Clinical trial NCT04396756
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Pliant Therapeutics, Inc.
Start date: 2020-03-03; Completion date: 2023-02-15
Enrollment: 120 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 2a, multicenter, 4-part, randomized, double-blind, dose-ranging, placebo-controlled study to evaluate the safety, tolerability, and PK of once-daily treatment with PLN-74809 in participants with idiopathic pulmonary fibrosis.

Detailed description:
Four part study:

Part A - 4 week treatment period evaluating PLN-74809 or matching placebo

Part B - 12 week treatment period evaluating PLN-74809 or matching placebo

Part C - 12 week treatment period evaluating up to two intermediatery PLN-74809 doses or matching placebo

Part D - ≥ 24 week treatment period evaluating higher PLN-74809 dose or matching placebo

Arms: arm 1: Placebo arm 2: PLN-74809 Dose Level 1 (Part A) - 4 weeks arm 3: PLN-74809 Dose Level 2 (Part A) - 4 weeks arm 4: PLN-74809 Dose Level 2 (Part B) - 12 weeks arm 5: PLN-74809 Dose Level 3 (Part C) - 12 weeks arm 6: PLN-74809 Dose Level 4 (Part C) - 12 weeks arm 7: PLN-74809 Dose Level 5 (Part D) - ≥ 24 weeks
Interventions: intervention 1: PLN-74809 intervention 2: Placebo
Intervention descriptions: intervention 1: PLN-74809 intervention 2: Placebo

Protocol documents:
Prot_002.pdf: 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
PLN-74809-IPF-202 
Study Title: 
A randomized, double-blind, dose-ranging, placebo-controlled Phase 2a 
evaluation of the safety, tolerability and pharmacokinetics of PLN-74809 in 
participants with idiopathic pulmonary fibrosis (IPF) (INTEGRIS-IPF) 
Study Number: 
PLN-74809-IPF-202 
Study Phase: 
2a 
Product Name: 
PLN-74809-000 
IND Number: 
139,998 
EUDRACT Number: 
2019-002709-23  
Indication: 
Treatment of idiopathic pulmonary fibrosis (IPF) 
Sponsor: 
Pliant Therapeutics Inc.  
260 Littlefield Avenue 
South San Francisco, CA 94080, USA 
Sponsor Study 
Director: 
 
   
 
 
  
 
 
 
 
Date 
Original Protocol (v1.0): 
11 June 2019 
Protocol Amendment 1 (v1.1): 
08 April 2020  
Protocol Amendment 2 (v2.0): 
30 November 2020 
Protocol Amendment 3 (v3.0): 
19 October 2021 
 
 
Confidentiality Statement 
This document is the property of Pliant Therapeutics. The confidential information in this document 
may not be used, published or disclosed without the prior written consent of Pliant Therapeutics 
except to the extent required under applicable laws or regulations.  


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SYNOPSIS 
Study Title: 
 
A randomized, double-blind, dose-ranging, placebo-controlled Phase 2a evaluation of 
the safety, tolerability and pharmacokinetics of PLN-74809 in participants with 
idiopathic pulmonary fibrosis (IPF) (INTEGRIS-IPF) 
Study Number: 
PLN-74809-IPF-202 
Study Phase:  
2a 
Objectives: 
Primary:  
• Assessment of the safety and tolerability of PLN-74809  
Secondary: 
• Assessment of pharmacokinetics (PK) of PLN-74809  
Exploratory: 
 
  
 
  
 
 
 
 
Study Design: 
This is a Phase 2a, multicenter, 4-part, randomized, double-blind, dose-ranging, 
placebo-controlled study to evaluate the safety, tolerability, and PK of once-daily 
(QD) treatment with PLN-74809 in participants with idiopathic pulmonary fibrosis 
(IPF).  
Each study part consists of an up to 28-day screening period, a 4-week (Part A), 
12-week (Parts B and C), or at least 24-week (Part D) treatment period, and a 2-week 
(±3 days) post-treatment follow-up period. Part A enrollment has been completed, so 
is not further described herein; no further participants will be enrolled or treated in this 
part of the study. Part B enrollment has been completed; no further participants will be 
enrolled or treated in this part of the study. Part C enrollment was initiated following 
Data Safety Monitoring Board (DSMB) review of the clinical data supporting the 
evaluation of 40 mg dosing. The DSMB recommended continuation of Study 
PLN-74809-IPF-202 to evaluate doses of 80 mg and 160 mg without modification. 
Part D enrollment will initiate following DSMB review of the 80 mg and 160 mg 
clinical data from Part C. The dose level of Part D is supported by the clinical data 
from study 
 and the duration is supported by the chronic toxicology 
data. 
Potential participants who provide written informed consent will be screened for study 
eligibility up to 28 days before administration of the first dose of study drug.  
In Parts B, C and D, eligible participants will be randomized on Day 1 (Visit 2). 
Randomization will be stratified by use of standard of care (SoC) IPF therapy 
(pirfenidone or nintedanib) (SoC use; yes or no). 
In Part B, 29 eligible participants were randomized in a 3:1 ratio (active:placebo) and 
treated for 12 weeks. 
In Part C, approximately 56 eligible participants will be randomized in a 3:3:2 ratio 
(80 mg PLN-74809:160 mg PLN-74809:placebo) and treated for 12 weeks in parallel 
treatment groups. 
In Part D, an additional PLN-74809 dose of 320 mg is planned for evaluation based on 
the following criteria: 
 
Part C has been completely enrolled (i.e., 56 participants have been randomized 


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 
Pending favorable review by the DSMB of: 
o 
All available safety and PK data from this study (Part C) 
o 
Safety and PK data from study 
, an ongoing Phase 1 
study evaluating the safety, tolerability, and pharmacokinetics of 
PLN-74809 at multiple doses ranging from 80 to 320 mg in healthy 
participants, as described in the Investigator’s Brochure   
In Part D, approximately 28 eligible participants will be randomized in a 3:1 ratio 
(320 mg PLN-74809:placebo) on  Day 1 (Visit 2). Randomization will be stratified by 
use of SoC IPF therapy (pirfenidone or nintedanib) (SoC use; yes or no). Study 
treatment will be administered for at least 24 weeks. Treatment will continue for all 
participants in Part D until the last participant enrolled in Part D reaches Week 24. 
Participants who discontinue study drug for safety reasons prior to completion of 
12 weeks (Parts B and C) or at least 24 weeks (Part D) of treatment will be asked to 
remain in the study to complete all remaining assessments; if this is not feasible, they 
will be asked to return to the clinic for an Early Termination (ET) visit for follow-up 
evaluations. 
The DSMB will assess participant safety at predetermined intervals during the study, 
including prior to initiating Part D and following the enrollment of the last participant 
in Part D. 
 
Study Population: 
Parts B, C and D of this study intend to enroll approximately 112 participants with 
mild-to-moderate IPF, who comply with the following eligibility criteria:  
 
Inclusion Criteria: 
1. Participants, aged 40 years or older 
2. Diagnosis of IPF for up to 5 years prior to screening based on American Thoracic 
Society (ATS)/ European Respiratory Society (ERS)/ Japanese Respiratory 
Society (JRS)/ Latin American Respiratory Society (ALAT) 2018 guidelines 
 
Note: If IPF diagnosis is within > 3 to ≤ 5 years at screening, the participant 
must have evidence of progression within the last 24 months, 
 
   
3. 
 
 
4. Diffusing capacity for carbon monoxide (DLco) (hemoglobin-adjusted) ≥ 30%; 
historical DLco for entry in the study is permitted if within 1 month of screening 
5. Participants currently receiving treatment for IPF with nintedanib or pirfenidone 
are allowed, provided these drugs have been given at a stable dose for at least 
3 months before the Screening visit and are expected to remain unchanged during 
the study (stable dose is defined as the highest dose tolerated by the participant 
during ≥ 3 months) 
6. Estimated glomerular filtration rate ≥ 50 mL/min, according to the Cockcroft-
Gault equation 
7. Female participants of non-childbearing potential must be surgically sterile or 
postmenopausal  
8. Female participants of childbearing potential must use a contraceptive method 
with a failure rate of < 1% per year or remain abstinent (refrain from heterosexual 
intercourse) during the treatment period and for 1 month after the last dose of 
study treatment. 
Male participants with female partners of childbearing potential must agree to use 
contraceptive measures or remain abstinent (refrain from heterosexual 
intercourse) during the treatment period and for at least 3 months after the last 
dose of study treatment. 


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9. Participants must agree to abstain from sperm or egg donation for the duration of 
the study, through to 3 months or 1 month, respectively, after administration of 
the last dose of study drug. 
10. Able to read and sign a written informed consent form (ICF) 
 
Exclusion Criteria: 
1. Receiving any nonapproved agent intended for treatment of fibrosis in IPF 
2. 
 
 
3. 
 
 
 
4. Any other condition that prevents the correct assessment of spirometry 
performance (for example a broken rib or chest pain of other origin that prevents 
adequate forced breathing)     
5. Known acute IPF exacerbation or suspicion by the Investigator of such, within 
6 months of screening 
6. The extent of emphysema is greater than the extent of fibrotic changes on the 
most recent high-resolution computerized tomography (HRCT) scan (as 
determined by central reader); a) HRCT scan performed within 2  years of the 
screening date may be used 
7. Severe pulmonary hypertension  
8. Smoking of any kind (not limited to tobacco) within 3 months of screening or 
unwilling to avoid smoking throughout the study 
9. Lower respiratory tract infection requiring antibiotics within 4 weeks prior to 
screening and/or during the screening period 
10. History of malignancy within the past 5 years or ongoing malignancy other than 
basal cell carcinoma, resected noninvasive cutaneous squamous cell carcinoma, or 
treated cervical carcinoma in situ 
11.  End-stage liver disease 
12. Renal impairment or end-stage kidney disease requiring dialysis 
13. History of unstable or deteriorating 
 or pulmonary disease (other than IPF) 
within the 6 months prior to screening, including but not limited to the following:  
a. 
  
b. 
 
 
c. 
 
 
d. 
 
 
 
 
14. Any of the following liver function test criteria above specified limits: total 
bilirubin > 1.5 × the upper limit of normal (ULN); aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) > 3 × ULN; alkaline phosphatase 
> 2.5 × ULN.  
Note: participants currently receiving nintedanib or pirfenidone as IPF SoC 
treatment, who have previously presented any liver function test elevations 
associated with nintedanib or pirfenidone treatment greater than that 
described above or resulting in dose reduction, treatment interruption, or 
discontinuation are not eligible. 


