Background and rationale {6a}

Frailty is an age-related multidimensional state with multiple causes and contributors and is characterized by diminished strength, endurance, and reduced physiologic function [1–3]. As deficits (symptoms, signs, illnesses, and disabilities) accumulate, older adults become more susceptible to adverse health outcomes, including delirium, falls, disability, hospitalization, and death [1,2,4,5]. These events are often triggered by relatively minor stressor events (e.g., changes in medication, urinary tract infection), which lead to sudden changes in health [5,6]. Our research suggests that approximately 23% of Canadians over the age of 65 are frail [7], and by the age of 85, this estimate increases to over 40% [8]. Older adults who are frail are high users of healthcare services [9], and those with moderate or severe frailty have an 8-fold greater relative risk of institutionalization (95% CI = 4.9--15.2) [10]. Frailty is dynamic in nature (i.e., may improve or worsen over time) [8] and has been demonstrated to be reversible or treatable [11].

Frailty and sarcopenia are distinct but interrelated disease processes with similar causalities, consequences, and treatment indications [12]. Sarcopenia is a progressive and generalized skeletal muscle disorder that is characterized by loss of muscle mass and strength and poor physical performance (i.e., whole-body function related to locomotion) [13]. Sarcopenia is a contributor to the development of physical frailty [13]; conversely, frailty may accelerate the development of sarcopenia [5]. Sarcopenia may also be secondary to other causal factors, including physical inactivity, disease-related immobility, and/or inadequate intake of energy or protein [13].

Frailty and sarcopenia treatment recommendations include exercise, oral nutritional supplementation, and vitamin D3 [14]. The reduction in polypharmacy is an additional important component of frailty management as part of a comprehensive geriatric assessment (CGA). Our network meta-analyses [15,16] demonstrated that physical activity interventions with or without nutritional supplementation are most effective; however, the quality of evidence is low, and more robust randomized controlled trials (RCTs) are needed. Frailty intervention trials have demonstrated that multimodal interventions based on geriatric and rehabilitation services significantly reduce frailty; however, these interventions require specialized assessment teams and are resource intensive [17]. The Frailty Intervention Trials utilized clinical teams for interventions, including clinical nutritional teams, physiotherapist teams, psychiatric teams, and geriatric and rehabilitation specialists, to conduct the trial [17]. Furthermore, it could not be determined whether exercise and nutrition alone are sufficient or whether additional CGA interventions, including polypharmacy management, are needed for adults with frailty. With our rapidly aging population and limited access to specialized geriatric services, developing accessible, cost-effective, community-based approaches to managing frailty is imperative for health systems. Our pilot work has demonstrated that delivering a community-based frailty intervention is feasible in Canada without the additional need for specialized assessment teams [18–20].

Although exercise is widely accepted as a beneficial means to improve physical function, frailty, and sarcopenia, there is limited evidence regarding the benefits of exercise alone in older adults with frailty. Therefore, this study will address whether a tailored group exercise intervention is enough to improve outcomes or whether additional components of frailty management (i.e., nutritional supplementation, medication optimization) are needed.

Our frailty rehabilitation model is based on international consensus guidelines that recommend a multimodal approach to reduce frailty [14] and the World Health Organization Public Health Framework for Healthy Ageing [21] to align community-based health services to meet the complex needs of older adults who are frail. This framework for action is built around the concept of building intrinsic capacity (defined as all the physical and mental capacities that an individual can draw on at any point in time). Intrinsic capacity can be enhanced by promoting behaviours within a supportive environment to enable functional ability (defined as health-related attributes that enable people to be and to do what they have reason to value) [21]. Drawing on the principles of a standardized approach to cardiac [22,23] and cancer rehabilitation [24,25], we have developed a structured frailty rehabilitation program called OPTIMAL Fitness (from the acronym: OPTimizing Independence, Mobility and Active Life). The Medical Research Council guidance on complex interventions supported the evaluation of the OPTIMAL Fitness program [26].

