Clinical trial NCT03581084
Conditions: Asthma
Sponsor: University of California, San Francisco
Start date: 2018-07-06; Completion date: 2018-10-06
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine the beneficial effect of n-acetylcysteine (NAC), an inhaled medication that breaks down mucus, on lung function. NAC is a medication approved by the US Food and Drug Administration (FDA) for the treatment of chronic diseases of the respiratory system, including asthma. With CT lung imaging, the investigators seek to identify a subgroup of patients with asthma with a 'mucus' profile. This is a single-arm study which means all participants will receive the same treatment.

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 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 single-arm study of participants 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.

Arms: arm 1: This study will look at the effects of a medication, called n-acetylcysteine or NAC, on lung function. NAC is already approved for use in people with chronic airway conditions, including asthma. However, it is not known who this medication works best in. We believe this medication will likely have the most benefit in people with asthma that have mucus in their airways or "mucus plugging." Initial study procedures will include lung function measurements, a low dose CT scan, a blood draw, and a sputum induction. The CT lung imaging will identify asthmatics with mucus plugs.
Interventions: intervention 1: N-acetylcysteine
Intervention descriptions: intervention 1: Research participants that meet the study inclusion criteria will be admitted to a medical-surgical ward in Moffitt-Long Hospital (UCSF Medical Center) for 6 days and 5 nights and treated with an inhaled mixture of NAC and albuterol four times per day spaced at 4 to 6 hours apart.

Protocol documents:
Prot_000.pdf: 
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JOHN V. FAHY, MD, MSC
Clinical Research Protocol
INPATIENT CLINICAL TRIAL OF NAC IN ASTHMA
NCT03581084 
Protocol Number:
17-24231
Version Date:
11/2/2018
Investigational Product:
n-acetylcysteine
Development Phase:
4
Sponsor:
John V. Fahy, MD, MSc
513 Parnassus Avenue, HSE 1307
San Francisco, CA 94143-0130
Funding Organization:
NIH
Principal Investigator:
Name: John V. Fahy, MD, MSc
Telephone: 415-476-9940
Fax: 415-476-5712
E-mail: John.Fahy@ucsf.edu
Medical Monitor:
Name: John V. Fahy, MD, MSc
Telephone: 415-476-9940
Fax: 415-476-5712
E-mail: John.Fahy@ucsf.edu


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Approval:
,  Professor
1/24/2018
PI or Sponsor Signature (Name and Title) 
Date


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This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time.  The information in this document 
may not be disclosed unless federal or state law or regulations require such disclosure.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.  


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PROTOCOL AGREEMENT
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and 
providing the Airway Clinical Research Center Quality Assurance Committee and the
UCSF Committee on Human Research with complete and timely information, as outlined 
in the protocol.  It is understood that all information pertaining to the study will be held 
strictly confidential and that this confidentiality requirement applies to all study staff at 
this site. Furthermore, on behalf of the study staff and myself, I agree to maintain the 
procedures required to carry out the study in accordance with accepted GCP principles 
and to abide by the terms of this protocol.
Protocol Number: 17-24231
Protocol Title:  Inpatient Clinical Trial of NAC in Asthma
Protocol Date:  01/24/2018
1/24/2018
Investigator Signature 
Date
John V. Fahy, Professor of Medicine
Print Name and Title
Site #
N/A
Site Name
University of California, San Francisco (UCSF)
Address
513 Parnassus Ave, HSE 1307
San Francisco, CA 94143-0130
Phone Number
415-476-9940


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Table of Contents
1
BACKGROUND..................................................................................................................10
1.1
Overview of Non-Clinical Studies..................................................................................................10
2
STUDY RATIONALE........................................................................................................11
2.1
Risk / Benefit Assessment ...............................................................................................................12
3
STUDY OBJECTIVES........................................................................................................12
3.1
Primary Objective................................................................................................................................12
3.2
Secondary Objectives.........................................................................................................................12
4
STUDY DESIGN.................................................................................................................12
4.1
Study Overview.....................................................................................................................................12
5
CRITERIA FOR EVALUATION ......................................................................................13
5.1
Primary Efficacy Endpoint...............................................................................................................13
5.2
Secondary Efficacy Endpoints........................................................................................................13
5.3
Safety Evaluations ...............................................................................................................................13
6
SUBJECT SELECTION......................................................................................................13
6.1
Study Population..................................................................................................................................13
6.2
Inclusion Criteria .................................................................................................................................13
6.3
Exclusion Criteria.................................................................................................................................14
7
CONCURRENT MEDICATIONS.....................................................................................14
7.1
Allowed Medications and Treatments........................................................................................14
7.2
Prohibited Medications and Treatments...................................................................................14
8
STUDY TREATMENTS....................................................................................................14
8.1
Method of Assigning Subjects to Treatment Groups............................................................14
8.2
Blinding....................................................................................................................................................15
8.3
Formulation of Test and Control Products...............................................................................15
8.4
Supply of Study Drug at the Site....................................................................................................15
8.5
Study Drug Accountability...............................................................................................................16
8.6
Measures of Treatment Compliance............................................................................................16
9
STUDY PROCEDURES AND GUIDELINES..................................................................16
9.1
Clinical Assessments...........................................................................................................................16
9.2
Clinical Laboratory Measurements..............................................................................................21
9.3
Research Laboratory Measurements ..........................................................................................22
10
EVALUATIONS BY VISIT ...........................................................................................22
10.1
Visit 1 (Day -14)....................................................................................................................................22
10.2
Visit 2 (Day -10)....................................................................................................................................22
10.3
Visit 2b (Day -7) **Optional.............................................................................................................22
10.4
Visit 3 (Day -5) ......................................................................................................................................23
10.5
Visit 4 (Day 1)........................................................................................................................................23
10.6
Visit 5 (Day 2)........................................................................................................................................23
10.7
Visit 6 (Day 3)........................................................................................................................................23
10.8
Visit 7 (Day 4)........................................................................................................................................24
10.9
Visit 8 (Day 5)........................................................................................................................................24
10.10
Visit 9 (Day 6)...................................................................................................................................24
10.11
Visit 10 (Day 48).............................................................................................................................24


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10.12
Visit 11 (Day 91).............................................................................................................................25
10.13
Early Withdrawal Visit (Before end of Visit 3)..................................................................25
10.14
Late Withdrawal Visit (After Visit 3 Completion) ............................................................25
11
ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION .....................25
11.1
Adverse Events .....................................................................................................................................25
11.2
Serious Adverse Experiences (SAE).............................................................................................27
11.3
Medical Monitoring.............................................................................................................................27
12
DISCONTINUATION AND REPLACEMENT OF SUBJECTS ................................27
12.1
Early Discontinuation of Study Drug...........................................................................................27
12.2
Withdrawal of Subjects from the Study .....................................................................................28
12.3
Replacement of Subjects...................................................................................................................28
13
PROTOCOL VIOLATIONS..........................................................................................28
14
DATA SAFETY MONITORING ..................................................................................29
15
STATISTICAL METHODS AND CONSIDERATIONS............................................29
15.1
Data Sets Analyzed..............................................................................................................................29
15.2
Demographic and Baseline Characteristics..............................................................................29
15.3
Analysis of Primary Endpoint.........................................................................................................29
15.4
Analysis of Secondary Endpoints..................................................................................................29
15.5
Interim Analysis ...................................................................................................................................29
15.6
Sample Size and Randomization ...................................................................................................29
16
DATA COLLECTION, RETENTION AND MONITORING.....................................30
16.1
Data Collection Instruments ...........................................................................................................30
16.2
Data Management Procedures.......................................................................................................30
16.3
Data Quality Control and Reporting ............................................................................................30
16.4
Archival of Data ....................................................................................................................................31
16.5
Availability and Retention of Investigational Records........................................................31
16.6
Monitoring ..............................................................................................................................................31
16.7
Subject Confidentiality ......................................................................................................................31
17
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS.................31
17.1
Protocol Amendments.......................................................................................................................32
17.2
Institutional Review Boards and Independent Ethics Committees...............................32
17.3
Informed Consent Form....................................................................................................................32
17.4
Publications............................................................................................................................................33
17.5
Investigator Responsibilities..........................................................................................................33


