Clinical Trial of NAC in Asthma
Phase: PHASE4
Conditions: Asthma
Sponsor: University of California, San Francisco

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JOHN V. FAHY, MD, MSC
Clinical Research Protocol
CLINICAL TRIAL OF NAC IN ASTHMA
Protocol Number:
15-17919
Version Date:
8/5/2016
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:
Stulbarg Endowed Chair and the Sandler Asthma Basic 
Research Center discretionary funds
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
Approval:
, Professor
11/11/2015
PI or Sponsor Signature (Name and Title) 
Date
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 participants 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:  15-17919
Protocol Title: Clinical Trial of NAC in Asthma 
Protocol Date: 11/11/2015
11/11/2015
Investigator Signature 
Date
John V. Fahy, Professor of Medicine
Print Name and Title
Site #
N/A
Site Name
University of California, San Francisco
Address
513 Parnassus Avenue, HSE 1307
San Francisco, Ca 94143-0130
Phone Number
415-476-9940

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TABLE OF CONTENTS
1
BACKGROUND.........................................................................................................11
1.1
Overview of Clinical Studies............................................................................................11
1.2
Overview of Non-Clinical Studies ...................................................................................12
STUDY RATIONALE .......................................................................................................13
1.3
Risk / Benefit Assessment................................................................................................13
2
STUDY OBJECTIVES ..............................................................................................14
2.1
Primary Objective.............................................................................................................14
2.2
Secondary Objectives .......................................................................................................14
3
STUDY DESIGN ........................................................................................................14
3.1
Study Overview................................................................................................................14
4
CRITERIA FOR EVALUATION.............................................................................15
4.1
Primary Efficacy Endpoint...............................................................................................15
4.2
Secondary Efficacy Endpoints .........................................................................................15
4.3
Safety Evaluations............................................................................................................15
5
PARTICIPANT SELECTION..................................................................................15
5.1
Study Population ..............................................................................................................15
5.2
Inclusion Criteria..............................................................................................................16
5.3
Exclusion Criteria.............................................................................................................16
5.4
Allowed Medications and Treatments..............................................................................16
6
STUDY TREATMENTS............................................................................................17
6.1
Method of Assigning Participants to Treatment Groups..................................................17
6.2
Blinding............................................................................................................................17
6.3
Formulation of Test and Control Products .......................................................................17
6.3.1
Formulation of Test Product......................................................................................................17
6.3.2
Formulation of Control Product................................................................................................18
6.3.3
Packaging and Labeling ............................................................................................................18
6.4
Supply of Study Drug at the Site......................................................................................18
6.4.1
Dosage/Dosage Regimen...........................................................................................................18
6.4.2
Dispensing..................................................................................................................................18
6.4.3
Administration Instructions .......................................................................................................18
6.5
Supply of Study Drug at the Site......................................................................................19
6.5.1
Storage .......................................................................................................................................20
6.6
Study Drug Accountability...............................................................................................20
6.7
Measures of Treatment Compliance.................................................................................20
7
STUDY PROCEDURES AND GUIDELINES ........................................................20
7.1
Clinical Assessments........................................................................................................20
7.1.1
Concomitant Medications ..........................................................................................................20
7.1.2
Medication Withholding.............................................................................................................20
7.1.3
Food & Beverage Withholding ..................................................................................................21
7.1.4
Demographics............................................................................................................................21
7.1.5
Medical History .........................................................................................................................21
7.1.6
Physical Examination ................................................................................................................21

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7.1.7
Vital Signs ..................................................................................................................................22
7.1.8
Oximetry.....................................................................................................................................22
7.1.9
Spirometry..................................................................................................................................22
7.1.10
Post-Bronchodilator Reversibility ........................................................................................22
7.1.11
Sputum Induction ..................................................................................................................23
7.1.12
Point of Care Urine Pregnancy Test.....................................................................................23
7.1.13
CT Imaging of the Thorax.....................................................................................................23
7.1.14
Adverse Events ......................................................................................................................24
7.2
Clinical Laboratory Measurements ..................................................................................24
7.2.1
Hematology................................................................................................................................24
7.3
Research Laboratory Measurements ................................................................................25
7.3.1
Sputum Cell Count and Differential ..........................................................................................25
7.3.2
Sputum Cytokine Gene Expression Measurements....................................................................25
7.3.3
Sputum Rheology .......................................................................................................................25
8
EVALUATIONS BY VISIT ......................................................................................25
8.1
Visit 1 ...............................................................................................................................25
8.2
Visit 2a..............................................................................................................................25
8.2.1
Visit 2b **Optional.........................................................................................................25
8.3
Visit 3 (Day 0)..................................................................................................................26
8.4
Visit 4 (Day 5)..................................................................................................................26
8.5
Visit 5 (Day 14)................................................................................................................27
8.6
Visit 6 (Day 28)................................................................................................................27
8.7
Visit 7 (Day 42)................................................................................................................27
8.8
Visit 8 (Day 47)................................................................................................................28
8.9
Early Withdrawal Visit.....................................................................................................28
9
ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION...............28
9.1
Adverse Events.................................................................................................................28
9.2
Serious Adverse Experiences (SAE)................................................................................30
9.2.1
Serious Adverse Experience Reporting......................................................................................30
9.3
Medical Monitoring..........................................................................................................30
10
DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS ................30
10.1
Early Discontinuation of Study Drug...............................................................................30
12.3
Withdrawal of Participants from the Study......................................................................31
12.4
Replacement of Participants.............................................................................................31
11
PROTOCOL VIOLATIONS.....................................................................................31
12
DATA SAFETY MONITORING..............................................................................32
13
STATISTICAL METHODS AND CONSIDERATIONS.......................................32
13.1
Data Sets Analyzed...........................................................................................................32
13.2
Demographic and Baseline Characteristics......................................................................32
13.3
Analysis of Primary Endpoint ..........................................................................................32
13.4
Analysis of Secondary Endpoints.....................................................................................32
13.5
Interim Analysis ...............................................................................................................33
13.6
Sample Size and Randomization......................................................................................33
14
DATA COLLECTION, RETENTION AND MONITORING...............................33
14.1
Data Collection Instruments.............................................................................................33
14.2
Data Management Procedures..........................................................................................34

