Frailty, Pre-Frailty
Conditions
Keywords
Cost-effectiveness, Digital health, Community-Dwelling Older Adults, Healthy Aging, Health Education, Online Education, Gut Microbiota, Physical activity, Frail Older Adults, Artificial Intelligence-Assisted Education, Frailty Index, Fried Frailty Phenotype, Cognitive Function, Cost-Utility Analysis, Malnutrition risk, Multidomain Health Education, Physical Function
Brief summary
The goal of this clinical trial is to determine whether a 6-month healthy-aging education program delivered in person, online, or in a hybrid format reduces frailty and is cost-effective compared with usual care in community-dwelling adults aged 65 years or older with pre-frailty or frailty. The main questions are: * Do the three educational programs, considered together, reduce the prespecified 40-item Frailty Index (40-FI) at 6 months more than usual care? * Are effects maintained 6 months after the programs end? * How do the in-person, online, and hybrid educational programs differ in multidomain frailty outcomes, implementation, costs, and quality-adjusted life-years? * Are changes in prespecified blood biomarkers and gut microbiota associated with changes in frailty and related outcomes? The study will enroll 276 participants. Randomization will occur at household level so that enrolled cohabitants receive the same assignment. Households will be allocated to in-person education, online education, hybrid education, or usual care. All three educational programs address physical activity, nutrition, cognitive and emotional well-being, and social connection. Assessments will occur at baseline, 6 months, and 12 months; blood and stool samples will be collected at baseline and 6 months. The trial will compare the average effect of the three active programs with usual care and will estimate modality-specific clinical and economic outcomes.
Detailed description
Frailty is a potentially modifiable state of reduced physiological reserve that increases vulnerability to falls, disability, hospitalization, loss of independence, and higher healthcare use. Multidomain programs addressing physical activity, nutrition, cognitive and emotional health, and social participation can improve frailty-related outcomes. However, it remains uncertain how in-person, online, and hybrid delivery differ in effectiveness, reach, implementation, resource use, and cost-effectiveness. The trial is not designed to establish equivalence or non-inferiority among the three active modalities. FRAGSALUD-ON builds on the previous FRAGSALUD program by comparing three delivery modalities within the same randomized trial and by integrating clinical, behavioral, biological, implementation, and economic evaluations. This is a 12-month, four-arm, parallel-group, household-cluster randomized controlled trial conducted in the province of Cadiz, Spain. The household is the unit of randomization: a participant without another enrolled cohabitant constitutes a cluster of one, and all enrolled cohabitants are assigned to the same study arm. Households, rather than individual participants, will be allocated in a 1:1:1:1 ratio to in-person education, online education, hybrid education, or usual care. The target enrollment is 276 participants; participant numbers per arm are expected to be approximately, but not necessarily exactly, equal. Randomization will be performed by an independent statistician who is not involved in recruitment or outcome assessment. Participants and intervention providers cannot be masked because of the nature of the programs. Outcome assessors will remain unaware of group allocation whenever feasible. Assessments will be conducted at baseline, at the end of the 6-month intervention, and 6 months after the intervention ends (12 months after baseline). Blood and stool samples will be obtained at baseline and 6 months. The three active interventions share four core domains: physical activity, nutrition, cognitive and emotional well-being, and social connection. The in-person group will attend four weekly group sessions during the first month and receive six reinforcement telephone calls during the following 5 months. The hybrid group will attend the same four group sessions plus a digital-platform onboarding session and will use the online platform for reinforcement during the following 5 months instead of receiving the telephone calls. The online group will receive an onboarding session and will use the platform as the main educational delivery method throughout the 6-month intervention. Educational materials were developed before participant recruitment with artificial-intelligence assistance and were subsequently reviewed, edited, and approved by the research team. Artificial intelligence was used solely to support the development of educational materials before participant recruitment. It will not receive participant data, interact with participants, personalize intervention content, monitor adherence, or