Pharmacol 2022;54:258-69
|How to cite this URL:|
Maheshwari N, Roy V. In search for a panacea for coronavirus disease-19: Analysis of ongoing clinical trials for the management of coronavirus disease-19 pandemic in India. Indian J Pharmacol [serial online] 2022 [cited 2023 Feb 7];54:258-69. Available from: https://www.ijp-online.com/text.asp?2022/54/4/258/357832
| » Introduction|| |
The beginning of 2020 found the world hit by a global pandemic of unseen proportions. It spread worldwide with 500,186,525 confirmed cases and 6,190,349 deaths globally. The coronavirus disease-19 (COVID-19) pandemic, a health emergency, also brought along with it a worldwide economic crisis, unemployment, people's migration, and social challenges. Mutations in the virus are further adding to the problem. To find cure and a prevention strategy became the priority for all health agencies. Developing new drugs is a time consuming and costly affair. A faster identified approach is to study existing therapies and repurposing of drugs. Hence, drug candidates and entities which showed in-vitro/in-vivo activity against the novel coronavirus (2019-nCoV) or against other viruses of the same family were chosen to be explored further. In India, multiple ancient, alternative systems of medicine prevail alongside allopathy, which also found a place in the spectrum of studies evaluating efficacy for COVID-19 disease.
A number of clinical trials are taking place in India, for the treatment, prevention, and supportive therapy of COVID-19. These have been registered on the Clinical Trial Registry of India (CTRI) portal. The aim of this study was to analyze the clinical trials registered for a year, in India, and comment on their status.
| » Materials and Methods|| |
A review was conducted for all trials registered on CTRI (since January 2020 till January 2021) for therapeutic, preventive, and supportive interventions for COVID-19. The key words used were coronavirus, COVID-19, severe acute respiratory syndrome coronavirus-2 (SARS-COV-2), and 2019-nCoV. These registered studies were analyzed under the following parameters: Total number of trials under the different systems of Medicine-Allopathy/Homeopathy/Ayurveda/Unani/Yoga/Naturopathy. The allopathic trials were studied in detail on the following parameters: nature of the study (observational/interventional), study design, center (single/multi), number of sites, number of study subjects (patients/healthy volunteers/contacts), control group (active comparator/placebo), duration of study, study end points, similarities/differences between clinical trials for evaluating the products, approval from the Institutional Ethics Committee (IEC), and clearance from Drugs Controller General of India (DCGI). For other systems of medicine, the number of interventions, sites, subjects and study design were focussed upon.
Following the use of keywords, a total of 1597 records were found. There were 657 records with “coronavirus,” 766 with “COVID-19”, 166 with “SARS-COV-2, and 8 with “2019-nCoV. After excluding the overlaps, repetition, behavioral, and other studies conducted to understand the diagnosis, epidemiology, disease progression, and pathogenesis, a total of 419 registered studies were included for the further analysis [Figure 1]. A total of 264 interventions had been registered in 419 clinical trials. Out of these 419 studies, 166 (39.6%) were in Ayurveda, 154 (36.7%) in Allopathy, 33 (7.8%) in Homeopathy, 30 (7%) in Unani/Siddha, 18 (4.3%) in Yoga and Naturopathy, and 18 (4.3%) in Nutraceuticals. Maximum number of subjects were enrolled in Ayurveda (60%), followed by homeopathy (20%), allopathy (12%), and Unani medicine (10%) [Figure 2].
|Figure 1: Flowchart of studies screened and included. N: Number of studies|
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Majority of these trials were single center (305/72.8%) and interventional (396/94.5%) in conduct. In 32% of the interventional studies, the test drug was compared to either a placebo or an active comparator, while for the rest 68% of the studies, it has been poorly defined. Some had either a single arm or a standard of care-control arm. The active comparator used along with the standard of care was not clearly specified in some of the trials which mentioned “active controlled trial” in their study design. The trials that had been prespecified to be a “placebo controlled study” did not highlight the details about the placebo as to whether it was a “matching placebo” or what were the contents of the placebo. The standard of care was not specified in all the trials, those that had specified it was as per Government of India/Ministry of Health and Family Welfare (MoHFW) guidelines. A total of 735,965 subjects had been enrolled in these 419 registered studies [Table 1] and [Figure 3].
Allopathy clinical trials
Allopathy trials conducted with the 67 interventional agents were classified into 10 broad categories based on the medical intervention as antiparasitic drugs, immunomodulator agents, antivirals and protease inhibitors, corticosteroids, antithrombotic drugs, vaccines, convalescent plasma therapy, miscellaneous agents including Atorvastatin, colchicine, montelukast, erythropoietin, dapagliflozin, Angiotensin Receptor Blocker, Doxycycline, Cotrimoxazole, Azithromycin, Edaravone, Lithium, Vitamin C, D, K, Zinc, and Topical Agents [Figure 4]. The 67 products investigated under all these broad categories had been registered by different researchers/organizations in differently designed protocols even when evaluating the same investigational product [Table 2]. For example, maximum number of trials (25) had been registered for Hydroxychloroquine (HCQ) in 25 differently designed protocols with variations in the comparator, duration of therapy as well as the primary end points.
