Methodological analysis of CTRI registered clinical trials on Ayurveda interventions for COVID-19 management.

The unexpected emergence of the Coronavirus disease-19 (COVID-19) pandemic has become a serious threat and a challenge to the entire world. In the last few months, several clinical trials evaluating AYUSH systems, especially Ayurveda, have been initiated in India. There is a higher number of Ayurveda trials for COVID -19 compared to other AYUSH systems on Clinical Trials Registry - India (CTRI) (113 out of 197 Until Aug 2020) (1). The clinical trial protocol provides guidance to individuals conducting the study, serves as the basis for study registration, and facilitates study appraisal by participants and external reviewers, including institutional review boards, regulators, funders, and journal editors. However, there is accumulating evidence that many protocols do not address important study elements (2). Therefore, it is critical to analyze the emerging clinical trial protocols (Datasets of protocols available) on CTRI regarding the use of Ayurveda for the prevention and/or treatment of COVID-19. The present study attempts to assess the characteristics of Ayurveda studies regarding COVID-19 registered on CTRI, and to understand the types and methodological aspects of these studies, using datasets available on CTRI.

Methods

We searched the CTRI database from the website www.ctri.nic.in, an official Clinical Trials Registry-India website. We searched all the interventional trials’ datasets regarding Ayurveda for COVID-19, registered between 1st Jan 2020 and 31st Dec 2021, using keywords: COVID-19, SARS-COV-2, Coronavirus, and Ayurveda, Ayurvedic intervention, Ayurvedic medicine. All interventional trials independent of their status were included (Complete/incomplete, recruiting/not recruiting, Published/Unpublished, single-arm/double arm/triple arm, Phase I/II/III). Information regarding the following characteristics has been extracted from the datasets:

CTRI number, Name of Principal investigator, Title, Place/site of the trial, Centre, Trial status, study design, Type (Prophylactic/Therapeutic), Number of arms, Inclusion/exclusion criteria, Population included Gender/age of the population, Randomization, Method of generating random sequence, Method of allocation concealment, Intervention, Duration of intervention, duration of the study, Control/comparator details, Blinding details, Target ample size, Primary outcome, Secondary outcome, Type and name of a sponsor.

To get additional data regarding some other important variables based on SPIRIT and PICOT, (3), we prepared google form questionnaires to be sent to Principal investigators of the studies, which included the following characteristics:

Study setting, Rationale of the study (here we enquired about ayurvedic rationale), Sample size calculation details (such as any statistical or clinical assumption, Type of randomization (Simple/stratified/block, etc.), Unblinding criteria, Data analysis plan, stopping guidelines for trial, Post-trial care, Plan to record/manage adverse events, Rationale for inclusion and exclusion criteria, Intervention as an adjunct or stand-alone treatment Sponsor (Government/Private/Pharmaceuticals), Presence of comorbidity, Method of disease diagnosis, Involvement of ayurvedic physician in the trial. Additionally, to assess the quality of the included trials, we used the 'Modified Jadad scale' (Details shown in Table 1 ) (4).

Table 1

Modified Jadad scale.

Question	Response	Possible score
Was the study described as randomized?	Yes/No	1/0
Was the method used to generate random sequence appropriate?	Yes/No	1/0
Was the study described as double-blinded?	Yes/No	1/0
Was the method of double-blinding appropriate?	Yes/No	1/0
Was there allocation concealment present?	Yes/No	1/0
Was the method for allocation concealment appropriate?	Yes/No	1/0
Total possible score:6Interpretation: Total score </=3: Not satisfactory and Total score >3: Satisfactory

Results

The month-wise distribution

The month-wise distribution of these trials has revealed that there were no studies registered until March 2020, the highest number of studies are registered in May, June, and July 2020, after which there is a decline in the number of studies registered. Geographical mapping of the study sites revealed that the maximum number of studies are conducted in the state of Maharashtra(n=31).

General characteristics of the studies

Investigators’ background suggests that the majority of the trials (n=87) involved ayurvedic physician in the study, while other (n=35) trials did not have an ayurvedic physician involved. A major number of trials (n=58) were sponsored by the Government of India and Governmental funding agencies such as the Ministry of Ayush, as compared to investigator-initiated/academic studies (n=37). There were 27 studies funded by pharmaceutical industries.79 studies included a population aged between 18-70 years, while 29 studies included participants above the age of 70(Maximum 99 years). 11studies included population below the age of 18 years, one study even included an age group of 1 day to 80 years. 3 studies included both sets of the population that is below 18 years and above 70 years.

