Effect of Low-Dose Versus High-Dose Alpha-Lipoic Acid on Oxidative Stress, Inflammation, and Clinical Outcomes in Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Acute exacerbations of chronic obstructive pulmonary disease (COPD) are characterized by an acute intensification of airway inflammation and oxidative stress, resulting in worsening airflow limitation, impaired gas exchange, and increased risk of morbidity and healthcare utilization. Oxidative stress is a key contributor to exacerbation pathophysiology, driven by excess generation of reactive oxygen species, depletion of endogenous antioxidant defenses, activation of redox-sensitive transcription pathways, and upregulation of pro-inflammatory mediators. These processes promote neutrophilic airway inflammation, epithelial damage, mucus hypersecretion, and decline in pulmonary function.

Alpha-lipoic acid (ALA) is an endogenous mitochondrial cofactor with established antioxidant and anti-inflammatory properties. It functions through redox cycling, direct scavenging of reactive oxygen species, regeneration of intracellular antioxidants (including glutathione), and modulation of redox-sensitive signaling pathways involved in inflammation. Although preclinical studies have demonstrated protective effects of ALA in models of oxidative lung injury, its clinical role in acute exacerbations of COPD has not been established.

This study is a prospective, randomized, double-blind, placebo-controlled, parallel-group clinical trial evaluating the adjunctive use of ALA in patients hospitalized with acute exacerbations of COPD. Participants will be randomized in a 1:1:1 ratio to receive placebo, ALA 600 mg/day, or ALA 1200 mg/day for 10 days, in addition to standard-of-care therapy in accordance with current guideline-based management. The intervention period aligns with the typical duration of acute-phase pharmacologic treatment and is intended to capture early biochemical and clinical responses.

The trial is designed to assess potential dose-response effects by comparing two dosing regimens of ALA against placebo under standardized treatment conditions. Randomization will be computer-generated with allocation concealment ensured through identical-appearing study medications to maintain blinding of participants, healthcare providers, and outcome assessors.

The primary objective is to evaluate the effect of adjunctive ALA on systemic oxidative stress and inflammatory biomarkers during the acute treatment period. Secondary objectives include assessment of clinical recovery parameters, respiratory function and gas exchange indices, symptom burden, healthcare utilization, and safety outcomes. Time to clinical stability will be evaluated using predefined objective physiological criteria.

Safety monitoring will include assessment of known potential adverse effects associated with ALA, including gastrointestinal symptoms, hypoglycemia, neurological manifestations, and hypersensitivity reactions. All adverse events will be recorded and evaluated for severity and causality.

The sample size has been calculated to detect clinically meaningful differences in oxidative stress markers between groups with 90% statistical power, accounting for multiple comparisons. Statistical analyses will be conducted using an intention-to-treat approach with appropriate adjustments for multiple testing.

This study aims to provide randomized clinical evidence on the efficacy and dose-dependent effects of alpha-lipoic acid as an adjunctive therapy in acute exacerbations of COPD, targeting the oxidative-inflammatory pathway to improve biochemical and clinical outcomes.

Inclusion criteria

• Confirmed diagnosis of COPD, supported by a previous spirometry report showing: Post-bronchodilator FEV₁/FVC < 0.70, consistent with GOLD criteria for persistent airflow limitation.

• History of frequent exacerbations, defined as two or more COPD exacerbations per year during the two years prior to enrollment.
• An exacerbation of COPD is an acute event characterized by increased dyspnea and/or cough and sputum that worsens within ≤14 days and often results in additional therapy, according to the most recent GOLD guidelines.

Exclusion criteria

• • Known allergy or intolerance to ALA.

• Cystic fibrosis or bronchiectasis.
• Patients with a history of asthma, pneumonia, interstitial lung disease, bronchiectasis, carcinoma of the bronchus, or other significant respiratory disease
• Active or recent infection with tuberculosis.
• Any other significant comorbid condition that could interfere with study participation or outcomes (e.g., severe liver or kidney disease, uncontrolled cardiovascular disease).