Effects of the Combined Intervention of Exercise, Fruit, and Vitamin Supplementation on Frailty in Older Adults (EFVF): Rationale, Design, and Methods

Effects of the Combined Intervention of Exercise, Fruit, and Vitamin Supplementation on Frailty in Older Adults (EFVF): Rationale, Design, and Methods | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Effects of the Combined Intervention of Exercise, Fruit, and Vitamin Supplementation on Frailty in Older Adults (EFVF): Rationale, Design, and Methods Xinyi Huang, Yan Lu, Lingling Jin, Hankun Xie, Linchi Wang, Wei Fan, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4407061/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Frailty is a complex, dynamic, age-related clinical condition. Muscle strength, a critical indicator of frailty, decreases with advancing age. It is not known whether community-dwelling older adults with frailty modifiable risk factors, such as low levels of physical activity and fruit intake, might benefit from lifestyle interventions at both population and individual levels. Methods EFVF is a cluster-randomized trial including older individuals aged 65–80 years old with low levels of physical activity and fruit intake living in eastern China. Totally 14 villages will be randomized into 2 arms with 1:1 ratio, overall including ≥ 934 participants. Participants in the intervention arm will receive the combined intervention of physical activity, fruit, and vitamin supplementation 3 times a week for 2 months (the 1st and 6th months). Standardized health education and communication sessions will be conducted as well. Participants in the control arm will not receive any intervention. The primary outcome is the change in handgrip strength at 12 months from baseline. Secondary outcomes include handgrip strength, frailty index, lipid parameters, fasting blood glucose, and a composite of all-cause death or hospitalization for myocardial infarction, angina, or stroke. The study also includes an assessment of the cultivation of physical activity and fruit intake habits, as well as an economic evaluation. Discussion The study will target older adults with modifiable risk factors for frailty, to investigate whether the combined intervention might limit the decline of grip strength, frailty progression, and reduce the incidence of adverse events. If effective, it could provide a well-established and cost-effective strategy for frailty prevention in community settings. Trial registration: Clinical Trails.gov PRS Protocol Registration and Results System, NCT06225271, (Jan 17, 2024). frailty cluster randomized trial multilevel intervention physical activity fruit intake handgrip strength Figures Figure 1 Introduction Frailty, a complex clinical condition, is characterized by the progressive loss of physiological capacity and increased vulnerability to stress ( 1 ) ( 2 ) ( 3 ). With a rapidly expanding aging population, frailty is highly prevalent ( 4 ). Depending on measurement tools or setting, its prevalence varies from 4%-59% ( 5 ). Frailty is associated with adverse outcomes, such as falls and fractures, hospitalization, disabilities, lower quality of life, dementia, and early mortality ( 6 ) ( 7 ) ( 8 ) ( 9 ). Undoubtedly, frailty is an emerging global health burden, and the associated health-care costs and use have increased significantly ( 10 ) ( 11 ) ( 12 ) ( 13 ) ( 14 ). Remarkably, frailty is a dynamic entity and transitions between different states (robust, pre-frail, and frail) occur frequently over time ( 15 ). Hence, preventing or slowing the progression of frailty before it precipitates significant functional decline is crucial for both clinical practice and public health. The identification of modifiable risk factors provides an opportunity for intervention to delay the progression of frailty. Evidence shows that a link between inadequate physical activity and low fruit consumption with frailty ( 16 ) ( 17 ) ( 18 ). Primary care interventions designed to encourage physical activity and fruit consumption could potentially limit the decline in physical function. Currently, there is no consensus on the definitive criteria for frailty, and various frailty manifestations have been proposed. Among these, decreased grip strength is generally recognized as an indispensable clinical manifestation of frailty ( 19 ) ( 3 ). It's worth noting that grip strength naturally declines with age, and this decline is particularly noticeable in hospitalized patients ( 20 ) ( 21 ). In the Chinese population, starting at the age of 50, men experienced a grip strength decline of 5kg per decade, while women experienced a decline of 3kg per decade ( 22 ). Despite a growing number of publications evaluating risk factors for frailty, only a limited subset has specifically investigated the potential impact of interventions on modifiable risk factors. Moreover, there are few studies exploring interventions that are suitable for long-term implementation in community settings. Thus, we will target older adults aged 65–80 years with modifiable risk factors for frailty (low levels of physical activity and fruit intake), investigating whether the combined intervention of exercise, fruit, and vitamin supplementation has benefits. It is hypothesized that participants submitted to the combined intervention will present better muscle strength, lower frailty index scores, lower blood lipid levels, lower blood sugar levels, lower risk of all-cause death or hospitalization for myocardial infarction, angina, or stroke. The cultivation of fruit intake and physical activity habits is also expected. If effective, this trial has the potential for implementation through other community-based effective organizing. Methods Study Design The prospective cluster-randomized, controlled, two-armed study is designed to assess the effect of the combined intervention of exercise, fruit, and vitamin supplementation on frailty among older adults aged 65–80 years with low levels physical activity and fruit intake. Participants in the intervention groups will receive the combined intervention at both population and individual levels, whereas those in the control groups will not receive active intervention. Participants will be followed for an additional 24 months, with primary outcome handgrip strength assessments performed at 6-month and 12-month follow-ups. Figure 1 illustrates the EFVF study design. Setting The evaluation will be conducted at community activity centers or day care centers in Wuzhong District, Suzhou. Suzhou, situated in the eastern part of China's Jiangsu Province, is a prominent economic center within the Yangtze River Delta region, boasting a well-developed infrastructure. Wuzhong District, located in the middle of Suzhou, is equipped with ample community activity centers that provide sufficient public space for the evaluation. Participant eligibility Inclusion Criteria Participants will be included in the study if they meet the following criteria: ( 1 ) permanent resident population aged 65 ~ 80 years; ( 2 ) ability to walk independently indoors and outdoors; ( 3 ) total physical activity less than 1400 metabolic equivalent task (MET)-min/week; ( 4 ) daily fruit intake less than 50g; ( 5 ) have not taken vitamin B and vitamin C supplementation in the past 3 months; ( 6 ) sufficient Chinese proficiency to provide informed consent. Exclusion Criteria Potential participants will be excluded if any of the following criteria are met: ( 1 ) with a history of fractures; ( 2 ) have been diagnosed with severe impairment of renal; ( 3 ) have been diagnosed with hepatic dysfunction; ( 4 ) currently engaged in or planning to engage in other similar studies; ( 5 ) have been previously diagnosed with neurological disorder. Hepatic dysfunction is defined as serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels above 100 U/L. Renal impairment is defined as estimated glomerular filtration rate (eGFR) < 45 mL/min, calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. Recruitment All eligible participates will be informed of the objectives of the study. Recruitment for the study started in February 2024 and is currently ongoing. Participant recruitment methods included telephone outreach and door-to-door publicity. The investigators will identify potentially eligible individuals and verify their eligibility for enrollment. Written informed