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LIST OF ABBREVIATIONS
AE
adverse event
CBC
complete blood count
CFR
Code of Federal Regulations
CRF
case report form
DMC
Data Monitoring Committee
DSMB
Data Safety Monitoring Board
FDA
Food and Drug Administration
FEF25%-75%
forced expiratory flow
FeNO
fractional exhaled nitric oxide
FEV1
forced expiratory volume over one second
FVC
forced vital capacity
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act of 1996
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IV
intravenous
mEq
milliequivalent
NAC
n-acetylcysteine
PEF
peak expiratory flow
PI
Principal Investigator
RV
residual volume
SAE
serious adverse experience
TLC
total lung capacity


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PROTOCOL SYNOPSIS
TITLE
Inpatient Clinical Trial of NAC in Asthma
SPONSOR
John V. Fahy, MD, MSc
FUNDING 
ORGANIZATION
Departmental funds, Division of Pulmonary and Critical Care
Medicine, Department of Medicine, UCSF
NUMBER OF SITES
1
RATIONALE
We show that airway mucus plugs are strongly associated with 
measures of airflow obstruction in chronic severe asthma, and this 
association provides the rationale for testing whether a mucolytic drug 
(n-acetylcysteine, “Mucomyst”) can decrease mucus plug scores and 
improve FEV1 values in patients with asthma.  It is perhaps surprising 
that inhaled NAC has not been tested in a clinical trial in asthma, but a 
significant reason has been the uncertainty outlined above for the role 
of mucus in chronic disease. Another factor has been that clinical 
trials of NAC in COPD and cystic fibrosis have not been consistently 
encouraging. However, these trials have not had a biomarker to select 
patients who might benefit and they have used orally administered 
NAC, which does not achieve detectable drug concentration in airway 
lining fluid6. Our proposal to test the efficacy of NAC in a specific 
patient subgroup identified by a biomarker (CT imaging) is timely and 
addresses a novel approach to asthma treatment.
STUDY DESIGN
This is a single arm, non-randomized interventional phase 4 study.
PRIMARY 
OBJECTIVE
The primary objective is to determine if inhaled NAC decreases 
mucus plugs and improves lung function in patients with asthma.
SECONDARY 
OBJECTIVES
The secondary objective is to determine the duration of benefit of 
inhaled NAC in asthma.
NUMBER OF 
SUBJECTS
30


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SUBJECT 
SELECTION
CRITERIA
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 ATS 
criteria
4.
Physiological evidence of airflow obstruction (FEV1 
bronchodilator reversibility of ≥ 12% or hyperreactivity to 
methacholine reflected by a methacholine 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
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.
Current participation in an investigational drug trial
5.
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
6.
Unwillingness to follow study procedures
7.
History of allergy or intolerance to study drug
8.
Any other criteria that places the subject at unnecessary risk 
according to the judgment of the Principal Investigator
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION
20% NAC (3 mL) and albuterol (.5 mL)
Product will be administered every 4-6 hours for 5 days during an 
inpatient stay at the hospital. Medication will be delivered by 
inhalation via nebulizer.  
CONTROL 
PRODUCT, DOSE 
No control product


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AND ROUTE OF 
ADMINISTRATION
DURATION OF 
SUBJECT 
PARTICIPATION AND 
DURATION OF STUDY
Subjects will be in the study for up to 91 days.
Screening:  up to 14 days
Treatment:  5 days (subjects to be admitted to the hospital)
Follow-up:  3 months
The total duration of the study is expected to be 24 months. Subject 
recruitment will happen on a rolling basis.
CONCOMMITANT 
MEDICATIONS
Prohibited: 
 
thiols and thiol derivatives

activated charcoal

inhaled insulin
EFFICACY 
EVALUATIONS
PRIMARY 
ENDPOINT
The primary endpoint is the FEV1.  Post-treatment FEV1 will be 
compared to pre-treatment baseline values.
SECONDARY 
ENDPOINTS
Secondary efficacy endpoints include:
 
CT mucus score

FVC

PEF (AM and PM)

Air trapping (RV/TLC ratio)

FeNO

Blood eosinophils
OTHER 
EVALUATIONS
SAFETY 
EVALUATIONS
Incidence of adverse events
PLANNED INTERIM 
ANALYSES 
No interim analysis is planned.
STATISTICS
Primary Analysis Plan
The primary analysis is a paired t-test analysis of the % change in 
FEV1 from the start to the end of the one week treatment period with 
four times daily NAC (Mucomyst-20). The secondary analysis will be 
to determine how the change in FEV1 relates to the change in CT 
mucus score.
Rationale for Number 
of Subjects
We propose a sample size of 30, which will provide us with the power 
to examine the effect of NAC in a subgroup of individuals with 
asthma who have CT evidence of intraluminal mucus and to identify 
the CT mucus score that performs best as a biomarker of treatment 
response to NAC. Participants will be enrolled if their CT mucus 
scores are ≥5.0. To calculate sample size for the one-week treatment 
period study, we used FEV1 measures from 219 adults with asthma 
published in Corren et al. NEJM, 20111. The authors found that the 
standard deviation for the change in FEV1 in liters from day 1 to day 


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7 was 19%. Using a standard deviation of 19 and a two-sided alpha of 
0.05, we calculate a sample size of 30 to have 80% power to detect a 
change in FEV1 of 10% (a reasonable effect size because early studies 
of Pulmozyme in CF reported a 10% increase in FEV1 at day 3 of 
treatment).7


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1
BACKGROUND
Mucus plugging of the airway is consistently found in fatal asthma2. Decades ago, Dunnill 
provided graphic descriptions in 20 cases of fatal asthma3 noting that "the cut surface of 
the lung showed a striking picture with numerous grey, glistening, mucous plugs scattered 
throughout the airway passages." He summarized that "pathologically, the outstanding 
feature of the asthmatic lung lies in the failure of clearance of the bronchial secretions." 
Others have confirmed these findings, and it is only a small minority of asthma deaths that 
are not associated with airway mucus impaction. 
In non-fatal or near-fatal asthma exacerbations, segmental collapse of lung lobes due to 
luminal occlusion is common. Lavage of these cases yields abnormal mucus plugs in the 
form of airway casts4. The combination of airway narrowing from concentric smooth 
muscle contraction with luminal obstruction by mucus marks asthma as uniquely 
dangerous among airway diseases in its propensity for sudden and sometimes fatal 
exacerbations. The role of mucus as a cause of airflow obstruction in acute severe asthma 
suggested to us that mucus plugs plays a role in the pathophysiology of airflow 
obstruction in chronic severe asthma as well. This role has been hard to prove, however, 
in large part because of difficulty in showing that mucus occludes the lumen in chronic 
severe disease. Lungs are available at autopsy to show mucus occlusion in fatal asthma, 
and it is notable that there is evidence of 
occlusion in asthmatics who die with 
asthma (rather than because of it)5. But 
the field has yet to be persuaded of a 
role for mucus in airway dysfunction in 
chronic forms of severe asthma.
1.1
Overview of Non-Clinical 
Studies
Against this background, the preliminary 
data we show in Figures 1 and 2 are very 
important, because we show how CT 
lung images can reveal mucus plugs in 
chronic severe asthma and how these 
plugs are associated with lower lung 
function. Specifically, we use CT 
imaging to uncover that a majority 
(58%) of asthmatics in the NHLBI 
Severe Asthma Research Program 
(SARP) have at least one lung segment 
with a mucus plug and 27% have more 
than four lung segments with mucus 
plugs. Notably, asthmatics with a high 
mucus score achieve a post albuterol 
FEV1 > 80% much less frequently than 
asthmatics who have a zero mucus score 
(Fig 3).
Figure 1: Intraluminal mucus in CT lung images 
of asthmatics. Mucus plugs in CT scan images 
(white arrows) were defined as complete occlusion 
of an airway lumen by mucus and were identified as 
tubular structures in longitudinal section with 
branching (A & B) or without branching (C) or as 
rounded opacities in cross-section (D). The latter 
were traced cephalad or caudad on adjacent slices to 
confirm their continuity with unoccluded bronchi 
(red arrow).