provide clinical advice during the trial. The platform will provide interactive educational modules, knowledge activities, navigation support, and automated reminders without artificial-intelligence processing of participant data. The usual-care group will continue its routine healthcare and health routines and will not receive the FRAGSALUD-ON educational program during the 12-month follow-up. After completing the 12-month assessment, participants in this group will be offered access to the online educational platform, in accordance with the ethics-approved protocol. The primary objective is to determine whether the average effect of the three active delivery modalities is superior to usual care in reducing the prespecified 40-item Frailty (40-FI) Index from baseline to 6 months. The primary analysis will follow the intention-to-treat principle and will use a linear mixed-effects analysis of covariance for the 6-month 40-FI, with fixed effects for study arm, baseline 40-FI, and the household-level baseline frailty stratum used in randomization (all enrolled household members prefrail versus at least one enrolled household member frail), and a random intercept for household. The confirmatory contrast will compare the equally weighted mean of the three active arms with usual care. Missing 6-month 40-FI values among surviving participants will be addressed using multiple imputation under a missing-at-random assumption, with prespecified missing-not-at-random sensitivity analyses. Death and other intercurrent events will be handled according to the estimand specified in SAP. If the primary joint contrast is statistically significant, each active modality will be compared with usual care using Dunnett adjustment to control the family-wise error rate. Direct comparisons among the three active modalities will be treated as secondary or exploratory and will be interpreted with confidence intervals rather than as tests of equivalence or non-inferiority. The target sample size is 276 participants, with 69 participants per group. It was selected to provide approximately 80% power for the primary joint contrast, assuming an adjusted between-group difference of 0.030 in the Frailty Index, a residual standard deviation of 0.070, a two-sided alpha level of 0.05, and 15% missing primary-outcome data at 6 months. Because enrolment of more than one participant from the same household is expected to be uncommon based on prior recruitment experience, the initial target assumes a negligible loss of efficiency from household clustering. During recruitment, an independent statistician blinded to treatment outcomes will conduct a prespecified review of the observed household cluster-size distribution. The enrollment target may be increased if the projected household design effect is not negligible. Secondary objectives are to assess whether effects persist at 12 months and to compare changes in physical frailty, physical performance, strength, balance, mobility, independence in daily activities, physical activity and 24-hour movement behavior, nutritional status and diet, cognition, mood, sleep, social support, health-related quality of life, falls, and other clinically relevant outcomes. Blood biomarkers and gut microbiota will be assessed at baseline and 6 months to characterize biological changes and examine within-participant associations between changes in these measures and changes in frailty, physical function, cognition, inflammation, diet, and gastrointestinal function. These longitudinal association analyses will not by themselves be interpreted as proving causation or mediation. A prospective within-trial economic evaluation over 12 months will compare the four alternatives using costs and quality-adjusted life-years. The primary economic analysis will adopt a societal perspective, with a healthcare-system perspective examined in sensitivity analyses. Incremental costs, incremental effects, cost-effectiveness, net monetary benefit, and decision uncertainty will be reported. Adherence, satisfaction, barriers, facilitators, and implementation experience will also be evaluated to help determine how the delivery modalities could be used in practice.
Interventions
BEHAVIORALIn-person healthy aging education program
A 6-month healthy aging educational program delivered face to face. The program includes four weekly group sessions of approximately 1 hour during the first month, followed by six telephone follow-up calls during the subsequent 5 months. Educational content addresses frailty awareness, physical activity, nutrition, cognitive and emotional well-being, and social health. Educational materials were developed before participant recruitment with artificial-intelligence assistance and were reviewed, edited, and approved by the research team before use. Telephone follow-up is used to reinforce the educational content, address participant questions, and support adherence to healthy lifestyle recommendations.
