Effect of Bronchitol on Mucociliary Clearance in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Modulator Treated Patients With Cystic Fibrosis With Moderate to Severe Lung Disease
Phase: PHASE4
Conditions: Cystic Fibrosis
Sponsor: University of North Carolina, Chapel Hill

 
Effect of Bronchitol on Mucociliary 
Clearance in CFTR-Modulator Treated 
Patients with Cystic Fibrosis with Moderate 
to Severe Lung Disease 
 
 
 
NCT number NCT05740618 
Document Date 03/14/2024 
 

CLINICAL STUDY PROTOCOL 
 
Effect of Bronchitol on Mucociliary 
Clearance in CFTR-Modulator Treated 
Patients with Cystic Fibrosis with 
Moderate to Severe Lung Disease 
Principal Investigator 
Subhashini Sellers, MD MSCR 
Sponsor 
Subhashini Sellers, MD MSCR 
130 Mason Farm Road, CB 7020, Chapel Hill NC 27599, United States 
 
Co-Sponsor 
Chiesi USA 
175 Regency Woods #600, Cary, NC, 27518, United States 
 
Protocol Version 
March 14, 2024 
version 1.4 
 
 
 
03/14/2024 
 
 
 
Confidentiality Statement: 
 
 
 

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Study Personnel 
Principal Investigator 
Subhashini Sellers 
Email: sasellers@med.unc.edu 
  
Co-Investigator 
 
 
 
Scott Donaldson 
Email: scott_donaldson@med.unc.edu 
 
  
 
 
 

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Synopsis 
Primary Objective 
The primary objective of this study is to measure the sustained effect of dry powder 
inhaled mannitol (Bronchitol) on whole lung mucociliary clearance (MCC) in persons with 
cystic fibrosis (PwCF) with moderate to severe lung disease who are using 
elexacaftor/tezacaftor/ivacaftor (E/T/I). 
Secondary Objectives (if applicable) 
Secondary objectives include determining whether Bronchitol leads to improvement in 
other measures of MCC, spirometry, respiratory symptoms, and treatment satisfaction in 
PwCF with moderate to severe lung disease who are using E/T/I. 
Study Duration 
Each subject will participate in 2-3 study visits, including a screening visit, over a 2-4 week 
period.  
The study is anticipated to begin enrollment in March 2022 with completion of study 
procedures by March 2023. 
Study Design 
This is an open-label, interventional study to assess the effect of Bronchitol on MCC in 
PwCF with moderate to severe lung disease who have been using E/T/I for more than 3 
months. Adult PwCF with an FEV1 of 30%-70% who are not using hypertonic saline (HS) 
or who are willing to withhold HS for 2 weeks prior to visit 1, will be approached for 
enrollment.  
Screening visit: After obtaining informed consent, eligibility will be confirmed at this visit, 
including a urine pregnancy test for women of childbearing potential. Patients using 
hypertonic saline will be asked to discontinue this treatment for the remainder of the study 
period. 
Visit 1: For patients who are currently not using HS, this can be done immediately 
following the screening visit; for patients using HS, this will be done 14 days after the 
screening visit to allow for complete washout of HS. Subjects will be asked to hold 
dornase alfa and bronchodilators on the morning of Visit 1. Baseline measures of MCC, 
spirometry, and patient reported outcomes (PROs) will be obtained. Following this, a 
Bronchitol tolerability test will be performed and if tolerated, subjects will be instructed on 
home use.  
Visit 2: This visit will be scheduled 14 +/- 2 days after Visit 1. Subjects will be asked to 
withhold their Bronchitol, dornase alfa and bronchodilators on the morning of the visit. 
MCC, spirometry, and PROs will be obtained.  
Study Population 

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The study population is adult PwCF with moderate to severe lung disease who are 
currently treated with E/T/I.  
Inclusion Criteria:  
1. Able to provide informed consent 
2. Age ≥ 18 at the time of screening 
3. Diagnosis of CF  
4. Regularly using E/T/I for ≥ 90 days 
5. FEV1 between 30% and 70%, inclusive, at time of screening 
6. Denies active smoking or vaping 
7. Clinically stable with no significant changes in health status within the 28 days prior to 
and including the screening visit 
8. Has no other conditions that, in the opinion of the Site Investigator/Designee, would 
preclude informed consent, make study participation unsafe, complicate interpretation of 
study outcome data, or otherwise interfere with achieving the study objectives 
 
Exclusion Criteria: 
1. Use of an investigational drug within 28 days prior to and including the screening visit 
2. Unable or unwilling to withhold HS for 4 weeks (2 weeks prior to Visit 1 and 2 weeks 
between Visit 1 and Visit 2) 
3. Unable or unwilling to withhold dornase alfa and bronchodilators on the morning of Visit 
1 and Visit 2, until completion of study procedures 
4. Initiation of new chronic CF pulmonary therapy (e.g. dornase alfa, azithromycin, inhaled 
antibiotic) within 28 days prior to and including the screening visit 
5. Acute use of antibiotics (oral, inhaled, or IV) or acute use of systemic corticosteroids for 
respiratory tract symptoms within 28 days prior to and including the screening visit. 
6. Chronic use of oral corticosteroids > 10 mg of prednisone daily or equivalent  
7. Unable to tolerate albuterol or any other bronchodilator 
8. History of intolerance to HS or inhaled mannitol 
9. Pregnancy or breast feeding 
10. Have had more than 2 chest CTs in the past year or a combination of procedures that 
are believed to have exposed the subject's lungs to >150 mSv  
11. History of significant hemoptysis (≥ 60 mL) in the last three months 
Number of Participants 

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The estimated number of participants in this study is 22 subjects, enrolled and completed. 
We anticipate enrolling up to 25 subjects to account for drop-out. 
Number of Study Sites 
This study will be conducted at up to 4 sites that are part of the CF Foundation MCC 
National Resource Center.  The central coordinating site and MCC scan reading site will 
be at the University of North Carolina at Chapel Hill.  
Primary Outcome Variables 
The primary outcome will be whole lung MCC from 0 to 60 minutes (MCC60).  
Secondary Outcome Variables  
1. Other MCC endpoints (e.g., central and peripheral lung clearance; cough clearance 
(CC); aerosol deposition homogeneity indices) 
2. Forced expiratory volume in one second (FEV1) % predicted  
3. Respiratory symptoms as measured by the respiratory domain of the Cystic Fibrosis 
Respiratory Questionnaire Revised (CFQR-R) and the Cystic Fibrosis Respiratory 
Symptom Diary and Chronic Respiratory Infection Symptom Score (CFRD-CRISS) 
4. Treatment satisfaction as measured by the Treatment Satisfaction Questionnaire (TSQ) 
Visit Schedule Table (Optional) 
Procedures 
Screening 
visit 
Visit 1 
Visit 2 
Informed Consent 
X 
 
 
Medical History 
X 
 
 
Vital signs 
X 
X* 
X 
Physical exam 
X 
X* 
X 
Urine pregnancy test (if applicable) 
X 
X 
X 
Spirometry 
 
X 
X 
Questionnaire administration 
 
X 
X 
MCC measurement 
 
X 
X 
Bronchitol tolerance test 
 
X 
 
Adverse event assessment 
 
 
X 
*Not required if visit 1 is done on the same day as screening visit 
 
 
 
 
 

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Abbreviations 
Abbreviation  
Explanation 
BMI 
Body mass index 
BTT 
Bronchitol tolerance test 
CC 
Cough clearance 
CFQ-R 
Cystic Fibrosis Respiratory Questionnaire 
Revised 
CFRSD-CRISS 
Cystic Fibrosis Respiratory Symptom 
Diary and Chronic Respiratory Infection 
Symptom Score 
CFTR 
Cystic Fibrosis Transmembrane 
Conductance Regulator 
CRF 
Case report form 
CTCAE v3. 
Common Terminology Criteria for Adverse 
Events Version 3.0 
E/T/I 
Elexacaftor/Tezacaftor/Ivacaftor 
FEV1 
Forced expiratory volume in one second 
HS 
Hypertonic saline 
ICF 
Informed consent form 
MCC 
Mucociliary Clearance  

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MCC60 
Average whole lung clearance through 60 
minutes  
PRO 
Patient reported outcome 
PwCF 
Persons with cystic fibrosis 
SpO2 
Oxygen saturation 
TSQ 
Treatment Satisfaction Questionnaire  
 
 