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14.3
Data Quality Control and Reporting.................................................................................34
14.4
Archival of Data ...............................................................................................................34
14.5
Availability and Retention of Investigational Records ....................................................34
14.6
Monitoring........................................................................................................................34
14.7
Participant Confidentiality................................................................................................35
15
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS..........35
15.1
Protocol Amendments ......................................................................................................35
15.2
Institutional Review Boards and Independent Ethics Committees ..................................35
15.3
Informed Consent Form ...................................................................................................36
15.4
Publications ......................................................................................................................36
15.5
Investigator Responsibilities ............................................................................................36

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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
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
NAC
n-acetylcystine 
PI
Principal Investigator
SAE
serious adverse experience

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PROTOCOL SYNOPSIS
TITLE
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
Mucus plugging of the airway is consistently found in fatal and near-
fatal asthma. The role of mucus as a cause of airflow obstruction in 
acute severe asthma suggests that mucus 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. Using a novel approach of scoring mucus occlusion, 
we have used CT imaging to uncover that a majority 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. 
Historically, studies of mucolytics, like n-acetylcystine (NAC), have 
not shown benefit in other obstructive lung diseases, like COPD. 
However, utilizing CT mucus scores as a biomarker, we believe that 
mucolytic treatment may prove useful for those with significant 
mucus impaction.
STUDY DESIGN
This is a randomized, double-blind, placebo-controlled phase 4 study.
PRIMARY 
OBJECTIVE
The primary objective is to assess the clinical efficacy as measured by 
the change in pulmonary function over the seven day treatment 
period.
SECONDARY 
OBJECTIVES
The secondary objectives are to assess the clinical efficacy as 
measured in a subgroup of participants by the change in CT mucus 
score from baseline to end of treatment, and identify characteristics of 
those participants who benefit from mucolytic treatment.
NUMBER OF 
PARTICIPANTS
30
PARTICIPANT 
SELECTION 
CRITERIA
Inclusion Criteria:
1.
Male or female between the ages of 18 and 70 years of age at 
Visit 0.
2.
Able to perform reproducible spirometry according to ATS 
criteria
3.
Clinical history consistent with moderate to severe asthma for 
1 year or greater. 

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4.
Post-bronchodilator FEV1 <90% of predicted
5.
Prescription and daily use of inhaled corticosteroid (ICS) 
equivalent to 80mcg of beclomethasone or greater
6.
CT mucus score >3 (determined during the initial screening 
process, provided the prior two conditions are met)
7.
Written informed consent obtained from participant and ability 
for participant to comply with the requirements of the study.
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.
History of intolerance to study medications.
4.
Current use of carbamazepine
5.
Angina which includes a treatment plan with PRN 
nitroglycerin or nitrites
6.
Smoking of tobacco or other recreational inhalants in last year 
and/or >10 pack-year smoking history
7.
Current participation in an investigational drug trial 
8.
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.
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION
20% NAC (5)
Product will be administered every 6-8 hours (3 times per day) for 7 
days.  Medication will be administered via a portable tabletop 
nebulizer. 
 
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION
0.9% saline (5mL)
Product will be administered every 6-8 hours (3 times per day) for 7 
days.  Medication will be administered via a portable tabletop 
nebulizer.  
DURATION OF 
PARTICIPATION 
AND DURATION OF 
STUDY
Participants will be enrolled in the study up to 132 days:
Screening:  up to 90 days
Treatment Period 1:  7 days 
Washout:  28 days
Treatment Period 2: 7 days

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The total duration of the study is expected to be 24 months.  
Participant recruitment will happen on a rolling basis.  
CONCOMMITANT 
MEDICATIONS
Prohibited:
 
Thiols and thiol derivatives

Carbamazepine

Nitroglycern and nitrates
EFFICACY 
EVALUATIONS
PRIMARY ENDPOINT

The primary outcome is the % change in FEV1 from the start to 
the end of the treatment period (either placebo or 20% NAC).
SECONDARY 
ENDPOINTS

Our secondary analysis is to determine the characteristics of 
participants that respond to NAC.
OTHER 
EVALUATIONS
Rheological properties of sputum.
SAFETY 
EVALUATIONS
Incidence of adverse events
PLANNED INTERIM 
ANALYSES 
When approximately 50% of patients have completed the study 
through Visit 6, an interim analysis for safety will be conducted by the 
UCSF Airway Clinical Research Study Quality Assurance Committee. 
Serious adverse events will be monitored by the committee on an 
ongoing basis throughout the study.
STATISTICS
Primary Analysis Plan
The primary outcome is the % change in FEV1 from the start to the 
end of the treatment period (either placebo or 20% NAC). The first 
analysis will be to test the assumption of negligible carryover effects 
from study period 1 to period 2. We will compare the sum of the 
outcome values measured in the two periods for each participant 
across the 2 sequence groups (placebo-20% vs. 20%-placebo) using 
an unpaired t-test. After no or negligible carryover effect has been 
confirmed, we will test for the difference in treatment effects between 
placebo and 20% NAC using a paired t-test.
Rationale for Number 
of Participants
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 >3.0. 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 

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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).

