By Suradip Das
What are Clinical Trials ?
Clinical Trials is the foundation on which modern medicine stands. Being performed on human subjects, clinical trials is the best method to evaluate the efficacy of new therapeutic, diagnostic or preventive measures pertaining to a specific medical condition. Such trials are usually classified under different phases (Phase I-IV) depending on how many participants are enrolled for the study. Although there are several other ways of classifying clinical trials depending on experimental design, these are broadly either Observational (where mostly behavioral/clinical data is collected with no form of physician intervention) or Interventional (where new treatments are tested and the physician intervenes to address clinical conditions).
COVID-19 Clinical Trials in India
COVID-19 has resulted in an explosion of clinical trials with over 1000 registered trials on WHO database till date with many more starting everyday. As per the national clinical trials registry, 81 trials have been registered till date in India and 7 of those are also listed with WHO. The COVID-19 clinical trials in India covers a myriad of observational and interventional measures with a combination of conventional Allopathic and alternative Ayurvedic/Homeopathic medicines. Since we are yet to find an effective drug specifically for SARS-COV-2, most of the clinical trials are focused towards repurposing existing drugs, alone or in combination with other molecules, towards efficacy testing in COVID-19 patients. Some of different categories of drugs being explored are listed here –
Anti-malarial drugs like Chloroquine and Hydroxychloroquine dominate the number of clinical trials in India (11/81) as is the case worldwide. Clinical trials evaluating the efficacy of Hydroxychloroquine as a prophylactic among healthy volunteers in tertiary care centers and healthcare workers directly exposed to COVID-19 patients have been registered in Kerala, Tamil Nadu, Karnataka and Delhi. Out of 8 interventional studies, 6 are aimed at evaluating therapeutic efficacy of Chloroquine and Hydroxychloroquine in mild to severe COVID-19 patients. National Cancer Institute at Pune has registered an interesting trial where they will be repurposing 0.03% Chloroquine eye drops generally used to treat Dry Eye Disease as Nasal drops to test for efficacy in reducing viral load among COVID-19 patients (CTRI/2020/04/024729). The principal investigator claims that using the nasal route will increase bioavalibilitty and a higher effective concentration can be achieved in the lungs using a very low initial dose of the drug (30mg/100ml).
In addition to antimalarial drugs, anti-helminthic drugs like Ivermectin and Niclosamide are also being evaluated across different hospitals in India. These drugs are usually prescribed during tapeworm (Niclosamide) or roundworm (Ivermectin) infections but have recently gained prominence as a potential therapy for COVID-19. Although their mechanisms of action are not clearly understood at this stage, the present hypothesis is that these drugs inhibit viral endocytosis and autophagy of virus infected cells as well as potentially interfere with nuclear transport of viral proteins. On the other hand, low bioavailability of these drugs remains a major challenge. South Korea has been leading research on repurposing anti-helminthic drugs for COVID-19 globally while in India, Max Super Specialty Hospital and Lady Hardinge Medical College in Delhi have initiated clinical trials.
Favipiravir, the Japanese Influenza drug, has been one of the anti-retroviral therapies in focus due to its ability in inhibiting viral RNA polymerase and preventing viral replication. In India, Glenmark has initiated a randomized clinical trial (CTRI/2020/05/025114) across 9 hospitals to test the efficacy of Favipiravir in accelerating cessation of viral shedding in COVID-19 patients. India is also part of an international consortium of 14 countries organized by WHO for conducting multicenter clinical trial evaluating a range of antiviral therapeutics like Remdesivir and Lopinavir/Ritonavir with or without Interferon (CTRI/2020/04/024773).
The BCG vaccine contains live Mycobacterium bovis and provides immunity against Tuberculosis. The non-specific immunomodulatory effect of BCG has been used in recent past in cancer immunotherapy and it has also been found to ameliorate viral infections (Curtis et al, Lancet, 2020). It has been observed that countries with routine BCG immunization had less COVID-19 cases. Although, such weak evidence from ecological reports can be merely a correlation, several countries have started investigating BCG for COVID-19. Australia and Netherlands have already started clinical trials studying the prophylactic efficacy of BCG vaccination towards COVID-19. India has gone step ahead and initiated 3 clinical trials till date for testing BCG as a possible therapy for COVID-19 patients (CTRI/2020/04/024749; CTRI/2020/04/024846; CTRI/2020/05/025013). One of these trials led by Cadila Pharmaceuticals proposes to inject heat killed Mycobacterium in critically ill COVID patients. One wonders the rationale behind such experimental design since BCG can also increase immune response and exacerbate symptoms in COVID patients.
Plasma is the liquid portion of blood that is left after separation of blood cells. Convalescent plasma is referred to as the plasma extracted from patient’s blood after that person has completely recovered from the disease. This plasma is rich in antibodies against the virus. Convalescent plasma therapy is a well established and decades old technique which have been effective in the past in treating H1N1 and SARS cases. In the limited number of clinical trials conducted so far, Convalescent plasma therapy has shown encouraging results in facilitating recovery of COVID-19 patients. India has initiated widespread clinical trials (5 till the time of this article) involving more than 30 hospitals across the country. It is estimated that plasma from one recovered COVID patient can be used to treat up to 4 critically-ill patients. With India having a very high recovery rate and almost 50,000 recovered population, Convalescent Plasms seems to be a promising approach.
