key: cord-0706903-hjlpqy6j
authors: Kataria, Sushila; Sharma, Pooja; Ram, Jai Prakash; Deswal, Vikas; Singh, Manish; Rana, Rakesh; Singhal, Richa; Tripathi, Arunabh; Kumar, Kuldeep; Trehan, Naresh
title: A Pilot Clinical study of an add on Ayurvedic formulation containing Guduchi and Pippali in mild to moderate Covid - 19
date: 2021-06-10
journal: J Ayurveda Integr Med
DOI: 10.1016/j.jaim.2021.05.008
sha: 7fc226973ac5d12c6c1812a57afd02ae572d7ae8
doc_id: 706903
cord_uid: hjlpqy6j

After declaration of Covid – 19 as pandemic by WHO, countries adopted several measures to contain the spread as well as test and treat the patients. Further, as no effective management protocols to address this pandemic were available, a need was felt to explore the integration of modern and traditional medicines to treat Covid 19 cases. In view of this an exploratory nonrandomized prospective study has been undertaken for comparing the outcomes of traditional Ayurvedic classical formulation of Tinospora cordifolia (Guduchi) and Piper longum (Pippali) as an add on to standard of care (SOC) using modern medicine with SOC alone. This has been done in mild and moderate Covid – 19 cases, at a tertiary care integrative Medicine hospital in the National Capital Region, Gurgaon, India. The outcomes have been evaluated in terms of the duration of hospital stay, the time to clinical recovery, safety and non-interference/interaction of Ayurvedic and Further, long term impact of Covid – 19 treatment has been evaluated using quality of life questionnaire after 3 months of discharge. Findings of present study reveals that the Ayurveda add-on formulation of Tinospora cordifolia (Guduchi) and Piper longum (Pippali) has reduced the length of hospital stay and improve the recovery time. General feeling of wellbeing and activity levels were better in the 3 month follow-up post discharge in the Ayurveda add-on group. It is suggested that this formulation needs further investigated to provide more information on effective and safe herbal add-on to SOC for better outcomes to treatment of COVID-19 disease.

Introduction: Alarming levels of spread and severity of disease forced the WHO to declare COVID -19 a pandemic on March 11, 2020 and no country has since been safe from its wrath. Countries have adopted several measures to detect, test, treat, isolate and, trace in order to stop the disease transmission and contain the spread among its populations. As there is no current standard best practice to treat the disease countries are working with all resources in the arsenal (1) .

There are claims from various quarters, especially from Traditional Chinese Medicine (TCM) Ren J-l, Zhang A.-H., Wang X.-J. Traditional Chinese medicine for covid-19 treatment and (2, 3) Korean oriental medicine (Association of Korean Medicine News 2020. Announcement of the first version of Oriental Medicice Clinical Practice Guideline by the National University Network of Traditional Medicine Department of Internal Medicine (4) and Indian systems of medicine, collectively known as AYUSH (Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homeopathy) (5) . Ayurveda is an experiential, intuitive and holistic, whereas that of the modern medicine is based more on experimental, analytical and reductive reasoning (6) .

Ministry of Health and Family Welfare (MoHFW) in India has published several clinical management protocols to standardize covid care over the months of March, April, May and June and have modified them in line with the international current best practices (7) . Ministry of AYUSH has also released several guidelines to each of its practitioners that suggest preventive and precautionary strategies (8). Ayurveda has potential and possibilities to be employed both for prevention and treatment of COVID-19.

Ayurvedic texts have proposed models to predict outbreaks and propagation of epidemics as well as general guidelines for prevention and management of epidemics. The Susruta Samhita, one of the classical text books of Ayurveda has described the possibility of epidemic outbreaks of severe respiratory illnesses exhibiting a spectrum of symptoms like cough, breathing difficulties, fever, headache, running nose and even anosmia (which is a symptom that has been reported in a subset of COVID-19 patients) (9).

An Ayurvedic assessment of the disease can help to classify the clinical presentations of COVID-19 on the basis of the Tridoṣa (three dosa which are Vata, Pitta, and Kapha) which forms the framework and logic around which Ayurveda understands disease and health. The standard methodology of deciphering the dosa base of the pathology through signs and symptoms using the algorithm of Ayurveda logic is equally applicable in understanding the disease spectrum of COVID-19 infection (10). At present, based on the available data, we have some preliminary understanding of the stages and the sub-stages of the pathogenesis of the disease. Our preliminary analysis of the clinical and laboratory data of 17 patients (14 Italian + 3 Indian) has helped us profile this disease as "Aganthuja Vatha Kapha Pradhana sannipathika Jwara".

According to Ayurveda (ref: A.H. Chi.1/60), the specific medication prescribed for the above pattern of dosa presentation and diagnosis is a combination of Tinospora cordifolia (Guduchi) and Piper longum (Pippali) . Both the herbs are very well studied and documented and are abundantly available in the Indian sub-continent.