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15. Any of the following at screening: hemoglobin < 10.0 g/dL, or neutrophils 
< 1500 /mm3, or platelets < 100,000 /mL 
16. Pregnant or lactating females 
17. Daily use of phosphodiesterase-5 (PDE-5) inhibitor drugs (e.g., sildenafil, 
tadalafil, other) (Note: Intermittent use for erectile dysfunction is allowed) 
18. A medical or surgical condition known to affect drug absorption (e.g., major 
gastric surgery)  
19. Surgical procedures planned to occur during the study period 
20. 
 
21. Has participated in a clinical study with an investigational agent in the 30 days 
prior to screening or 5 half-lives of the investigational drug, whichever is longer 
22. Likely to have lung transplantation during the study (being on transplantation list 
is acceptable) 
23. Any medical condition that, in the opinion of the Investigator, may make 
candidates not suitable for the study 
24. Hypersensitivity to PLN-74809 or to any of the excipients, or placebo 
25. 
 
 
 
 
 
 
 
  
Test Product, Dose, 
and Mode of 
Administration: 
Part B: 40 mg of PLN-74809 or matching placebo administered orally QD  
Part C: 80 mg or 160 mg of PLN-74809 or matching placebo administered orally QD 
Part D: 320 mg of PLN-74809 or matching placebo administered orally QD 
PLN-74809 will be supplied by Pliant as 
. Study drug 
will be taken once daily at approximately 24-hour intervals. Participants will take the 
study drug 
 
and will drink up to 240 mL (~1 cup of water) 
. 
Duration of 
Treatment: 
The duration for Parts B and C of the study will be up to 18 weeks each (up to 4 weeks 
of screening, 12 weeks of treatment with study drug, and 2 weeks of follow up). 
The duration for Part D of the study will be variable depending on the study 
enrollment rate; i.e. the time between enrolling the first and last participant. The 
minimum duration of participation will be up to 30 weeks for the last participant 
enrolled (up to 4 weeks of screening, 24 weeks of treatment with study drug, and 
2 weeks of follow up) and a maximum of up to 54 weeks for the first participant 
enrolled (up to 4 weeks of screening, up to 48 weeks of treatment with study drug, and 
2 weeks of follow up).  
The end of study will commence once the last participant reaches 24 weeks of 
treatment. At that time, all study participants will complete their next scheduled visit 
(End of Treatment [EoT]) and the 2 weeks of follow up (End of Study [EoS]). 
Exploratory Efficacy 
Assessments: 
 
 
 
 
 
 
 
 
 
 
 
 


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Pharmacokinetic, 
Pharmacodynamic, 
and 
Pharmacogenomic 
Assessments 
 
• PK: plasma samples for PK analysis (
 
) will be obtained 
• Biomarkers: urine, plasma, and serum samples will be obtained 
• Pharmacogenomics: a whole blood sample for deoxyribonucleic acid (DNA) 
isolation will be collected before dosing on Day 1 from each participant in the 
study 
Safety Assessments: 
Collection of adverse events (AEs), safety laboratory values, vital signs, physical 
examinations, and 
 
Statistical Methods: 
This is a safety study, 
 
  
 
 
 
 
 
 
In general, data will be summarized using statistical summary methods; graphic 
presentations of data may also be prepared. 


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TABLE OF CONTENTS 
CLINICAL TRIAL PROTOCOL ..............................................................................................1 
PLN-74809-IPF-202 ..................................................................................................................1 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS ...........................................................................................................7 
LIST OF IN-TEXT TABLES ..................................................................................................10 
LIST OF IN-TEXT FIGURES.................................................................................................10 
LIST OF APPENDICES ..........................................................................................................10 
LIST OF ABBREVIATIONS ..................................................................................................11 
1 
INTRODUCTION .................................................................................................14 
1.1 
Summary of Clinical Development .................................................................14 
1.1.1 
Completed Phase 1 Studies (Completed Clinical Conduct) ................15 
1.1.2 
Ongoing Phase 1 Studies .....................................................................16 
1.1.3 
Completed Phase 2 Studies (Completed Clinical Conduct) ................17 
1.1.4 
Ongoing Phase 2 Studies .....................................................................17 
1.2 
Study Rationale for PLN-74809-IPF-202 ........................................................18 
2 
STUDY OBJECTIVES (PARTS B, C, AND D) ...................................................20 
2.1 
Primary Objective ............................................................................................20 
2.2 
Secondary Objectives.......................................................................................20 
2.3 
Exploratory Objectives ....................................................................................20 
3 
INVESTIGATIONAL PLAN ................................................................................21 
3.1 
Overall Study Design and Plan ........................................................................21 
3.2 
Rationale for PLN-74809 Doses and Control Group .......................................24 
3.3 
Study Duration .................................................................................................26 
4 
STUDY POPULATION SELECTION .................................................................27 
4.1 
Study Population ..............................................................................................27 
4.2 
Inclusion Criteria .............................................................................................27 
4.3 
Exclusion Criteria ............................................................................................28 
5 
STUDY DRUG AND ACCOUNTABILITY ........................................................30 
5.1 
Description of Study Drug ...............................................................................30 
5.1.1 
Study Drug ...........................................................................................30 
5.1.2 
Placebo .................................................................................................30 
5.2 
Packaging and Labeling ...................................................................................30 
5.3 
Storage and Accountability ..............................................................................30 
5.4 
Treatment Compliance .....................................................................................31 
6 
STUDY TREATMENTS .......................................................................................32 
6.1 
Description of Treatments................................................................................32 
6.2 
Dose Modifications and Interruptions .............................................................32 


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6.3 
Selection and Timing of Dose for Each Participant .........................................32 
6.4 
Method of Assigning Participants to Treatment Groups .................................33 
6.5 
Blinding............................................................................................................33 
6.6 
Concomitant Therapy.......................................................................................33 
6.6.1 
Allowed Medications ...........................................................................33 
6.6.2 
Disallowed Medications.......................................................................35 
6.7 
Restrictions ......................................................................................................35 
6.7.1 
Prior Therapy .......................................................................................35 
6.7.2 
Fluid and Food Intake ..........................................................................35 
6.7.3 
Participant Activity Restrictions ..........................................................35 
6.7.4 
Contraception .......................................................................................35 
7 
STUDY PROCEDURES .......................................................................................37 
7.1 
Informed Consent.............................................................................................37 
7.2 
Medical History ...............................................................................................37 
7.3 
Demographic Information ................................................................................37 
7.4 
Physical Examination.......................................................................................37 
7.5 
Vital Signs ........................................................................................................37 
7.6 
 
7.7 
Clinical Laboratory Tests .................................................................................38 
7.7.1 
Laboratory Parameters .........................................................................38 
7.7.2 
Sample Collection, Storage, and Shipping ..........................................39 
7.8 
Dispensing Study Drug ....................................................................................40 
7.9 
Exploratory Efficacy Assessments ..................................................................40 
7.10 
Pharmacokinetic Assessments .........................................................................40 
7.11 
Pharmacodynamic Assessments (
 
7.12 
Pharmacogenomics ..........................................................................................43 
7.13 
Concomitant Medication and Adverse Event Assessments .............................43 
7.14 
Missed Assessments.........................................................................................43 
7.15 
Appropriateness of Measurements ...................................................................43 
8 
SAFETY ASSESSMENTS ....................................................................................44 
8.1 
Timing ..............................................................................................................44 
8.2 
Definition of an Adverse Event .......................................................................44 
8.3 
Severity of an Adverse Event ..........................................................................45 
8.4 
Causal Relationship of an Adverse Event ........................................................45 
8.5 
Outcome ...........................................................................................................46 
8.6 
Pregnancy .........................................................................................................46 
8.7 
Clinical Laboratory Adverse Events ................................................................47 
8.8 
Serious Adverse Events ...................................................................................47 


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8.8.1 
Definition of Serious Adverse Events..................................................47 
8.8.2 
Recording Adverse Events and Serious Adverse Events .....................48 
8.8.3 
Reporting Serious Adverse Events ......................................................48 
8.8.4 
Reporting SAEs to Regulatory Authorities and IRB/IEC/REB ...........49 
9 
 
 
10 
 
 
11 
EARLY DISCONTINUATION OF STUDY OR INDIVIDUAL 
PARTICIPANTS ...................................................................................................56 
12 
PLANNED STATISTICAL METHODS ..............................................................57 
12.1 
General Considerations ....................................................................................57 
12.2 
Determination of Sample Size .........................................................................57 
12.3 
Analysis Populations ........................................................................................57 
12.4 
Demographics and Baseline Characteristics ....................................................57 
12.5 
Primary Endpoints ...........................................................................................57 
12.5.1 
Primary Safety Endpoint ......................................................................57 
12.6 
Secondary Endpoints .......................................................................................58 
12.6.1 
Secondary Pharmacokinetic Endpoints................................................58 
12.6.2 
Secondary Pharmacodynamic Endpoints .............................................59 
12.7 
Exploratory Endpoints .....................................................................................59 
12.7.1 
Exploratory Efficacy Endpoints ...........................................................59 
12.8 
Other Assessments or Analyses .......................................................................59 
12.9 
Interim Analysis ...............................................................................................59 
13 
QUALITY CONTROL AND ASSURANCE .......................................................60 
14 
ADMINISTRATIVE CONSIDERATIONS ..........................................................61 
14.1 
Institutional Review Board, Independent Ethics Committee or Research 
Ethics Board Approval .....................................................................................61 
14.2 
Ethical Conduct of the Study ...........................................................................61 
14.3 
Participant Information and Consent ...............................................................61 
14.4 
Participant Confidentiality ...............................................................................62 
14.5 
Study Monitoring .............................................................................................62 
14.6 
Case Report Forms and Study Records ...........................................................62 
14.7 
Data Monitoring Committee ............................................................................63 
14.8 
Data Generation and Analysis .........................................................................63 
14.9 
Retention of Data .............................................................................................63 
14.10 
Financial Disclosure.........................................................................................63 
14.11 
Publication and Disclosure Policy ...................................................................64 
15 
REFERENCE LIST ...............................................................................................65 


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Appendix 1 
 Schedule of Events: Parts B and C .....................................................67 
Appendix 2 
 Schedule of Events: Part D .................................................................69 
Appendix 3 
 Sponsor Signature ...............................................................................75 
Appendix 4 
 Investigator’s Signature ......................................................................76 
 
LIST OF IN-TEXT TABLES 
Table 1 
Overview of Parts A, B, and C of Study PLN-74809-IPF-202 .................21 
Table 2 
List of Laboratory Tests .............................................................................39 
Table 3 
Reference Ranges for Key Central Laboratory Liver Function Tests .......50 
Table 4 
 
