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

NCT07275996 | Active Not Recruiting DMC

• 2 other identifiers: UBU-FB-CREHMB-CRXO-2025IR 24/2023
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

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 50 adults aged ≥65 years were enrolled and 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.

Conditions

Frailty; Sarcopenia; Aging; Malnutrition Elderly

Keywords

creatine; HMB; supplementation; multicomponent exercise; concurrent training; institutionalized older adults; nursing home; physical performance; quality of life; oxidative stress; inflammation; geriatric assessment; multi-omics; microRNA; proteomics

Outcome Measures

Primary Outcomes (3)

• 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.

  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.

  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.

  Baseline, Week 12 (end of intervention), and 3-month follow-up

Secondary Outcomes (29)

• Grip Strength

  Baseline, Week 12 (end of intervention), and 3-month follow-up

• Leg and Back Isometric Strength

  Baseline, Week 12 (end of intervention), and 3-month follow-up

• Seated Arm Curl Test

  Baseline, Week 12 (end of intervention), and 3-month follow-up

• Barthel Index

  Baseline, Week 12 (end of intervention), and 3-month follow-up

• Mini Nutritional Assessment (MNA)

  Baseline, Week 12 (end of intervention), and 3-month follow-up

Study Arms (4)

Creatine + HMB + Exercise

EXPERIMENTAL

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.

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

Placebo + Exercise

PLACEBO COMPARATOR

Participants receive a total of 6 g/day of cellulose (placebo), administered once daily, combined with a supervised multicomponent exercise program for 12 weeks.

Dietary Supplement: Placebo (Cellulose); Behavioral: Multicomponent Exercise Program

Creatine + Exercise

ACTIVE COMPARATOR

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.

Dietary Supplement: Placebo (Cellulose); Dietary Supplement: Creatine Monohydrate; Behavioral: Multicomponent Exercise Program

HMB + Exercise

ACTIVE COMPARATOR

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.

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

Interventions

Placebo (Cellulose) DIETARY_SUPPLEMENT

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.

Creatine + Exercise; HMB + Exercise; Placebo + Exercise

Creatine Monohydrate DIETARY_SUPPLEMENT

Sachets containing creatine monohydrate used as an active dietary supplement. Administered once daily during the intervention period.

Creatine + Exercise; Creatine + HMB + Exercise

Multicomponent Exercise Program BEHAVIORAL

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.

Creatine + Exercise; Creatine + HMB + Exercise; HMB + Exercise; Placebo + Exercise

β-Hydroxy-β-Methylbutyrate (HMB) DIETARY_SUPPLEMENT

Sachets containing calcium β-hydroxy-β-methylbutyrate used as an active dietary supplement. Administered once daily during the intervention period.

Creatine + HMB + Exercise; HMB + Exercise

Eligibility Criteria

• Age: 65 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Universidad de Burgos: lead

Study Sites (1)

Residencia de Mayores Fuentes Blancas (Diputación Provincial de Burgos)

Burgos, Castille and León, 09002, Spain

Location

Related Publications (9)

• Rezola-Pardo C, Rodriguez-Larrad A, Gomez-Diaz J, Lozano-Real G, Mugica-Errazquin I, Patino MJ, Bidaurrazaga-Letona I, Irazusta J, Gil SM. Comparison Between Multicomponent Exercise and Walking Interventions in Long-Term Nursing Homes: A Randomized Controlled Trial. Gerontologist. 2020 Sep 15;60(7):1364-1373. doi: 10.1093/geront/gnz177.

  PMID: 31845733 RESULT

• Fernandez-Landa J, Calleja-Gonzalez J, Leon-Guereno P, Caballero-Garcia A, Cordova A, Mielgo-Ayuso J. Effect of the Combination of Creatine Monohydrate Plus HMB Supplementation on Sports Performance, Body Composition, Markers of Muscle Damage and Hormone Status: A Systematic Review. Nutrients. 2019 Oct 20;11(10):2528. doi: 10.3390/nu11102528.