BEHAVIORALHybrid healthy aging education program
A 6-month healthy aging educational program combining face-to-face sessions and online follow-up. The program includes four weekly group sessions of approximately 1 hour during the first month. Educational content addresses frailty awareness, physical activity, nutrition, cognitive and emotional well-being, and social health. Participants also receive a familiarization session to support access to and use of the online educational platform. During the subsequent 5 months, reinforcement and follow-up activities are delivered through the platform. Educational materials were developed before participant recruitment with artificial-intelligence assistance and were reviewed, edited, and approved by the research team before use.
BEHAVIORALOnline healthy aging education program
A 6-month healthy aging educational program delivered through an online educational platform. Participants first receive an in-person familiarization and setup session of approximately 1 hour to support access to and use of the platform. Educational content addresses frailty awareness, physical activity, nutrition, cognitive and emotional well-being, and social health. During the intervention period, educational content and follow-up activities are delivered through the platform. Educational materials were developed before participant recruitment with artificial-intelligence assistance and were reviewed, edited, and approved by the research team before use.
Sponsors
University of Cadiz
Instituto de investigación e innovación biomédica de Cádiz
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Masking description
Participants and intervention providers cannot be masked because of the nature of the educational interventions. A designated investigator with no role in sequence generation, allocation release, recruitment, baseline assessment, intervention delivery, adherence monitoring, or access to unblinded operational data will remain unaware of group allocation and will oversee blinded outcome adjudication and prespecified analytic decisions. Primary and secondary outcome assessments will be performed by trained assessors who are independent of intervention delivery and unaware of group allocation. Participants will be reminded not to disclose their assigned group during assessment visits. Any accidental unmasking of an outcome assessor will be documented. Laboratory personnel and statisticians will work with coded group labels until the analysis dataset, derivation rules, and primary model have been finalized.
Intervention model description
This is a four-arm, parallel-group, household-clustered randomized controlled trial. The household is the unit of randomization: a participant living without another enrolled cohabitant constitutes a cluster of one, and all enrolled cohabitants are assigned to the same study group to minimize within-household contamination. Households will be allocated in a 1:1:1:1 ratio to usual care, in-person education, hybrid education, or online education. Randomization will be stratified by household-level baseline frailty status, defined as all enrolled household members being prefrail versus at least one enrolled household member being frail. Within each stratum, allocation will use a computer-generated sequence with randomly varying, undisclosed permuted block sizes. The sequence will be prepared by an independent statistician who has no role in recruitment, intervention delivery, or outcome assessment.
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Community-dwelling adults aged 65 years or older. * Presence of pre-frailty or frailty according to the prespecified operationalization of the Fried frailty phenotype, defined as meeting at least one of the five Fried criteria (pre-frailty: 1-2 criteria; frailty: 3-5 criteria). * Ability to understand spoken and written Spanish sufficiently to follow the intervention and study procedures. * Access at home to Wi-Fi or mobile data and to a smartphone, tablet, or computer capable of connecting to the internet. * Ability to attend the study assessments and, if randomized to the in-person or hybrid intervention, the scheduled face-to-face sessions. * Ability to understand the study information and provide written informed consent.
