Targeting fatigue in COPD with chronic respiratory failure undergoing pulmonary rehabilitation: a multicentre, randomised, placebo-controlled trial of L-arginine/liposomal vitamin C
In brief
L-arginine/vitamin C lowers fatigue score by one point in COPD rehab
In a double-blind trial of 98 oxygen-dependent COPD patients undergoing a 28-day pulmonary rehabilitation program, adding oral L-arginine and liposomal vitamin C reduced Fatigue Severity Scale scores by roughly one point compared with placebo, exceeding the minimal clinically important difference. The supplement did not improve walking distance, strength, dyspnea or quality-of-life measures, leaving its broader functional benefit uncertain.
- Journal
- Thorax (Q1)
- Published
- 18 September 2026
- Study design
- Randomized controlled trial
- Evidence level
- Level 1, High (CEBM 1b)
- Authors
- Mauro Maniscalco, Claudio Candia, Giuseppe Fiorentino, Luca Nicola Cesare Bianchi, Laura Fagetti, Sara Forlani, et al.
- PMID
- 42760127
- DOI
- 10.1136/thorax-2026-225106
Why clinicians should know about it
- Picked for Pulmonary and Respiratory Medicine (top studies of the week, 20 September 2026): L‑arginine/liposomal vitamin C reduces fatigue in COPD with CRF
Abstract
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.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.