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Figure 2. A. The CT mucus segment score is usually 0 in health but many asthmatics enrolled in the 
NHLBI Severe Asthma Research Program have scores above 0 with some as high as 15-19. B. The 
frequency distribution of mucus score in asthma shows that 42% of patients have a score of 0 (zero 
mucus score); among the remaining 58% of asthmatics, the median mucus score was 3.5, and we 
classified score between 0.5 and 3.5 as “low” and above 4.0 as “high”.
Examined another way, we find that all asthmatics 
with an FEV1 < 60% after albuterol treatment have 
abnormal mucus scores, whereas the majority of 
asthmatics with an FEV1 >80% with albuterol 
treatment have zero or low mucus scores (Fig 3). 
These data clearly implicate mucus plugs in the 
pathogenesis of airflow obstruction in asthma. One 
reason why this role for mucus plugging has been 
underappreciated in chronic severe asthma is that 
mucus-related symptoms are both insensitive and non-
specific indicators of mucus. 
2
STUDY RATIONALE
We show that airway mucus plugs are strongly 
associated with measures of airflow obstruction in 
chronic severe asthma, and this association provides 
the rationale for testing whether a mucolytic drug (n-
acetylcysteine, “Mucomyst”) can decrease mucus plug scores and improve FEV1 values 
in patients with asthma.  It is perhaps surprising that inhaled NAC has not been tested in a 
clinical trial in asthma, but a significant reason has been the uncertainty outlined above for 
the role of mucus in chronic disease. Another factor has been that clinical trials of NAC in 
COPD and cystic fibrosis have not been consistently encouraging. However, these trials 
have not had a biomarker to select patients who might benefit and they have used orally 
administered NAC, which does not achieve detectable drug concentration in airway lining 
fluid6. Our proposal to test the efficacy of NAC in a specific patient subgroup identified 
Figure 3. Mucus scores in 
asthmatics with different FEV1 
values (post 6-8 puffs of albuterol). 
Note that all asthmatics with an 
FEV1 <60% have abnormal mucus 
scores.


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by a biomarker (CT imaging) is timely and addresses a novel approach to asthma 
treatment. 
2.1
Risk / Benefit Assessment
Risk:  Inhaled n-acetylcysteine (NAC) is approved for the treatment of mucus associated 
airway disease, including asthma. The main side effect from inhaled n-acetylcysteine 
(NAC) is bronchospasm. We find that co-administering NAC and albuterol effectively 
prevents excessive bronchoconstriction in asthmatic patients. Specifically, in ten 
asthmatics that were given doses of 20% NAC as high as 3 mL together with 3 mL of 
albuterol, the largest FEV1 decline was 6%. 
Benefit:  Mucus plugs cause airway obstruction and symptoms of dyspnea. The role of 
mucolytics in decreasing plugs and increasing FEV1 has not been well studied. Our 
preliminary data, utilizing CT imaging and a novel scoring system, can identify and target 
a subgroup of patients who may benefit from inhaled mucolytic treatment more so than 
the asthmatic population as a whole.
To minimize risk, study participants will be admitted to a medical-surgical ward in the 
hospital and given all treatments under the supervision of a registered nurse and the 
covering medical team. Our study team of experienced clinicians will be available as 
needed.
3
STUDY OBJECTIVES
3.1
Primary Objective
The primary objective is to determine if inhaled NAC decreases mucus plugs and 
improves lung function in patients with asthma. 
3.2
Secondary Objectives
The secondary objective is to determine the duration of benefit of inhaled NAC in asthma 
and identify characteristics of those subjects who benefit from mucolytic treatment. 
4
STUDY DESIGN
4.1
Study Overview
This is a single center, single arm, non-randomized trial in 30 patients with asthma who 
demonstrate mucus plugging on a screening CT lung scan. Following outpatient screening 
studies, each subject will be admitted for 6 days/5 nights and receive NAC mixed with 
albuterol by nebulizer four times daily. After the active treatment phase, the subjects will 
be followed for 3 additional months as outpatient to track changes in CT lung scans in the 
off treatment period. Total duration of participation will be four months. Total duration of 
the study is expected to be 2 years.


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5
CRITERIA FOR EVALUATION
5.1
Primary Efficacy Endpoint
FEV1 will be the primary endpoint because it is the most robust measure of airflow 
obstruction in asthma.  We will compare post-treatment FEV1 to pre-treatment baseline 
values.  
5.2
Secondary Efficacy Endpoints
Secondary efficacy endpoints will include:
-
CT mucus score
-
FVC
-
PEF (AM and PM)
-
Air trapping (RV/TLC ratio)
-
FeNO
-
Blood eosinophils 
5.3
Safety Evaluations
The most important safety evaluations will be those that monitor for evidence of NAC-
induced bronchoconstriction.  In this regard, our plan is to measure peak flow (PEF) 
before and after each treatment. 
6
SUBJECT SELECTION
6.1
Study Population
Subjects with a diagnosis of asthma who meet the inclusion and exclusion criteria will be 
eligible for participation in this study. 
6.2
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 ATS criteria
4.
Physiological evidence of airflow obstruction (FEV1 bronchodilator reversibility of ≥ 
12% or hyperreactivity to methacholine reflected by a methacholine 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


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9.
CT mucus score ≥ 5
6.3
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.
Current participation in an investigational drug trial
5.
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
6.
Unwillingness to follow study procedures
7.
History of allergy or intolerance to study drug
8.
Any other criteria that places the subject at unnecessary risk according to the 
judgment of the Principal Investigator 
7
CONCURRENT MEDICATIONS
All subjects should be maintained on the same medications throughout the entire study 
period, as medically feasible, with no introduction of new chronic therapies.
7.1
Allowed Medications and Treatments
Standard therapy for asthma is allowed except for treatments noted in the exclusion 
criteria described above and as noted in the prohibited medications section below.  
7.2
Prohibited Medications and Treatments
The following medications are prohibited during the study and administration will be 
considered a protocol violation.

Thiols and thiol derivatives

Activated charcoal

Inhaled insulin
8
STUDY TREATMENTS
8.1
Method of Assigning Subjects to Treatment Groups
There is one treatment group all subjects will be assigned to.