Exclusion criteria
* Permanent residence in a nursing home or other long-term residential care institution. * Robust status according to the Fried frailty phenotype, defined as meeting none of the five Fried criteria. * Severe dementia or any cognitive, neurological, or psychiatric condition that precludes valid informed consent or the ability to understand and follow the study procedures. * Use of systemic antibiotics during the 3 months preceding baseline stool-sample collection. * Known terminal illness or receipt of end-of-life care, with an anticipated life expectancy of less than 12 months, based on available clinical documentation or assessment by a qualified clinician. * Current participation in another interventional study involving an investigational medicinal product or a structured physical activity, nutritional, cognitive, or social intervention that overlaps with the FRAGSALUD-ON intervention or follow-up period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Prespecified 40-Item Frailty Index Score at 6 Months | Baseline and 6 months | A prespecified 40-item deficit-accumulation Frailty Index (40-FI) will be calculated as the sum of observed deficit scores divided by the number of evaluable deficits. The 40-FI ranges from 0 to 1, with higher values indicating greater frailty. A score will be calculated when at least 32 of the 40 deficits (80%) are evaluable. Change will be calculated as the 6-month score minus the baseline score; negative values indicate improvement. The fixed item list, item-level coding rules, permitted intermediate values, denominator, and missing-data rules are defined in the version-controlled 40-FI Specification included as an annex to Protocol and SAP and finalized before enrolment of the first participant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Prespecified 40-Item Frailty Index Score at 12 Months | Baseline and 12 months | A prespecified 40-item deficit-accumulation Frailty Index (40-FI) will be calculated as the sum of observed deficit scores divided by the number of evaluable deficits. The 40-FI ranges from 0 to 1, with higher values indicating greater frailty. A score will be calculated when at least 32 of the 40 deficits (80%) are evaluable. Change will be calculated as the 12-month score minus the baseline score; negative values indicate improvement. The fixed item list, item-level coding rules, permitted intermediate values, denominator, and missing-data rules are defined in the version-controlled 40-FI Specification included as an annex to Protocol and SAP and finalized before enrolment of the first participant. |
| Change From Baseline in the Fried Frailty Phenotype Score at 6 and 12 Months | Baseline, 6 months, and 12 months | The Fried frailty phenotype will be scored at baseline, 6 months, and 12 months as the number of criteria present (0-5): unintentional weight loss, exhaustion, weakness, slowness, and low physical activity; higher scores indicate greater frailty. At baseline, weight loss is self-reported unintentional loss \>4.5 kg in the previous 12 months; at 6 and 12 months, it is measured loss ≥5% from baseline reported as unintentional. Exhaustion is present when either original CES-D item is reported ≥3 days in the previous week. Weakness uses the highest of three dominant-hand grip-strength trials and original sex- and BMI-specific cutoffs. Slowness uses usual-paced 4.57-m walk time and original sex- and height-specific cutoffs. Low activity is VREM \<1,250 MET-min/14 days. Each criterion scores 0 or 1. Separate changes are 6-month minus baseline and 12-month minus baseline (range, -5 to 5); negative values indicate improvement. All five criteria are required. |
| Change From Baseline in Maximum Dominant-Hand Grip Strength at 6 and 12 Months | Baseline, 6 months, and 12 months | Maximum dominant-hand grip strength will be measured in kilograms with a calibrated Jamar hydraulic dynamometer at handle position II. Higher values indicate greater strength. Participants will be seated with shoulder adducted and neutrally rotated, elbow flexed 90°, forearm neutral, wrist at 0-30° extension and 0-15° ulnar deviation, and feet supported. Three maximal contractions of 3-5 seconds will be performed with 60 seconds of rest and standardized encouragement. The highest valid value will be analyzed; if fewer than three trials are valid, the highest available value will be used. At least one valid trial is required. Changes will be calculated separately as 6-month minus baseline and 12-month minus baseline; positive values indicate improvement and negative values worsening. The baseline dominant hand and same device, handle setting, and protocol will be used at all visits. Values and reasons for invalid or missing trials will be recorded. |
