Sarcopenia and physical frailty are highly prevalent among institutionalized older adults and are major contributors to functional decline, reduced mobility, and loss of independence. Combined exercise and targeted nutritional strategies have emerged as promising approaches to mitigate these age-related impairments. This randomized, double-blind, placebo-controlled, parallel-group clinical trial aims to evaluate the independent and combined effects of creatine monohydrate (CRE) and β-hydroxy-β-methylbutyrate (HMB), administered alongside a supervised multicomponent exercise program, on physical function, body composition, cognitive performance, and quality of life in institutionalized older adults with physical frailty and sarcopenia. A total of 80 adults aged ≥65 years will be randomized to one of four intervention groups for 12 weeks: placebo plus exercise, creatine plus exercise, HMB plus exercise, or creatine plus HMB plus exercise. A supplement-free follow-up period will be conducted to evaluate the sustainability of intervention effects. In addition to clinical and functional outcomes, the study incorporates molecular and biological assessments to explore mechanistic pathways underlying functional adaptation and interindividual variability in response to the interventions.
This randomized, double-blind, placebo-controlled, parallel-group clinical trial is designed to evaluate the independent and combined effects of creatine monohydrate (CRE) and β-hydroxy-β-methylbutyrate (HMB) supplementation when administered alongside a structured multicomponent exercise program in institutionalized older adults with physical frailty and sarcopenia. Sarcopenia and frailty are highly prevalent in this population and are associated with functional disability, increased health care utilization, and reduced quality of life. Nutritional strategies targeting muscle metabolism, when combined with systematic exercise, may attenuate functional decline and improve health outcomes in this vulnerable group. Study Population and Design A total of 80 institutionalized adults aged ≥65 years will be recruited from nursing homes in the province of Burgos (Spain). Participants will be stratified by sex and randomized to one of four parallel intervention groups for a 12-week intervention period: placebo plus exercise, creatine plus exercise, HMB plus exercise, or creatine plus HMB plus exercise. All intervention groups will be followed by a supplement-free follow-up period to assess the persistence of intervention effects. Intervention Dietary supplementation will be administered once daily using identical sachets to ensure blinding and equivalent supplement volume across groups. Participants will receive a total of 6 g/day of powder, consisting of cellulose (placebo), creatine monohydrate, HMB, or their combinations, depending on group allocation. Supplement administration will be supervised by nursing staff and mixed with food or beverages according to standard procedures. All participants will complete a supervised multicomponent exercise program conducted four times per week (\~60 minutes per session). Exercise sessions will include resistance, balance, coordination, and flexibility training, with intensity individually adapted according to functional capacity using the Borg Rating of Perceived Exertion Scale. Outcomes and Assessments Clinical, functional, cognitive, and quality-of-life assessments will be conducted at baseline, post-intervention (Week 12), and during follow-up. Primary and secondary outcome measures focus on physical performance, muscle strength, body composition, cognitive function, activities of daily living, nutritional status, and quality of life. Molecular and Biological Assessments In addition to clinical outcomes, the study incorporates biological and molecular assessments to explore mechanistic pathways underlying functional adaptation and interindividual variability in response to supplementation and exercise. Venous blood samples will be collected for the analysis of inflammatory markers, oxidative stress and antioxidant status, hormonal profiles, and circulating and exosomal molecular signatures related to muscle metabolism and neuromuscular function. Body composition parameters will be assessed using dual-energy X-ray absorptiometry (DXA). Statistical Analysis Statistical analyses will be conducted using mixed-effects models appropriate for parallel-group randomized designs, with treatment group, time, and their interaction as fixed effects, and sex and age included as covariates where appropriate. Post-hoc pairwise comparisons will be adjusted for multiple testing. Statistical significance will be set at p \< 0.05. Ethics and Data Protection The study was approved by the Ethics Committee of the University of Burgos (IR 24/2023). Written informed consent will be obtained from all participants or their legal representatives. All data will be pseudonymized and managed in accordance with the General Data Protection Regulation (GDPR) and Spanish data protection laws.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
80
Sachets containing cellulose used as placebo filler to match supplement volume, appearance, and taste. Administered once daily, mixed with yogurt or juice, during the intervention period.
Sachets containing creatine monohydrate used as an active dietary supplement. Administered once daily during the intervention period.
Supervised exercise sessions, 4 times per week (\~60 minutes each), including resistance, endurance, balance, coordination, and flexibility training. Intensity adapted to participants' functional status (Borg scale 6-9). Conducted throughout the 12-week intervention period.
