Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
I wish all success to your journal and look forward to sending you any suitable similar article in future"



Dr Mohan Z Mani,
Professor & Head,
Department of Dermatolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011
Anuradha

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.


Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020

Important Notice

Original article / research
Year : 2022 | Month : February | Volume : 16 | Issue : 2 | Page : KC01 - KC07 Full Version

Evaluation of Efficacy and Safety of Clevira as an Add on Drug in Mild to Moderate COVID-19 Positive Patients: A Randomised Control Trial


Published: February 1, 2022 | DOI: https://doi.org/10.7860/JCDR/2022/51996.15940
R Narayanababu, S Ramesh Kannan, R Lenin, M Sakthibalan, KM Sudha, K Gowtham, Arther Paul, Esekia David

1. Dean, Department of Paediatrics, Government Medical College, Omandurar Government Estate, Chennai, Tamil Nadu, India. 2. Senior Assistant Professor, Department of Pharmacology, Institute of Pharmacology, Madras Medical College, Chennai, Tamil Nadu, India. 3. Senior Assistant Professor, Department of Pharmacology, Institute of Pharmacology, Madras Medical College, Chennai, Tamil Nadu, India. 4 Principal Investigator, Ki3, CRO, Department of Pharmacology, Sri Venkateshwaraa Medical College Hospital and Research Centre, Puducherry, India. 5. Professor and Head, Department of Pharmacology, Institute of Pharmacology, Madras Medical College, Chennai, Tamil Nadu, India. 6. Siddha (AYUSH) Physician, Apex Laboratory Pvt. Ltd., Chennai, Tamil Nadu, India. 7. Senior Manager, International Business, International Business and Research, Apex Laboratory Pvt. Ltd., Chennai, Tamil Nadu, India. 8. Lead Scientist, Research, Apex Laboratory Pvt. Ltd., Chennai, Tamil Nadu, India.

Correspondence Address :
S Ramesh Kannan,
Senior Assistant Professor, Department of Pharmacology, Institute of Pharmacology,
Madras Medical College, Chennai, Tamil Nadu, India.
E-mail: srkguruvarshan@gmail.com

Abstract

Introduction: Coronavirus Disease-2019 (COVID-19) has caused a devastating pandemic. Despite the worldwide efforts to find a therapeutic strategy and prophylaxis, we have not attained a complete success. Hence, there exists an urgent need for development of alternative solutions from Ayurveda system of medicine for COVID-19.

Aim: To evaluate clevira, a polyherbal ayurvedic formulation, for its efficacy and safety in treatment of mild to moderate COVID-19 patients as an add on drug.

Materials and Methods: This randomised control trial was carried out from May 2020 to July 2020, in 100 patients (50 in test group and 50 in control group) confirmed with COVID-19 infection (mild to moderate cases) by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) at a tertiary care Government Medical College and Hospital in Chennai, India. The test group received tablet clevira orally twice daily after food, in the morning and night for 14 days, as an add on, in addition to standard care of treatment as received by the control group. The primary outcome was assessment of clinical recovery, proportion of patients with swabs negative for COVID-19 in RT-PCR and reduction of viral cycle threshold ratio. The results of the both group were analysed and compared using Chi-square test and Student’s t-test.

Results: Total 100 patients were enrolled for the study, mean age of test group was 36.64 and control group was 31.08. Significant improvement (p-value=0.0338) was seen in patients on day 5, who got treated with clevira as add on drug. An 43 (86%) of patients turned out to be COVID-19 RT-PCR test negative on day 5 while in the control group 33 (66%) of patients turned out to be negative. There was a statistically significant difference (p-value=0.0196) between the test and control groups on comparing the mean difference in CT value results between day 1 and day 5. Clevira when given in addition to the standard of care, showed a significant improvement in signs and symptoms of COVID-19 infection.

Conclusion: Clevira, with its polyherbal ingredients showed a significant antiviral action against coronavirus when given in addition to the standard of care medications suggested by Indian Council of Medical Research (ICMR), over a period of 14 days in treatment of mild to moderate COVID-19 patients.

