Background: While outdoor walking exercise therapy could likely elicit multiple beneficial effects in persons with multiple sclerosis (pwMS), little evidence exists.

Objective: To evaluate the effects of a 7-week group-based outdoor walking exercise therapy intervention on walking capacity and mental well-being as well as additional outcomes in pwMS.

Methods: In this randomized controlled trial, n = 62 ambulatory pwMS (49/62, 79% females; 51 years [range, 27-68 years]), patient-determined disease steps 1.7 (range, 0-4) were assigned to either a WALK group (a 'personalized' program suited to the starting level of each participant, including one continuous and one intermittent supervised walking session per week at moderate-to-high intensity) or a CONTROL group (continuation of habitual lifestyle). Tests were carried out at baseline (Pre) and after the intervention (Post). Walking capacity included 6-minute walk test (6MWT; primary outcome), timed 25-foot walk test (T25FWT), and six spot step test (SSST). Walking fatigability indexes were calculated from 6MWT data. Patient-reported outcomes included 12-item MS Walking Scale (MSWS), modified fatigue impact scale (MFIS), 7-item falls efficacy scale-international (FES-I), World Health Organization five well-being index (WHO5; main secondary outcome), and 0-100 visual analogue scale health-related quality of life (HR-QoL).

Results: Across the 7-week intervention period, n = 17 (5/17, 27%) pwMS dropped out. No adverse events were reported. Across all WALK sessions, 78% of the time was spent on forest/gravel trails. Substantial between-group changes were observed (beneficial changes in WALK vs no changes in CONTROL) in 6MWT (mean change [95% CI]; +41 m [22;60]; deemed clinically relevant), T25FWT (+0.27 [0.15;0.39] m/s), SSST (-0.80 [-1.33;-0.27] s), WHO5 (+7.3 [0.1;14.5] points), MSWS (-5.1 [-9.2;-1.0] points), MFIS (-6.7 [-11.7;-1.7] points), FES-I (trend; -0.8 [-1.7;0.1] points), and HR-QoL (trend; +5.3 [-2.3;12.9] points). In contrast, walking fatigability indexes remained unaffected.

Conclusions: Outdoor walking exercise therapy elicited multiple beneficial effects in pwMS, especially evidenced by improvements in walking capacity and mental well-being. Background: ClinicalTrials.gov identifier NCT05415956.