 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Schematic for Part B of Study PLN-74809-IPF-202 .......................22 
Figure 2 
Study Schematic for Part C of Study PLN-74809-IPF-202 (Parallel 
Dosing) .......................................................................................................22 
Figure 3 
Study Schematic for Part D of Study PLN-74809-IPF-202 ......................23 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Events: Parts B and C ...........................................................67 
Appendix 2 
 Schedule of Events: Part D .......................................................................69 
Appendix 3 
 Sponsor Signature .....................................................................................75 
Appendix 4 
 Investigator’s Signature ............................................................................76 
 


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LIST OF ABBREVIATIONS 
ADL 
activities of daily living 
AE 
adverse event 
ALAT 
Latin American Respiratory Society 
ALT 
alanine aminotransferase 
 
 
 
 
 
 
 
 
ARDS 
acute respiratory distress syndrome 
AST 
aspartate aminotransferase  
ATS 
American Thoracic Society 
AUC0-24 
area under the plasma concentration-time curve from time zero to 24 hours 
BALF 
bronchoalveolar lavage fluid 
 
 
Cmax 
maximum observed drug concentration 
COVID-19 
coronavirus disease 2019 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
 
 
 
DLco 
diffusing capacity for carbon monoxide 
DNA 
deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
 
 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EoS 
end of study  
ERS 
European Respiratory Society 


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ET 
early termination 
 
  
FSH 
follicle-stimulating hormone 
 
 
GCP 
Good Clinical Practice 
HIPAA 
Health Information Portability and Accountability Act 
HRCT 
high-resolution computerized tomography 
IC50 
50% inhibitory concentration 
IC80 
80% inhibitory concentration 
IC90 
90% inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council on Harmonisation  
IEC 
independent ethics committee 
 
 
INR 
international normalized ratio 
IPF 
idiopathic pulmonary fibrosis 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
JRS 
Japanese Respiratory Society 
MAD 
multiple ascending dose 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger ribonucleic acid 
 
 
NOAEL 
no observed adverse effect level 
 
 
PCLS 
precision cut lung slices 
PD 
pharmacodynamic(s) 


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PDE-5 
phosphodiesterase -5 
PET 
positron emission tomography 
PK 
pharmacokinetic(s) 
PRO 
patient-reported outcome 
PSC 
primary sclerosing cholangitis 
pSMAD2/3 
phosphorylated SMAD2/3 
QD 
once daily 
 
 
 
 
 
 
REB 
research ethics board 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SoC 
standard of care 
SMAD2/3 
family of proteins similar to the gene products of the Drosophila gene 'mothers 
against decapentaplegic' (Mad) and the C. elegans gene Sma, 2 or 3 
SpO2 
peripheral capillary oxygen saturation 
TEAE 
treatment-emergent adverse event 
TGF-β 
transforming growth factor beta 
ULN 
upper limit of normal 
US 
United States 
 
 
 


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1 
INTRODUCTION 
Pliant Therapeutics Inc. (Pliant) is developing PLN-74809 for the treatment of idiopathic 
pulmonary fibrosis (IPF) and primary sclerosing cholangitis (PSC).  
IPF is a rare condition, usually of the elderly, characterized by dyspnea and progressive loss 
of lung function leading to death, with median survival of 3.8 years after diagnosis based on 
2014 data in the United States (US). The hallmark honeycomb appearance of IPF on 
high-resolution computerized tomography (HRCT) is the result of extensive fibrosis 
. Although not completely understood, IPF has been proposed 
to stem from ongoing microinjury to alveolar epithelial cells. Injured epithelium results in 
upregulation of profibrotic factors such as transforming growth factor beta (TGF-β), which 
promote fibroblast recruitment, proliferation, and differentiation into fibrogenic 
myofibroblasts 
. As the disease progresses, 
actively proliferating fibroblasts and myofibroblasts organize into fibroblastic foci and 
produce excessive fibrillar collagen that results in scarring of the lung which, in turn, leads to 
distortion of the tissue architecture and loss of function 
. 
As has also been indicated to be the case for other fibrotic conditions, signaling mediated by 
αv integrins is central to the control of fibrosis in the lungs. Specific roles proposed for αvβ6 
in epithelial cells and αvβ1 in myofibroblasts for induction of fibrosis are summarized in the 
Investigator’s Brochure for PLN-74809. 
PLN-74809 is a small molecule and a selective dual inhibitor of αvβ6 and αvβ1 integrins 
(50% inhibitory concentration [IC50] 
, respectively). Additionally, 
integrin-ligand binding assays have demonstrated that PLN-74809 is highly selective for αvβ6 
and αvβ1 over other integrin receptors, including those leukocyte-expressed integrins where 
therapeutic inhibition has previously been associated with significant toxicities (e.g., 
vedolizumab [47 inhibitor; increased risk of infections, potential risk of progressive 
multifocal leukoencephalopathy (PML); 
] and 
natalizumab [41 and 47 inhibitor; increased risk of PML; 
 
]). PLN-74809 reduced collagen synthesis in mice with bleomycin-induced lung 
injury, a commonly used experimental model for IPF (
). In ex vivo human 
IPF lung tissue (precision cut lung slices), treatment with PLN-74809 significantly decreased 
collagen type 11 messenger ribonucleic acid (mRNA) expression levels after a 3-day 
incubation period, providing an indication of antifibrotic activity in IPF. Mice completely 
deficient for αvβ6 function live a normal lifespan (
), suggesting that even 
full inhibition of such integrins is well tolerated.  
1.1 
Summary of Clinical Development 
PLN-74809 is currently being investigated for the treatment of IPF and PSC.  
Seven Phase 1 clinical studies in healthy participants have completed clinical conduct 
(Including Part 1 of Study 
), with safety data, pharmacokinetic (PK) data, 
and preliminary pharmacodynamic (PD) data available. 
 


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1.1.1 
Completed Phase 1 Studies (Completed Clinical Conduct) 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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1.1.2 
Ongoing Phase 1 Studies  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.1.3 
Completed Phase 2 Studies (Completed Clinical Conduct) 
 
 
 
 
 
 
1.1.4 
Ongoing Phase 2 Studies 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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1.2 
Study Rationale for PLN-74809-IPF-202 
PLN-74809 is a selective, small molecule antagonist of integrins αvβ6 and αvβ1, with 
antifibrotic activity. PLN-74809 prevents αvβ6 and αvβ1 from binding to the 
arginine-glycine-aspartate sequence of the latency associated peptide of the TGF-β precursor 
protein, thereby blocking the release of the activated form of TGF-β1 and preventing binding 
to its receptors and activation of pathways relevant to fibrogenesis. PLN-74809 was 
demonstrated to be a potent and selective inhibitor of αvβ6 and αvβ1 integrins (human and 
murine) exhibiting geometric mean 50% inhibitory concentration (IC50) values of 
 and 
 against the human receptors, respectively. 
Precision cut lung slices (PCLS) generated from IPF patient lungs collected during transplant 
were used to evaluate the ability of PLN-74809 to block TGF-β activation and collagen gene 
expression in fibrotic human lung tissue ex vivo. Following 7 days incubation with 
PLN-74809 (
), collagen gene expression and SMAD2 phosphorylation (a 
marker of TGF-β signaling) in IPF patient PCLS were significantly reduced by 
approximately 
. Further studies with bleomycin-injured mouse PCLS also showed 
significant reductions in collagen gene expression observed at concentrations of PLN-74809 
as low as 
.  
In vivo efficacy studies of PLN-74809 were performed using the bleomycin mouse model of 
pulmonary fibrosis. In a prophylactic treatment study (PLN-74809 administered orally or via 
minipump from 
 post-bleomycin challenge), PLN-74809 significantly decreased 
Ashcroft score, total hydroxyproline levels in lung tissue, and phosphorylation of 
 in 
lung tissue, confirming inhibition of collagen deposition and TGF- signaling.  Similar 
effects were observed with therapeutic treatment with PLN-74809 in the bleomycin model 
(oral administration from 
 days post-bleomycin challenge). Lung hydroxyproline 
levels were significantly reduced and morphometric analysis of lung tissue showed a dose-
dependent and significant reduction in interstitial fibrillar collagen deposition in mice treated 
with PLN-74809. 
The main purpose of the current study is to confirm that PLN-74809 is well tolerated by 
participants with IPF, whether as monotherapy or as an add-on to standard of care (SoC), and 
that the drug concentrations are similar to those previously found in healthy participants.  
 
 
 
 
  
 
Part D of the study will evaluate approximately 28 participants at the 320 mg dose for at least 
24 weeks to further characterize the safety profile of PLN-74809.  In Part D, ongoing safety 
and 
 assessments will continue until the last participant reaches 24 weeks of the study; 
therefore, safety and 
 assessments may extend to 48 weeks in participants randomized 
earlier in the study.  
 
 
  
The extended duration of exposure at the highest dose planned to be evaluated in Part D 


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(320 mg QD) is consistent with the intended use of PLN-74809 to treat the chronic and 
progressive fibrosis that characterizes IPF. 


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2 
STUDY OBJECTIVES (PARTS B, C, AND D) 
2.1 
Primary Objective  
• Assessment of the safety and tolerability of PLN-74809  
2.2 
Secondary Objectives 
• Assessment of PK of PLN-74809 
2.3 
Exploratory Objectives 
 
  
 
  
 
 
 
 
 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a Phase 2a, multicenter, 4-part, randomized, double-blind, dose-ranging, 
placebo-controlled study to evaluate the safety, tolerability, and PK of once-daily (QD) 
treatment with PLN-74809 in participants with IPF. The 4 parts of the study are summarized 
in Table 1.  
Each study part consists of an up to 28-day screening period, a  treatment period, and a 
2-week post-treatment follow-up period;  see study schematic in Figure 1 (Part B), Figure 2 
(Part C), and Figure 3 (Part D). 
Table 1 
Overview of Parts A, B, and C of Study PLN-74809-IPF-202 
Study 
Part 
Duration 
(Weeks) 
PLN-74809 
Formulation 
Randomization 
(active:placebo) 
Dose (mg) 
Regimen 
(QD) 
A  
4  
  
1:1:1 per treatment 
group 
20/40/0  
B 
12 
  
3:1 per treatment group 
40/0 
Following review of clinical data from Part B 
C 
12 
  
3:3:2 per treatment 
group 
80/160/0 
 
Following review of clinical data from Part C 
D 
At least 24 
 
3:1 per treatment group 
320/0 
QD = once daily 
  
Part A enrollment has been completed, so is not further described herein; no further 
participants will be enrolled or treated in this part of the study. 
Part B enrollment has been completed; no further participants will be enrolled or treated in 
this part of the study.  
Part C enrollment was initiated following Data Safety Monitoring Board (DSMB) review of 
the clinical data supporting the evaluation of 40 mg dosing. The DSMB recommended 
continuation of Study PLN-74809-IPF-202 to evaluate doses of 80 mg and 160 mg without 
modification. 
Part D enrollment will initiate following DSMB review of the 80 mg and 160 mg clinical 
data from Part C. The dose level of Part D is supported by the clinical data from study 
 and the duration is supported by the chronic toxicology data. 
Please refer to the Investigator’s Brochure for additional detailed information on chronic 
toxicology studies. 