Keywords

Andrographis paniculata, Antiviral, Coronavirus disease-2019, Piper nigrum, Tinospora cordifolia

Coronavirus, named Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV 2), has caused a pandemic of COVID-19. Coronavirus cause mild to severe type of respiratory tract infections. Mild illness include some cases of the common cold, while severe illness can cause SARS virus (Severe Acute Respiratory Syndrome) and MERS (Middle East Respiratory Symptoms) virus, which has led to a death toll of more than 4 million globally (1),(2). Though vaccination has been initiated for Coronavirus Disease-2019 (COVID-19), the effectiveness of the same in controlling the upcoming mutant strains of SARS-CoV-2 is still a debate (3). Hence, we are in need of a specific and effective antiviral therapy for SARS-CoV-2. Globally, there exists an urgent need for development of an alternative solutions for COVID-19.

In a country like India, there is a rich source of herbs having antiviral and antipyretic activity and Ayurvedic interventions can also be more relevant in management of such pandemics (4). In recent days the usage of many herbal formulations for various illnesses has increased worldwide and particularly for COVID-19 by the traditional Chinese medicines (5). Ministry of Ayurveda, Yoga, Naturopathy, Unani, Siddha, Sowa-Rigpa and Homoeopathy (AYUSH), Government of India has also issued guidelines for boosting immunity with Ayurvedic interventions (6).

Clevira is one among them which is a polyherbal formulation consisting of many ingredients. Clevira is a proprietary Ayurvedic Medicine of apex laboratories Pvt. Ltd., which has been approved by the Government of India and AYUSH for its use in mild to moderate COVID-19 patients as an add on drug to the standard of care treatment (7). The individual herbal ingredients used are known to have variety of medicinal properties against fever of viral origin and proven to have effective antipyretic, analgesic, antiviral and immuno regulatory properties. Composition of one clevira tablet includes extracts namely: Erandakarkati (Carica papaya) Leaf- 100 mg, Mahanimba (Melia azedarach) Leaf- 100 mg, Kalmegh (Andrographis paniculata) Herb- 100 mg, Usira (Vettivera zizanoides) Root- 35 mg, Patola (Tricosanthus dioica) whole plant- 35 mg, Musta (Cyperus rotundus) Rhizome- 35 mg, Sunthi (Zingiber officinale) Rhizome- 35 mg, Maricha (Piper nigrum) Fruit- 35 mg, Grismachatraka (Mollugo cerviana) Whole plant- 35 mg, Guduchi (Tinospora cordifolia) Stem- 10 mg (8).

It has shown in-vitro antiviral activity against Herpes Simplex Virus 1 and 2 [report attached as Annexure 1]. The antiviral activity of clevira Tablets-Granules and Syrup was carried out against Herpes Simplex Virus-1 (HSV-1) and HSV-2 viruses. The 100 TCID50 (Median Tissue Culture Infectious Dose) virus concentration was used for HSV-1 and HSV-2 viruses. The results includes that the granules showed good percentage of cell protection (71.55%) and selectivity index (CC50/IC50) {Half maximal cytotoxic concentration/Half maximal inhibitory concentration} of 11.66 when compare to syrup (55.6%) and selectivity index of 4.81 against HSV-1 virus. The granules of clevira also showed the activity against HSV-2 virus with percentage cell protection of 78.05% and selectivity index of 16.81 when compared with syrup (45.05%) and selectivity index of 3.39. The results clearly indicates that the granules of clevira showed the activity against both the viruses and more specifically with HSV-2 virus when compared to syrup. Clinical studies have shown its antiviral activity against dengue fever of viral origin (Ramesh Kannan S et al., 2019) (9). Docking studies also support the potential use of clevira against SARS-CoV-2. A total of 52 phytoconstituents present in medicinal plants incorporated in the clevira formulation were screened for their inhibitory potential through molecular docking studies against four targets namely the viral spike protein (S1), Ribonucleic Acid (RNA) dependent RNA polymerase (RdRp), SARS-CoV-2 main protease (3CLpro) and papain like protease (PLpro) that play a pivotal role in the SARS-CoV-2 infectivity and replication cycle [report attached as Annexure 2].

