Efficacy and safety of Ayush AGT gel-based cream in superficial external wounds: Study protocol of an open-label multicenter interventional single-arm trial

Amit K Rai; Shruti Khanduri; Sumeet Goel; Maheshwar Thugutla; Hemanta K Panigrahi; Avvaru J Sai Prasad; Anil Avhad; Richa Singhal; Rakesh Rana; Bhogavalli Chandrasekhararao; Narayanam Srikanth

doi:10.4103/jras.jras_112_22

PROTOCOL

Year : 2022 | Volume : 6 | Issue : 4 | Page : 200-205

Efficacy and safety of Ayush AGT gel-based cream in superficial external wounds: Study protocol of an open-label multicenter interventional single-arm trial

Amit K Rai¹, Shruti Khanduri¹, Sumeet Goel¹, Maheshwar Thugutla², Hemanta K Panigrahi³, Avvaru J Sai Prasad⁴, Anil Avhad⁵, Richa Singhal⁶, Rakesh Rana⁶, Bhogavalli Chandrasekhararao¹, Narayanam Srikanth⁷
¹ Department of Ayurveda, Central Council for Research in Ayurvedic Sciences, Ministry of Ayush, Govt. of India, New Delhi, India
² Dr. Achanta Lakshmipathi Regional Ayurveda Research Institute, Chennai, India
³ Central Ayurveda Research Institute, New Delhi, India
⁴ Regional Ayurveda Research Institute, Vijayawada, India
⁵ Regional Ayurveda Research Institute, Ahmedabad, India
⁶ Biostatistical Unit, Central Council for Research in Ayurvedic Sciences, Ministry of Ayush, Govt. of India, New Delhi, India
⁷ Deputy Director-General, Central Council for Research in Ayurvedic Sciences, Ministry of Ayush, Govt. of India, New Delhi, India

Date of Submission	04-Aug-2022
Date of Acceptance	14-Oct-2022
Date of Web Publication	05-Dec-2022

Correspondence Address:
Dr. Amit K Rai
Department of Ayurveda, Central Council for Research in Ayurvedic Sciences, Ministry of Ayush, Govt. of India, 61–65, Institutional Area, Opposite D-Block, Janak Puri, New Delhi 110058
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jras.jras_112_22

Abstract

BACKGROUND: Traditional medicine has been extensively used to manage skin wounds since ancient times. Central Council for Research in Ayurvedic Sciences has developed a coded herbal formulation, Ayush AGT gel-based cream, through a systematic drug development process for managing superficial skin wounds. OBJECTIVE: This clinical study is designed to determine the clinical efficacy and safety of Ayush AGT gel-based cream in healing superficial external wounds. MATERIALS AND METHODS: This open-label, multicenter, prospective, interventional single-arm trial is being conducted at three peripheral institutes of the Central Council for Research in Ayurvedic Sciences, Ministry of Ayush, Government of India viz. Central Ayurveda Research Institute, New Delhi, and Regional Ayurveda Research Institutes at Ahmedabad and Vijayawada, India. A total of 30 participants will be enrolled in the study from each of the three study sites. Patients of any sex aged 18–60 years with superficial external wounds requiring dressing and solitary wounds not less than 2.5 cm in diameter will be considered for enrollment in the study. The enrolled participants will be managed by the topical application of Ayush AGT gel-based cream on the wound bed once daily, followed by bandaging with the sterile material for four weeks. The outcome measures are time to complete re-epithelialization of the wound, incidence of wound infection, pain during the change of dressing (assessed through visual analog scale), incidence of blistering, and adverse events. DISCUSSION: Ayurveda interventions have been found effective in wound healing in routine clinical practice as well as in published experimental and clinical studies. Ethno-medicine practices also utilize different medicinal plants to manage skin wounds. Several patents on herbal interventions for wound healing have also been granted. However, clinical research to explore the standard wound management for superficial external wounds is not common. So, it is expected that the outcomes of this study will provide a significant lead in the search for safe and effective management options for skin wounds.

Keywords: Aloe vera, Ayurveda, Haridra, Kumari, Vrana, wound

How to cite this article:
Rai AK, Khanduri S, Goel S, Thugutla M, Panigrahi HK, Sai Prasad AJ, Avhad A, Singhal R, Rana R, Chandrasekhararao B, Srikanth N. Efficacy and safety of Ayush AGT gel-based cream in superficial external wounds: Study protocol of an open-label multicenter interventional single-arm trial. J Res Ayurvedic Sci 2022;6:200-5