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Table of Contents 
Synopsis ................................................................................................................................. 3 
Primary Objective ................................................................................................................ 3 
Study Duration ..................................................................................................................... 3 
Study Design ....................................................................................................................... 3 
Study Population ................................................................................................................. 3 
Number of Participants ........................................................................................................ 4 
Number of Study Sites ........................................................................................................ 5 
Primary Outcome Variables ................................................................................................ 5 
Secondary Outcome Variables ............................................................................................ 5 
Visit Schedule Table (Optional) ........................................................................................... 5 
Abbreviations .......................................................................................................................... 7 
1 - Introduction ...................................................................................................................... 12 
1.1 Introductory Statement ................................................................................................ 12 
2 - Background ...................................................................................................................... 13 
2.1.1 Preclinical Experience .......................................................................................... 13 
2.2 Relevance of Bronchitol in Cystic Fibrosis .................................................................. 14 
3 - Rationale/Significance ..................................................................................................... 15 
3.1 Problem Statement ...................................................................................................... 15 
3.2 Purpose of Study/Potential Impact .............................................................................. 15 
3.3.1 Potential Risks ...................................................................................................... 15 
3.3.2 Potential Benefits .................................................................................................. 16 
4 - Study Objectives .............................................................................................................. 17 
4.1 Hypothesis ................................................................................................................... 17 
4.2 Primary Objective ........................................................................................................ 17 
4.3 Secondary Objectives (if applicable) ........................................................................... 17 
5 - Study Design ................................................................................................................... 18 
5.1 General Design Description ........................................................................................ 18 
5.1.1 Study Date Range and Duration ........................................................................... 18 
5.1.2 Number of Study Sites .......................................................................................... 18 
5.2 Outcome Variables ...................................................................................................... 18 

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5.2.1 Primary Outcome Variables .................................................................................. 18 
5.2.2 Secondary Outcome Variables ............................................................................. 18 
5.3 Study Population ......................................................................................................... 19 
5.3.1 Number of Participants ......................................................................................... 19 
5.3.2 Eligibility Criteria/Vulnerable Populations ............................................................. 19 
6 - Methods ........................................................................................................................... 21 
6.1 Treatment - Drug ......................................................................................................... 21 
6.1.1 Identity of Investigational Product/New Drug ........................................................ 21 
6.1.2 Dosage, Admin, Schedule (if applicable) .............................................................. 21 
6.1.3 Packaging/Labelling .............................................................................................. 21 
6.1.4 Storage Conditions ............................................................................................... 21 
6.1.5 Concomitant therapy ............................................................................................. 21 
6.1.6 Restrictions ........................................................................................................... 22 
6.2 Assessments ............................................................................................................... 22 
6.2.1 Efficacy ................................................................................................................. 22 
6.2.2 Safety/Pregnancy-related policy ........................................................................... 22 
6.2.2.1 Adverse Events Definition and Reporting .......................................................... 22 
6.3 Study Procedures ........................................................................................................ 24 
6.3.1 Study Schedule ..................................................................................................... 27 
6.3.2 Informed Consent ................................................................................................. 28 
6.3.3 Screening .............................................................................................................. 28 
6.3.4 Recruitment, Enrollment and Retention ................................................................ 28 
6.3.6 End of Study and Follow-up .................................................................................. 28 
6.3.7 Removal of subjects ............................................................................................. 28 
6.4 Statistical Method ........................................................................................................ 29 
6.4.1 Statistical Design .................................................................................................. 29 
6.4.2 Sample Size Considerations .................................................................................... 29 
6.4.3 Planned Analyses ..................................................................................................... 29 
6.4.3.1 Primary Analyses ............................................................................................... 29 
6.4.3.2 Secondary Objectives Analyses ........................................................................ 30 
6.4.3.3 Safety/Pregnancy-related policy ........................................................................ 30 

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6.4.3.4 Analysis of Subject Characteristics .................................................................... 30 
6.4.5 Handling of Missing Data ......................................................................................... 30 
7 - Trial Administration .......................................................................................................... 31 
7.1 Ethical Considerations: Informed Consent/Assent and HIPAA Authorization ............. 31 
7.2 Institutional Review Board (IRB) Review ..................................................................... 31 
7.3 Subject Confidentiality ................................................................................................. 32 
7.4 Deviations/Unanticipated Problems ............................................................................ 32 
7.5 Data Collection ............................................................................................................ 32 
7.6 Data Quality Assurance ............................................................................................... 33 
7.7 Study Records ............................................................................................................. 33 
7.8 Data or Specimen Storage/Security ............................................................................ 33 
7.10 Retention of Records ................................................................................................. 33 
7.12 Data Safety Monitoring Plan ...................................................................................... 33 
7.13 Study Modification ..................................................................................................... 34 
7.14 Study Completion ...................................................................................................... 34 
7.15 Conflict of Interest Policy ........................................................................................... 34 
7.17 Funding Source ......................................................................................................... 34 
7.18 Publication Plan ......................................................................................................... 34 
Appendix 1 ............................................................................................................................ 35 
Appendix 2 ............................................................................................................................ 43 
References ............................................................................................................................ 44 
 
 
 

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1 - Introduction 
1.1 Introductory Statement 
This study will provide important mechanistic information regarding the effect of inhaled 
mannitol (Bronchitol) in PwCF with moderate to severe disease who are already using 
elexacaftor/tezacaftor/ivacaftor (E/T/I).  Many patients have already discontinued hypertonic 
saline and other pulmonary therapies because of the profound effect of E/T/I of their 
symptoms and lung function. Further, because both inhaled osmotic agents (i.e., Bronchitol, 
HS) and E/T/I are believed to exert their beneficial effects through improvements in 
mucociliary clearance (MCC), it is unknown if the combination of these therapies might be 
additive or are redundant in a population with moderate to severe disease where 
bronchiectasis and chronic infection persists, and where eventual decline in lung function is 
expected over time. This study, therefore, will be the first to determine whether “add on” 
therapy with inhaled Bronchitol is able to further accelerate MCC in E/T/I patients. These 
data would provide some guidance regarding the use of these approved therapies in PwCF.    
 
 

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2 - Background 
2.1.1 Preclinical Experience 
Mechanism of Action: Bronchitol improves the hydration of airway secretions by osmotically 
drawing water across the airway epithelium into the lumen. This, in turn, has been shown to 
acutely accelerate the rate of mucociliary clearance1. 
Pharmacodynamics: The pharmacodynamics of mannitol are unknown2. 
 
2.1.2 Clinical Experience2 
The efficacy of Bronchitol for the treatment of cystic fibrosis (CF) was evaluated in 3 
randomized, double-blind, controlled trials (Trials 1, 2, and 3). All three trials were 26-week, 
randomized, double-blind, controlled studies in patients with CF. Trial 1 (NCT02134353) 
evaluated patients 18 years of age or older with baseline FEV1 >40% to <90% of predicted. 
Trial 2 (NCT00446680) evaluated patients 6 years of age or older with baseline FEV1 >30% 
to <90% of predicted. Trial 3 (NCT00630812) evaluated patients 6 years of age or older with 
baseline FEV1 >40% to <90% of predicted. All three trials excluded CF patients with an 
episode of hemoptysis (>60 mL) in the 3 months prior to enrollment. The use of inhaled 
hypertonic saline was not permitted in any of the three trials but continued use of their other 
standard of care CF therapies were allowed (e.g., bronchodilators, inhaled antibiotics, and 
dornase alfa). While CF patients aged 6 to 17 years were included in Trials 2 and 3, 
Bronchitol is not approved for use in this age group. Patients were randomized to receive 
either Bronchitol 400 mg or control (50 mg inhaled mannitol) twice daily. Each dose of 
Bronchitol was preceded by use of an inhaled short-acting bronchodilator (albuterol or 
equivalent) taken 5 to 15 minutes prior to initiation of Bronchitol dosing. The primary efficacy 
endpoint in all three studies was improvement in lung function as determined by the mean 
change from baseline in pre-dose FEV1 (mL) over 26 weeks of treatment and was analyzed 
using the pattern mixture model with multiple imputation. Trial 1 evaluated 423 adult patients 
with a mean age of 28 years and a mean FEV1 63.9% predicted (range: 40.3% = minimum, 
89.6% = maximum). Treatment with Bronchitol resulted in a statistically significant 
improvement in FEV1. In Trial 1, the treatment difference between Bronchitol and control for 
the adjusted mean change in FEV1 from baseline over 26 weeks was 51 mL (95% CI 6 to 97 
mL) shown in the table below.  
 
Trials 2 and 3 evaluated 295 and 305 patients, respectively. For the adjusted mean 
difference in the change from baseline in FEV1 over 26 weeks in the intention-to-treat 
population in Trials 2 and 3, the treatment difference between Bronchitol and control was 68 
mL (95% CI: 24 to 113 mL) and 52 mL (95% CI: -3 to 107 mL), respectively. Post-hoc 
descriptive analyses of the adult subgroups from Trials 2 and 3 were performed. The adult 
subgroup analyses in Trial 2 and 3 evaluated 209 and 157 adult patients, respectively. In 

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Trial 2, there was an adjusted mean difference in the change from baseline in FEV1 over 26 
weeks in the intention-to-treat population of adults of 78 mL (95% CI: 21 to 135 mL). In Trial 
3, there was an adjusted mean difference in the change from baseline in FEV1 over 26 
weeks in the intention-to-treat population of adults of 78 mL (95% CI: 2 to 153 mL). 
 