The docking study results obtained showed several of the phytoconstituents present in clevira herbal formulation showed good computational binding affinity against the four targets and some of the phytoconstituents were observed to show computational binding affinity to more than one of the four targets investigated. The phytoconstituents orientin, chlorogenic acid, wogonin, and vitexin showed excellent computational affinity to SARS-CoV-2 papain-like protease whereas the phytoconstituents rutin, ninandrographolide, quercetin, and chlorogenic acid exhibited good computational affinity to SARS-CoV-2 main protease. Four phytoconstituents namely ninandrographolide, rutin, quercetin, tinosporide were predicted to have good binding affinity to SARS-CoV-2 RNA dependent RNA polymerase and four phytoconstituents namely caffeic acid, ninandrographolide, piperine and oroxylin A are predicted to efficiently bind to receptor binding domain of SARS-CoV-2 spike protein (S1) [10-13]. Hence, the present trial was planned with an aim to evaluate the efficacy and safety of clevira against SARS-CoV-2 as an add on drug.

Material and Methods

The present randomised, open label, parallel group interventional controlled trial was carried out in Government Medical College and Hospital, Chennai, Tamil Nadu, India during the period of May 2020 to July 2020. The study was approved by the Institutional Ethics committee of Government Medical College, Omandurar Government Estate, Chennai on 22/05/2020 (IEC:05/2020) and the DCGI was notified about the study initiation and the trial was registered in CTRI (CTRI No. CTRI/2020/05/025483).

Sample size calculation: Sample size of 100 was calculated, based on the hypothesis that the proportion of patients showing improvement in control group will be around 20% and proportion of patients showing improvement in treatment group will be around 50%. Hypothesis was postulated, as there were no similar previous studies conducted with ayurvedic medicine, at the time of study initiation. Considering α of 0.05 and β of 0.2, comparing two proportions using sample size calculator software version 1.0, the minimum sample size required per group was 39. Considering 20% dropouts, sample size was rounded off to 50 per group and hence the total sample size obtained was 100.

Inclusion criteria: The study included both male and female patients between the age of 18-60 years, newly diagnosed with mild to moderate COVID-19 associated disease as defined by the World Health Organisation (WHO) with confirmed SARS-CoV-2 infection as determined by RT-PCR, with an illness of 1-2 days of duration and febrile/afebrile (14). Febrile-defined as temperature ≥36.6°C armpit, ≥37.2°C oral, or ≥37.8°C rectal documented within 24 hours of consent.

Exclusion criteria: The study excluded patients who participated in any other clinical trial of an experimental treatment for COVID-19, concurrent treatment with other agents with direct antiviral activity against SARS-COV-2 like remdesivir and oseltamivir which was prohibited 24 hours prior to study medication initiation. The study also excluded pregnant women or women who were breastfeeding and immunocompromised; patients taking medication upon screening and with stage 4 severe chronic kidney disease or requiring dialysis {estimated glomerular filtration rate (eGFR) <30 mL/min) or with elevated liver enzymes-Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) >5 times of Upper Limit of Normal (ULN)}.

Screening was done for 119 patients and out of which, 108 patients confirmed with COVID-19 infection (mild to moderate cases) by RT-PCR and satisfying the inclusion and exclusion criteria were included in the study after getting proper written informed consent and randomised using computer software generated random number table (Table/Fig 1).

Procedure

The test group (n=54) was administered with tablet clevira orally twice daily after food, in the morning and night for 14 days, as an add on, in addition to standard care of treatment suggested by ICMR and the control group (n=54) received standard treatment of care as per ICMR guidelines.

Mild cases: The mild disease included symptomatic patients (fever, cough, fatigue, anorexia, shortness of breath, myalgia, sore throat, nasal congestion, headache, nausea, vomiting, diarrhoea, loss of smell and loss of taste) meeting the case definition of COVID-19 without evidence of viral pneumonia.

Moderate cases: Moderate disease included symptomatic patients with clinical signs of pneumonia (fever, cough, dyspnoea and fast breath) but no signs of severe pneumonia (14).