| Change From Baseline in Short Physical Performance Battery Total Score at 6 and 12 Months | Baseline, 6 months, and 12 months | The SPPB assesses lower-extremity performance using standing balance (side-by-side, semi-tandem, and tandem stances), usual-paced walking over 4 meters, and five chair rises performed as quickly as possible with arms folded. Each component is scored 0-4 according to standard rules, producing a total score from 0 to 12; higher scores indicate better performance. The faster valid time from two usual-paced 4-meter walks determines the gait score; if only one trial is valid, it is used. Participants unable to complete a component for physical or safety reasons receive 0 points. A usual walking aid may be used; its type will be recorded and kept constant when clinically appropriate. Separate changes are the 6-month total minus baseline and the 12-month total minus baseline (range, -12 to 12); positive values indicate improvement and negative values worsening. The same equipment, instructions, sequence, stopping rules, and scoring will be used at all assessments. |
| Change From Baseline in Best Eyes-Open 30-Second Single-Leg Stance Time at 6 and 12 Months | Baseline, 6 months, and 12 months | Eyes-open single-leg stance will be timed in seconds (0-30) on a firm nonslip surface; higher values indicate better balance. Barefoot participants will stand on the preferred stance limb selected at baseline, with arms crossed over the chest and eyes fixed on a target. Stable support may be used to assume the position but not during timing. Timing starts when the nonstance foot leaves the floor and stops if the arms uncross, the raised foot touches the stance limb or floor, the stance foot moves, support or assistance is required, or 30 seconds elapse. Two trials will be performed with 60 seconds of rest; the better valid time will be analyzed. If only one trial is valid, it will be used. Inability to release support and safely assume the position scores 0 seconds. Changes will be calculated separately as 6-month minus baseline and 12-month minus baseline; positive values indicate improvement and negative values worsening. The same limb and protocol will be used at all visits. |
| Change From Baseline in Fast-Pace 4-Meter Gait Speed at 6 and 12 Months | Baseline, 6 months, and 12 months | Fast gait speed will be measured over 4 meters from a static start and reported in m/s. In walking shoes, participants will stand with toes behind the start line and, on command, walk as quickly as safely possible without running, continuing past the finish line. Timing starts when the first foot crosses the start line and stops when the first foot crosses the 4-meter line; speed is calculated as 4/time in seconds. Two timed trials 60 seconds apart will be performed; the faster valid speed will be analyzed. If only one trial is valid, it will be used. The usual walking aid is permitted, recorded, and kept constant whenever feasible. A trial requiring physical assistance or involving running is invalid. Higher values indicate better performance. Changes will be calculated separately as 6-month minus baseline and 12-month minus baseline; positive values indicate improvement and negative values worsening. The same protocol will be used at all visits. |
| Change From Baseline in Estimated Relative Sit-to-Stand Mean Power at 6 and 12 Months | Baseline, 6 months, and 12 months | Estimated relative mean lower-limb muscle power during the five-repetition sit-to-stand test will be calculated in W/kg using the prespecified Alcazar equation: \[0.9 × 9.81 × (0.5 × body height \[m\] - chair height \[m\])\] / (5STS time \[s\] × 0.1). Baseline standing height and the measured 0.43-m chair height will be used at all visits; 5STS time will be the valid completion time obtained during the SPPB chair-stand test. Higher values indicate greater estimated relative power. Power will be calculated only for valid completed tests and will be missing when no valid completion time is available. Changes will be calculated separately as 6-month minus baseline and 12-month minus baseline; positive values indicate improvement and negative values worsening. The same equation, units, chair, and data-processing rules will be applied at all visits. |
| Change From Baseline in Barthel Index Total Score at 6 and 12 Months | Baseline, 6 months, and 12 months | The validated Spanish 10-item Barthel Index will assess actual performance in basic activities covering feeding, personal care, dressing, continence, toilet use, transfers, mobility, and stairs. A trained assessor will administer it face-to-face using participant report, an informed proxy when needed, and observation when available. Standard weighted categories produce a total score from 0 to 100; higher scores indicate greater independence. Scoring reflects what the participant actually does rather than potential capacity; supervision, assistance, and aids will be classified using standard Barthel rules. The total will be missing if any item is unclassifiable; scores will not be prorated. Changes will be calculated separately as 6-month minus baseline and 12-month minus baseline (range, -100 to 100); positive values indicate improvement and negative values worsening. The same version and scoring rules will be used at all visits. |