Objectives {7}

The purpose of this study is to determine whether OPTIMAL Fitness exercise or OPTIMAL Fitness multimodal interventions improve physical function over four months (as measured by the Short Physical Performance Battery (SPPB) and 400m Walk Test) versus control in community-dwelling older adults who are prefrail or frail. The secondary outcomes are to examine the impact of the interventions on frailty, sarcopenia, cognition, mood, activities of daily living, health-related quality of life (HR-QOL), and healthcare utilization (emergency room visits; hospitalization; home care service use; institutionalization). A subset of participants with sarcopenia will undergo (dual-energy X-ray absorptiometry) DXA and magnetic resonance imaging (MRI) scans to determine how the OPTIMAL Fitness exercise or OPTIMAL fitness multimodal interventions affect skeletal muscle biomarkers and body composition. We hypothesize that both the OPTIMAL Fitness exercise and OPTIMAL Fitness multimodal interventions will improve physical function, frailty, and sarcopenia in older adults with frailty and that the multimodal arm will offer greater benefits than the other arms. For the sarcopenia substudy, we hypothesize that both interventions will improve skeletal muscle biomarkers and muscle mass in older adults with sarcopenia, with the multimodal arm again offering enhanced benefits relative to the other arms. In addition, we aim to better understand the physical and functional capabilities of older adults with frailty, including their experiences with the program, and to make recommendations regarding the key elements of the OPTIMAL Fitness frailty rehabilitation model.

Trial design {8}

This study protocol describes an investigator-initiated, multiarm, parallel-group, partially blinded RCT in Southern Ontario, Canada, conducted by the Geras Centre for Aging Research, which is affiliated with Hamilton Health Sciences and McMaster University. An innovative feature of this intervention lies in the partnership between Hamilton Health Sciences, McMaster University, and the YMCA, which crosses sectors to create sustainable evidence-based community programs. Community-dwelling older adults (aged ≥65 years) with prefrailty or frailty will be randomized into one of three arms: control (usual care plus vitamin D) (Arm 1), OPTIMAL Fitness exercise only (Arm 2), or OPTIMAL Fitness multimodal (Arm 3) and stratified by sex and age for each cohort. Primary and secondary outcomes will be assessed in person by blinded assessors at baseline and four months, with healthcare utilization outcomes collected for an additional six months via telephone follow-up. This protocol is reported in accordance with the Standard Protocol Items: Recommendations for Intervention Trials guidelines [27].

Participant timeline {13}

The study schedule of enrolment, interventions, assessments, and visits for participants is presented in Fig 1.

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Fig 1. Schedule of enrolment, interventions, and assessments.

*Age, sex, gender, housing, education, smoking status, chronic conditions, past surgeries, falls and fracture history, healthcare utilization past 3 months, mobility aids, and participation in other activation/social programs. † Height and weight, heart rate, and blood pressure. ‡ Medications, dietary/oral nutritional supplements, vitamins/minerals. § Exercise barriers, side effects to exercise, barriers to transportation to the YMCA, facilitators/interests in having a healthy level of activity and eating well. || Fitness measure; post-400m walk test. ¶ Number of visits to primary care provider, walk-in clinic, specialist visits, physiotherapist, urgent care, emergency department; hospitalizations. Collect past 3 months at the baseline assessment. ** Up to 75 participants screened for sarcopenia based on the AWGS guidelines undergo dual-energy X-ray absorptiometry (DXA), and a subset of 36 participants of those 75 participants will undergo an MRI at a time (max. 1 month) separate from the primary baseline assessments. Participants who are invited to participate in this sarcopenia substudy will be randomly selected from all 3 study arms. †† Muscle Mass = Dual X-Ray Absorptiometry (DXA) and Magnetic Resonance Imaging (MRI); = JAMAR Hydraulic hand dynamometer.

https://doi.org/10.1371/journal.pone.0343338.g001

Trial status

This article outlines the protocol (V7.0 – May 15, 2024). Recruitment for the trial began on September 2, 2022. Recruitment and follow-up will be completed by approximately December 31, 2025. Study results will be made available after data analysis is completed.

Study design

The OPTIMAL Fitness study is a multiarm, parallel-group, partially blinded RCT that will compare the clinical and cost-effectiveness of OPTIMAL Fitness multimodal (group exercise, nutritional intervention (review and coaching/oral nutritional supplementation), medication review/optimization) versus OPTIMAL Fitness exercise only and control. The aim of the study is to determine whether OPTIMAL Fitness exercise or OPTIMAL Fitness multimodal interventions improve physical function versus control in community-dwelling older adults who are prefrail or frail. The main group comparisons will occur at four months. The trial has been registered with ClinicalTrials.gov ID NCT03824106. This protocol manuscript has been formatted according to the Structured Study Protocol Template [28], which embeds the 51 SPIRIT headings and item identifiers within the protocol itself and includes the standardized SPIRIT figure (schedule of enrolment, interventions, and assessments) [29]. The general study design is outlined in Fig 2.