Standard of care treatment given to all patient (as per hospital regulation) as per the ICMR guidelines are as follows (14); tab. hydroxychloroquine 400 mg twice daily on day 1, followed by 200 mg twice daily from day 2 to day 5. Tablet azithromycin 500 mg stat followed by 250 mg twice daily from day 2 to day 5. Tablet ivermectin 12 mg stat single dose, tablet vitamin C 500 mg, tablet multivitamin and zinc once daily for 14 days. Tablet cetrizine 10 mg at night and tab. paracetamol 500 mg was administered on need basis (14). This was the standard of care treatment given during the study period, as recommended by the Government of India, Ministry of Health and Family Welfare. All the RT-PCR and blood samples were analysed in a neutral independent NABL accredited laboratory (VRR Diagnostic services) in Chennai, India.

Primary outcome measure: The primary outcome measure was to assess the efficacy of clevira from day one of enrollement/treatment initiation, soon after the confirmation of COVID-19 illness, which is defined as time taken for clinical recovery i.e., normalisation of pyrexia and body pain, respiratory rate less than 24/minute, SpO2 rate greater than 94%, relief from cough and maintenance of above features for more than 72 hours and finally proportion of patients with swabs negative for COVID-19 in RT-PCR at day 5, 10 and 15 (time frame: upto 30 days calculated from day one of enrollement in the study soon after the confirmation of COVID-19 illness) and reduction of viral CT (Cycle Threshold) ratio from that of the baseline RT-PCR CT value.

Secondary outcome measures: The secondary outcome measures were improvement in laboratory parameters and clinical status of subjects at day 5, 10 and 15 on a 6 point ordinal scale namely:

1) Discharged having reached clinical recovery criteria;
2) Hospital admission, but not requiring supplemental oxygen;
3) Hospital admission, requiring supplemental oxygen;
4) Hospitalised, on non invasive ventilation or high flow oxygen devices;
5) Hospitalised, on invasive mechanical ventilation or Extra Corporeal Membrane Oxygenation (ECMO);
6) Death, assessed during a time frame upto 15 days.

The proportion of patients in each category of six point scale at day 5, 10 and 15 after randomisation was also recorded with details of all cause of death/mortality, duration of hospitalisation and adverse events if any.

Statistical Analysis

The results of the control and treatment arm were analysed and compared using Chi-square test and Student’s t-test using Statistical Package for the Social Sciences (SPSS) software version 21.0.

Results

The demographic details are mentioned in (Table/Fig 2), (Table/Fig 3). The male:female ratio (30:20 in test and 35:15 in control group) was comparable, but there was a significant difference between the groups with respect to mean age. The details of disease severity of COVID-19 patients enrolled in the study in listed out in (Table/Fig 4).

The primary outcome of the status of COVID-19 RT-PCR test results on day 5 and day 10, presented in (Table/Fig 5), (Table/Fig 6). There was a statistically significant improvement (p-value=0.0338) in the number of patients who turned out to be negative on day 5 and who got treated with clevira as add on drug. Out of 100 patients enrolled, 86% (43) of patients turned out to be COVID-19 RT-PCR test negative on day 5 while in the control group 66% (33) of patients turned out to be negative for COVID-19 RT-PCR test. There was no difference between the groups on day 10 as patients of both test and control group turned out to be negative for COVID-19 RT-PCR test.

(Table/Fig 7) depicts the comparison of CT value of test and control group on day 1. There was no statistically significant difference (p-value=0.788) between the test and control groups on comparing day 1 CT values (Table/Fig 8). Thus, both the groups have a comparable data on baseline.

(Table/Fig 9) depicts the comparison of CT value of test and control group on day 5. There was a statistically significant difference (p-value=0.018) between the groups on comparing with day 5 CT value results (Table/Fig 10). Hence, there was a significant improvement in the CT value in Test group when compared to control group on day 5.

Comparison of mean CT value between test and control groups on day 1 and day 5 is mentioned in (Table/Fig 11). Data was analysed using two tailed independent t-test. There was a statistically significant difference (p-value=0.0196) between the test and control groups on comparing the mean difference in CT value results between day 1 and day 5. Hence, there was a significant improvement in the CT value in test drug (clevira) treated group when compared to control group on day 5. Thus, the COVID-19 concentration has been brought down to significant levels in the test drug (clevira) treated group.

