JMIR Publications

ABSTRACT

Background:

Background:

Acute Mountain Sickness (AMS) poses a unique and formidable challenge to healthy personnel at high altitudes. This randomized controlled trial protocol was designed to assess the effectiveness of Ayurveda nutritional supplements in conjunction with a Yoga protocol in reducing the incidence and severity of AMS among healthy personnel stationed in the challenging high-altitude (HA) landscapes of the western Himalayas.

Methods:

The proposed open-label, parallel-group RCT was conducted in apparently healthy individuals of any gender aged 18-50 years. The study was conducted at two distinct HA stages within the western Himalayan region: Stage I, situated at an elevation ranging from 9,000 to 12,000 feet, and Stage II, spanning 12,000 to 15,000 feet. A total of 1,660 participants (830 per stage) underwent random assignment in a 1:1 ratio to receive either the existing acclimatization schedule (AS) for HA (Control Group-CG) or the Ayush intervention (AG) along with the AS. The participants in the AG received Ayurvedic nutritional supplements, namely, Ayur-Nutri Kit (Ayush Poshak Yoga, 25 gm, and Ayush CCT, 125 ml, twice daily), and a Yoga protocol (for 60 minutes daily) for 120 days. The primary outcome was the incidence of AMS assessed through the Lake Louise Scoring System 2018 (LLSS) and the proportion of participants with LLSS score ≥ 6 during the first seven days from baseline. The secondary outcome measures included the proportion of participants with thromboembolic events, change in coagulation and hemostasis activation markers, pro-inflammatory markers, and change in self-reported negative emotional states of depression, anxiety and stress, sleep quality and overall quality of life (assessed through DASS-21, PSQI, and SF-12 respectively) on day 60 and day 120 from baseline.

Results:

The recruitment of study participants has been completed. The analysis of the study data is in progress.

Conclusions:

This RCT was the first of its kind to explore the potential benefits of utilizing Ayurveda nutritional supplements and a yoga protocol alongside the standard AS to reduce the occurrence and intensity of AMS among healthy personnel. The outcomes of this trial can aid in better acclimatization and resilience among healthy personnel in HA. Trial registration: Clinical Trial Registry of India -CTRI/2023/03/051028

Objective:

The present RCT was designed to assess the effectiveness of a combination of Ayurveda nutritional supplements and Yoga protocol in reducing the incidence and severity of AMS compared to the standard acclimatization schedule at HA areas in the western Himalayan region. The key secondary objectives of this study included evaluating the impact of the Ayush intervention protocol (Ayur-nutrikit + Yoga) on subjective and assessment parameters of coagulation and hemostasis activation markers, pro-inflammatory markers, negative emotional states of depression, anxiety, and stress, sleep quality, and overall quality of life after 120 days. Another secondary objective was assessing the safety of Ayush interventions in AMS.

Methods:

