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
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 globally1.
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 globe2.
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 database3,4.
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 (Tables I-IV). 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 I.
Intervention | Number | Type of trial | Participant health condition |
---|---|---|---|
Modern medicine (n=42) | |||
Drug (n=28) | |||
Individual drugs | 24 | Therapeutic efficacy=19 Prophylactic efficacy=5 |
Healthy volunteers at high risk - 4 Healthy volunteers at moderate/high risk - 1 Mild COVID-19 - 5 Mild-to-moderate COVID-19 - 1 Moderate COVID-19 - 1 Moderate-to-severe COVID-19 - 2 Severe COVID-19 - 4 Severity not specified - 6 |
Combination drugs | 4 | Therapeutic efficacy=4 | Moderate COVID-19 - 1 Mild, moderate, severe COVID-19 - 1 Non-severe and severe COVID-19 - 1 Severity not specified - 1 |
Phytopharmaceutical (n=2) | |||
Phytopharmaceutical | 2 | Therapeutic efficacy=2 | Asymptomatic/mild COVID-19 - 1 Moderate COVID-19 - 1 |
Cell- and plasma-based therapies (n=9) | |||
Cell- and plasma-based therapies | 9 | Therapeutic efficacy=9 | Moderate COVID-19 - 1 Moderate-to-severe COVID-19 - 1 Severe COVID-19 - 5 Severity not specified - 2 |
Biological products (n=3) | |||
Vaccine | 3 | Therapeutic efficacy=2 Prophylactic efficacy=1 |
Healthy volunteers at high risk - 1 Moderate-to-severe COVID-19 - 1 Severe COVID-19 - 1 |
Traditional medicine (n=67) Ayurveda (n=45) | |||
Classical individual agents | 11 | Therapeutic efficacy=1 Prophylactic efficacy=10 |
Healthy volunteers at high risk - 1 Healthy volunteers in the community - 9 Asymptomatic/mild symptoms - 1 |
Classical combination preparations* | 10 | Therapeutic efficacy=4 Prophylactic efficacy=6 |
Healthy volunteers at high risk - 1 Healthy volunteers in the community - 5 Asymptomatic/mild symptoms - 3 Mild-to-moderate COVID-19 - 1 |
Patented products | 24 | Therapeutic efficacy=18 Prophylactic efficacy=6 |
Healthy volunteers at high risk - 5 Healthy volunteers in the community - 1 Asymptomatic/mild symptoms - 3 Asymptomatic/mild/moderate symptoms - 2 Mild symptoms - 4 Mild-to-moderate COVID-19 - 6 Moderate COVID-19 - 1 Moderate-to-severe COVID-19 - 1 Severe COVID-19 -1 |
Yoga (n=3) | |||
Yoga* | 3 | Therapeutic efficacy=2 Stress management=1 |
Healthy volunteers at high risk - 1 Asymptomatic/mild symptoms - 1 Asymptomatic/uncomplicated illness/mild pneumonia - 1 |
Unani (n=2) | |||
Unani | 2 | Prophylactic efficacy=2 | Healthy volunteers at risk - 2 |
Siddha (n=3) | |||
Siddha | 3 | Therapeutic efficacy=2 Prophylactic efficacy=1 |
Healthy volunteers in community and healthcare workers - 1 Asymptomatic - 1 Asymptomatic/mild/moderate symptoms - 1 |
Homeopathy (n=14) | |||
Homeopathy | 14 | Therapeutic efficacy=8 Prophylactic efficacy=6 |
Healthy volunteers in community - 3 Healthy volunteers at high risk - 3 Asymptomatic - 1 Asymptomatic/mild symptoms - 1 Mild - 4 Moderate - 1 Mild/moderate/severe symptoms - 1 |
Miscellaneous (n=13) | |||
Miscellaneous | 13 | Therapeutic efficacy=2 Prophylactic efficacy=1 Process-of-care changes=9 Diagnostic=1 |
Healthy volunteers - 4 Severe COVID-19 - 1 Severity not specified - 4 Other (non-COVID-19) - 4 |
#Registered trials as on June 5, 2020; *Two Ayurveda classical combination trials included yoga and one yoga trial included Ayurveda interventions. In addition, one Ayurveda trial was in combination with homeopathy and one miscellaneous trial with combination of modern medicine, Ayurveda and homeopathy
Table IV.
Serial number | CTRI number | Intervention details | Study design | Blinding | Phase | Sample size | Primary outcome | Sponsor and regulatory status | States and UTs |
---|---|---|---|---|---|---|---|---|---|
1 | CTRI/2020/05/025248 | Arm 1: Brief tele-counselling model for coping with psychological concerns associated with COVID-19 | Non-randomized, multiple-arm trial | N/A | N/A | 128 | Anxiety (assessed as a continuous variable on HADS) | PI initiated, MB Hospital RNT Medical College Udaipur DCGI approval: N/A | RJ |
2 | CTRI/2020/05/025492 | Arm 1: Tele-consultation Arm 2: Standard arm with routine follow up visits |
Randomized, parallel-group trial | Open label | N/A | 2978 | Need for emergency room visit or re-hospitalization | JIPMER, Puducherry DCGI approval: N/A |
PY |
3 | CTRI/2020/05/025331 | Arm 1: Home-based prehabilitation | Non-randomized, active controlled trial | NIL | N/A | 15 | Change in emotional functioning by DASS-21, physical functioning by change in performance score (Karnofsky Performance Scale) score and change in respiratory functional parameters | AIIMS, New Delhi DCGI approval: N/A |
DL |
4 | CTRI/2020/05/024962 | Arm 1: Povidone-iodine gargles and intranasal application Arm 2: Normal saline |
Randomized, parallel-group trial | N/A | N/A | 96 | Comparing the reduction in the progression, transmission of disease assessed by viral load | Win Medicare Pvt Ltd, Vijaywada DCGI approval: N/A |
AP |
5 | CTRI/2020/05/024983 | Arm 1: Topical lignocaine lozenges | Single-arm trial | N/A | N/A | 30 | Sensitivity of nasal and throat swabs for RT-PCR of COVID-19 after topical lignocaine use | AIIMS, New Delhi DCGI approval: N/A |
DL |
6 | CTRI/2020/04/024776 | Arm 1: Chest X-ray artificial intelligence module Arm 2: CT- scan of thorax AI module Arm 3: Voice sampling AI module Arm 4: Normal individuals’ chest X-ray, CT-scan thorax and voice sampling |
Non-randomized, multiple-arm trial | N/A | N/A | 1650 | Assess sensitivity and specificity of AI module by performing chest X-ray, CT-thorax and voice sampling | PI initiated RNT Medical College, Udaipur DCGI approval: N/A |
RJ (2 sites) |
7 | CTRI/2020/05/025071 | Arm 1: Lowest driving pressure-guided PEEP Arm 2: Conventional lung protective ventilation strategy |
Randomized, parallel-group trial | Participant blinded | Phase 3 | 40 | Difference in the area under the curve (adjusted to survival time) for Murray’s lung injury score in the first 4 days | AIIMS, New Delhi DCGI approval: N/A |
DL |
8 | CTRI/2020/05/025489 | Arm 1: CMAC video laryngoscope Arm 2: McGrath MAC video laryngoscope |
Randomized, parallel-group trial | Participant and outcome assessor blinded | N/A | 60 | Time to intubation | AIIMS, New Delhi DCGI approval: N/A |
DL |
9 | CTRI/2020/06/025522 | Arm 1: Touren non-channelled video laryngoscope Arm 2: King Vision channelled video laryngoscope |
Randomized, cross-over trial | Outcome assessor blinded | N/A | 50 | Time to intubation | AIIMS, New Delhi DCGI approval: N/A | DL |
10 | CTRI/2020/06/025589 | Arm 1: COVID barrier box with Ambu King vision video laryngoscope Arm 2: COVID barrier box with Macintosh laryngoscope |
Randomized, parallel-group, active controlled trial | NIL | N/A | 60 | Intubation time | AIIMS, Bhubaneswar DCGI approval: N/A | OR |
11 | CTRI/2020/04/024747 | Arm 1: Simulation-based training of ventilatory management of COVID-19 patients | Single-arm trial | Participant and outcome assessor blinded | N/A | 26 | Prepare a module for non-anaesthesiology trainees to handle ventilators in COVID-19 patients | GSL Medical College, Rajahmundry DCGI approval: N/A |
AP |
12 | CTRI/2020/05/025490* | Arm 1: Chlopromazine + NBE extract concoction + cholecalciferol + Azadirachta indica bark extract concoction + Arsenicum album + tea + Arm 2: Standard treatment | Randomized parallel-group active controlled trial | Participant and investigator blinded | Phase 2/3 | 110 | Protection from COVID-19 infection | Siddhartha Hospital, Agra DCGI approval: N/A |
