Creatine and Beta-Hydroxy-Beta-Methylbutyrate (HMB) Supplementation Plus Home-Based Exercise for Sarcopenia in Huntington's Disease

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.

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 \