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8.2
Blinding
Due to the objectives of the study, the identity of test and control treatments will be 
known to investigators, research staff, and patients.  Study treatments will not be blinded.
8.3
Formulation of Test and Control Products
NAC (trade name: Mucomyst) is manufactured by American Regent. The active drug 
studied here is 20% NAC. It will be delivered via nebulizer. 
8.3.1
Formulation of Test Product
20% NAC is an existing formulation of Mucomyst (Mucomyst-20), manufactured by 
American Regent, for aerosol administration in the management of patients with chronic 
bronchopulmonary disease. 20% NAC is a colorless solution that requires no 
reconstitution.
Albuterol sulfate inhalation solution is an existing formulation of Proventil Nebules, 
manufactured by Nephron Pharmaceuticals Corporation for oral inhalation in the 
management of patients with bronchospasm. Albuterol sulfate inhalation solution is a 
clear, colorless solution.
Table 1: Formulation and Measured pH of 20% NAC and albuterol
20% NAC
Albuterol
Active Ingredient, mg/mL
Acetylcysteine
200mg/mL
Albuterol sulfate
0.83mg/mL
Other ingredient, mg/mL
Edetate disodium, sodium 
hydroxide, purified water
Water, sodium chloride, 
sulfuric acid
pH
7
3-5
8.3.2
Packaging and Labeling
The test product will be in its original packaging and is provided by the UCSF Pharmacy. 
It will be ordered as a medication through the patient’s electronic medical record (EMR). 
8.4
Supply of Study Drug at the Site
The UCSF Pharmacy will order the study drug and albuterol per the patient’s medication 
administration record (MAR). It will be located in the Pyxis MedStation on the medical-
surgical ward the patient is admitted on. 
8.4.1
Dosage/Dosage Regimen
During each treatment, participants will receive a mixture of 3 mL of study drug and .5 
mL of albuterol. It will be delivered via nebulizer. Subjects will take four treatments a 
day, spaced at approximately 4 - 6 hour intervals. The treatment period is five days. No 
adjustments will be made based on weight or age. 


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8.4.2
Dispensing
Study medication will be dispensed from the Pyxis MedStation by the floor nurse. 
8.4.3
Administration Instructions 
3 mL of study drug and .5 mL of albuterol sulfate should be carefully added to the 
nebulizer.  
8.4.4
Storage
Study drug supply will be maintained by the UCSF Pharmacy and will be supplied 
following hospital pharmacy regulations according to the stocking and storage of the 
Pyxis Medstation. 
Study drug should be stored by the study site pharmacy at controlled room temperature, 
15 to 30ºC (59 to 86ºF). If the temperature of study drug storage in the pharmacy exceeds 
or falls below this range, this should be reported to the Sponsor or designee and captured 
as a deviation. Subjects and study staff will be instructed to store the medication in 
original packaging at room temperature according to the instructions outlined on the Drug 
Administration Instructions until ready for administration.
8.5
Study Drug Accountability
An accurate and current accounting of the dispensing of study drug for each participant 
will be maintained on an ongoing basis by the study nurse or study site staff. The number 
of study drug dispensed will be recorded. The study monitor will verify these documents 
throughout the course of the study.
8.6
Measures of Treatment Compliance
Participants will be monitored by a nurse or study staff. The nurse administering the study 
treatment will record the date and time the study drug was administered as well as any 
adverse events on a study case report form. Study staff will verify these documents 
throughout the course of the study. 
9
STUDY PROCEDURES AND GUIDELINES
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1.
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject.
9.1
Clinical Assessments
9.1.1
Concomitant Medications
All concomitant medication and concurrent therapies will be documented at Visits 1-4 and 
at early termination when applicable. Dose, route, unit frequency of administration, and 
indication for administration and dates of medication will be captured.


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9.1.2
Medication Withholding 
Maximum bronchodilator reversibility will be used to establish eligibility at Visit 2 and 
post-bronchodilator reversibility will be assessed at Visits 3, 4, 9, 10, 11. Since some 
asthma medications can blunt the response to bronchodilators, we will ask that 
participants withhold these medications according to the guidance provided in Table 2. 
Table 2. Medication Withholding Parameters
Medication
Withholding Period
Leukotriene modifiers
24 hrs
Ultra-long-acting bronchodilators 
(indacaterol, tiotropium)
24 hrs
Long-acting beta-agonists
12 hrs
Theophylline
12 hrs
Short-acting anticholinergic
6 hrs
Short-acting beta-agonists
4 hrs
Participants will be evaluated at Visit 1, without any medication holds, to establish the 
safety of withholding asthma medications. If a study clinicians feels the participant is not 
clinically stable enough to withhold medications, they may shorten the guidance (with 
appropriate documentation on the Visit 1 CRF Physician Attestation section) or they may 
excuse the participant from some or all of the medication withholds. 
Participants are reminded of these medication holds by phone 24 hours prior to their 
medication withholding visits and instructed to resume all medications should symptoms 
develop in the period prior to the visit.
Associated risks of medication withholding include a worsening of asthma control or 
asthma exacerbation. To mitigate these risks, participants are given clear instructions to 
resume asthma medications if symptoms arise.
9.1.3
Food and Beverage Withholding 
Participants are asked to withhold eating for one hour prior to the sputum induction at visit 
3 since recently digested food can contaminate sputum samples. Participants are also 
asked to withhold caffeine and alcohol-containing products for 6 hours prior to all study 
visits as these substances can influence lung function values.
9.1.4
Demographics
Demographic information (date of birth, gender, race) will be recorded at Visit 1.
9.1.5
Medical History
Relevant medical history, including history of current disease, other pertinent respiratory 
history, and information regarding underlying diseases will be recorded at Visit 1.


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Associated risks include discomfort evoked with some of the questions asked. To 
minimize risk, participants will be informed that they can defer answering any questions 
that make them feel uncomfortable. 
9.1.6
Physical Examination
A complete physical examination will be performed by either the investigator or a study 
clinician at Visit 1.   Qualified staff (MD, NP, RN, and PA) may complete the abbreviated 
physical exam at all other visits.  New abnormal physical exam findings must be 
documented and will be followed by a physician or other qualified staff at the next 
scheduled visit.
9.1.7
Vital Signs
Body temperature, blood pressure, pulse and respirations will be performed after resting 
for 5 minutes at all study visits.
9.1.8
Oximetry
Oximetry will be measured on room air with the subject at rest at all study visits at the 
Airway Clinical Research Center.
9.1.9
Spirometry
Spirometry will be performed at all study visits and in accordance with the current 
American Thoracic Society recommendations for the performance and interpretation of 
tests. 
Associated risks include the following:

Likely (>10%): Shortness of breath or cough during the six-second-exhalation 

Less Likely (<5%): Wheezing and chest tightness

Rare but serious (<1%): Syncope
In an effort to minimize risk, participants will be seated during the procedure to reduce 
any injury should a participant become dizzy and fall. Study staff will have albuterol 
available to administer to participants who develop wheeze or shortness of breath 
following spirometry. 
9.1.10 Post-Bronchodilator / Maximum Reversibility
Spirometry will be repeated 15 minutes following the administration of four to eight puffs 
of albuterol to assess bronchodilator reversibility. Maximal bronchodilation will be 
performed at Visit 2. Post-bronchodilator reversibility will be performed at Visit 3, 4, 9, 
10, 11 and 12.
Associated risks include the following:

Likely (>10%): Transient tachycardia, tremor, feeling nervous, rhinitis, 
pharyngitis, and nausea 

