Asthma
Conditions
Brief summary
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.
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.
Interventions
COMBINATION_PRODUCTn-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).
COMBINATION_PRODUCT0.9% 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).
Sponsors
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Mean Forced Expiratory Volume in One Second (FEV1) Liters at 2 Weeks | Baseline and 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. |
| Percent Change From Baseline in Mean Forced Expiratory Volume in One Second (FEV1) Percent Predicted at 2 Weeks | Baseline and 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mucus Plug Segment Score | 2 Weeks | 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. |
| Percent Change From Baseline in Mean Forced Vital Capacity (FVC) Liters at 2 Weeks | 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. |
| Percent Change From Baseline in Mean Forced Vital Capacity (FVC) Percent Predicted at 2 Weeks | 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. |
| Air Trapping | 2 Weeks | 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. |
| Fractional Exhaled Nitric Oxide Level (FeNO) | 2 Weeks | 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. |
| Absolute Eosinophil Count | 2 Weeks | Absolute eosinophil count is measured through blood tests. The absolute change in absolute eosinophil count at 2 weeks was calculated. |
| Percent Change From Baseline in Mean Peak Expiratory Flow (PEF) Liters/Second (L/s) at 2 Weeks | 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. |
| Percent Change From Baseline in Mean Peak Expiratory Flow (PEF) Percent Predicted at 2 Weeks | 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJohn Fahy, M.D, M.Sc.
University of California, San Francisco
Participant flow
Recruitment details
28 participants were screened for eligibility between February 2019 and March 2020 at the University of California, San Francisco (UCSF) Airway Clinical Research Center in San Francisco, California.
Pre-assignment details
4 of 28 participants were randomized. Of those not randomized, 22 did not meet inclusion criteria and 2 declined to participate.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Forced Expiratory Volume in One Second (FEV1) Measurement | 1.59 Liters STANDARD_DEVIATION 0.54 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment United States | 4 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 4 |
| other Total, other adverse events | 2 / 4 | 0 / 4 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 |
Outcome results
None listed