UP |
13 | CTRI/2020/04/024659 | Arm 1: Shreepad Shree Vallabh formulation | Single-arm trial | N/A | Phase 3 | 30 | Improvement in symptoms of ambulatory patients which include cough, fever with or without chills and difficulty in breathing | SSV Phytopharmaceuticals, Mumbai DCGI approval: N/A |
MH |
#Registered trials as on June 5, 2020, *Combination trials with modern medicine, Ayurveda and homeopathy. Table data are as per information provided by trialist. AIIMS, All India Institute of Medical Sciences; COVID-19, coronavirus disease 2019; JIPMER, Jawaharlal Institute of Postgraduate Medical Education and Research; MB Hospital RNT Medical College, Maharana Bhupal Hospital, Ravindra Nath Tagore Medical College; PI, principal investigator; AI, artificial intelligence; DCGI, Drugs Controller General of India; N/A, not applicable; HADS, hospital anxiety and depression scale; DASS-21, depression, anxiety and stress scale 21 items; RT-PCR, reverse transcription-polymerase chain reaction. States and Union Territories (UTs): AP: Andhra Pradesh; AR: Arunachal Pradesh; AS: Assam; BR: Bihar; CG: Chhattisgarh; GA: Goa; GJ: Gujarat; HR: Haryana; HP: Himachal Pradesh; JK: Jammu and Kashmir; JH: Jharkhand; KA: Karnataka; KL: Kerala; MP: Madhya Pradesh; MH: Maharashtra; MN: Manipur; ML: Meghalaya; MZ: Mizoram; N: Nagaland; OR: Odisha; PB: Punjab; RJ: Rajasthan; SK: Sikkim; TN: Tamil Nadu; TR: Tripura; UK: Uttarakhand; UP: Uttar Pradesh; WB: West Bengal; TS: Telangana; AN: Andaman and Nicobar Islands; CH: Chandigarh; DH: Dadra and Nagar Haveli; DD: Daman and Diu; DL: Delhi; LD: Lakshadweep; PY: Puducherry
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 I). 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 (Tables II-IV). 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.
Table II.
Serial number | CTRI number | Intervention details | Study design | Blinding | Phase | Sample size | Primary outcome | Sponsor and regulatory status | States and UTs |
---|---|---|---|---|---|---|---|---|---|
Drug trials (n=28) | |||||||||
Antivirals | |||||||||
1 | CTRI/2020/04/024773* Solidarity trial | Arm 1: Remdesivir and standard treatment Arm 2: Chloroquine or HCQ and standard treatment Arm 3: Lopinavir with ritonavir Arm 4: Lopinavir with ritonavir plus interferon and standard treatment Arm 5: Standard treatment |
Randomized, parallel-group, multiple-arm trial | Open label | Phase 3 | 1500 | All-cause mortality, subdivided by the severity of disease at the time of randomization, measured using patient records throughout the study | WHO and ICMR, New Delhi DCGI approval: Yes | RJ (2 sites), MP (2 sites), DL, TN (5 sites), MH (7 sites), GJ (4 sites), TS, GJ, AP |
2 | CTRI/2020/06/025575* | Arm 1: HCQ, ribavirin, standard treatment (NS) Arm 2: HCQ, ribavirin, standard treatment (S) Arm 3: Lopinavir, ritonavir, ribavirin, standard treatment (S) Arm 4: Standard treatment (NS) Arm 5: Standard treatment |
Randomized, parallel-group, multiple-arm trial | Open label | Phase 3/Phase 4 | 175 | 1. Time to clinical recovery 2. Time to 2019-nCoV RT-PCR negativity in upper respiratory tract specimen | AIIMS, Rishikesh DCGI approval: N/A | UK |
3 | CTRI/2020/05/025114 | Arm 1: Favipiravir Arm 2: Standard treatment |
Randomized, parallel-group trial | Open label | Phase 3 | 150 | Time until cessation of oral shedding of SARS-CoV-2 virus (time frame: up to 28 days) (time in days from randomization to a negative SARS-CoV-2 RT-PCR result of both oropharyngeal swab and nasopharyngeal swab) | Glenmark Pharmaceuticals Ltd, Mumbai DCGI approval: Yes | CG, MH (7 sites), GJ (3 sites), DL |
Antimalarials | |||||||||
4 | CTRI/2020/04/024479 | Arm 1: Chloroquine phosphate Arm 2: Standard treatment |
Randomized, parallel-group trial | Open label | N/A | 32 | Number of days of hospitalization | Command Hospital Airforce, Bengaluru DCGI approval: N/A | KA |
5 | CTRI/2020/04/024729 | Arm 1: Topical chloroquine and standard treatment Arm 2: Standard treatment |
Other | Open label | Phase 2 | 60 | 1. The Ct values on days 0, 3, 7, 10 shall be plotted on a graph for all patients. 2. The rate of decline for each patient shall be calculated. The time to cure (COVID-19 RT PCR -ve) shall be determined. 3. The two groups shall be compared for (i) rate of decline of Ct values; (ii) time to cure; (iii) rate of cure or alternate outcome |
AIIMS New Delhi DCGI approval: N/A | HR |
6 | CTRI/2020/03/024402 | Arm 1: HCQ Arm 2: HCQ (ICMR regimen) |
Randomized, parallel-group, active controlled trial | Open label | Phase 3 | 500 | Infected non-infected | PI initiated, Aster Malabar Institute of Medical Sciences, Kozikhode DCGI approval: N/A | KL |
7 | CTRI/2020/05/025022 | Arm1: HCQ Arm 2: Standard treatment |
Other | Open label | Phase 2 | 166 | Progression to moderate-to-severe disease | AIIMS, New Delhi DCGI approval: N/A |
DL |
8 | CTRI/2020/05/025067 | Arm 1: HCQ along with standard treatment Arm 2: Standard treatment |
Randomized, parallel-group trial | Open label | N/A | 6950 | Laboratory-confirmed symptomatic COVID-19 cases | George Institute for Global Health India, New Delhi DCGI approval: N/A | TN, KA, DL |
9 | CTRI/2020/04/024904* | Arm 1: HCQ Arm 2: HCQ (high dose) Arm 3: HCQ and Azithromycin |
Randomized, parallel group trial | Participant and outcome assessor blinded | Phase 3 | 300 | 1. Death 2. Hospitalized on invasive mechanical ventilation or extracorporeal mechanical ventilation 3. Hospitalized on non-invasive ventilation or high-flow nasal cannula oxygen therapy 4. Hospitalized on supplemental oxygen 5. Hospitalized not on supplemental oxygen 6. Not hospitalized with limitation of activity (due to continued symptoms) 7. Not hospitalized without limitation in activity (no symptoms) |
Armed Forces Medical Services, New Delhi DCGI approval: N/A | UP (4 sites), DL, GJ |
10 | CTRI/2020/05/025242 | Arm 1: HCQ | Other | N/A | N/A | 400 | Pharmacokinetics of HCQ | ICMR, New Delhi DCGI approval: N/A | MH |
Immunomodulators | |||||||||
11 | CTRI/2020/04/024948* | Arm 1: Ciclesonide Arm 2: HCQ Arm 3: Ivermectin Arm 4: Standard treatment |
Randomized, parallel-group trial | N/A | Phase 2 | 120 | Proportion of patients having virologic cure on day 6 in each of the groups | Lady Hardinge Medical College, New Delhi DCGI approval: N/A | DL |
12 | CTRI/2020/04/024806 | Arm 1: Imatinib Arm 2: Standard treatment |
Randomized, parallel-group trial | Open label | Phase 2 | 100 | 1. Proportion of patients with negative viral titre on day 7 2. Proportion of patients with negative viral titre on day 14 |
AIIMS New Delhi DCGI approval: N/A | DL |
13 | CTRI/2020/05/024959 | Arm 1: Itolizumab, Arm 2: Standard treatment |
Randomized, parallel-group, active controlled trial | Open label | Phase 2 | 30 | One-month mortality rate | Biocon Biologics India Limited, Bengaluru DCGI approval: Yes | DL (3 sites), MH (3 sites), KA |
14 | CTRI/2020/05/025369 | Arm 1: Tocilizumab and standard treatment Arm 2: Standard treatment |
Randomized, parallel-group, active controlled trial | Open label | Phase 3 | 180 | Proportion showing progressive COVID-19 disease from moderate to severe, or from severe disease to death | Medanta Institute of Education and Research, Gurgaon DCGI approval: Yes | TS, TN, MH (3 sites), HR (4 sites) DL, UP (2 sites) |
15 | CTRI/2020/04/024846 | Arm 1: Mycobacterium w and standard treatment Arm 2: Placebo and standard treatment |