Sachets containing calcium β-hydroxy-β-methylbutyrate used as an active dietary supplement. Administered once daily during the intervention period.
Residencia de Mayores Fuentes Blancas (Diputación Provincial de Burgos)
Burgos, Castille and León, Spain
Short Physical Performance Battery (SPPB)
The SPPB assesses lower-extremity physical function through balance, gait speed, and chair stand components, generating a total score ranging from 0 to 12 (higher scores indicate better physical performance). Only the total score will be analyzed as the primary outcome.
Time frame: Baseline, Week 12 (end of intervention), and 3-month follow-up
Timed Up and Go (TUG)
Time in seconds to rise from a chair, walk 3 meters, turn around, return, and sit down. Lower times indicate better mobility and balance.
Time frame: Baseline, Week 12 (end of intervention), and 3-month follow-up
Appendicular Lean Mass (ALM, kg) by DEXA
Appendicular lean mass (sum of arms and legs lean tissue) measured in kilograms using DEXA. Higher values indicate greater muscle mass in limbs.
Time frame: Baseline, Week 12 (end of intervention), and 3-month follow-up
Grip Strength
Maximal isometric handgrip strength measured in kilograms using a validated hydraulic dynamometer (e.g., Jamar Plus+). Each test performed with the dominant hand in seated position, elbow at 90°. Best of three attempts recorded.
Time frame: Baseline, Week 12 (end of intervention), and 3-month follow-up
Leg and Back Isometric Strength
Maximal isometric strength of leg and back extensors assessed in kilograms using a back/leg dynamometer (e.g., Baseline Evaluation Dynamometer). Participants stand on the platform and pull a fixed bar upwards. Best of two attempts recorded.
Time frame: Baseline, Week 12 (end of intervention), and 3-month follow-up
Seated Arm Curl Test
Dynamic strength/endurance of upper limbs measured as the number of full arm curl repetitions in 30 seconds using a 2 kg dumbbell for women and a 4 kg dumbbell for men. Participants are seated upright without armrests.
Time frame: Baseline, Week 12 (end of intervention), and 3-month follow-up
Barthel Index
Measure of independence in activities of daily living (feeding, bathing, mobility, toileting, etc.). Score ranges from 0 (total dependence) to 100 (independent).
Time frame: Baseline, Week 12 (end of intervention), and 3-month follow-up
Mini Nutritional Assessment (MNA)
Validated tool to screen and assess nutritional status in older adults. Score ranges from 0-30 (higher = better nutritional status).
Time frame: Baseline, Week 12 (end of intervention), and 3-month follow-up
Cognitive Function - Mini-Mental State Examination (MMSE)
Cognitive function assessed using the Mini-Mental State Examination (MMSE). Scores range from 0 to 30, with higher scores indicating better cognition.
Time frame: Baseline, Week 12 (end of intervention), and 3-month follow-up
Quality of Life - World Health Organization Quality of Life-Brief (WHOQOL-BREF)
26-item validated questionnaire covering physical, psychological, social and environmental domains. Scores range from 26 to 130; higher scores indicate better perceived quality of life.
Time frame: Baseline, Week 12 (end of intervention), and 3-month follow-up
Total Lean Mass (kg) by DEXA
Whole-body lean soft tissue mass measured in kilograms using DEXA (Hologic Discovery or GE Lunar system) with manufacturer's software and standardized positioning. Higher values indicate greater muscle mass.
Time frame: Baseline, Week 12 (end of intervention), and 3-month follow-up
Total Fat Mass (percent body weight) by DEXA
Whole-body fat mass measured with DEXA and expressed as a percentage of total body weight. Higher values indicate greater adiposity.
Time frame: Baseline, Week 12 (end of intervention), and 3-month follow-up
Visceral Adipose Tissue (VAT, cm³) by DEXA
Visceral adipose tissue (VAT) volume estimated by DEXA in the android region of interest, expressed in cubic centimeters (cm³). Higher values indicate greater central adiposity.
Time frame: Baseline, Week 12 (end of intervention), and 3-month follow-up
Whole-Body Bone Mineral Density (BMD, g/cm²) by DEXA
Whole-body BMD measured by DEXA, expressed as grams per square centimeter (g/cm²). Higher values indicate greater bone mineral density.
Time frame: Baseline, Week 12 (end of intervention), and 3-month follow-up
Cognitive Function - MEC (Spanish Adaptation of MMSE)
Cognitive function assessed using the MEC (Spanish version of the MMSE). Scores range from 0 to 35, with higher scores indicating better cognition.