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Fig 2. Study overview.

https://doi.org/10.1371/journal.pone.0343338.g002

Study setting {9}

The study takes place in a large, metropolitan area in Southern Ontario, Canada. The recruitment settings will occur within acute care, primary care, rehabilitation units, the community, home care, and external specialist outpatient clinics. The intervention of the OPTIMAL Fitness multimodal and exercise-only arms will occur at the YMCA of Hamilton|Burlington|Brantford, which are accessible locations with access to transportation. The outcome assessments will occur at the YMCA of Hamilton|Burlington|Brantford and via telephone for all three arms. The central site is affiliated with an academic health science centre with several hospital sites serving a catchment area of more than 2.3 million people [30].

Eligibility criteria {10}

Participants will be included if they are (1) ≥ 65 years of age, (2) able to ambulate 25 meters with or without a walking aid, (3) prefrail or frail (score of ≥2 FRAIL Scale) [31]), and (4) deemed safe to exercise and take oral protein/nutritional supplements (as determined by the referring clinician or primary care provider). Participants will be excluded for the following reasons: 1) unable to speak or understand English (2) currently attending a group exercise program (3) currently in a drug optimization study/program (4) currently taking oral protein/nutritional supplements daily (5) cognitive impairment that prevents them from following two-step commands (6) unstable angina or unstable heart failure; 7) terminal illness; 8) receiving palliative/end-of-life care; (9) travel/commitments that would involve missing >20% of the intervention phase; and (10) other household members enrolled in the study.

Ethics approval and consent to participate {24}

This study was approved by the Hamilton Integrated Research Ethics Board (#5500).

Who will obtain informed consent? {26a}

Referring clinicians will obtain initial verbal consent from interested participants, screen for eligibility, and complete the screening intake form, which is submitted to research staff. Interested individuals in the community may also self-refer by contacting the Geras research staff (phone number will be provided on advertising materials). Research staff will contact interested participants over the telephone to confirm eligibility, provide more information, and obtain informed verbal consent. If the participant agrees to participate in the trial, they must provide written consent by signing and dating two copies of the consent form (paper or electronic), which will also be dated and signed by the research staff (one original copy will be given to the participant, and the other copy will be filed by the research staff).

Study arms

The participants are randomly assigned to one of three arms (control, OPTIMAL Fitness exercise only, OPTIMAL Fitness multimodal). All participants will receive equal amounts of contact for outcome assessments and study adherence by research personnel (e.g., monthly phone calls, outcome assessments). Table 1 provides a summary of the components of each study arm.

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Table 1. Summary of Interventions by Study Arm.

https://doi.org/10.1371/journal.pone.0343338.t001

Explanation for the choice of comparators {6b}

Participants randomized to the control arm will not receive any of the exercise, nutritional, or medication interventions. Participants in all arms, including the control arms, will receive vitamin D3 1000 IU/daily [32]. Vitamin D3 is a low-cost, logistically simple intervention that is recommended for the management of patients with frailty. Furthermore, many older adults are already taking vitamin D3 routinely. Individuals already taking vitamin D3 (1000 IU/or greater) will continue with prescribed treatments.

Rationale/Evidence: Lower levels of vitamin D are consistently associated with lower muscle mass and physical function (including handgrip strength test and SPPB) [33–35]. Meta-analyses [36] have demonstrated a positive effect of daily vitamin D supplementation on muscle strength and balance in older adults, an effect influenced by baseline vitamin D deficiency [37,38]. There is good evidence that vitamin D3 supplementation preserves muscle strength and functional ability in high-risk groups, such as older adults with frailty [36,39].

Description of interventions {11a}

OPTIMAL fitness exercise only.