Randomized, parallel-group, placebo-controlled trial | Participant, investigator and outcome assessor blinded | N/A | 40 | Improvement in organ dysfunction (or occurrence of new organ dysfunction) based on change in SOFA score and ordinal scale | Cadila Pharmaceuticals Limited, Ahmedabad DCGI approval: Yes | CG, MP, DL, CH |
16 | CTRI/2020/05/025271 | Arm 1: Mycobacterium w and standard treatment Arm 2: Placebo and standard treatment |
Randomized, parallel-group, placebo-controlled trial | Participant, investigator and outcome assessor blinded | Phase 3 | 480 | Number of patients with increased disease severity | Cadila Pharmaceuticals Limited, Ahmedabad DCGI approval: Yes | DL, MP, CH |
17 | CTRI/2020/05/025277 | Arm 1: Mycobacterium w
Arm 2: Placebo |
Randomized, parallel-group, placebo-controlled trial | Participant, investigator and outcome assessor blinded | Phase 3 | 4000 | Numder of individuals acquiring COVID-19 infection | Cadila Pharmaceuticals Limited, Ahmedabad DCGI approval: Yes | MP, CG, DL, CH |
18 | CTRI/2020/05/025350 | Arm 1: Mycobacterium w, (heat killed) | Single-arm trial | Open label | Phase 2 | 50 | Clinical improvement, as defined by live discharge from the hospital, a decrease of at least two points from baseline on a modified ordinal scale. Conversion of COVID-19 status to negative | R D Gardi Medical College, Ujjain DCGI approval: N/A | MP |
19 | CTRI/2020/06/025613 | Arm 1: Melatonin Arm 2: Placebo |
Randomized, parallel-group, placebo-controlled trial | Participant and investigator blinded | Phase 4 | 200 | SARS-CoV-2 infection rate | PI initiated, AIIMS Rishikesh DCGI approval: N/A |
UK |
Anthelmintics | |||||||||
20 | CTRI/2020/04/024858 | Arm 1: Ivermectin and standard treatment Arm 2: Standard treatment |
Non-randomized, active controlled trial | Open label | N/A | 50 | Confirm the antivirus effectiveness of ivermectin on coronavirus i.e., COVID-19 then to explore its potential use in the combating to the COVID-19 pandemic | Max Super Speciality Hospital, New Delhi DCGI approval: N/A | DL |
21 | CTRI/2020/05/025068 | Arm 1: Ivermectin Arm 2: Standard treatment |
Randomized, parallel-group, active controlled trial | Open label | 50 | Reduction in the viral load in patients with haematological illnesses who are admitted with COVID-19 infection | Christian Medical College, Vellore DCGI approval: N/A | TN | |
22 | CTRI/2020/05/025224 | Arm 1: Ivermectin, and standard treatment Arm 2: Standard treatment |
Randomized, parallel-group trial | Open label | Phase 2 | 50 | Effect of ivermectin on eradication of virus. Test for virus at 1, 3 and 5 days from beginning of trial drug started for the patient in the hospital | RD Gardi Medical College, Ujjain DCGI approval: N/A | MP |
23 | CTRI/2020/05/025333 | Arm 1: Ivermectin Arm 2: No intervention |
Randomized, parallel-group trial | Open label | Phase 2 | 2000 | 1. Resolution of sign and symptoms of COVID-19 2. Negative RT-PCR done 48 h after ivermectin dose 3. Change/reduction in Ct value as reported in RT-PCR for SARS-CoV-2 virus assay |
R D Gardi Medical College, Ujjain DCGI approval: N/A | MP |
24 | CTRI/2020/04/024949 | Arm 1: Niclosamide Arm 2: Standard treatment |
Randomized, parallel-group trial | N/A | Phase 2 | 48 | Proportion of patients having virologic cure on day 6 | Lady Hardinge Medical College, New Delhi DCGI approval: N/A | DL |
Antihypertensive | |||||||||
25 | CTRI/2020/05/025319 | Arm 1: Losartan Arm 2: Placebo | Randomized, parallel-group, placebo-controlled trial | Participant and investigator blinded | Phase 3 | 186 | Percentage of patient with treatment failure: (i) fall in 1 score in Respiratory SOFA score; (ii) new requirement of respiratory assist devices (HFNC, NIV); (iii) new requirement of mechanical ventilation; (iv) mortality | SGPGI, Lucknow DCGI approval: N/A | UP |
Antioxidant/pro-oxidant | |||||||||
26 | CTRI/2020/05/025336 | Arm 1: Resveratrol-copper and standard treatment Arm 2: Sodium-copper- chlorophyllin and standard treatment Arm 3: Standard treatment |
Randomized, parallel-group, multiple-arm trial | Open label | Phase 3 | 300 | Proportion of patients who suffer clinical deterioration OR viral persistence at day 10 from the date of randomization (excluding the date of randomization) | Tata Memorial Centre, Mumbai DCGI approval: N/A | MH |
27 | CTRI/2020/05/025337 | Arm 1: Resveratrol-copper tablets, and standard treatment Arm 2: Sodium-copper- chlorophyllin and standard treatment Arm 3: Standard treatment |
Randomized, parallel-group, multiple-arm trial | Open label | Phase 2 | 200 | Time to clinical improvement, defined as a 2-point improvement on a 7-point ordinal scale | Tata Memorial Centre, Mumbai DCGI approval: N/A | MH |
Antineoplastic | |||||||||
28 | CTRI/2020/06/025664 | Arm 1: 2-deoxy-D-glucose and standard treatment Arm 2: Standard treatment |
Randomized, parallel-group, active controlled trial | Open label | Phase 2 | 40 | Time to clinical improvement | Dr Reddys Laboratories Limited, Hyderabad and INMAS, DRDO, Delhi DCGI approval: Yes | DL (2 sites), KA, TN, UP (2 sites), MH (4 sites), AP, GJ Phytopharmaceuticals (n=2) |
29 | CTRI/2020/05/025397 | Arm 1: Purified AQCH and standard treatment Arm 2: Standard treatment |
Randomized, parallel-group trial | Open label | Phase 2 | 210 | Proportion of patients showing clinical improvement. Clinical improvement defined as patient meeting discharge criteria OR a 2-point improvement (from time of enrolment) in disease severity rating on the 7-point ordinal scale |
Sun Pharmaceutical Industries Limited, Goregaon, Mumbai DCGI approval: Yes | CG, MH (6 sites), MP, TS, UP, HR, JK, DL, TN |
30 | CTRI/2020/05/025167 | Arm 1: Thymoquinone and standard treatment Arm 2: Standard treatment |
Non-randomized active controlled trial | Open label | Phase 2 | 100 | Characterize virologic and clinical response | Intas Pharmaceuticals Ltd, Ahmedabad DCGI approval: N/A | GJ (3 sites) |
Cell and plasma based therapies (n=9) | |||||||||
31 | CTRI/2020/04/024775 PLACID trial | Arm 1: Convalescent plasma Arm 2: Standard treatment |
Randomized, parallel-group, active controlled trial | N/A | Phase 2 | 452 | Composite measure of the avoidance of : (i) progression to severe ARDS (P/F ratio 100) or (ii) all-cause mortality at 28 days | ICMR, New Delhi DCGI approval: Yes | MH (7 sites), BR, MP (3 sites), TS (2 sites) GJ (6 sites), KA (4 sites), PY, UP (4 sites), DL, TN (5 sites), HR, CH, PB, RJ (2 sites) |
32 | CTRI/2020/04/024706 | Arm 1: Convalescent plasma and standard treatment Arm 2: Random donor plasma and standard treatment |
Randomized, parallel-group, active controlled trial | Open label | Phase 2 | 40 | Proportion of patients remaining free of mechanical ventilation in both groups | Institute of Liver and Biliary Sciences, New Delhi DCGI approval: Yes | DL (2 sites) |
33 | CTRI/2020/04/024915 | Arm 1: Convalescent plasma Arm 2: Standard treatment |
Randomized, parallel-group trial | Open label | Phase 2 | 100 | The primary outcome was a composite measure of the avoidance of : (i) progression to severe ARDS (P/F ratio 100) and (ii) all-cause mortality at 28 days | Max Super Speciality Hospital, New Delhi DCGI approval: Yes | DL |
34 | CTRI/2020/04/024804 | Arm 1: Convalescent plasma along with standard treatment Arm 2: Standard treatment |
Non-randomized, active controlled trial | N/A | Phase 1/2 | 24 | Safety, efficacy, side effects measured by chest radiograph. Improvement of clinical symptoms including duration of fever, respiratory distress, pneumonia, cough, sneezing, and diarrhoea within three days of the convalescent plasma transfusion | International Stemcell Services Ltd, Bengaluru DCGI approval: Yes | KA (2 sites) |