The total duration of these individual studies varied from 28 days to 28 months. The duration of therapy varied from a single dose to six months [Table 2]. Maximum number of participants (28,500) had been enrolled in the phase III study of Whole Virion Inactivated BBV15 vaccine followed by HCQ trials collectively, with 17,998 subjects. A total of 14 trials were part of multinational programs (global) with single/multiple sites undertaken in India enrolling 5052 subjects. These were the studies that investigated the role of HCQ versus Lopinavir/Ritonavir, HCQ versus Remdesivir versus Lopinavir/Ritonavir versus Lopinavir/Ritonavir + Interferon (IFN), BDB-001, DFV890, Olitimab (anti Granulocyte-Macrophage Colony Stimulating Factor Mab), Ruxolitinib, Bemcentinib, Baricitinib, Acalabrutinib, different doses of Dexamethasone, Leflunomide, Apixaban versus Enoxaparin, Enoxaparin and Dapagliflozin in the treatment of COVID-19 disease.
Respective IEC approvals had been taken for all of the studies, but clearance from DCGI had not been taken for all the studies despite the fact that majority of these studies were interventional studies and most of these agents even if repurposed, had never been previously tried nor approved for COVID-19 indication. These clinical trials had been designed in a variety of population including healthy volunteers, healthcare workers, elderly, individuals with comorbid conditions, close contacts of confirmed COVID 19 cases as well as individuals who had contracted mild, moderate or severe COVID-19 disease [Table 3]. Overall, there was a huge variation in the doses, dosage regimens and predefined primary outcome of these clinical trials even when the interventional agent was the same and patient population also of similar characteristics [Boxe 1] and [Boxe 2], [Table 4]]. In most of the studies, participants of >18 years of age had been enrolled except in two trials on confirmed COVID-19 cases which had enrolled patients as young as 14 years of age (HCQ study) and the other in which ivermectin was being prescribed to children as young as 6 years [Table 3]. In most of these trials patients who had concomitant comorbid conditions like liver, kidney disease, known coronary artery disease, prolonged QT interval, G-6PD deficiency, any retinal disease or an immunocompromised condition were excluded from enrolment.
|Table 4: Study outcomes of different group of drugs being evaluated in the clinical trials|
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Amongst the antiparasitic agents, maximum number of studies (67.5%) were with HCQ alone or in direct comparison and/or in addition to other class of drugs like antiviral agents, antibiotics, other antiparasitic agents and inhalational corticosteroids. Of the total number of participants enrolled in antiparasitic drug trials, 86.5% had been in HCQ trials across 83 sites in the country. HCQ was majorly tested as a prophylactic agent for SARS-CoV-2 infection in 77% population enrolled in HCQ trials followed by Ivermectin in over 2500 participants.
Five trials had been registered which compared different formulations of alternative forms of medicine like Siddha (one study) and Ayurveda (four studies-Ashwagandha, Tulsi immune, Spice Mix etc.,), head on with HCQ for both prophylaxis and treatment of COVID-19 disease.
Amongst the 31 trials registered for various immunomodulator agents, five had been evaluating different corticosteroid preparations in different doses and routes in 56% of total individuals participating in the immunomodulator trials. Majority of the studies enrolled patients with moderate-to-severe spectrum of the disease with an exception of Imatinib, Bemcentinib and Budesonide studies which were conducted in mild COVID-19 disease.
The convalescent plasma therapy trials did not lay uniform inclusion criteria for the plasma donor patients. Plasma donors who had complete resolution of COVID-19 symptoms 28 days prior could be included with or without at least one negative laboratory test for COVID-19 and in case of plasma donation prior to 28 days of full recovery, two negative nasopharyngeal swab tests for SARS-CoV-2, 24 h apart were considered for inclusion. The other detailed inclusion criteria for plasma donor individuals including the minimum desired level of IgG/IgM antibodies and neutralizing antibodies to nCOV-2 had been mentioned only in a couple of studies. It has not been made very clear as to on which day of illness the convalescent plasma therapy has to be started. None of the trials conducted for convalescent plasma therapy, enrolled patients showing mild form of the disease.
| » Discussion|| |
This study is the first of a kind to analyze in detail the clinical trials that have been registered in India across all the systems of medicine for over a year for COVID-19 disease. The unusual situation of a pandemic and immense pressure on the healthcare system, demanded urgent exploration of effective therapies for prophylaxis and treatment. This led to initiation of hundreds of studies across all “pathies” or systems of medicines. In our study, the total number of trials registered, exceeded by 1.5 times the number of drugs being investigated, reflecting the fact that multiple protocols with the same product, with either variation in doses, type of enrolled population (diseased or healthy) or different primary efficacy outcome, were being conducted. Majority of these trials were single center studies (>70%) approved by the respective IEC, but regulatory clearance had not been taken for many of these studies. This is a little surprising as, these repurposed agents do have established safety and efficacy profile for other indications, but their efficacy and safety had never been shown for COVID-19 disease. Our information is based on the open access content available on the CTRI website only.