The OPTIMAL Fitness exercise curriculum was developed by a physiotherapist and interdisciplinary team (rehabilitation, geriatric medicine fitness professionals), in conjunction with OPTIMAL Fitness investigators and collaborators (exercise physiologists, geriatricians, occupational therapists, and YMCA trainers), all of whom have expertise in managing older adults living with frailty and are based on prior randomized controlled trial evidence that exercises reduce falls and improve function [36].

Group Exercise: The group exercise intervention will be delivered at local YMCA sites by trained instructors and supported by a consultant physiotherapist. Exercises are individually tailored to the individual capabilities of the participants and reassessed monthly by the physiotherapist. YMCA instructors are provided with a structured curriculum and have undergone additional training on working with older adults living with frailty (www.gerascentre.ca).

The participants will attend a group exercise class twice weekly (one hour per class) for four months. The curriculum will emphasize functional movements specifically designed for older adults with frailty and mobility challenges, including modifications for canes/walkers. The exercise instructors were trained on ways to safely modify the exercises to meet the participants’ abilities and needs. The curriculum promotes concurrent training that is safe, progressive, and evidence-based and includes cardiovascular fitness (15 minutes), balance training (20 minutes), strength (15 minutes), and flexibility (5 minutes) [40] (each component is described in Table 2).

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Table 2. OPTIMAL Fitness Exercise Components.

https://doi.org/10.1371/journal.pone.0343338.t002

Supplemental Home Exercise: The physiotherapist will also perform a one-on-one assessment with each participant at baseline and provide them with a supplemental home exercise program. The participants will be provided with a tailored home-exercise program developed by a physiotherapist to gain an additional hour of physical activity (e.g., 3 sessions of 20 minutes). The home exercise program consists of 5 minutes of warm-up and cardiovascular training (e.g., seated marching), one balance exercise, and two functional strength exercises, followed by 5 minutes of cool down and stretching. Home exercises are modified and tailored every month by the physiotherapist. The study physiotherapist will attend the YMCA exercise class monthly to reevaluate the home-based exercises to ensure that the exercises are at the appropriate level of challenge and to troubleshoot any problems.

Rationale/Evidence: Concurrent training (i.e., combined strength and endurance training to increase both aerobic capacity and maximal strength simultaneously) performed at a moderate weekly frequency (i.e., two times per week) may promote marked gains in muscle hypertrophy, strength, and power in older adults living with frailty [42]. Adherence may also be optimized with concurrent training, as it reduces the number of weekly visits to a centre-based program. Our program also incorporates a high challenge to balance, which is a key component of successful exercise programs for vulnerable older adults [40,43] and is most effective for fall prevention [13]. Strong evidence from meta-analyses [40] on exercise to prevent falls in older adults demonstrates that programs that challenge balance and are of a higher dose (at least 180 minutes/week) have greater effects. Thus, our target for the OPTIMAL Fitness program is two centre-based sessions/week (120 minutes) and an additional 60 minutes of home-based exercise.

Criteria for discontinuing or modifying allocated interventions {11b}

For a given trial participant, the assigned study intervention may need to be modified or discontinued by trial investigators if the participant experiences harm, which could include injury, hospitalization, a decline in health or mobility status, which impacts the safety of exercise, or withdrawal of participant consent.

Strategies to improve adherence to interventions {11c}

Research personnel will use telephone call reminders every 6 weeks to follow-up with participants and ensure participants’ adherence to interventions (i.e., home and group exercises, oral nutritional supplementation, vitamin D, follow-up with family physicians, as appropriate) and assist with challenges pertaining to their intervention. YMCA instructors follow a standardized curriculum and have also been trained in working with older adults living with frailty to encourage safe and progressive exercise participation and foster social connections.

Outcomes {12}

Sample size {14}

We calculated the sample size based on our primary outcome of physical function. Our sample size parameters were informed by a study we did with a similar cohort of older adults who participated in an aerobic dance program twice weekly for 12 weeks (GERAS DANCE). Participants who had baseline SPPB scores ≤8 (i.e., indicative of sarcopenia and physical frailty) had a mean change in SPPB total scores of 1.45 (SD 1.97, p < 0.001) between baseline and 12 weeks [64,65]. Previous validation studies indicate that a minimal clinically important difference is an increase of 0.3–0.8 points for SPPB and 0.03–0.05 m/s for the 4 m gait speed. Substantial clinical change is considered an increase of 0.4–1.5 points for SPPB and 0.08 m/s for the 4 m gait speed [64]. The minimal clinically important difference for the 400m Walk Test is 20–30 seconds [64]. Substantial clinical change is considered 50–60 seconds for the 400m Walk Test [64]. We calculated the required sample size for each outcome individually. To ensure that the study is adequately powered to detect a meaningful effect on both outcomes, we adopted the larger of the two calculated sample sizes (SPPBs) as the final sample size for the trial. We conservatively expect at least a 1-point difference in SPPB total scores (SD = 2.0) between the intervention and control arms (multimodal vs control and exercise only vs control). Factoring a drop-out rate of up to 20%, with α = 0.05 and 1-β = 0.9, we need a total sample size of N = 324 (108 per arm).