2.2 Relevance of Bronchitol in Cystic Fibrosis 
Cystic Fibrosis (CF) lung disease is caused by dehydration of airway secretions that leads to 
mucus adhesion, infection and airways inflammation. A simple means to restore hydration of 
CF airway surfaces is to inhale an osmotic agent, such as hypertonic (3-7%) saline (HS) or 
Bronchitol. These osmotic agents draws water across the airway mucosa into the airway 
lumen. Rehydration of airway mucus and the airway surface liquid layer facilitates 
mucociliary clearance (MCC). Inhaled hypertonic saline twice daily has been shown to have 
both short-term benefits on pulmonary function, MCC and quality of life and long-term 
benefits on lung function and reduction in exacerbations3,4. As a result, hypertonic saline, 
delivered by nebulization twice daily, has long been standard of care for PwCF though 
considered burdensome by patients.  
In October 2019, the FDA approved the first triple combination therapy, 
elexacaftor/tezacaftor/ivacaftor (E/T/I), for patients 12 and older with cystic fibrosis who have 
at least one F508del mutation in the cystic fibrosis transmembrane conductance regular 
(CFTR) gene. Clinical trials demonstrated a substantial improvement in lung function in 
patients treated with E/T/I compared to placebo, as well as fewer pulmonary exacerbations 
and improved body mass index (BMI) and quality of life5,6. Given these potent effects of 
modulator therapies, the question of how to simplify the treatment burden of PwCF including 
reducing the need for laborious nebulizer therapies is now a research priority7. A large study 
of stopping chronic therapies in PwCF with mild-moderate lung function reduction 
(FEV1>60%) is currently underway8. However, this will not provide evidence to support 
reducing therapeutic burden in patients with more severe lung disease who may be more 
reliant on continued treatment with an inhaled osmotic agent.  
Mannitol, an osmotic agent delivered via dry powdered inhaler (Bronchitol), may provide a 
viable alternative to HS in PwCF with moderate to severe lung function reduction (FEV1 
30%-70%) currently taking E/T/I who still require treatment with an inhaled osmotic agent. In 
a randomized, double-blind, placebo-controlled trial conducted prior to E/T/I approval, PwCF 
treated with Bronchitol demonstrated a significant improvement in FEV1 and a reduction in 
exacerbations over one year9. Importantly, Bronchitol is delivered via a simple, hand-held 
inhaler, providing benefits of shorter delivery time, increased portability and no need for 
large, specialized equipment for delivery over nebulizer hypertonic saline.  
This study will provide foundational information regarding the effect of Bronchitol in a unique 
population of PwCF who would benefit from decreased treatment burden but should 
continue to use an inhaled osmotic agent for airway clearance due to their moderate to 
severe lung disease despite treatment with a CFTR modulator.  
 
 

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3 - Rationale/Significance 
3.1 Problem Statement 
In the era of highly effective CFTR modulator therapy, there is a renewed focus on reducing 
the treatment burden for PwCF while maintaining effective airway clearance to optimize lung 
function and reduce pulmonary exacerbation frequency. This is particularly important for 
patients who have moderate to severe lung disease despite treatment with E/T/I and may be 
particularly reliant on therapies that improve mucus clearance from airways.  
This study will provide foundational information regarding the effect of Bronchitol on MCC 
and treatment satisfaction in PwCF with moderate to severe lung disease who are already 
being treated with E/T/i.  
 
3.2 Purpose of Study/Potential Impact 
This trial is designed to test the hypothesis that Bronchitol leads to a sustained improvement 
in MCC in adults with CF who are receiving treatment with E/T/I. Secondary objectives 
include determining whether Bronchitol leads to other improvements in other MCC 
measures, FEV1, respiratory symptoms and treatment satisfaction.   
 
3.3.1 Potential Risks 
i. Related to Bronchitol: Inhaled mannitol can cause transient cough, bronchospasm, and 
hemoptysis2. Based on published reports, the overall rate of intolerability is after 
bronchodilator pretreatment appears to be ~6%10. To minimize risks, patients with a history 
of intolerance to hypertonic saline or mannitol and patients with significant hemoptysis (≥60 
mL) in the previous three months will be excluded. The ability to tolerate inhaled mannitol will 
be tested at Visit 1 (after baseline MCC measured), via a Bronchitol Tolerance Test (BTT). A 
20% drop in FEV1 or 10% drop in baseline SpO2 after serial increases in Bronchitol dose will 
preclude further study participation. A bronchodilator (albuterol or levalbuterol) via metered 
dose inhaler will be administered prior to each dose of the study medication. The multiple 
precautionary measures should substantially limit any risk associated with the use of this 
therapy.  
 
ii. Related to radiation exposure: The amount of radiation dose received during a given study 
(2 MCC scans) is approximately 0.9 mSV. The risk from the radiation dose received from 
this procedure is too small to be detected but is significantly less than the radiation dose 
received from the natural environment over the course of 1 year (3 mSv). Since radiation risk 
is a cumulative risk concern, an eligibility criterion has been added to exclude patients 
whose recent radiation exposure is greater than typical. Typically, significant additional 
radiation exposure in CF patients (above environmental exposure) would come from chest 
computed tomography (CT) procedures. Patients who have had more than 2 chest CTs in 
the past year or a combination of procedures that are believed to have exposed the subject's 

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lungs to >150 mSv would be excluded. In addition, a potential risk of radiation exposure to 
an unborn fetus exists among pregnant females. All those able to become pregnant will be 
required to undergo a pregnancy test at screening and before each MCC scan. 
 
3.3.2 Potential Benefits 
Potential benefits include improvement in transiently promoting the clearance of secretions 
and inhaled infectious agents, thereby improving respiratory symptoms, lung function, and 
exacerbation frequency in PwCF. 
 
 

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4 - Study Objectives 
4.1 Hypothesis 
This trial is designed to test the hypothesis that Bronchitol leads to a sustained improvement 
in MCC in adults with moderate to severe cystic fibrosis lung disease (FEV1 30% to 70%) 
who are being treated with E/T/I. 
 
4.2 Primary Objective 
The primary objective of this study is to measure the sustained effect of Bronchitol on whole 
lung mucociliary clearance from 0-60 minutes (MCC60) in PwCF with moderate to severe 
lung disease who are using E/T/I. 
 
4.3 Secondary Objectives (if applicable) 
Secondary objectives include determining whether Bronchitol leads to improvement in other 
measures of MCC, FEV1, respiratory symptoms, and treatment satisfaction in PwCF with 
moderate to severe lung disease who are using E/T/I. 
 
 

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5 - Study Design 
5.1 General Design Description 
The proposed study is an open-label, interventional study. Patients meeting inclusion criteria 
and having no exclusion criteria will be enrolled into the study, which will be conducted at up 
to four sites. Study treatment will be Bronchitol (dry powder mannitol) 400 mg twice a day by 
oral inhalation (the contents of 10 capsules administered individually) for 14 days +/- 2 days.  
 
The study will consist of a screening visit and two study visits separated by 14 +/- 2 days. 
Screening procedures may be completed on the same day as Visit 1 if a subject has not 
used nebulized hypertonic saline in the preceding 14 days. No study procedures will be 
completed prior to obtaining subject's informed consent. A medical history will be conducted 
at the screening visit, followed by physical exam. At Visit 1, PRO administration will be 
followed by a physical exam, spirometry, and MCC. Prior to completion of Visit 1, a BTT will 
be conducted followed by instruction on home use of Bronchitol. Subjects who do not pass 
the BTT will be excluded from the study and data analysis and will be replaced. Subjects 
who pass the BTT will be instructed to self-administer Bronchitol 400 mg twice a day via oral 
inhalation for the next 14 +/- 2 days until the day prior to Visit 2. At Visit 2, PRO 
administration, physical exam, spirometry, adverse event review and MCC will be performed. 
Subjects will be instructed to hold the study drug, home bronchodilators and dornase alfa on 
the day of Visits 1 and 2. 
 
5.1.1 Study Date Range and Duration 
The study is expected to take place over approximately 1 year. The estimated start date is 
March 1, 2022.  
 
5.1.2 Number of Study Sites 
This study will be conducted at up to 4 sites that are part of the CF Foundation MCC 
National Resource Center.  The central coordinating site and MCC scan reading site will be 
at the University of North Carolina at Chapel Hill.  
 
