Clinical trial NCT05954988
Conditions: Idiopathic Pulmonary Fibrosis
Keywords: IPF idiopathic pulmonary fibrosis
Sponsor: Rein Therapeutics
Start date: 2023-07-06; Completion date: 2024-09-25
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study will assess the safety and tolerability of inhaled LTI-03 in treatment naïve participants with newly diagnosed IPF.

Detailed description:
This is a randomized, double-blind, placebo controlled, multi-center, dose escalation, safety and tolerability study of LTI-03 or placebo administered by inhalation in participants recently diagnosed with idiopathic pulmonary fibrosis that have not received prior treatment with anti-fibrotic agents.

The study will contain 2 dose cohorts which will run sequentially.

Eligible participants will be randomized in a 3:1 ratio to either LTI-03 or placebo. Safety data will be reviewed on an ongoing basis. Enrollment in the second cohort will not begin until the Cohort 1 safety data has been reviewed.

The Treatment Period will be 14 days, with subjects self-administering study drug using a provided commercially available dry-powder inhaler.

Arms: arm 1: 2.5 mg LTI-03 BID x 14 days arm 2: 5 mg LTI-03 BID x 14 days arm 3: Matching placebo BID x 14 days
Interventions: intervention 1: LTI-03 intervention 2: Placebo
Intervention descriptions: intervention 1: Caveolin-1-Scaffolding-Protein-Derived Peptide intervention 2: Matching placebo

Protocol documents:
Prot_000.pdf: 
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Protocol No. LTI-03-1002
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CLINICAL STUDY PROTOCOL
TITLE:
A Randomized, Double-Blind, Placebo-Controlled, Phase 1b, Dose 
Escalation, Safety, Tolerability and Pharmacodynamic Biomarker 
Study of Caveolin-1-Scaffolding-Protein-Derived Peptide (LTI-03) in 
Recently Diagnosed, Treatment Naïve Subjects with Idiopathic 
Pulmonary Fibrosis
PROTOCOL NUMBER:
LTI-03-1002
EUDRACT NUMBER:
2022-000083-21
TEST PRODUCT:
LTI-03
SPONSOR: 
Lung Therapeutics, Inc.
3801 S. Capital of Texas Hwy Suite 330
Austin, Texas 78704
VERSION:
5.0
DATE OF PROTOCOL:
04 May 2023
SPONSOR PROTOCOL 
APPROVAL 
SIGNATURE:
Steven Shoemaker, MD
Acting Chief Medical Officer
CONFIDENTIALITY 
STATEMENT:
The information in this document is confidential and is not to be 
disclosed without the written consent of Lung Therapeutics Inc. except 
to the extent that disclosure would be required by law and for the 
purpose of evaluating and/or conducting a clinical study for Lung 
Therapeutics Inc. 
STATEMENT OF 
COMPLIANCE:
This study will be conducted in accordance with the ethical principles 
that have their origin in the Declaration of Helsinki, and clinical 
research guidelines established by the United States Code of Federal 
Regulations (21 CFR Parts 50, 56, and 312), and the International 
Council for Harmonisation (ICH) E6(R2) Guidelines on Good Clinical 
Practice (GCP).  This study will also adhere to the European Medicines 
Steven Shoemaker MD


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Authority (EMA), Medicines and Healthcare Products Regulatory 
Agency (MHRA), country, state and/or local regulatory requirements. 
 
 


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INVESTIGATOR AGREEMENT 
TITLE: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 1b, 
Dose Escalation, Safety, Tolerability and Pharmacodynamic 
Biomarker Study of Caveolin-1-Scaffolding-Protein-Derived 
Peptide (LTI-03) in Recently Diagnosed, Treatment Naïve 
Subjects with Idiopathic Pulmonary Fibrosis 
PROTOCOL NUMBER: 
LTI-03-1002 
TEST PRODUCT: 
LTI-03 
VERSION:  
5.0 
DATE OF PROTOCOL: 
04 May 2023 
 
This clinical study protocol has been subjected to critical review and has been released by the 
Sponsor.  The information it contains is consistent with current risk and benefit evaluation of the 
investigational medicinal product, as well as with the moral, ethical, and scientific principles 
governing clinical research as set out in the Declaration of Helsinki (Version 2013), and the 
guidelines on Good Clinical Practices (GCP) applicable to this clinical study.   
I have read the Protocol LTI-03-1002 and agree to conduct the study according to its terms.  I 
understand that all information relating to LTI-03 and this protocol supplied to me by Lung 
Therapeutics, Inc. is confidential. 
 
 
 
 
Principal Investigator's Name (print) 
 
Site Number 
 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of the signed 
form as instructed. 


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TABLE OF CONTENTS 
List of Abbreviations .................................................................................................................................. 8 
Protocol Synopsis ...................................................................................................................................... 12 
Key Study Contacts ................................................................................................................................... 18 
1 
Background Information And Scientific Rationale .................................................................. 19 
1.1 
Background Information ......................................................................................................... 19 
1.1.1 
LTI-03 ............................................................................................................................... 19 
1.2 
Scientific Rationale ................................................................................................................. 22 
1.2.1 
Dose Rationale .................................................................................................................. 22 
1.3 
Potential Risks and Benefits .................................................................................................... 22 
2 
Study Objectives And Endpoints ................................................................................................ 24 
2.1 
Objectives ................................................................................................................................ 24 
2.1.1 
Primary Objective ............................................................................................................. 24 
2.1.2 
Exploratory Objectives ..................................................................................................... 24 
2.2 
Endpoints ................................................................................................................................. 24 
2.2.1 
Primary Endpoint .............................................................................................................. 24 
2.2.2 
Other Safety Endpoints ..................................................................................................... 24 
2.2.3 
Exploratory Endpoints ...................................................................................................... 24 
3 
Study Design ................................................................................................................................. 25 
4 
Study Subjects .............................................................................................................................. 26 
4.1 
Eligibility Criteria.................................................................................................................... 26 
4.1.1 
Inclusion Criteria .............................................................................................................. 26 
4.1.2 
Exclusion Criteria ............................................................................................................. 26 
5 
Study Drug .................................................................................................................................... 29 
5.1 
Formulation, Packaging and Labeling ..................................................................................... 29 
5.2 
Storage and Stability ............................................................................................................... 29 
5.3 
Accountability ......................................................................................................................... 29 
5.4 
Administration and Management of Study Drug .................................................................... 29 
5.5 
Method of Assignment to Treatment ....................................................................................... 30 
5.6 
Concomitant and Prohibited Medications ............................................................................... 31 
6 
Study Procedures ......................................................................................................................... 32 
6.1 
Informed Consent .................................................................................................................... 32 
6.2 
Demographics and Medical History ........................................................................................ 32 
6.3 
Vital Signs ............................................................................................................................... 32 
6.4 
Physical Examination .............................................................................................................. 32 
6.5 
Clinical Laboratory Assessments ............................................................................................ 33 
6.5.1 
Pregnancy Test .................................................................................................................. 33 
6.6 
Electrocardiogram ................................................................................................................... 33 


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6.7 
Spirometry ............................................................................................................................... 34 
6.8 
Inhaler Use Assessment ........................................................................................................... 34 
6.9 
Bronchoscopy with Bronchoalveolar Lavage and/or Bronchoabsorption and Deep 
Bronchial Brushing.................................................................................................................. 34 
6.10 
Leicester Cough Questionnaire ............................................................................................... 35 
6.11 
Cough Visual Analogue Scale ................................................................................................. 35 
6.12 
Pharmacokinetic Sampling ...................................................................................................... 35 
6.13 
Exploratory Biomarker Sampling............................................................................................ 35 
6.14 
Treatment, Subject, Study and Site Discontinuation ............................................................... 36 
6.14.1 
Premature Discontinuation of Study Drug ........................................................................ 36 
6.14.2 
Subject Withdrawal of Consent ........................................................................................ 36 
6.14.3 
Replacement of Subjects ................................................................................................... 37 
6.14.4 
Study Discontinuation ....................................................................................................... 37 
6.14.5 
Site Discontinuation .......................................................................................................... 37 
7 
Study Schedule ............................................................................................................................. 38 
7.1 
Screening Period (Day -21 to Day -1) ..................................................................................... 38 
7.2 
Treatment Period ..................................................................................................................... 39 
7.2.1 
Day 1 ................................................................................................................................. 39 
7.2.2 
Days 2-6 ............................................................................................................................ 40 
7.2.3 
Day 7 ................................................................................................................................. 40 
7.2.4 
Days 8-13 .......................................................................................................................... 41 
7.2.5 
Day 14 ............................................................................................................................... 41 
7.3 
Follow-up Period and Day 21 Visit ......................................................................................... 42 
7.4 
Early Termination.................................................................................................................... 42 
8 
Assessment of Safety .................................................................................................................... 43 
8.1 
Specification of Safety Parameters .......................................................................................... 43 
8.2 
Definitions of Adverse Events ................................................................................................ 43 
8.2.1 
Adverse Event ................................................................................................................... 43 
8.2.2 
Serious Adverse Event ...................................................................................................... 43 
8.3 
Adverse Event Classification .................................................................................................. 44 
8.3.1 
Relationship to Investigational Product ............................................................................ 44 
8.3.2 
Severity ............................................................................................................................. 44 
8.4 
Collection and Reporting of Adverse Events .......................................................................... 45 
8.4.1 
Initial Reporting of Adverse Events ................................................................................. 45 
8.4.2 
Adverse Events Reporting Period ..................................................................................... 46 
8.4.3 
Follow-up of Adverse Events ........................................................................................... 46 
8.5 
Collection and Reporting of Serious Adverse Events ............................................................. 46 
8.5.1 
Initial Serious Adverse Event Reports .............................................................................. 46 
8.5.2 
Follow-up of Serious Adverse Events .............................................................................. 47 
8.5.3 
Reporting of Death ............................................................................................................ 47 


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8.6 
Post-Trial Adverse Events ....................................................................................................... 47 
8.7 
Pregnancy Reporting and Follow-up ....................................................................................... 47 
8.8 
Stopping Rules ........................................................................................................................ 48 
8.9 
Emergency Unblinding ............................................................................................................ 49 
8.10 
Emergency Sponsor Contact ................................................................................................... 49 
9 
Statistical Considerations ............................................................................................................ 50 
9.1 
Statistical and Analytical Plans ............................................................................................... 50 
9.1.1 
Randomization Procedures ............................................................................................... 50 
9.2 
Study Hypotheses .................................................................................................................... 50 
9.3 
Analysis Set ............................................................................................................................. 50 
9.3.1 
Safety Analysis Set ........................................................................................................... 50 
9.4 
Statistical Methods and Analysis ............................................................................................ 50 
9.4.1 
General Approach ............................................................................................................. 50 
9.4.2 
Demographics and Other Baseline Characteristics ........................................................... 50 
9.4.3 
Concomitant Medications ................................................................................................. 51 
9.4.4 
Primary Endpoint .............................................................................................................. 51 
9.4.5 
Other Safety Endpoints ..................................................................................................... 51 
9.4.6 
Analysis of Exploratory Endpoints ................................................................................... 52 
9.4.7 
Planned Interim Analyses ................................................................................................. 52 
9.5 
Sample Size Determination ..................................................................................................... 52 
10 
Data Handling and Record Keeping .......................................................................................... 53 
10.1 
Study Files and Subject Source Documents ............................................................................ 53 
10.2 
Data Collection Methods ......................................................................................................... 53 
10.3 
Retention of Records ............................................................................................................... 54 
10.4 
Protocol Deviations ................................................................................................................. 54 
11 
Quality Control and Quality Assurance .................................................................................... 55 
12 
Ethics / Protection of Human Subjects ...................................................................................... 56 
12.1 
Ethical Conduct of the Study ................................................................................................... 56 
12.2 
Ethics Committee Review ....................................................................................................... 56 
12.3 
Informed Consent Process ....................................................................................................... 56 
12.4 
Confidentiality of Information ................................................................................................ 57 
12.5 
Future Use of Stored Specimens ............................................................................................. 57 
12.6 
Publication Policy.................................................................................................................... 57 
13 
References ..................................................................................................................................... 59 
14 
Appendices .................................................................................................................................... 60 
14.1 
Appendix 1 Schedule of Assessments ..................................................................................... 60 
14.2 
Appendix 2  Visit and Procedure Windows ............................................................................ 62 
14.3 
Appendix 3 Leicester Cough Questionnaire ............................................................................ 63 
14.4 
Appendix 4 Cough Visual Analogue Scale ............................................................................. 64 


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14.5 
Appendix 5 Protocol Amendments ......................................................................................... 65 
 
LIST OF TABLES 
Table 1 
Instructions on Multiple Administrations taken at a Time and for Missing the 
Dose .................................................................................................................................. 30 
Table 2 
Clinical Laboratory Assessments ...................................................................................... 33 
Table 3 
Exploratory Biomarkers by Sample Source and Assumed Indicator Function ................. 35 
Table 4 
Adverse Event Severity Grading Scale for Events not Specifically Listed in 
NCI CTCAE ..................................................................................................................... 45 
Table 5 
Schedule of Assessments .................................................................................................. 60 
 
 
 


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LIST OF ABBREVIATIONS 
3H 
hydrogen isotope tritium 
AE 
adverse event 
AECs 
alveolar epithelial cells 
AEC2 
alveolar epithelial type 2 cells 
ALP  
alkaline phosphatase 
ALT  
alanine aminotransferase 
aPTT  
activated partial thromboplastin time 
AST  
aspartate aminotransferase 
ATS 
American Thoracic Society 
AV 
atrioventricular 
BA 
bronchoabsorption 
BAL 
bronchoalveolar lavage 
BALF 
bronchoalveolar lavage fluid 
BD 
twice daily 
BLM 
bleomycin 
BSA 
body surface area 
BUN 
blood urea nitrogen 
Cav-1 
caveolin-1 
CFR  
Code of Federal Regulations 
CK  
creatine kinase 
Cmax  
maximum plasma concentration 
Col-1 
type 1 collagen 
COVID-19 
coronavirus disease 2019 
CRA  
Clinical Research Associate 
CRF  
case report form 
CRO  
Contract Research Organization 
CRP  
C-reactive protein 
CSD 
caveolin-1 scaffolding domain 
Css 
steady state concentration  


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CTCAE 
Common Terminology Criteria for Adverse Events 
DLCO 
diffusion capacity of the lungs for carbon monoxide 
EC 
Ethics Committee 
ECG  
electrocardiogram 
ECM 
extracellular matrix 
eGFR  
estimated glomerular filtration rate 
ELF 
extracellular lining fluid 
EMA 
European Medicines Authority 
EOS  
end of study 
ERS 
European Respiratory Society 
EU 
European Union 
FEV1 
forced expiratory volume 1 
FLF 
fibrotic lung fibroblast 
FN 
fibronectin 
FOCBP 
female of childbearing potential 
FVC 
forced vital capacity 
GCP  
Good Clinical Practice 
GGT  
gamma glutamyltransferase 
GLP  
Good Laboratory Practice 
HDL-C  
high density lipoprotein cholesterol 
Hgb  
hemoglobin 
HR 
Heart rate 
HRCT 
high-resolution computed tomography 
IB 
investigator brochure 
ICF  
informed consent form 
ICH  
International Council for Harmonisation 
ILD 
interstitial lung disease 
IPF 
idiopathic pulmonary fibrosis 
IRT 
interactive response technology 
ITT  
intent-to-treat 


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LDH  
lactate dehydrogenase 
LDL-C  
low density lipoprotein cholesterol 
MAD  
multiple ascending dose 
MCH  
mean corpuscular hemoglobin 
MCHC  
mean corpuscular hemoglobin concentration 
MCV  
mean corpuscular volume 
MedDRA  
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
NCI 
National Cancer Institute 
NOAEL  
no observed adverse effect level 
PD 
Pharmacodynamic 
PK  
pharmacokinetic 
PP  
per protocol 
PT  
prothrombin time 
QD 
once daily 
QTcF  
QT interval corrected for heart rate calculated using Fridericia’s formula 
RBC  
red blood cell 
RDW  
red cell distribution width 
RNA 
ribonucleic acid 
RR 
Respiratory rate 
SAD  
single ascending dose 
SAE  
serious adverse event 
SAP  
statistical analysis plan 
SAS 
Statistical Analysis System 
α-SMA 
alpha-smooth muscle actin 
SOA 
schedule of assessment 
SOP 
Standard Operating Procedure 
SP-C 
surfactant protein-C 
TEAE  
treatment-emergent adverse event 
TN-C 
tenascin-C 


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US  
United States 
VAS 
visual analogue scale 
WBC  
white blood cell 
WHO-DD  
World Health Organization Drug Dictionary 
 


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PROTOCOL SYNOPSIS 
 
Sponsor 
Lung Therapeutics, Inc 
Protocol Number: 
LTI-03-1002 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 1b, Dose 
Escalation, Safety, Tolerability and Pharmacodynamic Biomarker Study of 
Caveolin-1-Scaffolding-Protein-Derived Peptide (LTI-03) in Recently 
Diagnosed, Treatment Naïve Subjects with Idiopathic Pulmonary Fibrosis 
Phase: 
1b 
Investigational Product  
Active Study Drug 
LTI-03 as micronized dry powder in hard 2-piece hypromellose capsules. 
Matching Placebo 
Placebo as micronized lactose powder in capsule. 
Inhalation device: 
Dry powder Inhaler.  
Study Subjects 
The study subject population will consist of patients with idiopathic 
pulmonary fibrosis (IPF) without treatment with anti-fibrotic agents within 
2 months of the Baseline bronchoscopy. 
Number of Subjects 
Planned 
Approximately 24 subjects will be randomized in the study.   
Duration of 
Participation 
Each subject’s duration of participation is up to 42 days, including 21 days 
of Screening Period, 14 days for Treatment Period, and 7 days 
post-treatment Follow-up Visit. 
Investigational Sites 
Approximately 9 investigational sites. 
OBJECTIVES 
Primary Objective: 
· 
To determine the safety and tolerability of inhaled LTI-03 in 
subjects with IPF  
Exploratory Objectives: 
· 
To assess the plasma pharmacokinetic (PK) of inhaled LTI-03 after 
the first dose and at steady state in subjects with IPF  
· 
To evaluate the pharmacodynamic (PD) biomarkers of inhaled LTI-
03 in subjects diagnosed with IPF  


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ENDPOINTS 
Primary Endpoint: 
· 
Incidence of treatment-emergent adverse events (TEAEs). 
Other Safety Endpoints: 
· 
Physical examination findings. 
· 
Vital signs. 
· 
Electrocardiogram (ECG). 
· 
Clinical laboratory measurements. 
· 
Spirometry. 
· 
Leicester Cough Questionnaire 
· 
Cough Visual Analogue Scale 
Exploratory Endpoints: 
· 
Plasma peak and trough concentration of LTI-03 after the first dose 
and at steady state. 
· 
Change from baseline over time for biomarkers related to the 
pathophysiology of IPF. 
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, multi-center, dose 
escalation, safety, and tolerability study of LTI-03 or placebo administered 
by inhalation in subjects with IPF who have not been treated with anti-
fibrotic agents within 2 months of the Baseline bronchoscopy.  An IPF 
diagnosis will be confirmed by high-resolution computed tomography 
(HRCT) of chest or lung biopsy within 3 years prior to Screening.   
The study will contain 2 dose cohorts which will run sequentially.  Subjects 
in the first, low-dose cohort will receive 2.5 mg of study drug (LTI-03 or 
placebo), administered twice daily approximately 10-12 hours apart (5 mg 
per day).  If the 5 mg per day dose is well tolerated, a second, high-dose 
cohort will receive 5 mg of study drug (LTI-03 or placebo), administered 
twice daily approximately 10-12 hours apart (10 mg per day). 
Eligible subjects will be randomized in a 3:1 ratio to either LTI-03 or 
placebo.  Each cohort will have 9 subjects randomized to LTI-03 and 
3 subjects randomized to placebo.  Safety data will be reviewed on an 
ongoing basis by the Sponsor’s medical officer and the Contract Research 
Organization (CRO)’s medical monitor.  A review of safety data including 
but not limited to adverse events, laboratory assessments, vital signs, and 
spirometry will be conducted after all 12 subjects from Cohort 1 have 
completed Day 14 assessments. Enrollment in the second cohort will not 
begin until the Cohort 1 safety data has been reviewed and a dose decision 


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made. A lower dose cohort may be added (2.5 mg administered once daily) 
or additional subjects (up to 12 subjects) may be added to the low-dose 
cohort (2.5 mg administered twice daily) if doses of 5 mg twice daily (10 
mg per day) are not tolerated.  In total, a maximum of approximately 24 
subjects will be randomized in the study.   
Screening assessments will take place over no more than 21 days prior to 
the Treatment Period.  Screening assessments will include but not be limited 
to a complete physical examination including vital signs, ECG, spirometry, 
safety laboratory parameters, medical history, and concomitant 
medications. A Baseline bronchoscopy will be performed during the 
Screening Period in subjects who meet the Screening criteria and will 
include bronchoalveolar lavage and/or bronchoabsorption, and deep 
bronchial brushings. 
The Treatment Period will be 14 days, with subjects self-administering the 
study drug using the provided commercially available dry powder inhaler.  
All subjects will be trained on the proper methods of inhaler use and will 
have access to site personnel trained to assist subjects remotely if questions 
arise.  Retraining may occur on Day 1 and 7, if required.   
Follow-up study assessments will be completed at Day 21 with all Day 14 
assessments repeated except dosing, bronchoscopy, and blood collection for 
biomarker and PK.  Also, complete physical examination will be replaced 
by brief physical examination. 
ELIGIBILITY 
CRITERIA 
Inclusion Criteria 
Individuals must meet all the following inclusion criteria to be eligible for 
participation in this study. 
1. Male or female subject of age 40 years or older.  
2. Willing and able to provide written informed consent.  
3. Diagnosis of IPF within 3 years of Screening as confirmed by HRCT 
of chest or lung biopsy as defined by ATS/ERS/JRS/ALAT guideline.  
4. Forced vital capacity (FVC) percent predicted ≥ 40%. 
5. Diffusion capacity of the lungs for carbon monoxide (DLCO) percent 
predicted ؅ 30 and ؄ 80.   
6. Forced expiratory volume 1 (FEV1)/FVC ؅ 0.7.  
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be 
enrolled in this study. 


