A clinical study of Ayurvedic formulations in the treatment of Mild to Moderate COVID-19 patients

Phase 2

Active, not recruiting

Conditions: Coronavirus as the cause of diseases classified elsewhere,

Registration Number: CTRI/2020/06/025557

Lead Sponsor: Ministry Of Ayush

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*](https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/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).

Detailed Description: Not available

Recruitment & Eligibility

Status: Closed to Recruitment of Participants

Sex: All

Target Recruitment: 420

Inclusion Criteria

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.

Exclusion Criteria

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 (â‰¥30 breaths per min) (ii) Oxygen saturation at rest â‰¤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.
Active cancer diagnosis, on palliative treatment or requiring current therapy with antimetabolic agents, immunotherapy or radiotherapy.
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.
Physician decision that involvement in the study is not in the patientÂ´s best interest.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
a)Mean time (days) for clinical recovery [Day of randomization to the day of clinical recovery (see criteria below)]	Baseline, Daily assessment during symptomatic phase or hospitalization phase till complete recovery, WEEK 4, week 8, and study completion week 12
b)Proportion of patients showing clinical recoveryâ€˜	Baseline, Daily assessment during symptomatic phase or hospitalization phase till complete recovery, WEEK 4, week 8, and study completion week 12

Secondary Outcome Measures

Name	Time	Method
1) Rate of patients with negative SARSCoV2 on nasal or throat swab RTPCR test	2) Timelines - COVID-19 symptoms onset and their elevation

Trial Locations

Locations (5): Banaras Hindu University
🇮🇳
Varanasi, UTTAR PRADESH, India
Datta Meghe Institute of Medical Sciences
🇮🇳
Nagpur, MAHARASHTRA, India
ESI Hospital and PGIMSR
🇮🇳
Mumbai, MAHARASHTRA, India
King George Medical University
🇮🇳
Lucknow, UTTAR PRADESH, India
RRA PODAR CARIC
🇮🇳
Mumbai, MAHARASHTRA, India
Banaras Hindu University
🇮🇳Varanasi, UTTAR PRADESH, India
Dr Jaya Chakravarty
Principal investigator
9453003725
tapadar@gmail.com