5.2 Outcome Variables 
 
5.2.1 Primary Outcome Variables 
The primary outcome will be the average rate of MCC measured in the whole right lung 
compartment over 60 minutes (MCC60), calculated using point estimates collected every 10 
minutes.  
 
5.2.2 Secondary Outcome Variables 

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Secondary MCC outcomes will include changes in the rate of cough clearance (CC) from 60-
90 minutes, MCC rates measured in other lung compartments (central, peripheral lung) and 
over other time domains (90 minutes, 6 hours). We will include an analysis of lung function 
(change in post-bronchodilator FEV1) as a secondary outcome.  
 
To assess the effect of Bronchitol on respiratory symptoms, we will use the validated 
respiratory symptom domain of the CFQ-R questionnaire and the CFRSD-CRISS11,12. As 
treatment burden is also a potential benefit to inhaler delivery of an osmotic agent for airway 
clearance, the score on the TSQ will be a secondary outcome13. 
 
5.3 Study Population 
 
5.3.1 Number of Participants 
We want to follow 22 PwCF with moderate to severe lung function decline who are currently 
being treated with E/T/I. We expect 10% of subjects to terminate early either due to failure of 
the BTT or for other reasons. Therefore, we will enroll 25 subjects in our study. 
 
5.3.2 Eligibility Criteria/Vulnerable Populations 
Inclusion Criteria:  
1. Able to provide informed consent 
2. Age ≥ 18 at the time of screening 
3. Diagnosis of CF  
4. Regularly using E/T/I for ≥ 90 days 
5. FEV1 between 30% and 70%, inclusive, at time of screening 
6. Denies active smoking or vaping 
7. Clinically stable with no significant changes in health status within the 28 days prior to and 
including the screening visit 
8. Patients on cycled inhaled antibiotics will need to be either on or off their antibiotic for 7 
days prior to Visit 1 and not scheduled to cycle during the 2-week treatment period until after 
Visit 2 
9. Has no other conditions that, in the opinion of the Site Investigator/Designee, would 
preclude informed consent, make study participation unsafe, complicate interpretation of 
study outcome data, or otherwise interfere with achieving the study objectives 
 
Exclusion Criteria: 
1. Use of an investigational drug within 28 days prior to and including the screening visit 

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2. Unable or unwilling to withhold HS for 4 weeks (2 weeks prior to Visit 1 and 2 weeks 
between Visit 1 and Visit 2) 
3. Unable or unwilling to withhold dornase alfa and bronchodilators on the morning of Visit 1 
and Visit 2, until completion of study procedures 
4. Initiation of new chronic CF pulmonary therapy (e.g. dornase alfa, azithromycin, inhaled 
antibiotic) within 28 days prior to and including the screening visit 
5. No acute use of antibiotics (oral, inhaled, or IV) or acute use of systemic corticosteroids 
for respiratory tract symptoms within 28 days prior to and including the screening visit. 
6. No chronic use of oral corticosteroids > 10 mg of prednisone or equivalent daily 
7. Unable to tolerate albuterol or other bronchodilator 
8. History of intolerance to HS or inhaled mannitol 
9. Pregnancy or breast feeding 
10. Have had more than 2 chest CTs in the past year or a combination of procedures that 
are believed to have exposed the subject's lungs to >150 mSv  
11. History of significant hemoptysis (≥ 60 mL) in the last three months 
 
This study will not enroll children, pregnant women, decisionally-impaired individuals, or 
other members of vulnerable populations. 
 
 

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6 - Methods 
6.1 Treatment - Drug 
 
6.1.1 Identity of Investigational Product/New Drug 
The study drug is Bronchitol - a sugar alcohol indicated as an add-on maintenance therapy 
to improve pulmonary function in adult patients 18 years of age and older with cystic fibrosis.  
 
6.1.2 Dosage, Admin, Schedule (if applicable) 
Bronchitol should be administered 400 mg (the contents of 10 capsules administered 
individually) via oral inhalation twice daily. A short-acting bronchodilator should be 
administered 5-15 minutes before each dose of Bronchitol. The Bronchitol inhaler should be 
discarded and replaced after 7 days of use.  
 
6.1.3 Packaging/Labelling 
The inhalation powder is a clear, colorless hard gelatin capsule imprinted with "PXS 40 mg" 
and contains 40 omg of mannitol per capsule. The accompanying white plastic inhaler is 
comprised of a mouthpiece, blue piercing buttons, capsule chamber and a removable cap. A 
blister pack consists of 10 capsules. After a capsule is placed in the capsule chamber and 
pierced by firmly pressing and releasing the buttons on the side of the device, the powder 
within the capsule becomes exposed and ready for dispersion into the airstream generated 
by the patient upon inhalation through the mouthpiece. Under standardized in vitro test 
conditions, the inhaler delivers 32.2 mg of mannitol per inhalation when tested at a flow rate 
of 60 L/min for 2 seconds. The actual amount of drug delivered to the lungs will depend on 
patient factors, such as inspiratory flow profile. 
 
6.1.4 Storage Conditions 
Bronchitol should be stored between 68°F-77°F (20°C-25°C) with excursions permitted 
between 59°F-86°F (15°C30°C). The drug should not be refrigerated or frozen.  
 
6.1.5 Concomitant therapy 
A short-acting bronchodilator should be administered 5-15 minutes prior to each dose of 
Bronchitol. 
 
Nebulized hypertonic saline should be held 1-2 weeks prior to Visit 1 and for the duration of 
the study until completion of Visit 2. 
 

Protocol Number 1.4 
14 Mar 2024 
22 
Dornase alfa and bronchodilators should be held on the morning of Visit 1 and the morning 
of Visit 2.  
 
6.1.6 Restrictions 
There are no other restrictions.  
 
6.2 Assessments 
 
6.2.1 Efficacy 
The primary efficacy outcome will be a significant change in the MCC60, the average rate of 
MCC measured in the whole right lung compartment over 60 minutes by 5.4% (absolute 
change). A treatment difference of this magnitude is considered to be both clinically 
meaningful and achievable, as it approximates the sustained effect observed with HS 
treatment in patients with cystic fibrosis.  
 
6.2.2 Safety/Pregnancy-related policy 
Women will undergo a urine pregnancy test at each visit to confirm they are not pregnant.  
  
6.2.2.1 Adverse Events Definition and Reporting 
Adverse Events 
An AE is any untoward medical occurrence during study participation that does not 
necessarily have a causal relationship with the study participation.  An AE is therefore any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom or 
disease temporally associated with participation in the study whether or not related to that 
participation.  An unexpected AE is one of a type not identified in nature, severity, or 
frequency than expected. 
The Investigator will discuss the subject's health status to identify the occurrence of AEs 
during each subject visit and record the information in the site's source documents.  AEs will 
be recorded in the subject CRF.  
AE Severity 
The National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0, as modified for CF, should be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant. The modified criteria can be found 
on the Study Website.  If the experience is not covered in the modified criteria, the 
guidelines shown in the 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. 

Protocol Number 1.4 
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23 
Severity 
(Toxicity 
Grade) 
Description 
Mild (1) 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Moderate (2)     Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate Instrumental activities of daily living (e.g., preparing 
meals, using the telephone, managing money) 
Severe (3)        Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self care activities of daily living (e.g., bathing, dressing, feeding 
self, using toilet, taking medications) 
Life-
threatening (4) 
Life-threatening consequences; urgent intervention indicated 
Death (5) 
Death related to AE 
  
AE Relationship to Study Procedures 
The relationship of an AE to study procedures should be assessed using the following 
guidelines. 
Relationship to 
Treatment Arm 
Assignment  
Comment 
Definitely 
An event that occurs follows a reasonable temporal sequence after  
a study procedure that is not explained by any other reasonable 
hypothesis. 
Probably 
An event that follows a reasonable temporal sequence after a study 
procedure; and that is not explained by any other reasonable 
hypothesis; and that is unlikely to be explained by the known 
characteristics of the subject's clinical state or by other interventions. 

Protocol Number 1.4 
14 Mar 2024 
24 
Possibly 
An event that follows a reasonable temporal sequence after a study 
procedure; but that could readily have been produced by a number 
of other factors. 
Unrelated 
An event that can be determined with certainty to have no 
relationship to a study procedure. 
Serious Adverse Experiences (SAE) 
An SAE is defined as any AE that results in any of the following outcomes: 
• 
death 
• 
a life-threatening adverse experience 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly/birth defect 
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to prevent 
one of the outcomes listed. 
 
Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur on an SAE Report Form.  The collection period 
for all SAEs will begin after informed consent is obtained and end after procedures for the 
final study visit (Visit 2) have been completed. 
All SAE Report Forms will be reviewed by the site investigator and sent to the coordinating 
site (UNC) within one business day of the site learning of the event.  Sites will send the SAE 
report by either: 
• 
Email (scanned copy) to: sasellers@med.unc.edu 
• 
Fax: (984) 974-2968 
The site will notify the coordinating site of additional information or follow-up to an initial SAE 
Report as soon as relevant information is available.  The coordinating site PI may request 
additional information related to the SAE. Follow-up information is reported on an SAE 
Report Form. 
In accordance with the standard operating procedures and policies of the Institutional 
Review Board (IRB), the site investigator will report SAEs to the IRB.   
  
6.3 Study Procedures 

Protocol Number 1.4 
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25 
Medical History and Physical Examination:  
During the screening visit, each patient will be questioned concerning medical history. 
Medical conditions, current medication use, and drug allergies will be recorded.  A complete 
physical examination will be performed by a physician investigator.  At Visits 1 and 2, inquiry 
into adverse events, new symptoms, and medication use will be performed, as will a focused 
physical examination (vital signs, head, neck, pulmonary and cardiac exams). 
Vital Signs:  
Temperature, respiration rate, heart rate, oxygen saturation, and blood pressure will be 
recorded at each study visit prior to pulmonary function tests.   
Spirometry:  
Spirometry will be performed at screening to determine eligibility. At visits 1 and 2, 
spirometry will be performed to assess efficacy. On each occasion, the best of 3 trials, based 
on ATS/ERS criteria.  The best FVC, FEV1 and FEF25-75 (from trial with highest FVC+FEV1 
sum) will be recorded (absolute value and % of predicted). If subject accidentally uses 
bronchodilator the morning of visit, spirometry will be collected in the same fashion at the 
next visit.  
Pregnancy Test:  
Every female of childbearing potential (first menses has occurred) will have a urine 
pregnancy test conducted before each study visit. If either of these tests is positive, the 
patient will be withdrawn from the study. 
Measurement of MCC:  
MCC measurement will be performed at baseline (Visit 1) and following 14 +/- 2 days of 
Bronchitol self-administration (Visit 2). Site staff will confirm that the subject meets other 
eligibility for the procedure (i.e., is not pregnant, symptomatic and has withheld the required 
medications before proceeding with the MCC procedure. A transmission scan (solid sheet 
containing Co57, placed in front of the body) of the subject's lungs will be obtained. Detailed 
instruction will be included in a Study Specific Procedure document. For each measure of 
MCC, the subject will inhale an aerosol of sulfur colloid labeled with Tc99m. Inhalation will 
occur until ~40 μCi of radioactivity is deposited in the lungs of subjects, which typically takes 
approximately two minutes. An initial deposition scan will then be recorded within 5 minutes 
of completing the inhalation, after clearing the oropharynx of activity by drinking a small 
glass of water. The subject will then remain seated in front of the gamma camera while 
continuous two-minute images are recorded. The subject will be expected to remain aligned 
on camera for the first 34 minutes of the scan and then for the first 4 minutes out of each 10-
minute epoch until 94 minutes has elapsed.  During the first 64 minutes of imaging, subjects 
will be encouraged to suppress spontaneous coughing so that cilia-driven clearance can be 
assessed. From 64—94 minutes, they will voluntarily cough through a peak flow meter, to 
achieve a total of 60 coughs during this interval, to assess cough clearance (CC). Voluntary 
coughs will be dispersed evenly during this interval. The peak airflow rate of every fifth 
voluntary cough will be recorded and averaged. Spontaneous cough frequency will be 

Protocol Number 1.4 
14 Mar 2024 
26 
recorded throughout the imaging period. Subjects will return to the lab for a 15-minute 
continuous scan of residual lung activity at 6 hours (±15 minutes) after the initial deposition 
scan. The images collected will be uploaded in dicom format to University of North Carolina, 
Chapel Hill through the secure Accellion MCC fileshare site. Detailed description of this 
procedure is contained in the SILP MCC Standard Operating Procedure Manual (Appendix 
1). 
Bronchitol Tolerance Test:  
Following completion of MCC at Visit 1, all subjects will undergo a Bronchitol Tolerance Test 
(BTT), which will be administered and performed under the supervision of a healthcare 
provider who is able to manage acute bronchospasm, to identify patients who will tolerate 
Bronchitol maintenance therapy. Patients will first have their baseline oxygen saturation 
(SpO2(Oxygen saturation)) measured and then will be instructed to use a short-acting 
bronchodilator 5-15 minutes prior to the first test dose of Bronchitol. They will then be 
instructed to inhale the contents of 1 capsule of Bronchitol (40 mg inhaled mannitol). One 
minute following this, the new oxygen saturation will be obtained; if below 90% of the 
baseline SpO2, the patient will be considered as having failed the BTT. If above 90% of the 
baseline SpO2, the patient will be instructed to inhale the contents of 2 capsules, one 
capsule at a time. After 1 minute, a new SpO2 and FEV1 will be obtained. If the SpO2 is 
lower than 90% of the baseline or the FEV1 is less than 80% of the baseline FEV1 obtained 
prior to MCC, the patient will be considered as having failed the BTT. If both measures are 
above the thresholds, the patient will then be instructed to inhale the contents of 3 capsules, 
one at a time. After 1 minute, a new SpO2 and FEV1 will be obtained. If the SpO2 is lower 
than 90% of the baseline or the FEV1 is less than 80% of the baseline FEV1 obtained prior 
to MCC, the patient will be considered as having failed the BTT. If both measures are above 
the thresholds, the patient will then be instructed to inhale the contents of 4 capsules, one at 
a time. After 1 minute, a new SpO2 and FEV1 will be obtained. If the SpO2 is lower than 
90% of the baseline or the FEV1 is less than 80% of the baseline FEV1 obtained prior to 
MCC, the patient will be considered as having failed the BTT. If both measures are above 
the thresholds, the patient is considered as having passed the BTT and will continue with 
home use of Bronchitol until Visit 2. If the patient fails the BTT at any time, they will be 
terminated from the study. Study staff will use the Bronchitol "Healthcare Practitioner 
Instructions for Use" worksheet to administer the BTT (Appendix 2).  
Quality of Life and Respiratory Symptoms:  
The CFQ-R is a detailed, rigorously designed and validated instrument designed to measure 
quality of life in patients with CF who are 14 years and older11. This instrument was 
developed as the first CF-specific, health-related QOL measure. The respiratory domain has 
a 0-100 scale, with higher values signifying less severe symptoms. The CRRSD-CRISS is 
an 8-item, patient-centered outcome measure evaluating symptom severity over the prior 24 
hours in 8 domains central to CF12. Both questionnaires will be administered during Visits 1 
and 2 to assess efficacy of the treatment on symptom burden as a secondary outcome.   
Treatment Satisfaction:  

Protocol Number 1.4 
14 Mar 2024 
27 
The TSQM is a 14-question standardize measure for assessment of treatment satisfaction 
and has been valued for use of inhaled medications in PwCF13.  It will be administered prior 
to MCC measurement at Visit 1 and Visit 2. The TSQM items are answered on 5- or 7-point 
Likert type scale and cover four domains, corresponding to distinct aspects related to the 
satisfaction of patients with their treatment (Effectiveness; Side effects; Convenience and 
Global satisfaction). The questionnaire is scored on a 0-100 scale, with higher values 
indicated greater satisfaction.  
 
6.3.1 Study Schedule 
The following procedures at the specified study visit will be performed in the listed order of 
conduct: 
A. Screening Visit 
• 
Informed consent 
• 
Medical history 
• 
Vital signs 
• 
Urine pregnancy test (for females of child-bearing potential) 
• 
Full physical examination 
B. Visit 1 (0 or 14+/-3 days after screening) 
• 
Questionnaire administration 
• 
Vital signs (not required if performed same day as screening) 
• 
Abbreviated physical examination (not required if performed same day as screening) 
• 
Urine pregnancy test (for females of child-bearing potential)  
• 
Spirometry  
• 
Mucociliary clearance measurement 
• 
Bronchitol tolerance test 
C. Visit 2 (14 +/- 3 days after Visit 1) 
• 
Questionnaire administration 
• 
Vital signs 
• 
Abbreviated physical examination 
• 
Adverse event assessment 
• 
Spirometry 
• 
Mucociliary clearance measurement 
 

Protocol Number 1.4 
14 Mar 2024 
28 
6.3.2 Informed Consent 
The patient agrees to participate in the study by signing and dating the informed consent 
form after the nature of the study has been fully explained and all questions have been 
satisfactorily answered.  
 