consent will obtain. The expected enrollment rate is 50% and targeted completion is 75%. Randomization To prevent contamination, individual randomization is not considered ( 23 ). Moreover, a cluster-randomized controlled design allows for the assessment of interventions at multiple levels ( 24 ). The randomization units are villages and the SAS PROC PLAN process will generate random sequence to assign 14 clusters (villages) to the intervention and control arms in a 1:1 allocation ratio. The project coordinator, facilitators and supervisors, and biostatistician will be unblinded to group assignment. Sample size Sample size was estimated using PASS (Power Analysis and Sample Size) software (version 15.0.5) based on data from previous studies. Previous studies showed that the Cohens’ d value was between 0.18 ~ 1.78 ( 25 ) ( 26 ) ( 27 ) ( 28 ) ( 29 ). With these data, we estimated effect size of Cohen’ d = 0.45, considering probabilities of 5% for type I error, 20% for type II error, and 0.05 for intraclass correlation coefficient (ICC). We randomized all 14 clusters (villages) into two arms with 1:1 ratio, and the total sample size was calculated to be 700 (50 participates per cluster). Estimating a conservative 25% loss to follow-up or drop-out, a total of 934 participants will be required. Study procedures 1 Population intervention After each intervention, a 15-minute communication and discussion session will be held. Community health workers will give brief popular science education on frailty in the local dialect, and will also encourage the participants to continue exercising and eating fruits at home. In addition, a health education activity will be organized at least once per month during the intervention, with a recommended minimum duration of 45 minutes. It is worth noting that the duration of each health education session is not limited, and the goal is to help participants truly understand in plain language and change unhealthy habits. 2 Individual intervention The intervention will be carried out 3 times a week for 2 months (the 1st and 6th months). 2.1 Physical activity The participants will be gathered at the nearest community activity center or day care center. Community workers will project fitness aerobics videos and act as trainers, calling on the participants to stand up and actively participate in the exercises. Investigators will record the start time simultaneously. The process is expected to last 20 minutes. Considering the participants' different physical conditions and personal preferences, our principle is to encourage rather than enforce participation in the fitness aerobics sessions for all individuals. In cases where participants are unwilling to participate in fitness aerobics, community workers will promptly distribute hand grip balls as an alternative option. Participants will be instructed to grip the hand grip ball with maximum strength, holding it for 2 seconds and then relaxing for 2 seconds. Finally, community workers will lead the participants to do some simple repetitive movements, such as finger exercises, clenching fists, rubbing hands, sitting leg lift shoulder shrug sitting leg lift palm clap leg, cross clap arm, and so on. The duration of exercise should be longer than 30 minutes. The investigators will supervise the entire process, ensuring participants' adherence to the exercise routine. They will actively remind and encourage participants to continue exercising if they pause or discontinue during the session. Exercise time and any discomfort symptoms during exercise will be recorded in detail. In addition, information will also be collected on the average daily physical activity time of participants at home between interventions. 2.2 Fruit supplementation The fruit will be divided into 50g servings. Various types of fruit, including cherry tomatoes, bananas, oranges, and more, will be prepared to meet the needs of different people. Participants will be required to eat on site (allowing for more than 50g), with the actual amount consumed being documented. In addition, information will be collected on the average daily fruit consumption of participants at home between interventions. 2.3 Vitamin supplementation During the intervention, the participants will be required to take one tablet of vitamin B complex plus one tablet of vitamin C daily. The medication compliance will be followed up. As the pills need to be taken with warm water, it may cause discomfort if taken alongside cold fruits. Thus, the tablets will be distributed before engaging in physical activities. Information on whether the participants take these medications at home between interventions will also be collected. Outcomes Primary outcome The primary outcome of the trial is the change in handgrip strength at 12 months from baseline. Handgrip strength will be measured using a hand-held grip dynamometer. Participants will be instructed to grip the dynamometer with left hand and right hand respectively while standing, maintaining their arm close to the body and straight down, exerting maximum force. This test will be conducted 3 times, and the values will be recorded in kilograms. Secondary outcome 1) The change in handgrip strength at 6 months from baseline. The definition and measurement method are the same as the primary outcome. 2) The change in frailty score at 6 months and 12 months from baseline. Outcome is defined as the change in the score of modifiable variables in the frailty index from baseline. The frailty index consisted more than 20 variables covering age, physical measurement, sleep quality, history of surgery, fall, and fracture, history of the disease, oral hygiene, respiratory function, and physical function self-assessment aspects. The frailty index is a continuous variable, with a higher value indicating a more frail status. 3) The change in physical activity volume and intensity at 12 months from baseline. Information on physical activity levels during the past week will be collected through the International Physical Activity Questionnaire Scale-Short Form (IPAQ-SF) ( 30 ). Physical activity volume will be determined by summing the metabolic equivalent task (MET)-min/week values. Higher values represent higher levels of physical activity. 4) The change in the quantity and frequency of fruit intake at 12 months from baseline. Fruit intake will be collected by questionnaire for the frequency of consumption and weights per intake. The frequency will be determined by filling in the number of times the participants eat fruit per week/day/monthly/year. Fruit quantity is determined by the product of frequency and weights of a single fruit intake. 5) A composite of all-cause death or hospitalization for myocardial infarction, angina, or stroke within 12 and 24 months after enrollment. Individual components of the outcome will also be examined. Angina will be defined by receiving treatment for any of the following ICD codes: I20. Myocardial infarction will be defined by receiving treatment for any of the following ICD codes: I21 or I22. Stroke will be defined by receiving treatment for any of the following ICD codes: I60-I64. 6) The change in lipid parameters at 12 months and 24 months from baseline. Lipid parameters will include low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG). 7) The change in fasting blood glucose at 12 months and 24 months from baseline. It will be measured by Glucose Oxidase (GOD) method. 