Study Design:

COVID-19 Guduchi And Pippali (COVIDGAP) was undertaken at an integrated tertiary care facility in National Capital Region to evaluate the impact of a classical formulation (Tinospora cordifolia (Guduchi) and Piper longum (Pippali) as an add on to standard of care (SOC) modern medicine in an integrative mode of management compared to SOC alone in mild and moderate, RTPCR-confirmed COVID-19 positive patients. The study was conducted in two phases. In Phase I, 30 participants enrolled in SOC + Ayurveda group by June 2020 and thereafter 30 participants recruited the SOC group (Study Flow Chart 1). The study was conducted between 27 th May 2020 and 3 rd July 2020.

Study Participants: Participants aged ≥18 years were eligible, based on their RTPCR testedpositive or a mild and moderate COVID-19 disease according to Ministry of Health and Family Welfare guidelines. All participants were admitted to hospital, based on the severity of disease as per investigator's discretion.

Participants who had no severe or critical stages of the disease, and were willing to consume Ayurveda medicine, and signed the informed consent for the same, and had no known allergies to the various drug components were considered eligible.

Participants were excluded if they had severe COVID 19 disease and other immunosuppressant disease as per investigator's discretion.

Participants provided written consent prior to participate in study specific activates, and the protocol was approved by Institutional Ethics committee. Considering the study design, safety of participants was also monitored by an Ayurvedic physician along with Allopathic team. The study was registered with the CTRI number: 2020/04/024882 . All participants were discharged from facility in compliance with discharge policy MoHFW. The study was conducted in accordance with International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) guidelines, the declaration of Helsinki, and local regulatory requirements. After and additional ethics committee review in November 2020, an extended follow up by telephonic visit was scheduled for all participants to identify sequalae, or prolongation of symptoms if any. Study Endpoints: The endpoint of the study was of hospital stay, the time to clinical recovery as well as patients whose condition worsened (severity of disease) as an exploratory outcome. We also evaluated for patient acceptability and any signs of drug-herb interaction between the study formulation and the SOC.

The drug dosage form called Kashaya (decoction) was given as a daily dose of 180-200 ml, made up of two equal doses of 90-100 ml each, once in the morning before breakfast and once in the evening, before dinner to all participants enrolled in Phase I of the study. CCRAS sourced the study formulation from the market from licensed Ayurvedic manufacturers; Tinospora codifolia stem powder was manufactured by M. P. State Co-operative undertaking unit and Pippali choorna was produced by IMPCL. The Kashaya were freshly prepared for each dose as follows: 25 grams of dry Tinospora cordifolia stem powder shall be boiled in 400 ml water till only 100 ml water remains. This Kashaya is strained and filtered to discard the solid part and mixed with two 2 grams ( 1 / 3 teaspoon) of finely powdered dried Piper longum fruit (11). This is one dose of the medicine.

The drug was administered by the duty nurses at the patient bed side. The treating modern medicine physician reserved the full authority to withhold the drug temporarily or withdraw the drug altogether at their discretion. All participants in Phase I were administered the Tinospora cordifolia and Piper longum combination, until discharge. In Phase II (Comparator arm) participant on standard of care medicines were considered.

Safety: Safety evaluation included physical examination, assessment of vital signs, clinical assessment, laboratory investigations, RT-PCR negativity and reporting of adverse events. The patient discharged were followed after three months to enquire about their health telephonically. The subjects were asked for their feedback on the following though a All analysis were done using SPSS software, version 24.0. IBM Bangalore India. Table 1 presents the distribution of subjects in SOC + Ayurveda and SOC groups according to gravity category of COVID-19 illness. It is observed that 29 subjects in each of the two groups were either asymptomatic or mildly symptomatic. Only 1 subject in each arm was moderately symptomatic. Thus, the subjects covered in two groups are comparable ( Table 1 ).

The reason for the smaller number of asymptomatic patients in the SOC group is that we started recruitment into the SOC group late in June, 2020, by which time the MoFHW regulation permitted home care for asymptomatic cases and most people opted for the same. It should also be noted that the Ayurveda add-on group had been recruited and cared for in the initial period of the pandemic and therefore had mandatorily spent more time in the hospital in comparison to the SOC group, who were recruited later in the study, owing to the revised provisions in the COVID-19 care protocol published by the government. Table 3) .

One of the important outcome parameters is the duration of hospital stay. Table 5 provides the results on duration of hospital stay for subjects in two arms and the statistical significance of difference. It is seen that the average hospital stay was lower (5.5 ± 2.4 days) for SOC + Ayurveda group as compared to SOC group (6.9 ± 3.1 days). The difference was 1.4 days, which was statistically significant (p = 0.027, one tailed) (Table 4) .

The patients of both the SOC + Ayurveda and SOC groups have been categorised into five sub-groups based on the SOC given to them: i. HCQ alone; ii. HCQ + Antibiotic / HCQ + Antibiotic + Antipyretic; iii. HCQ+ Antipyretic; iv.

