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Neuromuscular and Multi-Omics Synergy of Combined Creatine × HMB Supplementation Plus Exercise to Improve Muscle Function in Sarcopenic Frailty (MULTI-FRAIL)

U

Universidad de Burgos

Status

Begins enrollment this month

Conditions

Aging
Malnutrition Elderly
Frailty
Sarcopenia

Treatments

Dietary Supplement: Creatine Monohydrate
Behavioral: Multicomponent Exercise Program
Dietary Supplement: β-Hydroxy-β-Methylbutyrate (HMB)
Dietary Supplement: Placebo (Cellulose)

Study type

Interventional

Funder types

Other

Identifiers

NCT07275996
UBU-FB-CREHMB-CRXO-2025
IR 24/2023

Details and patient eligibility

About

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.

Full description

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.

Enrollment

80 estimated patients

Sex

All

Ages

65+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

  • Institutionalized older adults (≥65 years) residing in the Fuentes Blancas Nursing Home (Diputación de Burgos).
  • Clinical diagnosis of frailty or sarcopenia according to validated criteria (e.g., Fried phenotype, SPPB ≤ 9, or low ALMI by DEXA).
  • Ability to participate in an exercise program as assessed by the medical staff.
  • Written informed consent provided by the participant or, if cognitively impaired, by a legally authorized representative.

Exclusion criteria

  • Severe renal insufficiency (eGFR < 30 mL/min/1.73m²) or liver failure.
  • Advanced heart failure (NYHA class III-IV) or unstable cardiovascular disease.
  • Active cancer or other severe medical conditions that contraindicate participation.
  • Severe cognitive impairment (MMSE < 10) precluding adherence to the program without caregiver support.
  • Known allergy or intolerance to creatine, HMB, or inulin.
  • Participation in another clinical trial within the past 3 months.
  • Any condition that, in the opinion of the medical team, may compromise safety or adherence to the intervention.

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

Quadruple Blind

80 participants in 4 patient groups, including a placebo group

Creatine + HMB + Exercise
Experimental group
Description:
Participants receive a total of 6 g/day of powder consisting of 3 g/day of creatine monohydrate and 3 g/day of β-hydroxy-β-methylbutyrate (HMB), administered once daily, combined with a supervised multicomponent exercise program for 12 weeks.
Treatment:
Dietary Supplement: β-Hydroxy-β-Methylbutyrate (HMB)
Behavioral: Multicomponent Exercise Program
Dietary Supplement: Creatine Monohydrate
Placebo + Exercise
Placebo Comparator group
Description:
Participants receive a total of 6 g/day of cellulose (placebo), administered once daily, combined with a supervised multicomponent exercise program for 12 weeks.
Treatment:
Dietary Supplement: Placebo (Cellulose)
Behavioral: Multicomponent Exercise Program
Creatine + Exercise
Active Comparator group
Description:
Participants receive a total of 6 g/day of powder consisting of 3 g/day of creatine monohydrate and 3 g/day of cellulose (placebo filler), administered once daily, combined with a supervised multicomponent exercise program for 12 weeks.
Treatment:
Dietary Supplement: Placebo (Cellulose)
Behavioral: Multicomponent Exercise Program
Dietary Supplement: Creatine Monohydrate
HMB + Exercise
Active Comparator group
Description:
Participants receive a total of 6 g/day of powder consisting of 3 g/day of β-hydroxy-β-methylbutyrate (HMB) and 3 g/day of cellulose (placebo filler), administered once daily, combined with a supervised multicomponent exercise program for 12 weeks.
Treatment:
Dietary Supplement: Placebo (Cellulose)
Dietary Supplement: β-Hydroxy-β-Methylbutyrate (HMB)
Behavioral: Multicomponent Exercise Program

Trial contacts and locations

1

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Central trial contact

Juan Mielgo -Ayuso, PhD

Data sourced from clinicaltrials.gov

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