Characteristics of Hospital-based/COVID centre-based studies (n=106)

These studies can be further divided into prophylactic (n=39) and Therapeutic (n=83) studies, as per the study's primary aim. The Majority number of the therapeutic studies included Mild to moderate (N=75), followed by Asymptomatic to mild (N=7) and Severe (N=1) COVID-19 patients. The study which included severe COVID-19 patients was carried out on patients admitted at an indoor department of multispeciality dedicated COVID-19 hospital, while the study drug which was a Herbo mineral combination was administered for 12 days duration, along with standard treatment. The majority of the studies were having 2 arms (n=80), while others were having a single arm (n=25). One study included 3 arms. The most common method used for generating random sequences is Computer-generated randomization (n=44). Amongst 79 randomized studies, 57 studies mentioned having allocation concealment present, while 2 studies did not have allocation concealment. 18 studies mentioned allocation concealment either as “Not applicable” (n=16) or ‘Other” (n=2). ‘Open list of random numbers’ was the most frequently used method for allocation concealment (n=21). Out of 106 trials, 24 trials were blinded and 75 trials were Open-label studies. 7 studies mentioned blinding as "Not applicable". The major number of trials (N=63) involved 'Conventional/Standard care' as a control group/comparator. Duration of intervention for therapeutic trials was 7-15 days for a major number of the studies (N-47), while for prophylactic trials it was up to 3 months. The most common range of sample size included was 50-100 participants and the maximum sample size was 500. Primary outcomes in these studies were Time for clearance of infection either confirmed clinically or by laboratory tests Or Progression of the disease Or Incidence of infection, depending upon the aim of the study. Modified Jadad score: 70 studies had a modified Jadad score of 3.

Characteristics of community-based studies (n=16)

All of the community-based studies (n=16) were Prophylactic and Open-label studies. 11 studies were single-centered, and 5 studies were multi-centered. Duration of intervention ranged from 1 month to 3 months. The sample size in these studies was in the range of a minimum of 500 to a maximum of 50,000 participants. An obvious primary outcome in these trials was 'Incidence of infection'.

Intervention details for year 2020 studies

Guduchi (Tinospora cordifolia) has been used most frequently in both Hospital-based (n=20) and community-based studies (n=11) followed by Ashwagandha (Withania somnifera) (n=9) and Yashtimadhu (Glycyrrhiza gabra) (n=7).

The second most frequently used herb is Ashwagandha (n=12). Ashwagandha has been used as a Rasayana (rejuvenator), adaptogen, antioxidant, anxiolytic, anticancer, immunomodulating, and anti-inflammatory. It contains a range of constituents like withanolides, sitoindosides, and other alkaloids that protects cells from oxidative damage.

The third most used (n=8) herb is Yashtimadhu (Glycyrrhiza gabra)/Licorice. This plant contains different phytocompounds such as glycyrrhizin, glabrin A and B, and Isoflavones. It has anti-inflammatory, anti-viral, antioxidant properties,

AYUSH -64, a drug developed by CCRAS was used in hospital/COVID center-based studies. AYUSH -64 is a multi-herb formulation containing a combination of Saptaparna (Alstonia scholaris), Chirayata (Swertia chiraita), Katuki (Picorrhiza kurroo), and Kuberaksha (Caesalpinia crista).

AYUSH kwath, which is also recommended by the Ministry of Ayush for prophylaxis and contains a combination of Tulsi (Ocimum sanctum), Dalchini (Cinnamomum zeylanicum), Sunthi (Zingiber officinale), and Marich (Piper nigrum) was used in 2 hospital-based studies and 1 community-based study.

Curcumin was used in different forms such as curcumin tablet, powder, or Haridra Khand in hospital-based studies (n=5).

Chyavanprash which is recommended by the Ministry of Ayush as an immunity enhancer was used in hospital/COVID center-based studies (n=5) and community-based studies (n=4) as well.

There are different kwath/decoctions used which contains a combination of various herbs such as Surasadi kwath, Bharangyadi kwath, Pathyadi kwath, etc.(n=18)

Anu tail Nasya (through nasal route) was used in 3 hospital-based studies and 2 community-based studies. Til tail (Sesame seed oil) was used in 1 study.

There are other classical Ayurveda formulations used such as Malla chandrodaya, Sudarshan Vati, Pippali Rasayana, etc. in some of the studies (n=18).