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1. Interstitial lung disease other than IPF.  
2. Evidence of significant obstructive lung disease.    
3. Current diagnosis of asthma. 
4. Treatment with an approved or investigational antifibrotic therapy for 
IPF within 2 months of the Baseline bronchoscopy.  
5. Use of N-acetyl cysteine or other supplements within 7 days prior to 
dosing and throughout the Treatment Period. 
6. Inability to use study inhaler device appropriately.  
7. Pulmonary exacerbation within 6 months prior to Screening.   
8. Febrile illness within 7 days prior to dosing.  
9. Participation in a clinical study or treatment with an investigational 
drug or device within 30 days of the Screening Visit (or 5 half-lives of 
the investigational agent, whichever is longer). 
10. History or evidence at screening of significant renal impairment with 
eGFR < 30 mL/min. 
11. History or evidence at screening of significant hepatic impairment with 
bilirubin > 3 mg/dL (> 51.3 µmol/L) and albumin < 2.8 g/dL (<28 g/L) 
and PT prolongation > 6 sec or INR > 2.3. 
12. Serious or active medical or psychiatric condition which, in the opinion 
of the Investigator, may interfere with treatment, assessment, or 
compliance with the protocol. 
13. Vaccination within 2 weeks of start of dosing (Day 1) and throughout 
the Treatment Period.  
14. Subject has severe progressive or uncontrolled, clinically significant 
disease that in the judgment of the investigator or designee renders the 
subject unsuitable for the study. 
Contraception and Pregnancy  
15. Positive pregnancy test in female subjects of childbearing potential as 
defined below. 
16. Female subjects who are lactating. 
17. Females of childbearing potential (FOCBP) and men with partners of 
childbearing potential who do not agree to use an acceptable form of 
contraception for the duration of study treatment and for at least 90 days 
after the last dose of study drug.  Male subjects who do not agree to 
refrain from donating sperm during this same period.  


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− 
These methods of contraception are acceptable: Bilateral tubal 
ligation; male sterilization; hormonal contraceptives that 
inhibit ovulation; hormone-releasing intrauterine devices; 
and copper intrauterine devices.  
− 
True abstinence when this is in line with the preferred and 
usual lifestyle of the subject.  Periodic abstinence (e.g., 
calendar, 
ovulation, 
symptothermal 
post-ovulation 
methods) and withdrawal are not acceptable methods of 
contraception. 
− 
Male sterilization (with 
appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate).  For 
female subjects, the vasectomized male partner must be 
documented as the sole partner. 
Contraceptive requirements do not apply for subjects who are 
exclusively in same sex relationships.  If a subject who is in a same sex 
relationship at the time of signing the informed consent form (ICF) 
becomes engaged in a heterosexual relationship, they must agree to use 
contraception as described and as outlined in the protocol and ICF. 
NOTE: Female subjects who are surgically sterile or post-menopausal for 
at least 12 months without any other underlying medical cause are not 
considered to be of childbearing potential.   
STATISTICAL 
METHODS 
Sample Size Justification: 
Approximately 24 subjects are planned in 2 cohorts.  Each cohort will 
include 12 subjects (9 on LTI-03 and 3 on placebo).  Selection of sample 
size is based on prior experience to ensure that the safety and tolerability of 
LTI-03 will be adequately assessed while minimizing unnecessary subject 
exposure.  With 18 subjects receiving LTI-03 there is a 60% chance of 
detecting an adverse event (AE) with a true incidence rate of 5% and an 
85% chance of detecting a more common AE with a true incidence rate of 
10%.        
Statistical Analysis: 
The primary endpoint of the study is safety. No formal statistical hypotheses 
will be tested. 
All descriptive statistical analyses will be performed using the most recently 
released and available Statistical Analysis System (SAS) statistical software 
(version 9.4 or higher), unless otherwise noted.  For categorical variables, 
the number and percent of each category within a parameter will be 


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presented.  For continuous variables, the sample size (n), mean, median, 
and standard deviation, as well as the minimum and maximum values, will 
be presented.  Missing data will not be imputed unless otherwise stated.  
Subjects on Placebo from all cohorts will be pooled to form a combined 
placebo group for analysis.  
The primary endpoint of the study is incidence of TEAEs.  
Adverse events will be graded according to National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. 
Adverse events will be coded by preferred term and system organ class 
using the current version of Medical Dictionary for Regulatory Activities 
(MedDRA®) and summary tables for all AEs will be generated for the 
Safety Population.  Incidence rates and percentages will be summarized for 
each preferred term and system organ class.  Additional summary tables 
will be generated for the following population subsets: subjects with serious 
adverse events (SAE)s, subjects with related AEs, subjects with severe 
(Grade 3 or 4) AEs, and subjects who discontinue study drug due to AEs.  
Adverse events will be summarized by treatment and\or cohort. Severity, 
Investigator-attributed relationship to study drug, and action taken will also 
be recorded. 
Planned Interim Analysis: 
No formal interim analyses will be performed in the study. Cohort 1 
biomarker data may be analyzed before final database lock without 
changing the overall study conduct. 
 
 


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KEY STUDY CONTACTS 
A contact information list of the Sponsor will be provided separately.  
Sponsor Medical Officer: 
Name: 
Steven Shoemaker, MD 
 
Acting Chief Medical Officer 
 
Lung Therapeutics, Inc. 
Phone number: 
+ 1 720 560 2167 
Email: 
sshoemaker@nicosof.com 
 
Other Study Contact:  
Name:  
Anne Kinney, MSPH 
 
Associate Director, Clinical Operations 
 
Lung Therapeutics, Inc. 
Phone number:  
+1 737 802 1990 
Email:  
akinney@lungtx.com 
 
 


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1 BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
1.1 
Background Information 
1.1.1 LTI-03 
LTI-03 is being developed as a novel therapy for idiopathic pulmonary fibrosis (IPF) which is a 
progressive, fatal, age-associated lung disease with a median survival from diagnosis of 2-4 years 
and an incidence of 2.8 to 18 cases per 100,000 people per year in Europe and North America 
(Maher, Toby M., and Mary E. Strek. "Antifibrotic therapy for idiopathic pulmonary fibrosis: time 
to treat." Respiratory research 20.1 (2019): 1-9. 
Martinez et al., 2017).  The pathogenesis of IPF is characterized by apoptosis of alveolar epithelial 
type 2 cells (AEC2), proliferation and accumulation of activated myofibroblasts and fibrotic lung 
fibroblasts (FLF), deposition of extracellular matrix (ECM), and fibrosis, resulting in progressive 
dyspnea and loss of lung function (Lancaster, Lisa, et al. "Idiopathic pulmonary fibrosis: Physician 
and patient perspectives on the pathway to care from symptom recognition to diagnosis and disease 
burden." Respirology 27.1 (2022): 66-75. 
Lederer DJ, Martinez , 2018).  Idiopathic pulmonary fibrosis is rare in patients younger than 50 
years old, with a median age at diagnosis of approximately 65 years.  Most patients with IPF 
present with the advanced disease. The diagnosis is often delayed with the mean time between 
self-reported onset of symptoms and IPF diagnosis being 21.8 months for patients in the European 
IPF registry (Guenther et al., 2018) and the median time between self-reported onset of symptoms 
and IPF diagnosis being 13.6 months in the US IPF-PRO registry (Snyder et.al., 2020). Two anti-
fibrotic drugs, nintedanib and pirfenidone, have been shown to reduce decline in lung function in 
patients with IPF and are approved for marketing in the United States (US) and the European 
Union (EU).  Unfortunately, these two drugs provide only modest clinical benefit in IPF patients.  
These drugs slow the decline of lung function as measured by forced vital capacity (FVC).  
However, neither are curative and both are poorly tolerated leading to frequent drug 
discontinuations. Although the use of these drugs is increasing, a recent review of the time from 
diagnosis to treatment noted that only approximately 60% of IPF patients in Europe and the US 
were receiving nintedanib or pirfenidone (Maher et.al., 2019). Because these drugs are limited to 
only slowing the decline in lung function, there is a need to identify a more effective therapy for 
IPF or related interstitial lung disease (ILD). 
1.1.1.1 Physical, Chemical, and Pharmaceutical Information 
LTI-03 is a synthetic oligopeptide consisting of 7 natural L-amino acids which represent the mid 
portion of the caveolin-1 (Cav-1) scaffolding domain (CSD).  LTI-03 exhibits limited solubility in 
water.  It is formulated as a micronized dry powder in hard 2-piece hypromellose capsules.  
Encapsulated LTI-03 is self-administered- by subjects using a commercially available dry-powder 
inhaler device.  


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1.1.1.2 Non-clinical Background 
Data from published studies and internal research suggest that LTI-03 targets aberrant signaling in 
lung fibrotic tissue that is characterized by decreased viability of alveolar epithelial cells (AECs) 
and increased proliferation and differentiation of fibroblasts.  The restoration of homeostatic 
signaling by LTI-03 appears to increase AEC2 viability by decreasing senescence and apoptosis, 
while at the same time there appears to be an attenuation of a wide range of profibrotic signaling 
factors associated with less fibroblast proliferation and differentiation, and less ECM 
accumulation.   
In in vitro studies of AECs isolated from the lungs of patients with IPF, LTI-03 lowered p53 and 
another apoptosis-associated protein, activated caspase-3, and restored levels of surfactant 
protein-C (SP-C), a key marker of AEC viability and function.  LTI-03 had no effect on the 
expression of p53 in cultured AEC2s isolated from patients without pulmonary fibrosis.  In IPF 
lung tissue explants cultured ex vivo, a dose dependent increase in lysotracker staining was 
observed for 7 days, suggesting that LTI-03 supported lung epithelial cell survival and possibly 
epithelial regeneration.  In addition, in silico analyses using the Ingenuity Pathway Analyses 
software indicate that upregulation of Cav-1 may activate production of SP-C in AEC2 cells which 
is critical for lung homeostasis.  As LTI-03 is derived from Cav-1, it would be expected to serve 
the same biological function. 
Various tyrosine kinases play key roles in the pathologic activation of fibroblasts during 
fibrogenesis.  Receptor tyrosine kinases, including Platelet-Derived Growth Factor Receptor, 
vascular Endothelial Growth Factor Receptor, Epidermal Growth Factor Receptor, and Janus 
tyrosine kinase, as well as non-receptor tyrosine kinases, such as c-Abl and Src kinases, stimulate 
the pathological synthesis and release of ECM proteins.  In in vitro studies of primary FLFs, 
isolated from the lungs of patients with IPF or mice with established bleomycin (BLM)-induced 
pulmonary fibrosis, LTI-03 attenuated profibrotic signaling factors (p-PDGFRb, p-SMAD2/3), 
restored the expression of p53 to near normal levels, and inhibited the expression of fibrosis-
associated proteins including type 1 collagen (Col-1), alpha-smooth muscle actin (α-SMA), 
fibronectin (FN), and tenascin-C (TN-C).  Details on the LTI-03’s effects in vitro and in vivo in 
non-clinical models of pulmonary fibrosis can be found in the Investigator Brochure (IB). 
In summary, the potential mechanism of action of LTI-03 in lung fibrosis appears to be the 
restoration of homeostatic signaling associated with a novel, supportive, regenerative effect on 
lung epithelial cells and anti-fibrotic activity associated with attenuation of pro-fibrotic signaling 
in lung fibroblasts. 
In pharmacokinetic (PK) studies carried out in healthy volunteers, dry powder inhaled LTI-03 
appeared to be retained in the lung with slow or limited absorption into systemic circulation. As a 
result, systemic exposure is low and LTI-03 appears to be rapidly cleared from systemic 
circulation.  In non-clinical PK studies of LTI-03, delivered as an aerosol or intratracheal bolus, 


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high lung tissue concentrations of LTI-03 were observed post-exposure while there was minimal 
LTI-03 absorption into the systemic circulation.  
Pivotal 28-day Good Laboratory Practice (GLP) toxicity studies were performed in rats and dogs.  
These studies were designed such that the high dose levels would achieve at least a 50-fold margin 
over the proposed high clinical dose as recommended in International Council for Harmonisation 
(ICH)-M3(R2) guidelines.  In Sprague Dawley rats, LTI-03 was well tolerated and there were no 
adverse test item effects reported at delivered doses of 18.4, 58.5 and 109.3 mg/kg/day.  Histologic 
findings of goblet cell hypertrophy/hyperplasia of the nasal cavity, nasopharynx, trachea, and lungs 
observed in all dose levels and squamous metaplasia of the carina or nasopharynx seen at the mid 
and high doses were considered to be a nonspecific protective or adaptive response and were not 
adverse as they would not likely interfere with the functional or defensive capabilities of the 
respiratory tract.  The no observed adverse effect level (NOAEL) in the rat was considered to be 
the achieved delivered dose of 109.3 mg/kg/day. 
Similarly, in the dog, LTI-03 was well tolerated and no adverse effects were reported at achieved 
delivered doses of 8.9, 27.1 and 46.1 mg/kg/day.  Histologic findings of minimal bronchiolar 
goblet-cell hypertrophy/ hyperplasia in the lungs of some high-dose animals and minimal to mild 
bronchioloalveolar duct hyperplasia in the lungs observed in all high-dose male dogs were 
considered a test item-related adaptive change, similar to the lesions observed in rats.  The NOAEL 
in the dog was considered to be the achieved delivered dose of 46.1 mg/kg/day. 
1.1.1.3 
Clinical Background 
LTI-03 was initially assessed in a Phase 1a study, LTI-03-1001: A Randomized, Double-Blind, 
Placebo-Controlled, Phase 1a, First-in-Man, Single Ascending Dose (SAD) and Multiple 
Ascending Dose (MAD) Safety, Tolerability and PK Study of a Cav-1-Scaffolding-Protein-
Derived Peptide (LTI-03) in Healthy Adult Subjects.  Twenty-four subjects were administered LTI-
03 in 4 SAD cohorts at single doses of 10 mg, 40 mg, and 80 mg. At the 80 mg dose, subjects in 1 
cohort were administered 4 20 mg capsules by inhalation and in a second cohort subjects at this 
80 mg dose were administered 8 10 mg capsules by inhalation.  Eight subjects in the combined 
SAD cohorts were administered placebo. In the SAD cohorts, 21 of the 24 subjects (88%) who 
were administered LTI-03 experienced treatment -emergent adverse events (TEAE), the most 
frequent of which were mild dry coughs that were considered to be related to LTI-03.  
Twenty-nine subjects were administered LTI-03 by inhalation daily for up to 14 days in 5 MAD 
cohorts at doses of 2.5 mg once daily (QD), 5 mg QD, 5 mg twice daily (BID), 20 mg QD and 40 
mg QD.  The 2 higher dose MAD cohorts, 20 mg QD and 40 mg QD, were completed before the 
lower dose cohorts.  The 3 lower doses were well tolerated.  The most common TEAE in these 3 
cohorts was a mild dry cough. During dosing in the 40 mg QD MAD cohort 1 subject developed 
severe TEAEs and two other subjects developed moderate TEAEs secondary to pulmonary airflow 
limitations (decreased forced expiratory volume 1 [FEV1] and FEV1/FVC ratios) that appeared to 


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be due to reversible airway obstruction.  These events were considered to be dose limiting and 
related to LTI-03.  There was no evidence that the TEAEs in the 3 subjects described previously 
were secondary to an allergic response.  In the 20 mg QD MAD cohorts there were mild decreases 
in FEV1 in two subjects that were not associated with TEAEs.  These were not considered to be 
dose limiting.  There were no serious adverse events (SAEs). All TEAEs were resolved 7 days 
after the treatment period.  Further details can be found in the IB. 
1.2 
Scientific Rationale 
Based on the non-clinical studies demonstrating the anti-fibrotic effects of LTI-03, the current 
study will investigate the initial safety and tolerability of inhaled LTI-03 in IPF patients diagnosed 
within 3 years of Screening without exposure to anti-fibrotic agents within 2 months of the 
Baseline bronchoscopy.  Exploratory assessments will include evaluations of potential 
pharmacodynamic (PD) biomarkers. Newly diagnosed patients may be enrolled prior to beginning 
anti-fibrotic therapy. The potential 6-week delay in these patients in commencing therapy with 
pirfenidone or nintedanib is relatively short compared with the delay (approximately 14-22 
months) from the onset of symptoms to the diagnosis of IPF in many patients (Guenther et al., 
2018 and Snyder et.al., 2020). In addition to the time to diagnosis of IPF, there is frequently a delay 
in start of anti-fibrotic therapy post-diagnosis, with a recent physician reported survey reporting 4 
months as a best case, to greater than 1-year from diagnosis to the first IPF prescription (Lancaster, 
et al., 2021).  
1.2.1 Dose Rationale 
Recent data from in vitro and in vivo pharmacology studies have been used to predict the 
nominal dose of LTI-03 dry powder that might be efficacious in patients.  The predictions from 
the modeling suggest that a dose of between 1 and 10 mg LTI-03, inhaled by a patient using a 
commercially available dry-powder inhaler device, would result in a lung deposited dose likely 
to produce the desired pharmacological effect in the pulmonary compartment of the lung.  The 
modelling approach, and the assumptions inherent to the modelling exercise, are discussed in 
detail in the IB. 
Based on the modelling data, questionable or poor tolerability at 20 mg QD and greater in the 
MAD cohorts, and the good tolerability in lower dose MAD cohorts, the first cohort in this study 
will be dosed with LTI-03 2.5 mg administered BID (5 mg per day-low dose) for 14 days.  If this 
dose is well tolerated the second cohort will be dosed at 5 mg administered BID (10 mg per day-
high dose) for 14 days.  Both doses were safe and well tolerated in healthy volunteers and will 
provide the best probability of finding an effective dose.  Twice daily dosing is suggested by the 
limited non-clinical lung concentration time course data.  Thus, it appears that efficacy will be 
more likely with BID dosing to afford more continuous lung exposure.      