| Change From Baseline in Lawton Instrumental Activities of Daily Living Total Score at 6 and 12 Months | Baseline, 6 months, and 12 months | The validated Spanish eight-item Lawton IADL Scale will assess telephone use, shopping, food preparation, housekeeping, laundry, transportation, medication management, and financial management. It will be administered face-to-face by a trained assessor. Items are coded 1 (able) or 0 (unable or partially able), producing a total score from 0 to 8; higher scores indicate greater independence. All eight items will be assessed in women and men. An activity not routinely performed solely because of customary roles will not automatically be scored 0; functional ability will be established through standardized probing and, when needed, an informed proxy. The total will be missing if any item is unclassifiable; scores will not be prorated. Changes will be calculated separately as 6-month minus baseline and 12-month minus baseline (range, -8 to 8); positive values indicate improvement and negative values worsening. The same version and scoring rules will be used at all visits. |
| Change From Baseline in Accelerometer-Measured Moderate-to-Vigorous Physical Activity at 6 and 12 Months | Baseline, 6 months, and 12 months | Free-living moderate-to-vigorous physical activity (MVPA) will be measured using a triaxial GENEActiv accelerometer worn on the non-dominant wrist continuously (24 h/day) for 7 consecutive days at 60 Hz at baseline, 6 months, and 12 months. Raw acceleration will be processed using the same prespecified GGIR-compatible ENMOa pipeline at all assessments. Waking epochs with acceleration ≥98 mg will be classified as MVPA using the age- and wear-site-specific threshold validated for GENEActiv in older adults. The outcome is mean MVPA minutes/day across valid days; all qualifying epochs will count, without a minimum bout duration. A valid assessment requires ≥4 days with ≥10 h/day of waking wear, including ≥1 weekend day. Changes will be calculated separately as 6-month minus baseline and 12-month minus baseline. Positive values indicate increased MVPA. |
| Change From Baseline in Full Mini Nutritional Assessment Total Score at 6 and 12 Months | Baseline, 6 months, and 12 months | The official Spanish-language 18-item Full Mini Nutritional Assessment (MNA) will be administered to every participant at baseline, 6 months, and 12 months. All screening and assessment items will be completed regardless of the screening subsection score, with no skip pattern or use of the MNA-SF alone. The MNA combines anthropometric, general, dietary, and subjective assessments, including measured weight, height/BMI, mid-upper-arm circumference, and calf circumference. Items are scored according to the standard manual and summed to a total score from 0 to 30; higher scores indicate better nutritional status. Scores \<17 indicate malnutrition, 17-23.5 risk of malnutrition, and 24-30 normal nutritional status. Changes will be calculated separately as the 6-month total minus baseline and the 12-month total minus baseline (range, -30 to 30); positive values indicate improvement. The same version, equipment, procedures, and scoring rules will be used at all visits. |
| Change From Baseline in Montreal Cognitive Assessment Total Score at 6 and 12 Months | Baseline, 6 months, and 12 months | Global cognitive performance will be assessed using the official Spanish (Spain) MoCA Full version 8.1, administered face-to-face at baseline, 6 months, and 12 months. The same version will be used at all assessments to preserve linguistic and cultural equivalence. The MoCA assesses visuospatial/executive functions, naming, attention, language, abstraction, delayed recall, and orientation. The total score ranges from 0 to 30; higher scores indicate better cognitive performance. One point will be added for participants with 12 or fewer years of formal education, without exceeding 30 points. Changes will be calculated separately as the 6-month score minus baseline and the 12-month score minus baseline. Positive values indicate improvement and negative values worsening. Official administration and scoring instructions will be followed. |