Recruitment {15}

We anticipate a randomization rate of 1 enrolled participant per 6 screened and a target recruitment of approximately 3–4 participants/week, based on other studies with older adults living with frailty [18–20,65]. Rolling recruitment will occur over two years, with approximately 10 cohorts of 33 participants (approximately 11 participants per arm) being enrolled across several YMCA sites (Fig 2). Our study team will liaise and advertise the study across our clinical networks with referral sources, including specialist outpatient clinics, acute care, rehabilitation units, and primary care. The study will also be advertised via social media, traditional media, and via our YMCA partners and other community agencies. Interested individuals in the community may self-refer by calling research staff (phone numbers will be provided on advertising materials). Telephone prescreening by the Geras study staff will assist in identifying individuals prior to an eligibility assessment conducted via telephone.

Sequence generation {16a}

An independent statistician will prepare a computer-generated allocation sequence via SAS 9.4 software [66]. Stratified block randomization (1:1:1 allocation) will be used to randomly allocate eligible and consenting participants to one of three groups (the control group, OPTIMAL Fitness exercise, and OPTIMAL Fitness multimodal). Participants will be stratified by sex and age (<80 years or ≥80 years) with a block size of 3 within each stratum.

Concealment mechanism {16b}

To conceal the sequence, only a researcher who is not involved in the study will have a computer-generated allocation list. The list will be uploaded into the Research Electronic Data Capture (REDCap) randomization module.

Implementation {16c}

Once the study research assistant confirms the participant’s eligibility and obtains informed written consent, the research assistant will submit the eligibility form, consent form, and participant contact form to a team member (who is not part of the study) who will randomize the participant via REDCap. After providing consent, a blinded outcome assessor will contact the participants to set up a telephone appointment and perform an in-person baseline assessment at the YMCA. After the baseline assessment, the research staff will randomize participants within one week of their baseline assessment and inform the participants of their study group. During the first session, participants in the OPTIMAL Fitness exercise only and multimodal groups will receive an intervention-specific study manual, and instructors will provide an orientation for participants so that they are aware of the trial procedures that will follow. A detailed description of the outcome assessments and intervention can be found in Fig 3.

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Fig 3. Study intervention and outcome assessments.

https://doi.org/10.1371/journal.pone.0343338.g003

Who will be blinded {17a}

Outcome assessors, data entry personnel, data analysts who perform the final data analysis, the investigative team, and members of the steering committee will be blinded to the intervention assignments. The participants will also be blinded at the baseline assessment. Due to the nature of the intervention, research assistants, study intervention personnel (pharmacists, instructors) and participants will not be blinded.

Plans for assessment and collection of outcomes {18a}

The schedule for the study assessments and collection of outcomes is summarized in Fig 1. Blinded assessors will receive training in study procedures and data collection tools. Primary and secondary outcomes will be measured in person at baseline and 4 months. Outcome assessments will take place at a local YMCA site and via telephone. Healthcare utilization and medication/supplement use will be assessed through phone calls by research personnel at baseline, at 4 months, and on a monthly basis for 6 months following the intervention. Participants participating in the sarcopenia substudy will be booked to undergo DXA and MRI within a week of their baseline/4-month post-assessments. A description of the study instruments, along with their reliability and validity, is provided in Table 3.

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Table 3. Reliability and Validity of Outcomes.

https://doi.org/10.1371/journal.pone.0343338.t003

Plans to promote participant retention and complete follow-up {18b}

Adherence will be measured by a daily self-reported logbook developed specifically for the OPTIMAL Fitness trial to track adherence to home and group exercises, nutrition (oral nutritional supplements and vitamin D), medications, and falls/injuries. The participant logbooks will be collected during the post assessment by the research staff. Study personnel will conduct monthly check-ins by phone to monitor adherence and adverse events and to assess and assist with challenges pertaining to their assigned intervention.