8) Incremental cost-effectiveness ratio (ICER). It's calculated by dividing the difference in costs between the two interventions by the difference in their effects. Adherence to the intervention Completion of a single intervention is defined as engaging in at least 30 minutes of physical activity and consuming at least 50 grams of fruit supplementation. If the participants do not meet the criteria, the values will be recorded truthfully. Theoretically, participants in the intervention group are expected to attend 12 on-site interventions each month of the intervention period. Good compliance among participants is defined as completing 9 or more. If the study participant is absent more than 3 times in each intervention month, the expected intervention deadline should be postponed to complete the established number of interventions. If participants reject the plan, the reasons for their refusal will be recorded. Data collection and management All data collectors will be trained in questionnaire content and electronic device operation. The anthropometric will be trained prior to the formal investigation. In addition to blood pressure, height, blood oxygen, and heart rate variables, the remaining variables are recorded with precision up to two decimal places. Data will be collected using electronic device and a paper copy will be provided as a backup in case of electronic failure. Data quality checks are built into the e-questionnaire, for example limiting ranges of responses/measurements to the credible range, setting questions as ‘required’ to avoid missing questions, and checking for consistency between questions. Statistical analysis Categorical variables are presented as frequencies (n) and percentages (%). Continuous variables are reported as means and standard deviation (SD) or medians (interquartile range) for non-normality of distribution. Comparisons will be made using t tests or Wilcoxon rank sum tests for continuous variables or χ2 or Fisher exact tests for categorical variables, along with reporting of confidence intervals. The primary analyses will be done at the individual level, according to the intention-to-treat principle. For the primary analysis comparing the change in handgrip strength, generalized linear regression mixed model (GLMM) with fixed effect for study group and baseline handgrip strength value will be employed. And random cluster effects (villages) will be fitted to the data in order to account for intra-cluster correlations introduced by the cluster randomized controlled design. We will report differences from unadjusted and adjusted models. The adjusted models will include age, sex, education levels, smoking, drinking, baseline handgrip strength value, and chronic diseases. The estimated regression coefficient for study group will represent the estimated mean difference between study groups. Considering the potential for type I error due to multiple comparisons, analysis of secondary outcomes will be interpreted as exploratory. For physical activity and fruit intake, the least square mean will be compared between groups and before and after intervention. For other continuous data, tests for group differences will be performed as described for the primary analysis. The cumulative incidence of a composite of all-cause death, cardiovascular and cerebrovascular diseases and its individual components will be calculated using the Kaplan–Meier method and reported with 95% confidence intervals. The outcome will be compared between groups using a generalized-estimating-equation (GEE) regression model with Poisson distribution. The intervention effect will be reported as the cumulative incidence ratio (CIR) with multiplicity-adjusted 95% confidence intervals. We predefine subgroup analyses considering age, sex, physical activity, fruit intake and grip strength. We will use an interaction test between subgroup variables and study groups to test whether the effects vary by subgroups. Observed adverse events will be listed. Statistical significance is defined as P < 0.05. The analysis will be performed with the use of SAS software, version 9.4, and R soft-ware, version 3.6.1. Ethics and trial registration This trial has been approved by the Institutional Review Board of Nanjing Medical University (ID:2023588). The trial is registered at www.clinicaltrials.gov (ID: NCT06225271). Discussion In many cases, frailty onset starts before age 65 years. All older adults are at risk of developing frailty, especially those with unhealthy lifestyle habits, comorbidities, and low socioeconomic position. Frailty or prefrailty is potentially reversible. Given the serious consequences of frailty and its increasing prevalence, it is urgent to intervene on its modifiable risk factors. Identifying frailty risk factors that are potentially modifiable by specific interventions could provide direction for public health and preventive strategies. To date, few available trials focusing on the effects of combined interventions on frailty in older adults with modifiable risk factors. EFVF is a cluster-randomized trial to examine the possibility of a combined intervention of exercise, fruit, and vitamin supplementation for the older adults with modifiable risk factors (low levels of physical activity and fruit intake) for frailty. Better muscle strength, lower frailty index scores, lower blood lipid levels, lower blood sugar levels, and lower risk of cardiovascular and cerebrovascular disease and all-cause death are hypothesized to be present in participants. Low levels of physical activity and fruit intake are widely recognized as risk factors for frailty in Chinese older adults ( 31 ) ( 32 ). Interventions targeting on physical activity and fruit intake may be the key to delaying the progression of frailty and potentially reversing it. Additional benefits occur with more physical activity, both in terms of aerobic and muscle-strengthening physical activity ( 33 ). However, the benefits that older adults can derive from physical activity depend on their adherence to an exercise regimen and the satisfaction they experience from it. Non-compliance with recommended lifestyle changes remains a common and challenging obstacle to achieving these benefits ( 34 ) ( 35 ). Despite the government's long-term efforts to promote physical activity among residents, the prevalence of physical inactivity continues to increase. More than 20% of adults are not meeting the recommended level ( 36 ) ( 37 ). Considering the physical condition and preferences of older adults, it does not impose specific requirements on the intensity and mode of physical activity, which differs from previous studies. This research employs flexible and diverse methods for engaging in low to medium intensity physical activity, aiming to provide an opportunity for older individuals who may not typically enjoy exercise to discover the joy of being physically active and cultivate a sustainable habit. Research on promoting fruit intake in older adults is limited. In previous cross-sectional or cohort studies, vegetables and fruits were often examined together. Considering the practicality of on-site intervention and the existing low proportion of insufficient vegetable intake among older adults in Suzhou, we did not focus on interventions specifically for vegetable consumption. However, information on dietary intake, including vegetables, will be collected. We selected change in grip strength at 12 months from baseline as the primary outcome. The concept of frailty is gradually being used at primary medical and healthcare institutions, however, there is no consensus on the criteria for frailty. Currently, Fried frailty phenotype and the frailty index are the most commonly used definitions of frailty ( 3 ) ( 38 ). In any case, grip strength is considered an important clinical manifestation of frailty. Many studies have shown that low muscle strength is significantly associated with all-cause mortality and other adverse events. Besides, studies indicate that the Chinese population experiences an age-related decline in muscle strength ( 22 ). Therefore, the primary objective of this study is to examine the effects of the combined intervention on grip strength, assuming that participants in the intervention group will exhibit either an increase in grip strength or a slower rate of decline in grip strength compared to those in the control group. Overall, if effective, EFVF will yield evidence-based data and could provide a well-established and cost-effective strategy for frailty prevention in community settings. Declarations Ethics approval and consent to participate: This trial has been approved by the Institutional Review Board of Nanjing Medical University (ID:2023588). Study participants complete a written informed consent prior to participation in research activities. Consent for publication: Not applicable. Availability of data and materials: Not applicable. Competing interests: The authors declare that they have no competing interests. Funding: This study was funded by Public Health Special Project of GuSu College of Nanjing Medical University, Grant/Award Number: GSKY20230103. Authors' contributions: CS, YL, and LCW made contributions to the conception of the trial. CS, XYH, YL, LLJ, and HKX made contributions the design of the trial. XYH drafted the manuscript. WF and XFW made revisions to the manuscript. All authors have read and approved the final manuscript. Acknowledgements: Not applicable. References Morley JE, Vellas B, van Kan GA, Anker SD, Bauer JM, Bernabei R, et al. Frailty consensus: a call to action. Journal of the American Medical Directors Association. 