Many of the studies (n=25) used proprietary Ayurveda formulations. Details of ingredients of most of these formulations could not be retrieved from the protocols.

4 of the studies mentioned using personalized Ayurveda medicine according to various patient parameters and disease stages according to the physician’s judgment.

Total clinical trial dataset analysed from the year 2021 is 18

Out of these 18 studies, studies that were for treatment/prevention purposes are 8. The studies related to the COVID-19 vaccine were 2, while the studies related to post COVID syndrome were 6. The studies in which the nasal route for medication is used were 2.

Randomization: Out of these 18 studies, 11 studies were randomized.

Allocation concealment: 3 studies had ‘sequentially numbered, sealed, opaque envelopes and 2 studies had ‘an Open list of random numbers as a method of concealment. 4 studies involved ‘an Open list of random numbers’ while 2 had ‘Centralized’ and 1 has alternation.

Blinding: Only 5 studies were double-blinded (participant and outcome assessor-blinded) while 1 study was single-blinded (Outcome assessor blinded). All other studies (N=13) were Open labelled studies.

Primary outcome: In 8 studies, the primary outcome was ‘Time to recovery or Time for negative RTPCR’. In 2 studies related to the COVID-19 vaccine, the primary outcome was ‘Antibody titre’, while in the remaining 8 studies, it was ‘Time to symptomatic recovery’.

Secondary outcome: In these studies, the secondary outcome was either Occurrence of adverse events, Lab biomarkers, or Quality of life.

Sample size: Minimum sample size included is 30 while the maximum is 80000, which included a large cohort of Delhi Police.

Study duration: The duration of the study ranged from 1 Month to 1 year.

Discussion

Our review has considered Ayurveda trials for COVID-19 registered on CTRI from January 2020 to December 2021.

A steady decline in the number of registered studies is contradictory to the steady rise observed in the number of COVID-19 positive cases until October 2020 (As shown in Figure 1 )(9). State-wise distribution of the trials is in line with the fact of the presence of the highest number of cases in Maharashtra. The non-involvement of AYUSH experts in 35 studies is contradictory to the advisory by the Ministry of Ayush released on 2nd April 2019, which recommends the involvement of AYUSH experts in AYUSH trials' planning and conduct. Major funding by Government and its agencies indicates a positive step towards Ayurveda research. An almost equal number of trials conducted by Allopathic medical colleges as Ayurveda medical colleges point towards growing interest and recognition of the potential of Ayurveda by modern medical researchers. There is a need for more collaborative efforts between Ayurveda and modern institutes. The modified Jadad score of less than 3 of the majority of the trials suggests the need for improvement in the quality of these trials. Although ayurvedic medicines, when manufactured properly and prescribed in a proper therapeutic dose are considered safe even in children, the details of whether the dosages were adjusted according to the age of the participant are not mentioned in the protocols. Especially, caution should be considered when using ras aushadhi (Herbo mineral formulations) in children. Although guidance by the AYUSH ministry for management and use of specific ayurvedic formulations for COVID-19 cases with comorbidities such as diabetes, hypertension, and immunocompromised conditions has been provided, none of the studies included these populations in these trials. A personalized and holistic approach to treatment, which is a characteristic feature of Ayurveda has been used in only 4 of these trials. This approach should be encouraged in future studies. None of the registered trials mentioned any dietary restrictions or lifestyle modification advised. This might be because of the non-feasibility of these factors in hospitalized patients. However, it should be noted that not considering these factors can compromise the efficacy and success of Ayurveda interventions.

Figure 1

Monthwise distribution of Ayurveda trials for COVID-19 registered on CTRI till December 2021.

Many of the other characteristic features of Ayurveda such as Panchkarma include gargles with herbal decoctions, mouth rinses, steam inhalation, consuming hot water/medicated water, which may have potential in the management of COVID-19 can be explored in future clinical trials. As COVID-19 is a public health concern, the interventions or drug formulations such as Guduchi, chyavanprash, which are affordable to the general population, compared to conventional treatment should be investigated further.

12 of these trials had intervention duration

In community-based studies, the sample size ranged from 500 to 50,000, with the maximum number of trials including sample size below 2000. Although these studies involved a larger group of the population as expected in community-based studies, it is critical to assess the compliance of the participants to the intervention. In these trials, healthy volunteers with a high risk of exposure such as in hotspots were involved and study drug was distributed among these populations. Mostly Rasayana drugs such as Guduchi, ashwagandha, yashtimadhu, chyavanprash were used in these studies. It is difficult to find out whether these people were consuming some other medicines or adjuvants or any other immunomodulators. In this situation of ‘Infodemic' where huge information is available on public platforms, it was very obvious for the general public to try out various treatments/possible prevention interventions such as home remedies. Therefore, it is presumed that these confounding factors were taken care of by respective research teams.