Less Likely (<5%): Headache, cough, upper respiratory infection


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
Rare but serious (<1%): Chest pain, atrial fibrillation, hypertension, hypotension, 
diabetic ketoacidosis, hyperglycemia, hypersensitivity reactions, paradoxical 
bronchospasm
Given that the study population is made up of individuals with moderate-to-severe asthma, 
and that albuterol is a standard of care treatment for asthma, it is unlikely that participants 
will experience any of the side effects described above. However, if a potential participant 
describes previous sensitivity or side effects to treatment with albuterol, they will be 
excluded from participation for safety. Furthermore, albuterol will only be administered 
after a physician-administered history and physical, to ensure that it is okay for the 
participant to receive albuterol. 
9.1.11 Methacholine Challenge Testing
Methacholine challenge testing is performed to assess airway responsiveness. Only 
participants that are unable to achieve ≥ 12% improvement in FEV1% following 
administration of four to eight puffs of albuterol and who have a baseline FEV1 > 50% 
predicted will undergo methacholine challenge testing at Visit 2b. In the methacholine 
challenge test, increasing concentrations of methacholine are delivered until the FEV1 
falls by 20% or more compared to the reference (post-diluent baseline) level. When the 
provocative concentration that causes a 20% fall (PC20) is identified, the challenge is 
stopped. 
Associated risks include the following:

Likely (>10%): Shortness of breath 

Less Likely (<5%): Wheezing, chest tightness, or cough

Rare but serious (<1%): Rarely, patients may have severe bronchoconstriction 
during or following methacholine challenge
Additionally, methacholine has been shown to increase tone of the uterus, which could 
lead to preterm labor, in pregnancy laboratory animals; there are no human studies to 
verify this effect during pregnancy. However, because of this, methacholine has been 
placed in FDA Category C, meaning that exposure during pregnancy should be avoided. 
As such, pregnant women or women of reproductive age who are unwilling to practice 
pregnancy prevention strategies will be excluded from participation.
In an effort to minimize risk to participants, only those participants with a pre-diluent 
FEV1 of > 50% predicted and at least one liter will undergo the methacholine challenge 
testing, and only in the instance that they are not able to show 12% or greater 
improvement in FEV1 following bronchodilator administration. A study physician will be 
available during the challenge. Participants will not be discharged until their FEV1 is 
within 10% of their pre-diluent FEV1. Medications and personnel will be available to 
manage and treat bronchoconstriction.
9.1.12 Sputum Induction
A 12-minute sputum induction using nebulized 3% hypertonic saline will be performed at 
Visits 3 and 11. All participants will perform baseline spirometry after 4 or more puffs of 
albuterol administration prior to sputum induction. Peak flow measurements are done 


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every 2 minutes during the induced sputum collection to assess for excessive 
bronchoconstriction.
Associated risks include the following:

Likely (>10%): Salty after taste in the mouth, coughing, or a feeling of needing to 
swallow 

Less Likely (<5%): Sore throat, shortness of breath, wheezing, chest tightness, 
light-headedness, nausea, or headache, worsening of lung function

Rare but serious (<1%): Some patients have had a severe asthma attack or a 
reaction to the salty water that they breathe in
In an effort to minimize risk to participants, bronchodilator treatment will be available if 
sputum induction induces a worsening of asthma symptoms. The following safety 
procedures will be followed for the sputum induction procedure: only participants with a 
post-bronchodilator FEV1 of > 50% predicted will undergo sputum induction; a physician 
will be available during the induction; study staff will calculate and record the peak flow 
and FEV1 value that equals both a 10% and 20% fall in lung function based upon the 
recorded post-bronchodilator peak flow and FEV1 values; and participants will not be 
discharged until their FEV1 is within 10% of their post-bronchodilator FEV1. 
9.1.13 Point of Care Urine Pregnancy Test
A point of care urine pregnancy test will be obtained from female participants who are of 
childbearing potential prior to their participation in the study and routinely throughout 
their participation (see Appendix 1).
9.1.14 CT Imaging of the Thorax
A single inspiratory low dose CT scan of the thorax using a model based iterative 
reconstruction (MBIR) approach will be taken at the baseline eligibility visit (Visit 2) and 
following the treatment period over 3 months (Visit 9, 11 and 12). 
The risks associated with CT scanning are that of the additional amount of radiation 
exposure. The additional amount of radiation that each participant will receive as a result 
of participating in this study will be approximately 5 mSv, which is slightly greater than 
the yearly natural background of radiation in the US, which is 3 mSv. This amount of 
radiation may involve a low risk of cancer. A participant should not participate in this 
study if she is pregnant or breastfeeding. 
Additional risks are associated with the uncovering of abnormal findings. There is a risk 
of possible detection of an abnormality in the lung, which after testing or treatment, is 
found not to be disease causing. This includes possible misdiagnosis of lung cancer. Such 
findings may result in unnecessary anxiety for the participant, and increase his or her 
chance that an outpatient physician may believe that the abnormality is lung cancer and 
order further testing. This testing could include additional CT scans with additional 
radiation exposure, other types of scans to determine if the abnormalities are rapidly 
growing, a needle biopsy (taking a sample of the abnormality with a needle) or a lung 
biopsy, which requires surgery. Whether these additional studies would be performed 
would be a decision that the participant would make with his or her regular physician.


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In an effort to minimize risk to participants, scans will be read by radiologists that have 
expertise in interpreting findings of chest CTs. If there are any abnormalities, other than 
those that are usually found in asthmatic patients, observed by the clinical center 
radiologists, these would be reported to the principal investigator, who will in turn 
communicate these findings to the participant. The most likely abnormal result will be the 
identification of a spot on the lung that might be cancer.
9.1.15 Body Plethysmography 
Body plethysmography will be done to determine functional residual capacity (FRC), 
residual volume (RV), total lung capacity (TLC), and slow vital capacity (SVC) at Visit 3 
and 9. Plethysmography will be done with bronchodilation. If bronchodilation procedures 
are done, participants will follow the medication hold times as described in Section 9.1.2. 
In an effort to minimize risk to participants, patients with severe claustrophobia, inability 
to sit upright in a chamber, inability to perform the panting maneuver, inability to perform 
maximal inspiratory and expiratory efforts, and known perforated tympanic membrane 
without a snug-fitting earplug will be excluded from participation in the study.
9.1.16 Measurement of Fractionated Exhaled Nitric Oxide (FeNO)
Fractional exhaled nitric oxide measurement test will be performed at Visits 3-12. 
Subjects will inhale a full breath of air and then exhale it slowly through a mouthpiece 
while a device measures the concentration of nitric oxide in the air exhaled. Nitric oxide is 
a gas normally present in the air exhaled from the lungs.
9.1.17 Adverse Events
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation 
to study drug will be recorded on the case report form (CRF).
9.2
Clinical Laboratory Measurements 
9.2.1
Hematology
Blood will be obtained and sent to the clinical hematology lab for a complete blood count 
with 5-part differential (CBC-D) (hemoglobin, hematocrit, red blood cell count, white 
blood cell count, white blood cell differential, and platelet count) and serum IgE for 
assessment of systemic evidence for infection and inflammation. A CBC-D will be 
obtained at Visits 3, 9 and 11. A serum IgE will be obtained at Visit 3 only.
Risks associated with hematology include the following risks associated with 
venipuncture:

Lightheadedness or nausea while having blood drawn

Bruising at the site where the needle enters the skin and a remote risk of infection
In an effort to minimize risk to participants, aseptic technique will be used and pressure 
applied to site to prevent infection/bruising. Participants who have previously identified 


