Supplemental Material for: Digital rehabilitation using immersive Virtual Reality for Post-COVID fatigue: a double-blind randomized controlled trial

In this single-center, double-blind, parallel-group trial, German adults meeting WHO criteria for Post-COVID syndrome, with moderate-to-severe fatigue (Fatigue Severity Scale [FSS] ≥36) and no comorbidities better explaining fatigue were randomly assigned (1:1) to a supervised VR exercise therapy or to a supervised conventional exercise therapy. Both interventions comprised 12 sessions of 45min over 6 weeks. The primary endpoint was change in FSS from baseline to post-intervention, analyzed in the intention-to-treat population (DRKS00032059), follow-ups took place after 3 and 12 months post-treatment.</p><p dir="ltr">Results: Between March 2023, and May 2024, 100 participants were randomized (1:1) to a VR exercise group (VR-EG); or a conventional exercise group (Con-EG).

Fatigue severity improved in both groups (VR-EG –8•29; Con. EG –5•27), with no significant between-group difference (mean difference 3•03; 95% CI –1•02 to 7•06). Only the VR-EG exceeded the established minimal important difference (≥6•3 points).

Symptom worsening was less frequent with VR-EG than with Con-EG (9% vs 22%). Patient Global Impression of Change ratings favored VR-EG (overall improvement: 76•7% vs 56•5%). Improvements were sustained at 3 and 12 months.

Descriptively, women showed greater reductions in fatigue severity than men, especially in the VR-EG. Adverse events were mild and transient and most commonly included headaches, nausea, vertigo and musculosceletal pain.</p><p dir="ltr">Conclusion: Immersive VR exercise therapy did not significantly outperform an active comparator on the primary endpoint. However, the VR-EG reached the minimal important difference for fatigue at the group level, showed fewer cases of symptom worsening, and reported more favorable global improvement.

Considering the limited treatment options available for Post-COVID fatigue, these findings indicate a promising clinical signal warranting confirmation in larger, multicenter trials.</p>