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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 
suggests that mucus 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 asthma. 
1.1
Overview of Clinical Studies
Against this background, the preliminary 
data we show in Figs 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 scores achieve a post 
albuterol FEV1 > 80% much less 
frequently than asthmatics who have a 
zero mucus score (Fig 3). 
Examined another way, we find that all 
asthmatics with an FEV1 < 60% after 
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 unocculded bronchi 
(red arrow). 

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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. This is well illustrated in the table, which presents data for the prevalence of 
mucus-related symptoms in asthmatics with different mucus score categories. None of the 
mucus-related symptoms were significantly different in the zero, low or high mucus 
subgroups, and it is clear that these symptoms have very limited utility to investigate the 
role of mucus in asthma or to identify asthmatics who 
might benefit from mucus-directed treatments. 
1.2
Overview of Non-Clinical Studies
To test the hypothesis that airway mucus in asthma has 
abnormal elasticity, we performed rheology on induced 
sputum from 40 asthmatic participants recruited to 
UCSF as part of the SARP. The majority of these 
asthmatic participants (65%) had severe asthma. We 
compared the elastic modulus (G’) of these participants 
to induced sputum G’ in 11 healthy controls. We found 
that the G’ in the asthmatic group was significantly 
higher than normal (Fig 4A). Notably, we found a 
strong inverse correlation between G’ and FEV1 % 
(Fig 4B). This finding suggests that stiff mucus in the 
airway of asthmatics could be a mechanism of mucus 
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”.
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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impaction of airways and 
airflow obstruction. It further 
suggests that decreasing 
mucus G’ could be a treatment 
strategy to improve airflow. 
To determine if the G’ of 
asthmatic sputum is a result of 
excessive mucin disulfide 
bridges (as it is in CF), we 
measured the G’ in a subgroup 
of 6 asthmatics before and 
after the addition of n-
Acetylcystine (NAC) 
(61mM). We found that NAC 
markedly decreased the G’ at 
both 2 minutes and 12 minute 
time-points after the addition of NAC (Fig 4A & B). This indicates that disulfide bonds are 
a mechanism of high sputum elasticity and a target for mucolysis in asthma, and it suggests 
thiol-based compounds as a rational mucolytic strategy.
2
STUDY RATIONALE
Because we have shown that the high elasticity of asthmatic mucus can be markedly 
decreased with NAC ex vivo (Fig 4), we propose here an in vivo study to treat asthmatics 
with NAC to improve their lung function. 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 had 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. Although NAC is a suboptimal mucolytic, we are 
confident that high dose (20%) treatment will effectively lyse airway mucus to improve 
airflow and pave the way for later clinical trials of a thiol-saccharide.
2.1
Risk / Benefit Assessment
Inhaled NAC carries a relatively low risk profile. The main side effects from inhalational 
use are nausea, reported in 2-7% of cases, and vomiting, reported in 9-12% of cases. Other 
reported side effects without documented incidence rates include stomatitis, cough, 
hemoptysis, rhinorrhea, fever, and chills. Rarely, NAC has been associated with increased 
intracranial pressure and somnolence. Although these later side effects have been 
documented in the medical literature, our team of physicians, experienced in using NAC 
clinically, has not encountered these more serious side effects.
Mucus impaction and the concomitant airway obstruction are associated with severe 
activity limitation and disease-associated impairment. Currently, there are few effective 
Figure 4. A. Sputum in asthma has an increased elastic modulus 
(G’). B. The G’ of asthma sputum is significantly and inversely 
related to FEV1 (ex vivo data from 40 asthmatics and 11 healthy 
participants [red dots])

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mucolytics utilized as part of standard clinical care of patients with severe asthma. This is 
due in part to the lack of clinical trial data on the effectiveness of NAC, the only nebulized 
mucolytic currently indicated for asthma. 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, our study team of experienced clinicians will supervise the initial 
administrations of the study drug in a controlled environment located within a hospital 
setting.  
3
STUDY OBJECTIVES
3.1
Primary Objective
The primary objective is to assess the clinical efficacy as measured by the change in 
pulmonary function over the seven day treatment period.
3.2
Secondary Objectives
The secondary objectives are to assess the clinical efficacy as measured in a subgroup of 
participants by the change in CT mucus score from baseline to end of treatment, and 
identify characteristics of those participants who benefit from mucolytic treatment. 
4
STUDY DESIGN
4.1
Study Overview
This is a single center, double-blind, randomized, 2 period crossover trial.  We propose a 
sample size of 30. Following a five-day run-in period, during which participants will self-
administer 0.9% normal saline by nebulizer three times per day, each participant will be 
randomized to receive a nebulized dose of study drug three times per day for seven days of 
either 20% NAC (active) or 0.9% saline (placebo). Following a 28-day washout period, 
participants will be switched to the alternate group for 7 days of treatment. Participants will 
be assigned to the treatments in random order.  Evaluations will be taken at baseline, end of 
run-in, start of second treatment period, and at the end of each 7-day treatment period.
Screening data will be reviewed to determine participant eligibility.  Participants who meet 
all inclusion criteria and none of the exclusion criteria will be entered into the study. 
The following treatment regimens will be used:
 
Experimental treatment of NAC 20%

Placebo treatment of 0.9% saline
Total duration of participation will be nine weeks.  Total duration of the study is expected 
to be 2 years.