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1.3 
Potential Risks and Benefits 
Dose limiting toxicities appeared in the highest dose MAD cohort with 40 mg of LTI-03 
administered once daily by dry powder inhalation using 10 mg capsules.  One subject developed 
severe TEAEs, and 2 subjects developed moderate TEAEs secondary to pulmonary airflow 
limitations (decreased FEV1 and FEV1/FVC ratios) that appeared to be due to reversible airway 
obstruction. 
After consideration of recent in vitro and in vivo non-clinical and LTI-03 solubility studies, it is 
speculated that the 20 mg and 40 mg doses were supra-pharmacologic and may have resulted in a 
larger deposited insoluble fraction. According to the modelling data, these doses were 
approximately 20- to 40-fold in excess of a minimally efficacious dose, respectively.  Such high 
predicted extracellular lining fluid (ELF) concentrations alone, or in combination with excess 
insoluble particulate, may have led to conducting airway irritation and/or obstruction resulting in 
a drop in FEV1.  The lower dose MAD cohorts used 2.5 mg capsules at doses of 2.5 mg QD and 
progressed to 2.5 mg BID (5 mg total daily dose) and ended with 5 mg BID (10 mg total daily 
dose).  All three doses were well tolerated.  These doses are adequate to support the proposed 
efficacious range of 1-10 mg and provide adequate safety margins above the rat and dog NOAELs 
based on body surface area (BSA) scaling (refer to the IB for further details). 
IPF patients enrolled in this study will be administered study drug (LTI-03 or placebo) for 14 days. 
Given the short duration of treatment, subjects are not expected to experience a lung function 
benefit from administration of LTI-03 or placebo. In those newly diagnosed patients not previously 
exposed to antifibrotic agents, the potential 6-week delay in initiation of anti-fibrotic therapy 
following IPF diagnosis related to study participation is not expected to place these patients at 
undue risk as this delay is relative short compared with the common elapsed time from onset of 
symptoms to diagnosis in many patients, and from diagnosis to initiation of standard therapy. 
However, if the investigator determines that anti-fibrotic therapy should be started prior to study 
completion, study drug should be discontinued, and early termination procedures completed as per 
Section 7.4. 
There is no nonclinical or clinical evidence that LTI-03 would adversely affect an immune response 
to COVID-19 infection or immunization. However, in the interests of caution, any vaccination 
(including vaccination against COVID-19) within 2 weeks of starting dosing (Day 1) and during 
the treatment period is prohibited. 
 


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2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 Primary Objective 
· 
To determine the safety and tolerability of inhaled LTI-03 in subjects diagnosed with IPF 
within 3 years of Screening. 
2.1.2 Exploratory Objectives 
· 
To assess the plasma PK of inhaled LTI-03 after the first dose and at steady state in subjects 
with IPF diagnosed within 3 years of Screening.  
· 
To evaluate the PD biomarkers of inhaled LTI-03 in subjects diagnosed with IPF within 3 
years of Screening. 
2.2 
Endpoints 
2.2.1 Primary Endpoint 
· 
Incidence of TEAEs. 
2.2.2 Other Safety Endpoints 
· 
Other safety endpoints include:  
o Physical examination findings  
o Vital signs 
o Electrocardiogram (ECG) 
o Clinical laboratory measurements 
o Spirometry 
o Leicester Cough Questionnaire 
o Cough Visual Analogue Scale 
2.2.3 Exploratory Endpoints 
· 
To determine the plasma peak and trough concentration of LTI-03 after the first dose and 
at steady state. 
· 
Change from baseline over time for biomarkers related to the pathophysiology of IPF as 
outlined in Table 3. 
 


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3 STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, multi-center, dose escalation, safety and 
tolerability study of LTI-03 or placebo administered by inhalation in  subjects with IPF without 
=treatment with anti-fibrotic agents withing 2 months of the Baseline bronchoscopy.  An IPF 
diagnosis will be confirmed by high-resolution computed tomography (HRCT) of chest or lung 
biopsy within 3 years prior to Screening.  The study will contain 2 dose cohorts which will run 
sequentially.  Subjects in the first, low-dose cohort will receive 2.5 mg of study drug (LTI-03 or 
placebo), administered twice daily approximately 10-12 hours apart (5 mg per day).  If the 5 mg 
per day dose is well tolerated, a second, high-dose cohort will receive 5 mg of study drug (LTI-03 
or placebo), administered twice daily approximately 10-12 hours apart (10 mg per day). 
Eligible subjects will be randomized in a 3:1 ratio to either LTI-03 or placebo.  Each cohort will 
have 9 subjects randomized to LTI-03 and 3 subjects randomized to placebo.  Safety data will be 
reviewed on an ongoing basis by the Sponsor’s medical officer and the Contract Research 
Organization (CRO)’s medical monitor.  A review of safety data including but not limited to 
adverse events, laboratory assessments, vital signs, and spirometry will be conducted after all 12 
subjects from Cohort 1 have completed Day 14 assessments. Enrollment in the second cohort will 
not begin until the Cohort 1 safety data has been reviewed and a dose decision made.  A lower 
dose cohort may be added (2.5 mg administered once daily) or additional subjects (up to 12 
subjects) may be added to the low-dose cohort (2.5 mg administered twice daily) if doses of 5 mg 
twice daily (10 mg per day) are not tolerated.  In total, a maximum of approximately 24 subjects 
will be randomized in the study.   
The Treatment Period will be 14 days, with subjects self-administering the study drug using the 
provided commercially available dry powder inhaler.  All subjects will be trained on the proper 
methods of inhaler use and will have access to site personnel trained to assist subjects remotely if 
questions arise.  Retraining may occur on Day 1 and 7, if required.  During the Treatment Period, 
there will be on-site visits on Day 1, Day 7, and Day 14 and study assessments will occur at the 
investigational site on these days.  The first dose of study drug will be administered at the 
investigational site and subjects will be monitored for at least 1 hour after dosing.   
Screening assessments may take place over no more than 21 days prior to the Treatment Period.  
Screening assessments will include but not be limited to a complete physical examination 
including vital signs, ECG, spirometry, safety laboratory parameters, medical history, and 
concomitant medications. A Baseline bronchoscopy will be performed during the Screening Period 
in subjects who meet the Screening criteria and will include bronchoalveolar lavage (BAL) and/or 
bronchoabsorption (BA), and deep bronchial brushings. 
Treatment Period will include but not be limited to physical examinations with vital signs, ECG, 
spirometry, clinical laboratory assessments, adverse event (AE) assessment, Leicester cough 
questionnaire, cough visual analogue scale (VAS), and concomitant medications.  Bronchoscopies 


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with BAL and/or BA and deep bronchial brushings will also be performed on Day 14 
approximately 2-3 hours after morning dosing.  
Follow-up study assessments will be completed at Day 21 with all Day 14 assessments repeated 
except dosing, bronchoscopy, and blood collection for biomarkers and PK.  Also, a complete 
physical examination will be replaced by a brief physical examination. The end of the study is 
defined as the date of the last visit of the last participant in the study.  
4 STUDY SUBJECTS 
4.1 
Eligibility Criteria 
The study subject population will consist of patients with IPF without treatment with anti-fibrotic 
agents within 2 months of the Baseline bronchoscopy. 
4.1.1 Inclusion Criteria 
Individuals must meet all the following inclusion criteria to be eligible for participation in this 
study. 
1. Male or female subject of age 40 years or older.  
2. Willing and able to provide written informed consent. 
3. Diagnosis of IPF within 3 years of Screening as confirmed by HRCT of chest or lung biopsy 
as defined by ATS/ERS/JRS/ALAT guideline (Raghu G al, 2018).  
4. Forced vital capacity (FVC) percent predicted ≥ 40%. 
5. Diffusion capacity of the lungs for carbon monoxide (DLCO) percent predicted ؅ 30 and ؄ 
80.   
6. Forced expiratory volume 1 (FEV1)/FVC ؅ 0.7.  
4.1.2 Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be enrolled in this study. 
1. Interstitial lung disease other than IPF.  
2. Evidence of significant obstructive lung disease.    
3. Current diagnosis of asthma. 
4. Treatment with an approved or investigational anti-fibrotic therapy for IPF within 2 months of 
the Baseline bronchoscopy.  
5. Use of N-acetyl cysteine or other supplements within 7 days prior to dosing and throughout 
the Treatment Period. 
6. Inability to use study inhaler device appropriately.  


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7. Pulmonary exacerbation within 6 months prior to Screening.   
8. Febrile illness within 7 days prior to dosing.  
9. Participation in a clinical study or treatment with an investigational drug or device within 30 
days of the Screening Visit (or 5 half-lives of the investigational agent, whichever is longer). 
10. History or evidence at screening of significant renal impairment with eGFR < 30 mL/min. 
11. History or evidence at screening of significant hepatic impairment with bilirubin > 3 mg/dL (> 
51.3 µmol/L) and albumin < 2.8 g/dL (<28 g/L) and PT prolongation > 6 sec or INR > 2.3. 
12. Serious or active medical or psychiatric condition which, in the opinion of the Investigator, 
may interfere with treatment, assessment, or compliance with the protocol. 
13. Vaccination within 2 weeks of start of dosing (Day 1) and throughout the Treatment Period.  
14. Subject has severe progressive or uncontrolled, clinically significant disease that in the 
judgment of the investigator or designee renders the subject unsuitable for the study. 
Contraception and Pregnancy  
15. Positive pregnancy test in female subjects of childbearing potential as defined below. 
16. Female subjects who are lactating. 
17. Females of childbearing potential (FOCBP) and men with partners of childbearing potential 
who do not agree to use an acceptable form of contraception for the duration of study treatment 
and for at least 90 days after the last dose of study drug.  Male subjects who do not agree to 
refrain from donating sperm during this same period.  
These methods of contraception are acceptable:  
− 
Bilateral tubal ligation; male sterilization; hormonal contraceptives that inhibit ovulation; 
hormone-releasing intrauterine devices; and copper intrauterine devices.  
− 
True abstinence when this is in line with the preferred and usual lifestyle of the subject.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
− 
Male sterilization (with appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate).  For female subjects, the vasectomized male partner must be 
documented as the sole partner. 
Contraceptive requirements do not apply for subjects who are exclusively in same sex 
relationships.  If a subject who is in a same sex relationship at the time of signing the Informed 
Consent Form (ICF) becomes engaged in a heterosexual relationship, they must agree to use 
contraception as described and as outlined in the protocol and ICF. 


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NOTE: Female subjects who are surgically sterile or post-menopausal for at least 12 months 
without any other underlying medical cause are not considered to be of childbearing potential.  


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5 STUDY DRUG 
5.1 
Formulation, Packaging and Labeling 
LTI-03 is a Cav-1-scaffolding-protein-derived peptide and is an active study drug.  LTI-03 and 
matching placebo are provided as inhalation powders for oral inhalation use.  LTI-03 is an 
excipient-free, micronized dry powder that is placed into white opaque hypromellose two-piece 
capsules.  The placebo is micronized lactose powder that is placed into white opaque hypromellose 
two-piece capsules and is identical in appearance to LTI-03.  Individual capsules that contain 2.5 
mg of study drug (LTI-03 or placebo) are not labelled.  
5.2 
Storage and Stability 
Study drug (LTI-03 or placebo) is to be stored below 25°C and in the original package to protect 
from moisture. 
5.3 
Accountability 
Bottles containing study drugs (LTI-03 or placebo) will be supplied by the Sponsor.  Each bottle 
will be labeled with a unique packaging identification number. 
The Investigator is responsible for ensuring adequate accountability of all used and unused study 
drug.  The study site is responsible for maintaining drug accountability logs for tracking the 
administration of all study drug. Unused study drug may be returned to the Sponsor.  Subjects will 
return used capsules and unused study drug to the investigational site during the Day 7 and Day 
14 on-site visits. 
5.4 
Administration and Management of Study Drug 
Study staff will receive training from the Sponsor on the proper administration of study drug.   
All subjects will self-administer study drug using the provided commercially available dry-powder 
inhaler.  Study staff will train all subjects on proper use of the inhaler.  Subjects must demonstrate 
the ability to adequately inhale a minimum of 2 individual empty capsules using the inhaler device.  
Additional capsules may be used for training.  Study staff will assist with training and 
administration of this test inhalation and will make a determination of qualification of the subject.  
Subject retraining may occur at Day 1 and Day 7, if required.   
The first dose of study drug will be administered at the investigational site on Day 1 and subjects 
will be monitored for at least 1 hour after dosing.  Study staff will monitor subjects’ 
self-administration of study drug (most likely the morning dose) during on-site visits on Day 1, 
Day 7, and Day 14.   


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The first, low-dose cohort will receive 2.5 mg of study drug (LTI-03 or placebo), administered 
twice daily approximately 10-12 hours apart (5 mg per day).  If the 5 mg per day dose is well 
tolerated, a second, high--dose cohort will receive 5 mg of study drug (LTI-03 or placebo), 
administered twice daily approximately 10-12 hours apart (10 mg per day).   
As each capsule contains 2.5 mg of study drug (LTI-03 or placebo), two inhalations will be used 
i.e., using 2.5 mg capsule + 2.5 mg capsule to achieve a dose of 5 mg.  Subjects should wait 
1-2 minutes between these 2 inhalations and may drink a small amount of water (e.g., 15 mL to 
30 mL) between the inhalations.  These two inhalations should be administered within a 5-minute 
period.  
As mentioned, in Section 3, a lower dose cohort may be added (2.5 mg administered once daily) 
or additional subjects may be added to the low-dose cohort (2.5 mg administered twice daily). 
Table 1 
Instructions on Multiple Administrations taken at a Time and for Missing the 
Dose 
Study Drug 
Dosing per Day 
Instruction on Multiple 
Inhalations Taken at a 
Time 
Instructions on Missing the Dose 
Low Dose 
(5 mg/day) 
5 mg/day achieved 
by inhalation of one 
2.5 mg capsule, 
twice daily, 
approximately 10 to 
12 hours apart  
NA 
If the morning dose is missed, subject 
should administer the dose by noon 
(12:00 pm).  If the morning dose is not 
taken by noon, then it should be skipped, 
and evening dose should be taken at the 
regular time. 
NOTE: the morning dose can be taken 
after noon during in-clinic visits if 
scheduling does not allow for a morning 
administration.  
High Dose 
(10 mg/day) 
10 mg/day achieved 
by inhalation of two 
2.5 mg capsules, 
twice daily, 
approximately 10 to 
12 hours apart 
Subject 
will 
wait 
1-2 
minutes between multiple 
inhalations and may drink a 
small amount of water 
(e.g., 15 mL to 30 mL) 
between 
inhalations.  
Multiple inhalations should 
be administered within a 
5-minute period.   
Abbreviations: NA = not applicable. 
The complete details on administration of study drug will be provided to the site separately. 
5.5 
Method of Assignment to Treatment 
The actual treatment given to individual subjects is determined by a randomization schedule.  The 
associated treatment assignments giving details of individual subject treatment are available from 
the interactive response technology (IRT).  The IRT will assign bottle numbers in a blinded manner.  
Assigned bottles will be dispensed by appropriately delegated study staff. 


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Each bottle of study drug will be assigned a unique packaging identification number.  When a 
bottle of study drug is assigned to a subject, the packaging identification number will be recorded 
in the drug accountability records. 
5.6 
Concomitant and Prohibited Medications  
All medications (including over-the-counter medicines, herbal treatments, supplements, and 
vitamins) administered within 30 days of the Screening Visit through Study Day 21 will be 
recorded on the Case Report Form (CRF), using generic names when possible.    
If the subject had participated in any clinical study before entering this study, then treatment with 
the investigational product must have been discontinued within 30 days or 5 half-lives (whichever 
is longer) prior to Screening. 
Other anti-fibrotic therapies for the treatment of IPF are prohibited two months prior to the 
Baseline bronchoscopy until 1 week after the last dose of the study drug. If the investigator 
determines that anti-fibrotic therapy should be started before study completion, study drug should 
be discontinued, and early termination procedures completed as per Section 7.4.  
N-acetyl cysteine or quercetin is prohibited within 7 days of dosing (Day 1) and throughout the 
Treatment Period. 
Vaccines are prohibited within 2 weeks of dosing day (Day 1) and throughout the Treatment 
Period.    
 
 


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6 STUDY PROCEDURES 
The procedures and assessments that are outlined in this section will be performed at the time 
points specified by study visit in the schedule of assessments (SOA) (see Appendix 1 and Appendix 
2).  
For subjects receiving multiple administrations and having time-sensitive post-dose assessments, 
“Time 0” is defined as start of the administration of the first capsule of study drug. 
6.1 
Informed Consent 
Written informed consent must be provided by each subject prior to the initiation of any 
study-specific procedure or assessment that is not part of standard of care.  Informed Consent 
Forms for enrolled subjects and for subjects who are not subsequently enrolled will be maintained 
at the study site. 
All Screening evaluations must be completed and reviewed to confirm that subjects meet all the 
eligibility criteria before enrollment.  The Investigator will maintain a Screening log to record 
details of all patients screened and to confirm eligibility or record reasons for Screening failure, as 
applicable. 
6.2 
Demographics and Medical History 
Demographic data will include age, sex, and self-reported race and ethnicity. 
All ongoing conditions, any environmental/work exposure history and relevant or significant 
medical history from the past 5 years (including all major hospitalizations and surgeries) will be 
recorded.  Any neoplastic conditions, irrespective of the time of diagnosis, should be noted. 
Reproductive status and smoking history will be recorded. 
6.3 
Vital Signs 
Vital signs will be obtained after subject has been sitting for at least 1 minute and will include 
blood pressure, heart rate, respiratory rate, body temperature and hemoglobin oxygen saturation 
(via pulse oximetry). 
6.4 
Physical Examination 
A complete physical examination will include an evaluation of the head, eyes, ears, nose and throat, 
and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and 
neurologic systems.  Any abnormality identified at baseline (Screening Physical Exam) will be 
recorded as medical history. 
A brief physical examination will focus on systems affected by AEs and at a minimum should 
include the cardiovascular and respiratory systems.  


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Changes from baseline abnormalities should be recorded in subject notes.  New or worsened 
clinically significant abnormalities should be recorded as TEAEs. 
Height and weight will be recorded at Screening. 
6.5 
Clinical Laboratory Assessments 
Samples taken from subjects will be sent to a central laboratory for analyses.  Clinical laboratory 
assessments will be performed for variables provided in Table 2. 
Table 2 
Clinical Laboratory Assessments 
Hematology 
 
red blood cell (RBC) count  
red cell distribution width (RDW) 
mean corpuscular hemoglobin concentration 
(MCHC) 
hematocrit (Hct)  
mean corpuscular hemoglobin (MCH) 
hemoglobin (Hgb)  
mean corpuscular volume (MCV) 
white blood cell (WBC) count including differential count 
(lymphocytes, 
monocytes, 
neutrophils, 
eosinophils, 
basophils) and platelet count. 
Clinical chemistry  
 
bilirubin (total and conjugated) 
cholesterol (total, low density lipoprotein cholesterol 
[LDL-C], high density lipoprotein cholesterol [HDL-C]) 
Aspartate aminotransferase (AST) 
glucose 
alanine aminotransferase (ALT) 
blood urea nitrogen (BUN) 
alkaline phosphatase (ALP) 
creatinine 
gamma glutamyl transferase (GGT) 
sodium 
lactate dehydrogenase (LDH) 
potassium 
creatine kinase (CK) 
chloride 
protein 
calcium 
albumin 
magnesium 
 
C-reactive protein (CRP) 
Coagulation 
 
prothrombin time (PT) 
 
INR 
 
activated partial thromboplastin time (aPTT) 
 
Additional assessments may be added if clinically indicated and if there is no increase in required blood volume. 
6.5.1 Pregnancy Test 
Females of childbearing potential must have a negative urine or serum pregnancy test during 
Screening.  A urine or serum pregnancy test will also be performed on study days as mentioned in 
SOA (see Appendix 1). 
6.6 
Electrocardiogram 
A single standard 12-lead ECG will be performed.  Lead placement should be as consistent as 
possible.  ECG recordings must be performed after the subject has been resting in a supine position 
for at least 5 minutes.   