35 | CTRI/2020/05/025299 | Arm 1: Convalescent plasma Arm 2: Standard treatment |
Randomized, parallel-group trial | Open label | Phase 2 | 20 | Avoidance of progression to severe ARDS | Wockhardt Ltd, Mumbai DCGI approval: Yes |
MH |
36 | CTRI/2020/05/025346 | Arm 1: Convalescent plasma and standard treatment Arm 2: Standard treatment |
Randomized, parallel-group trial | N/A | N/A | 90 | Progression to severe ARDS (P/F ratio 100) and all-cause mortality at one month | Government of Tamil Nadu DCGI approval: Yes |
TN |
37 | CTRI/2020/05/025328 | Arm 1: Convalescent plasma Arm 2: Standard treatment |
Randomized, parallel-group, active controlled trial | N/A | Phase 2 | 100 | Composite measure of the (i) all-cause mortality at 28 days; (ii) improvement of SOFA score post transfusion | Apollo Hospitals Enterprise Limited, New Delhi DCGI approval: Yes | WB, TS, MH, TN, DL |
38 | CTRI/2020/05/025209 | Arm 1: Convalescent plasma Arm 2: Standard treatment |
Randomized, parallel-group trial | Open label | Phase 2 | 80 | 1. All-cause mortality 2. To identify the immune correlates for response to plasma therapy |
CSIR, New Delhi DCGI approval: Yes | WB |
39 | CTRI/2020/05/025432 | Arm 1: Cytokine cocktail therapy | Single-arm Trial | Open label | Phase 1 | 6 | Safety of cytokine cocktail therapy | International Stemcell Services Ltd, Bengaluru DCGI approval: Yes | KA |
Biological products (n=3) | |||||||||
Vaccines | |||||||||
40 | CTRI/2020/04/024749 | Arm 1: Recombinant BCG vaccine - VPM1002 Arm 2: Placebo |
Randomized, parallel-group, placebo controlled trial | Participant, investigator, outcome assessor and date-entry operator blinded | Phase 3 | 5946 | 1. Number of individuals with laboratory-confirmed COVID-19 infection 2. Number of individuals with laboratory-confirmed COVID-19 infection among other high risk individuals 3. Number of laboratory-confirmed COVID-19 infection with severe, critical or life-threatening disease as assessed by investigator among HCWs 4. Number of laboratory-confirmed COVID-19 infection with severe, critical or life-threatening disease as assessed by investigator among other high-risk individuals |
Serum Institute of India Pvt Ltd, Pune DCGI approval: Yes | OR, CG, MH (17 sites), DL (4 sites), GA, KL, AP, UP, WB, CH, HR, RJ, GJ, TN, KA (2 sites) |
41 | CTRI/2020/04/024833 | Arm 1: BCG-Denmark (Green Signal) Arm 2: Placebo |
Randomized, parallel-group, placebo controlled trial | Participant, investigator, outcome assessor and date-entry operator blinded | N/A | 1826 | Proportion of HCW with symptomatic COVID-19 disease | PI initiated, JIPMER, Puducherry DCGI approval: N/A | PY |
42 | CTRI/2020/05/025013 | Arm 1: BCG Arm 2: Saline plus standard treatment |
Non-randomized, active controlled trial | Participant blinded | Phase 2 | 60 | 1. Total duration of hospitalization with COVID-19 symptoms 2. Decrease in viral titre 3. Duration of COVID-19 symptoms |
Medical Education and Drugs Department, Mumbai DCGI approval: Yes | MH |
#Registered trials as on June 5, 2020, *Combination therapy trials are mentioned in only one category to avoid duplication. Table data are as per information provided by trialist. The keyword ‘Standard treatment’ has been used for uniformity and includes the following category as mentioned by the trialist i.e., standard of care, standard care of treatment and supportive management, standard treatment protocol, local-level standard treatment, best supportive care and treatment guidelines as per MoHFW. COVID-19, coronavirus disease 2019; AIIMS, All India Institute of Medical Sciences; ICMR, Indian Council of Medical Research, INMAS, Institute of Nuclear Medicine and Allied Sciences; DRDO, Defence Research and Development Organisation; HCQ, Hydroxychloroquine; R D Gardi Medical College, Ruxmaniben Deepchand Gardi Medical College; SGPGI, Sanjay Gandhi Postgraduate Institute of Medical Sciences; CSIR, Council of Scientific and Industrial Research; WHO, World Health Organization. PI, Principal investigator; N/A, not applicable; AQCH, aqueous extract of Cocculus hirsutus; CTRI, Clinical Trials Registry - India; HCQ, healthcare workers; RT-PCR, reverse transcription-polymerase chain reaction; SOFA, sequential organ failure assessment; NS, non-severe; S, severe; Ct, cycle threshold. States and Union Territories (UTs): AP: Andhra Pradesh; AR: Arunachal Pradesh; AS: Assam; BR: Bihar; CG: Chhattisgarh; GA: Goa; GJ: Gujarat; HR: Haryana; HP: Himachal Pradesh; JK: Jammu and Kashmir; JH: Jharkhand; KA: Karnataka; KL: Kerala; MP: Madhya Pradesh; MH: Maharashtra; MN: Manipur; ML: Meghalaya; MZ: Mizoram; N: Nagaland; OR: Odisha; PB: Punjab; RJ: Rajasthan; SK: Sikkim; TN: Tamil Nadu; TR: Tripura; UK: Uttarakhand; UP: Uttar Pradesh; WB: West Bengal; TS: Telangana; AN: Andaman and Nicobar Islands; CH: Chandigarh; DH: Dadra and Nagar Haveli; DD: Daman and Diu; DL: Delhi; LD: Lakshadweep; PY: Puducherry
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 I). 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 II, these are briefly discussed below.
Drug trials
Antivirals
Solidarity trial: The Solidarity trial is an international clinical trial initiated by the WHO to help find an effective treatment for COVID-195. 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 viruses6. 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).
Antimalarials
During this pandemic time, chloroquine and HCQ have generated much interest in the global community as potential therapeutic agents against COVID-197. An open-label non-randomized trial showed that HCQ - azithromycin was associated with viral load reduction in COVID-19 patients8.
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 workers9. 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 arrhythmias7, 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).
Immunomodulators
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 leukaemia10. 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 cells11,12. 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 cells13,14. 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-1915. 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-AIDS16,17. 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 well18. Melatonin has also been reported to possess significant immunomodulatory effects in cancer19. 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).
Anthelmintics
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-220. 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 activity21,22. 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).
Antihypertensive
Losartan: Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for SARS-CoV-2 infection and in the process causes internalization and destruction of ACE223. 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 losartan24. 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).
Antioxidant/pro-oxidant agent
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 sepsis25. The novel pro-oxidant combination of resveratrol and copper has been reported to inactivate cfCh and demonstrated improved survival in animal models of sepsis26.
The commonly used food colorant and dietary supplement, sodium copper chlorophyllin (SCC), has been reported to have significant antimutagenic and antioxidant properties27. 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).