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Figure 1 
Study Schematic for Part B of Study PLN-74809-IPF-202 
Screening 
Day -28 to 
Day -1 
 
Baseline 
Day 1 
 
Treatment 
Day 1 to Week 12 
 
Follow-up 
Week 14 
(±3 days) 
 
 
 
 
 
 
 
 
 
 
 
PLN-74809 40 mg QD 
 
 
Screening 
 
Randomization 
(3:1) 
 
 
 
 
 
 
 
 
Placebo QD 
 
  
QD = once daily 
 
Figure 2 
Study Schematic for Part C of Study PLN-74809-IPF-202 (Parallel 
Dosing) 
Screening 
Day -28 to 
Day -1 
 
Baseline 
Day 1 
 
Treatment 
Day 1 to Week 12 
 
Follow-up 
Week 14 
(±3 days) 
 
 
 
 
 
 
 
 
 
 
 
PLN-74809 80 mg QD 
 
 
 
 
 
 
 
 
 
Screening 
 
Randomization 
(3:3:2) 
 
PLN-74809 160 mg QD 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo QD 
 
  
QD = once daily 
 


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Figure 3 
Study Schematic for Part D of Study PLN-74809-IPF-202 
Screening 
Day -28 to 
Day -1 
 
Baseline 
Day 1 
 
Treatment 
Day 1 to at least Week 24* 
 
Follow-up  
Final On-
Treatment 
Visit 
+ 2 weeks  
(±3 days) 
 
 
 
 
 
 
 
 
 
 
 
PLN-74809 320 mg QD 
 
 
Screening 
 
Randomization 
(3:1) 
 
 
 
 
 
 
 
 
Placebo QD 
 
 
QD = once daily 
* Treatment will continue for all participants in Part D until the last participant enrolled in Part D reaches 
Week 24. All participants will complete visits every 8 weeks after the Week 24 visit until such time as the last 
participant enrolled has completed the Week 24 visit. At this time, all participants will be contacted to return 
and complete the Final On-Treatment Visit. All participants will have a Week 26 visit, which will be considered 
the End of Treatment Visit for the last participant to complete the Week 24 Visit. 
  
Potential participants who provide written informed consent will be screened for study 
eligibility up to 28 days before administration of the first dose of study drug.  
In Parts B, C and D, eligible participants will be randomized on Day 1 (Visit 2). 
Randomization will be stratified by use of SoC IPF therapy with pirfenidone or nintedanib 
(SoC use; yes or no). 
In Part B, 29 eligible participants were randomized in a 3:1 ratio (active:placebo) and treated 
for 12 weeks. 
In Part C, approximately 56 eligible participants will be randomized in a 3:3:2 ratio (80 mg 
PLN-74809:160 mg PLN-74809:placebo) and treated for 12 weeks in parallel treatment 
groups.  
In Part D, an additional PLN-74809 dose of 320 mg is planned for evaluation based on the 
following criteria:  
• Part C has been completely enrolled (ie, 56 participants have been randomized) 
• Pending favorable review by the DSMB of: 
- 
All available safety and PK data from this study (Part C) 
- 
Safety and PK data from study 
 
 
, as described in the Investigator’s Brochure  


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In Part D, approximately 28 eligible participants will be randomized in a 3:1 ratio (320 mg 
PLN-74809:placebo) on  Day 1 (Visit 2). Randomization will be stratified by use of SoC IPF 
therapy (pirfenidone or nintedanib) (SoC use; yes or no). Study treatment will be 
administered for at least 24 weeks. Treatment will continue for all participants in Part D until 
the last participant enrolled in Part D reaches Week 24. 
In Parts B and C, study drug will be administered at the investigational site on Day 1 and at 
Weeks 4 and 12. In Part D, study drug will be administered at the investigational site on 
Day 1 and at Weeks 4, 12, and 24. Participants will self-administer the study drug on an 
outpatient basis on all other days. In Parts B and C, participants will return to the study site 
for on-treatment evaluations on Day 1 and at Weeks 2, 4, 8, and 12 (see Schedule of Events 
in Appendix 1).  
 
In Part D, participants will return to the study site for on-treatment evaluations on Day 1 and 
at Weeks 2, 4, 8, 12, 14, 20, 24, 26, and every 8 weeks after Week 24 until the last participant 
enrolled in Part D has completed this Week 24 visit. At this time, all participants will be 
contacted to return and complete the Final On-Treatment Visit (see Schedule of Events in 
Appendix 2). Blood and urine specimens for safety laboratory assessments will be collected 
after at least an 8-hour fast. A final study visit will be conducted 2 weeks ± 3 days after the 
last dose of study drug (Week 14 ± 3 days for Parts B and C; 2 weeks after the final 
On-Treatment Visit [± 3 days] for Part D), when participants will undergo a final 
 
measurement, as well as follow-up end of study (EoS) evaluations.  
Participants who discontinue study drug for safety reasons prior to completion of 12 weeks 
(Parts B and C) or at least 24 weeks (Part D) of treatment will be asked to remain in the study 
to complete all remaining assessments; if this is not feasible, they will be asked to return to 
the clinic for an Early Termination (ET) visit for follow-up evaluations. 
 measurements will be obtained via spirometry and will be performed using 
study-standardized equipment and according to international guidelines (American Thoracic 
Society [ATS]/ European Respiratory Society [ERS]/ Japanese Respiratory Society [JRS]/ 
Latin American Respiratory Society [ALAT]). Spirometry reading will be centralized. 
 
  
The DSMB will assess participant safety at predetermined intervals during the study, 
including prior to initiating Part D and following the enrollment of the last participant in 
Part D. 
 
 
The total number of participants enrolled in Parts B, C, and D of the study will be 
approximately 112, with approximately 84 receiving PLN-74809 and 28 receiving placebo. 
3.2 
Rationale for PLN-74809 Doses and Control Group 
This study will be the first to characterize the safety, tolerability and PK of PLN-74809 in 
participants with IPF, with or without co-administration with SoC (pirfenidone or 


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nintedanib). The proposed randomized, double-blind study design allows a reduction in bias 
in the assessment of drug safety and tolerability. Stratification for background treatment with 
SoC will ensure a similar proportion of participants in each treatment group. The proposed 
sample size and 12-week treatment duration of Parts B and C are expected to provide 
meaningful PK information in the IPF population, as well as allow for preliminary evaluation 
of dose-dependent treatment effects on 
 study endpoints, comparing PLN-74809 
to placebo.  
The evaluation of  PLN-74809 40 mg in Part B of this study is supported by the 13-week 
toxicology data, safety and PK data at these doses from study 
, as well as 
the PD findings from study 
, where this dose led to reduction of TGF-β 
activation in the lungs of healthy participants following 7 days of dosing, as assessed by 
reduction in phosphorylated SMAD2 (pSMAD2)/SMAD2 ratio in BALF (See PLN-74809 
Investigator’s Brochure for more details).  
The evaluation of PLN-74809 80 mg and 160 mg doses in Part C is supported by all 
available safety and PK data from Parts A and B, as well as safety and PK data evaluating 
higher doses (80 and 160 mg) from study 
.  
The evaluation of PLN-74809 320 mg in Part D is supported by all available safety and PK 
data from Parts B and C, as well as safety and PK data evaluating the higher dose (320 mg) 
from study 
.  
In Study 
, PLN-74809 showed a favorable safety and tolerability profile in 
healthy participants after single doses of up to 
 mg and after 7 days of treatment at doses 
of up to 
 mg (Section 1.1.2). The safety margins determined after single doses of 
 
 mg and multiple doses of 
 mg were calculated using the NOAEL observed in 
toxicology studies in 
 for both area under the plasma concentration-time curve from 
time zero to 24 hours (AUC0-24) and Cmax for the measured 
 of 
PLN-74809. At all dose levels studied, there was a 
 between the unbound 
AUC0-24 and 
 no observed adverse effect level (NOAEL). See the PLN-74809 
Investigator's Brochure for more details. 
Comparison of the unbound AUC0-24 across all doses studied in the relevant dose escalation 
Phase 1 studies (i.e., 
) demonstrates that doses 
ranging from 
 in the SAD and 
 in the MAD remain 
 
 the NOAEL established in the 
 toxicology studies. 
The higher dose of 320 mg to be evaluated in Part D of this study provides a reasonable 
escalation and separation from the 80 and 160 mg doses evaluated in Part C, allowing for 
appropriate dose ranging 
 (please refer to the 
Investigator’s Brochure for further details).  
Emerging data indicate that a 320 mg QD dose of PLN-74809 achieves 
 
exposure, expected to provide greater levels of αvβ6 target engagement, PD response and 
potential clinical benefit. Interim findings from an ongoing investigation measuring uptake 
kinetics of the αvβ6 knottin PET radiotracer in the IPF lung indicate > 90% target saturation 


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at single doses of 
 mg PLN-74809 (Study PLN-74809-201). In addition, 
preliminary data investigating PK and PD effects in BALF from healthy participants 
demonstrate a dose- and concentration- dependent reduction of SMAD2 phosphorylation (a 
marker of reduced TGF-β signaling) when PLN-74809 was dosed at 
 mg QD for 
7 days (Study 
). These dose-dependent PD responses were associated with 
 PLN-74809 concentrations that exceeded the cell-based αvβ6 IC50 (protein binding-
corrected) for 6 hours (at 
 mg) or 24 hours (at 
 mg). A greater PD response is expected 
from a 320 mg dose, which is projected to achieve 
 concentrations that approach 
αvβ6 IC80 at steady-state. These higher 
 exposures achieved with a 320 mg QD dose 
are expected to elicit increased αvβ6 target engagement and additional PD response, leading 
to reduced TGF-β signaling in the lung and potentially slowing the clinical progression of 
pulmonary fibrosis. 
Part D initiation will be contingent on DSMB review of the above-mentioned data from 
Part C.  
Findings from this study will inform dose selection for future IPF studies. 
3.3 
Study Duration  
The duration for Parts B and C of the study will be up to 18 weeks each (up to 4 weeks of 
screening, 12 weeks of treatment with study drug, and 2 weeks of follow up). 
The duration for Part D of the study will be variable depending on the study enrollment rate; 
i.e. the time between enrolling the first and last participant. The minimum duration of 
participation will be up to 30 weeks for the last participant enrolled (up to 4 weeks of 
screening, 24 weeks of treatment with study drug, and 2 weeks of follow up) and a maximum 
of up to 54 weeks for the first participant enrolled (up to 4 weeks of screening, up to 
48 weeks of treatment with study drug, and 2 weeks of follow up).  
The end of study will commence once the last participant reaches 24 weeks of treatment. At 
that time, all study participants will complete their next scheduled visit (End of Treatment 
[EoT]) and the 2 weeks of follow up (End of Study [EoS]). 


