Inclusion criteria.

The study will include men and women aged 60 years or older who are residents of Bhubaneswar city and provide informed consent for participation [8]. The inclusion criteria also include participants diagnosed with multimorbidity (defined as having two or more chronic conditions) and having a Frailty Index score of ≥ 0.25 based on the deficit accumulation model. Multimorbidity will be assessed by the validated Multimorbidity Assessment Questionnaire for Primary Care (MAQ-PC) Plus tool [3].

Exclusion criteria.

Both male and female individuals will be excluded if they have severe cognitive impairment or dementia, as assessed by the Dementia Assessment by Rapid Test (DART). Individuals who are bedridden or have mobility-limiting conditions such as Grade III osteoarthritis, those with contraindications to physical activity, and those who are unable or unwilling to participate in follow-up assessments will also be excluded from the study [20].

Medical management.

Medical management intervention will include medication review, optimisation, adherence tracking via “health diary” which will be provided to them. The health diary would serve as a fidelity log and patient education tool. This will improve adherence to prescribed drugs and supplements and will enhance resilience among frail older adults with better functional outcomes compared to usual care without systematic supportive care [21,22].

Nutritional support.

The nutritional intervention includes dietary counselling and supplementation with Vitamin D3, calcium, iron, folic acid, and protein. This will provide individualized diet plans and targeted micronutrient and supplementation to address deficiencies and metabolic needs. By improving nutritional status, muscle strength and immunity will also improve along with capability of disease control with better functional and health outcome in frail elderly people [23–27].

Physiotherapy and physical activity.

The physical intervention program will include a standardized Timed Up-and-go (TUG) assessment to tailor home based exercise routines for frail older adults. Participants will receive individualized strength balance, endurance, stretching and cognitively engaging exercises matched to their functional capacity and comorbidity status. This structured, progressive approach will improve mobility, muscle strength, balance and mental agility while reducing fall risk and functional decline. [13,14,28].

Psychosocial support.

The psychosocial intervention integrates daily relaxation practices, need based psychological counselling and periodic group based social engagement to address emotional distress, stress, isolation and reduced coping capacity among the older people. Breathing, mediation and visualization techniques will enhance emotional regulation and reduce anxiety, while counselling supports adjustment to ageing and illness. Structured group activities, storytelling and therapeutic games will strengthen social connectedness and resilience. This intervention is expected to reduce psychological vulnerability, loneliness and functional decline leading to better quality of life [29–31].

The intervention package will be delivered after recruitment of the participants where a structured monthly contact schedule will be followed to maintain the health diary. A social media app based system for regular follow up will help to improve social networking and overall health monitoring among the frail older adults. The details of intervention delivery and frequency is summarised in (Table 1). All concomitant care is permitted during the trial.

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Table 1. Components of the Multi-FrAME intervention.

https://doi.org/10.1371/journal.pone.0351110.t001

Primary outcome.

Primary outcome will include change in HRQoL that will be measured by the EQ-5D-5L index at baseline, 6 months, and 12 months [9,10].

EQ-5D-5L index score, will be analysed as a continuous variable. Mean differences between intervention and control groups at 6 and 12 months, as well as change from baseline, will be assessed using independent t-tests (or Mann–Whitney U tests if non-normal). A linear mixed-effects model will be used to estimate the treatment effect over time, accounting for repeated measures and baseline values. Results will be reported as adjusted mean differences with 95% confidence intervals and p-values.

Secondary outcomes.

Secondary outcome will include changes in frailty status and will be measured using a continuous Frailty Index based on the 40-item cumulative deficit model and assessing functional ability through the Lawton-Brody scale for ADL/IADL. Additional outcomes encompass healthcare utilisation metrics such as the number of outpatient consultations, emergency visits, and hospitalisations, alongside healthcare expenditure captured through direct costs borne by participants. Medication adherence will be assessed using the Medication Adherence Reporting Scale (MARS) and patient satisfaction will be measured through a validated satisfaction scale. Additionally, all-cause mortality will be monitored throughout the study to capture any intervention-related survival benefits [8].

Secondary outcomes will be analyzed according to their data type: continuous variables will be assessed using t-tests and linear mixed-effects models, categorical variables using chi-square tests and mixed-effects logistic regression, and ordinal outcomes using ordinal logistic models where appropriate. Treatment effects will be reported as adjusted mean differences or odds ratios with 95% confidence intervals, comparing intervention and control groups over time while adjusting for baseline differences.

Exploratory outcomes.

