The Effect of NAC on Lung Function and CT Mucus Score (ENACT)

This study evaluates 20% n-acetylcysteine (NAC) in the treatment of moderate-to-severe asthma that is complicated by mucus in the airway, as determined by CT imaging. The study is a crossover design, which means that half the study participants will get 20% NAC in the first 14-day treatment period and placebo in the next 14-day treatment period; and the other half will get placebo in the first 14-day treatment period and 20% NAC in the next 14-day treatment period.

Study Overview

• Status: Terminated
• Conditions: Asthma
• Intervention / Treatment: Combination product: n-acetylcystine + albuterol; Combination product: 0.9% saline + albuterol

Detailed Description

N-acetylcystine (NAC) is a mucolytic medication, meaning that it breaks apart mucus. Investigators know that mucus is a factor in severe asthma attacks. However, mucus may be a factor in chronic severe asthma as well. This role has been hard to prove because of difficulty in showing that mucus occludes the lumen in chronic severe disease. Using a novel approach of scoring mucus occlusion, investigators have used CT imaging to uncover that a majority of people with severe asthma have at least one lung segment with a mucus plug and 27% have more than four lung segments with mucus plugs.

Historically, studies of mucolytics, like NAC, have not shown benefit in other obstructive lung diseases, like Chronic Obstructive Pulmonary Disease (COPD). However, utilizing CT mucus scores as a biomarker, investigators believe that mucolytic treatment may prove useful for those with significant mucus impaction.

This is a randomized, double-blind, placebo-controlled phase 4 study of 20% NAC in patients with asthma who also have evidence of mucus in their lungs as determined by CT imaging. Investigators hypothesize that by treating asthmatics, chosen based on the presence of mucus in the airways, with a mucolytic like NAC, will result in an improvement of lung function.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • UCSF Airway Clinical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female between the ages of 18 and 80 years of age at Visit 1
2. Written informed consent obtained from subject and ability for subject to comply with the requirements of the study.
3. Able to perform reproducible spirometry according to American Thoracic Society (ATS) criteria
4. Physiological evidence of airflow obstruction (FEV1 bronchodilator reversibility of ≥ 12% or hyperreactivity to methacholine reflected by a methacholine provocative concentration that results in a 20% fall in FEV1(PC20) ≤ 16 mg/mL)
5. Clinical history of asthma per patient report or medical record
6. Pre-bronchodilator FEV1 > 35% predicted
7. Post-bronchodilator FEV1 > 40% but < 90% predicted
8. Asthma requiring treatment with inhaled corticosteroids (ICS) for 3 months or greater
9. CT mucus score ≥ 5
10. Ability to tolerate study drug reflected by a post-treatment FEV1 ≥ 80% of pre- treatment, pre-bronchodilator FEV1

Exclusion Criteria:

1. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study
2. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data
3. Smoking of tobacco or other recreational inhalants in last year and/or >10 pack-year smoking history
4. Adherence to study drug ≤ 70% after first treatment period
5. Current participation in an investigational drug trial
6. Other chronic pulmonary disorders, including (but not limited to) cystic fibrosis, chronic obstructive pulmonary disease, chronic bronchitis, vocal cord dysfunction (that is the sole cause of respiratory symptoms and at the PI's discretion), severe scoliosis or chest wall deformities that affect lung function, or congenital disorders of the lungs or airways
7. Unwillingness to follow study procedures
8. History of allergy or intolerance to study drug
9. Any other criteria that places the subject at unnecessary risk according to the judgment of the Principal Investigator

