CTRI Number	CTRI/2020/06/025557 [Registered on: 02/06/2020] Trial Registered Prospectively
Last Modified On:	13/04/2021
Post Graduate Thesis	No
Type of Trial	Interventional
Type of Study	Drug Ayurveda
Study Design	Randomized, Parallel Group, Active Controlled Trial
Public Title of Study Modification(s)	A clinical study of Ayurvedic formulations in the treatment of Mild to Moderate COVID-19 patients
Scientific Title of Study Modification(s)	A Randomized, Open Label, Parallel Efficacy, Active Control, Multi-Centre Exploratory Drug Trial to Evaluate Efficacy and Safety of an Ayurvedic Formulation as Adjunct Treatment to Standard of Care for the management of Mild to Moderate COVID-19 Patients
Secondary IDs if Any	Secondary ID  Registry  AYUSH-CSIR-TRT-01  Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study) Modification(s)	Name  DR ARVIND CHOPRA  Address  11, Hermes Elegance, 1988, Convent Street, CAMP. PUNE Pune MAHARASHTRA 411001 India  Phone  91-20-26344099   Fax  91-20-26350084   Email  crdp5624@gmail.com
Details Contact Person Scientific Query Modification(s)	Name  DR ARVIND CHOPRA  Address  11, Hermes Elegance, 1988, Convent Street, Camp. Pune Pune MAHARASHTRA 411001 India  Phone  91-20-26344099   Fax  91-20-26350084   Email  crdp5624@gmail.com
Details Contact Person Public Query	Name  DR ARVIND CHOPRA  Address  11, HERMES ELEGANCE, 1988, CONVENT STREET, CAMP. PUNE MAHARASHTRA 11, HERMES ELEGANCE, 1988, CONVENT STREET, CAMP. PUNE Pune MAHARASHTRA 411001 India  Phone  91-20-26344099   Fax  91-20-26350084   Email  crdp5624@gmail.com
Source of Monetary or Material Support	AYUSH AND CSIR
Primary Sponsor Modification(s)	Name  Ministry Of Ayush  Address  Ayush Bhawan, GPO Complex, New Delhi 110023  Type of Sponsor  Government funding agency
Details of Secondary Sponsor Modification(s)	Name  Address  Council of Scientific and Industrial Research   Anusandhan Bhawan, 2, Rafi Marg, Delhi 110001
Countries of Recruitment	India
Sites of Study Modification(s)	No of Sites = 5   Contact Person  Name of Site  Site Address  Phone/Fax/Email  Dr Jaya Chakravarty  Banaras Hindu University  Dept of General Medicine, IMS Varanasi 221005 Varanasi   9453003725 tapadar@gmail.com  Dr Dilip Gode  Datta Meghe Institute of Medical Sciences  Nagpur 440022 Nagpur   9822737919 dilipgode@yahoo.com  Dr Deepti Talmohite  ESI Hospital and PGIMSR  Akurli Road, Kandivali (East) Mumbai 400 101 Mumbai   9869268694 dr.deeptir.talmohite@esic.nic.in  Dr Himanshu Reddy  King George Medical University  Lucknow 226003 Lucknow   9839266822 dr.himanshureddy@gmail.com  Vaidya Manohar Gundeti  RRA PODAR CARIC  PODAR MEDICAL CAMPUS MUMBAI 400 018 Mumbai   9004960133 drmanoharccras@gmail.com
Details of Ethics Committee Modification(s)	No of Ethics Committees= 5   Name of Committee  Approval Status  DATTA MEGHE INSTITUTE OF MEDICAL SCIENCES, INSTITUTIONAL ETHICS COMMITTEE  Approved  INSTITUTE OF MEDICAL SCIENCES, BANARAS HINDU UNIVERSITY, INSTITUTIONAL ETHICS COMMITTEE  Approved  Institutional Ethics Committee, Employees State Insurance- Postgraduate Institute of Medical Sciences and Research Model Hospital  Approved  KING GEORGE MEDICAL UNIVERSITY, INSTITUTIONAL ETHICS COMMITTEE  Approved  R R A Podar Central Ayurveda Research Institute for Cancer  Approved
Regulatory Clearance Status from DCGI	Status  Not Applicable
Health Condition / Problems Studied Modification(s)	Health Type  Condition  Patients  Coronavirus as the cause of diseases classified elsewhere
Intervention / Comparator Agent	Type  Name  Details  Intervention  i)AYUSH-64 ii)Yashtimadhu iii)Sanshamani Vati Plus  i)AYUSH-64, 500 mg tablet, 2 tablets bid, ii)Yashtimadhu 300 mg tablet, 2 tablets bid iii)Sanshamani Vati Plus,Each tablet to contain 300 mg Guduchi plus 75 mg Pippali, 2 tablets bid Each of these 3 Ayurvedic formulations will be assessed in 3 separate drug trial studies with a randomized two arm active controlled design using common protocol and methods  Comparator Agent  Standard Care as per the Ministry of Health and family welfare guidelines for COVID19 and updated.   