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that they experience lightheadedness during blood draws will have blood drawn while 
lying supine on an exam room table.
9.3
Research Laboratory Measurements 
9.3.1
Sputum Measurements
Sputum for determination of airway inflammation will be collected and processed. Airway 
inflammation measurements may include cell count and differential, cytokine gene 
expression measurements, and rheology.
10 EVALUATIONS BY VISIT
10.1 Visit 1 (Day -14)
1.
Review the study with the subject and obtain written informed consent and HIPAA 
authorization.
2.
Assign the subject a unique screening number.
3.
Record demographics data.
4.
Record medical history, including a history of asthma, diagnosis date, and asthma-
related healthcare utilization and exacerbation frequency.
5.
Record concomitant medications.
6.
Perform a complete physical examination.
7.
Perform and record vital signs.
8.
Perform and record oximetry.
9.
Perform and record urine pregnancy test.
10.
Perform and record spirometry.
11.
Schedule participant for Visit 2.
10.2 Visit 2 (Day -10)
1.
Record changes to concomitant medications.
2.
Perform and record vital signs.
3.
Perform and record oximetry.
4.
Perform and record urine pregnancy test.
5.
Perform and record spirometry.
6.
Perform and record maximum bronchodilator spirometry.
7.
Obtain a CT scan of the thorax.
8.
Schedule participant for Visit 3 if CT mucus plug sore is equal to or greater than 5.
10.3 Visit 2b (Day -7) **Optional
1.
Record changes to concomitant medications.
2.
Perform and record vital signs.
3.
Perform and record oximetry.
4.
Perform and record urine pregnancy test.
5.
Perform and record spirometry.
6.
Perform methacholine challenge testing.
7.
Obtain a CT scan of the thorax.
8.
Schedule participant for Visit 3 if CT mucus plug score is equal to or greater than 5.


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10.4 Visit 3 (Day -5)
1.
Record changes to concomitant medications.
2.
Perform and record vital signs.
3.
Perform and record oximetry.
4.
Perform and record urine pregnancy test.
5.
Perform and record fractional exhaled nitric oxide (FeNO) measurement.
6.
Perform and record spirometry.
7.
Collect blood sample for clinical laboratory tests.
8.
Perform and record plethysmography with bronchodilation.
9.
Collect induced sputum.
10.
Schedule participant for Visit 4.
10.5 Visit 4 (Day 1)
1.
Record changes to concomitant medications.
2.
Perform and record vital signs.
3.
Perform and record oximetry.
4.
Perform and record fractional exhaled nitric oxide (FeNO) measurement.
5.
Perform and record spirometry.
6.
Perform and record 3 peak flow AM measurements before first treatment of the day.
7.
Perform and record post-bronchodilator reversibility. 
8.
Admit patient to medical-surgical floor. 
9.
Administer study drug treatment three times over the course of the day, spaced 
every 4-6 hours. Peak flow measurements should be taken before and after each 
treatment.
10.
Perform and record 3 peak flow PM measurements after all treatments have been 
completed.
10.6 Visit 5 (Day 2)
1.
Perform and record fractional exhaled nitric oxide (FeNO) measurement.
2.
Perform and record spirometry.
3.
Perform and record 3 peak flow AM measurements before first treatment of the day.
4.
Administer study drug treatment four times over the course of the day, spaced every 
4-6 hours. Perform peak flow measurements before and after each treatment.
5.
Perform and record 3 peak flow PM measurements after all treatments have been 
completed.
10.7 Visit 6 (Day 3)
1.
Perform and record fractional exhaled nitric oxide (FeNO) measurement.
2.
Perform and record spirometry.
3.
Perform and record 3 peak flow AM measurements before first treatment of the day.
4.
Administer study drug treatment four times over the course of the day, spaced every 
4-6 hours. Perform peak flow measurements before and after each treatment.
5.
Perform and record 3 peak flow PM measurements after all treatments have been 
completed.


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10.8 Visit 7 (Day 4)
1.
Perform and record fractional exhaled nitric oxide (FeNO) measurement.
2.
Perform and record spirometry.
3.
Perform and record 3 peak flow AM measurements before first treatment of the day.
4.
Administer study drug treatment four times over the course of the day, spaced every 
4-6 hours. Perform peak flow measurements before and after each treatment.
5.
Perform and record 3 peak flow PM measurements after all treatments have been 
completed.
10.9 Visit 8 (Day 5)
1.
Perform and record fractional exhaled nitric oxide (FeNO) measurement.
2.
Perform and record spirometry.
3.
Perform and record 3 peak flow AM measurements before first treatment of the day.
4.
Administer study drug treatment four times over the course of the day, spaced every 
4-6 hours. Perform peak flow measurements before and after each treatment.
5.
Perform and record 3 peak flow PM measurements after all treatments have been 
completed.
10.10 Visit 9 (Day 6)
1.
Discharge patient from medical-surgical floor.
2.
Perform and record vital signs.
3.
Perform and record oximetry.
4.
Perform abbreviated physical exam.
5.
Perform and record urine pregnancy test.
6.
Perform and record fractional exhaled nitric oxide (FeNO) measurement.
7.
Perform and record spirometry.
8.
Perform and record post-bronchodilator reversibility. 
9.
Perform and record plethysmography with bronchodilation.
10.
Obtain a CT scan of the thorax.
11.
Collect blood sample for clinical laboratory tests
10.11 Visit 10 (Day 13)
1.     Perform and record vital signs.
2.     Perform and record oximetry.
3.     Perform and record fractional exhaled nitric oxide (FeNO) measurement.
4.     Perform and record spirometry.
5.     Perform and record post-bronchodilator reversibility. 
10.12 Visit 11 (Day 48)
1.
Perform and record vital signs.
2.
Perform and record oximetry.
3.
Perform and record urine pregnancy test.
4.
Perform and record fractional exhaled nitric oxide (FeNO) measurement.


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5.
Perform and record spirometry.
6.
Perform and record post-bronchodilator reversibility. 
7.
Obtain a CT scan of the thorax.
8.
Collect blood sample for clinical laboratory tests.
9.
Collect induced sputum.
10.13 Visit 12 (Day 91)
1.
Perform and record vital signs.
2.
Perform and record oximetry.
3.
Perform and record urine pregnancy test.
4.
Perform and record fractional exhaled nitric oxide (FeNO) measurement.
5.
Perform and record spirometry.
6.
Perform and record post-bronchodilator reversibility. 
7.
Obtain a CT scan of the thorax.
10.14 Early Withdrawal Visit (Before end of Visit 3)
1.
Record any adverse experiences.
2.
Record changes to concomitant medications.
3.
Perform and record vital signs.
4.
Perform and record oximetry. 
5.
Perform abbreviated physical examination.
6.
Perform and record spirometry.
10.15 Late Withdrawal Visit (After Visit 3 Completion)
1.
Record any adverse experiences.
2.
Record changes to concomitant medications.
3.
Perform and record vital signs.
4.
Perform and record oximetry. 
5.
Perform abbreviated physical examination.
6.
Perform and record fractional exhaled nitric oxide (FeNO) measurement.
7.
Perform and record spirometry.
8.
Perform and record post-bronchodilator reversibility.
9.
Collect blood sample for clinical laboratory tests.
10.
Obtain a CT scan of the thorax.
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION
11.1 Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment.  An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated 
with the administration of an investigational product, whether or not related to that 
investigational product.  An unexpected AE is one of a type not identified in nature, 


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severity, or frequency in the current Investigator’s Brochure or of greater severity or 
frequency than expected based on the information in the Investigator’s Brochure.
The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents.  
Adverse events will be recorded in the patient CRF.  Adverse events will be described by 
duration (start and stop dates and times), severity, outcome, treatment and relation to 
study drug, or if unrelated, the cause.
AE Severity
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 should be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant. The modified criteria can be 
found in the study manual.  If the experience is not covered in the modified criteria, the 
guidelines shown in Table 3 below should be used to grade severity.  It should be pointed 
out that the term “severe” is a measure of intensity and that a severe AE is not necessarily 
serious.
Table 3.  AE Severity Grading
Severity (Toxicity Grade)
Description
Mild (1)
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well.
Moderate (2)
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required.
Severe (3)
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible.
Life-threatening (4)
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe.
AE Relationship to Study Drug
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 4.
Table 4.  AE Relationship to Study Drug
Relationship
to Drug
Comment
Definitely
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis.
Probably
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions.