Antineoplastic
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 morbidity28. Recent in vitro studies suggest the potential benefits of using 2-DG to mitigate COVID-19 infection29,30. 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 infection31. The trial is proposed to be conducted at 14 sites across the country on patients with moderate COVID-19 (CTRI/2020/05/025397).
Thymoquinone
Nigella sativa, commonly known as black cumin, has shown a wide spectrum of biological activities, the most prominent being antioxidant, anti-inflammatory and antimicrobial activities32. 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 epidemics33,34,35. 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
Vaccines
As per reports, vaccine against COVID-19 is being developed in about 90 institutions worldwide36. 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 rates37. In India, mass immunization with BCG has been underway since 194838. The global interest in BCG was recently sparked when Miller et al39, 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 care40. 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 III).
Table III.
Serial number | CTRI number | Intervention details | Study design | Blinding | Phase | Sample size | Primary outcome | Sponsor and regulatory status | States and UTs |
---|---|---|---|---|---|---|---|---|---|
Ayurveda (n=45) | |||||||||
Classical (n=21) | |||||||||
Individual agents (n=11) | |||||||||
1 | CTRI/2020/06/025525 | Arm 1: Guduchi Ghana Vati
Arm 2: Nil |
Other | Open label | N/A | 20000 | Incidence rate of COVID-19 infection | IPGTRA, Jamnagar DCGI approval: N/A | GJ (5 sites) |
2 | CTRI/2020/05/025488 | Arm 1: Guduchi Ghana Vati
Arm 2: Nil |
Randomized, parallel-group trial | Open label | Phase 2/3 | 12000 | Comparative assessment of incidence of COVID-19 | NIA, Jaipur DCGI approval: N/A | RJ |
3 | CTRI/2020/05/025485 | Arm 1: Guduchi Ghana Vati
Arm 2: Standard prophylactic care |
Non-randomized, active controlled trial | Open label | Phase 2/3 | 5000 | Comparative assessment of occurrence of COVID-19 infection | NIIMH (CCRAS), Hyderabad DCGI approval: N/A | TS |
4 | CTRI/2020/05/025385 | Arm 1: Guduchi Ghan Vati
Arm 2: Standard prophylactic care |
Non-randomized, multiple-arm trial | N/A | N/A | 40000 | Comparative assessment of occurrence of COVID-19 infection | CCRAS, New Delhi DCGI approval: N/A | WB, PB, TN, KL (2 sites), MH (2 sites), NL, MP, RJ (2 sites), UP, AS, BR (2 sites), KA, HP, GJ (2 sites), AP |
5 | CTRI/2020/05/025370 | Arm 1: Guduchi Ghana Vati | Single-arm trial | Open label | N/A | 40 | Clinical cure rate: Time to get a negative status of COVID-19 | Ayurved University, Jodhpur DCGI approval: N/A | RJ (2 sites) |
6 | CTRI/2020/05/025213 | Arm 1: Guduchi Ghana Vati | Single-arm trial | N/A | N/A | 1500 | Incidence of COVID-19-positive cases as confirmed by RT-PCR | CCRAS, New Delhi DCGI approval: N/A | HP |
7 | CTRI/2020/05/025088 | Arm 1: Guduchi
Arm 2: Standard prophylactic care |
Randomized, parallel-group trial | N/A | Phase 1/2 | 1200 | Comparative assessment of occurrence of COVID-19 infection in healthy volunteers | CCRAS, New Delhi DCGI approval: N/A | AP |
8 | CTRI/2020/05/025429 | Arm 1: Ashwagandha + standard prophylactic care Arm 2: Standard prophylactic care |
Non-randomized, active controlled trial | Open label | Phase 2/3 | 5000 | Comparative assessment of occurrence of COVID-19 infection | NIIMH (CCRAS), Hyderabad DCGI approval: N/A | TS |
9 | CTRI/2020/05/025332 | Arm 1: Ashwagandha
Arm 2: HCQ |
Randomized, parallel-group, active controlled trial | Open label | Phase 2 | 400 | (i) Proportion of SARS- CoV-2 infection-free participants on completion of study (ii) Proportion of participants contracting COVID-19 during the study period |
Ministry of AYUSH; CSIR, New Delhi DCGI approval: N/A | MH |
10 | CTRI/2020/05/025166 | Arm 1: Ashwagandha | Randomized, parallel-group trial | Open label | Phase 2/3 | 1200 | Comparative assessment of occurrence of COVID-19 infection | Ministry of AYUSH, New Delhi DCGI approval: N/A | AP |
11 | CTRI/2020/05/025093 | Arm 1: Yashtimadhu | Other | N/A | Phase 2/3 | 1200 | Comparative assessment of occurrence of COVID-19 infection | Ministry of AYUSH, New Delhi DCGI approval: N/A | AP |
Combination interventions (n=10) | |||||||||
12 | CTRI/2020/05/025171 | Arm 1: Guduchi Ghana Vati
2.Anu taila 3.Rock salt and turmeric 4. Ayush preventive guidelines Arm 2: Standard prophylactic care |
Randomized, parallel-group trial | Open label | Phase 2 | 50000 | Improvement in bala of an individual Immuno-stimulation leading to non-development of symptoms of COVID-19 in risk population exposed to infected individuals (Bala will be assessed by using specialized proforma including dasvidhapareeksha and other questionnaires which will reveal the physical and mental health of an individual) |
AIIA, New Delhi DCGI approval: N/A | DL |
13 | CTRI/2020/05/025069 | Arm 1: Guduchi Ghana Vati (Sanshamani Vati) or Sudarshana Ghanavati or Ashwagandha | Single-arm trial | Open label | Phase 3/4 | 1324 | Incidence of COVID-19- positive cases (as confirmed by RT-PCR) | CCRAS, New Delhi DCGI approval: N/A | DL (3 sites) |
14 | CTRI/2020/05/025482 | Arm 1: Curcumin with black pepper Arm 2: Standard treatment |
Randomized, parallel-group trial | Investigator blinded | N/A | 50 | COVID-19 test and acute phase reactants such as D-dimer, CRP, LDH, CBC, ferritin, troponin, cardiac myoglobin, PT INR and appearance of respiratory symptoms | Siddhivinayak Pain Relief Center, Pune DCGI approval: N/A | MH |
15 | CTRI/2020/06/025637 | Arm 1: Piper betel with the combination of swarnabhasma (herbomineral combination) | Cluster randomized trial | Participant and investigator blinded | N/A | 10 | Complete blood picture, serum ferritin, C-reactive protein, LDH, troponin, nucleic acid amplification test and RT-PCR | ABVGMC, Vidisha DCGI approval: N/A | MP |
16 | CTRI/2020/05/025341* | Arm 1: Kiratiktadi Kwath; Ashwagandha churna; Yoga exercises; immunobooster Ayush Kwath
Arm 2: Standard treatment |
Randomized, parallel-group trial | N/A | N/A | 30 | Efficacy in the management of mild and asymptomatic cases of COVID-19 patients | GS Ayurveda Medical College and Hospital, Ghaziabad DCGI approval: N/A | UP |
17 | CTRI/2020/04/024731* | Arm 1: Samshamani Vati, Sudarshan Ghana Vati, Khadiradi Vati, Murrchhita Tila Taila (for Nasya, Arsenic Album 30 | Single-arm trial | Open label | Phase 3 | 50 | Episodes and severity of symptoms of respiratory tract infection (cold, sore throat, dry cough, breathlessness) | Parul Institute of Ayurved, Vadodara DCGI approval: N/A | GJ |
18 | CTRI/2020/04/024882 | Arm 1: Kashaya (decoction) of Tinospora cordifolia stem Piper longum fruit, and standard treatment Arm 2: Standard treatment |
Non-randomized, active controlled trial | N/A | Phase 3 | 60 | 1. Percentage of patients progressing to serious/critical stage of disease 2. Progress of disease as per clinical severity score (COCSS) 3. Number of days of treatment, hospitalization, type of care and site of treatment at hospital, oxygen support requirement, days of ventilation required, period of convalescence and return to normal life activity 4. Number of days taken to test negative for COVID, total days to discharge from hospital 5. Profiling according to tridosha 6. Defining the disease according to Ayurveda |