(Table/Fig 12) shows the clinical (signs and symptoms) recovery status of the patients on day 15 post enrollment. There was a statistically significant difference (p-value=0.0001) between the test and control groups on comparing the mean day of relief of signs and symptoms. Thus, the test group shows better improvement of signs and symptoms of COVID-19 infection by 4.1 days when compared to control group where it was 6.28 days.

(Table/Fig 13) shows the clinical improvement status using 6 point ordinal scale. There was no statistically significant difference (p-value=0.93) between the test and control groups on comparing the mean duration of hospital stay and 6 point ordinal scale data. However, there was improvement in the mean ordinal scale from 2.5 on day 1 to 1.6 on day 5 with an improvement of 0.9 in the test group. While there was improvement in the mean ordinal scale from 2.06 on day 1 to 1.85 on day 5 with an improvement of 0.21 in the control group.

(Table/Fig 14) shows the haematological and biochemical laboratory data analysis on day 1, day 5 and day 15/post study. There was a statistically significant difference (p-value <0.01) on comparing the mean values of total White Blood Cells (WBC) count, platelet count, lymphocytes, neutrophils, Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) of day 1, day 5 and day 15 of test group (clevira). And there was significant difference (p-value <0.01) on comparing the mean values of ALT, AST and creatinine levels on comparing day 1 and day 15 of control group.

There was a significant increase in the White Blood Cell (WBC) count on day 5 and 15 in clevira treated test group and there was also a significant increase (p-value <0.01) in the lymphocyte count (Table/Fig 15) on comparing day 1 and day 15 of test group, which acts as an indicator of immunoregulatory property of clevira.

There was also a significant increase in the platelet count on day 5 and day 15 in clevira treated test group, which confirms the proved fact that clevira can be used in patients with thrombocytopenia.

There was also a moderate decrease in the Erythrocyte Sedimentation Rate (ESR) levels from day 1 to day 5 in clevira treated group when compared to control group, which proves the anti-inflammatory property of clevira, which will be beneficial in treating COVID-19 positive patients (Table/Fig 16).

There was a significant decrease (p-value <0.05) in the AST and ALT levels in both test and control groups on day 15.

All the patients recovered of the above mentioned adverse events without any specific medical intervention. There were no documented Serious Adverse Event (SAE) or death (mortality) of the study participants, during the entire study period (Table/Fig 17). All the patients enrolled in the study recovered from the COVID-19 illness and are staying healthy, as confirmed by our post study follow-up on day 30.

Discussion

The pandemic of COVID-19 caused by novel coronavirus (SARS-CoV-2) infection is a public health emergency of international concern for the World Health Organisation (WHO) and for Indian Council of Medical Research (ICMR) (India). At present, the efforts of various countries are focused on the rapid diagnosis and isolation of patients, as well as to find a cure for COVID-19 in order to combat the serious impact of the disease. The number of reported COVID-19 virus infections is still increasing globally. In the lack of confirmed effective treatments, due to public health emergencies, it is vital to study the promising effects of various existing approved antivirals drugs for SARS-CoV-2 like Ivermectin, which has been suggested to be an effective and safe chemoprophylactic drug in management of COVID-19 (15).

Traditional Indian medical practices like ayurveda, siddha, unani, and homeopathy are a vast reservoir of knowledge about various medicinal plants. The pharmacological properties of these plants have paved way for developing novel therapeutic options against coronavirus infection. By identifying various phyto compounds, it is possible to effectively characterise medicinal herbs that could help to alleviate COVID-19 infection. Hence, by repurposing the Indian medicinal plants, more innovative treatment options can be penned down for their role in defeating this viral transmission. At the time of worldwide anxiety, it is imperative to find long term solutions to prevent the transmissions of such pandemics.