2013;14(6):392-7. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet (London, England). 2013;381(9868):752-62. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. 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The Physical Activity Guidelines for Americans. Jama. 2018;320(19):2020-8. Brach M, de Bruin ED, Levin O, Hinrichs T, Zijlstra W, Netz Y. Evidence-based yet still challenging! Research on physical activity in old age. European review of aging and physical activity : official journal of the European Group for Research into Elderly and Physical Activity. 2023;20(1):7. Stonerock GL, Blumenthal JA. Role of Counseling to Promote Adherence in Healthy Lifestyle Medicine: Strategies to Improve Exercise Adherence and Enhance Physical Activity. Progress in cardiovascular diseases. 2017;59(5):455-62. Chaoqun Wu, Xi Li, Jiapeng Lu, Bowang Chen, Yichong Li, Yang Yang, et al. Distribution of cardiovascular disease risk factors in Chinese residents. China circulation journal. 2021;36(01):4-13. Zhang M, Ma Y, Xie X, Sun M, Huang Z, Zhao Z, et al. Trends in insufficient physical activity among adults in China 2010-18: a population-based study. The international journal of behavioral nutrition and physical activity. 2023;20(1):87. Rockwood K, Mitnitski A. Frailty in relation to the accumulation of deficits. The journals of gerontology Series A, Biological sciences and medical sciences. 2007;62(7):722-7. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4407061","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":304204257,"identity":"e4db436e-5689-4688-a800-e7f16cf3c8b4","order_by":0,"name":"Xinyi Huang","email":"","orcid":"","institution":"Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xinyi","middleName":"","lastName":"Huang","suffix":""},{"id":304204258,"identity":"6e239964-847e-46f4-ad35-cae9969b44eb","order_by":1,"name":"Yan Lu","email":"","orcid":"","institution":"Suzhou Center for Disease Control and Prevention","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Lu","suffix":""},{"id":304204259,"identity":"1d325e52-5c00-4ec9-95a2-a860b5bf344b","order_by":2,"name":"Lingling Jin","email":"","orcid":"","institution":"Suzhou Center for Disease Control and Prevention","correspondingAuthor":false,"prefix":"","firstName":"Lingling","middleName":"","lastName":"Jin","suffix":""},{"id":304204260,"identity":"5eb5521d-e6f5-4eeb-829c-72b9a814f4c7","order_by":3,"name":"Hankun Xie","email":"","orcid":"","institution":"Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hankun","middleName":"","lastName":"Xie","suffix":""},{"id":304204261,"identity":"572b0290-615c-4155-a3d0-87c56acc0e8e","order_by":4,"name":"Linchi Wang","email":"","orcid":"","institution":"Suzhou Center for Disease Control and Prevention","correspondingAuthor":false,"prefix":"","firstName":"Linchi","middleName":"","lastName":"Wang","suffix":""},{"id":304204262,"identity":"e6ee5edf-4722-49a7-a254-f0ec997a5903","order_by":5,"name":"Wei Fan","email":"","orcid":"","institution":"Suzhou Center for Disease Control and Prevention","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Fan","suffix":""},{"id":304204263,"identity":"d76e257b-df2a-4b2c-ba77-6d7e00567ddc","order_by":6,"name":"Xuefei Wu","email":"","orcid":"","institution":"Suzhou Center for Disease Control and Prevention","correspondingAuthor":false,"prefix":"","firstName":"Xuefei","middleName":"","lastName":"Wu","suffix":""},{"id":304204264,"identity":"b37ee33a-75c1-4c2e-b30c-9c44e435593b","order_by":7,"name":"Chong Shen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAoklEQVRIiWNgGAWjYFACxoYDCRUScvwkaGFufPDhjIWxZAPxWtibDWe2VSRuIFqLfPvBNmneeRKMGxiYHz66QYwWgzOJQC3bJJjNGdiMjXOI0iLBCNbCZtnAwyZNlBb5GSAtcyR4DA4Qq4XhBiPQ+w0SEsRrAfoFGMjHJAwkm4n1i3z78QcHEmrq6vvZmx8+Js5hcMBMmvJRMApGwSgYBfgAABUuLfjg8CH5AAAAAElFTkSuQmCC","orcid":"","institution":"Nanjing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Chong","middleName":"","lastName":"Shen","suffix":""}],"badges":[],"createdAt":"2024-05-12 03:23:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4407061/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4407061/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57298770,"identity":"2358fa91-35e9-4d40-9ef6-a7f60980cf38","added_by":"auto","created_at":"2024-05-28 20:44:46","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":222419,"visible":true,"origin":"","legend":"\u003cp\u003eEFVF study design.\u003c/p\u003e","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4407061/v1/ab6d735b7376f6944ec04905.png"},{"id":65590040,"identity":"4513aaee-f615-4ff0-b206-701803581404","added_by":"auto","created_at":"2024-09-30 09:53:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":685922,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4407061/v1/125f737a-138b-4884-b710-c45ee674a003.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effects of the Combined Intervention of Exercise, Fruit, and Vitamin Supplementation on Frailty in Older Adults (EFVF): Rationale, Design, and Methods","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFrailty, a complex clinical condition, is characterized by the progressive loss of physiological capacity and increased vulnerability to stress (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). With a rapidly expanding aging population, frailty is highly prevalent (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Depending on measurement tools or setting, its prevalence varies from 4%-59% (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Frailty is associated with adverse outcomes, such as falls and fractures, hospitalization, disabilities, lower quality of life, dementia, and early mortality (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Undoubtedly, frailty is an emerging global health burden, and the associated health-care costs and use have increased significantly (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRemarkably, frailty is a dynamic entity and transitions between different states (robust, pre-frail, and frail) occur frequently over time (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Hence, preventing or slowing the progression of frailty before it precipitates significant functional decline is crucial for both clinical practice and public health.\u003c/p\u003e \u003cp\u003eThe identification of modifiable risk factors provides an opportunity for intervention to delay the progression of frailty. Evidence shows that a link between inadequate physical activity and low fruit consumption with frailty (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Primary care interventions designed to encourage physical activity and fruit consumption could potentially limit the decline in physical function.\u003c/p\u003e \u003cp\u003eCurrently, there is no consensus on the definitive criteria for frailty, and various frailty manifestations have been proposed. Among these, decreased grip strength is generally recognized as an indispensable clinical manifestation of frailty (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). It's worth noting that grip strength naturally declines with age, and this decline is particularly noticeable in hospitalized patients (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). In the Chinese population, starting at the age of 50, men experienced a grip strength decline of 5kg per decade, while women experienced a decline of 3kg per decade (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite a growing number of publications evaluating risk factors for frailty, only a limited subset has specifically investigated the potential impact of interventions on modifiable risk factors. Moreover, there are few studies exploring interventions that are suitable for long-term implementation in community settings. Thus, we will target older adults aged 65\u0026ndash;80 years with modifiable risk factors for frailty (low levels of physical activity and fruit intake), investigating whether the combined intervention of exercise, fruit, and vitamin supplementation has benefits. It is hypothesized that participants submitted to the combined intervention will present better muscle strength, lower frailty index scores, lower blood lipid levels, lower blood sugar levels, lower risk of all-cause death or hospitalization for myocardial infarction, angina, or stroke. The cultivation of fruit intake and physical activity habits is also expected. If effective, this trial has the potential for implementation through other community-based effective organizing.