How to cite this URL:
Rai AK, Khanduri S, Goel S, Thugutla M, Panigrahi HK, Sai Prasad AJ, Avhad A, Singhal R, Rana R, Chandrasekhararao B, Srikanth N. Efficacy and safety of Ayush AGT gel-based cream in superficial external wounds: Study protocol of an open-label multicenter interventional single-arm trial. J Res Ayurvedic Sci [serial online] 2022 [cited 2023 Mar 25];6:200-5. Available from: http://www.jrasccras.com/text.asp?2022/6/4/200/362650

Introduction

Any break or interruption in the continuity of the body surface is referred as a skin wound. It may be caused by trauma, burns, surgery, vascular disease, and other disorders. Skin wounds may be broadly categorized as acute or chronic. Acute wounds show well-defined healing characteristics within 4 weeks, whereas chronic wounds require prolonged time for routine wound healing. The morbidity associated with the wounds can also impact the patient’s quality of life.^[1] Wound healing is a complex process involving three overlapping phases, i.e., inflammation, proliferation, and remodeling. Various local and systemic factors can interfere in the process of normal wound healing. A lack of growth factors, hypoxia, microbial infection, unstable moisture environment, necrosed tissue, localized edema, immunosuppression, peripheral vascular disease, protein insufficiency, diabetes mellitus, obesity, smoking, alcohol consumption, etc., have an impact on the healing process.^[2] The main objectives of the wound care include accelerated re-epithelialization, reducing pain and discomfort, and preventing microbial infection.^[3] The healing process is frequently thought to be self-evident in superficial external wounds. Still, to avoid complications and ensure a satisfactory cosmetic outcome, these wounds benefit from a moist environment created through topical ointments and dressings to encourage optimal wound healing.^[4] Topical application of interventions having antioxidant, anti-inflammatory, and antimicrobial properties is found to be effective in wound healing.^[4] However, clinical research examining the standard wound management for superficial external wounds is still uncommon. Further, the available options from conventional medicine for wound management did not effectively impact the tissue-repairing process.^[5]

Traditional medicine has been used considerably to manage skin wounds since ancient times. In Ayurveda, Acharya Sushruta has described the definition, classification, presentation, prognosis, management, and complications of Vrana (wound) in a precise and scientific manner.^[6] Sixty Upakrama (measures) have been suggested for wound management in Sushruta Samhita.^[6] Some research studies and case reports are also available on the Ayurveda interventions in the wound management.^{[7],[8],[9],[10]} The Central Council for Research in Ayurvedic Sciences (CCRAS), Ministry of Ayush, Government of India, has developed a herbal formulation, Ayush AGT gel-based cream, through a systematic drug development process for the management of superficial skin wounds. This study is planned to determine the wound healing effect of a coded Ayurveda intervention in managing superficial external wounds.

Objective

The objective of the study is to evaluate the clinical efficacy and safety of Ayush AGT gel-based cream in healing superficial external wounds.

Materials and Methods

Study design and setting

This study is an open-label, multicenter, prospective, interventional single-arm trial. The study is being conducted at Central Ayurveda Research Institute (CARI), New Delhi, and Regional Ayurveda Research Institute (RARI) at Ahmedabad and Vijayawada, India.

Study participants

Inclusion criteria

Patients of either sex aged 18–60 years with superficial external wounds requiring dressing and solitary wounds not less than 2.5 cm in diameter will be enrolled in the study.

Exclusion criteria

Patients having wound associated with fracture or skin disorders; wound requiring full-thickness graft; neurological deficit at the wound site; reference wound that cannot be treated in isolation from other wounds; varicose veins/deep vein thrombosis; known case of HIV infection or other sexually transmitted diseases, hepatitis B, uncontrolled diabetes mellitus (HbA1c > 8.0%), malignancy, coagulation disorders, hepatic or renal dysfunction; treatment with immunosuppressive medications; hemoglobin level below 7.0 g/dL, and serum albumin below 3 g/dL will not be considered for the study. Patients with known hypersensitivity to any of the ingredients of the trial drug or any of the components of the dressing; any other clinical condition that the investigator thinks may jeopardize the study; who have completed participation in any other clinical trial during the past six months, and pregnant and lactating women will also not be included in the trial.

Study intervention

Study participants with superficial external wounds will be managed by the Ayush AGT gel-based cream for a period of four weeks. They will be advised to apply the cream in sufficient quantity on the wound bed once daily and bandaged with the sterile material. The study participants will be requested to visit the study site every week for the assessment of the wound.

The Ayush AGT gel-based cream (each tube of 20 g) is procured from Indian Medicines Pharmaceutical Corporation Limited (IMPCL), a GMP-certified company, under the Ministry of Ayush, Government of India. Ayush AGT gel-based cream is a coded herbal formulation consisting of Haridra (Curcuma longa L.) and Kumari (Aloe vera (L.) Burm. f.). The physicochemical standards of this intervention have been developed by the CCRAS, Ministry of Ayush, Government of India. Quality control and safety parameters of the constituents and the formulation are as laid down in the Ayurveda Pharmacopoeia of India.