Ministry Of AYUSH, New Delhi DCGI approval: N/A | HR |
19 | CTRI/2020/05/025178 | Arm 1: Tab Samshamani Vati; Herbal tea; application of Anu taila; Haridra khanda
Arm 2: Standard prophylactic care |
Randomized, parallel-group trial | Open label | Phase 2 | 140 | Improvement in bala of an individual Bala will be assessed by using specialised proforma including dashavidhapareeksha and other questionnaires which will reveal the physical and mental health of an individual | AIIA, New Delhi DCGI approval: N/A | DL |
20 | CTRI/2020/05/025276 | Arm 1: Sanshamani Vati (Tinospora cordifolia); Nagaradi kwath (decoction of Zingiber officinale, Terminalia chebula and Tinospora cordifolia); Amalaki Churna (powder of Phyllanthus emblica); Golden Milk (milk with Curcuma longa) | Single-arm trial | N/A | Phase 3 | 50 | Time taken and number of patients progressing from asymptomatic to symptomatic condition | Ch Brahm Prakash Ayurved Charak Sansthan, New Delhi DCGI approval: N/A | DL |
21 | CTRI/2020/05/025398* | Arm 1: Kiratiktadi Kwath (Astadashang Kwath) Sharangdhar Samhita -kwath prakaran; Ashwgandhachurna with milk; Yoga | Single-arm trial | N/A | N/A | 30 | 1. Efficacy in boosting Vyadhikshamatwa and prevention against communicable diseases. 2. Will help in overcoming the anxiety level and stress of HCQs |
GS Ayurveda Medical College and Hospital, Hapur DCGI approval: N/A | UP |
Patented products (n=24) | |||||||||
22 | CTRI/2020/06/025557 | Arm 1: AYUSH-64 as add on to standard treatment Arm 2: Yashtimadhu as add on to standard treatment Arm 3. Sanshamani Vati Plus; as add-on standard treatment Arm 4: Standard treatment |
Randomized, parallel-group, active controlled trial | Open label | Phase 2 | 420 | 1. Mean time (days) for clinical recovery 2. Proportion of patients showing clinical recovery |
Ministry of AYUSH, New Delhi DCGI approval: N/A | MH |
Patented products (n=24) | |||||||||
23 | CTRI/2020/05/025156 | Arm 1: AYUSH-64 Arm 2: Standard treatment |
Randomized, parallel-group, active controlled trial | Open label | Phase 3/4 | 60 | Clinical cure rate: Time to negative conversion of SARS-CoV-2 | CCRAS, New Delhi DCGI approval: N/A | MH |
24 | CTRI/2020/05/025335 | Arm 1: AYUSH-64 | Single-arm trial | N/A | Phase 3 | 40 | 1. Mean time (days) for clinical recovery as per defined clinical recovery criteria 2. Number of patients showing ‘clinical recovery’ |
CCRAS, New Delhi DCGI approval: N/A | DL |
25 | CTRI/2020/05/025338 | Arm 1: AYUSH-64 | Single-arm trial | N/A | Phase 2/3 | 40 | 1. Mean time (days) for clinical recovery as per defined clinical recovery criteria 2. Number of patients showing ‘clinical recovery’ |
CCRAS, New Delhi DCGI approval: N/A | DL |
26 | CTRI/2020/05/025214 | Arm 1: AYUSH-64 Arm 2: Standard treatment |
Randomized, parallel-group, active controlled trial | Open label | Phase 2/3 | 80 | 1. Mean time (days) for clinical recovery (day of randomization to the day of clinical recovery) 2. Proportion of patients showing ‘clinical recovery’ |
CCRAS, New Delhi DCGI approval: N/A |
CH |
27 | CTRI/2020/05/025484 | Arm 1: Chyawanprash Arm 2: Standard prophylactic care |
Non-randomized, active controlled trial | Open label | Phase 2/3 | 5000 | Comparative assessment of occurrence of COVID-19 infection | NIIMH (CCRAS), Hyderabad DCGI approval: N/A | TS |
28 | CTRI/2020/05/025425 | Arm 1: Chyawanprash | Single-arm trial | N/A | Phase 3/4 | 50 | Percentage of participants with SARS CoV-2 positivity as estimated by RT-PCR of nasopharyngeal swab | CCRAS, New Delhi DCGI approval: N/A | DL |
29 | CTRI/2020/05/024981 | Arm 1: Chyawanprash with milk Arm 2: Milk |
Randomized, parallel-group trial | Open label | N/A | 600 | 1. Comparative assessment of incidence of COVID-19 2. Comparative assessment of incidence of other non-COVID-19 infections |
Dabur India Ltd, Ghaziabad DCGI approval: N/A | GJ (2 sites), MH (2 sites), RJ |
30 | CTRI/2020/05/025275 | Arm 1: Chyawanprash Arm 2: Standard prophylactic care |
Randomized, parallel-group trial | N/A | Phase 3 | 200 | Percentage of participants with SARS CoV-2 positivity as estimated by RT-PCR | CCRAS, New Delhi DCGI approval: N/A |
DL |
31 | CTRI/2020/06/025592 | Arm 1: Shakti drops; turmeric plus; Tulsi arka | Single-arm trial | Open label | Phase 3/4 | 50 | Recovery in the signs and symptoms as fever and respiratory distress | Sri Sri Tattva, Bangalore DCGI approval: N/A | KA |
32 | CTRI/2020/06/025590 | Arm 1: Astha-15 capsule and standard treatment Arm 2: Placebo and standard treatment |
Randomized, parallel-group, placebo-controlled trial | Participant, investigator and outcome assessor blinded | Phase 3 | 120 | 1. Changes in scores of the St. George Respiratory Questionnaire from baseline to EOT visit 2. Changes in scores of the Leicester Cough Questionnaire from baseline to EOT visit |
Dalmia Centre for Research and Development, Noida DCGI approval: N/A | AP, RJ, DL, MH |
33 | CTRI/2020/05/025483 | Arm 1: Clevira tablet Arm 2: Standard treatment |
Randomized, parallel-group trial | N/A | Phase 3/4 | 100 | 1. Time taken for clinical recovery, which is defined as: (i) normalization of pyrexia and body pain; (ii) respiratory rate <24/minute; (iii) SpO2 rate >94%; (iv) relief from cough and maintenance of above for > 72 h 2. Proportion of patients with swabs negative for COVID-19 in RT-PCR at day 5, 10 and 15 |
Apex Laboratories Pvt Ltd, Chennai DCGI approval: N/A | TN |
34 | CTRI/2020/05/025334 | Arm 1: SUVED + Reimmungen | Single-arm trial | N/A | Phase 2 | 30 | Prevention of onset or complications of COVID infection | Health Solutions, Pune DCGI approval: N/A | MH |
35 | CTRI/2020/05/025343 | Arm 1: SUVED + Reimmungen | Single-arm trial | N/A | Phase 2/3 | 30 | Mortality | Health Solutions, Pune DCGI approval: N/A | MH |
36 | CTRI/2020/05/025340 | Arm 1: ShatPlus and standard treatment Arm 2: Standard treatment |
Randomized, parallel-group trial | Open label | Phase 1/2 | 60 | 1. Number of days for negative PCR confirmatory test from nasopharyngeal swab for SARS-CoV-2 2. Serum levels of CD4, CD8, NK cell panel CD16/CD56, CRP, IgM, IgG |
BVG Life Sciences Ltd, Pune DCGI approval: N/A | MH |
37 | CTRI/2020/05/025161 | Arm 1: Aayudh advance bacteria, viruses Arm 2: Standard treatment |
Randomized, parallel-group, active controlled trial | Open label | Phase 2 | 120 | 1. Rate of recovery 2. Symptom resolution: fever 3. Symptom resolution: cough 4. Symptom resolution: shortness of breath |
Shukla Ashar Impex Pvt Ltd, Rajkot DCGI approval: N/A | GJ |
38 | CTRI/2020/04/024883 | Arm 1: ZingiVir H Arm 2: N/A |
Other | Outcome assessor blinded | Phase 4 | 112 | The odds of ratio for improvement on a 7-point ordinal scale on day 15 Each day, the worst score from the previous day will be recorded | Pankajakasthuri Herbal Research Foundation, Thiruvananthapuram DCGI approval: N/A | KA (2 sites), MH |
39 | CTRI/2020/05/024967 | Arm 1: MyVir tablets Arm 2: Standard treatment |
Single-arm trial | N/A | Post marketing surveillance | 30 | Improvement in patients who are assessed daily for symptoms which include cough, fever with or without chills and difficulty in breathing for the period they are in quarantine | Mi Lab LifeSciences Pvt Ltd, Bengaluru, DCGI approval: N/A | KA |
40 | CTRI/2020/06/025527 | Arm 1: Amrta Karuna syrup Arm 2: Standard treatment |