  PMID: 31635165 RESULT

• Fernandez-Landa J, Fernandez-Lazaro D, Calleja-Gonzalez J, Caballero-Garcia A, Cordova A, Leon-Guereno P, Mielgo-Ayuso J. Long-Term Effect of Combination of Creatine Monohydrate Plus beta-Hydroxy beta-Methylbutyrate (HMB) on Exercise-Induced Muscle Damage and Anabolic/Catabolic Hormones in Elite Male Endurance Athletes. Biomolecules. 2020 Jan 15;10(1):140. doi: 10.3390/biom10010140.

  PMID: 31952174 RESULT

• Fernandez-Landa J, Fernandez-Lazaro D, Calleja-Gonzalez J, Caballero-Garcia A, Cordova Martinez A, Leon-Guereno P, Mielgo-Ayuso J. Effect of Ten Weeks of Creatine Monohydrate Plus HMB Supplementation on Athletic Performance Tests in Elite Male Endurance Athletes. Nutrients. 2020 Jan 10;12(1):193. doi: 10.3390/nu12010193.

  PMID: 31936727 RESULT

• Holecek M. Beta-hydroxy-beta-methylbutyrate supplementation and skeletal muscle in healthy and muscle-wasting conditions. J Cachexia Sarcopenia Muscle. 2017 Aug;8(4):529-541. doi: 10.1002/jcsm.12208. Epub 2017 May 10.

  PMID: 28493406 RESULT

• Cadore EL, Rodriguez-Manas L, Sinclair A, Izquierdo M. Effects of different exercise interventions on risk of falls, gait ability, and balance in physically frail older adults: a systematic review. Rejuvenation Res. 2013 Apr;16(2):105-14. doi: 10.1089/rej.2012.1397.

  PMID: 23327448 RESULT

• Devries MC, Phillips SM. Creatine supplementation during resistance training in older adults-a meta-analysis. Med Sci Sports Exerc. 2014 Jun;46(6):1194-203. doi: 10.1249/MSS.0000000000000220.

  PMID: 24576864 RESULT

• Beaudart C, Zaaria M, Pasleau F, Reginster JY, Bruyere O. Health Outcomes of Sarcopenia: A Systematic Review and Meta-Analysis. PLoS One. 2017 Jan 17;12(1):e0169548. doi: 10.1371/journal.pone.0169548. eCollection 2017.

  PMID: 28095426 RESULT

• Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyere O, Cederholm T, Cooper C, Landi F, Rolland Y, Sayer AA, Schneider SM, Sieber CC, Topinkova E, Vandewoude M, Visser M, Zamboni M; Writing Group for the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), and the Extended Group for EWGSOP2. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019 Jan 1;48(1):16-31. doi: 10.1093/ageing/afy169.

  PMID: 30312372 RESULT

MeSH Terms

Conditions

Frailty; Sarcopenia; Inflammation

Interventions

Cellulose; Creatine

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Muscular Atrophy; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Atrophy; Pathological Conditions, Anatomical; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Glucans; Biopolymers; Polymers; Macromolecular Substances; Polysaccharides; Carbohydrates; Biomedical and Dental Materials; Manufactured Materials; Technology, Industry, and Agriculture; Guanidines; Amidines; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Juan Mielgo-Ayuso, PhD

  Universidad de Burgos

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Triple-blind design: Participants, care providers (exercise supervisors and supplement distributors), investigators, and outcome assessors will remain blinded to allocation. Supplements will be provided in identical sachets.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Full Professor of Physiology, Principal Investigator

Model Details: Randomized, double-blind, placebo-controlled, parallel-group clinical trial with four study arms. Participants will receive 12 weeks of dietary supplementation combined with a supervised multicomponent exercise program, followed by a 3-month follow-up period without supplementation.

Study Record Dates

• First Submitted: September 29, 2025
• First Posted: December 10, 2025
• Study Start: March 10, 2026
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): May 30, 2027
• Last Updated: May 4, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, ANALYTIC CODE
• Time Frame: Beginning 6 months after publication of the main results, for at least 5 years.
• Access Criteria: Researchers may request access by contacting the Principal Investigator (Prof. Juan Mielgo-Ayuso, Universidad de Burgos). Requests will be reviewed by the study steering committee. Access will be granted to qualified researchers whose proposals are scientifically and ethically sound, and who agree to sign a data access agreement.

Locations

ES (1)