Maximum studies that had been registered with the CTRI were of AYUSH systems (60%) out of which 67% were Ayurveda studies. This is a positive observation as the Government of India (GOI) is promoting the development of AYUSH systems of medicine. It indicates a step toward evidence-based medicine. Any evidence, obtained in these studies will help in furthering the cause, both of benefit to patients and to AYUSH systems of medicines.
The rationale for selecting some of the interventional agents like the antiparasitic and antiviral was based on their in vitro potential in inhibiting the SARS-CoV-2 virus or other viruses. For example, HCQ and Ivermectin have been shown to inhibit cellular entry and transport of coronavirus in vitro, while Favipiravir and Umifenovir have been tried for the treatment of influenza, while Sofosbuvir,, has been used in hepatitis infection. A variety of other agents are being explored owing to their known immunomodulatory actions in various inflammatory pathologies. Nafamostat as well as ulinastatin have been used for their anti-inflammatory action in pancreatitis, acute respiratory distress syndrome, etc., To address the hyper inflammatory response and cytokine storm in COVID-19 disease, the role of various immunomodulators like tocilizumab, itolizumab, imatinib, thalidomide, IFN-gamma, IFN alpha-2beta, and others along with glucocorticoids was explored.
Some of these investigational agents being explored in trials were in the Indian Council of Medical Research (ICMR) advisory released in March 2020 like HCQ, an inexpensive, age old antimalarial drug, which was recommended in either health care workers or primary close contacts of confirmed COVID-19 cases. For prophylaxis in healthcare workers and high risk contacts, an advisory by the ICMR and GOI recommended HCQ 400 mg twice on Day 1 followed by 400 mg once a week for three weeks. According to the MoHFW-Clinical Management protocol COVID-19, Tab HCQ (400mg) twice daily on the 1st day followed by 400mg once a day for four days (after ECG Assessment) in Mild-Moderate COVID-19 disease led to 24 clinical trials. However, six different dosing regimens were being tested in the registered studies with HCQ, for prophylaxis and treatment of COVID-19 disease. Although such vast variation in doses can be explained on the basis of HCQ usage in different dosage regimens in other diseases such as malaria, diabetes, rheumatoid arthritis and pharmacokinetic/pharmacodynamic in silico studies which have contributed in estimating the safe and effective doses of HCQ based on the published EC50 values for COVID-19 disease; a study evaluating the doses recommended in the ICMR advisory in a large sample size may have given more useful information.
Later, other drugs like Ivermectin, Tocilizumab (Off label use), Remdesivir (Emergency Use Authorization), methylprednisolone, dexamethasone, and enoxaparin found a place in the GOI clinical guidance for the treatment of COVID-19 disease, on the basis of published international trial data [Box 3]. In July 2020, the RECOVERY collaborative group announced mortality benefit with low cost intravenous dexamethasone (IV) 6 mg once a day when given to patients receiving oxygen support and mechanical ventilation. In July 2020, Itolizumab also found a recommendation from the DCGI on compassionate grounds in patients presenting with cytokine syndrome. Recently, the results of EMPACTA study, a randomized, double blinded, placebo controlled, multicenter study were published, which clearly stated the benefit of Tocilizumab in limiting the progression to death or requirement of mechanical ventilation, significantly. The results of PLACID trial, an open label, multicentric study conducted in India in which Convalescent Plasma Therapy was prescribed in moderate COVID-19 disease patients within three days of admission, have been published recently. The trial, though showed significant improvement in shortness of breath and a higher negative conversion of reverse transcription-polymerase chain reaction at day 7, but these results could not translate into a significant reduction in the composite primary outcome of 28 day mortality and progression to severe disease. Recently the RECOVERY collaborative group announced the results from 11,558 patients showing no benefit in 28 day mortality with the use of convalescent plasma therapy. Further to this GOI has removed convalescent plasma from its COVID-19 treatment recommendation.
