Huntington Disease, Sarcopenia, Frailty
Conditions
Keywords
Creatine, Beta-hydroxy-beta-methylbutyrate (HMB), Multicomponent exercise, microRNA, Extracellular vesicles, Proteomics, Pharmacogenetics, Neuromuscular function
Brief summary
Huntington's disease (HD) is a rare neurodegenerative disorder in which accelerated loss of muscle mass, strength and autonomy (physical frailty and sarcopenia) contributes to functional decline. This randomized, double-blind, placebo-controlled, four-arm parallel trial will include adults with HD and physical frailty/sarcopenia. All participants will follow a 12-week individualized, home-based multicomponent exercise program (VIVIFRAIL-based, with weekly remote monitoring) and will be randomized 1:1:1:1 to placebo, creatine (CRE), beta-hydroxy-beta-methylbutyrate (HMB) or combined CRE+HMB. The study will test whether combined CRE+HMB produces synergistic improvements in functional capacity, neuromuscular performance, body composition, cognition and quality of life, and will use multi-omic profiling (circulating and extracellular-vesicle microRNAs, plasma proteomics and genetics) to identify mechanisms and predictive signatures of response. Durability of effects will be assessed 6 months after the end of the intervention.
Detailed description
Design: randomized, double-blind, placebo-controlled, four-arm parallel-group trial conducted at the Neurology Department of Hospital Universitario de Burgos (HUBU; recruitment, clinical assessment, biological sampling) and the University of Burgos (UBU; exercise physiology, functional testing and multi-omic analyses). Randomization: computer-generated permuted blocks of variable size (REDCap), 1:1:1:1 allocation, stratified by sex, antipsychotic use, participation in structured exercise programs and diabetes. Allocation is performed and concealed by an independent pharmacist (HUBU Pharmacy Service). Participants, intervention staff, outcome assessors and data analysts are blinded; supplements are packed in identical coded sachets. Interventions: once daily for 12 weeks, dissolved in 100 mL fruit juice with the evening meal: (1) 3 g creatine monohydrate + 3 g microcrystalline cellulose; (2) 3 g beta-hydroxy-beta-methylbutyrate (HMB) + 3 g cellulose; (3) 3 g creatine + 3 g HMB; (4) placebo, 6 g microcrystalline cellulose. All participants follow a Mediterranean-style diet (protein 1.2-1.5 g/kg/day) and an individualized home-based multicomponent exercise program based on VIVIFRAIL, prescribed and supervised by an occupational therapist, with weekly phone calls to monitor adherence, perceived exertion (target Borg rating of perceived exertion \[RPE\] 12-15) and adverse events. Adherence is monitored by intake logs and sachet counts. Assessments: baseline (T0), week 12 (T1, end of intervention) and 6-month follow-up (T2). Functional capacity (Unified Huntington's Disease Rating Scale \[UHDRS\] Total Functional Capacity \[TFC\], Functional Assessment Scale, Independence Scale, gait speed, Short Physical Performance Battery \[SPPB\]), body composition (multifrequency bioimpedance), neuromuscular function (rate of force development and peak force during isometric knee extension), cognition (Mini-Mental State Examination \[MMSE\], Symbol Digit Modalities Test \[SDMT\], Stroop test, Trail Making Test \[TMT\], verbal fluency), quality of life (12-Item Short Form Health Survey \[SF-12\]) and adverse events. Fasting blood samples for small RNA sequencing (RNA-seq) of circulating and extracellular-vesicle microRNAs (with quantitative polymerase chain reaction \[qPCR\] validation), plasma proteomics (Olink Reveal, 1,034 proteins) and pharmacogenetics (15 single nucleotide polymorphisms \[SNPs\] in SLC6A8, CKM, GATM, MTOR, AKT1, PTEN; genome-wide genotyping in a subset). Sample size: 64 participants (16 per arm) are needed to detect a small-to-moderate effect (f = 0.20) on change in TFC (alpha 0.05, power 0.80, r = 0.50); allowing for 25-30% dropout, 84-88 participants will be enrolled. Statistical analysis: intention-to-treat and per-protocol analyses; linear mixed-effects models with Group x Time interaction and pre-specified contrasts of creatine (CRE)+HMB versus each single supplement and placebo; multi-omic integration (mixOmics/DIABLO, MOFA+, elastic net, random forest) with repeated nested cross-validation to identify predictive signatures of response.