6.3.3 Screening 
Screening will be conducted by a member of the study staff. After initial chart review 
indicating preliminary inclusion/exclusion criteria are met, study staff will discuss the study 
with the patient in the clinic or via telephone, and if they are agreeable, arrange for a 
screening visit. At the screening visit, inclusion and exclusion criteria will again be reviewed 
and if met, informed consent will be obtained. Following this, subjects will undergo medical 
history review, physical examination, medication review, urine pregnancy testing (if 
applicable) and spirometry measurement.  
 
6.3.4 Recruitment, Enrollment and Retention 
Following screening procedures, informed consent and enrollment into the study, a member 
of the study staff will determine when Visit 1 can be scheduled based on subjects' last 
reported use of nebulizer hypertonic saline. Visit 1 can be scheduled as early as the same 
day as screening, but the subject must report no use of nebulized hypertonic saline within 14 
days of Visit 1. If the subject has used hypertonic saline on the day of the Screening Visit, 
Visit 1 must be scheduled at least 14 days from that point and the subject will be required to 
withhold hypertonic saline during that time. Study staff will send the subject a reminder prior 
to Visit 1 via telephone or electronic communication. 
 
At the completion of Visit 1, once the subject has been determined to pass the BTT, study 
staff will schedule Visit 2 in 14 +/- 2 days. Study staff will send the subject a reminder prior to 
the visit via telephone or electronic communication. 
 
6.3.6 End of Study and Follow-up 
Subject participation will be complete at the end of Visit 2 or at the time of withdrawal for 
subjects who elect to withdraw early or do not pass the BTT. No further attempts will be 
made to contact subjects beyond this point for study purposes.  
 
6.3.7 Removal of subjects 
Subjects will be withdrawn from the study if they report pregnancy or test positive on 
pregnancy testing or if they fail the BTT. Subjects may choose to withdraw voluntarily at any 
time during the study for any reason. If subject has been given Bronchitol to use at home at 
the time of withdrawal, study staff will ask that the Bronchitol and inhaler be discarded and 

Protocol Number 1.4 
14 Mar 2024 
29 
that the subject return to use of airway clearance regimen as prescribed by their primary 
provider. Subjects who prematurely withdraw will be replaced.  
 
Who6.4 Statistical Method 
 
6.4.1 Statistical Design 
To determine the effect of visit, and thus Bronchitol administration on clearance, the MCC60 
will be analyzed with a paired t-test. As a second step, we will include the effect of skew in a 
repeated measure model. Inclusion of deposition skew as a covariate in the primary 
assessment of MCC is an important consideration because increased deposition 
skew/heterogeneity is associated with faster observed MCC rates. This change in MCC rate 
reflects increased radio-aerosol deposition in large airways, which have intrinsically faster 
MCC rates. The described mixed effect model will, therefore, allow us to determine whether 
there is an effect of treatment (reflected by the visit covariate) on MCC independent of any 
potential changes in deposition skew. Exploration of other parameters including site location, 
age, sex, etc. will be performed by visualizing box plots and scatter plots of MCC60 organized 
by each variable. Remaining secondary outcomes will be evaluated using paired t-tests to 
determine differences before and after treatment with Bronchitol.  
 
6.4.2 Sample Size Considerations 
The proposed sample size of 22 patients enrolled and completing two visits should provide 
approximately 80% power at a two-sided significance level of 0.05 to detect a treatment effect 
of 5.4% (absolute change in MCC60).  This calculation is based upon prior data, which 
revealed a standard deviation of within-patient difference of 8.5%.  A treatment difference of 
this magnitude is considered to be both clinically meaningful and achievable, as it 
approximates the sustained effect observed with HS treatment in patients with CF. 
 
6.4.3 Planned Analyses 
 
6.4.3.1 Primary Analyses 
The primary outcome, MCC60 will be reported using means and standard deviation, with 
associated 95% confidence intervals at each visit. The mean change of MCC60 between the 
2 visits will also be reported with associated 95% confidence intervals. The data will also be 
plotted in box plots. MCC60 between the 2 visits will be analyzed with a 2-sided paired t-test. 
We know from previous studies that skew affect MCC60. Therefore, MCC60 will also be 
analyzed using a linear repeated measure model including visit number, skew of the 
deposition histogram as fixed effects. The effect of (visit x skew) as an interaction term will 
be explored, and if significant, will be included in the model. P-values below 0.05 will be 
considered significant.  

Protocol Number 1.4 
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30 
 
6.4.3.2 Secondary Objectives Analyses 
All secondary outcomes, including CC, average clearance over alternative intervals (90 
minutes), MCC clearance of central and peripheral lung regions, and pre-bronchodilator 
FEV1 will all be reported using means and standard deviations, with associated 95% 
confidence intervals at each visit. Total CFQ-R, CFRSD-CRISS, and TSQ scores will be 
considered continuous and will also reported using means and 95% confidence intervals.    
The effect of treatment will be evaluated using 2-sided paired t-tests on all secondary 
outcomes. A repeated measures model will also be used to analyze MCC90 with visit number 
and skew as fixed effects. P-values below 0.05 will be considered significant.  
Exploration of the effect of site location, age, sex, %FEV1 and CFQ-R and TSQ scores on 
MCC60 will be explored using repeated measure models. 
 
6.4.3.3 Safety/Pregnancy-related policy 
Adverse events will be collected and coded per MedDRA, version 9 or higher, and tabulated 
by treatment exposure. The proportion of patients experiencing an adverse event for each 
treatment exposure will be reported, and 95% confidence intervals will be computed for the 
proportions using exact binomial methods.  
6.4.3.4 Analysis of Subject Characteristics 
The following clinico-demographic information from subjects will be collected via chart review 
and at the screening assessment: Age, gender, race/ethnicity, height, weight, BMI, baseline 
FEV1 % predicted, clinical microbiology, CFTR genotype, CF-related comorbidities, and 
concomitant CF medications. Data will be tabulated and means with standard deviations 
reported.  
 
6.4.5 Handling of Missing Data 
Subjects who do not complete the 2 visits will be listed and reasons for drop-off will be 
reported. The final dataset will include all subjects who complete both visits per protocol. If 
any value is missing, it will be considered missing at random and will not be replaced.  
 
 

Protocol Number 1.4 
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31 
7 - Trial Administration 
7.1 Ethical Considerations: Informed Consent/Assent and HIPAA Authorization 
This protocol 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). 
 
Prior to enrolling a subject in the trial, the Investigator must explain the purpose of the study, 
describe the procedures that will be performed, how the study medication will be use, and 
explain the potential risks associated with participation in the trial to the subject. Subjects will 
be informed that their participation is voluntary, and they may withdraw consent to participate 
at any time. In order to participate in the study, each subject must sign the informed consent 
(and other locally required documents) after the nature of the study has been fully explained. 
The consent form must be signed and dated prior to performance of any study-related 
activity. Subjects must be given the opportunity to ask questions. The subject will be given 
sufficient time to read the informed consent and to ask additional questions. After this 
explanation and before entry into the trial, consent should be appropriately recorded by 
means of either the subject's dated signature or the signature of an independent witness 
who certifies the subject's consent in writing. After having obtained the consent, a copy of 
the informed consent form (ICF) must be given to the subject. If the subject is unable to 
read, an impartial witness must attest the informed consent.  
 
The collection and processing of personal data from subjects enrolled in this trial will be 
limited to those data that are necessary to investigate the safety, quality, and utility of the 
investigational agent used in this trial. These data will be processed with adequate 
precautions to ensure confidentiality. Confidentiality will be maintained throughout the 
complete data processing.  
 
7.2 Institutional Review Board (IRB) Review 
The protocol and consent forms will be reviewed and approved by the IRB on record prior to 
study initiation.  SAEs regardless of relationship to study procedures will be reported to the 
IRB in accordance with the standard operating procedures and policies of the IRB, and the 
Investigator will keep the IRB informed as to the progress of the study.  The Investigator will 
obtain assurance of IRB compliance with regulations. 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol 
amendments, consent forms, information concerning patient recruitment, payment or 
compensation procedures, or other pertinent information) will be submitted to the IRB.  The 
IRB's 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's unconditional 
approval statement will be transmitted by the Investigator to the Sponsor or designee prior to 

Protocol Number 1.4 
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32 
the shipment of study supplies to the site.  This approval must refer to the study by exact 
protocol title and number and should identify the documents reviewed and the date of 
review. 
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB approval except when necessary to eliminate immediate hazards to the subjects 
or when the change(s) involves only logistical or administrative aspects of the study.  Such 
modifications will be submitted to the IRB and written verification that the modification was 
submitted and subsequently approved should be obtained.   
The IRB 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. 
 
