**Background:** Stroke is a leading cause of death and disability in Brazil, with approximately two-thirds of patients experiencing incomplete recovery. Malnutrition, dysphagia, reduced consciousness, and enteral feeding commonly impair nutritional status in the acute phase, and patients malnourished at ictus have higher complication rates and mortality. Sarcopenia after stroke differs from age-related sarcopenia by its rapid onset—muscle changes occur within 4 hours, and weakness develops on both the affected and contralateral sides within 7 days. Catabolic signals from brain damage, hypermetabolism, insulin resistance, and inflammation compound muscle loss. While 1.2–1.5 g protein/kg/day plus exercise is recommended for sarcopenia prevention in older adults, limited data exist for acute stroke. Creatine supplementation has improved muscle mass in healthy older individuals even after short-term use and shows promise in pathological conditions. This trial aims to verify the effectiveness of creatine supplementation on functional capacity, strength, and muscle mass during stroke hospitalization compared to usual care, with an exploratory subanalysis of inflammatory profiles and 90-day follow-up.
**Methods:** This is a randomized, double-blind, unicenter, parallel-group superiority trial conducted at the Stroke Unit of the Clinical Hospital of Botucatu Medical School, Brazil. Thirty participants aged ≥60 years with acute ischemic stroke, no prior disability (mRs ≤2), and consent within 24 hours of ictus will be randomized 1:1. Exclusion criteria include hemodynamic instability, mechanical ventilation, pacemakers/metallic prostheses, prior kidney disease (CrCl ≤30 mL/min/1.73 m²), disabsorptive gastrointestinal surgery, parenteral nutrition, or allergies to study products. The intervention group (n=15) receives 10 g creatine twice daily; the control group (n=15) receives 10 g maltodextrin twice daily. Both groups receive identical protein supplementation (powdered milk protein serum isolate to achieve 1.5 g protein/kg/day) and standard physiotherapy (contracture prevention, limb/trunk strengthening, gait training, independence training) starting after 24 hours. Supplementation continues for the 7-day hospitalization. At discharge, all receive dietary guidance per Brazilian Ministry of Health guidelines.
Primary outcomes assessed at baseline (24 hours) and day 7 include: functional capacity (mRs, Timed Up and Go), muscle strength (handgrip dynamometry, NIHSS lower limb score), and muscle mass (ultrasonography of rectus femoris and biceps brachii using BodyMetrix BX-2000 with 2.5-MHz transducer, multifrequency SECA mBCA525 bioimpedance at 6 frequencies, and D3-methylhistidine stable isotope tracer analysis in 10 of 30 participants via liquid chromatography-mass spectrometry at the University of Nottingham). Secondary outcomes at 90 days include mRs, Timed Up and Go, handgrip strength, NIHSS lower limb score, 30-s chair stand test, EuroQol-5D quality of life, and mortality (via death certificates). Additional assessments include anthropometrics (weight, height, arm circumference, tricipital skinfold, adductor pollicis muscle thickness, BMI, arm muscle area), Barthel Index for dependence, Hospital Anxiety and Depression Scale, and biochemical dosages (insulin, IL-6 by ELISA, metalloprotease 2 and 9 activity by zymography).
Randomization uses a cell phone application with 1:1 allocation in blocks of 10, performed by a person uninvolved in data collection. Participants, supplement administrators, and assessors are blinded; the statistician is unblinded. Blinding may be broken only for serious adverse events. The Full Analysis Set (all randomized receiving ≥1 dose) will be used for efficacy; Per-Protocol and Safety Analysis Sets for sensitivity. Missing data will use multiple imputation. Continuous variables will be compared by t-test or Mann-Whitney; biomarker, muscle mass, and strength changes over time by mixed regression models; 90-day survival by Kaplan-Meier curves and Cox regression. All tests are two-sided at 5% significance. The sample size (n=30) was based on a prior creatine study in 18 healthy older adults and a meta-analysis of ~600 patients from 60 studies averaging 10 per arm, with 50% added as a convenience margin.
**Key Results:** This is a study protocol; no results are reported. The trial was registered on January 21, 2019 (ReBEC RBR-9q7gg4). Recruitment began March 2019 with expected completion June 2023. Ethics approval was obtained (CAAE: 79844317.3.0000.5411, Consubstantiated Opinion no. 2.421.189, December 7, 2017), with two approved amendments (April 5, 2019; June 8, 2022).
**Clinical Implications:** If creatine supplementation during acute stroke hospitalization improves functional capacity, strength, and muscle mass preservation, it would provide a safe, low-cost, readily implementable adjunct to standard stroke care. The study addresses a critical evidence gap—no multimodal therapy combining protein and creatine with physiotherapy has been tested in acute stroke. The 90-day follow-up for mortality and quality of life will provide preliminary data on longer-term impact. Limitations include the small sample size (n=30), single-center design, and challenges of compliance in stroke patients with dysphagia or reduced consciousness. However, rigorous conduct within a stroke unit with intake control and standardized care strengthens internal validity. Results will inform sample size calculations and feasibility for larger multicenter trials.