Time frame: Baseline, Week 12 (end of intervention), and 3-month follow-up
Number of Falls
Incidence of falls recorded by nursing staff during the study period. Unit: number of events per participant. Lower numbers indicate better outcomes.
Time frame: Baseline to 3-month follow-up
Number of Hospitalizations
Incidence of hospital admissions for any cause. Unit: number of events per participant. Lower numbers indicate better outcomes.
Time frame: Baseline to 3-month follow-up
Incidence of Respiratory and Urinary Infections
Number of documented respiratory and/or urinary tract infections. Unit: number of events per participant. Lower numbers indicate better outcomes.
Time frame: Baseline to 3-month follow-up
Incidence of Pressure Ulcers
Number of new pressure ulcers recorded by nursing staff. Lower numbers indicate better outcomes.
Time frame: Baseline to 3-month follow-up
Incidence of Urinary or Fecal Incontinence
Occurrence of urinary and/or fecal incontinence episodes recorded in clinical charts. Lower numbers indicate better outcomes.
Time frame: Baseline to 3-month follow-up
Serum C-reactive protein (CRP, mg/L)
CRP will be measured in serum samples using a high-sensitivity ELISA. Results expressed in mg/L. Higher values indicate greater systemic inflammation.
Time frame: Baseline, Week 12 (end of intervention)
Interleukin-6 (IL-6, pg/mL)
Serum IL-6 concentration will be measured by ELISA and expressed in pg/mL. Higher values indicate greater systemic inflammation.
Time frame: Baseline, Week 12 (end of intervention)
Tumor Necrosis Factor-alpha (TNF-α, pg/mL)
Serum TNF-α concentration will be determined by ELISA and expressed in pg/mL. Higher values indicate greater systemic inflammation.
Time frame: Baseline, Week 12 (end of intervention)
Reduced Glutathione (GSH, µmol/L)
Plasma reduced glutathione measured by colorimetric assay and expressed in µmol/L. Higher values indicate better antioxidant status.
Time frame: Baseline, Week 12 (end of intervention)
Oxidized Glutathione (GSSG, µmol/L)
Plasma oxidized glutathione measured by colorimetric assay and expressed in µmol/L. Higher values indicate greater oxidative stress.
Time frame: Baseline, Week 12 (end of intervention)
Thiobarbituric Acid Reactive Substances (TBARS, nmol MDA equivalents/mL plasma)
Lipid peroxidation index measured as TBARS and expressed in nmol MDA equivalents/mL of plasma. Higher values indicate greater oxidative stress.
Time frame: Baseline, Week 12 (end of intervention)
Malondialdehyde (MDA, µmol/L)
Plasma MDA determined spectrophotometrically and expressed in µmol/L. Higher values indicate greater oxidative stress.
Time frame: Baseline, Week 12 (end of intervention)
Total Antioxidant Capacity (TAC, mmol Trolox equivalents/L)
Plasma TAC measured using colorimetric assay and expressed as mmol Trolox equivalents/L. Higher values indicate better antioxidant defense.
Time frame: Baseline, Week 12 (end of intervention)
Relative expression levels of selected circulating microRNAs
Changes in the relative expression levels of selected circulating microRNAs associated with muscle metabolism, neuromuscular function, inflammation, oxidative stress, and anabolic signaling pathways. MicroRNAs will be quantified from peripheral blood samples using molecular profiling techniques.
Time frame: Baseline, Week 12 (end of intervention), and 3-month follow-up
Relative expression levels of selected exosome-derived microRNAs
Changes in the relative expression levels of selected exosome-derived microRNAs related to muscle function, inflammation, and metabolic regulation, analyzed from circulating extracellular vesicles isolated from plasma samples.
Time frame: Baseline and Week 12
Frequency of selected genetic variants related to creatine and HMB responsiveness
Analysis of the frequency of selected genetic variants related to muscle metabolism, anabolic signaling, and exercise responsiveness to explore interindividual variability in functional and molecular responses to creatine and HMB supplementation.
Time frame: Baseline
Relative abundance of selected circulating proteins involved in muscle and inflammatory responses
Changes in the relative abundance of selected circulating proteins involved in muscle metabolism, inflammation, oxidative stress, and functional adaptation in response to creatine and HMB supplementation combined with exercise. Protein abundance will be assessed using targeted proteomic approaches.
Time frame: Baseline and Week 12
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