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

Chronic Obstructive Pulmonary Disease (COPD) is a progressive inflammatory lung disease characterized by persistent airflow limitation and enhanced oxidative stress. Acute exacerbations of COPD (AECOPD) significantly increase morbidity, accelerate lung function decline, and worsen clinical outcomes. Oxidative stress plays a central role in AECOPD pathophysiology by amplifying inflammation through mediators such as IL-8 and TNF-α, leading to airway injury and impaired gas exchange.

Alpha Lipoic Acid (ALA) is a potent antioxidant and anti-inflammatory agent that scavenges reactive oxygen species, regenerates endogenous antioxidants, and modulates redox-sensitive inflammatory pathways. Although preclinical evidence supports its protective role in respiratory diseases, no randomized clinical trial has evaluated ALA in AECOPD or compared different dosing strategies.

Aim

This study aims to evaluate and compare the effects of low-dose (600 mg/day) versus high-dose (1200 mg/day) ALA on oxidative stress markers, inflammatory biomarkers, clinical recovery, pulmonary oxygenation, gas exchange, and safety in patients with AECOPD.

Methods

This is a prospective, double-blind, randomized controlled trial conducted in the ICU at El Matareya Teaching Hospital. Adult patients (40-70 years) with confirmed COPD and frequent exacerbations were randomized (1:1:1) into three groups:

Group A: Standard therapy + placebo

Group B: Standard therapy + 600 mg/day oral ALA

Group C: Standard therapy + 1200 mg/day oral ALA

All patients received guideline-based AECOPD management according to GOLD recommendations, including bronchodilators, systemic corticosteroids, antibiotics (when indicated), oxygen therapy, and ventilatory support as needed.

Assessments

Baseline and Day 10 evaluations included:

Primary Outcomes:

Oxidative stress marker: Malondialdehyde (MDA)

Inflammatory markers: Interleukin-8 (IL-8) and C-reactive protein (CRP)

Secondary Outcomes:

Time to clinical stability

ICU and hospital length of stay

Need for non-invasive or invasive ventilation

Early relapse (14 days) and 30-day readmission

Gas Exchange: ABGs (pH, PaO₂, PaCO₂, P/F ratio)

Patient-Reported Outcomes: COPD Assessment Test (CAT) and mMRC dyspnea scale

Safety: Monitoring for adverse effects including gastrointestinal symptoms, hypoglycemia, dizziness, and hypersensitivity reactions.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Exacerbation Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Drug: Alpha Lipoic Acid 600 MG Oral Tablets; Drug: Alpha Lipoic Acid; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 75
• Phase: Phase 3

Contacts and Locations

Study Locations

• Egypt
  • Cairo, Egypt, 11856
    • Matareya Teaching Hospital
    • Contact: Amir Eskander Hanna, MD; Phone Number: +201227933624; Email: amireskanderhanna@gmail.com
    • Principal Investigator: Mariam Elsayed, Bachelor of Pharmacy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Low dose Alpha lipoic acid; Patients in this group will receive standard AECOPD therapy in addition to 600 mg of oral ALA per day for 10 days	Drug: Alpha Lipoic Acid 600 MG Oral Tablets; Alpha lipoic acid tablets 600 mg
Active Comparator: High dose Alpha lipoic acid; Patients in this group will receive standard AECOPD therapy in addition to 1200 mg of oral ALA per day for 10 days	Drug: Alpha Lipoic Acid; Alpha lipoic acid tablets 1200 mg
Placebo Comparator: Placebo; Patients in this group will receive standard therapy for AECOPD along with matching placebo capsules administered orally for 10 days.	Drug: Placebo; Patients in this group will receive standard therapy for AECOPD along with matching placebo capsules administered orally for 10 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oxidative Stress & Inflammatory Biomarkers	Malondialdehyde (MDA); Interleukin-8 (IL-8)	Measured at baseline (Day 0) and Day 10

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of hospital stay		From the date of randomization until hospital discharge, assessed during the index hospitalization for up to 30 days after randomization.
COPD Assessment Test (CAT) score	The COPD Assessment Test (CAT) is a simple, validated 8-item questionnaire used to assess the impact of Chronic Obstructive Pulmonary Disease on a patient's health status and daily life.	It will be assessed at baseline of the study and after 10 days
Clinical stability	Clinical stability: Defined as the time from initiation of the study intervention until the patient achieves clinical stability, characterized by meeting all of the following criteria and maintaining them for at least 24 consecutive hours: Resolution of fever: Temperature ≤ 37.5°C; Stable hemodynamics: Heart rate ≤ 100 beats/min and systolic blood pressure ≥ 90 mmHg; Stable respiratory status: Respiratory rate ≤ 24 breaths/min; Improved oxygenation: Oxygen saturation ≥ 90% on room air or stable supplemental oxygen (or baseline if known to be lower); No need for rescue medications beyond the scheduled regimen	From the date of randomization until the date clinical stability is first achieved and maintained for at least 24 consecutive hours, assessed daily during hospitalization for up to 10 days after randomization.

Collaborators and Investigators

• Sponsor: Ain Shams University

Study record dates

Study Major Dates

• Study Start (Estimated): February 28, 2026
• Primary Completion (Estimated): May 28, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: February 26, 2026
• First Submitted That Met QC Criteria: March 4, 2026
• First Posted (Actual): March 6, 2026

Study Record Updates

• Last Update Posted (Actual): March 30, 2026
• Last Update Submitted That Met QC Criteria: March 25, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: adjuvant therapy; Alpha lipoic acid; Acute exacerbations of COPD
• Additional Relevant MeSH Terms: Sulfur Compounds; Organic Chemicals; Fatty Acids; Lipids; Carboxylic Acids; Enzymes and Coenzymes; Coenzymes; Thiophenes; Thioctic Acid
• Other Study ID Numbers: HM000218

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No