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThe prospective cluster-randomized, controlled, two-armed study is designed to assess the effect of the combined intervention of exercise, fruit, and vitamin supplementation on frailty among older adults aged 65\u0026ndash;80 years with low levels physical activity and fruit intake. Participants in the intervention groups will receive the combined intervention at both population and individual levels, whereas those in the control groups will not receive active intervention. Participants will be followed for an additional 24 months, with primary outcome handgrip strength assessments performed at 6-month and 12-month follow-ups. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates the EFVF study design.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSetting\u003c/h2\u003e \u003cp\u003eThe evaluation will be conducted at community activity centers or day care centers in Wuzhong District, Suzhou. Suzhou, situated in the eastern part of China's Jiangsu Province, is a prominent economic center within the Yangtze River Delta region, boasting a well-developed infrastructure. Wuzhong District, located in the middle of Suzhou, is equipped with ample community activity centers that provide sufficient public space for the evaluation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eParticipant eligibility\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eInclusion Criteria\u003c/h2\u003e \u003cp\u003eParticipants will be included in the study if they meet the following criteria: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) permanent resident population aged 65\u0026thinsp;~\u0026thinsp;80 years; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) ability to walk independently indoors and outdoors; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) total physical activity less than 1400 metabolic equivalent task (MET)-min/week; (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) daily fruit intake less than 50g; (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) have not taken vitamin B and vitamin C supplementation in the past 3 months; (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) sufficient Chinese proficiency to provide informed consent.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eExclusion Criteria\u003c/h2\u003e \u003cp\u003ePotential participants will be excluded if any of the following criteria are met: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) with a history of fractures; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) have been diagnosed with severe impairment of renal; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) have been diagnosed with hepatic dysfunction; (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) currently engaged in or planning to engage in other similar studies; (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) have been previously diagnosed with neurological disorder.\u003c/p\u003e \u003cp\u003eHepatic dysfunction is defined as serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels above 100 U/L. Renal impairment is defined as estimated glomerular filtration rate (eGFR)\u0026thinsp;\u0026lt;\u0026thinsp;45 mL/min, calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eRecruitment\u003c/h2\u003e \u003cp\u003eAll eligible participates will be informed of the objectives of the study. Recruitment for the study started in February 2024 and is currently ongoing. Participant recruitment methods included telephone outreach and door-to-door publicity. The investigators will identify potentially eligible individuals and verify their eligibility for enrollment. Written informed consent will obtain. The expected enrollment rate is 50% and targeted completion is 75%.\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003eRandomization\u003c/h2\u003e \u003cp\u003eTo prevent contamination, individual randomization is not considered (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Moreover, a cluster-randomized controlled design allows for the assessment of interventions at multiple levels (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). The randomization units are villages and the SAS PROC PLAN process will generate random sequence to assign 14 clusters (villages) to the intervention and control arms in a 1:1 allocation ratio. The project coordinator, facilitators and supervisors, and biostatistician will be unblinded to group assignment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eSample size was estimated using PASS (Power Analysis and Sample Size) software (version 15.0.5) based on data from previous studies. Previous studies showed that the Cohens\u0026rsquo; d value was between 0.18\u0026thinsp;~\u0026thinsp;1.78 (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). With these data, we estimated effect size of Cohen\u0026rsquo; d\u0026thinsp;=\u0026thinsp;0.45, considering probabilities of 5% for type I error, 20% for type II error, and 0.05 for intraclass correlation coefficient (ICC). We randomized all 14 clusters (villages) into two arms with 1:1 ratio, and the total sample size was calculated to be 700 (50 participates per cluster). Estimating a conservative 25% loss to follow-up or drop-out, a total of 934 participants will be required.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStudy procedures\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003e1 Population intervention\u003c/h2\u003e \u003cp\u003eAfter each intervention, a 15-minute communication and discussion session will be held. Community health workers will give brief popular science education on frailty in the local dialect, and will also encourage the participants to continue exercising and eating fruits at home. In addition, a health education activity will be organized at least once per month during the intervention, with a recommended minimum duration of 45 minutes.\u003c/p\u003e \u003cp\u003eIt is worth noting that the duration of each health education session is not limited, and the goal is to help participants truly understand in plain language and change unhealthy habits.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e2 Individual intervention\u003c/h2\u003e \u003cp\u003eThe intervention will be carried out 3 times a week for 2 months (the 1st and 6th months).\u003c/p\u003e \u003cp\u003e2.1 Physical activity\u003c/p\u003e \u003cp\u003eThe participants will be gathered at the nearest community activity center or day care center. Community workers will project fitness aerobics videos and act as trainers, calling on the participants to stand up and actively participate in the exercises. Investigators will record the start time simultaneously. The process is expected to last 20 minutes.\u003c/p\u003e \u003cp\u003eConsidering the participants' different physical conditions and personal preferences, our principle is to encourage rather than enforce participation in the fitness aerobics sessions for all individuals. In cases where participants are unwilling to participate in fitness aerobics, community workers will promptly distribute hand grip balls as an alternative option. Participants will be instructed to grip the hand grip ball with maximum strength, holding it for 2 seconds and then relaxing for 2 seconds.\u003c/p\u003e \u003cp\u003e Finally, community workers will lead the participants to do some simple repetitive movements, such as finger exercises, clenching fists, rubbing hands, sitting leg lift shoulder shrug sitting leg lift palm clap leg, cross clap arm, and so on.\u003c/p\u003e \u003cp\u003eThe duration of exercise should be longer than 30 minutes. The investigators will supervise the entire process, ensuring participants' adherence to the exercise routine. They will actively remind and encourage participants to continue exercising if they pause or discontinue during the session. Exercise time and any discomfort symptoms during exercise will be recorded in detail. In addition, information will also be collected on the average daily physical activity time of participants at home between interventions.