Electrophilic Fatty Acid Derivatives in Asthma (EFADA)

Asthma is an inflammatory disease, which means it causes swelling in the lungs to cause shortness of breath and/or wheezing. There are several asthma medications that help to reduce this problem.

The objective of this research study is to characterize the presence of electrophilic fatty acids in the bronchial airway of subjects with controlled asthma at baseline and after treatment with Aspirin, Indomethacin, or no treatment at all. The presence of electrophilic fatty acids may indicate inflammation. Aspirin and Indomethacin are known to respectively increase and inhibit the formation of electrophilic fatty acids. By gaining a better understanding of how electrophilic fatty acids work and how they respond to different treatment, researchers hope to be able to find better ways to lessen airway inflammation in asthma in the future.

Study Overview

• Status: Completed
• Conditions: Asthma; Electrophilic Fatty Acids
• Intervention / Treatment: Drug: Aspirin; Drug: Indomethacin

Detailed Description

Relevant to asthma, the chemical identities and potent anti-inflammatory signaling actions of endogenously-produced Electrophilic Fatty acid OXidation products (EFOXs) have recently been described. Endogenous EFOXs include nitro and alpha and beta-unsaturated ketone derivatives of unsaturated fatty acids that are generated as byproducts of a) fatty acid oxidation and nitration by inflammatory-derived reactive species and b) enzymatic fatty acid oxygenation reactions catalyzed by cyclooxygenase-2 and lipoxygenases. Recent data reveal that multiple salutary post-translational protein modifications are induced by EFOXs. Specifically, the covalent adduction of functionally-significant thiols in signaling proteins occurs, with these reactions modulating critical inflammatory signaling pathways. These signaling proteins include the nuclear lipid receptor PPARg and the redox-sensitive transcription factors NF kappaB and Keap1/Nrf2. This proposed research investigates the concept that the reversible reaction of EFOXs with critical transcription factors results in the regulation of adaptive responses to inflammation.

In this clinical study, bronchoalveolar lavage fluid (BAL) will be obtained from asthmatics treated with COX-2 inhibitors that enhance (aspirin) and inhibit (indomethacin) COX-2 dependent EFOX generation, as well as from those assigned to no intervention. BAL will be obtained from healthy, non-smoking adults with controlled asthma having at least a 12% increase in FEV1 after short-acting bronchodilator treatment or a positive methacholine response (reduction in FEV1 ≥ 20% at or before 16 mg/ml). A total of 30 asthmatic subjects will be randomized (10 per arm) to a) aspirin, b) indomethacin or c) no intervention groups

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of mild to moderate asthma
• No evidence of a previous asthma exacerbation in the preceding 6 weeks (defined as increased severity of respiratory symptoms requiring systemic steroids or escalation of therapy; b) asthma control questionnaire (ACQ) score less than 1.

Exclusion Criteria:

• Diagnosis of severe asthma, vocal cord dysfunction, cystic fibrosis, COPD, CAD, hypertension, diabetes or renal failure that is not well controlled
• Greater than 10 pack-year history of smoking;
• Stopped smoking less than 1 year prior to study,
• Taking any aspirin or other NSAIDS on the week prior to bronchoscopy,
• Taking omega-3 fatty acid supplements
• If a subject is currently taking an omega-3 fatty acid supplement and is interested in the study, after a 30 day wash out, the participant can be re-screened and evaluated for participation.
• Taking pioglitazone or rosiglitazone (synthetic thiazolidinedione PPARg ligands);
• other known pulmonary diseases;
• Inability to undergo bronchoscopy,
• Contraindications or allergy to aspirin or indomethacin,
• Asthmatics with known hypersensitivity to aspirin, and
• Steroid (systemic) dependent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control
Active Comparator: Aspirin	Drug: Aspirin; 500 mg/8 h for 5 days
Active Comparator: Indomethacin	Drug: Indomethacin; 25 mg/8 h for 5 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Airway concentration of electrophilic fatty acids	Patients undergo a baseline bronchoscopy, afterwhich they are randomized to 5 days of a)indomethacin, b) aspirin, c) nothing . After treatment, another bronchoscopy is done. Outcomes are determined after each bronchoscopy	Change in the bronchoalveolar lavage concentration of electrophilic fatty acids from the first to the second bronchoscopy

Collaborators and Investigators

• Sponsor: Sally E. Wenzel MD
• Investigators: Principal Investigator: Fernando Holguin, MD MPH, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start: October 1, 2011
• Primary Completion (Actual): September 1, 2016
• Study Completion (Actual): June 1, 2017

Study Registration Dates

• First Submitted: November 15, 2012
• First Submitted That Met QC Criteria: November 26, 2012
• First Posted (Estimate): November 27, 2012

Study Record Updates

• Last Update Posted (Actual): July 11, 2017
• Last Update Submitted That Met QC Criteria: July 5, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: Inflammation; Asthma; Electrophilic Fatty Acids
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Reproductive Control Agents; Gout Suppressants; Tocolytic Agents; Aspirin; Indomethacin
• Other Study ID Numbers: U10HL098177 (U.S. NIH Grant/Contract)