Interventions
DIETARY_SUPPLEMENTCreatine monohydrate
3 g/day creatine monohydrate (with 3 g microcrystalline cellulose when given alone, or with 3 g beta-hydroxy-beta-methylbutyrate (HMB) in the combined arm), dissolved in 100 mL fruit juice and taken once daily with the evening meal for 12 weeks, in identical coded sachets.
DIETARY_SUPPLEMENTBeta-hydroxy-beta-methylbutyrate (HMB)
3 g/day HMB (with 3 g microcrystalline cellulose when given alone, or with 3 g creatine monohydrate in the combined arm), dissolved in 100 mL fruit juice and taken once daily with the evening meal for 12 weeks, in identical coded sachets.
DIETARY_SUPPLEMENTPlacebo (microcrystalline cellulose)
6 g/day microcrystalline cellulose, suspended in 100 mL fruit juice and taken once daily with the evening meal for 12 weeks, in sachets identical in appearance to the active supplements.
12-week individualized home-based multicomponent exercise program (strength, balance, gait and endurance) based on VIVIFRAIL, adapted to Huntington's disease (HD)-specific motor and cognitive limitations, prescribed and supervised by an occupational therapist, with weekly training logs and phone calls to monitor adherence, perceived exertion (target Borg rating of perceived exertion \[RPE\] 12-15) and adverse events. All participants also receive Mediterranean-style dietary advice (protein 1.2-1.5 g/kg/day).
Sponsors
Universidad de Burgos
Hospital Universitario de Burgos
Instituto de Salud Carlos III
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Data analysts are also masked. Active supplements and placebo are provided in identical coded sachets prepared by an independent hospital pharmacist and administered in the same vehicle (100 mL fruit juice).
Intervention model description
Four-arm parallel-group trial (placebo, creatine, beta-hydroxy-beta-methylbutyrate \[HMB\], creatine+HMB); all arms also receive the same individualized home-based multicomponent exercise program. Allocation ratio 1:1:1:1. 12-week intervention followed by a 6-month supplementation-free follow-up.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 18 years or older with genetically confirmed Huntington's disease (HD) (cytosine-adenine-guanine \[CAG\] repeat expansion in the huntingtin \[HTT\] gene). * Symptomatic HD, defined by a Unified Huntington's Disease Rating Scale (UHDRS) total motor score \> 4, in early-intermediate stages according to Total Functional Capacity (TFC). * Physical frailty and/or sarcopenia, defined as Short Physical Performance Battery (SPPB) score \<= 10 and/or gait speed \< 1.0 m/s and/or European Working Group on Sarcopenia in Older People 2 (EWGSOP2) sarcopenia criteria (low strength and low muscle quantity/quality assessed by validated bioelectrical impedance analysis (BIA)-derived indices). * VIVIFRAIL category B (frail) or C1/C2 (pre-frail). * Stable pharmacological treatment for at least 4 weeks before baseline. * Clinical judgement of the neurologist and occupational therapist that the participant can safely perform a prescribed home-based exercise program with weekly remote monitoring. * Written informed consent from the participant or legally authorized representative (with participant assent whenever possible).