The study protocol has been drafted following the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines [26]. Study design and setting This clinical study was an open-label, randomized, controlled parallel-group trial. HA areas are classified as stage I (9000-12000 feet), stage II (12,000-15,000 feet), and stage III (more than 15,000 feet) [27]. The study was conducted at stage I and II HA areas in the western Himalayan region. Study Participants Apparently healthy personnel of any gender aged 18-50 years deemed physically fit for deployment to HA areas (of western Himalayan regions) and willing to provide written informed consent were included in the study. The study population encompassed individuals being deployed for the first time at HA and those who resumed deployment following a break. Individuals with history of underlying cardiovascular disease or a clinically significant ECG abnormality, cerebrovascular disease, pulmonary disease, neurological disease, psychiatric illness, major venous thromboembolism (deep vein thrombosis/ pulmonary embolism/ cerebrovascular thrombosis), sickle-cell disease, metabolic disorders, malignancy, glaucoma; history of pulmonary edema or severe physiological response to high altitude (such as HAPE); having evidence of uncontrolled diabetes mellitus (HbA1c more than 8.0%), uncontrolled hypertension (more than 140/90 mm Hg) even after medications, abnormal hepatic function (AST and/or ALT more than two times the upper limit of normal) or abnormal renal function (serum creatinine more than 1.2 mg%); BMI ≥ 30 kg/m2 were excluded from the study. Similarly, those with a history of any surgery within the past six months, transfusion of blood or any blood product within 90 days before screening; those taking any concomitant conventional medication regularly; history of chain smoking, alcohol use disorder, substance abuse; and the presence of any other clinical condition which the investigator thinks may jeopardize the safety of the study participants were not considered for the study. Study intervention The eligible participants in the Ayush group (AG) received a comprehensive Ayush-AMS protocol, which includes the use of an Ayur-nutri kit and a Yoga protocol along with the existing acclimatization schedule (AS), for 120 days while deployed at HA regions [27]. The Ayur-nutri kit contains two herbal products, viz., an Ayurveda nutritional supplement, Ayush Poshak Yoga, and an herbal tea, Ayush CCT (Ayush cardiac care tea), developed by the Central Council for Research in Ayurvedic Sciences, Ministry of Ayush, Government of India to address nutritional supplementation requirements and to maintain healthy well-being at high altitude regions. The Ayush Poshak Yoga powder contains a diverse blend of nuts and seeds, including cashews, almonds, pistachios, walnuts, pumpkin seeds, and cucumber seeds. It also contains herbs such as Withania somnifera (L.) Dunal, Piper longum L., Tinospora cordifolia (Willd.) Miers ex Hook.f, Piper nigrum L., Zingiber officinale Roscoe., Foeniculum Vulgare Mill., renowned for their nutritional and therapeutic benefits (Table 1). The Ayush CCT is a novel herbal tea combining the heritage of traditional tea with a combination of herbal ingredients such as Terminalia arjuna (Roxb.) Wight & Arn, saffron, cardamom, and cinnamon that can promote cardiovascular health, overall well-being, and healthy circulation (Table 1). Ayush CCT was made into an infusion by dipping one Ayush CCT tea bag in 125 ml hot water for five minutes, allowing appropriate steeping time, and then used warm. Ayush Poshak Yoga was given in the dose of 25 gm twice daily (morning and evening, one hour before meals), along with 125 ml of Ayush CCT. The Yoga protocol (High Altitude Illness Prevention Protocol of Yoga) has been tailor-made for HA by the Central Council for Yoga & Naturopathy, Ministry of Ayush, Government of India. The participants performed the yoga protocol under the supervision of a qualified yoga instructor. It involved sessions beginning with breathing exercises, moving onwards to performing Asanas in standing posture (05 Asanas), followed by Asanas in supine (05), prone (02), and sitting postures (02). The yoga session concluded with a sequence of Pranayama and meditation/breathing exercises, with each session totalling approximately 60 minutes each day. The schedule of Yoga followed an alternating pattern throughout the 120 days (Table 2). Incorporating diverse Asanas within varying postures, strategically arranged in specific patterns, ensured that each sequence effectively addressed certain aspects, such as the targeted engagement of distinct muscle groups and nurturing mental well-being. The participants in the control group followed the existing AS for HA deployment. The research team, consisting of a medicine expert, an Ayurveda practitioner, and a Yoga instructor, administered the Ayush interventions at the study sites throughout the study. The participants were monitored at frequent intervals at both study sites. Ayush CCT was provided by the Indian Medicines Pharmaceutical Corporation Limited, India, and Ayush Poshak Yoga by MARC Laboratories Ltd, India. Discontinuation of the study interventions If any participant developed any adverse effects, such as gastrointestinal symptoms, allergic response, or change in biochemical assessment parameters, the administration of the Ayur-nutri kit was temporarily halted, and the participant was closely monitored. If symptoms recur after reintroducing the nutritional supplements, the participant were withdrawn from the study after assessing the causality of AE/ADR. All such events were recorded and reported in the AE/ADR reporting format. Compliance with the Ayush-AMS protocol during the study All the participants in the AG group were provided with an information leaflet containing the instructions for the use (dose, frequency, time of administration) and storage of the Ayur-nutri kit. The participants were also issued a compliance form during the baseline to subsequent follow-up visits to self-report their consistent or irregular use of Ayush interventions in the Ayur-nutri kit and to record any missed dose with remarks for missing, which enabled assessment of adherence to the dosing pattern as per the study protocol. During each follow-up visit, the participants were asked to return the used/unused/partially used sachets of the Ayur-nutri kit to the investigators to assess adherence and cross-check with the participant's self-reported compliance form. The participants were advised to maintain an open communication channel with the research team to address any issues faced by the participants, including missed doses, adverse effects, and any general health-related queries. The participants who do