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5
CRITERIA FOR EVALUATION
5.1
Primary Efficacy Endpoint
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.
5.2
Secondary Efficacy Endpoints
We intend to examine the effect of the treatment on CT mucus score in a subset of 
participants. Because the CT mucus score is a novel measurement, we do not have 
preliminary data to describe the natural history of mucus in the airway over time or with 
treatment. Therefore, for the purpose of this study, we intend to describe any changes we 
observe.
With respect to drug tolerability, we will first analyze the two treatment periods to assess 
any negligible carryover effects and then describe frequencies of reported side effects. 
5.3
Safety Evaluations
All participants will have their first dose of treatment or normal saline administered in the 
clinical laboratory environment under the supervision of a study nurse or study clinician. 
Participants will receive instruction on nebulizer use utilizing a teach-back method to 
ensure comprehension. Participants who are unable to successfully teach back nebulizer 
setup or drug self-administration will be excluded from continued participation.
Additionally, while acute anaphylactoid reactions have only been observed in the setting of 
IV administered NAC, each participant will be observed for 30 minutes following initiation 
of each new study period by a study nurse or study clinician.
All participants will be asked to complete a log of study drug administration, concomitant 
medications, and any subjective side effects (appendix A). Additionally, participants will 
have access via pager to a study nurse or clinician 24 hours a day, 7 days a week. 
Interim safety evaluations will be triggered if anticipated adverse events exceed 
frequencies documented in the literature, unanticipated adverse events occur, or rare but 
serious adverse events occur. Definitions of these terms and details of our safety evaluation 
plan are described in section 14. 
6
PARTICIPANT SELECTION
6.1
Study Population
Participants with a diagnosis of asthma who meet the inclusion and exclusion criteria will 
be eligible for participation in this study.  

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6.2
Inclusion Criteria
1.
Male or female between the ages of 18 and 70 years of age at Visit 0.
2.
Able to perform reproducible spirometry according to ATS criteria
3.
Clinical history consistent with moderate to severe asthma for 1 year or greater. 
4.
Post-bronchodilator FEV1 <90% of predicted
5.
Prescription and daily use of inhaled corticosteroid (ICS) equivalent to 80mcg of 
beclomethasone or greater
6.
CT mucus score >3 (determined during the initial screening process, provided the 
prior two conditions are met)
7.
Written informed consent obtained from participant and ability for participant to 
comply with the requirements of the study.
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.
History of intolerance to study medications.
4.
Current use of carbamazepine
5.
Angina which includes a treatment plan with PRN nitroglycerin or nitrites
6.
Smoking of tobacco or other recreational inhalants in last year and/or >10 pack-year 
smoking history
7.
Current participation in an investigational drug trial 
8.
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.
All participants should be maintained on the same medications throughout the entire study 
period, as medically feasible, with no introduction of new chronic therapies.
6.4
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.  
Prohibited Medications and Treatments
The following medications are prohibited during the study and administration will be 
considered a protocol violation.

Thiols and thiol derivatives

Carbamazepine

Nitroglycern and nitrates

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7
STUDY TREATMENTS
7.1
Method of Assigning Participants to Treatment Groups
Up to 30 eligible patients will be randomly assigned to receive either the experimental 
treatment (20% NAC) or the placebo treatment (0.9% saline) during period 1 in a 1:1 ratio 
using a SAS-based computer-generated randomization scheme developed by the study data 
manager.  The investigational pharmacy, who will supply the prepared study medication 
packets, will complete a randomization worksheet at the end of run-in and log group 
assignment. This log will be shared with investigators upon study completion or in the 
event of a serious safety concern. 
7.2
Blinding
Due to the objectives of the study, the identity of experimental and placebo treatments will 
not be known to investigators, research staff, or patients.  The following study procedures 
will be in place to ensure double-blind administration of study treatments.  
Access to the randomization code will be strictly controlled.  
Packaging and labeling of experimental and placebo treatments will be identical to 
maintain the blind. 
The study blind will be broken on completion of the clinical study and after the study 
database has been locked.  
During the study, the blind may be broken only in emergencies when knowledge of the 
patient’s treatment group is necessary for further patient management. When possible, the 
Investigator should discuss the emergency with a Quality Assurance officer and a 
representative from the Committee on Human Research prior to unblinding.  Should 
unblinding become necessary the Investigator will contact the investigational pharmacist 
directly.  
7.3
Formulation of Test and Control Products
NAC (trade name: Mucomyst) is manufactured by American Regent. The active drug 
studied here is 20% NAC delivered via nebulizer. The placebo is 0.9% saline. Both 
solutions will be delivered by the Sponsor’s compounding pharmacy in single-use rubber-
topped glass vials. 
7.3.1
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. 

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Table 1: Formulation and Measured pH of 20% NAC and Control Product
20% NAC
0.9% Saline
Active Ingredient, mg/mL
Acetylcysteine 200mg/mL
Other ingredient
Edetate disodium
Sodium hydroxide
Purified water
Sodium chloride
Purified water
pH
7
5.7
7.3.2
Formulation of Control Product
A placebo solution of 0.9% saline will be prepared by the UCSF Drug Products Services 
Laboratory in single-use rubber-topped glass vials.
7.3.3
Packaging and Labeling
Study drug is supplied in a package containing 24 single-use rubber-topped glass vials (3 
extra vials in the event of breakage). 
Each package of study drug will be labeled with the required FDA warning statement, the 
protocol number, a treatment number, the name of the sponsors, and directions for patient 
use and storage.  
7.4
Supply of Study Drug at the Site
The UCSF Drug Products Services Laboratory will prepare Study Drug and deliver it to the 
Airway Clinical Research Center. Study drug kits will be delivered upon successful 
completion of the run-in period on an individual participant basis. 
7.4.1
Dosage/Dosage Regimen
During each treatment period (see Appendix B), participants will nebulize one vial of study 
drug using a tabletop nebulizer. Participants will be instructed to take three doses per day, 
spaced at approximately 6-8 hour intervals. No adjustments will be made based weight or 
age. Because NAC can cause transient lung irritation, participants will be instructed to take 
2 puffs of supplied albuterol 15 minutes prior to each study treatment.  
7.4.2
Dispensing
Study medication will be dispensed by either a study nurse or physician and only after 
direct observation of the administration of the first dose of each treatment period. 
7.4.3
Administration Instructions 
Nebulizer and Air Compressor Assembly
a.
Place the compressor on a clean flat surface where it can safely reach its power 
source and where the ON/OFF switch can be reached.
b. Wash hands prior to preparing each treatment. 
c.
Use a clean nebulizer. 