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ECG parameters to be evaluated include HR and the RR, QT, QRS, and PR intervals.  In addition, 
Fridericia’s formula should be used to calculate the QT interval corrected for heart rate (QTcF). 
ECG morphology statements will also be evaluated with particular attention paid to waveform 
morphology findings of: ST segment abnormal, T wave changes, abnormal U waves, 
atrioventricular (AV) block, arrhythmia (supraventricular, ventricular, atrial fibrillation/flutter, 
etc.), and others including infarction, ischemia, and hypertrophy.  ECG abnormalities will be 
recorded as AEs only if they are considered to be clinically significant by the Investigator. 
6.7 
Spirometry 
Spirometry to assess FEV1, FVC, FEV1/FVC and the percent predicted for each of the parameters 
will be performed during Screening, Day 1, Day 7, Day 14, and Day 21.  DLCO will be assessed 
only at Screening.  Percent predicted will be calculated based on height, age, and ethnicity.  
Spirometry will be performed according to the current American Thoracic Society (ATS) / 
European Respiratory Society (ERS) Task Force guidelines (Miller et al., 2005). Spirometry will 
be performed on Days 1, 7, and 14 pre-dose and post-dose at 30 and 60 minutes. Unscheduled 
spirometry may as be performed as needed for respiratory symptoms. If bronchospasm is 
suspected, spirometry may also be performed before and after a rescue beta-adrenergic agonist 
inhalation.  
6.8 
Inhaler Use Assessment 
As part of study Screening, subjects must demonstrate the ability to adequately inhale a minimum 
of two individual empty capsules using the inhaler device.  Additional capsules may be used for 
training.  Study staff will assist with training and administration of this test inhalation and will 
make a determination of qualification of the subject.  Retraining may occur on Day 1 and Day 7, 
if required.   
6.9 
Bronchoscopy with Bronchoalveolar Lavage and/or Bronchoabsorption and Deep 
Bronchial Brushing 
A baseline bronchoscopy will be performed during the Screening Period and may be part of the 
IPF initial assessment of a recently diagnosed IPF subject who has provided informed consent for 
bronchoscopy.  Bronchoalveolar lavage and/or BA, alternate methods of sampling airway lining 
fluid, and deep (small airway) bronchial brushings will be performed.  Details of the BAL, BA, 
and brushing procedures are provided in a separate manual.  Bronchoscopy with BAL and/or BA, 
and deep bronchial brushings will be repeated on Day 14 approximately 2-3 hours after the 
morning dose. Subjects who underwent BAL at the baseline bronchoscopy should have BAL 
performed at the Day 14 bronchoscopy. In a similar manner, BA should be performed at the Day 
14 bronchoscopy in those subjects who underwent BA at the baseline bronchoscopy.    Subjects 
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Study personnel performing BAL, BA and deep bronchial brushing will be documented as 
qualified to perform the procedures on the delegation log.  
6.10 
Leicester Cough Questionnaire 
The Leicester Cough Questionnaire is a subject self-report, health related quality of life 
questionnaire (see Appendix 3) that will be collected as mentioned in the SOA (see Appendix 1). 
6.11 
Cough Visual Analogue Scale 
The cough VAS is a 100 mm scale (see Appendix 4) on which subject will be asked to mark 
between ‘no cough’ and ‘the worst cough severity’.  This assessment will be collected as mentioned 
in the SOA (see Appendix 1) 
6.12 
Pharmacokinetic Sampling 
Plasma and BAL samples for PK assessment will be collected as mentioned in SOA (see Appendix 
1 and Appendix 2). 
6.13 
Exploratory Biomarker Sampling 
Exploratory biomarkers will be assessed in peripheral blood cells (as feasible), platelet rich plasma, 
BALF, BA samples, and deep bronchial brushings as outlined in Table 3.  Ribonucleic acid (RNA) 
transcription analysis from whole blood may be substituted for any assays using peripheral blood 
cells.  Samples will be collected at the time of bronchoscopy during the Screening Period and Day 
14 as shown in Appendix 1.  Additional biomarkers may be added as new information is generated 
about the potential effects of CSD signaling. 
Permission to collect these samples and their future analyses will be included in the informed 
consent. 
Sample collection, processing and shipping instructions will be provided in a separate document 
(Laboratory Manual).  Sample analysis will be performed in the Sponsor assigned laboratory. 
Table 3 
Exploratory Biomarkers by Sample Source and Assumed Indicator Function 
Sample source / 
Indicator of 
Epithelial damage / 
repair 
Fibrosis 
Inflammation 
Thrombosis 
Peripheral blood 
cells b 
- 
p-AKTb, IL-11 
CXCL7 
- 
Platelet rich 
plasma (PRP) 
CYFRA 21-1, SP-D, 
CA-19-9, KL-6, 
sRAGE, Galectin 7 
MMP-7, Tenascin C 
(TNC), Periostin, IL-11, 
MYDGF, MMP-2 
CCL18, CXCL13, 
slCAM1, IL-11, 
sCD163, CXCL7 
PAI-1 


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BAL and/or BAa 
Galectin 7, SP-D, 
sRAGE 
MYDGF, MMP-2, TNC, 
MMP-7, periostin, IL-11 
CCL18, CXCL13, 
slCAM1, IL-11, 
sCD163, CXCL7 
PAI-1 
Deep bronchial 
brushings 
- 
p-SMAD2/3 
- 
- 
Abbreviations: BAL = bronchoalveolar lavage. BA = bronchoabsorption 
a LTI-03 levels will also be measured on BAL samples. LTI-03 will not be measured in BA samples 
b Ribonucleic acid transcription analysis may be substituted for assays using peripheral blood cells. 
 
6.14 
Treatment, Subject, Study and Site Discontinuation  
6.14.1 Premature Discontinuation of Study Drug 
Subjects meeting any of the following criteria will discontinue study drug: 
· Initiation of a prohibited concomitant medications (see Section 5.6). 
· Unacceptable AE or failure to tolerate study drug. 
· Decrease from Baseline in FEV1 of 15% associated with a decrease from Baseline in the 
FEV1/ FVC ratio. 
· Changes in the subject’s condition or development of an intercurrent illness or if subject 
contracts Corona virus disease-19 (COVID-19) infection that renders the subject unsuitable 
for further study drug in the judgment of the Investigator. 
· Subject request to discontinue the study drug. 
· Subject is lost to follow-up. 
· Discretion of the Investigator or Sponsor. 
· Termination of the study by the Sponsor. 
The primary reason for the discontinuation of study drug should be documented.  
Wherever possible, post-treatment follow-up should be completed for these subjects.  
6.14.2 Subject Withdrawal of Consent 
Subjects may withdraw their consent to participate in the study at any time and for any reason 
without prejudice to their future medical care by the physician at the institution.  
In addition, the Investigator has the right to withdraw a subject from the study at any time.  Reasons 
for withdrawal from the study may include, but are not limited to, the following: 
· Subject withdrawal of consent. 
· Study termination or site closure. 


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If a subject withdraws consent, the date and stated reason for consent withdrawal should be 
documented.  No further follow-up will be done on these subjects, although study information 
collected up to the time of withdrawal of consent will be included in the clinical study report.  
6.14.3 Replacement of Subjects 
The Investigator and Sponsor may elect to replace subjects in a given cohort following subject 
discontinuation or withdrawal if the discontinuation or withdrawal occurs for reasons other than 
the safety or tolerability of the study drug.  The Investigator will document the decision and 
rationale for subject replacement if this action is taken.  
6.14.4 Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating the study 
may include, but are not limited to, the following: 
· The incidence or severity of AEs in this or other studies indicates a potential health hazard to 
subjects. 
· Subject enrollment is unsatisfactory. 
The Sponsor will notify the Investigator if the Sponsor decides to discontinue the study. 
6.14.5 Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may include, but 
are not limited to, the following: 
· Excessively slow recruitment. 
· Poor protocol adherence. 
· Inaccurate or incomplete data recording. 
· Non-compliance with the ICH guideline for GCP. 
 
 


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7 STUDY SCHEDULE 
Written Institutional Review Board (IRB) / Independent Ethics Committee (IEC) approval of the 
protocol, informed consent and any additional subject information will be obtained prior to starting 
patient Screening and enrollment.  
7.1 
Screening Period (Day -21 to Day -1) 
During Screening, a unique study-assigned subject number will be assigned to each subject who 
signs the informed consent for the study.  Once subjects are in Screening or are enrolled in the 
study, they will only be identified by the assigned identification number. A subject may be re-
screened once, providing that additional written informed consent is obtained.  
The reason(s) why a subject is not eligible for the study will be collected. 
The following procedures and assessments will be performed during the Screening Period to 
confirm eligibility.   
· Obtain written informed consent  
· Record demographics and medical history 
· *Record prior and concomitant medications taken within 30 days prior to first dose of study 
drug (Day 1) 
· Obtain vital signs (blood pressure, heart rate, respiratory rate, body temperature, and 
hemoglobin oxygen saturation via pulse oximetry) 
· *Perform a complete physical examination (including documentation of height and weight) 
· Assess ability to use inhaler 
· Single 12-lead ECG 
· Perform spirometry with DLCO 
· Collect blood sample for the following: 
o Hematology 
o Clinical chemistry  
o Coagulation 
o *Biomarker assessments 
· Collect urine or serum sample for pregnancy test, if applicable 
· Confirm eligibility according to inclusion/exclusion criteria. 
· *Leicester Cough Questionnaire and Cough VAS prior to bronchoscopy 


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· *Adverse event assessment 
· Baseline bronchoscopy with BAL and/or BA and deep bronchial brushings for biomarkers 
will be performed during the Screening Period in those subjects who have provided informed 
consent.  Prior to bronchoscopy, the assessments with * in Section 7.1 will be performed. 
7.2 
Treatment Period 
7.2.1 Day 1  
The first dose of study drug will be administered at the investigational site and subjects will be 
monitored for at least 1 hour after dosing.  Study staff will provide retraining on inhaler use, if 
required.    
Assessments and procedures performed prior to dosing include: 
· Confirmation of eligibility  
· Concomitant medication assessments 
· Adverse event assessment 
· Brief physical examination 
· Vital signs 
· Single 12-lead ECG 
· Collect urine or serum sample for pregnancy test. 
· Randomization 
· Collect blood for the following: 
o Hematology 
o Clinical chemistry  
o PK (pre-dose) 
· Leicester Cough Questionnaire and Cough VAS  
· Spirometry 
· Dispense study medication and inhaler kit and administer Study Drug 
Assessments and procedures performed after dosing include: 
· Adverse event assessment 
· Vital signs 
· Collection of blood sample for the PK at 5 minutes (+ 5 minutes) after dosing  


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· Spirometry at 30 minutes (+ 10 minutes) and 1 hour (+ 10 minutes) after dosing 
7.2.2 Days 2-6 
Subjects will self-administer study drug at home and will be contacted on Day 4 (+ 2 days) by 
study staff to check on compliance and for potential AEs. 
7.2.3 Day 7 
Subjects will return to the clinic on Day 7 (+ 1 day).  Subjects will be instructed to hold the morning 
administration of study drug until subject arrives at their clinical visit.  Study staff will note the 
time of the dose and provide retraining on inhaler use, if required and check on compliance.    
Assessments and procedures performed before dosing during this visit include: 
· Concomitant medication assessments 
· Adverse event assessment 
· Brief physical examination 
· Vital signs 
· Single 12-lead ECG 
· Collect urine or serum sample for pregnancy test. 
· Collect blood for the following: 
o Hematology 
o Clinical chemistry 
o  PK (pre-dose) 
· Leicester Cough Questionnaire and Cough VAS  
· Spirometry 
· Subject will return the used and unused study drug  
· Dispense and administer Study Drug 
Assessments and procedures performed after dosing include:  
· Adverse event assessment 
· Vital signs 
· Collect blood for the following: 
o PK at 5 minutes (+ 5 minutes) after dosing  


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· Spirometry at 30 minutes (+ 10 minutes) and 1 hour (+ 10 minutes) after dosing  
7.2.4 Days 8-13 
Subjects will self-administer study drug at home and will be contacted on Day 10 (+ 2 days) by 
study staff to check on compliance and for potential AEs. 
7.2.5 Day 14 
Subjects will return to the clinic on Day 14 (±1 day) and the follow-up bronchoscopy will be 
performed.  Subjects will be instructed to hold the morning administration of study drug until 
arrival at their clinical visit.  Study staff will note the time of the dose and check on compliance.  
Follow-up bronchoscopy should occur approximately 2-3 hours after morning dosing. The second 
study drug dose will not be administered on Day 14.   
All assessments and procedures will be performed prior to bronchoscopy.   
Assessments and procedures performed before dosing during this visit include: 
· Concomitant medication assessments 
· Adverse event assessment 
· Complete physical examination 
· Vital signs 
· Single 12-lead ECG 
· Collect urine or serum sample for pregnancy test. 
· Collect blood for the following: 
o Hematology 
o Clinical chemistry 
o PK pre-dose  
o Biomarker assessments 
· Leicester Cough Questionnaire and Cough VAS  
· Spirometry  
· Subject will return the used and unused study drug  
· Administer Study Drug 
Assessments and procedures performed after dosing include:  
· Adverse event assessment 


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· Vital signs 
· Collect blood for the following: 
· PK at 5 minutes (+ 5 minutes) after dosing  
· Spirometry at 30 minutes (+ 10 minutes) and 1 hour (±10 minutes) after dosing 
· Bronchoscopy with BAL and/or BA and deep bronchial brushings after all other Day 14 
assessments are complete  
7.3 
Follow-up Period and Day 21 Visit 
All subjects will be followed for the assessment of safety for 7 days (±2 days) after the last dose 
of study drug and will return to the clinic for an End of Study (EOS) visit 7 days (±2 days) after 
their last dose of study drug.  Assessments and procedures at the EOS visit include: 
· Concomitant medication assessments 
· Adverse event assessment 
· Brief physical examination 
· Vital signs 
· Single 12-lead ECG 
· Collect urine or serum sample for pregnancy test. 
· Collect blood for the following: 
o Hematology 
o Clinical chemistry  
· Leicester Cough Questionnaire and Cough VAS  
· Spirometry 
7.4 
Early Termination 
If a subject discontinues study drug before Day 14, the Day 14 assessments (other than study drug 
dosing), where feasible should be performed in the clinic as close as possible to the day of 
discontinuation.  The EOS assessments should be performed 7 days after the last dose of study 
drug (assuming the subject has not withdrawn consent). 
 
 


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8 ASSESSMENT OF SAFETY 
8.1 
Specification of Safety Parameters 
Safety will be evaluated through continuous monitoring of AEs, physical examinations, vital signs, 
clinical laboratory measurements, spirometry, and ECGs. 
8.2 
Definitions of Adverse Events 
8.2.1 Adverse Event 
According to the ICH guideline for GCP, an AE is any untoward medical occurrence in a subject 
or clinical investigation subject administered a pharmaceutical product, and which does not 
necessarily have to have a causal relationship with the treatment.  An AE can therefore be any of 
the following: 
· Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
· Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition).  
· Recurrence of an intermittent medical condition (e.g., headache) not present at baseline. 
· Any deterioration in a laboratory value or other clinical test (e.g., ECG) that is associated with 
symptoms or leads to a change in study treatment or concomitant treatment or discontinuation 
from study drug. 
· Adverse events that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., Screening invasive procedures such as biopsies). 
8.2.1.1 Treatment-Emergent Adverse Events 
In this study protocol, AEs which begin or increase in severity or frequency at or after the 
administration of first dose of study drug are to be considered as TEAEs.  Safety analyses will 
focus on TEAEs.  
8.2.2 Serious Adverse Event  
An SAE is any AE that meets any of the following criteria: 
· Is fatal (i.e., the AE actually causes or leads to death). 
· Is life threatening (i.e., the AE, in the view of the Investigator, places the subject at immediate 
risk of death). 


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This does not include any AE that, had it occurred in a more severe form or was allowed to 
continue, might have caused death. 
· Requires or prolongs inpatient hospitalization.  
· Results in persistent or significant disability / incapacity (i.e., the AE results in substantial 
disruption of the subject's ability to conduct normal life functions). 
· Is a congenital anomaly/birth defect in a neonate / infant born to a mother exposed to study 
drug. 
· Is a significant medical event in the Investigator's judgment (e.g., may jeopardize the subject 
or may require medical / surgical intervention to prevent one of the outcomes listed above) 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room (ER) or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization. 
Severity and seriousness need to be independently assessed for each AE. 
SAEs are required to be reported by the Investigator to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event) by submission of a SAE Notification Form.   
8.3 
Adverse Event Classification 
8.3.1 Relationship to Investigational Product 
The Investigator’s assessment of causality must be provided for all AEs (serious and non-serious).  
An Investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE. 
· Not related: The AE is clearly not related to the study drug, or the temporal relationship of the 
onset of the AE relative to administration of the product is not reasonable, or the AE can be 
explained by another cause such as an underlying medical condition or other concomitant 
medication, or the AE has no plausible relationship to study drug. 
· Related: The AE is probably related to the study drug.  The temporal relationship of the AE 
to administration of the product is reasonable and there is no other cause to explain the event.  
Adverse events should be classified as related if the Investigator feels there is evidence to 
suggest a causal relationship between the study drug and the AE. 
8.3.2 Severity 
All adverse Events will be assessed according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), Version 5.   


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Table 4 will be used for assessing severity for AEs that are not specifically listed in the NCI 
CTCAE. 
Table 4 
Adverse Event Severity Grading Scale for Events not Specifically Listed in NCI 
CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not 
indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate 
instrumental activities of daily living [a] 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living 
[b, c] 
4 
Life-threatening consequences or urgent intervention indicated [d] 
5 
Death related to adverse event [d] 
a. 
Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b. Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, using 
the toilet, and taking medications, as performed by patients who are not bedridden. 
c. 
If an event is assessed as a "significant medical event," it must be reported as a serious adverse event, per the 
definition of serious adverse event in Section 8.2.2. 
d. Grade 4 and 5 events must be reported as serious adverse events, per the definition of serious adverse event in 
Section 8.2.2. 
Reference source: Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 published on 
November 27, 2017. 
8.4 
Collection and Reporting of Adverse Events 
8.4.1 Initial Reporting of Adverse Events 
Any event occurring prior to administration of the first dose of study drug will be recorded in the 
Medical History on eCRF unless the AE is serious and related to a protocol-mandated intervention 
as per Section 8.2.1.  A pre-existing medical condition should be recorded as an AE only if the 
frequency, severity, or character of the condition worsens during the study.  
All AEs from time of first dose through the EOS will be collected, regardless of relationship to 
study drug.  
A clinically relevant deterioration in laboratory assessments or other clinical findings, as assessed 
by the Investigator, is considered an AE, and must be recorded on the AE CRF if it meets the 
reporting time frames above.  In addition, an abnormal test finding will be classified as an AE if 
one or more of the following criteria are met: 
· The test finding is accompanied by clinically significant symptoms. 


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· The test finding necessitates additional diagnostic evaluation(s) or medical / surgical 
intervention, including additional concomitant drug treatment or other therapy.  Note: simply 
repeating a test finding, in the absence of any of the other listed criteria, does not constitute an 
AE. 
· The test finding leads to a change in study drug dosing or discontinuation of subject 
participation in the clinical research study. 
· The test finding is considered an AE by the Investigator. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified.  However, if an observed or reported sign or symptom is not 
associated with a specific disease or syndrome, the individual sign or symptom should be recorded 
as a separate AE.  Laboratory data are to be collected as stipulated in this protocol. Clinical 
syndromes associated with laboratory abnormalities are to be recorded as appropriate (e.g., 
diabetes mellitus rather than hyperglycemia). 
8.4.2 Adverse Events Reporting Period 
After informed consent has been obtained but prior to initiation of study drug, only AEs 
caused by a protocol-mandated intervention (e.g., invasive procedures, discontinuation of 
medications) should be reported. 
After initiation of study drug, all TEAEs (regardless of causal assessment to study drug) will be 
recorded until one week after the final dose of study drug (Day 21 Visit or EOS). 
8.4.3 Follow-up of Adverse Events 
All AEs considered to be related to study drug will be followed until resolution or stabilization. 
8.5 
Collection and Reporting of Serious Adverse Events 
8.5.1 Initial Serious Adverse Event Reports 
All SAEs that occur up to and including EOS must be reported by the Investigator to the Sponsor 
within 24 hours of awareness of the event by submission of a SAE Notification Form.  
Investigators must report to the Sponsor any SAE, whether or not considered drug related, 
including those listed in the protocol or IB.  
The initial report must contain at a minimum the protocol number, a subject study identifier code, 
subject’s initials, subject’s data of birth, an event term, the suspected product and an assessment 
of causality.  An Investigator may be requested by the Sponsor to obtain specific follow-up 
information in an expedited fashion.  This information may be more detailed than that captured on 
the AE CRF.  In general, this will include a description of the SAE in sufficient detail to allow for 
a complete medical assessment of the case and independent determination of possible causality.  


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Information on other possible causes of the event, such as concomitant medications and illnesses 
must be provided.  In the case of a subject death, a summary of available autopsy findings must be 
submitted as soon as possible to the Sponsor.  
8.5.2 Follow-up of Serious Adverse Events 
All SAEs should be followed up until resolution or stabilization. The timelines and procedure for 
follow-up reports are the same as those for the initial report. 
New information regarding an SAE that becomes available after the submission of the initial SAE 
Notification Form must be reported by the Investigator to the Sponsor by completion of a SAE 
Follow-up Report Form or through other written documentation (e.g., laboratory tests, discharge 
summary, postmortem results).  Follow-up reports and/or written documentation must be provided 
to the Sponsor within 24 hours of the Investigator’s receipt of the information. 
8.5.3 Reporting of Death 
Death is an outcome of an SAE and not an SAE itself.  When death is an outcome, the event(s) 
resulting in death should be reported (e.g., “pulmonary embolism” with a fatal outcome).   
8.6 
Post-Trial Adverse Events 
Any AE that occurs outside of the protocol-specified observation period or after the end of the 
study but is considered to be caused by the investigational product must be reported to the Sponsor. 
Instructions for how to submit these AEs will be provided separately. 
8.7 
Pregnancy Reporting and Follow-up 
Pregnancy in a female clinical trial subject is not an SAE, however, complications of such 
pregnancies, for example, spontaneous abortion, may qualify as an SAE and should be reported as 
an SAE even if they occur after the SAE reporting period has ended. 
The Investigator must notify the Sponsor via telephone or e-mail within 24 hours of awareness of 
a pregnancy in a study subject and must complete the Pregnancy Notification Form and submit it 
to the Sponsor within 2 working days of being notified.  If the female subject is pregnant, then 
subject will not receive any further doses of their assigned study drug.  The pregnancy must be 
followed to determine outcome, including spontaneous or voluntary termination, details of birth, 
and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications.  This follow-up should occur even if the intended duration of safety 
follow-up for the trial has ended.  Information regarding the course of the pregnancy, including 
perinatal and postnatal offspring outcome up to 8 weeks of age should be reported as follow-up 
information on the Pregnancy Notification Form. 