not adhered to the study protocol, or do not have 80% or more compliance, or those who developed any study-related adverse events due to which the participant preferred to withdraw from the study, or those who withdrew their voluntary consent for participation in the study, were withdrawn from the study. If participants consented to data collection during the scheduled follow-ups or at the end of the 120 days, data were collected and recorded in the CRF. The data from completed assessments available till the withdrawal was used for analysis. Concomitant care The investigators monitored the participants for any concomitant treatment they received during the study period. In case of the onset of any adverse events, use of rescue medication, under the investigators' discretion, was permitted. All instances of concomitant care were carefully documented in the CRF. However, any study participant prescribed any conventional medication for a longer duration during the study period has to discontinue using the Ayush intervention during that period. The same was documented in the CRF. If any participant developed a Serious Adverse Event (SAE) or Treatment-Emergent Adverse Event (TEAE) during the study period, the participant was withdrawn from the study and given appropriate incidental care at the hospital. The government authorities and the Ethics Committee were notified about the same within two working days, along with appropriate justification. Outcome measures The primary outcome was the incidence of AMS assessed through the Lake Louise Scoring System 2018 (LLSS). AMS is defined as an LLSS score of three or more points from the four rated symptoms (headache, nausea/vomiting, fatigue, and dizziness/light-headedness), including at least one point from headache.9 The grading of LLSS score is mild AMS 3-5 points, moderate AMS 6-9 points, and severe AMS 10-12 points.[9] The participants were assessed daily for the first seven days at the stage I HA area using the LLSS score to record the incidence and evaluate the severity of AMS. The primary outcome will be reported as the proportion of participants who display symptoms of AMS and the proportion of participants with a score of more than six as per the LLSS. The participants enrolled for stage II were again assessed daily during their first four days at that altitude for the incidence and severity of AMS. The secondary outcome measures included the proportion of participants who developed thromboembolic events (DVT, PE, CVT, MI, etc.) during the study, change in the levels of markers of coagulation and hemostasis activation (total red blood cell count, hemoglobin, packed cell volume, D-dimer, lactate dehydrogenase, creatine kinase, creatine kinase-myoglobin binding (CK-MB), fibrinogen, activated partial thromboplastin time, prothrombin time), changes in the levels of pro-inflammatory markers (high sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-α), self-reported change in negative emotional states of depression, anxiety and stress assessed through DASS-21 scale, change in sleep quality assessed through Pittsburgh sleep quality index (PSQI), and quality of life assessed through SF-12 questionnaire. The secondary outcomes were evaluated on day 60 and day 120 from baseline. However, the participants enrolled for the stage II HA area were also assessed on day 10 (day 4 of the acclimatization schedule at that altitude) and on the day of descent, in case of early descent before day 120. Resting heart rate, systolic and diastolic blood pressure, respiratory rate, and oxygen saturation (SpO2) were also documented daily till day 7 alongside LLSS at stage I HA and till day 10 in the participants at stage II HA, and then on the scheduled follow-up visits. Safety assessment The safety of the Ayush interventions was determined by recording the incidence of adverse events (AE), if any, during scheduled follow-up visits in a structured format. All AEs during the study were recorded and monitored as per ICH-Good Clinical Practice guidelines. The safety was also evaluated by assessment of liver function test, kidney function test, and lipid profile on day 60 and day 120 from baseline. Sample size Based on the findings from a previous study on similar conditions, the anticipated incidence of AMS within the control group was 25%, while the assumed incidence in the AG was 18% [7]. To achieve a statistical power of 90% and a confidence level of 95%, an initial sample size of 722 per group was calculated. Accounting for an expected attrition rate of 15%, the final sample size for each group was determined to be 830 participants (1660 in total). The sample size of 1660 participants was stratified as Stage I and Stage II HA. A total of 830 participants were included in the study, from those deployed at stage II HA, while the remaining 830 were from stage I HA. The participants deployed at each of the two stages of altitude were randomly allocated to AG and CG. Recruitment of study participants During the study, the database of healthy personnel at HA areas of the western Himalayan region was utilized to identify and recruit potential subjects. The investigators at the study site screened subjects based on the defined inclusion and exclusion criteria. The eligible participants were allocated to either of the two groups based on a computer-generated randomization schedule. The screening process was continued until the target sample size for the study was achieved. Randomization Block randomization with unequal block sizes randomly assigned the participants to either AG or CG with a 1:1 allocation. Statistical Package for Social Sciences (SPSS) version 28.0 was used to generate the random number sequences. An independent statistician not involved in the participants’ enrollment and assessment generated the randomization sequence. Allocation concealment Sequentially numbered opaque sealed envelopes were used to ensure the allocation concealment. The participant’s enrolment number was printed on the top of the envelope, and a slip in which the participant's allocated group was printed was kept inside the envelope. After completing all baseline assessments, the research staff provided the sealed envelope to the eligible participant. The participant opened the envelope and was then allocated to the groups as per the slip inside the envelope. The opened envelope and the printed slip were attached to the participant’s CRF for record and trial monitoring. Participants assigned to the two study groups were housed in separate barracks throughout the study to prevent any protocol violations and minimize the risk of contamination bias. Data collection The baseline demographics, clinical, and physical examination aspects were collected by qualified Ayush study personnel and