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d. Inspect your nebulizer and ensure that the green exhalation valve on the mouthpiece 
is pointing down. 
e.
Connect one end of the tubing to the bottom of the nebulizer and the other end to 
the air outlet on the compressor.  Ensure that both ends are securely attached. 
f.
Make sure the nebulizer top is in breath actuated mode.  
g. Remove one vial of study drug from refrigerator and carefully add to the nebulizer. 
Prior to Beginning Study Drug Treatment
a.
Take 2 puffs of the albuterol inhaler (provided by study) 15 minutes before starting 
treatment. 
Beginning Study Drug Treatment
a.
Place the mouthpiece in your mouth, making sure your lips are sealed around the 
edge but are not covering the exhalation valve. 
b. Hold the nebulizer in an upright position. This prevents spilling and promotes 
nebulization.
c.
Breathe in slowly and deeply and then exhale normally through the device.  
d. Occasionally tapping the side of the nebulizer helps the solution drop to where it 
can be misted. 
e.
Continue taking slow, deep breaths until the noise created by the device changes—
this sound is sometimes referred to as a ‘sputter’.  
f.
Switch off compressor when finished with treatment.
Care and Cleaning of Nebulizer Equipment after Each Use
a.
Wash hands.
b. Remove tubing from nebulizer. 
c.
Open nebulizer cup and shake out any remaining liquid.  
d. Empty the supplied saline bullet into the nebulizer cup.  Swirl in cup and empty out 
excess.  
e.
Remove nebulizer top and mouthpiece from the nebulizer cup. 
f.
Shake the nebulizer parts to remove excess liquid. 
g. Thoroughly air dry parts on drying rack before reassembling.  
Care and Cleaning of Nebulizer Equipment Every Other Treatment Day
a.
Wash hands.
b. Take the nebulizer apart.
c.
Put all of the parts, except tubing and compressor, in boiling water for 10 minutes.
d. After boiling the nebulizer shake off any excess water, taking care not to burn skin. 
e.
Thoroughly air dry parts on drying rack before reassembling.  
7.5
Supply of Study Drug at the Site
Study drug supply will be maintained by the UCSF Investigational Pharmacy and will be 
supplied on a per participant basis. 7-day study drug supplies will be delivered to the 
clinical laboratory within 1 hour of study visit corresponding to the start of each treatment 

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period. Replacement kits will be available for up to 8 participants, should replacement 
participants be needed in order to obtain the final enrolled cohort of 30 participants. 
7.5.1
Storage
Study drug should be stored by the study site at controlled room temperature, 15 to 30ºC (59 to 
86ºF). If the temperature of study drug storage in the clinic/pharmacy exceeds or falls below 
this range, this should be reported to the Sponsor or designee and captured as a deviation. 
Participants will be instructed to store the medication in original packaging at room 
temperature according to the instructions outlined on the Drug Administration Instructions.
7.6
Study Drug Accountability
An accurate and current accounting of the dispensing and return of study drug for each 
participant will be maintained on an ongoing basis by a member of the study site staff.  The 
number of study drug dispensed and returned by the participant will be recorded on the 
Investigational Drug Accountability Record.  The study monitor will verify these 
documents throughout the course of the study.
7.7
Measures of Treatment Compliance
Participants will be asked to keep a patient diary noting the day and date they take their 
study drug and any adverse events. They will be asked to bring their patient diary to each 
study visit along with all used and unused study drug containers (Appendix A).
8
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 B.
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 participant.  
8.1
Clinical Assessments
8.1.1
Concomitant Medications
All concomitant medication and concurrent therapies will be documented at 
Baseline/Screening and at visits 4, 5, and at early termination when applicable.  Dose, 
route, unit frequency of administration, and indication for administration and dates of 
medication will be captured.
8.1.2
Medication Withholding
Bronchodilator reversibility will be used to establish eligibility at Visits 2, 5, and 8. 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. 

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Table 2. Medication Withholding Parameters
Medication
Withholding period
Leukotriene modifiers
24h
Ultra-long-acting bronchodilators (indacaterol, tiotropium)
24h
Long-acting beta-agonists
12h
Theophylline
12h
Short-acting anticholinergic
6h
Short-acting beta-agonists
4h
Participants will be evaluated at visit 1, without any medication holds, to establish the 
safety of withholding asthma medications. If a study clinician 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 instruction to 
resume asthma medications if symptoms arise. 
8.1.3
Food & Beverage Withholding
Participants are asked to withhold eating for our hour prior to sputum induction visits (2,5, 
and 8) and 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. 
8.1.4
Demographics 
Demographic information (date of birth, gender, race) will be recorded at Screening.
8.1.5
Medical History 
Relevant medical history, including history of current disease, other pertinent respiratory 
history, and information regarding underlying diseases will be recorded at Screening.
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. 