\u003c/p\u003e \u003cp\u003e2.2 Fruit supplementation\u003c/p\u003e \u003cp\u003eThe fruit will be divided into 50g servings. Various types of fruit, including cherry tomatoes, bananas, oranges, and more, will be prepared to meet the needs of different people. Participants will be required to eat on site (allowing for more than 50g), with the actual amount consumed being documented. In addition, information will be collected on the average daily fruit consumption of participants at home between interventions.\u003c/p\u003e \u003cp\u003e2.3 Vitamin supplementation\u003c/p\u003e \u003cp\u003eDuring the intervention, the participants will be required to take one tablet of vitamin B complex plus one tablet of vitamin C daily. The medication compliance will be followed up. As the pills need to be taken with warm water, it may cause discomfort if taken alongside cold fruits. Thus, the tablets will be distributed before engaging in physical activities. Information on whether the participants take these medications at home between interventions will also be collected.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003ePrimary outcome\u003c/h2\u003e \u003cp\u003eThe primary outcome of the trial is the change in handgrip strength at 12 months from baseline. Handgrip strength will be measured using a hand-held grip dynamometer. Participants will be instructed to grip the dynamometer with left hand and right hand respectively while standing, maintaining their arm close to the body and straight down, exerting maximum force. This test will be conducted 3 times, and the values will be recorded in kilograms.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSecondary outcome\u003c/b\u003e \u003c/p\u003e \u003cp\u003e1) The change in handgrip strength at 6 months from baseline. The definition and measurement method are the same as the primary outcome.\u003c/p\u003e \u003cp\u003e2) The change in frailty score at 6 months and 12 months from baseline. Outcome is defined as the change in the score of modifiable variables in the frailty index from baseline. The frailty index consisted more than 20 variables covering age, physical measurement, sleep quality, history of surgery, fall, and fracture, history of the disease, oral hygiene, respiratory function, and physical function self-assessment aspects. The frailty index is a continuous variable, with a higher value indicating a more frail status.\u003c/p\u003e \u003cp\u003e3) The change in physical activity volume and intensity at 12 months from baseline. Information on physical activity levels during the past week will be collected through the International Physical Activity Questionnaire Scale-Short Form (IPAQ-SF) (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Physical activity volume will be determined by summing the metabolic equivalent task (MET)-min/week values. Higher values represent higher levels of physical activity.\u003c/p\u003e \u003cp\u003e4) The change in the quantity and frequency of fruit intake at 12 months from baseline. Fruit intake will be collected by questionnaire for the frequency of consumption and weights per intake. The frequency will be determined by filling in the number of times the participants eat fruit per week/day/monthly/year. Fruit quantity is determined by the product of frequency and weights of a single fruit intake.\u003c/p\u003e \u003cp\u003e5) A composite of all-cause death or hospitalization for myocardial infarction, angina, or stroke within 12 and 24 months after enrollment. Individual components of the outcome will also be examined. Angina will be defined by receiving treatment for any of the following ICD codes: I20. Myocardial infarction will be defined by receiving treatment for any of the following ICD codes: I21 or I22. Stroke will be defined by receiving treatment for any of the following ICD codes: I60-I64.\u003c/p\u003e \u003cp\u003e6) The change in lipid parameters at 12 months and 24 months from baseline. Lipid parameters will include low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG).\u003c/p\u003e \u003cp\u003e7) The change in fasting blood glucose at 12 months and 24 months from baseline. It will be measured by Glucose Oxidase (GOD) method.\u003c/p\u003e \u003cp\u003e8) Incremental cost-effectiveness ratio (ICER). It's calculated by dividing the difference in costs between the two interventions by the difference in their effects.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eAdherence to the intervention\u003c/h2\u003e \u003cp\u003eCompletion of a single intervention is defined as engaging in at least 30 minutes of physical activity and consuming at least 50 grams of fruit supplementation. If the participants do not meet the criteria, the values will be recorded truthfully. Theoretically, participants in the intervention group are expected to attend 12 on-site interventions each month of the intervention period. Good compliance among participants is defined as completing 9 or more.\u003c/p\u003e \u003cp\u003eIf the study participant is absent more than 3 times in each intervention month, the expected intervention deadline should be postponed to complete the established number of interventions. If participants reject the plan, the reasons for their refusal will be recorded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eData collection and management\u003c/h2\u003e \u003cp\u003eAll data collectors will be trained in questionnaire content and electronic device operation. The anthropometric will be trained prior to the formal investigation. In addition to blood pressure, height, blood oxygen, and heart rate variables, the remaining variables are recorded with precision up to two decimal places. Data will be collected using electronic device and a paper copy will be provided as a backup in case of electronic failure. Data quality checks are built into the e-questionnaire, for example limiting ranges of responses/measurements to the credible range, setting questions as \u0026lsquo;required\u0026rsquo; to avoid missing questions, and checking for consistency between questions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eCategorical variables are presented as frequencies (n) and percentages (%). Continuous variables are reported as means and standard deviation (SD) or medians (interquartile range) for non-normality of distribution. Comparisons will be made using t tests or Wilcoxon rank sum tests for continuous variables or χ2 or Fisher exact tests for categorical variables, along with reporting of confidence intervals.\u003c/p\u003e \u003cp\u003eThe primary analyses will be done at the individual level, according to the intention-to-treat principle. For the primary analysis comparing the change in handgrip strength, generalized linear regression mixed model (GLMM) with fixed effect for study group and baseline handgrip strength value will be employed. And random cluster effects (villages) will be fitted to the data in order to account for intra-cluster correlations introduced by the cluster randomized controlled design. We will report differences from unadjusted and adjusted models. The adjusted models will include age, sex, education levels, smoking, drinking, baseline handgrip strength value, and chronic diseases. The estimated regression coefficient for study group will represent the estimated mean difference between study groups.\u003c/p\u003e \u003cp\u003eConsidering the potential for type I error due to multiple comparisons, analysis of secondary outcomes will be interpreted as exploratory. For physical activity and fruit intake, the least square mean will be compared between groups and before and after intervention. For other continuous data, tests for group differences will be performed as described for the primary analysis. The cumulative incidence of a composite of all-cause death, cardiovascular and cerebrovascular diseases and its individual components will be calculated using the Kaplan\u0026ndash;Meier method and reported with 95% confidence intervals. The outcome will be compared between groups using a generalized-estimating-equation (GEE) regression model with Poisson distribution. The intervention effect will be reported as the cumulative incidence ratio (CIR) with multiplicity-adjusted 95% confidence intervals.