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Possibly
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors.
Unrelated
An event that can be determined with certainty to have no relationship to the study 
drug.
11.2 Serious Adverse Experiences (SAE)
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes:

death

a life-threatening adverse experience

inpatient hospitalization or prolongation of existing hospitalization

a persistent or significant disability/incapacity

a congenital anomaly/birth defect 
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to 
prevent one of the outcomes listed. 
11.2.1 Serious Adverse Experience Reporting
Study sites will document all SAEs that occur (whether or not related to study drug) per 
UCSF CHR Guidelines.  The collection period for all SAEs will begin after informed 
consent is obtained and end after procedures for the final study visit have been completed.
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report 
SAEs to the IRB/IEC.  
11.3 Medical Monitoring
John Fahy, MD, MSc should be contacted directly at these numbers to report medical 
concerns or questions regarding safety.
Phone: (415) 476-9940
Mobile: (415) 317-3259  
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS
12.1 Early Discontinuation of Study Drug 
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to continue.  
The following is a list of possible reasons for study treatment discontinuation: 
Subject withdrawal of consent
Subject is not compliant with study procedures
Adverse event that in the opinion of the investigator would be in the best interest 
of the subject to discontinue study treatment


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Protocol violation requiring discontinuation of study treatment
Lost to follow-up
Sponsor request for early termination of study
Positive pregnancy test (females)
If a subject is withdrawn from treatment due to an adverse event, the subject will be 
followed and treated by the Investigator until the abnormal parameter or symptom has 
resolved or stabilized.  
All subjects who discontinue study treatment should come in for an early discontinuation 
visit as soon as possible and then should be encouraged to complete all remaining 
scheduled visits and procedures.
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice.
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents. Refer to Section 10 for early termination procedures.
12.2 Withdrawal of Subjects from the Study
A subject may be withdrawn from the study at any time if the subject, the investigator, or 
the Sponsor feels that it is not in the subject’s best interest to continue.  
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice.
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents.  As noted above, subjects who discontinue study 
treatment early (i.e., they withdraw prior to Visit 8) should have an early discontinuation 
visit. Refer to Section 10 for early termination procedures.  Subjects who withdraw after 
Visit 8 but prior to Visit 11 should be encouraged to come in for a final visit (and the 
procedures to be followed would include those for their next scheduled visit).  
12.3 Replacement of Subjects
Subjects who withdraw from the study treatment will be replaced.  
Subjects who withdraw from the study will be replaced.  
13 PROTOCOL VIOLATIONS
A protocol violation occurs when the subject or investigator fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety and primary 
endpoint criteria.  Protocol violations for this study include, but are not limited to, the 
following:
Failure to meet inclusion/exclusion criteria
Use of a prohibited concomitant medication


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Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The Sponsor will determine if a protocol violation will result in 
withdrawal of a subject.
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a 
Sponsor representative and the Investigator. A copy of the form will be filed in the site’s 
regulatory binder and in the Sponsor’s files.
14 DATA SAFETY MONITORING
Adverse events will be monitored by the Clinical PIs (Drs. Fahy, Woodruff and Lazarus) 
in real-time. Safety and tolerability data will be summarized quarterly. Adverse event 
rates will be coded by body system and MedDra classification term.  Adverse events will 
be tabulated and will include the number of patients for whom the event occurred, the rate 
of occurrence, and the severity and relationship to study drug.  All AEs will be reviewed 
quarterly in the regularly scheduled quality assurance meetings of UCSF Airway Clinical 
Research Center, which is attended by Drs. Fahy, Woodruff, Lazarus and Boushey.
15 STATISTICAL METHODS AND CONSIDERATIONS
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will 
be written describing all analyses that will be performed.  The SAP will contain any 
modifications to the analysis plan described below.  
15.1 Data Sets Analyzed
All eligible patients who receive at least one dose of the study drug (the Safety 
Population) will be included in the safety analysis.
15.2 Demographic and Baseline Characteristics
The following demographic variables at screening will be summarized: race, gender, age, 
height, weight, baseline FEV1, and baseline post-bronchodilator FEV1.  
15.3 Analysis of Primary Endpoint
The primary analysis is a paired t-test analysis of the % change in FEV1 from the start to 
the end of the one week treatment period with four times daily NAC (Mucomyst-20). The 
secondary analysis will be to determine how the change in FEV1 relates to the change in 
CT mucus score.
15.4 Analysis of Secondary Endpoints
As a secondary analysis we will explore if NAC treatment decreases levels of NO in 
exhaled breath or the numbers of eosinophils in peripheral blood.
15.5 Interim Analysis
No interim analysis is planned.


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15.6 Sample Size and Randomization
We propose a sample size of 30, which will provide us with the power to examine the 
effect of NAC in a subgroup of individuals with asthma who have CT evidence of 
intraluminal mucus and to identify the CT mucus score that performs best as a biomarker 
of treatment response to NAC. Participants will be enrolled if their CT mucus scores are 
≥5.0. To calculate sample size for the one-week treatment period study, we used FEV1 
measures from 219 adults with asthma published in Corren et al. NEJM, 20111. The 
authors found that the standard deviation for the change in FEV1 in liters from day 1 to 
day 7 was 19%. Using a standard deviation of 19 and a two-sided alpha of 0.05, we 
calculate a sample size of 30 to have 80% power to detect a change in FEV1 of 10% (a 
reasonable effect size because early studies of Pulmozyme in CF reported a 10% increase 
in FEV1 at day 3 of treatment).7
16 DATA COLLECTION, RETENTION AND MONITORING
16.1 Data Collection Instruments
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject treated with the 
study drug.  
Study personnel at each site will enter data from source documents corresponding to a 
subject’s visit into the protocol-specific paper CRF when the information corresponding to 
that visit is available.  Subjects will not be identified by name in the study database or on 
any study documents to be collected by the Sponsor (or designee), but will be identified 
by a site number, subject number and initials. If a correction is made on a CRF, the study 
staff member will line through the incorrect data, write in the correct data and initial and 
date the change.
The Investigator is responsible for all information collected on subjects enrolled in this 
study.  All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the Investigator.  A copy of the CRF will remain at the 
Investigator’s site at the completion of the study.
16.2 Data Management Procedures
The data will be entered into a validated database.  The Data Management group will be 
responsible for data processing, in accordance with procedural documentation.  Database 
lock will occur once quality assurance procedures have been completed.
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials.
16.3 Data Quality Control and Reporting
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis. 
Query reports (Data Clarification Requests) pertaining to data omissions and 
discrepancies will be forwarded to the clinical research coordinators for resolution.  The 


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study database will be updated in accordance with the resolved queries.  All changes to 
the study database will be documented.
16.4 Archival of Data
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with 
any updates or changes to the database.  
At critical junctures of the protocol (e.g., production of interim reports and final reports), 
data for analysis is locked and cleaned per established procedures.
16.5 Availability and Retention of Investigational Records
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., 
FDA) inspectors upon request.  A file for each subject must be maintained that includes 
the signed Informed Consent, HIPAA Authorization and copies of all source 
documentation related to that subject.  The Investigator must ensure the reliability and 
availability of source documents from which the information on the CRF was derived.
All study documents (patient files, signed informed consent forms, copies of CRFs, Study 
File Notebook, etc.) must be kept secured for a period of two years following marketing of 
the investigational product.  There may be other circumstances for which the Sponsor is 
required to maintain study records and, therefore, the Sponsor should be contacted prior to 
removing study records for any reason.
16.6 Monitoring
Monitoring visits will be conducted by representatives of the Sponsor according to the 
U.S. CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6). By signing 
this protocol, the Investigator grants permission to the Sponsor (or designee), and 
appropriate regulatory authorities to conduct on-site monitoring and/or auditing of all 
appropriate study documentation.
16.7 Subject Confidentiality
In order to maintain subject confidentiality, only a site number, subject number and 
subject initials will identify all study subjects on CRFs and other documentation submitted 
to the Sponsor.  Additional subject confidentiality issues (if applicable) are covered in the 
Clinical Study Agreement.
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312).
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All participant 
interviews/visits are conducted in private testing rooms. Information about study 