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8.1.6
Physical Examination
A complete physical examination will be performed by either the investigator or a study 
clinician who is a physician 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.
8.1.7
Vital Signs
Body temperature, blood pressure, pulse, and respirations will be performed after resting 
for 5 minutes at all study visits. 
8.1.8
Oximetry
Oximetry will be measured on room air with the participant at rest at all study visits.
8.1.9
Spirometry
Spirometry will be performed at visits 1-8 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 part.

Less Likely (<5%)
·
Wheezing and chest tightness.

Rare but serious (<1%)
·
Syncope
In an effort to minimize risk to participants will be seated during the procedure to reduce 
any injury should a participant become dizzy and fall. Coordinators will have albuterol 
available to administer to participants who develop wheeze or shortness of breath following 
spirometry.
8.1.10 Post-Bronchodilator Reversibility 
Spirometry will be repeated 15 minutes following the administration of four puffs of 
albuterol to assess bronchodilator reversibility. This procedure will be performed at visits 
2-8. 
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. 
8.1.11 Methacholine Challenge Testing
Methacholine challenge testing will be done according to the steps laid out in the UCSF 
Airway Clinical Research Center Methacholine Challenge Test Manual of Procedures 
(Appendix C). Only participants that are unable to achieve 12% improvement in FEV1% 
following administration of 4 puffs of albuterol and who have a baseline FEV1 >50% 
predicted will undergo methacholine challenge testing. 
Associated risks include the following: 

Likely (>20%)
·
Shortness of breath.

Less Likely (< 20%)
·
Wheezing, 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 pregnant laboratory animals; there are no human studies to verify this
effect during human 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 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 
prediluent FEV1. Medications and personnel will be available to manage and treat
bronchoconstriction.

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8.1.12 Sputum Induction 
A 12 minute sputum induction using 3% hypertonic saline will be performed at visits 2, 5, 
and 8. The procedure will be carried out according to the UCSF Airway Clinical Research 
Center Sputum Induction Manual of Procedures (Appendix C). 
Associated risks include the following:

Likely (>25%)
·
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.
8.1.13 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 B). 
8.1.14 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 baseline (visit 2) and following both 
treatment periods (visits 5 and 8). 
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 4 mSv, which is slightly greater than the 
yearly natural background of radiation in the US, which is 3mSv. 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 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 

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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/her regular physician.
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 will 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.
8.1.15 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).
8.2
Clinical Laboratory Measurements 
8.2.1
Hematology
Blood will be obtained and sent to the clinical hematology lab for a complete blood count 
(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 
inflammation.
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 
that they experience lightheadedness during blood draws will have blood drawn while lying 
supine on an exam room table. 
8.3
Research Laboratory Measurements 
8.3.1
Sputum Cell Count and Differential
Sputum for determination of total and differential cell counts will be collected at visits 2, 5, 
and 8. Specimens will be collected and processed according to the UCSF Airway Clinical 
Research Center Sputum Induction Manual of Procedures (Appendix C).  
8.3.2
Sputum Cytokine Gene Expression Measurements
Sputum for determination of RNA gene expression of a number of airway-specific genes 
will be collected at visits 2, 5, and 8. Specimens will be collected and processed according 

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to the UCSF Airway Clinical Research Center Sputum Induction Manual of Procedures 
(Appendix C).  
8.3.3
Sputum Rheology
Sputum for the determination of rheological properties will be collected at visits 2, 5, and 
8. The rheological measurements may be made using a portion of the sample collected at 
this time. 
9
EVALUATIONS BY VISIT
9.1
Visit 1 
1.
Review the study with the participant and obtain written informed consent and 
HIPAA authorization.
2.
Assign the participant a unique screening number.
3.
Record demographics data.
4.
Record medical history, including history of asthma, diagnosis date, and asthma-
related healthcare utilization & 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 in 7 days.
9.2
Visit 2a
1.
Concomitant medications review.
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 post-bronchodilator spirometry. 
7.
Collect blood for clinical laboratory tests.
8.
Obtain a CT scan of the thorax.
9.
Collect induced sputum.
10.
Schedule participant for Visit 3. 
8.2.1 Visit 2b **Optional
1.      Perform and record vital signs.
2.    Perform and record oximetry.
3.
Perform and record urine pregnancy test. 

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4.
Perform and record spirometry.
5.
Perform methacholine challenge testing. 
6.
Collect blood for clinical laboratory tests.
7.
Obtain a CT scan of the thorax.
8.
Collect induced sputum.
9.
Schedule participant for Visit 3. 
9.3
Visit 3 (Day 0)
1.
Record changes to concomitant medications.
2.
Perform abbreviated physical examination.
3.
Perform and record vital signs.
4.
Perform and record oximetry.
5.
Perform and record urine pregnancy test. 
6.
Perform and record spirometry.
7.
Perform and record post-bronchodilator spirometry. 
8.
Provide education on use of personal nebulizer and administration of study 
medication. 
9.
Dispense study drug and initiate study diary.
10.
Perform RN/MD supervised administration of first run-in dose of nebulized 0.9% 
normal saline. 
11.
Schedule participant for Visit 4 in 5 days.
9.4
Visit 4 (Day 5)
1.
Record any adverse experiences and/or review participant diary for adverse 
experiences and exclusionary medication use.
2.
Record changes to concomitant medications.
3.
Perform abbreviated physical examination.
4.
Perform and record vital signs.
5.
Perform and record oximetry.
6.
Perform and record urine pregnancy test. 
7.
Perform and record spirometry.
8.
Perform and record post-bronchodilator spirometry.
9.
Collect any unused study drug. 
10.
Review diary card. 
11.
Randomize if adherence is greater than or equal to 80% during run-in. 
12.
Provide education on use of personal nebulizer and administration of study 
medication. 
13.
Dispense study drug and initiate study diary.
14.
Perform RN/MD supervised administration of first dose of nebulized study drug. 
15.
Schedule participant for Visit 5 in 7 days.