There is no specific therapy for COVID-19. All patients will be treated under strict supervision of a qualified physician. Triage will be performed in all patients on initial diagnosis to assess severity and repeated as per clinical judgement. Patients with moderate disease will need to be treated as inpatients. Taking preventive measures to avoid spread of infection from the patient is essential including PPE and suitable masks. However symptomatic treatment will be given in Mild and Moderate cases to treat fever and cough. Empiric antimicrobials will be used to treat all likely pathogens causing uncomplicated pneumonia and SARI. Uncomplicated cases with mild hypoxia may need supplemental oxygen. Hydroxychloroquine and macrolide maybe considered as an off label agent in patients with severe progressive disease. Steroids are not recommended for use in mild and moderate disease. Patients with severe disease and requiring intensive care will be withdrawn from the study and continued management as per the guidelines
Inclusion Criteria	Age From  20.00 Year(s) Age To  69.00 Year(s) Gender  Both  Details  i.Typical clinical presentation of acute onset febrile illness with cough and a RT_PCR based laboratory confirmation test for COVID-19 ii. Patients with either sex, 20 to 69 years age iii. Patients with mild to moderate patients iv. All patients must agree not to share medication v. Patients willing to participate and sign an informed consent
ExclusionCriteria	Details  Patients suffering from severe COVID-19 Disease as judged by a physician and fulfilling at least two of the following three criteria (i) Respiratory distress at room ambience (≥30 breaths per min) (ii) Oxygen saturation at rest ≤93% (peripheral digital arterial oxymetry) and requiring oxygen support for over one hour to normalize (iii) Any of the known COVID-19 complications and emergency procedures which may require shift/admission in intensive care unit such as respiratory failure, adult respiratory distress syndrome, requirement of oxygen support for over 1 hour, requirement of mechanical ventilation, septic shock, or severe non-respiratory organ dysfunction or failure. (Adapted and modified from the reference: Yang Liu et al. Lancet Infect Dis 2020, 2020 https://doi.org/10.1016/ S1473-3099(20)30232-2) ii. Chronic, Severe, Unstable, Uncontrolled co-existent medical illness such as Diabetes, Hypertension, Cardiac disorders, liver, kidney disorders and lung disorders or other disease of concern which may put the patient at increased risk during the study iii. History of immunosuppression: solid organ or bone marrow transplant, use of immunosuppressive antimetabolic and biologic agents, intrinsic immunodeficiencies, HIV infection. iv. Active cancer diagnosis, on palliative treatment or requiring current therapy with antimetabolic agents, immunotherapy or radiotherapy. v. Patients on parenteral nutrition vi. Patients with known sensitivity or contraindication to any of the ingredients of study medication vii. History of bleeding haemorrhoids, haemoptysis, acid peptic diseases, ulcers and pulmonary diseases (tuberculosis, asthma, etc.) viii. Patients who are likely to worsen or planed ICU admission or ventilator support due to any reason ix. Pregnancy and lactation x. Participation in a drug interventional clinical drug trial of any nature in the three month period preceding onset of COVID-19 xi. Participation in any other clinical trial of an experimental agent treatment for COVID-19 xii. Patients on any kind of Ayurveda treatment or any other alternative and complementary medicinal systems such as Homeopathy, Unani, Siddha and in particular requiring oral therapy of any kind. xiii. Physician decision that involvement in the study is not in the patient´s best interest
Method of Generating Random Sequence	Permuted block randomization, fixed
Method of Concealment	Not Applicable
Blinding/Masking	Open Label
Primary Outcome	Outcome  TimePoints  a) Mean time (days) for clinical recovery [Day of randomization to the day of clinical recovery (see criteria below)] b) Proportion of patients showing clinical recovery‘   Baseline, Daily assessment during symptomatic phase or hospitalization phase till complete recovery, WEEK 4, week 8, and study completion week 12