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
This study intends to enroll participants with mild-to-moderate IPF, with a life-expectancy of 
at least 6 months, who may or may not be receiving treatment with pirfenidone or nintedanib, 
and who otherwise do not present with other major health conditions that could affect the 
study drug or confound the study outcomes.  
4.2 
Inclusion Criteria 
Each participant must meet the following criteria to be enrolled in this study: 
1. Participants, aged 40 years or older 
2. Diagnosis of IPF for up to 5 years based upon ATS/ERS/JRS/ALAT 2018 guidelines 
  
Note: If IPF diagnosis is within > 3 to ≤ 5 years at screening, the participant must 
have evidence of progression within the last 24 months, 
 
   
3. 
 
 
4. Diffusing capacity for carbon monoxide (DLco) (hemoglobin-adjusted) ≥ 30%; historical 
DLco for entry in the study is permitted if within 1 month of screening 
5. Participants currently receiving treatment for IPF with nintedanib or pirfenidone are 
allowed, provided these drugs have been given at a stable dose for at least 3 months 
before the Screening visit and are expected to remain unchanged during the study (stable 
dose is defined as the highest dose tolerated by the participant during ≥ 3 months) 
6. Estimated glomerular filtration rate ≥ 50 mL/min, according to the Cockcroft-Gault 
equation 
7. Female participants of non-childbearing potential must be surgically sterile or 
postmenopausal (refer to Section 6.7.4)  
8. Female participants of childbearing potential must use a contraceptive method with a 
failure rate of < 1% per year or remain abstinent (refrain from heterosexual intercourse) 
during the treatment period and for 1 month after the last dose of study treatment (refer to 
Section 6.7.4). 
Male participants with female partners of childbearing potential must agree to use 
contraceptive measures (refer to Section 6.7.4) or remain abstinent (refrain from 
heterosexual intercourse during the treatment period and for at least 3 months after the 
last dose of study treatment. 
9. Participants must agree to abstain from sperm or egg donation for the duration of the 
study, through to 3 months or 1 month, respectively, after administration of the last dose 
of study drug. 
10. Able to read and sign a written informed consent form (ICF) 


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4.3 
Exclusion Criteria 
Participants who meet any of the following criteria will be excluded from the study. 
1. Receiving any nonapproved agent intended for treatment of fibrosis in IPF. 
2. 
 
 
3. 
 
 
4. Any other condition that prevents the correct assessment of spirometry performance (for 
example a broken rib or chest pain of other origin that prevents adequate forced 
breathing).     
5. Known acute IPF exacerbation or suspicion by the Investigator of such, within 6 months 
of screening. 
6. The extent of emphysema is greater than the extent of fibrotic changes on the most recent 
HRCT scan (as determined by central reader); a HRCT scan performed within 2 years of 
the screening date may be used. 
7. Severe pulmonary hypertension. 
8. Smoking of any kind (not limited to tobacco) within 3 months of screening or unwilling 
to avoid smoking throughout the study. 
9. Lower respiratory tract infection requiring antibiotics within 4 weeks prior to screening 
and/or during the screening period. 
10. History of malignancy within the past 5 years or ongoing malignancy other than basal 
cell carcinoma, resected noninvasive cutaneous squamous cell carcinoma, or treated 
cervical carcinoma in situ. 
11. End-stage liver disease. 
12. Renal impairment or end-stage kidney disease requiring dialysis. 
13. 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 


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14. Any of the following liver function test criteria above specified limits: total bilirubin 
> 1.5× the upper limit of normal (ULN); aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) > 3× ULN; alkaline phosphatase > 2.5× ULN.  
Note: participants currently receiving nintedanib or pirfenidone as IPF SoC treatment, 
who have previously presented any liver function test elevations associated with 
nintedanib or pirfenidone treatment greater than that described above or resulting in 
dose reduction, treatment interruption, or discontinuation are not eligible. 
15. Any of the following at screening: hemoglobin < 10.0 g/dL, or neutrophils < 1500 /mm3, 
or platelets < 100,000 /mL. 
16. Pregnant or lactating females. 
17. Daily use of phosphodiesterase-5 (PDE-5) inhibitor drugs (e.g., sildenafil, tadalafil, 
other) (Note: Intermittent use for erectile dysfunction is allowed.). 
18. A medical or surgical condition known to affect drug absorption (e.g., major gastric 
surgery).  
19. Surgical procedures planned to occur during the study period. 
20. 
 
21. Has participated in a clinical study with an investigational agent in the 30 days prior to 
screening or 5 half-lives of the investigational drug, whichever is longer. 
22. Likely to have lung transplantation during the study (being on transplantation list is 
acceptable). 
23. Any medical condition that, in the opinion of the Investigator, may make candidates not 
suitable for the study. 
24. Hypersensitivity to PLN-74809 or to any of the excipients, or placebo. 
25. Currently receiving and expected to remain on treatment during the study with: 
 
 
 
  
 


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5 
STUDY DRUG AND ACCOUNTABILITY 
5.1 
Description of Study Drug 
5.1.1 
Study Drug 
 
  
Parts A, B and C of this study used the 
. PLN-74809 drug product for Part B and 
Part C of the study is supplied as 40-mg 
. These PLN-74809 
 
 
 
In Part D of this study, 
. PLN-74809 drug product for Part D 
of the study is supplied as 80-mg 
. These 
PLN-74809 
 
 
 
 
5.1.2 
Placebo 
A corresponding matching placebo will be provided. 
5.2 
Packaging and Labeling 
The Part B portion of the study evaluating a dose of 40 mg QD has been completed.  
For the Part C portion of the study evaluating doses of 80 mg and 160 mg QD, the 
PLN-74809 
.   
For the Part D portion of the study evaluating a dose of 320 mg QD, the PLN-74809 
 
 
  
 
Details are provided in the Pharmacy Manual. 
5.3 
Storage and Accountability 
For Parts B and C (
), the study drug should be stored 
 
, whether at the site pharmacy or at the participant’s 
home. 
For Part D (80-mg 
), the study drug should be stored 
 
 whether at the site pharmacy or at the participant’s home. 


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All used and unused study medication must be returned to the study site at the visits specified 
in the Schedule of Events (Appendix 1 [Parts B and C] and Appendix 2 [Part D]) in order to 
perform accountability. 
5.4 
Treatment Compliance 
Dosing will be performed in the presence of site staff every time the participant is on site on 
dosing days. For offsite dosing, participants will be provided with a dosing log in which they 
will collect dosing information for PLN-74809 and, if applicable, nintedanib or pirfenidone 
doses taken at home. Participants should return all used and unused medication vials or 
bottles to the site at each site visit.  
Treatment compliance will be calculated comparing the amount of drug dispensed and drug 
returned. 


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6 
STUDY TREATMENTS 
6.1 
Description of Treatments 
Part B: 40 mg of PLN-74809 or matching placebo administered orally QD  
Part C: 80 mg or 160 mg of PLN-74809 or matching placebo administered orally QD 
Part D: 320 mg of PLN-74809 or matching placebo administered orally QD 
PLN-74809 will be supplied by Pliant 
. Study drug will be 
taken once daily at approximately 24-hour intervals.  
6.2 
Dose Modifications and Interruptions 
There will be no dose modifications of the study drug. If the study drug needs to be 
interrupted for safety or tolerability issues, this should happen, as feasible, in consultation 
with the Medical Monitor and Study Director, who together with the Investigator will assess 
and decide whether the study drug interruption should be temporary or permanent on a case-
by-case basis. Participants who discontinue study drug for safety reasons prior to completion 
of 12 weeks of treatment will be asked to remain in the study to complete all remaining 
assessments; if this is not feasible, then they will be asked to return to the clinic for an early 
termination visit. 
Dose modifications or interruptions of pirfenidone or nintedanib treatment may be 
implemented only for safety and tolerability reasons 
 
, in accordance with their corresponding prescribing information and in 
consultation with the Medical Monitor and Study Director. This should not affect the 
administration of the study drug or the continuation of participants in the study.  
6.3 
Selection and Timing of Dose for Each Participant 
Participants will be encouraged to take their study drug at the same time of the day, each day. 
Participants will take 
 
) and will drink up to 240 mL (~1 cup of water) 
 
.  
 
A dose will be considered missed if the participant cannot take the dose within 12 hours of 
their regular dosing time.  
• If a participant has missed a dose of study drug and is still within 12 hours of the time it 
is usually taken, the participant should take a dose of the missed drug as soon as possible. 
The participant may then continue the usual dosing schedule. 
• If the participant has missed a dose of study drug more than 12 hours after the time it is 
usually taken, the participant should not take the missed dose and should resume the 
usual dosing at the next scheduled time. The participant should not take a double dose to 
make up for a missed dose. 


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6.4 
Method of Assigning Participants to Treatment Groups 
Up to approximately 112 participants may be enrolled in study Parts B (n = 28), C (n = 56) 
and D (n = 28). The randomization for each of the dose cohorts in Parts B, C, and D will be 
3:1 (active:placebo). Randomization will be stratified by use of SoC IPF therapy (pirfenidone 
or nintedanib) (SoC use; yes or no). 
• In Part B, 28 eligible participants were randomized on Day 1 (Visit 2) in a 3:1 ratio 
(40 mg PLN-74809:placebo). 
• In Part C, 56 eligible participants will be randomized on Day 1 (Visit 2) in a 3:3:2 ratio 
(80 mg PLN-74809:160 mg PLN-74809:placebo).  
• In Part D, 28 eligible participants will be randomized on Day 1 (Visit 2) in a 3:1 ratio 
(320 mg PLN-74809:placebo).  
 