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9.5
Visit 5 (Day 14)
1.
Record any adverse experiences and/or review participant diary for adverse 
experiences and exclusionary medication use.
2.
Record changes to concomitant medications.
3.
Perform abbreviated physical examination.
4.
Perform and record vital signs.
5.
Perform and record oximetry.
6.
Perform and record spirometry.
7.
Perform and record post-bronchodilator spirometry.
8.
Collect any unused study drug. 
9.
Review diary card. 
10.
Obtain a CT scan of the thorax.
11.
Collect induced sputum.
12.
Schedule participant for Visit 6 in 14 days. 
9.6
Visit 6 (Day 28)
1.
Record changes to concomitant medications.
2.
Perform and record vital signs.
3.
Perform and record oximetry.
4.
Perform and record spirometry.
5.
Perform and record post-bronchodilator spirometry.
6.
Schedule participant for Visit 7 in 14 days. 
9.7
Visit 7 (Day 42)
1.
Record changes to concomitant medications.
2.
Perform abbreviated physical examination.
3.
Perform and record vital signs.
4.
Perform and record oximetry.
5.
Perform and record urine pregnancy test. 
6.
Perform and record spirometry.
7.
Perform and record post-bronchodilator spirometry.
8.
Provide education on use of personal nebulizer and administration of study 
medication.
9.
Dispense study drug and initiate study diary.  
10.
Perform RN/MD supervised administration of first dose of nebulized study drug.
11.
Obtain a CT scan of the thorax.
12.
Collect induced sputum.
13.
Schedule participant for Visit 8 in 7 days.  

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9.8
Visit 8 (Day 47)
1.
Record any adverse experiences and/or review participant diary for adverse 
experiences and exclusionary medication use.
2.
Record changes to concomitant medications.
3.
Perform abbreviated physical examination.
4.
Perform and record vital signs.
5.
Perform and record oximetry.
6.
Perform and record spirometry.
7.
Perform and record post-bronchodilator spirometry.
8.
Collect any unused study drug. 
9.
Review diary card.
10.
Obtain a CT scan of the thorax.
11.
Collect induced sputum.
9.9
Early Withdrawal Visit
1.
Record any Adverse Experiences and/or Review participant diary for adverse 
experiences and exclusionary medication use.
2.
Record changes to concomitant medications.
3.
Perform abbreviated physical examination.
4.
Perform and record vital signs.
5.
Perform and record oximetry.
6.
Perform and record urine pregnancy test. 
7.
Perform and record spirometry.
8.
Perform and record post-bronchodilator spirometry.
9.
Collect any unused study drug. 
10.
Review dairy card. 
10 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION
10.1 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, 
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 participant, for the occurrence of AEs 
during each participant visit and record the information in the site’s source documents.  
Adverse events will be recorded in the participant CRF.  Adverse events will be described 

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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  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 participant 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 participant 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 .
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 participant’s clinical state or by other 
interventions.
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.

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Unrelated
An event that can be determined with certainty to have no relationship to the study 
drug.
10.2 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 participant or require intervention to 
prevent one of the outcomes listed. 
10.2.1 Serious Adverse Experience Reporting
The study site 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.  
10.3 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
11 DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS
11.1 Early Discontinuation of Study Drug 
A participant may be discontinued from study treatment at any time if the participant, the 
investigator, or the Sponsor feels that it is not in the participant’s best interest to continue.  
The following is a list of possible reasons for study treatment discontinuation: 
Participant withdrawal of consent 
Participant is not compliant with study procedures
Adverse event that in the opinion of the investigator would be in the best interest of the 
participant to discontinue study treatment
Protocol violation requiring discontinuation of study treatment
Lost to follow-up

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Sponsor request for early termination of study
Positive pregnancy test (females)
If a participant is withdrawn from treatment due to an adverse event, the participant will be 
followed and treated by the Investigator until the abnormal parameter or symptom has 
resolved or stabilized.  
All participants who discontinue study treatment should come in for an early 
discontinuation visit as soon as possible.
All participants 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 participant 
withdrawals.  The reason for the participant’s withdrawal from the study will be specified 
in the participant’s source documents Refer to Section 10 for early termination procedures.
12.3
Withdrawal of Participants from the Study
A participant may be withdrawn from the study at any time if the participant, the 
investigator, or the Sponsor feels that it is not in the participant’s best interest to continue.  
All participants 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 participant 
withdrawals.  The reason for the participant’s withdrawal from the study will be specified 
in the participant’s source documents.  As noted above, participants who discontinue study 
treatment early (i.e., they withdraw prior to Visit 9) should have an early discontinuation 
visit. Refer to Section 10 for early termination procedures.  
12.4
Replacement of Participants
Participants who withdraw from the study treatment will be replaced.  
Participants who withdraw from the study will be replaced.  
12 PROTOCOL VIOLATIONS
A protocol violation occurs when the participant or investigator fails to adhere to 
significant protocol requirements affecting the inclusion, exclusion, participant 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, with the exception of the use of unanticipated 
nitroglycerin and/or nitrates as part of treatment for cardiovascular emergency. 
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 participant.
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 