Outcome measures

The primary outcome measure is the time to complete re-epithelialization of the wound. The assessment will be done through the Bates-Jensen wound assessment tool on day 7, 14, 21, and 28. The secondary outcome measures are the incidence of wound infection (evident by the presence of excessive erythema, edema, pain, purulence, fever, and lymphadenitis till day 28), pain during the change of dressing (assessed through the visual analog scale of 0–10 till day 14), incidence of blistering (assessed till day 7), and adverse events, and change in laboratory parameters (complete blood count and liver and kidney function tests) from baseline to day 28. High-quality digital photo documentation of the wound site will be done at baseline and on each of the scheduled follow-up visits on day 7, 14, 21, and 28.

The schedule of enrolment, intervention, assessments, and follow-up visits for the study participants is given in [Table 1].

Table 1: Study schedule

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Safety outcomes

The safety of the trial intervention will be evaluated by recording the incidence of adverse events on every scheduled follow-up visit. All adverse events during the study will be recorded and monitored as per Good Clinical Practice (GCP-ICH) guidelines.

Withdrawal criteria

If any participant developed serious adverse events (SAE) or treatment-emergent adverse events during the study period, then they will be withdrawn from the study. Such cases will be given appropriate incidental care or referred to a higher medical facility. The participants who do not adhere to the study protocol or are unwilling to continue their participation will also be withdrawn from the study. The reasons for the withdrawal will be recorded in the participant’s case record form (CRF). The Sponsor and the Ethics Committee will be notified of the decision to withdraw a participant from the trial because of SAE within 2 working days, along with proper justification.

Sample size

The sample size for the study is calculated based on the mean time to complete re-epithelialization of the wound. Based on the clinical experience, it is assumed that the mean time to complete re-epithelialization will be 18 days without intervention, and a reduction of 6 days is anticipated in this duration after the topical application of the trial intervention. With a standard deviation of 10 days, 80% power, and 95% confidence interval, a sample size of 22 would be enrolled in the study. Adding an attrition rate of 25%, the sample size will be 28, which is rounded off to 30. Therefore, 30 participants will be enrolled in the study from each study center.

Recruitment

After obtaining written informed consent, patients with superficial external wounds will be screened for eligibility to participate in the study. The participants will be enrolled from the outpatient department of the study sites based on the predefined inclusion and exclusion criteria.

Compliance

Compliance will be monitored by assessing the frequency of application of the trial medication during the stipulated period through the compliance assessment form issued to the participant. The patient will be continued in the study if the compliance is more than or equal to 80%.

Concomitant and rescue medication

Study participants will be instructed to consult the investigators before taking other medications for any ailment. The study investigators will record the medication(s) prescribed to alleviate the participant’s any other ailment. The use of any rescue medication will be permitted to alleviate any medical emergency. However, the same will have to be documented appropriately in the CRF.

Data collection and documentation

The clinical data relevant to the study outcomes will be collected from the participants on the scheduled follow-up visits. The data collected during the follow-up visits will be entered in the respective CRFs. The data will be subsequently recorded in an e-format for statistical analysis and record. Attempts will be made to collect the data from the drop-out participants through intermittent follow-up or telephonic conversation, if they agreed to do so.

Statistical analysis

Categorical data on baseline characteristics will be presented as numbers (percentage). Normally distributed data will be presented as mean (±SD), and 95% confidence interval and non-normally distributed data will be presented as median and interquartile range. The analysis will be done using paired sample t-test for normal data, whereas Wilcoxon signed-rank test will be used for non-normal data. A P < 0.05 will be considered statistically significant. The per-protocol analysis of the study data will be done. Data analysis will be performed using the SPSS version 28.0.

Monitoring

The study will be monitored by the concerned officers of the funding agency through regular site visits. The biostatistical unit of the funding agency will review the e-format of the CRFs every fortnight.

Trial audit

The investigators will ensure access to all the source documents, CRFs, and other study documents for the onsite audit or inspection by the regulatory authorities, institutional ethics committee, or the funding agency.

Ethics and dissemination

The study protocol is prepared following the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. The study is approved by the Institutional Ethics Committee of the CARI New Delhi (vide letter no. 1–12/2015-ACRI/Tech/IEC/Part-II dated 02.04.2019), RARI Vijayawada (vide letter no. 4–22/2014-RARISD/VJA/Tech-IEC/699 dated 01.08.2019), and RARI Ahmedabad (dated 08.08.2019) and is registered prospectively at the Clinical Trial Registry of India (CTRI/2020/04/024658). Written informed consent will be obtained from the eligible patients by the investigators before enrollment. The study will be conducted in accordance with the ICMR National Ethical Guidelines for Biomedical and Health Research on Human Participants (2017). The study outcomes will be disseminated through research articles in peer-reviewed scientific journals and presentations at national conferences.