Data management {19}

Study data will be entered by data entry personnel via REDCap electronic data capture tools. The study database will be password protected and kept on a secure network system. All data entered in REDCap will be audited by a research assistant to assess accuracy and missing data. Only the research team and biostatistician will have access to the final trial database.

Confidentiality {27}

All the data collected, shared, and maintained will be deidentified to protect confidentiality before, during, and after the trial. Zoom for Healthcare will be used to deliver the nutritional review nutrition component of the intervention. Zoom for Healthcare is HIPAA/PIPEDA compliant. It is security compliant and includes 256-bit Advanced Encryption Standard (AES) encryption, password protection, and waiting room features to ensure the participant’s privacy of information.

Statistical methods for primary and secondary outcomes {20a}

The study statistician will analyze the study data and report it in accordance with the CONSORT criteria after data collection is completed [92]. A generalized linear model analysis will be used to compare differences between the intervention groups (multimodal vs control and exercise alone vs control) and the control group for both primary and secondary outcomes. The link function in the generalized linear model will depend on the outcome type. For continuous outcomes, we will use an identity link, and for binary outcomes, we will use a logit link. Tukey’s honestly significant difference will be used to analyze the SPPB and 400m Walk Test results. The primary comparisons will be after 4 months. Stratification will be used to increase the precision of the overall estimates in the ANOVA, leading to more precise estimates of the overall treatment effect. We will report between-group differences in means or percentages with 95% confidence intervals at the 4-month post-assessment. All analyses will be an intention to treat.

Economic analysis: A trial-based economic evaluation will be conducted to compare the costs and quality-adjusted life years (QALYs) between the treatment arms. The study conduct and reporting will follow Canadian [93] and international [94–96] guidelines for economic evaluations of healthcare programs. The cost of developing and administering the OPTIMAL Fitness exercise and the OPTIMAL Fitness multimodal interventions will be captured as part of the trial. Healthcare resource utilization data (e.g., hospitalization, emergency department visits, physician visits, and visits to other healthcare professionals) will be collected at baseline, 4 months, and each month post-intervention for 6 months via a short-economic questionnaire that will be developed for the study. Health utility scores derived from the EQ-5D-5L questionnaire [97] collected at baseline and 4 months will be weighted by time spent in health states using an area-under-the-curve approach to calculate QALYs. To address sampling uncertainty, bootstrap techniques [98] will be used, and cost-effectiveness acceptability curves (CEACs) [99] will present the probability of the intervention being cost-effective at different willingness-to-pay thresholds (e.g., $50,000/QALY gained; $100,000/QALY gained). All analyses will be conducted via SAS.

Interim analyses {21b}

There will be no interim analyses.

Methods for additional analyses (e.g., subgroup analyses) {20b}

Sensitivity analysis will be performed to examine the per-protocol cohort (participants who completed the trial) and the influence of covariates on our dependent variables, including adherence. We will use a generalized linear model analysis to determine the impact of both stratified variables (age and sex) on the outcome measures. On the basis of the ICEMAN criteria in a randomized controlled trial, we hypothesize that there will be a greater change in the primary outcomes for both women (compared with men) and older adults (compared with younger individuals) [100]. This direction is based on biological evidence [101,102]. In addition, we will also compare differences in both primary and secondary outcomes between the multimodal and exercise alone groups.

Methods in analysis to handle protocol nonadherence and any statistical methods to handle missing data {20c}

To handle missing data from the intention-to-treat perspective, we will conduct multiple imputation using a Markov chain Monte Carlo method that includes 10 imputed datasets [103]. For sensitivity analysis, a per-protocol analysis will also be performed, including only participants who complete 75% of the intervention. The 75% adherence was selected given that it is a feasible, realistic expectation that is consistent with prior studies [104].

Ancillary and posttrial care {30}

In the case of research-related side effects or injury as a direct result of taking part in this study, participants will be referred for appropriate medical care. There are no other plans for additional health care or compensation.