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participants is kept in study binders in a locked storage closet, and in our password 
protected secure electronic file, and is only accessible to authorized study personnel. 
Clinical information will not be released without written permission of the subject, except 
as necessary for monitoring by the FDA.  The Investigator must also comply with all 
applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act 
of 1996, EU Data Protection Directive 95/46/EC).
17.1 Protocol Amendments
Any amendment to the protocol will be written by the Sponsor.  Protocol amendments 
cannot be implemented without prior written IRB/IEC approval except as necessary to 
eliminate immediate safety hazards to patients.  A protocol amendment intended to 
eliminate an apparent immediate hazard to patients may be implemented immediately, 
provided the IRBs are notified within five working days.
17.2 Institutional Review Boards and Independent Ethics Committees
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  Serious adverse experiences regardless of 
causality will be reported to the IRB/IEC in accordance with the standard operating 
procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC 
informed as to the progress of the study.  The Investigator will obtain assurance of 
IRB/IEC compliance with regulations.
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
patient recruitment, payment or compensation procedures, or other pertinent information) 
will be submitted to the IRB/IEC.  The IRB/IECs written unconditional approval of the 
study protocol and the informed consent form will be in the possession of the Investigator 
before the study is initiated.  The IRB/IECs unconditional approval statement will be 
transmitted by the Investigator to the Sponsor or designee prior to the shipment of study 
supplies to the site.  This approval must refer to the study by exact protocol title and 
number and should identify the documents reviewed and the date of review.
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB/IEC approval except when necessary to eliminate immediate hazards to 
the patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB/IEC and written verification that 
the modification was submitted and subsequently approved should be obtained.  
The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; 
an annual update and/or request for re-approval; and when the study has been completed.
17.3 Informed Consent Form 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 


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50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations.
The Investigator will prepare the informed consent form and HIPAA authorization for 
submission to the IRB/IEC.  The consent form generated by the Investigator must be 
acceptable and be approved by the IRB/IEC.  The written consent document will embody 
the elements of informed consent as described in the International Conference on 
Harmonisation and will also comply with local regulations. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written 
form and subjects must be given ample opportunity to inquire about details of the study. A 
copy of the signed consent form will be given to the subject and the original will be 
maintained with the subject’s records.
17.4 Publications 
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor and participating institutions.  The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the 
Health Insurance Portability and Accountability Act of 1996. 
17.5 Investigator Responsibilities
By signing the Agreement of Investigator form, the Investigator agrees to:
1.
Conduct the study in accordance with the protocol and only make changes after 
notifying the Sponsor (or designee), except when to protect the safety, rights or 
welfare of subjects.
2.
Personally conduct or supervise the study (or investigation).
3.
Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56.
4.
Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64.
5.
Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments.
6.
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with the Sponsor (or designee).
7.
Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study.
8.
Promptly report to the IRB and the Sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to subjects or others (to 
include amendments and IND safety reports).
9.
Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects.


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10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312.


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APPENDIX 1. SCHEDULE OF STUDY VISITS
VISIT
1
2
3
4
5
6
7
8
9
10
11
12
DAY
-14a
-10a
-5a
1
2
3
4
5
6
13
48a
91a
Consent and Eligibility
X
Physical Exam
X
Xb
Vital Signs & Oximetry
X
X
X
X
X
X
X
X
Urine Pregnancy Test 
X
X
X
X
X
X
X
FeNO
X
X
X
X
X
X
X
X
X
X
Spirometry
X
X
X
X
X
X
X
X
X
X
X
X
Post-Bronchodilator Reversibility
Xc
X
X
X
X
X
X
Blood Sample
Xd
X
X
Sputum Induction
X
X
CT Thorax
Xe
X
X
X
Plethysmography
X
X
Inpatient Stay
X
X
X
X
X
Administration of Study Drug
X
X
X
X
X
AM & PM Peak Flow Monitoring
X
X
X
X
X
Treatment Peak Flow Monitoring
X
X
X
X
X
a
  2 days
b
abbreviated physical exam
c
maximum reversibility
d
blood sample to include CBC with 5 part differential and serum IgE
e
CT mucus plug score ≥ 5 for eligibility


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Protocol Template © CFFT TDN   Effective: 12 SEP 2007
References
1. Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with
asthma. N Engl J Med. 2011;365(12):1088-1098.
2. Hays SR, Fahy JV. The role of mucus in fatal asthma. Am J Med. 2003;115(1):68-69.
3. Dunnill MS. The pathology of asthma, with special reference to changes in the
bronchial mucosa. J Clin Pathol. 1960;13:27-33.
4. Lang DM, Simon RA, Mathison DA, Timms RM, Stevenson DD. Safety and possible
efficacy of fiberoptic bronchoscopy with lavage in the management of refractory asthma
with mucous impaction. Ann Allergy. 1991;67(3):324-330.
5. Green FH, Williams DJ, James A, McPhee LJ, Mitchell I, Mauad T. Increased
myoepithelial cells of bronchial submucosal glands in fatal asthma. Thorax. 2010;65(1):32-
38.
6. Cotgreave IA, Eklund A, Larsson K, Moldeus PW. No penetration of orally administered
N-acetylcysteine into bronchoalveolar lavage fluid. Eur J Respir Dis. 1987;70(2):73-77.
7. McCoy K, Hamilton S, Johnson C. Effects of 12-week administration of dornase alfa in
patients with advanced cystic fibrosis lung disease. pulmozyme study group. Chest.
1996;110(4):889-895.

SAP_001.pdf: 
Protocol 17-24231 
Confidential 
 
Version 11/8/2018 
 
1 
JOHN V. FAHY, MD, MSC 
Clinical Research Protocol 
INPATIENT CLINICAL TRIAL OF NAC IN ASTHMA (ICON) 
Protocol Number: 
17-24231 
NCT Number 
NCT03581084 
Investigational Product: 
n-acetylcysteine 
Development Phase: 
4 
Sponsor: 
John V. Fahy, MD, MSc 
513 Parnassus Avenue, HSE 1307 
San Francisco, CA 94143-0130 
Funding Organization: 
NIH 
Principal Investigator: 
Name: John V. Fahy, MD, MSc 
 
Telephone: 415-476-9940 
 
Fax: 415-476-5712 
 
 
E-mail: John.Fahy@ucsf.edu  
 
STATISTICAL ANALYSIS PLAN 
 
Our overarching method (experimental approach) is to test the efficacy of inhaled NAC 
delivered for 5 days to asthma patients who have baseline evidence of mucus plugs on CT 
lung scans. We will assess if the NAC treatment causes the mucus plugs to go away by the 
end of the treatment period and we will assess for reappearance of mucus plugs at 6 weeks 
and 3 months time.  We will also examine whether any NAC associated decrease in 
mucus plugs is associated with improvement in FEV1. A primary analysis will be paired 
T-test analysis of the change in CT mucus plug score and in FEV1 from baseline to end 
treatment. Secondary analyses will look at the 6 week and 3 month time points.