Deviation from the protocol

The investigators will not alter or deviate from the protocol without prior approval from the IEC and the funding agency. All substantial amendments affecting patient safety or study integrity will need prior approval from the IEC before implementation in the study.

Confidentiality

All the study-related data will be stored securely at the trial site with password-protected access systems. All the information related to the study participants will be stored in areas with limited access. All the records and documents that contain personal identifiers will be stored separately from the study records identified by a code number. The study participant’s data will be coded to maintain participant confidentiality.

Ancillary and post-trial care

No ancillary studies are proposed with this clinical study. The study participants will be given routine medical care if required, after the completion of the study period.

Discussion

Skin wounds and impaired wound healing have been challenging public health issues since ancient times. Skin wound healing is a complex physiological process involving numerous cell types, growth factors, cytokines, and chemokines.^[11],[12] The cellular and biochemical events in the wound healing process include inflammatory reaction, cell proliferation, the synthesis of extracellular matrix, and the tissue remodeling phase.^[13] Generally, superficial external wounds heal without any complications. However, several local and systemic factors impact the normal wound healing process.

Traditionally, medicinal plants and plant-based constituents have been extensively utilized for wound healing purpose.^[14],[15] In Ayurveda, the description of Vrana (wound) and its management has been emphasized in detail in Sushruta Samhita and other classical textbooks. Several Ayurveda interventions have been found effective in wound healing in routine clinical practice as well as in published studies and case reports.^{[7],[8],[9],[10]} Further, various experimental studies have also reported the wound healing properties of Ayurveda medicinal plants such as Haridra (Curcuma longa L.), Mandukaparni (Centella asiatica (L.) Urb.), Kumari (Aloe vera (L.) Burm.f.), Nimba (Azadirachta indica A. Juss.), Manjistha (Rubia cordifolia L.), Yashtimadhu (Glycyrrhiza glabra L.), Doorva (Cynodon dactylon (L.) Pers.), etc.^{[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30]} These medicinal plants contain various natural bioactive substances that hasten wound healing and promote tissue regeneration at the wound site. Ethno-medicine and local health tradition practices also utilize various medicinal plants to manage skin wounds. Several patents on herbal interventions for wound healing have also been granted.^[31]

CCRAS has developed Ayush AGT gel-based cream containing Haridra (Curcuma longa L.) and Kumari (Aloe vera (L.) Burm. f.) through a systematic drug development process. Preclinical safety–efficacy studies have been undertaken on this formulation by the CCRAS, which include dermal toxicity (acute and subacute) on Wistar rats and skin irritation test in rabbits. Ayush AGT was found safe on topical application in these studies. The formulation was also assessed for wound healing activity on experimental models and demonstrated wound healing action. Further, Curcuma longa has significant wound healing properties because of its antioxidant, antimicrobial, and anti-inflammatory properties. Curcumin in C. longa, stimulates fibroblast proliferation, granulation tissue formation, and collagen deposition, which help in the healing of skin wounds.^{[16],[17],[18]} Further, Aloe vera has shown antimicrobial and antioxidant activity and significantly reduces the time for wound re-epithelialization.^[22],[23]

So, it is expected that the outcomes of this study will provide a significant lead in the search for safe and effective management options for skin wounds.

Acknowledgment

The authors are thankful to Prof. Rabinarayan Acharya, Director-General, Central Council for Research in Ayurvedic Sciences, Ministry of Ayush, Government of India, for his valuable guidance and administrative support.

Financial support and sponsorship

The study is funded by the Central Council for Research in Ayurvedic Sciences, Ministry of Ayush, Government of India. The funding agency also provided technical support in the study design and development of the study protocol.

Conflict of interest

There are no conflicts of interest.

Access to data

The funding agency, i.e., CCRAS, will have access to the final study data.

Authors’ contributions

SK, SG, and TM conceived the study and initiated the study design. HP, SP, and AA drafted the initial study protocol. AKR finalized the study protocol and drafted the article. The protocol was finalized with inputs from BC and NS. RS and RR provided the statistical inputs. All authors contributed to the study protocol’s refinement and approved the article’s final draft.

Trial status

Participant recruitment for the study started at all the three designated study sites.

Protocol number

CCRAS-IMR-AGT-01 version: 2.0 dated 03.12.2021.

Appendix A

Supplementary file 1: SPIRIT checklist.

Supplementary Information

The online version contains supplementary materials available at DOI: 10.4103/jras.jras_112_22.

Supplementary file 1: SPIRIT checklist

SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*

Click here to view

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