Assignment will be performed in a blinded manner using interactive response technology 
(IRT) based on a previously generated randomization code. Randomization will occur 
immediately prior to dosing on the morning of the first dose (Day 1). 
6.5 
Blinding 
The placebo treatment will resemble the active treatment 
. This 
ensures that the participant, Investigator, clinical site staff, and Sponsor are unaware of the 
treatment allocation during the conduct of the study. The PLN-74809 or placebo will be 
provided as blinded kits and will be assigned to participants using a randomization code. 
Procedures will be in place to allow prompt breaking of the blind by the investigator if 
needed for the safety management of a participant. Unblinding at the study site for any other 
reason will be considered a protocol deviation. The investigator is strongly encouraged to 
contact the sponsor’s Study Director before unblinding any participant’s treatment 
assignment, but must do so within one working day after the event. A written explanation of 
the reason for unblinding should be provided to the sponsor within 24 hours of breaking the 
blind. Refer to the IRT User Guide for a description regarding how investigators may access 
treatment information via the IRT system.  
6.6 
Concomitant Therapy 
6.6.1 
Allowed Medications 
During screening, all medications including over the counter medications and herbal 
supplements taken during the 30 days prior to screening will be recorded and reviewed by the 
Investigator in consultation with the sponsor Study Director to determine whether the 
participant is suitable for inclusion. For other concomitant medications needed during the 
study conduct, the Investigator should consult with the sponsor Study Director as soon as 
feasible.  


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Only treatment with approved SoC for IPF (nintedanib or pirfenidone) is allowed. These 
drugs must have been given at a stable dose for at least 3 months before initiation of 
screening and be expected to remain unchanged during the study. In addition, for participants 
receiving nintedanib or pirfenidone, the time of drug administration should be collected each 
day samples are obtained for assessing PLN-74809 PK. Treatments to address IPF disease 
symptoms, (e.g., cough, gastroesophageal reflux disease, etc.) are allowed. 
Preliminary results from a 
 
 
. 
Other medications to provide reasonable patient care of comorbidities are allowed during the 
study; however, these should only be used if necessary because, at this stage of development, 
limited formal drug-drug interaction studies with PLN-74809 have been performed. If used, 
all concomitant medications including both prescription and nonprescription drugs should 
first be discussed with the Investigator and Sponsor's Study Director before administration. 
This requirement does not apply in the case of urgent, necessary treatment of AEs. In all 
cases, medications, including over the counter medications and herbal supplements, taken by 
participants during the course of the study will be recorded using the generic name of the 
medication.  
Prolonged treatment with high doses of 
 
; if such treatment is required, this must be discussed and 
approved by the Medical Monitor. 
In vitro, PLN-74809 
 
 
 
 
 
 
 
 
 
 
 
 
 
 The 
Medical Monitor and Sponsor Study Director should be notified within 24 hours of any 
suspected or confirmed onset of 
.  
As this will be the first study where multiple doses of PLN-74809 and nintedanib may be co-
administered, participants receiving nintedanib should be monitored for potential 
tolerability issues, 
 
 


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6.6.2 
Disallowed Medications 
Preliminary results from a 
 
 
 
 
.   
Co-administration of PLN-74809 with 
 
 
Use of 
 
 
 
. 
 
. 
Treatment with a disallowed medication, other investigational drug or investigational device 
is prohibited within 30 days or, in the case of medications, 5 half-lives (whichever is longer) 
before screening. 
6.7 
Restrictions 
6.7.1 
Prior Therapy 
Previous use of IPF SoC treatment (pirfenidone or nintedanib) is allowed for participation in 
this study.  
6.7.2 
Fluid and Food Intake  
Participants should be dosed with the study drug 
 
). Dosing should be accompanied by approximately 240 mL 
water (1 cup). 
6.7.3 
Participant Activity Restrictions 
Smoking of any kind is not permitted within 3 months of screening and throughout the study. 
6.7.4 
Contraception  
Female Participants of Childbearing Potential 
Female participants of childbearing potential must agree to use a contraceptive method with a 
failure rate of <1% per year or remain abstinent (refrain from heterosexual intercourse) 
during the treatment period and for 1 month after the last dose of study treatment.   
A woman is considered to be of childbearing potential if:   


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 She has not reached a postmenopausal state, defined as ≥12 continuous months of 
amenorrhea with no identified cause other than menopause or 6 months of 
spontaneous amenorrhea with serum follicle-stimulating hormone [FSH] levels 
>40 mIU/mL 
 She has not undergone surgical sterilization, defined as hysterectomy, bilateral 
salpingectomy, and/or bilateral oophorectomy 
Examples of contraceptive methods with a failure rate of < 1% per year include: 
 Bilateral tubal ligation  
 Male sterilization (>3 months from Day 1 or provide a zero sperm count) 
 Hormonal contraceptives that inhibit ovulation (initiated >3 months from Day 1) 
 Hormone-releasing intrauterine devices (initiated >3 months from Day 1) 
 Copper intrauterine devices (initiated >3 months from Day 1) 
Male Participants 
Male participants, including those who are surgically sterile, must agree to use contraceptive 
measures as defined below, or alternately to remain abstinent (refrain from heterosexual 
intercourse)   
 Male participants, with female partners of childbearing potential, must use a condom 
plus an additional contraceptive method that together result in a failure rate of < 1% 
per year or remain abstinent during the treatment period and for at least 3 months 
after the last dose of study treatment. 
 
Male participants with pregnant female partners are excluded from this study 
 Male participants whose female partners become pregnant during the study must stop 
the medication immediately as outlined in Section 8.6 
 
 
Highly effective methods of birth control are defined as those with a failure rate of < 1% per 
year 
 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception. Complete abstinence is considered a highly effective 
method when refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatment.   


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7 
STUDY PROCEDURES 
The Schedule of Events with study activities is provided in Appendix 1 (Parts B and C) and 
Appendix 2 (Part D). 
When several assessments are required at the same time point, evaluations should be 
completed so that the PK sample is collected at the required time. It is understood that other 
assessments such as 
, vital signs, etc. will be performed as close to the time point as 
possible. 
Obtaining informed consent and acquisition of the HRCT must be conducted at the clinical 
site.  All other study visits and procedures may be conducted by a qualified research nurse at 
the participant’s home (per participant and site preference).     
7.1 
Informed Consent 
Written and dated informed consent, describing the study and all anticipated risks of 
participation must be obtained from each study participant prior to any study-related 
procedures being performed. 
7.2 
Medical History 
Medical history of the previous 5 years will be reviewed and recorded at screening. It should 
also include any relevant information or condition relevant to the purposes of this study, 
regardless of the timeframe. 
7.3 
Demographic Information 
Date of birth, sex, ethnicity, and race will be recorded at screening.  
7.4 
Physical Examination 
Complete and targeted physical examinations will be performed at the time points specified 
in the Schedule of Events (Appendix 1 [Parts B and C] and Appendix 2 [Part D]). Complete 
physical examinations include general appearance, head, ears, eyes, nose, throat, dentition, 
thyroid, chest (heart, lungs), abdomen, skin, neurological, extremities, back, neck, 
musculoskeletal, and lymph nodes. Targeted physical examination after screening will only 
be performed based on prior findings in the general exam, and includes head, ears, eyes, 
nose, throat, heart, lungs, abdomen, skin, musculoskeletal and lymph nodes, and any 
pertinent system based on any prior findings. Physical examinations may be performed at 
various unscheduled time points if deemed necessary by an Investigator. 
7.5 
Vital Signs 
Blood pressure and heart rate will be recorded with participants having rested for at least 
3 minutes in a supine position. Body temperature (preferably by ear) will be measured and 
peripheral capillary oxygen saturation (SpO2) will be measured using a finger pulse oximeter.  


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7.6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.7 
Clinical Laboratory Tests 
7.7.1 
Laboratory Parameters 
Participants will be in a seated or supine position during blood collection. Safety laboratory 
tests (hematology, serum chemistry and coagulation) will be collected from fasting (at least 
8 hours) participants where appropriate. A detailed list of laboratory tests is provided in 
Table 2. Creatinine clearance will be calculated using the Cockcroft-Gault equation. 
 


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Table 2 
List of Laboratory Tests 
Hematology: 
- 
Hematocrit (Hct) 
- 
Hemoglobin (Hgb) 
- 
Mean corpuscular hemoglobin (MCH) 
- 
Mean corpuscular hemoglobin concentration 
(MCHC) 
- 
Mean corpuscular volume (MCV) 
- 
Platelet count 
- 
Red blood cell (RBC) count  
- 
White blood cell (WBC) count with 
differential  
 
Coagulation:  
- 
International normalized ratio (INR) 
 
Urinalysis:  
- 
Appearance 
- 
Bilirubin 
- 
Color 
- 
Glucose 
- 
Ketones 
- 
Microscopic examination of sediment  
- 
Nitrite  
- 
Occult blood 
- 
pH 
- 
Protein 
- 
Specific gravity 
- 
Urobilinogen 
 
 
 
Serum and urine human chorionic gonadotropin 
(hCG) (females) 
Serum Chemistry: 
- 
Alanine aminotransferase (ALT) 
- 
Albumin (ALB) 
- 
Alkaline phosphatase (ALP) 
- 
 
- 
Amylase (reflex lipase if amylase 
≥ 1.5 × ULN) 
- 
Aspartate aminotransferase (AST) 
- 
Bilirubin (total and direct) 
- 
Blood urea nitrogen (BUN) 
- 
Calcium (Ca) 
- 
Chloride (Cl) 
- 
Creatinine 
- 
Creatine kinase (CK)  
- 
Gamma-glutamyl transferase (GGT) 
- 
Globulin 
- 
Glucose 
- 
High-sensitivity C-reactive protein (hsCRP) 
- 
Lactate dehydrogenase (LDH) 
- 
Phosphorus 
- 
Potassium (K) 
- 
Sodium (Na) 
- 
Total cholesterol 
- 
Total protein 
- 
Triglycerides 
- 
 
- 
Uric acid 
 
7.7.2 
Sample Collection, Storage, and Shipping 
Refer to the study manual for details regarding sample collection, storage, and shipping. 


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7.8 
Dispensing Study Drug 
Participants will receive study drug at the timepoints indicated in the Schedule of Events.  
7.9 
Exploratory Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.10 
Pharmacokinetic Assessments 
 plasma samples for PLN-74809 PK analysis will be obtained predose and 
at least 2 hours postdose at the visits indicated in the Schedule of Events (Appendix 1 [Parts 
B and C] and Appendix 2 [Part D]). Samples will be obtained and stored as detailed in the 
study manual.  
The actual collection time of each sample, as well as the dosing time, must be recorded in the 
source data and on the eCRF. If the participant discontinues the study early, a plasma sample 
for PK should be taken at the ET visit if possible. 
Aliquots of these PK samples may be used to measure nintedanib and/or pirfenidone 
concentrations in those participants who are receiving background SoC.  
 