A total of 264 interventions involving over 7 lakh subjects were being evaluated in different clinical trials that are registered on CTRI. It is now, nearly two years since the pandemic began. As the COVID-19 pandemic is still unfolding, it would be useful to know the findings of the studies that were registered last year. If the trials are not completed, then an interim analysis of trials investigating drugs, that have been recommended by the GOI would be of much use. This may help inform the health care workers, on how best to prevent and treat COVID-19 infection in India. These could provide valuable India centric data, regarding interventions to handle COVID-19. It may be difficult to generalize the results, since the patient population included and outcomes measured are different. But the information would still add to the doctors' armamentarium, handling the COVID 19 patients. Keeping these points in our mind, we did an active search to find out how many allopathic trials have been completed and published in the last six months. We found only 25 out of 154 trials published in different scientific journals. These studies brought some very meaningful insights on agents like Itolizumab, BBV152-Covaxin, IV immunoglobulin, Pegylated IFN-α2b, Topical lignocaine, 8.4% sodium bicarbonate, Cotrimoxazole, PNB001, Convalescent plasma therapy, BCG vaccine, Favipiravir, Otilimab, Baricitinib, Tocilizumab, Dapagliflozin, Aspirin, Atorvastatin and Thymosin alpha. After studying each of these trials in depth, we found only the former eight agents listed here, met the predefined primary outcomes to show statistically significant benefit in the treatment of COVID-19 disease. Clinical trials on Pegylated IFN-α2b, PNB001, Itolizumab, IV immunoglobulin, were Phase II studies conducted in ≤100 subjects each, showing statistically significant improvement in the clinical status (calculated on WHO ordinal scale) with the former two agents, while the latter two showed mortality benefit and shorter duration of hospital stay, respectively. The BBV152-Covaxin trial was a large multicentric Phase III clinical trial demonstrating vaccine efficacy of 77.8%. While studies on Topical lignocaine, Cotrimoxazole and 8.4% sodium bicarbonate assessing the comfort of the procedure of oropharyngeal sampling and clinical/inflammatory parameters, respectively showed positive results, but these were small studies with weak study designs.,,,,,,,
The conduct of so many trials indicates enthusiasm, desire for research, creative thinking and planning. A lot of effort has gone on the part of investigators in planning the research studies, the IEC in granting approval and involvement of many patients, volunteers, health care workers. It is important that all the effort be used to improve outcomes, for the public suffering misery from COVID-19. For this, all evidence regarding therapies, that are beneficial would help.
While the conduct of these studies and information derived therewith would be crucial to all research stakeholders and for the benefit of mankind, such multiple small studies would not generate the strong evidence, required to estimate the relative effectiveness of these potential treatments.
Instead of conducting multiple small, single center, nonrandomized studies, evaluating different end points, a more rational approach could be, to conduct a single large, multiple arms, randomized, multicentric trial enrolling a large number of participants and evaluating multiple, potential, unproven therapies for some common yet important outcomes. A larger pool of recruited patients could be more helpful in generating relevant scientific information, as in the global WHO Solidarity Trial, with rigorous and stringent trial procedures, yet simple to conduct. The Solidarity Trial enrolled over 14,000 patients, across 600 sites worldwide and compared 4 active unproven therapies viz., HCQ, Lopinavir/Ritonavir, Remdesivir and IFN beta1alpha. An interesting feature of the trial was, that it was an adaptive design, wherein the unpromising drugs could be dropped and the trial could be carried forward by adding other potential agents, that were identified to be repurposed, at a later date. Similarly, the RECOVERY trial conducted by the University of Oxford is another example of world's largest, international, randomized clinical trial evaluating multiple therapies in 45,981 patients, from across the globe. The trial has tested Lopinavir-Ritonavir, Dexamethasone, HCQ, Convalescent plasma, Azithromycin, Tocilizumab, Antibody cocktail, Aspirin and Colchicine in the past and is continuing to test other agents like Baricitinib, Dimethyl fumarate, High dose versus Standard dose Corticosteroids, Empagliflozin and Sotrovimab.
Since the pandemic is yet far from over, we hereby recommend (i) An interim analysis of all trials registered in CTRI for COVID-19 to see if any of the results can be applied and used in the efforts to treat and prevent COVID-19, (ii) Identification of a list of interventions, that need to be studied on priority, with a standard protocol and clinically useful end points, that can enable informed decision making faster. This protocol can be studied at multiple centres in the country, to enable adequate powering of the study. ICMR would be the best agency to spearhead this process and take it to its logical conclusion.
| » Conclusions|| |
In response to the COVID-19 pandemic, Indian researchers came forward from all systems of medicine to evaluate interventions for prophylaxis or treatment of the disease. The involvement of AYUSH systems of medicine was specifically more in this regard. The same interventions had been evaluated in multiple trials, with variations in methodology and measured outcomes. A wide variation and heterogeneity in doses was observed in trial designs, which might make it difficult to generalize the study results, when they are made available. A collaborative effort from researchers at key central research organizations of the country could help in generating more robust data on the repurposed molecules and give answers which can be applied in the current pandemic.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]