The exploratory outcomes of the Multi-FrAME trial focus on biological markers that may mediate or reflect the effects of the intervention. These include biochemical and haematological parameters such as hemoglobin, glycated hemoglobin (HbA1c), random blood sugar (RBS), lipid profile, and liver and kidney function tests. Micronutrient will be evaluated by measuring levels of vitamin D, iron, calcium, and magnesium levels [23–27]. In addition, hormone profile will include Thyroid Stimulating Hormone (TSH), Triiodothyronine (T3), Thyroxine (T4), and sex hormones. These outcomes are intended to provide mechanistic insights into how the multicomponent intervention impacts on physiological and metabolic health. A summary of outcome assessments with time points is provided in (Table 2).

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Table 2. Outcome measures and time points.

https://doi.org/10.1371/journal.pone.0351110.t002

Sample size.

The sample size calculation was done by detecting a clinically meaningful improvement in the primary outcome, the EQ-5D-5L health-related quality of life index. Assumptions used in the calculation: Mean EQ-5D-5L utility score in the control group: 0.87, SD = 0.17, minimum clinically important difference: 10% improvement, power: 90%, significance level (two-sided): 0.05, intra cluster correlation coefficient (ICC): 0.24 (31), expected attrition: 25%. Based on an a priori power calculation using a two-sided significance level of 0.05 and 90% power, the required sample size was estimated to be 430 participants, with 215 participants in each arm. This sample size was considered sufficient to detect a clinically meaningful difference in primary outcomes between the intervention and usual care groups.

These participants were distributed across 10 clusters, each comprising 43 individuals. Clusters were randomly allocated in a 1:1 ratio, with five clusters (n = 215 participants) assigned to the intervention arm and five clusters (n = 215 participants) to the control arm.

A two-sample t-test was first used to estimate the required sample size per arm assuming individual randomisation. This was then adjusted using the design effect to account for cluster randomisation: Design effect (DE)=1+(m − 1)×ICC (where m is the average cluster size). Final sample size estimates were inflated for the design effect and anticipated attrition.

Sequence generation and allocation.

Clusters (UPHCs) will be randomly assigned in a 1:1 ratio to either the intervention or control arm using computer-generated random numbers. Randomisation is stratified by UPHC characteristics (e.g., population served, catchment area demographics) to ensure balance across arms.

Allocation concealment.

An independent statistician who is not involved in implementation or data collection will conduct the randomisation. Allocation concealment will be maintained until clusters are enrolled.

Implementation.

The study coordinator will enrol PHCs and assign them to the intervention or control group according to the concealed allocation list.

Blinding.

Blinding of participants and providers is not feasible because of the nature of intervention. However, observer blinding will be maintained strictly. Outcome assessors responsible for administering the EQ-5D-5L, frailty index, and laboratory measurements will not be informed of group allocation.

Blinding will be further reinforced by segregated teams for intervention delivery and outcome assessment, lab sample coding and de-identified central analysis and health diaries collected in sealed envelopes to prevent unbinding during transport or entry.

Data analysts will also remain blinded to group allocation until the database is locked. Unblinding will be done if ethically required due to reporting of new health concerns.

Data collection methods.

Primary and secondary outcomes will be collected at 0, 6, and 12 months using validated instruments. Health diaries will be maintained by participant’s record adherence, intervention exposure, and healthcare events. Trained assessors, fluent in local languages will conduct structured interviews using standard operating procedures (SOPs) derived from the Manual of Operating Procedures (MOP). Refresher trainings and inter-rater reliability assessments will be held at every 6 months.

The study uses standardized measurements and questionnaires to assess participant characteristics, intervention fidelity, outcomes, and safety across the trial period. Eligibility is established at screening using an Eligibility CRF, while baseline socio-demographic characteristics, medical history, and health status will be collected using the Recruitment/Baseline CRF. Follow-up assessments will be conducted at 6 and 12 months using structured follow-up CRFs. All questionnaires will be administered by trained field investigators through interviewer led assessments to ensure consistency and minimize literacy-related bias.

The primary outcome, health-related-quality-of-life will be measured using the EQ-5D-5L,which is a standardized instrument capturing participant-reported health status across five dimensions using ordinal severity levels. Secondary outcomes include frailty, which will be assessed using a cumulative deficit Frailty Index based on 40 health-related variables, functional status measured using the Lawton and Brody ADL/IADL scale, medication adherence assessed with the Medication Adherence Reporting Scale using Likert-type responses, and patient satisfaction evaluated through structured interviews. Healthcare utilization and expenditure will be collected monthly using recall-based questionnaires and participant diaries, supplemented by healthcare records where available. Mortality and safety outcomes, including adverse and serious adverse events, will be monitored continuously, alongside standardized assessments of vital signs and laboratory investigations at baseline, 6, and 12 months.