 
 (See Sections 9 and 10). 
7.11 
Pharmacodynamic Assessments (Biomarkers in Urine, Plasma, and 
Serum 
Urine, plasma and serum samples will be obtained at predetermined times as indicated in the 
Schedule of Events (Appendix 1 [Parts B and C] and Appendix 2 [Part D]). These samples 


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will be used to measure specific proteins, peptides, metabolites and/or mRNA transcripts that 
may be elevated in patients with inflammatory/fibrotic disease or act as PD markers that may 
change with inhibition of vβ6. 
 
 
 
Details of sample collection, storage, and assay will be provided in the study manual.  
A table of exploratory biomarkers of interest and evidence for their prognostic or 
pharmacodynamic value is presented below.  


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Category 
Biomarker 
Evidence of Prognostic or Pharmacodynamic Value  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.12 
Pharmacogenomics  
A whole blood sample for deoxyribonucleic acid (DNA) isolation will be collected before 
dosing on Day 1 from each participant in the study. The DNA samples will be analyzed to 
evaluate drug metabolic enzyme and transporter polymorphisms that may contribute to the 
variability in PK of PLN-74809. Detailed instructions for the handling and shipping of 
samples will be provided in the study manual. 
7.13 
Concomitant Medication and Adverse Event Assessments 
At each study visit, participants will be asked about how they are feeling and what 
medications they are taking (have started/stopped, adjusted dose, etc.). 
7.14 
Missed Assessments 
Missed assessments will reported as such and will not be imputed. 
7.15 
Appropriateness of Measurements 
Collection of AEs, safety labs, vital signs, physical examinations and 
 are 
standard well-established parameters to assess the safety and tolerability of pharmacological 
agents.  
PK samples will be analyzed according to predefined validated analytical methods to assess 
the concentrations of PLN-74809 in plasma. 
 
 
 
  
When available, appropriate standard guidelines will be used. 


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8 
SAFETY ASSESSMENTS 
8.1 
Timing 
In this study, AEs will be collected from the time the participant signs the ICF until the 
participant's last study visit. 
8.2 
Definition of an Adverse Event  
An AE is any event, side effect, or other untoward medical occurrence that occurs in 
conjunction with the use of a study drug in humans, whether or not considered to have a 
causal relationship to this treatment. An AE can, therefore, be any unfavorable and 
unintended sign (that could include a clinically significant abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a study drug, whether or not 
considered related to the study drug. Events meeting the definition of an AE include:  
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study drug administration even though it may 
have been present prior to the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or 
a concomitant medication (overdose per se will not be reported as an AE/SAE). Events 
that do not meet the definition of an AE include: 
- 
Medical or surgical procedure (eg, endoscopy, appendectomy); the condition that 
leads to the procedure is an AE. 
- 
Situations where an untoward medical occurrence did not occur (eg, social and/or 
convenience admission to a hospital). 
- 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
• If there is evidence of an AE through report or observation, the Investigator or designee 
will evaluate further and record the following information:  
- 
Time of onset and resolution 
- 
Severity 
- 
Causality/relation to study treatment 
- 
Action taken regarding study drug 
- 
Outcome 
 


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8.3 
Severity of an Adverse Event 
Grading the severity of AEs will use the Common Terminology Criteria for Adverse Events 
(CTCAE) grading system (
 as described below. The clinical significance of the 
AE is determined by the Investigator. The Investigator is encouraged to consult with the 
Study Director.  
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
A semi-colon indicates ‘or’ within the description of the grade. 
*Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
 
 
 
8.4 
Causal Relationship of an Adverse Event 
The Investigator will assess the relationship between study drug and the occurrence of each 
AE. The Investigator’s assessment of the relationship of each AE to study drug will be 
recorded in the source documents and the eCRF. Alternative causes, such as medical history, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study drug should be considered and investigated, if appropriate. The following definitions 
are general guidelines to help assign grade of attribution.  


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The relationship or association of the AE to a study drug (PLN-74809 or placebo) should be 
assessed using clinical judgment and the following considerations: 
No  
(not related): 
Evidence exists that the AE has an etiology other than the study drug. For 
SAEs, an alternative causality must be provided (eg, pre-existing condition, 
underlying disease, intercurrent illness, or concomitant medication). 
Yes 
(related): 
A temporal relationship exists between the AE onset and administration of the 
study drug that cannot be readily explained by the participant’s clinical state 
or concomitant therapies. Furthermore, the AE appears with some degree of 
certainty to be related, based on the known therapeutic and pharmacologic 
actions or AE profile of the study drug. In case of cessation or reduction of 
the dose, the AE abates or resolves and reappears upon re-challenge. 
 
The relationship to study procedures (such as venipuncture) should be assessed using the 
following considerations: 
No 
(not related): 
Evidence exists that the AE has an etiology other than the study procedure. 
Yes 
(related): 
The AE occurred as a result of protocol-mandated procedures. 
 
8.5 
Outcome  
The outcome of an AE will be recorded on the AE eCRF as follows:  
• Recovered / Resolved 
• Recovering / Resolving 
• Recovered / Resolved with Sequelae 
• Not Recovered / Not Resolving 
• Fatal 
• Unknown 
 
8.6 
Pregnancy 
A pregnancy is not an AE. If a female participant or the female partner of a male study 
participant becomes pregnant while enrolled in the study following administration of study 
drug and within 30 or 90 days, respectively, after administration of the last dose of study 
drug, the Sponsor must be notified within 24 hours of the Investigator learning of the 


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pregnancy. Administration of study drug will be discontinued immediately, and the 
participant or the female partner of a male study participant will be followed through the 
outcome of the pregnancy. The Investigator is required to provide all the relevant information 
to the Sponsor using the Pregnancy Information Form to do so. 
The pregnancy will be followed through delivery. If the pregnancy results in a congenital 
anomaly/birth defects/miscarriage, this will be considered and reported as an SAE as per 
definition detailed in Section 8.8. 
8.7 
Clinical Laboratory Adverse Events 
Abnormal laboratory findings (eg, clinical chemistry, hematology and urinalysis) or other 
abnormal assessments (eg, 
, vital signs) per se are not reported as AEs. However, those 
abnormal findings that are deemed clinically significant or are associated with signs and/or 
symptoms must be recorded as AEs if they meet the definition of an AE, as described in 
Section 8.2 (or recorded as an SAE if they meet the criteria of being serious, as described in 
Section 8.8). Clinically significant abnormal laboratory or other abnormal findings that are 
detected after consent or that are present at baseline and worsen after consent are included as 
AEs (and SAEs if serious). 
The Investigator should exercise his/her medical and scientific judgment in deciding whether 
an abnormal laboratory finding or other abnormal assessment is clinically significant. 
Usually, the abnormality should be associated with a clinically evident sign or symptom, or 
be likely to result in an evident sign or symptom in the near term, to be considered clinically 
significant. A clinically significant laboratory abnormality in the absence of clinical 
symptoms may jeopardize the participant and may require intervention to prevent immediate 
consequences. For example, a markedly low serum glucose concentration may not be 
accompanied by coma or convulsions, yet be of a magnitude to require glucose 
administration to prevent such sequelae. 
8.8 
Serious Adverse Events 
8.8.1 
Definition of Serious Adverse Events 
A SAE is any untoward medical occurrence that at any dose:  
• Is life-threatening 
- 
An AE is considered life-threatening if, in the opinion of either the Investigator or the 
Sponsor, its occurrence places the participant at immediate risk of death. It does not 
include an AE that, had it occurred in a more severe form, might have caused death. 
• Results in death 
• Requires inpatient hospitalization (ie, admission) or prolongation of existing 
hospitalization. Except: 
- 
An emergency room visit without hospitalization is not considered fulfilling the 
serious criteria of hospitalization. 


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- 
Planned hospitalization or surgical procedures for an illness or disease which existed 
before the participant was enrolled in the clinical trial is not considered an SAE 
unless the condition deteriorated in an unexpected manner. 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect/miscarriage 
• Is an important medical event 
- 
An event that does not fulfill any of the serious criteria above, but is considered to be 
clinically significant and may jeopardize the participant, or when medical or surgical 
intervention may be required to prevent one of the outcomes listed above.  
- 
Examples of such events include but are not limited to: laboratory abnormalities 
 
 
 that lead to permanent study drug discontinuation, allergic 
bronchospasm requiring intensive treatment at an emergency room or at home, 
blood dyscrasias, convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.  
 
8.8.2 
Recording Adverse Events and Serious Adverse Events 
All AEs and SAEs spontaneously reported by the participant and/or in response to an open 
question from study personnel or revealed by observation, physical examination or other 
diagnostic procedures will be recorded on the appropriate page of the eCRF. Any clinically 
relevant deterioration in laboratory assessments or other clinical finding is considered an AE 
and must be recorded on the appropriate pages of the eCRF. When possible, signs and 
symptoms indicating a common underlying pathology should be noted as one comprehensive 
event. 
8.8.3 
Reporting Serious Adverse Events 
In order to meet the requirements for expedited reporting of SAEs meeting specific 
requirements to applicable regulatory authorities and Institutional Review Boards (IRBs)/ 
Independent Ethics Committee (IECs)/ Research Ethics Boards (REBs), all SAEs must be 
reported to the Sponsor within 24 hours from the time site personnel first become aware of 
the event by completing the SAE form and emailing it to the below:  
 
Initial notification of an SAE by telephone must be confirmed in writing within 24 hours by 
completing the SAE form. As further information regarding the SAE becomes available, such 
follow up information should be documented and sent to 
 
All SAEs must be followed by the Investigator to resolution or medical stabilization. 


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Withdrawal from the study in the event of a SAE and therapeutic measures taken shall be at 
the discretion of the Investigator. A full explanation for the discontinuation from the study 
should be made in the eCRF. 
8.8.4 
Reporting SAEs to Regulatory Authorities and IRB/IEC/REB  
The reporting of any SAEs to applicable regulatory authorities will be the responsibility of 
the Sponsor in compliance with applicable country regulations. All SAEs must be reported to 
the IRB/IEC/REB by the Investigator in accordance with their regulations. 