Alternative Medicines – AYUSH
India is home to innumerable medicinal plants and herbs. Due to the richness of her traditional knowledge based medicines, India also has a dedicated wing of the government that investigates Ayurvedic, Unani, Siddha and Homeopathic (AYUSH) research; documenting and objectively evaluating some of these formulations. Till date, India has 28 interventional clinical trials investigating different AYUSH strategies for prophylactic and therapeutic efficacy against COVID-19. For the sake of brevity, let us look at some of the interesting studies –
Myvir and ZingiVir-H – These are both polyherbal formulations while ZingiVir contains additional minerals. Tinospora cordifolia, Zingiber officinale, Ocimum sanctum and Curcuma longa are some of the medicinal plants/herbs being used due to their potential antiviral properties. Myvir is a product of Karnataka based MiLab Lifesciences who have also sponsored the clinical trial in Bangalore Medical College. An herbal research foundation from Kerala have initiated randomized, controlled, single blinded clinical trials on their product ZingiVir-H to be carried out at Mysore Medical College.
Thymoquinone – Thymoquinone is one of major constituents of Nigella sativa (Black Cumin/ “Kala-jeera”). There are some empirical reports on possible immunomodulatory effects of Thymoquinone, attributed mostly to its quinine group. Intas pharmaceuticals is supporting a non-randomized clinical trial in Gujarat with the aim to enroll 64 COVID-19 patients to evaluate therapeutic potential of Black Cumin (CTRI/2020/05/025167).
Chyawanprash – Chyawanprash is a popular dietary supplement made by Dabur, India and found almost in every household in the country. It is made of a unique blend of herbs and spices and is believed to enhance immunity especially during flu season. Dabur has initiated a large (600 subjects), randomized but open labelled clinical trial in Ayurvedic hospitals across Maharashtra, Gujarat, and Rajasthan to evaluate the prophylactic potential of Chyawanprash against COVID-19 when given to healthy volunteers (CTRI/2020/05/024981). They do not propose to control for susceptibility of exposure which considerably weakens the study.
Arsenicum album – Homeopathic practice is widespread in India and one of the drugs that is being touted by Homeopaths for COVID-19 is Arsenicum album (made by serial dilution of Arsenic trioxide -up to a point where no traceable amount of Arsenic is present). Currently there are a couple of ongoing clinical trials involving Arsenicum album testing its prophylactic and therapeutic efficacy. The study conducted by CCRH, India has a placebo control group which will make the outcomes more reliable. The US-FDA has already warned against use of any homeopathic medication for COVID-19, but in India millions of people have been under homeopathic treatments for decades.
One of the most important yet least discussed and studied area is Mental Health. We have recently published an article showing how this pandemic has affected the mental health of working people especially health care professionals who are working long shifts, are separated from family and looking at deaths every day (For more please click here). Max Super Specialty Hospital in Delhi and Tata Memorial Center, Maharashtra are conducting observational trials to assess the psychological wellbeing, anxiety, and stress in healthcare workers. Further, yogic breathing techniques like Pranayama and meditation are also being evaluated among healthcare professionals especially nurses in JIPMER, Chandigarh for its efficacy in promoting psychological wellbeing (CTRI/2020/05/025162).
According to a recent report released by Medidata, the pandemic has adversely affected enrollment in new and ongoing clinical trials related to non-covid areas like cardiovascular (70% decrease), endocrine (80% decrease) and oncology (48% decrease). We do not have data at present to analyze how COVID-19 has impacted other clinical studies in India. However, Max Super Specialty Hospital, Delhi, has started a few observational studies to evaluate how the pandemic and national lockdown has impacted the treatment and care of adult and child cancer patients (CTRI/2020/05/025219, CTRI/2020/05/025070).
As of now, a large proportion of clinical trials in India is based on AYUSH therapies. Although, the application of alternative medicine as an immune booster and potential prophylactic should be studied, the therapeutic application of such remedies in moderate/critical COVID patients can be dangerous. Further, the non-existence of placebo control in most of these studies which are sponsored by the manufacturers themselves weaken the experimental design and raises conflict of interest concerns. On the other hand, proponents of AYUSH can argue that COVID-19 has provided the perfect opportunity to test these drugs when regulatory approvals are easy to obtain, and eligible test subjects are in abundance.
Lastly, most of these clinical trials, globally as well as nationally, lack in vitro or preclinical data with little clarity on mechanism of action. Hence, in a normal world, many of the clinical trials would not have been approved. However, drastic times call for drastic measures – we have to accept this reality and be hypervigilant about any outcome.
P.S. Search results from Clinical trial registry India using keyword “covid-19” accessed on 17th May, 2020 – https://getinsightdotblog.files.wordpress.com/2020/05/search-resultclinical-trials-registry-india-ctri.pdf
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