\u003c/p\u003e \u003cp\u003eWe predefine subgroup analyses considering age, sex, physical activity, fruit intake and grip strength. We will use an interaction test between subgroup variables and study groups to test whether the effects vary by subgroups. Observed adverse events will be listed. Statistical significance is defined as \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. The analysis will be performed with the use of SAS software, version 9.4, and R soft-ware, version 3.6.1.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eEthics and trial registration\u003c/h2\u003e \u003cp\u003e This trial has been approved by the Institutional Review Board of Nanjing Medical University (ID:2023588). The trial is registered at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.clinicaltrials.gov\u003c/span\u003e\u003cspan address=\"http://www.clinicaltrials.gov\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (ID: NCT06225271).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn many cases, frailty onset starts before age 65 years. All older adults are at risk of developing frailty, especially those with unhealthy lifestyle habits, comorbidities, and low socioeconomic position. Frailty or prefrailty is potentially reversible. Given the serious consequences of frailty and its increasing prevalence, it is urgent to intervene on its modifiable risk factors. Identifying frailty risk factors that are potentially modifiable by specific interventions could provide direction for public health and preventive strategies. To date, few available trials focusing on the effects of combined interventions on frailty in older adults with modifiable risk factors.\u003c/p\u003e \u003cp\u003eEFVF is a cluster-randomized trial to examine the possibility of a combined intervention of exercise, fruit, and vitamin supplementation for the older adults with modifiable risk factors (low levels of physical activity and fruit intake) for frailty. Better muscle strength, lower frailty index scores, lower blood lipid levels, lower blood sugar levels, and lower risk of cardiovascular and cerebrovascular disease and all-cause death are hypothesized to be present in participants.\u003c/p\u003e \u003cp\u003eLow levels of physical activity and fruit intake are widely recognized as risk factors for frailty in Chinese older adults (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Interventions targeting on physical activity and fruit intake may be the key to delaying the progression of frailty and potentially reversing it. Additional benefits occur with more physical activity, both in terms of aerobic and muscle-strengthening physical activity (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). However, the benefits that older adults can derive from physical activity depend on their adherence to an exercise regimen and the satisfaction they experience from it. Non-compliance with recommended lifestyle changes remains a common and challenging obstacle to achieving these benefits (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e) (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Despite the government's long-term efforts to promote physical activity among residents, the prevalence of physical inactivity continues to increase. More than 20% of adults are not meeting the recommended level (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e) (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). Considering the physical condition and preferences of older adults, it does not impose specific requirements on the intensity and mode of physical activity, which differs from previous studies. This research employs flexible and diverse methods for engaging in low to medium intensity physical activity, aiming to provide an opportunity for older individuals who may not typically enjoy exercise to discover the joy of being physically active and cultivate a sustainable habit.\u003c/p\u003e \u003cp\u003eResearch on promoting fruit intake in older adults is limited. In previous cross-sectional or cohort studies, vegetables and fruits were often examined together. Considering the practicality of on-site intervention and the existing low proportion of insufficient vegetable intake among older adults in Suzhou, we did not focus on interventions specifically for vegetable consumption. However, information on dietary intake, including vegetables, will be collected.\u003c/p\u003e \u003cp\u003eWe selected change in grip strength at 12 months from baseline as the primary outcome. The concept of frailty is gradually being used at primary medical and healthcare institutions, however, there is no consensus on the criteria for frailty. Currently, Fried frailty phenotype and the frailty index are the most commonly used definitions of frailty (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). In any case, grip strength is considered an important clinical manifestation of frailty. Many studies have shown that low muscle strength is significantly associated with all-cause mortality and other adverse events. Besides, studies indicate that the Chinese population experiences an age-related decline in muscle strength (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Therefore, the primary objective of this study is to examine the effects of the combined intervention on grip strength, assuming that participants in the intervention group will exhibit either an increase in grip strength or a slower rate of decline in grip strength compared to those in the control group.\u003c/p\u003e \u003cp\u003eOverall, if effective, EFVF will yield evidence-based data and could provide a well-established and cost-effective strategy for frailty prevention in community settings.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate: This trial has been approved by the Institutional Review Board of Nanjing Medical University (ID:2023588). Study\u003c/p\u003e\n\u003cp\u003eparticipants complete a written informed consent prior to participation in research activities.\u003c/p\u003e\n\u003cp\u003eConsent for publication: Not applicable.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials: Not applicable.\u003c/p\u003e\n\u003cp\u003eCompeting interests: The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding: This study was funded by Public Health Special Project of GuSu College of Nanjing Medical University, Grant/Award Number: GSKY20230103.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions: CS, YL, and LCW made contributions to the conception of the trial. CS, XYH, YL, LLJ, and HKX made contributions the design of the trial. XYH drafted the manuscript. WF and XFW made \u0026nbsp;revisions to the manuscript. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgements: Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMorley JE, Vellas B, van Kan GA, Anker SD, Bauer JM, Bernabei R, et al. Frailty consensus: a call to action. Journal of the American Medical Directors Association. 2013;14(6):392-7.\u003c/li\u003e\n\u003cli\u003eClegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet (London, England). 2013;381(9868):752-62.\u003c/li\u003e\n\u003cli\u003eFried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. The journals of gerontology Series A, Biological sciences and medical sciences. 2001;56(3):M146-56.\u003c/li\u003e\n\u003cli\u003eHoogendijk EO, Afilalo J, Ensrud KE, Kowal P, Onder G, Fried LP. Frailty: implications for clinical practice and public health. 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Lancet (London, England). 2023;402 Suppl 1:S42.\u003c/li\u003e\n\u003cli\u003eFung TT, Struijk EA, Rodriguez-Artalejo F, Willett WC, Lopez-Garcia E. Fruit and vegetable intake and risk of frailty in women 60 years old or older. The American journal of clinical nutrition. 2020;112(6):1540-6.\u003c/li\u003e\n\u003cli\u003eRuangsuriya J, Wongpoomchai R, Srichairatanakool S, Sirikul W, Buawangpong N, Siviroj P. Guava Fruit and Acacia pennata Vegetable Intake Association with Frailty of Older Adults in Northern Thailand. Nutrients. 2022;14(6).\u003c/li\u003e\n\u003cli\u003eGarc\u0026iacute;a-Esquinas E, Rahi B, Peres K, Colpo M, Dartigues JF, Bandinelli S, et al. Consumption of fruit and vegetables and risk of frailty: a dose-response analysis of 3 prospective cohorts of community-dwelling older adults. The American journal of clinical nutrition. 