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Male study subjects will be instructed to notify the Investigator if a female partner becomes 
pregnant during the study.  The Investigator must notify the Sponsor within 24 hours via telephone 
or e-mail and must complete the Pregnancy Notification Form and submit it to the Sponsor within 
2 working days of being notified.  The Investigator should obtain informed consent from the 
subject’s partner using an EC-approved ICF, allowing the Investigator to obtain information 
regarding the pregnancy and its outcome.  If the subject’s partner provides informed consent, the 
Investigator should follow the pregnancy until outcome as described above for female study 
subjects and report the follow-up information on the Pregnancy Notification Form. 
8.8 
Stopping Rules  
Safety data will be reviewed on an ongoing basis by the Sponsor’s Medical Officer and the CRO 
Medical Monitor (Section 3) who will monitor subject safety during study conduct and can make 
decisions regarding individual subject drug, group/cohort treatment, and/or subsequent dosing 
regimens. The grading of events can be used to help determine these decisions, taking into 
consideration the subject’s baseline parameters and the possibility for differences based on 
demographics.  
Potential safety signals that will trigger a meeting of the Sponsor and CRO medical personnel, and 
subsequent written recommendation about study conduct include the following: 
· Any SAE considered to be related to study drug 
· Any related clinical NCI CTCAE ≥ grade 3 (severe) AE 
· Any unrelated similar SAE or clinical NCI CTCAE > grade 3 (severe) AE in > 2 subjects.  
For example, wheezing and chest tightness would be considered similar because they may 
both be related to airway obstruction. 
As noted in Section 6.14.1 study drug will be discontinued in subjects with a decrease from 
Baseline in FEV1 of > 15% associated with a decrease from Baseline in the FEV1/FVC ratio. 
Related AEs or suspected adverse drug reactions means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility, i.e., there is evidence to suggest a 
causal relationship.   
When a potential safety signal as defined above occurs, enrollment will be halted pending review 
by the Sponsor Medical Officer and CRO Medical Monitor and study treatment will be stopped in 
the individual experiencing the safety signal AE.  All potential safety signals will be reviewed 
within 7 days by the Sponsor Medical Officer and CRO Medical Monitor that could recommend: 
· Re-start subject enrollment. A protocol amendment summarizing available data and 
justification will be required to continue enrollment at the dose level associated with a stopping 
rule or any higher dose. 


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· Add a new lower dose cohort 
· Add more subjects to a cohort without dose limiting toxicities 
· Continued pausing of enrollment 
· Permanently discontinuing enrollment into the study  
8.9 
Emergency Unblinding 
The blind may be broken for an individual subject at the discretion of the Investigator if knowledge 
of the type of study drug administered is required to guide appropriate treatment decisions.  The 
Sponsor’s Medical Officer should be notified within 24 hours of the Investigator’s decision to 
unblind. 
8.10 
Emergency Sponsor Contact 
In a medical emergency (i.e., an event that requires immediate attention regarding operation of the 
clinical study and/or the use of investigational study drug), study site staff will apply appropriate 
medical intervention according to current standards of care and contact the Sponsor’s Medical 
Officer. 
 
 


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9 STATISTICAL CONSIDERATIONS 
9.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be created, which will provide a more technical and detailed 
description of the proposed data analysis methods and procedures. 
The results of the final analysis, as well as any deviations from planned statistical analyses, will 
be presented in the clinical study report. 
9.1.1 Randomization Procedures 
Subjects will be randomized to receive LTI-03: placebo in sequential cohorts, as per the study 
design.  Randomization codes and unique subject identification numbers will be generated by the 
IVRS.  All study staff will remain blinded to study drug assignment.  
9.2 
Study Hypotheses 
The primary endpoint of the study is safety.  No formal statistical hypotheses will be tested. 
9.3 
Analysis Set 
The populations for analysis will include at a minimum a Safety Analysis Set. Other potential 
analysis sets will be defined in the SAP. 
9.3.1 Safety Analysis Set 
The Safety Analysis Set will consist of all subjects randomized to study drug and received at least 
1 dose of study drug. 
9.4 
Statistical Methods and Analysis 
9.4.1 General Approach 
All descriptive statistical analyses will be performed using the most recently released and available 
Statistical Analysis System (SAS) statistical software (version 9.4 or higher), unless otherwise 
noted.  For categorical variables, the number and percent of each category within a parameter will 
be presented.  For continuous variables, the sample size (n), mean, median, and standard deviation, 
as well as the minimum and maximum values, will be presented.  Missing data will not be imputed 
unless otherwise stated.  Subjects on Placebo from all cohorts will be pooled to form a combined 
placebo group for analysis. 
9.4.2 Demographics and Other Baseline Characteristics 
Demographics and other baseline disease characteristics will be summarized by treatment and\or 
cohort. 


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9.4.3 Concomitant Medications 
Concomitant medications will be coded using the latest version of the World Health Organization 
Drug Dictionary (WHO-DD).  
9.4.4 Primary Endpoint 
The primary endpoint of the study is incidence of TEAEs.  
Adverse events will be graded according to National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE), Version 5. 
Adverse events will be coded by preferred term and system organ class using the current version 
of Medical Dictionary for Regulatory Activities (MedDRA®) and summary tables for all AEs will 
be generated for the Safety Population.  Incidence rates and percentages will be summarized for 
each preferred term and system organ class.  Additional summary tables will be generated for the 
following population subsets: subjects with SAEs, subjects with related AEs, subjects with severe 
(Grade 3 or 4) AEs, and subjects who discontinue study drug due to AEs.  Adverse events will be 
summarized by treatment and cohort.  
9.4.5 Other Safety Endpoints 
Other safety endpoints are based on clinical evaluations, changes in clinical laboratory tests, vital 
signs, ECGs and spirometry.   
9.4.5.1 
Clinical Evaluations 
Clinical evaluations used for the assessment of the safety will include physical examination 
findings, vital signs, spirometry, and ECG results.  
Clinically significant changes in vital signs and new findings on physical examination will be 
recorded as AEs.  Incidences of subjects with changes from normal physical examination findings 
at baseline to abnormal during the study may be generated. 
Information on ECGs and spirometry will be presented in listings.    Summary of mean / median 
changes in ECG intervals and mean / median changes in spirometry parameters may be generated 
on a data-driven basis. The incidence of subjects with changes from normal findings at baseline to 
abnormal during the study will be generated as appropriate. 
9.4.5.2 
Laboratory Assessments 
All hematology, clinical chemistry and coagulation results will be listed by subject for each 
assessment and descriptive statistics may be tabulated for select criteria.  Changes from baseline 
may be summarized by treatment. 


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9.4.6 Analysis of Exploratory Endpoints 
9.4.6.1 
Biomarkers 
Details of the biomarker analysis will be provided in the SAP. 
9.4.6.2 
Pharmacokinetic 
Details of the PK analysis will be provided in the SAP. 
9.4.7 Planned Interim Analyses 
No formal interim analyses are planned for the study. Cohort 1 biomarker data may be analyzed 
before final database lock without changing the overall study conduct.    
9.5 
Sample Size Determination 
Approximately 24 subjects are planned in 2 cohorts.  Each cohort will include 12 subjects (9 on 
LTI-03 and 3 on placebo).  Selection of sample size is based on prior experience to ensure that the 
safety and tolerability of LTI-03 will be adequately assessed while minimizing unnecessary subject 
exposure.  With 18 subjects receiving LTI-03 there is a 60% chance of detecting an AE with a true 
incidence rate of 5% and an 85% chance of detecting a more common AE with a true incidence 
rate of 10%.        
 


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10 DATA HANDLING AND RECORD KEEPING 
10.1 
Study Files and Subject Source Documents 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents include 
the subject’s clinical source documents and Investigator’s Study Files. 
Subject clinical source documents may include, but are not limited to, hospital / clinic records, 
physician’s and nurse’s notes, appointment book, original laboratory reports, spirometry, ECG, 
radiograph, pathology and special assessment reports and consultant letters. 
The Investigator will ensure the Study Files are maintained, including the CRFs and query forms, 
protocol/amendments, EC and regulatory approvals with associated correspondence, signed ICFs, 
study treatment records, staff curriculum vitae and authorization forms, all correspondence and 
other appropriate documents. Such data shall be secured in order to prevent loss. 
The Investigator will allow personnel authorized by the Sponsor access to all study data at any 
time. 
10.2 
Data Collection Methods 
Data collection is the responsibility of the study staff at the site under the supervision of the site 
Investigator.  The Investigator is responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported.  A CRF must be completed for each subject who signs informed 
consent, regardless of the duration of their trial participation.  The reason(s) why subjects are not 
enrolled will be tracked for any subject who signs an ICF. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  When making changes or corrections, cross out the original entry with a 
single line, and initial and date the change. Do not erase, overwrite, or use correction fluid or tape 
on the original.  Documents (including laboratory reports, hospital records subsequent to SAEs, 
etc.) transmitted to the CRO or the Sponsor should include the study-assigned subject number but 
should not include the subject’s name in order to ensure confidentiality. 
CRFs will be provided for recording data for each subject enrolled in the study.  Data reported in 
the CRF derived from source documents should be consistent with the source documents or the 
discrepancies should be explained and maintained in the subject’s official electronic study record.  
The Investigator should consult the eCRF Completion Guidelines for comprehensive instructions 
for completing the CRFs. 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered into the data capture system.  The data system includes 
password protection and internal quality checks, such as automatic range checks, to identify data 


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that appear inconsistent, incomplete, or inaccurate.  Clinical data will be entered directly from the 
source documents. 
10.3 
Retention of Records 
All clinical study documents must be retained by the Investigator until at least two years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region; or, if no application is filed or if the 
application is not approved for such indication, until two years after the investigation is 
discontinued and regulatory authorities have been notified.  Investigators may need to retain 
documents longer if required by applicable regulatory requirements or if requested by the Sponsor.  
The Investigator must notify the Sponsor prior to destroying any clinical study records.  Should 
the Investigator wish to assign the study records to another party or move them to another location, 
the Sponsor must be notified in advance.  It is the responsibility of the Sponsor to inform the 
Investigator when these documents no longer need to be retained. 
If the Investigator cannot guarantee the archiving requirement at the study site for any or all of the 
documents, special arrangements must be made between the Investigator and the Sponsor to 
securely store the documents in an off-site storage location so that documents can be returned to 
the Investigator in case of a regulatory audit.  Where source documents are required for the 
continued care of the subject, appropriate copies should be made for off-site storage. 
10.4 
Protocol Deviations 
The Investigator and the study site staff are responsible for ensuring the study is conducted in 
accordance with the schedule of procedures and assessments described in this protocol and in 
accordance with GCP.  The site must use continuous vigilance to identify and report deviations 
within 24 hours of knowledge of their occurrence.  CRO Standard Operating Procedures (SOPs) 
will be followed for the reporting of study deviations. 
Intentional deviations from the protocol shall not be made without discussion with the Sponsor 
except in a medical emergency, when the intent is to reduce immediate risk to the subject. In such 
cases, the Sponsor, CRO, the EC and regulatory authorities, as appropriate, should be notified, in 
accordance with local requirements.  In all other cases, the nature of the deviation, the justification 
for the deviation, and prior written approval of the Sponsor must be documented. 
Changes to the protocol may be made only when a written substantial protocol amendment has 
been approved by the Sponsor and submitted to the EC and applicable regulatory agencies in 
accordance with local requirements.  Appropriate approval(s) must be obtained before changes can 
be implemented. 
 
 


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11 QUALITY CONTROL AND QUALITY ASSURANCE 
Quality Control procedures will be implemented beginning with the data entry system, and data 
quality control checks will be run on the database.  Any missing data or data anomalies will be 
communicated to the site(s) for clarification / resolution. 
The CRO is responsible for ensuring the proper conduct of the study with regard to protocol 
adherence and validity of data recorded in the CRFs by assigning clinical research associates 
(CRAs) to the site.  The CRA is responsible for reviewing the CRFs at regular intervals throughout 
the study, verifying adherence to the protocol, assuring completeness, consistency and accuracy of 
the data, reviewing study files and drug accountability.  The data will be verified against the 
original medical records as part of source document verification to ensure validity of the data as 
outlined in a separate Monitoring Plan.  The Investigator’s responsibility is to ensure that any 
issues detected in the course of a monitoring visit are resolved. 
To ensure compliance with GCP and all applicable regulatory requirements, a quality assurance 
audit may be conducted by the Sponsor or the Sponsor’s designee.  Regulatory agencies may also 
conduct a regulatory inspection of this study.  Such audits / inspections can occur at any time 
during or after completion of the study.  If an audit or inspection occurs, the Investigator and 
institution agree to allow the auditor / inspector direct access to all relevant documents and to 
allocate the Investigator and the time of Investigator’s staff to the auditor / inspector to discuss 
findings and any relevant issues. 
The Investigator and study staff are responsible for maintaining a comprehensive and accurate 
filing system of all study-related documentation that will be suitable for inspection at any time by 
the Sponsor, its designees, and/or regulatory agencies.  In signing this protocol, the Investigator 
understands and agrees to give access to the necessary documentation and files. 
 
 


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12 ETHICS / PROTECTION OF HUMAN SUBJECTS 
This section of the protocol is subject to the terms of the Clinical Trial Agreement between the 
Sponsor and the study center.  In the event of a discrepancy between the Clinical Trial Agreement 
and this protocol, the terms of the Clinical Trial Agreement shall control. 
12.1 
Ethical Conduct of the Study 
This study will be conducted in compliance with the ICH GCP guidelines, US regulations for the 
ethical conduct of clinical studies under 21 Code of Federal Regulations (CFR) Parts 50, 56 and 
312, the Declaration of Helsinki, and with ICH guidelines regarding scientific integrity (E4, E8, 
E9 and E10), or national laws, if applicable.  This study will also adhere to all Medicines and 
Healthcare Products Regulatory Agency (MHRA), state and local regulatory requirements and 
requirements for data protection. 
12.2 
Ethics Committee Review 
Before trial initiation, the Investigator and institution must have written and dated approval from 
an accredited IRB/IEC for the study protocol, written ICF, subject recruitment procedures (e.g., 
advertisements), and any written information to be provided to subjects.  Any amendment to the 
protocol will require review and approval by the IRB/IEC before the changes are implemented to 
the study.  All changes to the ICF will be IRB/IEC approved; a determination will be made 
regarding whether previously consented subjects need to be re-consented. 
Appropriate reports on the progress of the study will be made by the Investigator to the IRB/IEC 
and the Sponsor in accordance with applicable regulations.  All correspondence with the IRB/IEC 
should be retained in the Investigator’s Study File.  Copies of IRB/IEC approvals should be 
forwarded to the Sponsor or its designee. 
12.3 
Informed Consent Process 
The ICF must be approved by the IRB/IEC prior to being presented to potential study subjects.  
Any changes to the ICF must be approved by the Sponsor 
Subjects may agree to participate in the clinical trial only after the risks and possible benefits of 
their participation have been explained and extensively discussed.  The Investigator or designee 
will explain the purposes, procedures, and potential risks of the research study in terms suited to 
their comprehension, as well as their rights as a research subject.  Subjects will have the 
opportunity to carefully review the written ICF, discuss the study with their surrogates, and ask 
questions prior to signing.  Written informed consent must be obtained from each study subject or 
the subject’s legally acceptable representative prior to conducting any study-related procedures. 
The Investigator must use the most current EC-approved ICF for documenting written consent.  
Each informed consent will be appropriately signed and dated by the subject or the subject’s legally 


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acceptable representative and by the person obtaining consent.  The site must retain the original 
signed ICF and provide a copy to the subject. 
12.4 
Confidentiality of Information 
Individual subject medical information obtained as a result of this study is considered confidential.  
The Investigator and the study center will adhere to all applicable laws relating to the protection 
of subject information.  To assure that subject confidentiality is maintained, subject data will be 
identified only by a study-assigned subject number on any Sponsor forms, reports, publications, 
or in any other disclosures, except where required by law. 
All personnel working for, or representing, the Sponsor and CRO will handle subject data in a 
confidential manner in accordance with applicable regulations governing clinical research. Subject 
records will be inspected only in connection with this research project.  Information generated as 
a result of a subject’s participation in this study may be disclosed to third parties for research, 
regulatory, and other purposes in any country as determined by the Sponsor.  However, subjects 
will not be individually identified but will be referred to by the study-assigned subject number. 
12.5 
Future Use of Stored Specimens 
Data collected for this study will be analyzed and stored at the CRO.  After the study is completed, 
the de-identified, archived data will be transmitted to and stored at the Sponsor’s facility or a 
delegated contract long-term storage vendor, for use by the Sponsor and its research collaborators.  
With the subject’s approval and as approved by the IRB/IEC, de-identified biological samples will 
be stored at the Central Laboratory and then a long-term storage vendor.  These samples could be 
used for future research performed by the Sponsor or its collaborators. 
12.6 
Publication Policy 
Publication and/or disclosure of information or data related to this protocol is subject to and 
governed by the Clinical Trial Agreement between the Sponsor and the clinical site to which the 
Investigator is a signatory. 
After conclusion of the study, Investigators in this study may make oral presentations of study 
results or publish such results in scientific journals or other scholarly media without prior written 
approval from the Sponsor, only after the following conditions have been met: 
· The results of the study in their entirety have been publicly disclosed by or with the consent 
of the Sponsor in an abstract, manuscript or presentation forum; 
· The Investigator has complied with the terms of the Clinical Trial Agreement and all requests 
from the Sponsor to delete any references to its confidential information (other than study 
results); 


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· The study has been completed for at least two years. 
 