Antibiotic + Antipyretic and v. No COVID related medicine given. The table 5 given below provides the details on duration of hospital stay according to concomitant medication used together with number of patients in each group. It may be noted that irrespective of the sub-categorisation based on the allopathic medicine prescribed for COVID-19, across all sub-groups the Ayurveda add-on (SOC + Ayurveda) group had shorter duration of stay (mean number of days) in the hospital compared to the SOC (SOC + Ayurveda) group. Table 6 clearly shows this advantage in the Ayurveda add-on group and is reflecting even in the sub-group where no allopathic medication was given. It should be noted that the higher number of 'No medications given' (n=12) in the SOC group in comparison to the Add-on group (n=3) is reflective of the change in prevalent COVID management protocol at the time the respective patients were admitted in the hospital. Nevertheless, it was interesting to note that, despite the mandatory extensive hospitalisation requirements during months of April and May (2020), the mean value of the number of days of hospitalisation in patients who received no allopathic medication for COVID is shorter in the Ayurveda add-on sub-group.

Following J o u r n a l P r e -p r o o f Considering the primacy given to the drug HCQ in the management of COVID-19 disease from the initial phase of the pandemic, we also did an analysis of the number of days of hospitalisation of patients in both groups categorising them based on the use of HCQ in their COVID-19 management.

It is evident that in both the categories the patients in the Ayurveda add-on group had shorter duration of stay at the hospital in terms of mean number of days. Further among these two sub-categories of patients, those who received HCQ seemed to have spent lesser number of days in the hospital.

The graph 1 presented below provides information on time to recovery for both the groups.

It is observed that from the graph 1 that the patients in the Ayurveda group started getting discharged from day 3 of admission and all were discharged by the 11 th day. On the contrary in the SOC group, the patients started discharging on Day 4 and continued till day 14 for getting discharged. The average time of discharge for SOC + Ayurveda group (6.6±2.4 days) was less than one day as compared to SOC group (7.6±2.7 days).

Data regarding movement of patients to upward severity categories, adverse drug reactions, drug herb interactions and mortality were analysed for each of the two groups. The salient findings are as under: - No patients in either of the groups moved upwards in the classification of severity and all were discharged, alive and well from the hospital.  There was no mortality reported.  There were no adverse drug reactions observed and reported in this study.  No case of drug-herb interaction causing deterioration of clinical condition or quality of life of the patient was reported in the Ayurveda add-on group.  28 patients in the Ayurveda add-on group reported the Ayurvedic drug as acceptable and 2 reported it as being very bitter.

The patient discharged were followed after three months to enquire about their health telephonically. The details of those who responded are given in Table 7 below. It is noted that 28 in the SOC + Ayurveda group and 29 in SOC group responded to phone calls. The overall non response was 5% which is within acceptable limits ( Table 7) . The results are summarised in Table 8 below. The salient findings are as under:

 As to general health, relatively higher proportion in the SOC + Ayurveda group reported their health as Very Good and Much better now since discharge as compared to SOC group.  As to the Limitations on Activities, higher percentage in SOC group reported tiredness as compared to SOC + Ayurveda group. Relatively higher proportion in SOC group reported that work efficiency has been affected as compared to SOC + Ayurveda group.

 The problems of frequent headaches, sleep disorder, felt nervous and stressed, irritations and angered were reported 10 -15% in both the groups. The problem of lack of confidence and coping were reported by none in both the groups.  Respiratory, cardiac, dermatological (Skin), Burning Feet related problems were reported less in SOC + Ayurveda group as compared to SOC group. The need for oxygen support at home after discharge from hospital was reported by none in both the groups. Cardiac sequelae was not statistically significant between the SOC + Ayurveda and SOC groups (p > 0.05) ( Table 9 ). J o u r n a l P r e -p r o o f Based on the present study the Ayurveda add-on formulation (SOC + Ayurveda) seems to have influenced the better outcomes of patients in comparison to the SOC group. Our observations in this study strongly suggests that the addition of the Ayurveda add-on formulation Tinospora cordifolia and Piper longum has reduced the time to recovery (absence of clinical symptoms of COVID-19 disease and subsequent discharge from the hospital) for the patients in the SOC + Ayurveda group. It has also given considerable evidence of safety of the formulation, and proof of its non-interference with the action of the allopathic drugs prescribed. This formulation should be further investigated to provide an effective and safe herbal add-on to improve the outcomes of COVID-19 disease, reduce the incidences of its severity, and provide a viable and effective adjuvant to enhance the effectiveness of COVID-19 management.

J o u r n a l P r e -p r o o f

Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review

Traditional Chinese medicine for COVID-19 treatment. Pharmacological research

Traditional Chinese medicine for treatment of coronavirus disease 2019: a review

Ayurveda rasayana in prophylaxis of COVID-19

Ayurvedic research and methodology: Present status and future strategies

Clinical management protocol: Covid-19