Non-randomized, active controlled trial | N/A | Post marketing surveillance | 30 | 1. Improvement in patients who are assessed daily for symptoms which include cough, fever with or without chills and difficulty in breathing | Vopec Pharmaceuticals Pvt Ltd, Chennai DCGI approval: N/A | KA |
41 | CTRI/2020/05/025326 | Arm 1: Tab Pinak | Single-arm trial | N/A | Phase 2 | 30 | Early recovery and reduced mortality | Shree Bharadi Ayurvedic, Maharashtra DCGI approval: N/A | MH |
42 | CTRI/2020/05/025273 | Arm 1: Tablet pure Ashwagandha 500 mg; Pure Giloy extract; tablet pure tulsi extract; Anu Taila; Swasari Ras
Arm 2: Placebo therapy |
Randomized, parallel-group, placebo- controlled trial | NIL | N/A | 120 | Virological clearance as measured by RT-PCR of nasopharyngeal swab | Patanjali Research Institute, Haridwar; NIMS, Jaipur DCGI approval: N/A | RJ |
43 | CTRI/2020/05/025222 | Arm 1: AOIM - Z Tablet | Single-arm trial | N/A | Phase 4 | 275 | Prevention of incidence of COVID-19 infection | Shree Dhootapapeshwar Limited, Mumbai DCGI approval: N/A | MH |
44 | CTRI/2020/05/025434 | Arm 1: Zingivir-H | Randomized, parallel-group, placebo- controlled trial | Outcome assessor blinded | Phase 4 | 135 | The odds of ratio for improvement on a 7-point ordinal scale on day 15 and clearance of medically attended lung infection due to RT-PCR confirmed COVID-19 infection | Pankajakasthuri Herbal Research Foundation, Thiruvananthapuram DCGI approval: N/A | KA (2 sites), MH |
45 | CTRI/2020/06/025556 | Arm 1: Virulina Arm 2: Standard treatment |
Randomized, parallel-group, placebo- controlled trial | Participant and investigator blinded | N/A | 30 | 1. Time to a negative SARS-CoV-2 RT-PCR result of both oropharyngeal swab and nasopharyngeal swab. 2. Clinical cure based on clinician’s assessment of symptoms a. Change in positive COVID-19 status on day 8 and day 15 3. Clinical outcomes a. Proportion of patients on WHO progression scale 0 to 10 on day 8 and day 15 |
Natural Solutions, Mumbai DCGI approval: N/A | AP |
Yoga and Naturopathy (n=3) | |||||||||
46 | CTRI/2020/06/025523 | Arm 1: Meditation and breathing exercises and standard treatment Arm 2: Standard treatment |
Randomized, parallel-group trial | N/A | N/A | 84 | Depression, anxiety and stress levels in patients assessed using DASS-21 questionnaire | National Cancer Institute, Jhajjar DCGI approval: N/A DCGI approval: N/A | HR |
47 | CTRI/2020/05/025162 | Arm 1: Alternate nostril breathing and guided meditation; (1) Nadi Shodhan Pranayama; (2) Panchakosha meditation Arm 2: The control group will not receive the intervention. |
Randomized, parallel-group trial | N/A | N/A | 200 | PSQI for sleep quality | JIPMER, Puducherry DCGI approval: N/A | PY |
48 | CTRI/2020/05/025320* | Arm 1: Yoga and Naturopathy, immune-boosting agents such as ginger Tulsi pepper, Adhimaduram, turmeric, gargling, steam inhalation, Sun bath aromatherapy Arm 2: Standard treatment |
Nonrandomized, active controlled trial | N/A | Phase 3/4 | 658 | Time to progress to next stage of severity i.e., from asymptomatic/uncomplicated/mild pneumonia to moderate/severe stages | Government Yoga And Naturopathy Medical College, Chennai DCGI approval: N/A | TN (4 sites) |
Unani (n=2) | |||||||||
49 | CTRI/2020/06/025650 | Arm 1: Joshanda (decoction) of the following: Behidana (Cydonia oblonga), Unnab (Zizyphus jujube), Sapistan (Cordia myxa) and Khameera Marwareed | Other | Open label | Phase 2 | 4000 | 1. Incidence of COVID-19 cases 2. Improvement in immune status using ISQ |
Ministry of AYUSH, New Delhi DCGI approval: N/A | KA |
50 | CTRI/2020/05/025254 | Arm 1: Joshanda (decoction) and Khameera Marwareed
Arm 2: Joshanda (decoction) and Tiryaq e Arba Arm 3: Standard prophylactic care |
Non-randomized, multiple-arm trial | N/A | Phase 3 | 40000 | 1. Incidence of COVID-19 cases 2. Improvement in immune status using ISQ |
CCRUM, New Delhi DCGI approval: N/A | UP, KA, TS, JK, MH, DL |
Siddha (n=3) | |||||||||
51 | CTRI/2020/06/025625 | Arm 1: Kabasura Kudineer and Bramanandhabairavam
Arm 2: Standard treatment |
Other | Open label | Phase 2 | 86 | Proportion of patients confirmed as negative for SARS-CoV-2 in two consecutive throat/nasal swabs (taken 24 h apart) at day 15/day16 | Eminentlabs Business Solutions Pvt Ltd, Chennai DCGI approval: N/A | TN |
52 | CTRI/2020/05/025298 | Arm 1: Kabasura Kudineer Nilavembukudineer; Arm 2: Standard prophylactic care |
Non-randomized, active controlled trial | N/A | N/A | 21500 | Occurrence of COVID-19 infection | CCRS, Chennai; Ministry of AYUSH, New Delhi DCGI approval: N/A | TN |
53 | CTRI/2020/05/025215 | Arm 1: Kabasura Kudineer
Arm 2: Vitamin C, zinc supplementation |
Randomized, parallel-group trial | Open label | Phase 1/2 | 50 | Reduction in incidence of clinical symptoms of COVID-19, negative conversion of SARS-CoV-2, reduction in viral load of SARS-CoV-2 at the end of treatment and examine the levels immune markers and inflammatory markers | Government Stanley Medical College, Chennai DCGI approval: N/A | TN |
Homeopathy (n=14) | |||||||||
54 | CTRI/2020/06/025530 | Arm 1: Aconite 30 + Arsenic album 30 + Allium cepa 30 + Influenzum 30 + Gelsmium 30 + Eupatorium 30 + Echinacia 0 + Thuja 0 | Non-randomized, active controlled trial | N/A | N/A | 10000 | Number of patients with viral fever/COVID-19 | Cancer Aid Society, Lucknow DCGI approval: N/A | UP |
55 | CTRI/2020/05/025491 | Arm 1: Arsenic album 30c Arm 2: Bryonia alba 30c Arm 3: Camphora 1M Arm 4: Coronavirus-related nosodes (30c potency); Arm 5: Matching placebo pills |
Cluster randomized trial | Participant and outcome assessor blinded | Phase 2 | 1000 | Number of patients turning symptomatic | Life Force Foundation Trust, Mumbai DCGI approval: N/A | MH |
56 | CTRI/2020/05/025272 | Arm 1: Arsenicum album 30 Arm 2: No. 40 size globules medicated with alcohol 90% v/v is used as placebo |
Cluster randomized trial | Participant and investigator blinded | N/A | 800 | COVID-19 in quarantined persons | Government Homeo Dispensary, Kerala Government Homeo Dispensary, Kerala | KL |
57 | CTRI/2020/05/025205 | Arm 1: Arsenicum album 30c Arm 2: No intervention |
Cluster randomized trial | N/A | Phase 2/3 | 33000 | Confirmation of diagnosis for COVID-19 infection based on RT-PCR/end of quarantine period | CCRH, New Delhi DCGI approval: N/A | TN, DL, AP, TS, RJ, WB, KL, MH, UP, GJ |
58 | CTRI/2020/05/025049 | Arm 1: Arsenic album 30c | Cluster randomized trial | Open label | Phase 2/3 | 100 | Clinical recovery (COVID-19 negative) or death | Sai Nidan Homeopathy Clinic, Chhattisgarh DCGI approval: N/A | CG |
59 | CTRI/2020/05/024986 | Arm 1: Arsenic album 30c | Single-arm trial | N/A | N/A | 10000 | Confirmation of diagnosis for COVID-19 infection/end of quarantine period as per standard protocol | CCRH, New Delhi DCGI approval: N/A | DL |
60 | CTRI/2020/05/024969 | Arm 1: Arsenic album 30c (variable dose potency and frequency) and standard treatment Arm 2: Placebo and standard treatment |
Randomized, parallel-group, placebo-controlled trial | Open label | Phase 2/3 | 100 | Clinical outcome in terms of recovery of patient or requirement of life support (ventilator)/death | Naiminath Homoeopathic Medical College Hospital and Research Centre, Agra DCGI approval: N/A | UP |
61 | CTRI/2020/04/024926 | Arm 1: Arsenic album, Bryonia alba, Gelsemium, Antimonium tartaricum, Crotalus horridus | Single-arm trial | Participant blinded | Phase 3 | 100 | Clinical recovery (COVID-19 negative) or appearance of symptoms requiring conventional treatment | Naiminath Homoeopathic Medical College Hospital and Research Centre, Agra DCGI approval: N/A | UP |