| Change From Baseline in Pittsburgh Sleep Quality Index Global Score at 6 and 12 Months | Baseline, 6 months, and 12 months | Sleep quality will be assessed using the validated Spanish version of the Pittsburgh Sleep Quality Index (PSQI), referring to the preceding month. Nineteen self-reported items are used to derive seven component scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. Each component ranges from 0 to 3 and the components are summed to produce a global score from 0 to 21; higher scores indicate poorer sleep quality. Changes will be calculated separately as the 6-month score minus baseline and the 12-month score minus baseline. Negative values indicate improvement and positive values indicate worsening. The same Spanish version, reference period, administration procedure, and scoring rules will be used at all assessments. |
| Change From Baseline in Depressive Symptoms Assessed With the 15-Item Geriatric Depression Scale at 6 and 12 Months | Baseline, 6 months, and 12 months | Depressive symptoms will be assessed using the validated Spanish 15-item Geriatric Depression Scale (GDS-15; Yesavage). The scale contains 15 yes-or-no items referring to how the participant has felt during the preceding week. Each response indicative of a depressive symptom scores 1 point, producing a total score from 0 to 15; higher scores indicate more depressive symptoms. The GDS-15 is a screening measure and will not be used to establish a clinical diagnosis of depression. Changes will be calculated separately as the 6-month score minus baseline and the 12-month score minus baseline. Negative values indicate improvement and positive values indicate worsening. The same Spanish version, administration procedure, reference period, and scoring rules will be used at all assessments. |
| Change From Baseline in EQ-5D-5L Index Value at 6 and 12 Months | Baseline, 6 months, and 12 months | Health-related quality of life will be assessed using the official Spanish version of the EQ-5D-5L. Its descriptive system assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, with five severity levels per dimension. Each health-state profile will be converted into an index value using the Spanish EQ-5D-5L value set (Ramos-Goñi hybrid model, 2018). Index values range from -0.416 to 1, where 1 represents full health, 0 represents a health state equivalent to being dead, and negative values represent states valued as worse than dead; higher values indicate better health-related quality of life. Changes will be calculated separately as the 6-month value minus baseline and the 12-month value minus baseline. Positive values indicate improvement and negative values worsening. An index value will not be calculated if any dimension is missing. |
| Change From Baseline in EQ Visual Analogue Scale Score at 6 and 12 Months | Baseline, 6 months, and 12 months | Self-rated overall health will be assessed using the EQ Visual Analogue Scale (EQ VAS) included in the official Spanish EQ-5D-5L. Participants rate their health on the day of assessment on a vertical scale from 0, representing the worst health they can imagine, to 100, representing the best health they can imagine; higher scores indicate better perceived health. Changes will be calculated separately as the 6-month score minus baseline and the 12-month score minus baseline. Positive values indicate improvement and negative values indicate worsening. The same official Spanish version, instructions, and administration procedures will be used at all assessments. |
| Rate of Falls During the 12-Month Follow-up | From randomization through 12 months | A fall will be defined as an unexpected event in which the participant comes to rest on the ground, floor, or a lower level. Falls will be recorded prospectively from randomization through 12 months using daily fall calendars returned monthly. Missing or unclear calendars will be followed up using standardized telephone contact applied equally across study groups, without medical-record review. For each fall, the date, circumstances, injury, mobility-aid use, and participant- or caregiver-reported healthcare use, including emergency attendance and hospitalization, will be recorded. The outcome is the total number of falls divided by observed follow-up time and expressed as falls per person-year. Separate falls experienced by the same participant will be retained as recurrent events. The principal fall comparison covers months 0-12; rates during months 0-6 and 6-12 will be supportive analyses. |
| Change From Baseline in Perceived Functional Social Support Assessed With the Duke-UNC-11 at 6 and 12 Months | Baseline, 6 months, and 12 months | Perceived functional social support will be assessed using the validated Spanish 11-item Duke-UNC Functional Social Support Questionnaire (Duke-UNC-11). The questionnaire assesses affective and confidant support. Each item is rated from 1, indicating much less support than desired, to 5, indicating as much support as desired. Item scores are summed to produce a total score ranging from 11 to 55; higher scores indicate greater perceived functional social support. Changes will be calculated separately as the 6-month total score minus baseline and the 12-month total score minus baseline. Positive values indicate improvement and negative values indicate worsening. The same Spanish version, administration method, item coding, and scoring procedures will be used at all assessments. |