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13 REFERENCES 
Adams TS, Schupp JC, Poli S, et al. Single-cell RNA-seq reveals ectopic and aberrant lung-
resident cell populations in idiopathic pulmonary fibrosis Sci Adv. 2020 Jul 8;6(28):eaba1983. doi: 
10.1126/sciadv.aba1983. eCollection 2020 Jul. 
Birring SS, Prudon B, Carr AJ, et al. Development of a symptom specific health status measure 
for patients with chronic cough: Leicester Cough Questionnaire (LCQ). Thorax 2003;58:339–343. 
http://dx.doi.org/10.1136/thorax.58.4.339. 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 published on 
November 27, 2017. 
Guenther A, Krauss E, Tello S, et al. The European IPF registry (eurIPFreg): baseline 
characteristics and survival of patients with idiopathic pulmonary fibrosis. Respir Res 
2018;19(1):141. DOI: 10.1186/s12931-018-0845-5. 
Lancaster, Lisa, et al. "Idiopathic pulmonary fibrosis: Physician and patient perspectives on the 
pathway to care from symptom recognition to diagnosis and disease burden." Respirology 27.1 
(2022): 66-75. 
Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med. 2018;378:1811–23. 
doi:10.1056/NEJMra1705751. 
Maher, Toby M., and Mary E. Strek. "Antifibrotic therapy for idiopathic pulmonary fibrosis: time 
to treat." Respiratory research 20.1 (2019): 1-9. 
Martinez FJ, Collard HR, Pardo A, Raghu G, et al. Idiopathic pulmonary fibrosis. Nat Rev Dis 
Prim. 2017;3:17074. doi:10.1038/nrdp.2017.74. 
Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 
2005;26:319-38.   
Raghu G, Jardin MR, Myers JL., et al. Diagnosis of idiopathic pulmonary fibrosis. An official 
ATS/ERS/JRS/ALAT Clinical practice guideline. Am. J. Respir. Crit. Care Med. 2018;198:44-68. 
Snyder LD, Mosher C, Holtze CH, et al. Time to diagnosis of idiopathic pulmonary fibrosis in the 
IPF-PRO Registry. BMJ Open Respir Res 2020;7(1). DOI: 10.1136/bmjresp-2020-000567. 
Spinou A and Birring S. An Update on Measurement and Monitoring of Cough: What are the 
Important Study Endpoints? J Thorac Dis. 2014 Oct; 6(Suppl 7): S728–S734. Doi: 
10.3978/J.Issn.2072-1439.2014.10.08 
 
 
 


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14 APPENDICES 
14.1 
Appendix 1 
Schedule of Assessments  
Table 5 
Schedule of Assessments 
 
Screening Period 
Treatment Period1 
Follow-Up 
Early  
Termination2 
 
(Day -21 to Day -1) 
Day 1 
Day 7  
(± 1 day) 
Day 14  
(± 1 day) 
Day 21 
(+ 2 days) 
 
Informed consent 
x 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
x 
 
 
 
 
Demographics, Medical History 
x 
 
 
 
 
 
Prior medications 
x 
 
 
 
 
 
Concomitant medications 
 
Complete physical examination3 
x 
 
 
x 
 
x 
Brief physical examination4 
 
x 
x 
 
x 
 
Vital Signs 
x 
x 
x 
x 
x 
x 
ECG (12-Lead ECG), single 
x 
x 
x 
x 
x 
x 
Bronchoscopy with BAL and/or BA and deep 
bronchial brushings biopsy 
x  
 
 
x 
 
x 
Blood for biomarker assessments5 
x 
 
 
x 
 
x 
Pregnancy test6 
x 
x 
x 
x 
x 
x 
Safety Laboratory parameters7 
x 
x 
x 
x 
x 
x 
Randomization 
 
x 
 
 
 
 
Blood collection for PK8  
 
 
 x 
x 
x 
 
 
Assessment of ability to use inhaler 
x 
 
 
 
 
 
Leicester Cough Questionnaire & Cough VAS 
x 
x 
x 
x 
x 
x 
Spirometry9 
x 
x 
x 
x 
x 
x 
Dosing10 
 
x 
x 
x 
 
 
Subjects returning unused study drug 
 
 
x 
x 
 
 
Adverse Events  
x 
 


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Abbreviations: BAL = bronchoalveolar lavage; BA = bronchoabsorption; DLCO = diffusion capacity of the lungs for carbon monoxide; ECG = electrocardiogram; 
PK = pharmacokinetics; VAS = visual analogue scale 
Note:  
1. On Days 2 to 6 and Days 8 to 13, subjects will self-administer study drug at home and will be contacted on Day 4 (± 2 days) and Day 10 (± 2 days) by study 
staff to check on compliance and for potential adverse events. Day 1, 7, and 14 will be clinic visit. Study staff will monitor subjects self-administrating study 
drug (most likely the morning dose) on Day 1, Day 7, and Day 14.   
2. If a subject discontinues study drug before Day 14, the Day 14 assessments (other than study drug dosing) where feasible should be performed in the clinic as 
close as possible to the day of discontinuation.  The EOS assessments should be performed 7 days after the last dose of study drug (assuming the subject has 
not withdrawn consent). 
3. A complete physical examination will include an evaluation of the head, eyes, ears, nose and throat, and the cardiovascular, dermatologic, musculoskeletal, 
respiratory, gastrointestinal, and neurologic systems.  Any abnormality identified at baseline (Screening Day) will be recorded as medical history. 
4. A brief physical examination will focus on systems affected by AEs and at a minimum should include the cardiovascular and respiratory systems.  
5. Biomarker assessment will be for peripheral blood cells, platelet rich plasma, bronchoalveolar lavage fluid (BALF), BA samples, and deep bronchial brushings. 
6. Serum or urine test required for any FOCBP, defined as pre-menopausal or < 12 months of amenorrhea post-menopause or no history of surgical sterilization 
7. Safety laboratory assessments include hematology, chemistries, and coagulation.  Coagulation will be performed only at Screening. 
8. Blood for PK will be collected pre-dose (trough) and +5 minutes after dosing.  
9. Spirometry: DLCO on Screening only.  On treatment days (Day 1, 7, 14), it will be done before dosing and post dose at 30 and 60 minutes. 
10. Study staff will monitor subjects self-administrating study drug (most likely the morning dose) on Day 1, Day 7, and Day 14.  On Day 1, the first dose of study 
drug will be administered at the investigational site and subjects will be monitored for at least 1 hour after dosing. Study drug is dispensed on Day 1 and Day 
7.  


Lung Therapeutics, Inc. 
04 May 2023 
Protocol No. LTI-03-1002 
 
 
Version 5.0 
Proprietary and Confidential 
 
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14.2 
Appendix 2  
Visit and Procedure Windows 
Procedure 
Visit 
Window 
Pharmacokinetics 
Day 1 
5 minutes + 5 minutes post-dose 
Day 7 
5 minutes + 5 minutes post-dose 
Day 14 
5 minutes + 5 minutes post-dose 
Spirometry 
Day 1 
30 minutes + 10 minutes post-dose and 
60 minutes + 10 minutes post-dose  
Day 7 
30 minutes + 10 minutes post-dose and 
60 minutes + 10 minutes post-dose  
Day 14 
30 minutes + 10 minutes post-dose and 
60 minutes + 10 minutes post-dose  
 
 
 
 


Lung Therapeutics, Inc.
04 May 2023
Protocol No. LTI-03-1002
Version 5.0
Proprietary and Confidential
Page 63 of 66
14.3
Appendix 3
Leicester Cough Questionnaire 
Reference source: Development of a symptom specific health status measure for patients with chronic 
cough: Leicester Cough Questionnaire (LCQ). http://dx.doi.org/10.1136/thorax.58.4.339.


Lung Therapeutics, Inc.
04 May 2023
Protocol No. LTI-03-1002
Version 5.0
Proprietary and Confidential
Page 64 of 66
14.4
Appendix 4
Cough Visual Analogue Scale 


Lung Therapeutics, Inc. 
04 May 2023 
Protocol No. LTI-03-1002 
 
 
Version 5.0 
Proprietary and Confidential 
 
Page 65 of 66 
14.5 
Appendix 5 
Protocol Amendments  
Protocol Amendment and Date 
Section and Summary of Changes 
Reason 
Version 5 27Apr2023 
· 
Section 4.1.1 – Changed 
diagnosis to within last 3 years, 
removed FVC upper limit, 
updated DLCO upper limit to 80, 
and allowed historical treatment 
of previous anti-fibrotic therapy 
to within 2 months of the 
Baseline bronchoscopy  
· 
Section 7.2 – Update PK sample 
to 5 minutes post-dose instead of 
30 minutes 
· 
Allows for a broader subject 
population 
 
 
 
 
 
· 
More likely to measure LTI-03 
level above lower limit of 
detection 
Version 4 04Jan2023 
· 
Administrative Changes 
· 
Section 6.1.4 – Added 
discontinuation for decrease from 
Baseline in FEV1 of 15% 
· 
Section 6.7 – Added additional 
post-dose and as needed 
spirometry  
· 
Section 8.8 – Added unrelated 
similar SAE or severe or higher 
AE in > 2 subjects’ criterion to 
stopping rules 
 
· 
Administrative changes 
· 
Added safety measure 
 
· 
Additional monitoring for 
potential airway obstruction 
 
· 
Additional safety measure 
Version 3 06Oct2022 
· 
Section 1.1.1, 1.2, and 1.3 – 
Update language to include 
rationale for placebo and SOC 
medication 
· 
Section 2.2.2 – Added Leicester 
Cough Questionnaire and Cough 
Visual Analogue Scale to safety 
endpoints 
· 
Provides rationale for SOC 
medication restriction during 
dosing of LTI-03 
 
· 
Data to be summarized as 
endpoints 
 


Lung Therapeutics, Inc. 
04 May 2023 
Protocol No. LTI-03-1002 
 
 
Version 5.0 
Proprietary and Confidential 
 
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· 
Section 3 – Describe safety 
reviews 
 
· 
Section 4.12 – Update exclusion 
criteria to match investigator’s 
brochure 
· 
Section 5.6 – Add language to 
allow investigators to use SOC 
medications 
· 
Section 6.0 and 6.9 – Update to 
provide both BAL and BA can be 
completed.  
· 
Section 8.8 – Update to clarify 
stopping rules and describe 
protocol amendment requirements 
· 
Section 9.3 – Remove analysis 
populations 
· 
Section 9.4.7 Added data analysis 
description after Cohort 1 
· 
Administrative changes  
· 
Update to provide details 
regarding the safety review 
meetings to occur prior to dose 
escalation 
· 
Updated to match investigator’s 
brochure special populations 
 
· 
Provides flexibility for 
investigators to allow SOC 
medications if necessary 
· 
Allows for flexibility for 
investigational site to use SOC 
procedures 
 
· 
Provide clear details when 
stopping rules would apply  
 
· 
Details to be provided in the 
SAP 
 
· 
Allows for analysis of Cohort 1  
 
· 
Administrative changes  
Version 2 17Jun2022 
· 
Section 3.0 and 6.9 - Addition of 
bronchoabsorption 
 
· 
Section 4.1 - Addition of serum to 
pregnancy test 
 
· 
Section 7.1 - Allowing 
rescreening of subjects 
· 
Section 7 – Administrative 
changes  
· 
Allows for flexibility for 
investigational site to use SOC 
procedures 
· 
Allows for flexibility for 
investigational site to use SOC 
procedures based on local 
regulations 
· 
Subjects can be re-screened once 
 
· 
Administrative changes 

SAP_001.pdf: 
 
Confidential 
 
 
 
 
 
 
 
 
Lung Therapeutics, Inc. 
 
LTI-03-1002 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase 1b, Dose Escalation, 
Safety, Tolerability and Pharmacodynamic Biomarker Study of Caveolin-1-
Scaffolding-Protein-Derived Peptide (LTI-03) in Recently Diagnosed, Treatment 
Naïve Subjects with Idiopathic Pulmonary Fibrosis 
 
10OCT2024 
 
Statistical Analysis Plan 
 
Version 2.0 
 
 
 
 
 
Prepared by: 
 
 
PPD 
929 North Front Street Wilmington 
NC 28401-3331 
 
 
 
 


Lung Therapeutics, Inc.
   Statistical Analysis Plan, Version 2.0
LTI-03-1002
Date Issued: 10OCT2024
II
Client:
Lung Therapeutics Inc.
Protocol Number:
LTI-03-1002
Document Description:
Final Statistical Analysis Plan
SAP Title:
A Randomized, Double-Blind, Placebo-Controlled, Phase 
1b, Dose Escalation, Safety, Tolerability and
Pharmacodynamic Biomarker Study of Caveolin-1-
Scaffolding-Protein-Derived Peptide (LTI-03) in Recently 
Diagnosed, Treatment Naïve Subjects with Idiopathic 
Pulmonary Fibrosis
SAP Version Number:
2.0
Effective Date:
10OCT2024
Author(s):
For PPD: Ichraq Latar,  Senior Biostatistician I
For Lung Therapeutics: Mikki Behnke, Statistical Consultant
Approved by:
Ichraq Latar Part of Thermo Fisher Scientific
Date (DD-MMM-YYYY)
Mikki Behnke, Statistical Consultant,
Lung Therapeutics Inc.
Date (DD-MMM-YYYY)
Mi
M kki Behnke, Statistical Consulta
Lu
L ng Therapeutics Inc.
Ic
Ic
Ic
Ic
Ic
Ic
Ic
I hraq Latar Part of Thermo Fishe


Lung Therapeutics, Inc. 
 
     Statistical Analysis Plan, Version 2.0  
 
LTI-03-1002 
 
 Date Issued: 10OCT2024 
 
  
 
 
 
III
DOCUMENT HISTORY
Version 
Date 
Changes 
Version 1.0 01Sep2023 
Initial version 
Version 2.0 10Oct2024 
Protocol deviation severity and significant status defined, 15% 
baseline FEV1 replaced by 15% decrease from Baseline FEV1, 
rule for BLQ value in biomarkers data 


Lung Therapeutics, Inc. 
 
     Statistical Analysis Plan, Version 2.0  
 
LTI-03-1002 
 
 Date Issued: 10OCT2024 
 
  
 
 
 
IV
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... VI 
1. 
INTRODUCTION............................................................................................................. 1 
2. 
OBJECTIVES ................................................................................................................... 1 
2.1. PRIMARY OBJECTIVE .......................................................................................................... 1 
2.2. EXPLORATORY OBJECTIVES ............................................................................................... 1 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 1 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 1 
3.2. STUDY ENDPOINTS ............................................................................................................. 2 
3.2.1.  Primary Endpoint .......................................................................................................... 2 
3.2.2 
Other Safety Endpoints ............................................................................................... 2 
3.2.3.  Exploratory Endpoints .................................................................................................. 2 
3.3. TREATMENTS ...................................................................................................................... 3 
3.4. DOSE ADJUSTMENT/MODIFICATIONS ................................................................................. 3 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 3 
4.1. BASELINE, END OF STUDY AND STUDY DAY ...................................................................... 4 
4.2. MISSING/INCOMPLETE START AND STOP DATES ................................................................ 4 
4.3. SAMPLE SIZE ...................................................................................................................... 5 
4.4. RANDOMIZATION AND BLINDING ....................................................................................... 5 
4.5. ANALYSIS SETS .................................................................................................................. 5 
4.5.1. 
Enrolled Set ................................................................................................................. 5 
4.5.2. 
Randomized Set ........................................................................................................... 5 
4.5.3. 
Safety Set ..................................................................................................................... 6 
4.5.4. 
Pharmacokinetics (PK) Set ......................................................................................... 6 
4.5.5. 
Pharmacodynamics (PD) Set ...................................................................................... 6 
5. 
SUBJECT DISPOSITION AND PROTOCOL DEVIATIONS ................................... 6 
5.1. SUBJECT DISPOSITION ........................................................................................................ 6 
5.2. PROTOCOL DEVIATIONS ..................................................................................................... 6 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................... 7 
6.1. DEMOGRAPHICS AND BASELINE CHARACTERISTICS ........................................................... 7 
6.2. MEDICAL HISTORY ............................................................................................................. 7 
6.2.1. 
General Medical History ............................................................................................ 7 
6.2.2. 
Disease-Specific History ............................................................................................. 7 
6.3. INCLUSION AND EXCLUSION CRITERIA ............................................................................... 7 
7. 
TREATMENTS AND MEDICATIONS ......................................................................... 8 
7.1. PRIOR AND CONCOMITANT MEDICATIONS .......................................................................... 8 
7.1.1. 
Prior Medications ....................................................................................................... 8 
7.1.2. 
Concomitant Medications ........................................................................................... 8 
7.2. CONCOMITANT PROCEDURES ............................................................................................. 8 
7.3. EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE RATE ............................................ 8 


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     Statistical Analysis Plan, Version 2.0  
 
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V 
8. 
SAFETY ANALYSIS........................................................................................................ 8 
8.1 ADVERSE EVENTS ................................................................................................................... 9 
8.1.1. 
Incidence of Treatment-Emergent Adverse Events ..................................................... 9 
8.1.2. 
Relationship of Adverse Events to Study Drug ........................................................... 9 
8.1.3. 
Severity of Adverse Event.......................................................................................... 10 
8.1.4. 
Serious Adverse Events ............................................................................................. 11 
8.1.5. 
Adverse Events Leading to Treatment Discontinuation............................................ 11 
8.1.6. 
Adverse Events Leading to Death ............................................................................. 11 
8.2. CLINICAL LABORATORY EVALUATIONS ........................................................................... 11 
8.2.4. 
Hematology ............................................................................................................... 12 
8.2.5. 
Serum Chemistry ....................................................................................................... 12 
8.2.6. 
Coagulation............................................................................................................... 13 
8.2.7. 
Pregnancy Test.......................................................................................................... 13 
8.3. VITAL SIGN MEASUREMENTS ........................................................................................... 13 
8.4. PHYSICAL EXAMINATION ................................................................................................. 13 
8.5. ELECTROCARDIOGRAM ..................................................................................................... 14 
8.6. SPIROMETRY ..................................................................................................................... 14 
8.7. LEICESTER COUGH QUESTIONNAIRE ................................................................................ 15 
8.8. COUGH VISUAL ANALOGUE SCALE .................................................................................. 15 
9. 
PHARMACOKINETICS ............................................................................................... 15 
10. 
EXPLORATORY BIOMARKER SAMPLING .......................................................... 15 
11. 
INTERIM ANALYSIS ................................................................................................... 16 
12. 
CHANGES IN THE PLANNED ANALYSIS .............................................................. 17 
13. 
REFERENCES ................................................................................................................ 18 
14. 
APPENDICES ................................................................................................................. 19 
14.1. 
SCHEDULE OF ASSESSMENTS ......................................................................................... 19 
14.2.  LEICESTER COUGH QUESTIONNAIRE ................................................................................. 21 
14.3. 
COUGH VISUAL ANALOGUE SCALE ............................................................................... 22 


Lung Therapeutics, Inc. 
 
     Statistical Analysis Plan, Version 2.0  
 
LTI-03-1002 
 
 Date Issued: 10OCT2024 
 
  
 
 
 
VI
List of Abbreviations 
AE 
Adverse Event 
AEC2 
Alveolar Epithelial Type 2 Cells 
ALP  
Alkaline Phosphatase 
ALT  
Alanine Aminotransferase 
aPTT  
activated Partial Thromboplastin Time 
AST  
Aspartate Aminotransferase 
ATS 
American Thoracic Society 
AV 
Atrioventricular 
BA 
Bronchoabsorption 
BAL 
Bronchoalveolar Lavage 
BALF 
Bronchoalveolar Lavage Fluid 
BID 
Twice daily 
BUN 
Blood Urea Nitrogen 
CK  
Creatine Kinase 
CRF  
Case Report Form 
CRO  
Contract Research Organization 
CRP  
C-reactive protein 
CSD 
Caveolin-1 Scaffolding Domain 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System   
DLCO 
Diffusion Capacity of the Lungs for Carbon Monoxide 
ECG  
Electrocardiogram 
ECM 
Extracellular Matrix 
EOS  
End of Study 
ERS 
European Respiratory Society   
EU 
European Union 
FEV1 
Forced Expiratory Volume 1 
FLF 
Fibrotic Lung Fibroblast 
FN 
Fibronectin 
FOCBP 
Female of Childbearing Potential 
FVC 
Forced Vital Capacity 


Lung Therapeutics, Inc. 
 
     Statistical Analysis Plan, Version 2.0  
 
LTI-03-1002 
 
 Date Issued: 10OCT2024 
 
  
 
 
 
VII 
GGT  
Gamma Glutamyltransferase 
HDL-C  
High Density Lipoprotein Cholesterol 
Hgb  
Hemoglobin 
HR 
Heart Rate 
HRCT 
High-resolution Computed Tomography 
IB 
Investigator’s Brochure 
ICH  
International Council for Harmonization 
ILD 
Interstitial Lung Disease 
IPF 
Idiopathic Pulmonary Fibrosis 
IVRS 
Interactive Voice Response System  
LCQ 
Leicester Cough Questionnaire 
LDH  
Lactate Dehydrogenase 
LDL-C  
Low Density Lipoprotein Cholesterol 
MCH  
Mean Corpuscular Hemoglobin 
MCHC  
Mean Corpuscular Hemoglobin Concentration 
MCV  
Mean Corpuscular Volume 
MedDRA  
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
PD 
Pharmacodynamic 
PR 
P to R interval 
PK  
Pharmacokinetic 
PT  
Prothrombin Time 
QD 
Once Daily 
QRS 
QRS wave 
QT 
Q to T interval 
QTcF 
QT interval corrected for heart rate calculated using Fridericia’s formula 
RBC  
Red blood cell 
RDW  
Red cell Distribution Width 
RR 
R to R interval for ECGs 
SAE  
Serious Adverse Event 
SAP  
Statistical Analysis Plan 
SAS 
Statistical Analysis System 


Lung Therapeutics, Inc. 
 
     Statistical Analysis Plan, Version 2.0  
 
LTI-03-1002 
 
 Date Issued: 10OCT2024 
 
  
 
 
 
VIII
SOA 
Schedule of Assessments 
TEAE  
Treatment-Emergent Adverse Event 
VAS 
Visual Analogue Scale 
WBC  
White Blood Cell 
WHODD  
World Health Organization Drug Dictionary 


Lung Therapeutics, Inc. 
 