7.3 Subject Confidentiality 
The collection and processing of data from subjects enrolled in this trial will be limited to 
those data that are necessary to investigate the safety, quality and utility of the 
investigational agent(s) used in this trial. These data will be processed with adequate 
precautions to ensure confidentiality. Only a site number and subject number will identify all 
study subjects on CRFs and other documentation submitted to the Sponsor. Confidentiality 
will be maintained throughout the complete data processing.  
 
7.4 Deviations/Unanticipated Problems 
A protocol violation occurs when the subject, investigator, or the Sponsor fails to adhere to 
significant protocol requirements affecting the eligibility, subject safety and primary endpoint 
criteria.  Protocol violations for this study include, but are not limited to, the following: 
• 
Failure to meet eligibility criteria 
• 
Defined “major” errors in MCC SOP execution (see Appendix 1) 
 
7.5 Data Collection 
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject who signs 
informed consent. 
Study personnel at each site will enter data from source documents corresponding to a 
subject's visit into the protocol specific CRF when the information corresponding to that visit 
is available.  Scanned paper CRFs will be uploaded along with study images (DICOM 
format) to the central reading site via a secure Accellion file transfer system. A REDCap 
database will be designed to house non-image data. Study images will be stored in a secure 
file location with daily electronic back-up. Subjects will not be identified by name in the study 

Protocol Number 1.4 
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33 
database or on any study documents to be collected by the Sponsor (or designee) but will 
be identified by a site number and subject number. Signed consent forms will be saved in a 
regulatory binder maintained in a locked office at each site. 
The Investigator is responsible for all information collected on subjects enrolled in this study.  
All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the Investigator.  
 
7.6 Data Quality Assurance 
After data have been entered into the study database, data validation checks will be applied 
on a regular basis. Queries will be generated as needed to clarify and confirm submitted 
data.  The study database will be updated in accordance with the resolved queries. 
 
7.7 Study Records 
The Investigator must make study data accessible to authorized representatives of the 
Sponsor (or designee), IRB, and Regulatory Agency (e.g., FDA) inspectors upon request. 
MCC image data will be maintained electronically. All paper hard copies including ICF, 
HIPAA authorization, source documents and CRFs will be stored in a regulatory binder at 
the study site in a locked office. Site PIs must ensure the reliability and availability of source 
documents from which the information on the CRF was derived. 
 
7.8 Data or Specimen Storage/Security 
MCC image data will be transmitted to and maintained by the central reading site via a 
secure Accellion file transfer system. Visit log sheets and paper CRFs will also be uploaded 
via the Accellion file transfer system.  Key data elements will then be recorded into, a 
secure, web-based REDCap database. Only study staff will have access to the database.  
 
7.10 Retention of Records 
All study documents must be kept secured for a period of two years after database lock. 
 
7.12 Data Safety Monitoring Plan 
The Sponsor, Dr. Sellers, is an Assistant Professor of Medicine with experience in clinical 
research. It will be her responsibility to review any unanticipated problems and adverse 
events that occur during the conduct of the study. 
Adverse events will be collected at study visits by the clinical research coordinator and/or 
other members of the study team.  Each event will be recorded into the study record. The 
attribution (related, unrelated), severity, and outcome of each event will be reviewed by a 
site physician investigator. All IRBs of record will be notified of any serious adverse events 
and any unanticipated, suspected adverse reactions within 48 hours of becoming aware of 
the event. Other adverse events will be summarized and reported at least annually. 

Protocol Number 1.4 
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34 
 
7.13 Study Modification 
The primary investigator assumes responsibility for reporting protocol amendments and any 
necessary ICF revisions to the IRB.  
 
7.14 Study Completion 
The expected completion date of the study is March 1, 2023. The primary investigator will 
notify the IRB of study completion at that time. 
 
7.15 Conflict of Interest Policy 
 
7.17 Funding Source 
Pending. 
 
7.18 Publication Plan 
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual 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. 
 
 

Protocol Number 1.4 
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Appendix 1 
Slow Inhalation Large Particle (SILP) Procedure  
  
A. Introduction and Rationale  
The SILP MCC Procedure is designed to deliver large (~9 um MMAD) particle aerosol in a 
controlled delivery at a slow inhalation flow rate (55 ml/sec). This method increases large 
and small airway deposition while reducing oral and alveolar deposition, and is 
accomplished without requiring a dosimeter.  
  
B. Equipment and supplies  
Pari compressor (Trek-S)  
Rotameter (range 0-20 L/min)  
Steam sterilizer (Phillips Avent)  
Large syringe for leak test (e.g. 1L, 3L spirometry syringe)  
Nose clips  
SILP Aerosol Delivery Assembly: (provided by MCC NRC Coordinating Center)  
Mouth piece (disposable)  
Pari SPRINT XLent nebulizer (single patient use)  
Tubing for connecting nebulizer to compressor  
Curved connector (top of nebulizer to exhalation path)  
Short straight connector (curved connector to Pall BB50T filter)  
Pall BB50T exhalation filter (disposable)  
Y-connector (Pall BB50T exhalation filter to exhalation valve and pressure 
transducer)  
Rudolph one way valve to fit in exhalation tubing  
Tubing to connect Y-valve to Magnehelic pressure gauge  
Magnehelic pressure gauge   
Lead shielded case for delivery components  
  
  
C. Camera quality control procedures:  
  
1. Perform sensitivity test for any camera to be used (once; see below) and is 
known/documented  
a. Take a 10 min image without nearby activity to assess background; record 
total field of view value (kcps) and save for future reference  

Protocol Number 1.4 
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36 
b. Obtain 50 uCi of Tc99m and place in a petri dish in adequate volume to cover 
bottom of dish  
c. Place dish containing Tc99m on top of horizontally positioned camera head 
and record for 1 min.  Save kcps value for future reference. This should be at 
least 6x background value  
2. Ensure automatic decay correction is turned off (perform test if unknown/uncertain)  
a. Open acquisition protocol to be used in MCC study (serial 2 min images; 
dynamic)  
b. Place petri dish containing 50 uCi of Tc99m onto camera and record for 60 
min  
c. If decay correction is turned off, a ~10% reduction in kcps should be observed 
at the end of the imaging period relative to t=0  
3. Perform flood image to assess camera homogeneity at least monthly, as per local 
guidelines.   
  
  
  
 

Protocol Number 1.4 
14 Mar 2024 
37 
D. Aerosol delivery setup  
• 
See Figures 1,2,3.  
• 
Before setting up aerosol delivery assembly, inspect the nebulizer jet and use a fine 
needle to clean the holes if you observe any residual sulfur colloid or foreign material.  
 
Figure 1: SILP Aerosol Delivery Assembly Schematic  
  
Figure 2: SILP Aerosol Delivery Assembly Setup  
  
SUBJECT 
Pari air
compressor
Pari XL 
PALL BB50T Filter 
One way  v alve - open  
to exhalation 
Magnehelic flow
gauge

Protocol Number 1.4 
14 Mar 2024 
38 
  
Figure 3: Mouthpiece setup  
Figure 4: Compressor flow test  
  
E. Testing of equipment  
1. Check compressor flow (Fig. 4): Connect the compressor to the rotameter (flow 
meter), turn on the compressor, the flow should be between 8-10 L/min.  
  
2. Aerosol delivery system leak test (Fig 5): After assembling the aerosol delivery unit, 
connect a large syringe (e.g. 1L or 3L spirometry calibration syringe) to the aerosol 
outlet of the Pari SPRINT XLent nebulizer (in place of mouthpiece).   
a. Gently pull the syringe handle until the needle on Magnehelic pressure gauge 
deflects toward the left (about ½ way to maximum value);   
  
  
Figure 5: System Leak Test.  In left panel, note leftward deflection of needle on Magnehelic 
pressure gauge while gentle aspirating with large volume syringe from nebulizer aerosol output. 

Protocol Number 1.4 
14 Mar 2024 
39 
In right panel, note that the needle stabilizes leftward of zero while obstructing the open port 
on back of Magnehelic with finger, after releasing suction on syringe.  
b. With syringe in place, use your fingertip to block the bottom/open outlet of the 
Magnehelic to determine whether there is a leak – the needle deflection should 
be stable. Release the fingertip quickly then block again check if the needle 
moves then again remains stable. If the needle keeps moving towards zero after 
blocking the outlet it means that there is an air leak somewhere in the nebulizer 
setup, in which case you need to check all the connections, then repeat the test 
until a satisfactory result is obtained.  
  
3. Nebulizer airflow test (Fig 6): With 
assembled aerosol delivery uni, turn on the 
compressor and use your hand with clean 
gloves to block the nebulizer mouth piece 
outlet. The needle on the Magnehelic 
pressure gauge should increase 0.2 inches 
of water) which corresponds to about 55 
ml/sec in this setup.  
  
