Comparison of the Effects of Different Doses of Combined Aerobic-Resistance Exercise on Neuroaxonal Injury and Clinical Outcomes in Patients With Relapsing-Remitting Multiple Sclerosis

The aim of this study is to determine the effects of different doses of combined aerobic-resistance exercise on neuroaxonal injury, inflammatory biomarkers, and clinical outcomes in patients with relapsing-remitting multiple sclerosis. The primary objective is to identify the exercise intensity threshold associated with reductions in serum neurofilament light chain (sNfL) as a biomarker of neuroaxonal injury.

A phase II, randomized, three-arm, parallel-group clinical trial with blinded outcome assessment in 120 patients with RRMS. Participants will be allocated in a 1:1:1 ratio using stratified variable block randomization based on sex and EDSS.

The study will be conducted in specialized MS centers. After baseline assessment, participants will be randomly assigned to groups and complete a 16-week exercise program. Outcome assessors and laboratory personnel will remain blinded to group allocation.

Patients with RRMS; age 25–45 years; EDSS 1–4.5; no relapse or corticosteroid treatment during the previous 3 months; stable therapy ≥6 months; ability to exercise. Exclusion criteria: progressive MS; medical contraindications to exercise; severe mobility limitations; severe cognitive impairment; pregnancy; recent treatment changes.

Three groups will perform combined aerobic-resistance exercise with low, moderate, and high doses. Low-dose: 50–60% HRR and 50–60% 1RM; moderate-dose: 65–75% HRR and 60–70% 1RM; high-dose: 80–85% HRR and 70–80% 1RM. All groups will train for 16 weeks, three sessions per week.

Changes in serum neurofilament light chain (sNfL) levels; aerobic capacity (VO₂peak); disease-related fatigue; walking performance; cognitive function; and health-related quality of life.

Eligible participants will be randomly allocated in a 1:1:1 ratio to low-dose, moderate-dose, or high-dose exercise groups after completion of baseline assessments. Individual randomization will be performed using variable block randomization. Stratified randomization will be applied according to sex (female/male) and baseline disability level based on the Expanded Disability Status Scale (EDSS ≤3.5 and >3.5) to minimize potential confounding effects. The random allocation sequence will be generated by an independent researcher using statistical software. Group allocation will be concealed using sequentially numbered, opaque, sealed envelopes prepared by a researcher who is not involved in participant recruitment or intervention delivery.

Participants and exercise trainers will not be blinded due to the nature of the exercise intervention. The principal investigator and intervention staff will be aware of group allocation. However, outcome assessors, laboratory personnel responsible for biomarker analyses, and the statistician will remain blinded to treatment allocation. Biological samples will be analyzed using coded identifiers, and group assignments will remain concealed until completion of the primary statistical analysis.

De-identified individual participant data, study protocol, statistical analysis plan, analysis codes, and data dictionary will be made available to qualified researchers after publication of the primary study results. Requests will be reviewed by the research team based on scientific and ethical considerations.

Access to data and documents will begin 6 months after publication of the primary study results and will remain available for 5 years.

Academic researchers, scientists from research institutions, and qualified investigators submitting a valid scientific request will be eligible for access.

Data will be available for scientific research purposes, valid analyses, and advancing knowledge in multiple sclerosis and exercise science. Data reuse must comply with research ethics principles and must not attempt participant re-identification.

Requests for data access should be submitted to the corresponding investigator through the official email address of the research center. Final contact information will be provided after publication of the primary study results.

Requests will be reviewed by the research team. After scientific and ethical approval, a data use agreement will be completed and access to de-identified data will be provided.