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 20% n-acetylcystine (NAC); Participants will self-administer nebulized 20% NAC (3 mL) and 2.5 mg albuterol inhalation solution (0.5 mL) 3 times per day for 14 days.	Combination product: n-acetylcystine + albuterol; NAC (trade name: Mucomyst) is a mucolytic drug manufactured by American Regent. The active drug studied here is 20% NAC (3 mL) and 2.5 mg albuterol bronchodilator inhalation solution (0.5 mL).; Other Names: NAC; Mucomyst; n-acetylcystine
Placebo Comparator: 0.9% saline; Participants will self-administer nebulized 0.9% saline (3 mL) and 2.5 mg albuterol inhalation solution (0.5 mL) 3 times per day for 14 days.	Combination product: 0.9% saline + albuterol; The placebo comparator in this study is 0.9% normal saline (3 mL) and 2.5 mg albuterol inhalation solution (0.5 mL).; Other Names: Normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Mean Forced Expiratory Volume in One Second (FEV1) Liters at 2 Weeks	FEV1 Liters was assessed with participants in a seated position. FEV1 Liters was measured with a PC-based spirometer until at least 3 acceptable and 2 repeatable maneuvers were captured. The highest maneuver was recorded. The percent change in mean FEV1 Liters from baseline to 2 weeks after treatment was calculated.	Baseline and 2 Weeks
Percent Change From Baseline in Mean Forced Expiratory Volume in One Second (FEV1) Percent Predicted at 2 Weeks	FEV1 percent predicted was assessed with participants in a seated position. FEV1 percent predicted was measured with a PC-based spirometer until at least 3 acceptable and 2 repeatable maneuvers were captured. The highest maneuver was recorded. The percent change in mean FEV1 percent predicted from baseline to 2 weeks after treatment was calculated.	Baseline and 2 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mucus Plug Segment Score	Participants completed a chest computed tomography (CT) scan at the start and end of each 2-week treatment period. Two radiologists independently reviewed each CT scan to determine the number of mucus-plugged bronchopulmonary segments present in the scan, ranging from 0 to 20. A higher number of mucus-plugged bronchopulmonary segments indicates a greater number of mucus plugs. The absolute change in mucus-plugged segments at 2 weeks was reported.	2 Weeks
Percent Change From Baseline in Mean Forced Vital Capacity (FVC) Liters at 2 Weeks	FVC Liters was assessed with participants in a seated position. FVC Liters was measured with a PC-based spirometer until at least 3 acceptable and 2 repeatable maneuvers were captured. The highest maneuver was recorded. The percent change in mean FVC Liters from baseline to 2 weeks after treatment was calculated.	2 Weeks
Percent Change From Baseline in Mean Forced Vital Capacity (FVC) Percent Predicted at 2 Weeks	FVC percent predicted was assessed with participants in a seated position. FVC percent predicted was measured with a PC-based spirometer until at least 3 acceptable and 2 repeatable maneuvers were captured. The highest maneuver was recorded. The percent change in mean FVC percent predicted from baseline to 2 weeks after treatment was calculated.	2 Weeks
Air Trapping	Air trapping is measured as the ratio of residual volume (RV) to total lung capacity (TLC). The absolute change in air trapping at 2 weeks was calculated. The RV and TLC are measured through body plethysmography.	2 Weeks
Fractional Exhaled Nitric Oxide Level (FeNO)	FeNO is measured as the concentration of nitric oxide in the air exhaled by each participant into an inhaled nitric oxide machine. The absolute change in FeNO levels at 2 weeks was calculated.	2 Weeks
Absolute Eosinophil Count	Absolute eosinophil count is measured through blood tests. The absolute change in absolute eosinophil count at 2 weeks was calculated.	2 Weeks
Percent Change From Baseline in Mean Peak Expiratory Flow (PEF) Liters/Second (L/s) at 2 Weeks	PEF Liters/second was assessed with participants in a seated position. PEF L/s was measured with a PC-based spirometer until at least 3 acceptable and 2 repeatable maneuvers were captured. The highest maneuver was recorded. The percent change in mean PEF L/s from baseline to 2 weeks after treatment was calculated.	2 Weeks
Percent Change From Baseline in Mean Peak Expiratory Flow (PEF) Percent Predicted at 2 Weeks	PEF percent predicted was assessed with participants in a seated position. PEF percent predicted was measured with a PC-based spirometer until at least 3 acceptable and 2 repeatable maneuvers were captured. The highest maneuver was recorded. The percent change in mean PEF percent predicted from baseline to 2 weeks after treatment was calculated.	2 Weeks

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Investigators: Principal Investigator: John Fahy, M.D, M.Sc., University of California, San Francisco

Publications and helpful links

General Publications

• Hays SR, Fahy JV. The role of mucus in fatal asthma. Am J Med. 2003 Jul;115(1):68-9. doi: 10.1016/s0002-9343(03)00260-2. No abstract available.
• DUNNILL MS. The pathology of asthma, with special reference to changes in the bronchial mucosa. J Clin Pathol. 1960 Jan;13(1):27-33. doi: 10.1136/jcp.13.1.27.

Study record dates

Study Major Dates

• Study Start (Actual): February 20, 2019
• Primary Completion (Actual): February 21, 2025
• Study Completion (Actual): February 21, 2025

Study Registration Dates

• First Submitted: December 14, 2018
• First Submitted That Met QC Criteria: January 28, 2019
• First Posted (Actual): January 30, 2019

Study Record Updates

• Last Update Posted (Actual): June 11, 2026
• Last Update Submitted That Met QC Criteria: May 15, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Asthma; Amino Acids, Peptides, and Proteins; Sulfur Compounds; Organic Chemicals; Pharmaceutical Preparations; Amines; Inorganic Chemicals; Chlorine Compounds; Amino Acids; Crystalloid Solutions; Isotonic Solutions; Solutions; Alcohols; Amino Alcohols; Ethanolamines; Phenethylamines; Ethylamines; Cysteine; Amino Acids, Sulfur; Sodium Compounds; Chlorides; Hydrochloric Acid; Acetylcysteine; N-monoacetylcystine; Albuterol; Saline Solution; Sodium Chloride
• Other Study ID Numbers: 18-26680

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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No