Targeting fatigue in COPD with chronic respiratory failure undergoing pulmonary rehabilitation: a multicentre, randomised, placebo-controlled trial of L-arginine/liposomal vitamin C

Background: Pulmonary rehabilitation (PR) is the cornerstone of non-pharmacological treatment for chronic obstructive pulmonary disease (COPD), yet fatigue often persists despite rehabilitation. We conducted a multicentre, randomised, double-blind, placebo-controlled trial to evaluate whether oral L-arginine plus liposomal vitamin C improves fatigue in patients with advanced COPD and chronic respiratory failure (CRF) undergoing PR. Methods: Consecutive patients with stable COPD and CRF receiving long-term oxygen therapy were randomised to L-arginine/liposomal vitamin C or placebo during a standardised 28-day PR programme. Fatigue was assessed using the Fatigue Severity Scale (FSS). The primary analysis used a longitudinal linear mixed-effects model including repeated FSS measurements, treatment group, time, treatment-by-time interaction and prespecified covariates. Secondary outcomes included 6 min walk distance, sit-to-stand test, handgrip strength, COPD Assessment Test and modified Medical Research Council dyspnoea score. Results: 98 participants were randomised. A significant difference was found in FSS changes between groups (mean difference -0.90; 95% CI -1.50 to -0.29; p=0.004), confirmed by the adjusted treatment-by-time interaction analysis (adjusted between-group difference -0.72; 95% CI -1.25 to -0.20; p=0.009). The point estimate exceeded the prespecified minimal clinically important difference (0.6 points). A higher proportion of participants achieved an FSS score <4 in the intervention group versus placebo group (57% vs 36%; p=0.059). No significant between-group differences were observed for secondary outcomes. Conclusions: In patients with COPD and CRF undergoing PR, adjunctive oral L-arginine plus liposomal vitamin C was associated with a greater reduction in perceived fatigue, without significant improvements in functional or patient-reported secondary outcomes. Trial registration number: NCT06439875.