Clevira is one such proprietary ayurvedic medicine where the individual herbal ingredients used are known to have variety of medicinal properties against fever of viral origin and proven to have effective antipyretic, analgesic, antiviral and immune regulatory properties. It provides faster relief in conditions of viral fever in chikungunya and dengue, which has been proved clinically (9),(16),(17). The present study has shown that there was a significant improvement in the patients on day 5, who got treated with clevira as add on drug. Total 43 (86%) of patients turned out to be COVID-19 RT-PCR test negative on day 5 while in the control group 33 (66%) of patients turned out to be negative for COVID-19 RT-PCR test. There was also a significant improvement in the CT value in Test drug treated group when compared to control group on day 5. The present study shows, that the COVID-19 concentration has been brought down to significant levels in the test drug treated group.

This effect is probably due to the presence of antiviral property of Andrographis paniculata, Carica papaya, Tinospora cordifolia and Melia azedarach which are the active ingredient of clevira. Andrographis paniculata a medicinal plant which has been reported to have anti-HIV, antipathogenic bacteria and immunoregulatory activities which also possess blood purifying activity and thus eliminates the toxic metabolites and have anti-inflammatory, antipyretic and analgesic activity (18),(19). Recent studies have shown that Andrographis paniculata modulates NOD-Like Receptor Protein 3 (NLRP3), caspase-1, and interleukin-1 β molecules which are extensively involved in the pathogenesis of SARS-CoV and likely SARS-CoV-2 as well. Docking studies have also shown that Andrographis paniculata is a potential inhibitor of the main protease of SARS-CoV-2 (Mpro) (10),(20).

Tinospora cordifolia an active ingredient of clevira, is known to strengthen host immune system by activating macrophages, NF-kappa beta translocation and cytokine production. It has antipyretic, antiviral and hepato-protective activity (21), it has also shown to have antiviral properties against SARS-CoV-2 (11),(13),(22). Also, docking studies have shown that Limonoids from Melia azedarach (an ingredient of clevira) are also a potential inhibitor of SARS-CoV-2 proteins (12). Limonoids from Melia azedarach fruits has inhibitory activity on Flaviviruses and Mycobacterium tuberculosis (23),(24). Carica papaya, another active ingredient of clevira is also known for its antiviral activity against Dengue virus which is also single stranded RNA virus similar to SARS-CoV-2. Its efficacy has been well proved in various clinical studies and it also has platelet augmentation activity (9),(16),(17).

The study results also illustrate a significant increase in the WBC count on day 5 and day 15 in clevira treated test group with a significant increase in the lymphocyte count on day 15, which suggests the immune regulatory property of clevira. Andrographis paniculata, Tinospora cordifolia and Piper nigrum (ingredients of clevira) have proven immunomodulatory activity (18),(19),(21),(25). This helps in combating COVID-19 infection and hence can be used for SARS-CoV-2 infected patients as an add on drug.

Studies have shown that COVID-19 infection decreases the total and differential WBC count, which starts improving from 8th day onwards (26). The present study has shown that on intervention with clevira plus standard treatment, the WBC count and lymphocyte count increased on day 5 and day 15. Thus, clevira will be beneficial in improving WBC count and help in early recovery of COVID-19 positive patients.

Studies also showed that there is a decrease in the platelet count in COVID-19 positive patients and is associated with an increased risk of severe disease and mortality (26),(27). The present study results showed a significant increase in the platelet count on day 5 and day 15 in clevira treated test group which will play a vital role in decreasing the severity of the infection and preventing the mortality. This platelet augmentation activity is mainly due to the effect of Carica papaya (active ingredient of clevira) which is also known for its antidengue property. It is reported to be having enhancement of arachidonate 12- lipoxygenase and the platelet activating factor receptor gene expression which is responsible for increased platelet production (16),(17). Also, Vettivera zizanoides (another ingredient of clevira) has an effective antiviral property. Docking studies have shown that Ethyl 4-(4-methylphenyl)-4-pentenoate from Vetiveria Zizanioides inhibits dengue NS2B-NS3 protease and prevents viral assembly (28).