2016;104(1):132-42.\u003c/li\u003e\n\u003cli\u003eFan J, Yu C, Guo Y, Bian Z, Sun Z, Yang L, et al. Frailty index and all-cause and cause-specific mortality in Chinese adults: a prospective cohort study. The Lancet Public health. 2020;5(12):e650-e60.\u003c/li\u003e\n\u003cli\u003eHughes VA, Frontera WR, Wood M, Evans WJ, Dallal GE, Roubenoff R, et al. Longitudinal muscle strength changes in older adults: influence of muscle mass, physical activity, and health. The journals of gerontology Series A, Biological sciences and medical sciences. 2001;56(5):B209-17.\u003c/li\u003e\n\u003cli\u003eVan Ancum JM, Scheerman K, Jonkman NH, Smeenk HE, Kruizinga RC, Meskers CGM, et al. Change in muscle strength and muscle mass in older hospitalized patients: A systematic review and meta-analysis. Experimental gerontology. 2017;92:34-41.\u003c/li\u003e\n\u003cli\u003eMan Wu, Yuxia Wei, Canqing Yu, Huaidong Du, Jun Lv, Yu Guo, et al. Descriptive analysis of skeletal muscle mass and hand grip strength in adults in 10 regions of China. Chinese Journal of Epidemiology.2019;40(4):376-81.\u003c/li\u003e\n\u003cli\u003eBarbui C, Cipriani A. Cluster randomised trials. Epidemiology and psychiatric sciences. 2011;20(4):307-9.\u003c/li\u003e\n\u003cli\u003eHemming K, Taljaard M. Key considerations for designing, conducting and analysing a cluster randomized trial. International journal of epidemiology. 2023;52(5):1648-58.\u003c/li\u003e\n\u003cli\u003eKwon J, Yoshida Y, Yoshida H, Kim H, Suzuki T, Lee Y. Effects of a combined physical training and nutrition intervention on physical performance and health-related quality of life in prefrail older women living in the community: a randomized controlled trial. Journal of the American Medical Directors Association. 2015;16(3):263.e1-8.\u003c/li\u003e\n\u003cli\u003eHaider S, Dorner TE, Luger E, Kapan A, Titze S, Lackinger C, et al. Impact of a Home-Based Physical and Nutritional Intervention Program Conducted by Lay-Volunteers on Handgrip Strength in Prefrail and Frail Older Adults: A Randomized Control Trial. PloS one. 2017;12(1):e0169613.\u003c/li\u003e\n\u003cli\u003eKim H, Suzuki T, Kim M, Kojima N, Ota N, Shimotoyodome A, et al. Effects of exercise and milk fat globule membrane (MFGM) supplementation on body composition, physical function, and hematological parameters in community-dwelling frail Japanese women: a randomized double blind, placebo-controlled, follow-up trial. PloS one. 2015;10(2):e0116256.\u003c/li\u003e\n\u003cli\u003eChen B, Li M, Zhao H, Liao R, Lu J, Tu J, et al. Effect of Multicomponent Intervention on Functional Decline in Chinese Older Adults: A Multicenter Randomized Clinical Trial. The journal of nutrition, health \u0026amp; aging. 2023;27(11):1063-75.\u003c/li\u003e\n\u003cli\u003eKapan A, Winzer E, Haider S, Titze S, Schindler K, Lackinger C, et al. Impact of a lay-led home-based intervention programme on quality of life in community-dwelling pre-frail and frail older adults: a randomized controlled trial. BMC geriatrics. 2017;17(1):154.\u003c/li\u003e\n\u003cli\u003eCraig CL, Marshall AL, Sj\u0026ouml;str\u0026ouml;m M, Bauman AE, Booth ML, Ainsworth BE, et al. International physical activity questionnaire: 12-country reliability and validity. Medicine and science in sports and exercise. 2003;35(8):1381-95.\u003c/li\u003e\n\u003cli\u003eLi L, Fu X, He N, Gan W, Zhao Y, Xie RH. Association of frailty with activity levels and sedentary behaviours in patients with hepatitis B cirrhosis: A cross-sectional study. Nursing open. 2024;11(1):e2056.\u003c/li\u003e\n\u003cli\u003eGao J, Jia Y, Dai J, Fu H, Wang Y, Yan H, et al. Association of Fruit and Vegetable Intake and Frailty among Chinese Elders: A Cross-Sectional Study in Three Cities. The journal of nutrition, health \u0026amp; aging. 2019;23(9):890-5.\u003c/li\u003e\n\u003cli\u003ePiercy KL, Troiano RP, Ballard RM, Carlson SA, Fulton JE, Galuska DA, et al. The Physical Activity Guidelines for Americans. Jama. 2018;320(19):2020-8.\u003c/li\u003e\n\u003cli\u003eBrach M, de Bruin ED, Levin O, Hinrichs T, Zijlstra W, Netz Y. Evidence-based yet still challenging! Research on physical activity in old age. European review of aging and physical activity : official journal of the European Group for Research into Elderly and Physical Activity. 2023;20(1):7.\u003c/li\u003e\n\u003cli\u003eStonerock GL, Blumenthal JA. Role of Counseling to Promote Adherence in Healthy Lifestyle Medicine: Strategies to Improve Exercise Adherence and Enhance Physical Activity. Progress in cardiovascular diseases. 2017;59(5):455-62.\u003c/li\u003e\n\u003cli\u003eChaoqun Wu, Xi Li, Jiapeng Lu, Bowang Chen, Yichong Li, Yang Yang, et al. Distribution of cardiovascular disease risk factors in Chinese residents. China circulation journal. 2021;36(01):4-13.\u003c/li\u003e\n\u003cli\u003eZhang M, Ma Y, Xie X, Sun M, Huang Z, Zhao Z, et al. Trends in insufficient physical activity among adults in China 2010-18: a population-based study. The international journal of behavioral nutrition and physical activity. 2023;20(1):87.\u003c/li\u003e\n\u003cli\u003eRockwood K, Mitnitski A. Frailty in relation to the accumulation of deficits. The journals of gerontology Series A, Biological sciences and medical sciences. 2007;62(7):722-7.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"frailty, cluster randomized trial, multilevel intervention, physical activity, fruit intake, handgrip strength","lastPublishedDoi":"10.21203/rs.3.rs-4407061/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4407061/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eFrailty is a complex, dynamic, age-related clinical condition. Muscle strength, a critical indicator of frailty, decreases with advancing age. It is not known whether community-dwelling older adults with frailty modifiable risk factors, such as low levels of physical activity and fruit intake, might benefit from lifestyle interventions at both population and individual levels.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eEFVF is a cluster-randomized trial including older individuals aged 65\u0026ndash;80 years old with low levels of physical activity and fruit intake living in eastern China. Totally 14 villages will be randomized into 2 arms with 1:1 ratio, overall including\u0026thinsp;\u0026ge;\u0026thinsp;934 participants. Participants in the intervention arm will receive the combined intervention of physical activity, fruit, and vitamin supplementation 3 times a week for 2 months (the 1st and 6th months). Standardized health education and communication sessions will be conducted as well. Participants in the control arm will not receive any intervention. The primary outcome is the change in handgrip strength at 12 months from baseline. Secondary outcomes include handgrip strength, frailty index, lipid parameters, fasting blood glucose, and a composite of all-cause death or hospitalization for myocardial infarction, angina, or stroke. The study also includes an assessment of the cultivation of physical activity and fruit intake habits, as well as an economic evaluation.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eThe study will target older adults with modifiable risk factors for frailty, to investigate whether the combined intervention might limit the decline of grip strength, frailty progression, and reduce the incidence of adverse events. If effective, it could provide a well-established and cost-effective strategy for frailty prevention in community settings.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e \u003cp\u003eClinical Trails.gov PRS Protocol Registration and Results System, NCT06225271, (Jan 17, 2024).\u003c/p\u003e","manuscriptTitle":"Effects of the Combined Intervention of Exercise, Fruit, and Vitamin Supplementation on Frailty in Older Adults (EFVF): Rationale, Design, and Methods","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-28 20:44:41","doi":"10.21203/rs.3.rs-4407061/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7e0f4f8e-7eea-4df9-9ffa-128a1a4628da","owner":[],"postedDate":"May 28th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-09-30T09:53:10+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-28 20:44:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4407061","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4407061","identity":"rs-4407061","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}