| Total Societal Cost per Participant Over 12 Months | From baseline through 12 months | Total costs accrued per participant during the 12-month study period will be estimated from a societal perspective and expressed in euros for the prespecified study price year. Costs will include intervention delivery, personnel time, training, technology, facilities, materials and support; healthcare use; participant and caregiver time; and travel. Research-only costs that would not be required for routine implementation will be excluded. Resource use will be collected prospectively at prespecified intervals and valued using official Spanish unit-cost sources. Because the time horizon is 12 months, costs will not be discounted. A healthcare-system perspective will be examined in a sensitivity analysis. |
| Quality-Adjusted Life-Years Accrued Over 12 Months | From baseline through 12 months | Quality-adjusted life-years (QALYs) accrued during the 12-month study period will be estimated from EQ-5D-5L index values measured at baseline, 6 months, and 12 months using the Spanish value set. QALYs will be calculated using the area-under-the-curve method with linear interpolation between consecutive assessments. Higher values indicate more time lived in better health. Between-group comparisons of QALYs will be adjusted for baseline EQ-5D-5L utility. Missing data and deaths, if applicable, will be handled according to the prespecified health economic analysis plan. |
| Change From Baseline in Gut Microbiota Shannon Diversity Index at 6 Months | Baseline and 6 months | Gut microbial alpha diversity will be assessed in stool samples using the Shannon diversity index derived from amplicon sequence variant profiles obtained through 16S rRNA gene sequencing. The Shannon index is unitless and incorporates both richness and evenness; higher values indicate greater within-sample microbial diversity but do not necessarily represent better health. Change will be calculated as the 6-month index minus baseline; positive values indicate increased diversity and negative values decreased diversity. DNA extraction, sequencing controls, minimum sequencing depth, filtering, normalization, batch handling, and the bioinformatics pipeline will be prespecified and applied consistently. Antibiotic exposure and relevant medication changes will be recorded for sensitivity analyses. |
| Change in Overall Gut Microbiota Community Composition at 6 Months | Baseline and 6 months | Overall gut microbial community composition will be assessed in quality-controlled stool samples collected at baseline and 6 months using 16S rRNA gene sequencing. The primary analysis will use centered-log-ratio-transformed abundance profiles and Aitchison distance. The intervention effect will be estimated as the group-by-time interaction in a prespecified repeated-measures permutational multivariate model. The permutation scheme will preserve paired observations within participants and treatment assignment at household level, with adjustment for the household-level baseline frailty stratum used in randomization. Bray-Curtis distance and one prespecified phylogenetic distance will be examined in sensitivity analyses. Results will be reported as global multivariate test statistics and effect-size measures. Taxon filtering, zero replacement, sequencing-depth, batch, covariate, and multiplicity rules will be frozen before analysis and treatment-code unblinding. |
| Change From Baseline in Serum High-Sensitivity C-Reactive Protein Concentration at 6 Months | Baseline and 6 months | Systemic low-grade inflammation will be assessed using serum high-sensitivity C-reactive protein (hs-CRP), measured with a validated high-sensitivity laboratory assay and reported in mg/L. Higher concentrations indicate greater systemic inflammation but are not specific to frailty. Change will be calculated as the 6-month concentration minus baseline; negative values indicate reduced inflammation. Morning blood samples will be collected after an 8-12-hour overnight fast using standardized procedures. Acute infection, recent vaccination, vigorous exercise, and relevant medication use will be recorded. Paired baseline and 6-month samples will be allocated to the same analytical batch whenever possible, with study groups balanced across assay plates. Handling of values below the quantification limit and values above 10 mg/L will be prespecified, including sensitivity analyses excluding concentrations potentially reflecting acute inflammation. |
Countries
Spain
Contacts
CONTACTCristina Casals, PhD
CONTACTDepartamento de Didáctica de la Educación Física, PyM
PRINCIPAL_INVESTIGATORCristina Casals, Phd, Assistant professor
University of Cadiz (SPAIN)
Outcome results
None listed