62 | CTRI/2020/04/024905 | Arm 1: Arsenic album, Bryonia alba, Gelsemium, Antimonium tartaricum, Crotalus horridus
Arm 2: Placebo |
Randomized, parallel-group, placebo-controlled trial | Participant blinded | Phase 3 | 100 | Clinical recovery (COVID-19 negative) or death. | Naiminath Homoeopathic Medical College Hospital and Research Centre, Agra DCGI approval: N/A | UP |
63 | CTRI/2020/04/024857 | Arm 1: Arsenic album, Camphora, Bryonia alba, Helleborus niger, Justicia adhatoda | Cluster randomized trial | Open label | Phase 1/2 | 100 | Percentage of patient admissions to critical care | Welling Healthcare Private Limited, Mumbai DCGI approval: N/A | MH |
64 | CTRI/2020/06/025558 | Arm 1: Bryonia alba 30C Arm 2: Identical placebo |
Randomized, parallel-group, placebo-controlled trial | Participant and investigator blinded | Phase 4 | 300 | Prophylactic effect | Aarogya Homoeopathic Medical College and Hospital, Jaipur; Ministry of AYUSH, New Delhi DCGI approval: N/A | RJ |
65 | CTRI/2020/04/024947 | Arm 1: Cadamba 200 | Randomized, parallel-group, active controlled trial | N/A | Phase 3 | 100 | Serologically negative blood test for COVID-19 | PI initiated, Homeo clinic, Gondia-Maharashtra DCGI approval: N/A | MH |
66 | CTRI/2020/05/025496 | Arm 1: CNV01 | Single-arm trial | Open label | Phase 1 | 10 | Safety measure in terms of investigations (PCR) blood parameters | Life Force Foundation Trust, Mumbai DCGI approval: N/A | MH |
67 | CTRI/2020/04/024925 | Arm 1: Homoeopathic medicine and standard treatment Arm 2: Placebo and standard treatment |
Randomized, parallel-group, placebo-controlled trial | Open label | Phase 2 | 100 | Clinical recovery of patient or requirement of life support (ventilator)/death | Bajaj Auto Ltd, Maharashtra DCGI approval: N/A | MH (2 sites) |
#Registered trials as on June 5, 2020, *Trials with combination therapy (involving more than one system of AYUSH) are mentioned in only one category to avoid duplication. AYUSH includes Ayurveda, Yoga, Unani, Siddha, Homeopathy trials. Table data are as per information provided by trialist. The keyword ‘Standard treatment’ and has been used for uniformity and includes the following category as mentioned by the trialist i.e., standard of care, standard care of treatment and supportive management, standard treatment protocol, local-level standard treatment, best supportive care, treatment guidelines as per MOHFW. The term ‘Standard prophylactic care’ has been used for uniformity which represents the terminologies used by the trialist for standard preventive measures against COVID-19. AAIA, All India Institute of Ayurveda; ABVGMC, Atal Bihari Vajpayee Government Medical College; AYUSH, Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homeopathy; COVID-19, coronavirus disease 2019; CCRAS, Central Council for Research in Ayurvedic Sciences; CCRUM, Central Council for Research in Unani Medicine; CCRS, Central Council for Research in Siddha; CCRH, Central Council for Research in Homoeopathy; CSIR, Council of Scientific and Industrial Research; IPGTRA, Institute for Post Graduate Teaching and Research in Ayurveda; JIPMER, Jawaharlal Institute of Postgraduate Medical Education and Research; NIA, National Institute of Ayurveda; NIIMH (CCRAS), National Institute of Indian Medical Heritage (CCRAS); NIMS, National Institute of Medical Sciences Jaipur; PI, Principal investigator; N/A, not applicable; ISQ, immune status questionnaire; PSQI, Pittsburgh Sleep Quality Index; HCQ, healthcare worker; RT-PCR, reverse transcription polymerase chain reaction; DASS-21, depression, anxiety and stress scale - 21items; DCGI, Drugs Controller General of India; CRP, C-reactive protein; LDH, lactate dehydrogenase; CBC, complete blood count; PT INR, prothrombin time international normalized ratio; NK, natural killer. States and Union Territories (UTs): AP: Andhra Pradesh; AR: Arunachal Pradesh; AS: Assam; BR: Bihar; CG: Chhattisgarh; GA: Goa; GJ: Gujarat; HR: Haryana; HP: Himachal Pradesh; JK: Jammu and Kashmir; JH: Jharkhand; KA: Karnataka; KL: Kerala; MP: Madhya Pradesh; MH: Maharashtra; MN: Manipur; ML: Meghalaya; MZ: Mizoram; N: Nagaland; OR: Odisha; PB: Punjab; RJ: Rajasthan; SK: Sikkim; TN: Tamil Nadu; TR: Tripura; UK: Uttarakhand; UP: Uttar Pradesh; WB: West Bengal; TS: Telangana; AN: Andaman and Nicobar Islands; CH: Chandigarh; DH: Dadra and Nagar Haveli; DD: Daman and Diu; DL: Delhi; LD: Lakshadweep; PY: Puducherry
Ayurveda
Ayurveda is a comprehensive system of medicine that has been practiced in India for >5000 years41. A total of 45 Ayurveda trials (Tables I and III) 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 I).
Classical interventions
Guduchi: Tinospora cordifolia, commonly named as Guduchi, is used in a variety of conditions in the traditional Ayurvedic literature42. 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-1943. 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 III).
Ashwagandha: Withania somnifera (Ashwagandha) is well known for its anti-inflammatory, antitumour, anti-stress, antioxidant, immunomodulatory, hemopoietic and rejuvenating properties44. In addition, it has been demonstrated to inhibit certain RNA viruses45. 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 candidate46. 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.
Patented products
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 effects47. One of its components, Glycyrrhiza glabra or Yashtimadhu, has demonstrated potential as a wound-healing, anti-ulcer and anti-inflammatory agent48. In addition, recent studies reveal that Yashtimadhu may interfere with viral entry as well as replication, thereby impacting the severity of infection49. Further, AYUSH-64 along with standard care has been shown to be effective in influenza-like illnesses with potential for better outcomes50. 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 III).
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 supplement51. 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 III).
Yoga and naturopathy
Stress is known to suppress the immune system and is believed to be the harbinger of many diseases including respiratory infections52,53. Evidence supports the role of meditation in regulating the stress response and impacting virus-specific immune response54,55. Further, Pranayama has been shown to have a positive impact on lung function56. 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 drugs57. 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 III).
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 medicine58. 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 III).
Homeopathy
Homeopathy focuses on patient characteristics rather than disease per se59. There has been a call to utilize the benefits of homeopathy as a therapeutic system suitable to cope with this pandemic60,61. 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 III).
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 I). 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 IV). 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.
Footnotes
Financial support & sponsorship: None.
Conflicts of Interest: None.
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