Composition of the coordinating centre and trial steering committee {5d}

The coordinating centre for the study is at the Geras Centre for Aging Research, Hamilton Health Sciences. The study research assistants will be responsible for submitting and maintaining REB documents, liaising with clinical partners for recruitment, enrolling participants, receiving and storing consent forms, monitoring adherence and adverse events, overseeing data collection and entry, and all other trial day-to-day operations. To provide overall supervision of the trial, the study steering committee will meet every 6 months or more frequently, as needed.

Composition of the data monitoring committee, its role and reporting structure {21a}

The Data and Safety Monitoring Board (DSMB) is an independent multidisciplinary group consisting of a biostatistician and clinicians who, collectively, have experience in the management of older adults who are prefrail or frail and in the conduct and monitoring of randomized clinical trials. For each DSMB meeting, Open and Closed Reports will be provided. Open Reports, available to all individuals who attend the DSMB meeting, will include data on recruitment and baseline characteristics and pooled data on eligibility violations, completeness of follow-up, and compliance. Closed Reports, available only to those attending the Closed Sessions of the DSMB meeting, will include analyses of AEs and symptom severity and Open Report analyses that are displayed by the intervention group.

Adverse event reporting and harms {22}

Study personnel will conduct monthly check-ins by phone to monitor for adverse events. The participants will also be instructed to contact the study coordinator if they experience any unfavourable signs or symptoms. Adverse events or harm from any source will be reported to the research team and recorded in a structured form. Any serious adverse events will be reported to the Research Ethics Board within 24 hours. The independent DSMB described above will review safety data from the trial and advise the investigators and the Steering Committee on the future management of the trial.

Frequency and plans for auditing trial conduct {23}

There are no plans for auditing to be conducted.

Strengths and limitations

The strengths of our proposed study include (1) a large sample size that is sufficient to attain adequate power to detect a difference in outcomes and robust conclusions may be drawn; (2) a study design that allows us to consider the additive effects of multimodal interventions that include other important components for comprehensive frailty and sarcopenia management (e.g., socialization, nutrition, protein, and medication support) in addition to exercise; (3) rigorous methodological safeguards to avoid potential bias, including a centralized randomization system, assessment of baseline measures prior to randomization, and blinding outcome assessors, study biostatistician, the investigative team, and the steering committee to intervention assignments; and (4) engagement of all key stakeholders in the process of implementation, including patients, interdisciplinary healthcare teams, researchers, and community organizations, as indicated in the Medical Research Council guidance for complex interventions [26]; and (5) although our central site is in a community with an academic health science centre, our community-based model allows the potential for uptake in smaller centres with the ability to incorporate additional consultation via virtual methods. We have recently demonstrated that virtual frailty rehabilitation is a viable approach [19].

The limitations of this study include: (1) the inability to blind research assistants, intervention personnel (pharmacists, instructors), and participants, which may introduce bias; this is mitigated by using objective primary outcomes and blinding outcome assessors and the biostatistician conducting the analyses; (2) the limited follow-up period inherent to the RCT design, which prevents assessment of long-term benefits or harms; (3) exclusion of participants with significant cognitive impairment or those unable to speak English, which may limit generalizability; and (4) the multifaceted nature of the intervention (exercise, nutrition, and medication evaluation), which prevents isolation of the effects of individual components.

Dissemination plans {31a}

As a CIHR-designated Canadian Research Centre on Aging, the Geras Centre for Aging Research is aligned with the CIHR Strategic Plan 2021–2031 [107] bridging research and implementation to promote knowledge mobilization (KMb) and evidence-based practices in healthcare. Our KMb approach includes engaging stakeholders with lived experience (older adults are part of our advisory board, fostering partnerships with policymakers, healthcare providers, and community organizations, and disseminating findings through multiple channels (e.g., peer-reviewed publications, conference presentations, social media, and local geriatric networks). The research findings will be shared with an extensive network of institutes and centres (e.g., the McMaster Institute for Research on Aging (MIRA)), health professionals, policymakers, educators, community stakeholders (e.g., the Hamilton Council on Aging, YMCA), and participants and their families and/or caregivers.

Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}

All protocol updates (i.e., changes to eligibility criteria, outcomes, procedures, etc.) will be communicated to relevant parties (i.e., investigators, research teams, participants, etc.) and submitted to the ethics board for review.