     Statistical Analysis Plan, Version 2.0  
 
LTI-03-1002 
 
 Date Issued: 10OCT2024 
 
  
 
 
 
1
1. Introduction 
This Statistical Analysis Plan (SAP) defines the statistical methods and data presentations for 
the Lung Therapeutics, Inc. protocol LTI-03-1002 study entitled “A Randomized, Double-Blind, 
Placebo-Controlled, Phase 1b, Dose Escalation, Safety, Tolerability and Pharmacodynamic 
Biomarker Study of Caveolin-1-Scaffolding-Protein-Derived Peptide (LTI-03) in Recently 
Diagnosed, Treatment Naïve Subjects with Idiopathic Pulmonary Fibrosis”. 
This SAP covers all specified analysis for the final study reports based on the study protocol 
Version 5.0 dated 04 May2023.  
2. Objectives 
2.1.   Primary Objective 
· To determine the safety and tolerability of inhaled LTI-03 in subjects diagnosed with IPF 
within 3 years of Screening. 
2.2. Exploratory Objectives 
· To assess the plasma pharmacokinetic (PK) of inhaled LTI-03 after the first dose and at 
steady state in subjects with IPF diagnosed within 3 years of Screening.  
· To evaluate the pharmacodynamic (PD) biomarkers of inhaled LTI-03 in subjects 
diagnosed with IPF within 3 years of Screening. 
3. Investigational Plan 
3.1. Overall Study Design and Plan 
This is a randomized, double-blind, placebo-controlled, multi-center, dose escalation, safety and 
tolerability study of LTI-03 or placebo administered by inhalation in subjects with IPF without 
prior treatment with anti-fibrotic agents within 2 months of the Baseline bronchoscopy. An IPF 
diagnosis will be confirmed by high-resolution computed tomography (HRCT) of chest or lung 
biopsy within 3 years prior to Screening. The study will contain 2 dose cohorts which will run 
sequentially. Subjects in the first, low-dose cohort (Cohort 1) will receive 2.5 mg of study drug 
(LTI-03 or placebo), administered twice daily approximately 10-12 hours apart (5 mg per day). 
If the 5 mg per day dose is well tolerated, a second, high-dose cohort (Cohort 2) will receive 
5 mg of study drug (LTI-03 or placebo), administered twice daily approximately 10-12 hours 
apart (10 mg per day). 
Eligible subjects will be randomized in a 3:1 ratio to either LTI-03 or placebo. Each cohort will 
have 9 subjects randomized to LTI-03 and 3 subjects randomized to placebo. Safety data will be 
reviewed on an ongoing basis by the Sponsor’s medical officer and the Contract Research 
Organization (CRO)’s medical monitor. A review of safety data including but not limited to 
adverse events, laboratory assessments, vital signs, and spirometry will be conducted after all 12 
subjects from Cohort 1 have completed Day 14 assessments. Enrollment in the second cohort 
will not begin until the Cohort 1 safety data has been reviewed and a dose decision made. A 
lower dose cohort may be added (2.5 mg administered once daily) or additional subjects (up to 
12 subjects) may be added to the low-dose cohort (2.5 mg administered twice daily) if doses of 


Lung Therapeutics, Inc. 
 
     Statistical Analysis Plan, Version 2.0  
 
LTI-03-1002 
 
 Date Issued: 10OCT2024 
 
  
 
 
 
2
5 mg twice daily (10 mg per day) are not tolerated. In total, a maximum of approximately 24 
subjects will be randomized in the study.   
The Treatment Period will be 14 days, with subjects self-administering the study drug using the 
provided commercially available dry powder inhaler. All subjects will be trained on the proper 
methods of inhaler use and will have access to site personnel trained to assist subjects remotely 
if questions arise.  Retraining may occur on Day 1 and 7, if required. During the Treatment 
Period, there will be on-site visits on Day 1, Day 7, and Day 14 and study assessments will 
occur at the investigational site on these days. The first dose of study drug will be administered 
at the investigational site and subjects will be monitored for at least 1 hour after dosing.   
Screening assessments may take place over no more than 21 days prior to the Treatment Period.  
Screening assessments will include but not be limited to a complete physical examination 
including vital signs, electrocardiogram (ECG), spirometry, safety laboratory parameters, 
medical history, and concomitant medications. A Baseline bronchoscopy will be performed 
during the Screening Period in subjects who meet the Screening criteria and will include 
bronchoalveolar lavage (BAL) and/or bronchoabsorption (BA), and deep bronchial brushings. 
Treatment Period will include but not be limited to physical examinations with vital signs, ECG, 
spirometry, clinical laboratory assessments, adverse event (AE) assessment, Leicester cough 
questionnaire, cough visual analogue scale (VAS), and concomitant medications.  
Bronchoscopies with BAL and/or BA and deep bronchial brushings will also be performed on 
Day 14 approximately 2-3 hours after morning dosing.  
Follow-up study assessments will be completed at Day 21 with all Day 14 assessments repeated 
except dosing, bronchoscopy, and blood collection for biomarkers and PK. Also, a complete 
physical examination will be replaced by a brief physical examination. The end of the study is 
defined as the date of the last visit of the last participant in the study.  
3.2. Study Endpoints 
3.2.1.  Primary Endpoint 
· Incidence of Treatment Emergent Adverse Events (TEAE). 
3.2.2 Other Safety Endpoints 
· Other safety endpoints include: 
o Physical examination findings 
o Vital signs 
o ECG 
o Clinical laboratory measurements 
o Spirometry 
o Leicester Cough Questionnaire (LCQ) 
o Cough VAS 
3.2.3.  Exploratory Endpoints 
· To determine the plasma peak and trough concentration of LTI-03 after the first dose 
and at steady state. 


Lung Therapeutics, Inc. 
 
     Statistical Analysis Plan, Version 2.0  
 
LTI-03-1002 
 
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3
· Change from baseline over time for biomarkers related to the pathophysiology of IPF.   
3.3. Treatments   
LTI-03 and matching placebo will be provided as inhalation powders for oral inhalation use. 
LTI-03, as an excipient-free, micronized dry powder, will be placed into white opaque 
hypromellose two-piece capsules. The placebo will be micronized lactose powder that is placed 
into white opaque hypromellose two-piece capsules and will be identical in appearance to LTI-
03. Individual capsules containing 2.5 mg of study drug (LTI-03 or placebo) will not be 
labelled. 
3.4. Dose Adjustment/Modifications 
No dose adjustment is planned. A lower dose cohort may be added (2.5 mg administered once 
daily (QD)) or additional subjects may be added to the low-dose cohort (2.5 mg administered 
BID) if doses of 5 mg BID (10 mg per day) are not tolerated. If a lower dose cohort is added, the 
treatments will be appropriately described/updated and summarized in the TFLs. 
4. General Statistical Considerations 
This section presents general rules for the derivation and reporting of study data. If a subsequent 
section related to a specific derivation or analysis differs from this general guidance, the 
subsequent section takes precedence. 
Continuous data will be presented using descriptive statistics (i.e. n, mean, standard deviation, 
median, minimum, and maximum). Categorical data will be presented using frequency counts 
and percentages in each category. For the summary statistics of all numerical variables (unless 
otherwise specified), minimum and maximum will be displayed to the same level of precision of 
the raw data. Mean and median will be displayed to one level of precision greater than the data 
collected. Standard deviation will be displayed to two levels of precision greater than the data 
collected.  
When count data are presented, the percentage will be suppressed when the count is zero in 
order to draw attention to the non-zero counts. A row denoted “Missing” will be included in 
count tabulations where specified on the shells to account for missing values. The denominator 
for all percentages will be the number of subjects in that treatment group within the analysis set 
of interest, unless otherwise specified. Percentages will be presented to one decimal place except 
for the display of 100% frequency which will be displayed as ‘XX (100)’. 
In general, all tables will be presented by treatment (active treatments, active treatment total, and 
pooled placebo). Subjects from all cohorts who took placebo will be combined to form a pooled 
placebo group for analyses. All study data will be presented in by-subject data listings. 
“No data available for this report” will be presented when there are no data available to report. 
The primary endpoint of the study is safety and no formal statistical hypotheses will be tested. 
All descriptive statistical analyses will be performed using Statistical Analysis System (SAS) 
statistical software (version 9.4 or higher). Missing data will not be imputed unless otherwise 
stated.     


Lung Therapeutics, Inc. 
 
     Statistical Analysis Plan, Version 2.0  
 
LTI-03-1002 
 
 Date Issued: 10OCT2024 
 
  
 
 
 
4
4.1. Baseline, End of Study and Study Day 
Unless otherwise specified, baseline will be defined as the last non-missing evaluation prior to 
the date and time that the first dose of treatment is taken. Baseline values for spirometry are the 
mean of the Day 1 pre-dose and the  value collected during screening using the same spirometry 
equipment (see Section 8.6).  
A participant will have completed the study if all visits are completed and the End of Study 
eCRF is marked as completed. The end of study date for each participant is defined as the date 
of the last visit as recorded on the End of Study eCRF. 
Study day is defined in relation to the date of first dose of study drug (on Day 1). Therefore, 
when an assessment date is before the first dose: 
         Study day = assessment date - first dose date of study drug 
and when an assessment is on or after the first dose: 
         Study day = assessment date - first dose date of study drug + 1 
4.2. Missing/Incomplete Start and Stop Dates 
For the purpose of inclusion in tables, incomplete start and stop dates and times for AEs and 
prior/concomitant medications will be imputed as follows: 
Missing start dates (where UK, UNK and UNKN indicate unknown or missing day and month 
respectively) will be handled as follows: 
· 
UK-MMM-YYYY:  
· 
If the month and year are different from the month and year of the first dose of 
study drug, assume 01-MMM-YYYY.  
· 
If the month and year are the same as the first dose of study drug month and 
· 
the end date (after any imputation) is on or after the first dose of study 
drug, then the start date is assumed to be the date of the first dose of study 
drug. 
· 
the end date (after any imputation) is prior to the first dose of study drug, 
then assume the end date for the start date. 
 
· 
DD-UNK-YYYY/UK-UNK-YYYY: 
· 
 If the year is different from the year of first dose of study drug, assume 01-JAN-
YYYY of the collected year.  
· 
If the year is the same as the first dose of study drug year and 
· 
 the end date (after any imputation) is on or after the first dose of study 
drug, then the start date is assumed to be the date of the first dose of study 
drug. 
· 
the end date (after any imputation) is prior to the first dose of study drug, 
then the start date is assumed to be the end date for the start date.  
If the start date is not recorded on eCRF then no date imputation will be performed. 


Lung Therapeutics, Inc. 
 
     Statistical Analysis Plan, Version 2.0  
 
LTI-03-1002 
 
 Date Issued: 10OCT2024 
 
  
 
 
 
5
Missing start times will be imputed as follows: If the missing time of an actual or imputed start 
date is the same as a study drug dosing date, the dosing time will be used as the imputed time. 
Otherwise, the earliest possible time of the actual or imputed start date (i.e. 00:01) will be used 
as the imputed time.  
Missing stop dates (where UK and UNK indicate unknown or missing day and month 
respectively) will be handled as follows:  
· UK-MMM-YYYY: Stop date is assumed to be the last day of the month; 
· DD-UNK-YYYY/UK-UNK-YYYY: Stop date is assumed to be 31-DEC-YYYY. 
If a subject dies during the study, the stop date will be imputed as the date of death if the imputed 
stop date is after date of death. 
Missing stop times will be imputed as the latest possible time of the actual or imputed stop date 
(i.e. 23:59). 
4.3. Sample Size 
Approximately 24 subjects are planned in 2 cohorts. Each cohort will include 12 subjects (9 on 
LTI-03 and 3 on placebo). Selection of sample size is based on prior experience to ensure that 
the safety and tolerability of LTI-03 will be adequately assessed while minimizing unnecessary 
subject exposure. With 18 subjects receiving LTI-03 there is a 60% chance of detecting an 
adverse event (AE) with a true incidence rate of 5% and an 85% chance of detecting a more 
common AE with a true incidence rate of 10%.        
4.4. Randomization and Blinding 
Subjects will be randomized to receive LTI-03: placebo in sequential cohorts, as per the study 
design. Randomization codes and unique subject identification numbers will be generated by the  
Interactive Voice Response System (IVRS).  All study staff will remain blinded to study drug 
assignment throughout the trial.  
An unblinded team of Biostatistics personnel will be set up to handle unblinded data until the 
study is unblinded after data lock. 
4.5. Analysis Sets 
The following analyses sets will be used for the various analyses outlined in this SAP. 
4.5.1. Enrolled Set 
The Enrolled Set will consist of all subjects who signed the informed consent form (ICF), to 
include screen failures. 
A screen failure is defined as a subject who consents to participate in the study but is not 
subsequently randomized. 
4.5.2. Randomized Set 
The Randomized Set will consist of all subjects who were enrolled and randomized to study 
drug. 


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4.5.3. Safety Set 
The Safety Set will consist of all subjects randomized to study drug and received at least one 
dose of study drug. The Safety Set will be used for all safety analyses and subjects will be 
analyzed according to the study drug actually received. 
4.5.4. Pharmacokinetics (PK) Set 
The PK Set will consist of all subjects who receive at least one dose of LTI-03 and have at least 
one evaluable PK concentration. 
4.5.5. Pharmacodynamics (PD) Set 
The PD Set will consist of all subjects who received at least one dose of  LTI-03 and  have at 
least one measured value at a scheduled PD time point after the start of dosing for at least one 
PD analyte. 
5. Subject Disposition and Protocol Deviations 
5.1. Subject Disposition 
Subjects will be summarized by the number and percent of subjects dosed, completed the study, 
discontinued from the study (with discontinuation reasons), completed treatment, and 
discontinued from treatment (with treatment discontinuation reasons). The number of subjects 
randomized (i.e., subjects with a randomization date/time/number recorded on the eCRF) will 
also be summarized. Subject disposition summary will be presented by treatment (active 
treatments, active treatment total, and pooled placebo) and overall. 
All subject disposition data recorded on the eCRF, including for subjects not randomized will be 
listed by subject using the Enrolled Set. 
5.2. Protocol Deviations 
All protocol deviations will be recorded and documented according to the Study Deviation  
Rules document in PPD’s Clinical Trial Management System (CTMS ) system. Once the 
deviations have been finalized, a MS Excel file with all deviations will be converted into a SAS 
dataset and used as the source for the SDTM DV domain to generate a listing. Protocol 
deviations will be tabulated by severity (i.e., Major/Minor). The summary table will include the 
number of subjects reporting protocol deviations and as a percent of the number of subjects 
dosed by treatment (active treatments, active treatment total, and pooled placebo) and overall. If 
a subject reports protocol deviations at more than one level of severity, both categories will be 
summarized during analysis.  
The following definitions will be used: 
- 
Major protocol deviations are defined as those deviations with substantial effect on 
patient safety or data integrity. 
- 
Minor protocol deviations are defined as those deviations with non-substantial effect on 
patient safety or data integrity. 
- 
Significant protocol deviations are defined as those deviations which affect the analysis 
population. 


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- 
Non-significant protocol deviations are defined as those deviations which do not affect 
the analysis population. 
 
The summary and listing of the protocol deviations will be provided for the Safety Set. 
6. Demographics and Baseline Characteristics 
6.1. Demographics and Baseline Characteristics 
The number and percentage of subjects by sex (Male, Female), reproductive status (Of Child-
bearing Potential, Surgically Sterile, Post-menopausal), race (White, Black or African 
American, Asian, American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, 
Not Reported, Unknown and Other) and ethnicity (Hispanic or Latino, Not Hispanic or Latino, 
Not Reported and Unknown) will be summarized.    
The baseline characteristics consist of age (years), baseline height (cm), baseline weight (kg), 
baseline body mass index (BMI) (kg/m2), number of cigarettes (or the equivalent) per day (pack-
years (applicable only to subjects with past and/or current tobacco use)), and Diffusion Capacity 
of the Lungs for Carbon Monoxide (DLCO) (measured value only, in units of mmol/min/kPa), 
baseline spirometry (FVC), baseline LCQ total score and baseline cough VAS score. 
Demographics and baseline characteristics will be summarized descriptively.  
Body mass index is calculated as (body weight in kilograms) / (height in meters)2. A subject’s 
age in years is calculated using the date of the informed consent and date of birth.  
Cigarette consumption will be calculated in pack-years using: (the number of cigarettes smoked 
per day/20) * number of years smoked. 
The summary of subject demographics and baseline characteristics will be presented by 
treatment (active treatments, active treatment total, and pooled placebo) and overall. Subject 
demographics and baseline characteristics will be listed. The summary and listing of 
demographics and baseline characteristics will be provided for the Safety Set. 
6.2. Medical History 
6.2.1. General Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 26.0 or higher by system organ class (SOC) and preferred term (PT).  
Subject medical history data including specific details as collected in the eCRF will be presented 
in a listing for the Safety Set.  
6.2.2. Disease-Specific History 
Details of IPF diagnosis (diagnostic method and date of test) will be listed for the Safety Set.  
6.3. Inclusion and Exclusion Criteria 
The details of the inclusion and exclusion criteria can be found in Sections 4.1.1 and 4.1.2 of the 
study protocol. The status of eligibility criteria met, inclusion criteria not met, or exclusion 
criteria met details will be listed for the Enrolled Set. 


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7. Treatments and Medications 
7.1. Prior and Concomitant Medications 
All medications (including over-the-counter medicines, herbal treatments, supplements, and 
vitamins) administered within 30 days of the Screening Visit through Study Day 21 will be 
recorded on the Case Report Form (CRF), using generic names when possible.    
Prior and concomitant medication will be coded according to the latest World Health 
Organization Drug Dictionary (WHODD) version March, 2023 or later. Missing/partial start and 
stop dates will be imputed as specified in  Section 4.2. 
The listing of prior and concomitant medications will be provided for the Safety Set. All prior 
and concomitant medications will be presented in the same listing. 
7.1.1. Prior Medications 
A prior medication is defined as a medication that ends prior to the first study drug 
administration.   
7.1.2. Concomitant Medications 
A concomitant medication is defined as a medication that ends at the time of or after the first 
study drug administration.    
7.2. Concomitant Procedures 
All concomitant procedures recorded during the study will be listed. The listing will be provided 
for the Safety Set. 
7.3. Extent of Exposure and Treatment Compliance Rate 
Exposure to study drug is defined as administration of any amount of study drug. Duration of 
exposure is defined as the total number of days a subject is exposed to study drug and will be 
presented as the total number of days from the first dose date and time (Day 1) to the last dose 
date and time (date of last dose minus the date of first dose + 1) as recorded in the eCRF.  
Drug compliance over the total dosing period will be assessed as the rate of compliance. The rate 
of compliance (%) will be calculated as follows and recorded on the eCRF: [(number of capsules 
used/number of capsules expected to be used)]*100. 
The extent of exposure and rate of compliance will be summarized by treatment (active 
treatment arms, total of active arms, pooled placebo) and overall. A listing of exposure and 
compliance rate data will be presented.  
The summary table and listing of exposure and compliance rate will be provided for the Safety 
Set.  
8. Safety Analysis 
Safety will be evaluated through continuous monitoring of AEs, physical examinations, vital 
signs, clinical laboratory measurements, spirometry, and ECGs. 
Safety summaries and listings will be presented for the Safety Set. 


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    8.1 Adverse Events 
According to the International Council for Harmonization (ICH) guideline for GCP, an AE is 
any untoward medical occurrence in a subject or clinical investigation subject administered a 
pharmaceutical product, and which does not necessarily have to have a causal relationship with 
the treatment.  An AE can therefore be any of the following: 
· Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
· Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition).  
· Recurrence of an intermittent medical condition (e.g., headache) not present at baseline. 
· Any deterioration in a laboratory value or other clinical test (e.g., ECG) that is associated 
with symptoms or leads to a change in study treatment or concomitant treatment or 
discontinuation from study drug. 
· Adverse events that are related to a protocol-mandated intervention, including those that 
occur prior to assignment of study treatment (e.g., Screening invasive procedures such as 
biopsies). 
Adverse events will be coded using the current version of Medical Dictionary for Regulatory 
Activities (MedDRA® Version 26.0 or higher). Missing/partial AE dates and times will be 
imputed as specified in Section 4.2. In general, summaries will be provided for the Safety Set 
and presented by SOC, PT and treatment (active treatments, active treatment total, and pooled 
placebo) and overall. Participants will be counted only once within each SOC or PT.  
All AEs will be presented in a listing.     
8.1.1. Incidence of Treatment-Emergent Adverse Events 
AEs which begin or increase in severity or frequency at or after the administration of first dose 
of study drug are to be considered as TEAEs.  
An overall summary of TEAEs will include the number and percentage of participants with at 
least one TEAE, any TEAE with CTCAE severity Grade 3 or higher, any related TEAE, any 
serious TEAE, any fatal TEAE, and any TEAEs leading to discontinuation of study drug. 
The number and percentage of participants with TEAEs and the total number of TEAEs will be 
summarized by SOC and PT for each treatment (active treatments, active treatment total, and 
pooled placebo) and overall.  
8.1.2. Relationship of Adverse Events to Study Drug 
The Investigator’s assessment of causality must be provided for all AEs (serious and non-
serious). An Investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that the investigational product caused or contributed to an AE. 
· Not related: The AE is clearly not related to the study drug, or the temporal relationship of 
the onset of the AE relative to administration of the product is not reasonable, or the AE can 


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be explained by another cause such as an underlying medical condition or other concomitant 
medication, or the AE has no plausible relationship to study drug. 
· Related: The AE is probably related to the study drug.  The temporal relationship of the AE 
to administration of the product is reasonable and there is no other cause to explain the event.  
Adverse events should be classified as related if the Investigator feels there is evidence to 
suggest a causal relationship between the study drug and the AE. 
 