Secondary Outcome	Outcome  TimePoints  1) Rate of patients with negative SARSCoV2 on nasal or throat swab RTPCR test 2) Timelines - COVID-19 symptoms onset and their elevation 3) Proportion of patients developing a serious complication that warrants withdrawal 4) Improvement in selected laboratory parameters 6) Serological Antibody assay 7) Radiological Improvement on digital chest Xray 8) Drug related side effects and toxicity, and tolerability 9) Health status WHO QOL bref, health related behavior fitness questionnaire.   Baseline, Daily assessment during symptomatic phase or hospitalization phase till complete recovery, WEEK 4, week 8, and study completion week 12
Target Sample Size	Total Sample Size="420" Sample Size from India="420"
Phase of Trial	Phase 2
Date of First Enrollment (India)	11/06/2020
Date of First Enrollment (Global)	No Date Specified
Estimated Duration of Trial	Years="0" Months="3" Days="0"
Recruitment Status of Trial (Global) Modification(s)	Not Applicable
Recruitment Status of Trial (India)	Closed to Recruitment of Participants
Publication Details Modification(s)	NIL
Brief Summary	Coronavirus Disease-19 (COVID-19) pandemic has unleashed immense damage to life and livelihood. There is no specific therapy and the vaccine is likely to be ready by early 2021. All the global strategies are focussed on stringent preventive measures. India is under lockdown since early March 2020 and the situation though grim is fairly stable. Research is an integral part of any epidemic. There is a dire need to identify newer effective drugs and improve the current standard care. India should not lag behind in this regard. Several Rasayana drugs in Ayurveda are well known to enhance the host immunity which is pivotal to fight any infection. COVID- 19 is no exception.  It is predominantly a febrile infection of the upper airways and lungs but in a severe progressive situation can lead to respiratory failure and multiple organ system dysfunction. In the latter. It can lead to severe blood coagulation abnormalities in the microcirculation. It is evident that severe cases experience a highly exuberant and chaotic  immune mediated inflammatory response (cytokine storm) and end organ damage. Therefore, there may be a potent role of drugs that are  immune system modulators and/or enhance immune system in an orderly fashion. It is against this perspective that the Ministry of AYUSH and Council of Scientific & Industrial Research (CSIR) have initiated an ambitious and comprehensive research program to evaluate the therapeutic usefulness of Ayurveda formulations in the medical management of COVID- 19. It is proposed to initially evaluate the selected Ayurveda formulations as an add-on adjunct therapy to standard modern care in the medical management of patients of COVID-19 in randomized two arm, parallel efficacy, open label, active control (only standard care) exploratory multicentre studies. The COVID-19 medical centres are generally following the guidelines issues by the Ministry of Health and Family Welfare on the subject as standard care. It is difficult if not impossible to expect a uniform nature of standard care in this study but at each site this will be diligently recorded. The three Ayurveda formulations selected are AYUSH-64 (a proprietary formulation of AYUSH), Guduchi Pippali (Sanshamani Vati Plus) and Yashtimadhu. Each of these formulations will be evaluated in a separate two arm study using common and uniform methods as contained in this protocol. AYUSH-64, a multi-plant formulation, has been demonstrated useful in several research studies carried out over several decades to treat febrile infections including malaria and is considered to be anti-inflammatory and immunomodulatory. Sanshamani Vati Plus contains a combination of Tinospora cordifolia (Guduchi) and Piper longum (Pippali) and is well documented for anti-viral, anti-inflammatory and immunomodulatory potential (Rasayana) and in particular respiratory infections (Shvasa, Kasa, Jvara).  