Exclusion criteria
* Unstable cardiovascular, renal, hepatic or musculoskeletal disease contraindicating exercise or supplementation. * Severe chorea or postural instability preventing safe training; uncontrolled psychiatric symptoms or active substance abuse. * Severe dysphagia preventing safe intake of thickened liquids (unless a clinically acceptable alternative exists). * Allergy or intolerance to any supplement component. * Pregnancy or lactation. * Use of protein supplements in the month before inclusion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total Functional Capacity (TFC) | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | Unified Huntington's Disease Rating Scale (UHDRS) Total Functional Capacity score, range 0-13; higher scores indicate better functional capacity. Change from baseline will be compared across the four arms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Functional Assessment Scale (FAS) | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | UHDRS Functional Assessment Scale, 25 yes/no items, range 0-25; higher scores indicate better function. |
| Change in Independence Scale (IS) | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | UHDRS Independence Scale, range 10-100 in 5-point steps; higher scores indicate greater independence. |
| Change in Gait Speed | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | Usual gait speed (m/s) measured over a standardized walking course. |
| Change in Rate of Force Development (RFD) 0-200 ms | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | Rate of force development (RFD) from 0 to 200 ms (N/s) during maximal isometric knee extension measured with a force transducer (best of three 5-s trials). |
| Change in Peak Force | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | Peak force (N) during maximal isometric knee extension measured with a force transducer (best of three 5-s trials). |
| Change in Contraction Time | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | Contraction time (ms) during maximal isometric knee extension measured with a force transducer (best of three 5-s trials). |
| Change in Fat-Free Mass (FFM) | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | Fat-free mass (FFM, kg) assessed by multifrequency bioelectrical impedance analysis (BIA). |
| Change in Fat Mass (FM) | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | Fat mass (FM, kg) assessed by multifrequency bioelectrical impedance analysis (BIA). |
| Change in Fat-Free Mass Index (FFMI) | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | Fat-free mass index (FFMI, kg/m\^2) assessed by multifrequency bioelectrical impedance analysis (BIA). |
| Change in Fat Mass Index (FMI) | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | Fat mass index (FMI, kg/m\^2) assessed by multifrequency bioelectrical impedance analysis (BIA). |
| Change in Mini-Mental State Examination (MMSE) Score | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | MMSE total score, range 0-30; higher scores indicate better global cognitive function. Part of the Enroll-HD cognitive battery. |
| Change in Symbol Digit Modalities Test (SDMT), Oral Version | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | Number of correct responses in 90 seconds on the oral version of the SDMT; higher scores indicate better performance. Part of the Enroll-HD cognitive battery. |
| Change in Stroop Test Performance | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | Number of correct responses in 45 seconds on the Stroop test; higher scores indicate better performance. Part of the Enroll-HD cognitive battery. |
| Change in Trail Making Test Part A (TMT-A) Completion Time | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | Time to complete Trail Making Test Part A (seconds); lower values indicate better performance. Part of the Enroll-HD cognitive battery. |
| Change in Trail Making Test Part B (TMT-B) Completion Time | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | Time to complete Trail Making Test Part B (seconds); lower values indicate better performance. Part of the Enroll-HD cognitive battery. |
| Change in Semantic Verbal Fluency | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | Number of words produced in 60 seconds in a semantic (category) verbal fluency task; higher scores indicate better performance. Part of the Enroll-HD cognitive battery. |
| Change in Phonemic Verbal Fluency | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | Number of words produced in 60 seconds in a phonemic (letter) verbal fluency task; higher scores indicate better performance. Part of the Enroll-HD cognitive battery. |
| Change in 12-Item Short Form Health Survey (SF-12) Physical Component Summary (PCS) | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | SF-12 Physical Component Summary score, range 0-100; higher scores indicate better physical health-related quality of life. |
| Change in 12-Item Short Form Health Survey (SF-12) Mental Component Summary (MCS) | Baseline, week 12 (end of intervention) and 6 months after the end of intervention | SF-12 Mental Component Summary score, range 0-100; higher scores indicate better mental health-related quality of life. |
| Number of Participants With Adverse Events and Falls | From informed consent until 30 days after the end of supplementation (week 16), plus clinically relevant events up to 6 months after the end of intervention | Adverse events and serious adverse events (including falls, emergency visits and hospitalizations) related or unrelated to supplementation, exercise or blood sampling; causality assessed with the Spanish Pharmacovigilance System algorithm. |
Countries
Spain
Contacts
CONTACTMiriam Saiz Rodríguez, PhD
CONTACTJuan Francisco Mielgo Ayuso, PhD
PRINCIPAL_INVESTIGATORMiriam Saiz Rodríguez, PhD
Universidad de Burgos
PRINCIPAL_INVESTIGATORJuan Francisco Mielgo Ayuso, PhD
Universidad de Burgos
Outcome results
None listed