4. Nebulizer aerosol test: Put about 0.2ml 
normal saline in the nebulizer, turn on the 
compressor, check if the nebulizer  
generates the aerosol. Once aerosol 
generation is confirmed, let the 
compressor run until there is no more aerosol leaving the nebulizer.   
  
After testing the nebulizer, securely attach the mouthpiece to the front of the inhalation 
box for subject use.  
  
F. Placement of Americium-241 sources: Place two Americium-241 sources (1 uCi; shielded 
side facing patient) along the centerline of the subject’s back. The upper marker should 
be placed over the C7 vertebra; the lower marker should be placed below the inferior 
lung margin (~13 inches) but within the camera field of view.  Use a surgical marker to 
circle each source, to allow accurate replacement at the 6 hours and/or 24 hours follow-
up scan.  Tape the Americium sources in place with paper tape. Record the distance 
between the two Americium markers (log sheet).  
  
G. Transmission scan:   
1. Adjust laser pointer to shine on a tape marker placed on subject’s neck (near sternal 
notch) while patient is sitting upright, against camera.  Adjust a mirror to allow subject 
to keep the laser pointer spot on the tape to help maintain alignment later during 
scanning.  
2. Make sure the appropriate camera acquisition protocol is opened (dual isotope state 
imaging with Co and Am windows). Position the subject in front of camera with the 
  
Figure 6: Nebulizer airflow test  

Protocol Number 1.4 
14 Mar 2024 
40 
camera head tilted to 75 degrees. The subject should sit with their back against 
camera while you place the Co57 flat source in front of the subject (~13-15 inches 
from camera head, resting the Co57 source on the chair arms and angling it parallel to 
camera head (i.e. 75 degrees). Check the image on the computer screen and adjust 
the camera height to make sure the image is in the right position.   
3. Start the scan, noting start time (log sheet) and being aware of approximate Co57 
exposure time that is expected (see table)  
4. Remove the Co57 source from camera vicinity once a clear image of the lung outline 
is seen (record exposure time; log sheet)  
5. End the transmission scan acquisition once activity from the Am241 sources can be 
visualized in the appropriate channel. Note time of scan completion (log sheet). Be 
aware that the total transmission scan time will be longer than the time exposed to 
Co57 in most cases. The Co57 exposure time depends on the subject size and activity 
of the Co57 source (see scan time reference table below).  Record height and angle of 
camera head (to be replicated at subsequent studies).   
Current Co57 activity  
Time for Co57 exposure  
15-20 mCi  
30 seconds  
10-15 mCi  
1 minute  
7.5 –10 mCi  
90 seconds  
5 - 7.5 mCi  
2 minutes  
2.5 – 5 mCi  
2 ½ minutes  
< 2.5 mCi (time to get a new source)  
3 minutes  
  
H. Background scan:   
1. Ensure subject is aligned and laser pointer shines on the tape marker (do not move 
the tape) while patient is sitting upright against camera.  Adjust mirror to allow subject 
to keep the laser pointer spot on the tape to help maintain alignment during later 
scanning.   
2. With subject appropriately aligned against the camera, begin a 15-minute 
background scan for use as the current visit background.  Ensure that all radioactive 
sources (except Am241 sources on the patient) are removed from the room. Record 
the average background rate (kcps; read off camera in real time; log sheet).  
  
I. Inhalation Procedure:  
1. Subject positioning and preparation: Ensure the proper camera protocol (Tc99 and 
Am241 windows) is selected. Have the subject wear a disposable gown and gloves. 
Ask the subject to sit in front of the gamma camera, adjust a bedside table to the 
proper height to make sure the subject’s head is level with the aerosol delivery 
assembly, without needing to bend neck or slouch once the mouthpiece is in their 

Protocol Number 1.4 
14 Mar 2024 
41 
mouth. During the maneuvers, they should sit with both feet on ground. Place nose 
clips on subject once ready to proceed with practice manuevers.  
Practice maneuvers: Before loading any radioaerosol, the inhalation maneuvers 
should be practiced. After placing nose clips and putting the mouthpiece in their 
mouth, have the subject briefly hold their breath as you turn on the compressor. If the 
subject is indeed holding their breath the magnehelic pressure should increase 0.2 in 
of water (as with nebulizer airflow test – Fig 6). The subject should then immediately 
begin to gently inhale from the nebulizer for a period of 6 seconds, using a 
metronome to indicate the inhalation time. The closed inhalation loop limits their 
inspiratory flow to that provided by the compressor (55 ml/sec). The magnehelic 
pressure should decrease from the zero setting (leftward; greater than 0.5 inches) in 
which case the subject is receiving the 55 ml/sec delivered from the nebulizer.  At the 
end of 6 second inhalation the subject should exhale at a constant rate (rightward 0.5 
inches of water on Magnehelic) until the compressor has been turned off. **Make 
sure the subject does not come off the mouthpiece until instructed by the operator and the 
compressor has been turned off; otherwise aerosol will be emitted into the room (causing 
contamination if done during radioaerosol inhalation).  
2. Radioaerosol Inhalation Maneuver: After the subject has demonstrated the proper 
breathing technique, load the nebulizer with Tc99m-sulfur colloid (3 mCi in 3ml of 
sterile saline) and begin the inhalation as described above. The subject will come off 
the mouthpiece (after compressor is turned off, as described above) after each 
breath of radioaerosol. Following a momentary rest, repeat the next inhalation breath. 
Generally, 6-10 breaths are required to deposit 40-50 uCi of Tc-SC in the lungs. Use 
the gamma camera to monitor the deposited isotope dose in kcps with their back 
pressed against the camera. The target deposited dose of 40-50 uCi should yield 
camera counts similar to that observed during camera sensitivity test with 50 uCi of 
Tc isotope, and should be well above the background rate.  
After completing the final inhalation, immediately remove the aerosol delivery 
assembly from room, have the subject drink a small cup of water to flush mouth activity into 
the stomach, and remove any contaminated materials (gown, glove, etc.). J. Dynamic scan:   
1. Ensure the subject is lined up properly, using the laser pointer and tape marker on 
neck. Alignment should be accomplished as soon as possible (ideally within 2-3 min) 
of completing the aerosol delivery steps.   
2. Once aligned, simultaneously start a digital timer and dynamic image acquisition 
(consecutive 2 minute images; dual windows for Tc99m and Am241).  Record the 
acquisition start time in study log.   
3. Ask the patient to refrain from coughing if possible (for first 64 minutes of scan).  
Record any spontaneous coughs during the dynamic scan period on the data log 
sheet.   
4. Ensure the patient maintains alignment for the first 34 minutes (17 frames); then 
allow a <6-minute break.  Subsequently, it is extremely important that alignment is 
achieved for the entirety of the first 4 minutes of each ten min period.   
5. Terminate data acquisition at the 94 time point.    
6. Remove the Am241 sources, ensuring their position is adequately marked for 
placement at later time points (e.g. 3, 6, and 24 hours).  

Protocol Number 1.4 
14 Mar 2024 
42 
  
K. Static images at later time points (e.g. 3,6, or 24 hours):   
1. Ensure the camera/chair are returned to the prior recorded positions (height and 
angle).  
2. Replace the Am241 sources to their previous locations on the subject.    
3. Position the subject in front of the camera using the laser point and mirror.   
4. Begin a 15 minute static image acquisition for interval time points < 6 hrs after 
inhalation; use a 30-minute static image acquisition if collecting a later (e.g. 24 hours) 
time point.    
5. Note start/stop time of the image in logsheet. Static images should be performed 
within 15 min of the nominal timepoint up to 6 hrs; 24-hr images should be within 6 
hours of nominal timepoint.   
  
L. Cleaning procedures:   
1. After completing the radioaerosol inhalation, leave the nebulizer and connectors in a 
shielded area (e.g. the lead-shielded delivery box) until the activity has decayed to an 
acceptable level.   
2. When ready to clean, disassemble the delivery apparatus. Discard disposable items 
(Pall BB50T filter; mouthpiece).   
3. Separate the nebulizer, connectors, and mouthpiece and rinse with running water, 
then soak in a warm clear dish soap solution for 5 minutes, followed by a second 
rinse in running water. Finally, place all re-usable components into the steam 
sterilizer, following manufacturer directions to disinfect the equipment. After this 
disinfection step, all components should be allowed to air dry on a clean paper towel, 
then stored appropriately. You should use the same nebulizer (Pari XLent) for all 
visits conducted by an individual subject, then dispose.  
  
 
 

Protocol Number 1.4 
14 Mar 2024 
43 
Appendix 2 
Instructions for Bronchitol Tolerance Test (BTT) 
 
 
 

Protocol Number 1.4 
14 Mar 2024 
44 
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