Data management.

A secure and validated electronic data capture (EDC) platform will be used to enter data and unique IDs will be generated for anonymise participant data. Along with that a unified database management system (DBMS) with audit trails will ensure data integrity. Double-entry verification and logic checks will be used to identify inconsistencies.

Data will be stored securely for a minimum of five years after trial completion, in accordance with Indian Council of Medical Research (ICMR) and ethics committee requirements.

Monitoring and quality assurance.

Internal monitoring will be conducted monthly by the study QA team. External monitoring will be scheduled quarterly by an independent monitor. A Drug and Data Safety Monitoring Board (DSMB) meet will be conducted at predefined milestones (33%, 66%, 100%) to review safety and adherence data. Any protocol deviations will be logged and reviewed for their impact on study validity.

Ethical approval.

This study protocol has been approved by the Institutional Human Ethics Committee of the ICMR-Regional Medical Research Centre (ICMR-RMRC), Bhubaneswar (approval ID: ICMR-RMRC/IHEC-2024/015). All procedures adhere to the ICMR National Ethical Guidelines for Biomedical and Health Research Involving Human Participants (2017), and conform to the principles of the Declaration of Helsinki.

Informed consent.

Written informed consent will be collected from all participants before any trial-related procedures. Field investigators, trained in ethics and communication will explain the study details in participants’ preferred language (Odia, Hindi, or English), including consent for biological samples and testing, and storage. Visual aids and lay explanations will be used to enhance comprehension. All participants will be provided the copies of signed consent form and participant information sheet.

In cases of limited literacy, a witness is present, and thumbprints are accepted per regulatory standards.

Confidentiality and data protection.

Participant confidentiality will be protected at all stages of the study. All identifiable information will be stored separately from analytic datasets and accessed only by authorised personnel. Databases will be password-protected, encrypted, and backed up regularly. All physical records will be stored in locked cabinets at the central coordinating centre. Results will be reported in aggregate form without disclosing individual identities. Data will be retained for at least five years post-trial, as per ICMR guidelines.

Dissemination plan.

Findings from this trial will be disseminated through publications in international peer-reviewed journals and presentations at national and international scientific conferences. Policy briefs will be developed, and results will be shared during stakeholder meetings with state and national health authorities. Additionally, a lay summary of the findings will be provided to participants and community representatives.

Data and safety monitoring board (DSMB).

An independent DSMB will supervise safety, adherence, and interim efficacy data during 33% enrolment, 66% enrolment and at trial completion. The board comprises senior clinicians, statisticians, and ethicists. The DSMB is empowered to recommend continuation, modification, or early termination of the trial based on predefined stopping rules (e.g., safety signals, futility).

Auditing and monitoring.

This include internal and external monitoring. During internal monitoring monthly site-level checks will be done by the QA team. External monitoring will be conducted by trained monitors unaffiliated with the trial team, focusing on consent documentation, protocol adherence, and CRF accuracy. All adverse events, protocol deviations, and data inconsistencies will be reviewed by the core coordinating team and rectified promptly.

Definitions.

Any undesirable medical occurrence during the trial, regardless of causal relationship is defined as Adverse Event (AE) whereas any event that leads to death, life-threatening, needs hospitalisation, or causes significant disability is termed as Serious Adverse Event (SAE).

Reporting procedures.

Reporting for any AEs and SAEs will be done within 24 hours to the Principal Investigator and documented in the Case Report Forms (CRFs). SAEs will also be reported to the Ethics Committee within seven working days. Causality will be assessed by a blinded clinical adjudication panel. All SAEs are followed to resolution or stabilisation.

Anticipated harms.

Risks associated with the intervention include supplement-related effects: (e.g., hypercalcemia, GI disturbances from iron or calcium), exercise-related injuries: e.g., musculoskeletal strain, fatigue), Emotional distress (arising from counselling sessions).

Mitigation strategy.

Mitigation strategy consist of individualised dosing based on lab values, pre-exercise screening and physiotherapist supervision and psychological first-aid protocols and escalation pathways. The trial will be conducted at public health facilities and all ancillary care will be provided there, free of cost to the participants.