 
Study drug related TEAEs will be summarized by SOC and PT for each treatment (active 
treatments, active treatment total, and pooled placebo) and overall.  
8.1.3. Severity of Adverse Event 
 
All AEs will be assessed according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), Version 5.   
Table 1 will be used for assessing severity for AEs that are not specifically listed in the NCI 
CTCAE. 
Table 1:  Adverse Event Severity Grading Scale for Events not Specifically Listed in NCI 
CTCAE 
 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting age-
appropriate instrumental activities of daily living [a] 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living [b, c] 
4 
Life-threatening consequences or urgent intervention indicated [d] 
5 
Death related to adverse event [d] 


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a. Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b. Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c. If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event, per the definition of serious adverse event in Section 8.1.4. 
d. Grade 4 and 5 events must be reported as serious adverse events, per the definition of serious 
adverse event in Section 8.1.4. 
Reference source: Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
published on November 27, 2017. 
 
CTCAE severity grade will be presented in the AE listing. TEAEs by maximum severity will be  
summarized by SOC and PT for each treatment (active treatments, active treatment total, and 
pooled placebo) and overall.  
8.1.4. Serious Adverse Events 
Serious Adverse Events include adverse events that result in death, require either inpatient 
hospitalization or the prolongation of hospitalization, are life-threatening, result in a persistent 
or significant disability/incapacity, result in a congenital anomaly/birth defect, or are a 
significant medical event in the Investigator’s judgement. 
All serious TEAEs will be presented in a separate listing. 
8.1.5. Adverse Events Leading to Treatment Discontinuation  
The AEs where the answer to “Action Taken” on the AE eCRF is “Drug Withdrawn” will be 
identified in the AE listing. 
8.1.6. Adverse Events Leading to Death 
The AEs where the answer to “Outcome” on the AE eCRF is “Death” will be identified in the 
AE listing.  
8.2.  Clinical Laboratory Evaluations 
Clinical laboratory assessments will be performed by a central laboratory and collected 
according to the SOA (see Appendix 14.1).  
For all numeric serum chemistry and hematology laboratory values, descriptive statistics for 
observed and change from baseline values will be presented for each laboratory test by 
scheduled visit and treatment (active treatments, active treatment total, and pooled placebo) and 
overall for the Safety Set. Listings will include all measured values. 
All relevant clinical laboratory tests will be classified as Low, Normal, and High according to 
the normal ranges. This categorical data will be summarized in shift tables comparing the 
minimum post-baseline value, maximum post- baseline value, and the results at timepoint of 
interest post-baseline visit with those at the baseline visit. Shift table summaries will be 


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presented by treatment (active treatments, active treatment total, and pooled placebo) and 
overall for the Safety Set.  
8.2.4. Hematology 
The following hematology laboratory tests will be included:  
· red blood cell (RBC) count 
· mean corpuscular hemoglobin concentration (MCHC) 
· mean corpuscular hemoglobin (MCH) 
· mean corpuscular volume (MCV)  
· red cell distribution width (RDW) 
· hematocrit (Hct) 
· hemoglobin (Hgb) 
· white blood cell (WBC) count  
· including differential count (neutrophils, eosinophils, basophils, lymphocytes, 
monocytes) 
· platelet count  
 
Summary tables will be presented as described in Section 8.2 and data will be provided in a 
listing.   
8.2.5. Serum Chemistry 
The following serum chemistry laboratory tests will be included:  
 
· bilirubin (total and conjugated) 
· aspartate aminotransferase (AST) 
· alanine aminotransferase (ALT) 
· alkaline phosphatase (ALP) 
· gamma glutamyl transferase (GGT) 
· lactate dehydrogenase (LDH) 
· creatine kinase (CK) 
· protein 
· albumin  
· cholesterol (total, low density lipoprotein cholesterol (LDL-C)) 
· high density lipoprotein cholesterol (HDL-C)  
· glucose 
· blood urea nitrogen (BUN) 
· creatinine 
· sodium 
· potassium  
· chloride  
· calcium 
· magnesium 
· C-reactive protein (CRP)  
 


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Summary tables will be presented as described in Section 8.2 and data will be provided in a 
listing.   
8.2.6. Coagulation 
The following coagulation laboratory tests will be included:  
· prothrombin time (PT)  
· INR 
· activated partial thromboplastin time (aPTT)  
 
Since coagulation data are collected only at the screening visit, only a listing will be presented.     
8.2.7. Pregnancy Test 
Females of childbearing potential must have a negative urine or serum pregnancy test during 
screening. A urine or serum pregnancy test will also be performed on study days as mentioned 
in the schedule of assessments (SOA) (see Appendix 14.1).  
A listing showing pregnancy test date and time, test result and reason for not doing pregnancy 
test (if not done) will be presented for the Safety Set.  
8.3.  Vital Sign Measurements 
Vital signs will be obtained after subject has been sitting for at least 1 minute and will include 
systolic blood pressure (mmHg), diastolic blood pressure (mmHg), heart rate (beats/minute), 
respiratory rate (breaths/minute), body temperature (C) and hemoglobin oxygen saturation (%) 
(via pulse oximetry). 
Descriptive statistics for observed and change from baseline values will be presented for each 
vital sign test by scheduled visit and treatment (active treatments, active treatment total, and 
pooled placebo) and overall for the Safety Set. 
Vital signs data will be presented in a listing for the Safety Set. 
8.4.   Physical Examination 
A complete physical examination will include an evaluation of the head, eyes, ears, nose and 
throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and 
neurologic systems.  Any abnormality identified at baseline (Screening Physical Exam) will be 
recorded as medical history. 
A brief physical examination will focus on systems affected by AEs and at a minimum should 
include the cardiovascular and respiratory systems. Height and weight will be recorded at 
screening. 
Changes from baseline abnormalities should be recorded in subject notes. New or worsened 
clinically significant abnormalities should be recorded as TEAEs. A categorical summary of 
physical examination results will be presented by scheduled visit and treatment (active 
treatments, active treatment total, and pooled placebo) and overall for the Safety Set. 
Physical examination data will be presented in a listing for the Safety Set. 


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8.5.  Electrocardiogram 
A single standard 12-lead ECG will be performed at each scheduled visit. Lead placement 
should be as consistent as possible. ECG recordings must be performed after the subject has 
been resting in a supine position for at least 5 minutes.   
ECG parameters to be evaluated include heart rate (HR) and the R to R interval  (RR), Q to T 
(QT), P to R (PR) intervals and QRS duration. In addition, Fridericia’s formula should be used 
to calculate the QT interval corrected for heart rate (QTcF). ECG morphology statements will 
also be evaluated with particular attention paid to waveform morphology findings of: ST 
segment abnormal, T wave changes, abnormal U waves, atrioventricular (AV) block, arrhythmia 
(supraventricular, ventricular, atrial fibrillation/flutter, etc.), and others including infarction, 
ischemia, and hypertrophy. ECG abnormalities will be recorded as AEs only if they are 
considered to be clinically significant by the Investigator.  
Descriptive statistics for observed and change from baseline values will be presented for each 
ECG measurement by scheduled visit and treatment (active treatments, active treatment total, 
and pooled placebo) and overall for the Safety Set. 
All ECG data will be listed with flags for QTcF values > 450 msec and increase from baseline > 
30 msec. 
8.6.  Spirometry 
Spirometry to assess forced expiratory volume 1 (FEV1), FVC, FEV1/FVC and the percent 
predicted for each of the parameters will be performed during Screening, Day 1, Day 7, Day 14, 
and Day 21. DLCO will be assessed only at Screening. Percent predicted will be calculated 
based on height, age, and ethnicity. Spirometry will be performed according to the current 
American Thoracic Society (ATS) / European Respiratory Society (ERS) Task Force guidelines 
(Miller et al., 2005). Spirometry will be performed on Days 1, 7, and 14 pre-dose and post-dose 
at 30 and 60 minutes (See Protocol section 7). Unscheduled spirometry may as be performed as 
needed for respiratory symptoms. If bronchospasm is suspected, spirometry may also be 
performed before and after a rescue beta-adrenergic agonist inhalation. 
It is important to note that baseline values for spirometry are the mean of the Day 1 pre-dose and 
the  value collected during screening using the same spirometry equipment. For example, if the 
initial spirometry for screening is done in a central spirometry laboratory, but Day 1 and 
subsequent spirometry is done with portable equipment in the clinic, then a second spirometry 
should be done in the screening period using the same portable equipment used in the clinic. The 
baseline value for each spirometry would thus be the mean of screening value using portable 
equipment and the Day 1 pre-dose value using portable equipment.   
Descriptive statistics for observed and change from baseline values will be presented for each 
spirometry measurement by scheduled visit, timepoint, and treatment (active treatments, active 
treatment total, and pooled placebo) and overall for the Safety Set. 
Line graphs  of FEV1, FVC and 15% decrease from Baseline FEV1 will be presented by subject 
and visit for the Safety Set.  
Spirometry data will be presented in a listing for the Safety Set.  


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8.7.  Leicester Cough Questionnaire 
The Leicester Cough Questionnaire (LCQ) is a subject self-report, health related quality of life 
questionnaire (see Appendix 14.2) that will be collected per SOA (see Appendix 14.1). The 
LCQ consists of three domains where domain scores are equal to the total score from the 
questions in the domain divided by the number of questions in the domain (domains scores 
range from 1 to 7): 
1. Physical: Questions 1, 2, 3, 9, 10, 11, 14, and 15 
2. Psychological: Questions 4, 5, 6, 12, 13, 16, and 17 
3. Social: Questions 7, 8, 18, and 19 
LCQ total score is equal to the sum of the domain scores (total score range from 3 to 21) with a 
lower score indicating greater impairment of health status due to cough. The LCQ domain and 
total scores will be derived for use during analysis. If a response is not provided to a question, 
the domain score will be calculated as the average of the scores to the answered questions within 
the domain. If a subject responds to less than 80% of questions in a domain, the LCQ domain 
score will not be calculated and will be treated as missing during analysis. If it is not possible to 
calculate all domain scores following this criteria, total score will not be calculated and will be 
treated as missing during analysis.  
Descriptive statistics for observed and change from baseline values will be presented for LCQ 
domain and total scores by scheduled visit and treatment (active treatments, active treatment 
total, and pooled placebo) and overall for the Safety Set. 
LCQ data will be presented in a listing for the Safety Set. 
8.8.   Cough Visual Analogue Scale 
The cough VAS is a 100 mm scale (See Appendix 14.3) on which a subject will be asked to 
mark between ‘no cough’ (0 mm) and ‘the worst cough severity’ (100 mm).   
Descriptive statistics for observed and change from baseline values will be presented for cough 
severity VAS by scheduled visit and treatment (active treatments, active treatment total, and 
pooled placebo) and overall for the Safety Set. 
Cough VAS data will be presented in a listing for the Safety Set. 
9. 
Pharmacokinetics 
Plasma and BAL samples for PK assessment will be collected as indicated in the SOA (see 
Appendix 14.1). Plasma PK analyses and BAL bioanalytical results will be covered by a vendor 
reported by the sponsor in a separate document.  
10. Exploratory Biomarker Sampling 
Exploratory biomarkers will be assessed in peripheral blood cells (as feasible), platelet rich 
plasma, BALF, BA samples, and deep bronchial brushings as outlined in Table 2. Ribonucleic 
acid (RNA) transcription analysis from whole blood may be substituted for any assays using 
peripheral blood cells. Samples will be collected at the time of bronchoscopy during the 
screening period and Day 14 as shown in Appendix 14.1. Additional biomarkers may be added 
as new information is generated about the potential effects of CSD (caveolin-1 scaffolding 
domain) signaling. 


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Table 2: Exploratory Biomarkers by Sample Source and Assumed Indicator Function 
Sample source / 
Indicator of 
Epithelial 
damage / repair 
Fibrosis 
Inflammation 
Thrombosis 
Peripheral 
blood cells b 
- 
p-AKTb, IL-11 
CXCL7 
- 
Platelet rich 
plasma (PRP) 
CYFRA 21-1, SP-
D, CA-19-9, KL-
6, sRAGE, 
Galectin 7 
MMP-7, Tenascin 
C (TNC), 
Periostin, IL-11, 
MYDGF, MMP-2 
CCL18, 
CXCL13, 
slCAM1, IL-11, 
sCD163, CXCL7 
PAI-1 
BAL and/or 
BAa 
Galectin 7, SP-D, 
sRAGE 
MYDGF, MMP-2, 
TNC, MMP-7, 
periostin, IL-11 
CCL18, 
CXCL13, 
slCAM1, IL-11, 
sCD163, CXCL7 
PAI-1 
Deep bronchial 
brushings 
- 
p-SMAD2/3 
- 
- 
Abbreviations: BAL = bronchoalveolar lavage. BA = bronchoabsorption 
a LTI-03 levels will also be measured on BAL samples. LTI-03 will not be measured in BA 
samples. 
b Ribonucleic acid transcription analysis may be substituted for assays using peripheral blood 
cells. 
For each PD biomarker, concentrations, change from baseline, percent change from baseline, 
and/or fold change, as applicable, will be summarized by scheduled visit and treatment (active 
treatments, active treatment total, and pooled placebo) and overall for all subjects in the Safety 
Set.  
Biomarker results that are Below the Limit of Quantification will be treated as zero for 
calculation of concentration descriptive statistics. Percent change and fold change will be 
estimated for subjects with both baseline and post-baseline results, but will not be estimated in 
cases where the baseline result is zero. 
Biomarker data will be presented in a listing for the Safety Set. 
11. Interim Analysis 
No formal interim analyses are planned for the study. Cohort 1 biomarker data may be analyzed 
before final database lock without changing the overall study conduct. If required, these 
analyses will be handled by Lung Therapeutics.  PPD Biostatistics will provide relevant blinded 
SDTM and ADaM datasets to Lung Therapeutics to conduct the analyses. If requested, 
unblinded PPD Biostatistics personnel will be assigned and appropriate documentation updated 
to detail the unblinding event.   


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12. Changes in the Planned Analysis 
Section 8.6: Line graphs of 15% Baseline FEV1 is updated to 15% decrease from Baseline 
FEV1. 
 
 


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13. References 
Guenther A, Krauss E, Tello S, et al. The European IPF registry (eurIPFreg): baseline  
characteristics and survival of patients with idiopathic pulmonary fibrosis. Respir Res  
2018;19(1):141. DOI: 10.1186/s12931-018-0845-5. 
Lancaster, Lisa, et al. "Idiopathic pulmonary fibrosis: Physician and patient perspectives on the  
pathway to care from symptom recognition to diagnosis and disease burden." Respirology 27.1  
(2022): 66-75. 
Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med. 2018;378:1811–23.  
doi:10.1056/NEJMra1705751.  
Maher, Toby M., and Mary E. Strek. "Antifibrotic therapy for idiopathic pulmonary fibrosis: 
time to treat." Respiratory research 20.1 (2019): 1-9. 
Martinez FJ, Collard HR, Pardo A, Raghu G, et al. Idiopathic pulmonary fibrosis. Nat Rev Dis  
Prim. 2017;3:17074. doi:10.1038/nrdp.2017.74. 
Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 
2005;26:319-38.   
Snyder LD, Mosher C, Holtze CH, et al. Time to diagnosis of idiopathic pulmonary fibrosis in 
the IPF-PRO Registry. BMJ Open Respir Res 2020;7(1). DOI: 10.1136/bmjresp-2020-000567. 
 
 


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14. Appendices  
14.1.  Schedule of Assessments 
 
Screening 
Period 
Treatment Period1 
Follow-Up 
Early  
Termination2 
 
(Day -21 to Day 
-1) 
Day 1 
Day 7  
(± 1 day) 
Day 14  
(± 1 day) 
Day 21 
(+ 2 days) 
 
Informed consent 
x 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
x 
 
 
 
 
Demographics, Medical History 
x 
 
 
 
 
 
Prior medications 
x 
 
 
 
 
 
Concomitant medications 
 
Complete physical examination3 
x 
 
 
x 
 
x 
Brief physical examination4 
 
x 
x 
 
x 
 
Vital Signs 
x 
x 
x 
x 
x 
x 
ECG (12-Lead ECG), single 
x 
x 
x 
x 
x 
x 
Bronchoscopy with BAL and/or BA 
and deep bronchial brushings biopsy 
x  
 
 
x 
 
x 
Blood for biomarker assessments5 
x 
 
 
x 
 
x 
Pregnancy test6 
x 
x 
x 
x 
x 
x 
Safety Laboratory parameters7 
x 
x 
x 
x 
x 
x 
Randomization 
 
x 
 
 
 
 
Blood collection for PK8  
 
 
 x 
x 
x 
 
 
Assessment of ability to use inhaler 
x 
 
 
 
 
 
Leicester Cough Questionnaire & 
Cough VAS 
x 
x 
x 
x 
x 
x 
Spirometry9 
x 
x 
x 
x 
x 
x 


Lung Therapeutics, Inc.                                                                                                                                                                                                           Statistical Analysis Plan, Version 2.0 
LTI-03-1002                                                                                                                                                                                                                                                 Date Issued:10OCT2024 
  
 
 
 
20 
Dosing10 
 
x 
x 
x 
 
 
Subjects returning unused study drug 
 
 
x 
x 
 
 
Adverse Events  
x 
 
Abbreviations: BAL = bronchoalveolar lavage; BA = bronchoabsorption; DLCO = diffusion capacity of the lungs for carbon 
monoxide; ECG = electrocardiogram; PK = pharmacokinetics; VAS = visual analogue scale 
Note:  
1. On Days 2 to 6 and Days 8 to 13, subjects will self-administer study drug at home and will be contacted on Day 4 (± 2 days) and 
Day 10 (± 2 days) by study staff to check on compliance and for potential adverse events. Day 1, 7, and 14 will be clinic visit. Study 
be clinic visit. Study staff will monitor subjects self-administrating study drug (most likely the morning dose) on Day 1, Day 7, and 
Day 14.   
2. If a subject discontinues study drug before Day 14, the Day 14 assessments (other than study drug dosing) where feasible should be 
performed in the clinic as close as possible to the day of discontinuation.  The EOS assessments should be performed 7 days after the 
last dose of study drug (assuming the subject has not withdrawn consent). 
3. A complete physical examination will include an evaluation of the head, eyes, ears, nose and throat, and the cardiovascular, 
dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems.  Any abnormality identified at baseline 
(Screening Day) will be recorded as medical history. 
4. A brief physical examination will focus on systems affected by AEs and at a minimum should include the cardiovascular and 
respiratory systems.  
5. Biomarker assessment will be for peripheral blood cells, platelet rich plasma, bronchoalveolar lavage fluid (BALF), BA samples, 
and deep bronchial brushings. 
6. Serum or urine test required for any FOCBP, defined as pre-menopausal or < 12 months of amenorrhea post-menopause or no 
history of surgical sterilization. 
7. Safety laboratory assessments include hematology, chemistry, and coagulation.  Coagulation will be performed only at Screening. 
8. Blood for PK will be collected pre-dose (trough) and +5 minutes after dosing (peak).  
9. Spirometry: DLCO on Screening only.  On treatment days (Day 1, 7, 14), it will be done before dosing and post dose at 30 and 60 
minutes. 
10. Study staff will monitor subjects self-administrating study drug (most likely the morning dose) on Day 1, Day 7, and Day 14.  On 
Day 1, the first dose of study drug will be administered at the investigational site and subjects will be monitored for at least 1 hour 
after dosing. Study drug is dispensed on Day 1 and Day 7. 


Lung Therapeutics, Inc.                                                                                                                         Statistical Analysis Plan, Version 2.0 
LTI-03-1002                                                                                                                                                              Date Issued:10OCT2024 
  
 
 
 
21
14.2.  Leicester Cough Questionnaire  
 


Lung Therapeutics, Inc.                                                                                                                         Statistical Analysis Plan, Version 2.0 
LTI-03-1002                                                                                                                                                              Date Issued:10OCT2024 
  
 
 
 
22
14.3. Cough Visual Analogue Scale  
 
 
 
 


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