This formulation is described to treat Vata Kapha Pradhana Sannipatika Jwara (fevers related to dominant vata kapha doshas as per Ayurveda description) which has some striking similarity to COVID-19. Yashtimadhu (Glycyrrhiza glabra) is commonly  known as licorice or mulati (local language) and is a popular household remedy from Ayurveda pharmacopeia to treat common cold, flu like illness and sore throat. It is well known to have anti-inflammatory and immunomodulatory properties. The doses of each of the 3 drugs are fixed as per expert Ayurveda advise and will be administered daily  under supervision of the study Ayurveda physician. In this study, patients suffering from symptomatic mild to moderate COVID-19 will be selected as per the inclusion-exclusion criteria of the protocol. This would essentially mean that irrespective of the severity of the disease, patients should not have respiratory  distress requiring emergency measures that include invasive methods of oxygen administration, mechanical ventilation and other ICU based critical support systems. While on management in the study, if the patient worsens  and requires any kind of critical intensive care as described above, he/she will be withdrawn from the study and continue standard care under supervision of the ICU physician.   At the study conclusion, comparisons are being made for efficacy and safety between two study arms- standard care and standard care plus Ayurveda formulation. This is an exploratory study with a randomization prospective control design  and the convenience sample size for each Ayurvedic formulation has been fixed at 140 patients (70 in each arm) as per expert opinion; level of significance will be two sided p <0.05. It will be intention to treat analysis for all data using standard statistical tests and software.  The primary outcome efficacy measure is the time (days) to complete clinical recovery and the proportion of patients with complete recovery as defined in the study protocol and over a pre-defined period of time. There are several secondary efficacy measures within a predefined time frame work which includes several timelines for disease complications and their recovery, negative conversion of swab based RT-PCR for viral RNS, appearance of protective anti-COVID antibodies, improvement in quality of life and pertaining to drug toxicity. The statistical analysis will also look at predictors of clinical recovery. The study will also describe descriptive of COVID-19. Also several variables of importance from the Ayurveda clinical perspective and documented in the study case record form will also be analyzed for efficacy and safety. The duration of the study for all participants will be 12 weeks with a view to capture data on both physical and mental health which is important  from an Ayurveda perspective. After clinical recovery all patients will be followed daily using a simple mobile app till study completion (12 weeks). Both  Ayurvedic and Allopathic physicians will examine the patients  at scheduled visits and review the patients daily during the hospitalization phase. They will also follow all patients who are withdrawn irrespective of the reason till study completion to document the outcome in all cases, more so if the study patient worsens while in study and is withdrawn and shifted to only standard care. All patients are being investigated for laboratory and other relevant tests as per protocol and physician judgment.   Cytokine assays will also be carried out to evaluate the pathophysiology of COVID-19 and more so of severe stage (cytokine storm). A WHO Quality of life (QOL) questionnaire (with permission from WHO)   and a general health related questionnaire (HR-BHF) will be used as per the protocol. Standard documentation and reporting of adverse events (AE) will be carried out. The drug trial will adhere to the standard guidelines on drug trials (especially human subjects, GCP, adverse event reporting) from Declaration of Helsinki, WHO and ICH  (2017), ICMR (2018) and AYUSH/CCRAS (2018).