This study is a randomised, double-blind, placebo-controlled trial investigating the effects of Hesperidin supplementation on cognitive function, fatigue, and stress.

Participants will be randomly assigned to receive either 500mg of Hesperidin or a matching placebo daily for 12 weeks. The primary outcome is fatigue, with secondary outcomes including cognitive performance and mood. The trial seeks to determine if this dietary intervention offers symptom-alleviating benefits.

Multiple Sclerosis (MS) is a chronic autoimmune condition characterized by neuro-inflammation, oxidative stress, and demyelination, often resulting in debilitating fatigue and cognitive dysfunction. While disease-modifying therapies exist, there is a significant need for accessible, low-risk adjunct interventions to manage these daily symptoms.

Hesperidin is a flavanone found primarily in citrus fruits (e.g., oranges, lemons). Preclinical research using Experimental Autoimmune Encephalomyelitis (EAE)-the standard animal model for MS-has demonstrated that hesperidin supplementation can reduce disease severity and incidence, likely due to its potent anti-inflammatory and antioxidant properties. However, there is a paucity of randomized controlled trials translating these findings to human MS populations.

Study Design & Methodology. This study is a remote, randomised, double-blind, placebo-controlled, parallel-group trial in adults with Multiple Sclerosis. Participants will be randomized to receive either 500mg/day of Hesperidin or a matching placebo for a duration of 12 weeks.

Statistical Analysis Plan. Data will be analysed using linear mixed-effects models. For the primary outcome (MFIS total score) and each secondary outcome, change from baseline to week 12 will be compared between intervention and placebo using fixed effects for group, time (baseline, week 12), and the group × time interaction, with a participant-level random intercept. The treatment effect will be estimated from the group × time interaction. Exploratory analyses will test whether baseline habitual diet modifies the intervention effect by adding a diet × group × time interaction term, with habitual diet operationalised using FFQ-derived polyphenol intake (energy-adjusted) and the Dietary Inflammatory Index (DII). In addition, exploratory symptom network analyses will examine whether the pattern of associations among symptoms differs between groups and changes from baseline to week 12.

Inclusion Criteria:

• Diagnosis of Multiple Sclerosis, Aged 18 years or older.

Exclusion Criteria:

• Known food allergies, intolerances, or significant gastrointestinal (GI) problems, Participants under the age of 18 years.