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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.
13 DATA SAFETY MONITORING 
Adverse events will be monitored by the Clinical PIs (Drs. Fahy, Woodruff and Lazarus) in 
real-time. In addition, 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.
14 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.  
14.1 Data Sets Analyzed
All eligible participants who are randomized into the study and receive at least one dose of 
the study drug (the Safety Population) will be included in the safety analysis.
14.2 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.  
14.3 Analysis of Primary Endpoint
The primary outcome is the % change in FEV1 from the start to the end of the treatment 
period (either placebo or 20% NAC). The first analysis will be to test the assumption of 
negligible carryover effects from study period 1 to period 2. We will compare the sum of 
the outcome values measured in the two periods for each participant across the 2 sequence 
groups (placebo-20% vs. 20%-placebo) using an unpaired t-test. After no or negligible 
carryover effect has been confirmed, we will test for the difference in treatment effects 
between placebo and 20% NAC using a paired t-test.
14.4 Analysis of Secondary Endpoints
As a secondary outcome, we will include an analysis that examines the change associated 
with the 7-day treatment with 0.9% saline. Our secondary analysis is to determine the 
characteristics of participants that respond to NAC. We will classify participants in four 
groups based on their post-bronchodilator FEV1 in response to NAC. FEV1 of 0-4% 
change will define non-responders and FEV1 of 5-9%, 10-14%, or > 15% will define the 3 
categories of responders. We will examine NAC responders and non-responders to 
determine if baseline CT mucus scores, lung function measures, or sputum G’ measures 
predict treatment response. We will construct ROC curves to determine the CT score that 
predicts NAC response thereby identifying a CT biomarker for future thiol saccharide 
trials. In addition, we will examine how the CT mucus score changes with NAC treatment 
using a subset of the participants following second period treatment. Finding a decrease in 
CT score in the 20% NAC group compared to the placebo group will provide support for 

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our hypothesis that NAC improves lung function by decreasing intraluminal mucus. Other 
analyses will be to examine the effects of treatment on sputum elasticity (G’).
Safety and tolerability data will be summarized by treatment group.  
Adverse event rates will be coded by body system and MedDra classification term. 
Adverse events will be tabulated by treatment group and will include the number of 
patients for whom the event occurred, the rate of occurrence, and the severity and 
relationship to study drug.  
14.5 Interim Analysis
When approximately 50% of patients have completed the study through Visit 6, an interim 
analysis for safety will be conducted by the UCSF Airway Clinical Research Study Quality 
Assurance Committee. Serious adverse events will be monitored by the committee on an 
ongoing basis throughout the study.
14.6 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 
>3.0. 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 
15 DATA COLLECTION, RETENTION AND MONITORING
15.1 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 participant treated with 
the study drug.  
Study personnel at each site will enter data from source documents corresponding to a 
participant’s visit into the protocol-specific paper CRF when the information corresponding 
to that visit is available. Participants 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, participant number and initials.
The Investigator is responsible for all information collected on participants 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.

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15.2 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.
15.3 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 study database 
will be updated in accordance with the resolved queries.  All changes to the study database 
will be documented.
15.4 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.
15.5 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 participant must be maintained that includes the 
signed Informed Consent, HIPAA Authorization and Assent Form and copies of all source 
documentation related to that participant.  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.
15.6 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.

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15.7 Participant Confidentiality
In order to maintain participant confidentiality, only a site number, participant number and 
participant initials will identify all study participants on CRFs and other documentation.  
Additional participant confidentiality issues (if applicable) are covered in the Clinical 
Study Agreement.
16 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 
participants is kept in binders in a locked storage closet, and in our password protected 
secure electronic files, and is only accessible to authorized study personnel. Clinical 
information will not be released without written permission of the participant, 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).
16.1 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.
16.2 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 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.

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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.
16.3 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 
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, assent and HIPAA authorization 
and provide the documents to the IRB/IEC for approval prior.  The consent form generated 
by the Investigator must 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 participant prior 
to entering the participant into the trial.  Information should be given in both oral and 
written form and participants must be given ample opportunity to inquire about details of 
the study.  A copy of the signed consent form will be given to the participant and the 
original will be maintained with the participant’s records.
16.4 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. 
16.5
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 participants.
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.

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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 participants 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/ participants.
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 A.  DRUG DIARY

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Appendix B. CONA Schedule of Events
Visit 
1
2a
2b*
3
4
51
6
7
81
Consent and eligibility
x
Questionnaires
x
x
x
x
x
x
x
Physical Exam
x
x3
x3
x3
x3
x3
Vital signs & oximetry
x
x
x
x
x
x
x
x
x
Spirometry
x
x
x
x
x
x
x
x
x
Post-bronchodilator reversibility
x
x
x
x
x
x
x
Methacholine challenge
x
Urine pregnancy test
x
x
x
x
x
x
x
Sputum induction
x
x
x
x
Blood sample2
x
x
CT thorax
x
x
x
x
Nebulizer & diary card education & teach-back
x
x
x
RN/MD supervised medication administration
x
x
x
Randomization
x
* Participation in visit 2b is dependent on post-bronchodilator reversibility test results obtained at visit 2a. The visit 2 sputum induction, blood sample and CT 
thorax will only be obtained at visit 2a or 2b.  
1.
Visits have a ±5 day grace period; however, visits 5 and 8 must happen 7 days following the initiation of treatment. 
2.
Blood sample to include CBC with 5 part differential, serum IgE, and serum & plasma collection
3.
Abbreviated physical exam.
Screening & Eligibility
0.9% NS 
TID
20% NAC 
TID
0.9% NS 
TID
20% 
NAC
0.9% NS 
TID
Washout
Washout
Period 1
Period 2

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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.