The present study outcome also elicits a moderate decrease in the ESR levels from day 1 to day 5 in test product treated group when compared to control group, which supports the anti-inflammatory property of clevira, which will be beneficial in treating COVID-19 positive patients. The various ingredients of clevira like Andrographis paniculata, Tricosanthus dioica, Mollugo cerviana, Piper nigrum, Zingeber officinaleis and Cyperus rotandus have potent anti-inflammatory property (29),(30),(31),(32),(33) and also antipyretic property which will be beneficial in curing the symptoms of COVID-19 positive patients like fever, headache and myalgia. The various chemical constituents present in Tricosanthus dioica are vitamin A, vitamin C, tannins, saponins, alkaloids, mixture of noval peptides, proteins tetra and pentacyclic triterpenes which possess antipyretic and anti-inflammatory property (32). This effect of the test product is evident from the present study outcome which shows that patients treated with clevira along with standard of care treatment show a significant improvement in signs and symptoms of COVID-19 infection by 4.1 days when compared to control group where it was 6.28 days.

Various studies (34) have shown that there is a frequent incidence of liver injury in COVID-19 patients, and it is often manifested as transient elevation of serum amino transferases (AST and ALT). In the present study, there were 12 subjects who presented with elevated levels of serum amino transferases and it got normalised on treatment with clevira along with standard of care treatment. There was also a significant decrease in the AST and ALT levels on day 15. It may be due to the property of Piper nigrum, which protects the liver and neutralizes the endotoxins and detoxifies pathogenic remnants from liver and blood (33). Also, Mollugo cerviana has hepatoprotective efficiency and photo-protective capacity due to the presence of phytochemicals like carbohydrates, saponins, tannins, terpenoids, flavonoids, steroids, phenols, proteins and alkaloids (29). Presence of Zingeber officinale in clevira helps in the recovery of appetite and digestion by stimulating the secretion of gastric enzyme (33).

Limitation(s)

The major limitation of the study was placebo controlled double blinded study was not conducted, as during the first COVID-19 outbreak it was not feasible. Immunological blood markers were not tested, as much insight was not available during the first COVID-19 outbreak. Pre and Post analysis of clinical signs and symptoms improvement within group was not performed. Further phase 4 clinical trial with larger sample size and with added testing parameters like the immunological markers can be conducted in future.

Conclusion

The results obtained in this study concluded that clevira, with its poly herbal ingredients shows a significant antiviral action against COVID-19 when given in addition to the medications suggested by WHO/ICMR, over a period of 14 days. On treatment with tab. clevira along with standard of care treatment 86% of patients turned out to be COVID-19 RT-PCR test negative on day 5 and 100% of patients turned out to be COVID-19 RT-PCR test negative on day 10 with a significant reduction in the RT-PCR CT-values. Clinical improvement of signs and symptoms of COVID-19 infection was achieved by 4.1 days. It is also eliciting a probable immune regulatory property and certain platelet augmenting property, with no serious side effects of concern. Clevira has a very good patient compliance with twice daily administration over a period of 14 days. It is also hepato-protective in nature. Thus, clevira can be given as an add on therapy in treating patients with mild to moderate COVID-19 positive patients and help in early recovery. Thus, it may be helpful in reducing the disease transmission and bring down the incidence of COVID-19. Further prospective studies for determining the prophylactic use of clevira are on the docket.

Acknowledgement

Authors acknowledge Mr. S.S. Vanangamudi, Chairman, Apex Laboratories Pvt. Ltd., Ms. Subashini Vanangamudi, Executive Director Mr. Vishagan Vanangamudi, Executive Director, K.M. Nagarajan, Vice President, apex laboratories Pvt. Ltd. and Dr. Gayathri Sivakumar, Vice President, Ki3(CRO) for their support in conducting the trial.

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DOI and Others

DOI: 10.7860/JCDR/2022/51996.15940

Date of Submission: Aug 18, 2021
Date of Peer Review: Sep 28, 2021
Date of Acceptance: Dec 12, 2021
Date of Publishing: Feb 01, 2022

AUTHOR DECLARATION:
• Financial or Other Competing Interests: Funded by Apex Laboratories Pvt. Ltd., and
Lab analysis done in NABL Accredited lab (VRR Diagnostics- Chennai, India)
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. NA

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