reported in a CRF designed for the purpose. The subjective and objective outcome assessments were done as per the protocol (Table 3). The incidence of AMS and its severity were assessed through the LLSS AMS score, according to which the onset of AMS is diagnosed by having a headache score of at least one point and a total score of at least 3 points [9]. This was assessed daily for the first seven days in participants at Stage I HA and for four more days in case of participants who ascended to Stage II HA. The self-reported emotional states of depression, anxiety, and stress were reported by adding scores of the relevant items in the three subscales of the Depression, Anxiety, and Stress Scale - 21 Items (DASS-21) [28]. The quality of sleep and overall quality of life were assessed through validated scales, the Pittsburgh Sleep Quality Index (PSQI) and the SF-12 questionnaire, respectively [29-34]. The secondary outcomes, such as DASS-21, PSQI, and SF-12, were assessed at baseline and follow-ups at day 60 and day 120. The serum sample for the objective assessment parameters, such as coagulation and hemostasis activation markers, pro-inflammatory markers, LFT and RFT, etc, was collected on baseline, day 60, and 120 and transported to an NABL-accredited laboratory, and the data received from the lab were entered in the CRF and e-CRF. The research team underwent training on the study protocol, SoP for the conduct of the study, storage, and dispensing of interventions, handling of biological samples, data collection, and recording to ensure compliance with GCP principles while ensuring participant safety, data accuracy, and reliability. Data Management Data management in this clinical study adhered to stringent guidelines to ensure the accuracy, reliability, and integrity of collected information. Upon the participant's assessment, the research team promptly entered the data into CRFs and e-CRFs. Source documents and CRFs were securely stored in restricted-access areas, limited solely to the study team. Electronic CRFs were password-protected and stored in secure, access-restricted computer systems. Data entered by the study personnel was subjected to meticulous cross-verification by the principal investigators at the study site, ensuring the reliability of the data. Rigorous quality measures were implemented, such as regular audits, to identify and address any discrepancies in data. The data management practices adhered to regulatory guidelines and ethical principles, prioritizing the protection of participant rights. Statistical methods The categorical data will be presented as numbers (percentages) and will be compared between groups using the chi-square test, while within-group comparison will be done by using the McNemar/Cochrane Q-test. Continuous data following normal distribution will be reported as Mean ± SD, and between-group comparison will be done by independent sample t-test. Within-group comparison for normal data will be done by paired sample t-test/repeated measure ANOVA. The non-normal data will be reported as Median (First Quartile, Third Quartile), and between-group comparison will be done using the Mann-Whitney test. Within-group comparison will be done using the Wilcoxon signed-rank test/Friedman test. Regression analysis will be performed to study the effect of confounding variables on the incidence of AMS. The data of participants having early descent will be analyzed with censored data models. A p-value less than 0.05 will be considered significant. Statistical Package for Social Sciences (SPSS) version 28.0(Chicago, Illinois, USA) is being used for statistical analysis. Monitoring The Data and Safety Monitoring Board (DSMB) monitored the study for quality and regulatory compliance. The DSMB reviewed the progress of the study every three months till the end of the study period. Trial Audit The on-site monitoring visit by an independent committee constituted by the sponsor was planned to ensure that the study procedures and data collection processes were as per the existing regulatory standards and to check the accuracy, completeness, legibility, and timeliness of the reported study data. Ethical considerations The Institutional Ethics Committee has approved the study protocol to ensure compliance with ethical standards and safeguard the rights and well-being of the participants. The study has been registered prospectively at the Clinical Trial Registry of India (CTRI/2023/03/051028). The study was undertaken following the principles of the Declaration of Helsinki, ICMR’s National Ethical Guidelines for Biomedical and Health Research on Human Participants (2017), and ICH Good Clinical Practices guidelines. No substantial amendments in the study protocol were made that may affect patient safety or study integrity. Before undergoing any study-related procedure, the potential participants received a participant information sheet (PIS) in Hindi or their native language. The PIS comprehensively outlined the various aspects of the study, equipping the participants with the necessary information to make an informed decision regarding participation in the study. The written consent was obtained in the consent form, signed by the participant and the study personnel delegated for the task. The results and findings of the study will be disseminated following the best practices in scientific publishing, ensuring that the knowledge generated will benefit the scientific community and the public in general through publications in peer-reviewed, indexed medical journals and presentations at national and international conferences. Confidentiality All the relevant study data were stored securely at the study site with password-protected access systems in areas with limited access. To maintain participant confidentiality, a coded enrolment identification number was used to identify all laboratory specimens, reports, data collection, and relevant forms. All records containing names or other personal identifiers, such as informed consent forms, were stored separately from the study records, identified by a code identification number in an area with limited access. Ancillary and Post-trial care No ancillary studies were proposed with the present clinical study. If required, the participants were provided routine medical care after completing the study period.

Results:

The recruitment of study participants has been completed, and the study data is currently being analyzed.

Conclusions:

The outcomes of the present RCT are expected to help in the optimum utilization of limited resources through better acclimatization, the need for lesser ascent time, and rapid induction of troops at HA regions during exigency situations. Clinical Trial: Clinical Trial Registry of India -CTRI/2023/03/051028