There are only 18 studies meeting the eligibility criteria in the year 2021. This number is very less compared to the studies conducted in 2020(N=122). Despite the second wave of the COVID-19 in 2021, the number of studies conducted has not escalated. There are some studies related to the COVID vaccine, to assess the add-on effect of Ayurveda intervention after the vaccine dose. Few studies also explored the effect of add-on Ayurveda intervention in Post COVID syndrome symptoms such as fatigue, cough, etc. The percentage of randomized studies in the year 2021 has decreased as compared to the year 2020(75% vs 60%). In terms of blinding, there is still the same trend as the year 2020. Very few studies are blinded. The primary and secondary outcomes remained consistent (it is obvious). However, in some studies (N=3) authors wrongly mentioned the study outcome/expected impact of the study as the primary/secondary outcome. There is a large variation in sample size smallest being 30 while the largest cohort included 80000 participants. Interventions/herbs used in these studies mostly focused on boosting immunity, such as Ashwagandha, Guduchi, Yashtimadhu, Pippali, Chyavanprash and other proprietary products such as Immuzan tablets, Pulmocard capsules, etc. In some studies (n=5) duration of the intervention is not mentioned 1. (Refer to Table 2 ). This lack of reporting about details of the intervention in the protocol on CTRI can be overcome by providing structured intervention details template in the protocol format.

Table 2

Intervention details for year 2021 studies.

Study No.	Name of the intervention	Duration of intervention
1.	Tab Gorochanadi Vati	3 days
2.	SwasVimochan, SwasanRakshak,Swasamrite, Immune EnergyTablets	7 days
3.	Noxguard nasal spray	14 days
4.	CIM-Meg19 (kalmegh and minerals)	21 days
5.	Inhaler containing Cinnamomum Camphora and Trachyspermum ammi	28 days
6.	NOQ19 500 mg (Ashwagandha +Yashtimadhu)	28 days
7.	AEV01 (root extract of Kutki (Picrorhiza kurroa))	30 days
8.	Ayush 64 capsule, Sanshamani Vati, Vatashleshma Jwarhar Kwatha	30 days
9.	Vardhmana Pippali	30 days
10.	Chatushashti Prahari Pippali	8 weeks
11.	Zandu Chyawanprash, Zandu Pure Honey, Trishun Tablets and Immuzan Tablets	8 Weeks
12.	Ashwagandha Capsule	12 weeks
13.	Ashwagandha Tablet	24 Weeks
14.	Balchaturbhadrika Churna, Laghu Malini BasantRasa	Not mentioned
15.	AYUR RAKSHA Kit
16.	NF2 and NF4 (Ayurvedic medicine)
17.	PulmoCard caps, Acalogen caps, Opthoxy eye drops and ZingiVir-H tablets
18.	Sadangpaniya kwath, Viyosadi churn tablet, Vyasthapan kasay ghana tablet

Conclusion

Although there is a surge of clinical trials on CTRI regarding Ayurveda for COVID -19, the methodological quality is not up to the mark and there is large scope for improvement.

Recommendations

Randomization methods such as restricted randomization (especially in the case of a small sample) should be considered.

Maximum allocation concealment and appropriate methods of concealment should be taken into consideration.

Blinding should be implemented as much as possible.

Larger sample sizes with statistical sample size calculation by considering parameters such as expected power of the study, level of significance, effect sizes, should be considered. Further, follow-up studies with larger samples are needed.

There is a need to implement characteristic features of Ayurveda in clinical trials such as personalized approaches, dietary and lifestyle modifications, and panchakarma therapies as well.

CTRI dataset format can be improved further by including details of some sections such as randomization details, Sample size calculations, statistical analysis plan, Intervention details such as nature of the intervention (The whole herb, extract, etc) and duration, Specification of the terms such as 'Other' wherever mentioned.

Limitation

The present study considered only available protocol datasets on CTRI, which are not complete protocols. Further detailed analysis may have been possible with complete protocols. Additional information regarding some characteristics of the studies could not be retrieved from respective Principal investigators, which may limit the analysis.

Declaration

There is no conflict of interest.

Uncited References

5; 6; 7; 8; 10; 11.