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10 
MONITORING AND MANAGEMENT OF 
 
ABNORMALITIES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Clinical evaluation must include the following:  
• Ruling out comorbidities and potential risk factors 
 
 
• 
 
• Review of potential concomitant medications 
 
 
 


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. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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11 
EARLY DISCONTINUATION OF STUDY OR INDIVIDUAL 
PARTICIPANTS 
In accordance with the Declaration of Helsinki, participants have the right to withdraw from 
the study at any time for any reason. The Investigator or Sponsor may withdraw a participant 
from the study or discontinue study drug for any of the following reasons: 
• Noncompliance with protocol procedures including those relating to administration of 
study drug 
• A serious or intolerable AE occurs 
• Infection with COVID-19 that precludes safe participation in the study 
• A clinically significant change in a laboratory parameter occurs 
• 
 
 
• 
 
  
• The Sponsor or Investigator terminates the study 
• The participant requests to be discontinued from the study 
 
If a participant is withdrawn from the study or discontinues study drug, they will undergo 
early termination assessments; refer to the Schedule of Events for Parts B and C (Appendix 
1) and Part D (Appendix 2). 
 


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12 
PLANNED STATISTICAL METHODS 
12.1 
General Considerations 
This is a safety study with exploratory efficacy and biomarker assessments; as such, no 
statistical hypotheses are being tested. In general, data will be summarized using statistical 
summary methods; graphic presentations of data may also be prepared. The contract research 
organization (CRO) will be responsible for the preparation of tables and listings and will 
assist in the preparation of figures, which may be done by Sponsor personnel. A statistical 
analysis plan (SAP), prepared and agreed before final database lock, will describe the 
analytic approach and methods in more detail. 
12.2 
Determination of Sample Size 
The sample size of approximately 21 participants receiving PLN-74809 per dose level is 
expected to provide a meaningful evaluation of PLN-74809 safety, tolerability and PK in the 
target population.  
12.3 
Analysis Populations  
Safety Population: All randomized participants who receive at least one dose of study drug 
will be included in the safety analyses. 
PK Analysis Population: All randomized participants who have sufficient PLN-74809 
concentration data for PK calculation will be included in the PK analyses.  
PD Analysis Population: All randomized participants who receive any amount of study drug 
and who have results from Baseline and from at least one post-baseline PD assessment will 
be included in the PD analyses. 
Efficacy Intent-to-Treat (ITT) Population: All randomized participants.  
Efficacy Per Protocol Population: Subset of the ITT population who complete the study 
without any major protocol violations. 
12.4 
Demographics and Baseline Characteristics 
Data will be summarized using statistical summary methods. 
12.5 
Primary Endpoints 
12.5.1 
Primary Safety Endpoint 
• Nature and proportion of AEs between PLN-74809 and placebo groups (descriptive) 
 
Safety data from all participants who received at least one dose of study drug will be 
incorporated into the final safety analysis. Further details of the safety analyses will be 


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provided in the SAP. AEs will be collected from the time the participant signs the ICF until 
the last study visit. Treatment-emergent adverse events (TEAEs) are defined as AEs that 
emerged or worsened in severity after the first administration of study drug. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®). All 
AEs will be graded for severity per the CTCAE grading scale and listed by participant and 
summarized by last treatment taken at onset of AE. All AEs will be listed by participant and 
summarized by last treatment taken at onset of AE. 
The incidence of AEs, the incidence of TEAEs, the incidence of treatment-related AEs, and 
the severity of AEs will be summarized by system organ class, preferred term, and maximum 
severity. In cases where a participant reports multiple occurrences of the same event 
(preferred term), the greatest severity will be included in the summary. The number and 
percentage of participants with SAEs and treatment-related SAEs and participants who 
withdraw prematurely due to an AE will be tabulated by study treatment and dose. 
Clinical laboratory test parameters will be graded using the CTCAE grading scale for 
individual participants and values outside the reference ranges will be flagged. The incidence 
of treatment-emergent laboratory abnormalities will be summarized by severity and treatment 
group. For each parameter, summary statistics will be calculated for each measure and 
summarized by treatment and dose. 
Individual 
results will be listed for each participant. Summaries of 
 by treatment 
and dose will include changes from baseline for each parameter. 
Vital sign measurements other laboratory tests, concomitant medications, medical history and 
changes in physical examinations at each time point will be listed by participant. The number 
and percentage of participants with abnormal 
 will be summarized by treatment and 
dose. 
Concomitant medications will be coded using the most current World Health Organization 
drug dictionary available. 
12.6 
Secondary Endpoints 
12.6.1 
Secondary Pharmacokinetic Endpoints 
Plasma PLN-74809 concentrations (
) at each sampling 
timepoint will be presented in listings and descriptive summary statistics by dose and visit. 
The data will also be presented graphically.  
Further details of the analyses will be provided in the SAP to be prepared and agreed prior to 
final ‘database lock’ at the end of the study. The PK analysis plan and report may be 
prepared separately from the SAP as appropriate. 


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12.6.2 
Secondary Pharmacodynamic Endpoints 
Urine, plasma and serum samples will be analyzed for biomarkers (presence or actual 
concentration). These samples will be used to determine the levels of these markers in 
participants and the relationship between these markers. Results will be presented by listings, 
descriptive summary statistics and in graphical form by treatment and dose and expressed as 
the relative change (and or absolute) for each participant.  
In addition, relationships between PK and PD may be evaluated in an 
 
and presented in graphical manner. 
12.7 
Exploratory Endpoints 
12.7.1 
Exploratory Efficacy Endpoints 
 
 
 
 
 
 
 
   
 
 
 
  
12.8 
Other Assessments or Analyses 
 
 
12.9 
Interim Analysis 
Interim analyses will be conducted at the time points indicated below: 
 Following full enrollment and 12-week treatment duration with 40, 80, or 160 mg 
PLN-74809 (completion of Parts B and C) 
 Following 12-week treatment duration with 320 mg PLN-74809 (Part D) 


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13 
QUALITY CONTROL AND ASSURANCE 
During the study, the Sponsor and/or representatives of the Sponsor may visit the site to 
conduct an audit of the study. The purpose of this visit will be to determine the Investigator’s 
adherence to the protocol, applicable regulations, and the Sponsor’s procedures, in addition 
to assessing the accuracy of the study data. Prior to initiating this audit, the Investigator will 
be contacted by the Sponsor to arrange a convenient time for this visit. The Investigator and 
staff are expected to cooperate with the auditors and allow access to all participant records 
supporting the eCRFs and other study-related documents. 
At some point during the development program for the study drug, a regulatory authority 
may visit the Investigator to conduct an inspection of the study and the site. The Investigator 
and staff are expected to cooperate with the inspectors and allow access to all source 
documents supporting the eCRFs and other study related documents. The Investigator must 
immediately notify the Sponsor when contacted by any regulatory authority for purposes of 
conducting an inspection. 


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14 
ADMINISTRATIVE CONSIDERATIONS 
14.1 
Institutional Review Board, Independent Ethics Committee or Research 
Ethics Board Approval 
The Investigator must inform and obtain approval from the IRB/IEC/REB for the conduct of 
the study at named sites, for the protocol, the participant ICF, and any other written 
information that will be provided to the participants and any advertisements that will be 
used. Written approval must be obtained prior to recruitment of participants into the study 
and shipment of investigational agent.  
Proposed amendments to the protocol and aforementioned documents must be discussed 
between the Sponsor and CRO, and then submitted to the IRB/IEC/REB for approval as well 
as submitted to regulatory authorities for approval prior to implementation. Amendments 
may be implemented only after a copy of the local IRB/IEC/REB approval letter has been 
transmitted to the Sponsor. Amendments that are intended to eliminate an apparent 
immediate hazard to participants may be implemented prior to receiving Sponsor 
or IRB/IEC/REB approval. However, in this case, approval must be obtained as soon as 
possible after implementation.  
The Investigator is responsible for reporting protocol deviations to the IRB/IEC/REB as 
required by local requirements. The Investigator will be responsible for ensuring that an 
annual update is sent to the IRB/IEC/REB to facilitate their continuing review of the trial (if 
needed) and that the IRB/IEC/REB is informed about the end of the study. Copies of the 
update, subsequent approvals and final letter must be sent to the Sponsor.  
14.2 
Ethical Conduct of the Study 
The study will be carried out in accordance with the current version of the Declaration of 
Helsinki, concerning medical research in humans. The study will be conducted in adherence 
to the study protocol and Good Clinical Practice (GCP), as defined in Title 21 of the US 
Code of Federal Regulations Parts 50, 54 56, 312 and Part 11 as well as International Council 
on Harmonisation (ICH) E6: Guideline for Good Clinical Practice (ICH GCP) consolidated 
guidelines (E6) and applicable regulatory requirements. 
14.3 
Participant Information and Consent 
It is the Investigator’s responsibility to obtain written informed consent from the 
participant after adequate explanation of the objectives, methods, anticipated benefits, and 
potential hazards of the study and before any study procedures are commenced.  
The participant should be given a copy of the ICF in their native language. The 
informed consent process should be recorded in the source documentation. The original copy 
of the signed and dated informed consent must be retained in the institution’s records and be 
available for inspection by representatives of the Sponsor, or representatives from regulatory 
agencies.  


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The participant will be informed that he/she can freely withdraw consent and stop 
participation in the study at any time with no prejudice to further treatment. It is 
the participant’s responsibility to communicate this decision to the Investigator.  
14.4 
Participant Confidentiality 
The Investigator must ensure that the participant’s privacy is maintained. On the 
CRF and other documents submitted to the Sponsor, participants will be identified by 
a participant study number only. Documents that are not submitted to the Sponsor 
(eg, signed ICF) should be kept in a strictly confidential file by the Investigator.  
The Investigator shall permit authorized representatives of the Sponsor, regulatory 
agencies, and IRBs/IECs/REBs to review the portion of the participant’s medical record that 
is directly related to the study. As part of the required content of informed 
consent, the participant must be informed that his/her records will be reviewed in this 
manner. 
Applicable data privacy laws and regulations must be adhered to. The Investigator and the 
Sponsor are responsible for ensuring that sensitive information is handled in accordance with 
local requirements (eg Health Insurance Portability and Accountability Act [HIPAA]). 
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) 
of protected information must be obtained. 
14.5 
Study Monitoring 
The Investigator must allow the Study Monitors to periodically review, at mutually 
convenient times, during the study and after the study has been completed, all eCRFs and 
office, hospital, and laboratory records supporting the participation of each participant in the 
study (source data). The eCRFs and other documentation supporting the study must be kept 
up to date by the Investigator and the research staff at the investigative site. These study 
materials must be available for review by the Study Monitor, and/or other qualified 
representatives of the Sponsor, at each monitoring visit. 
It is the monitor’s responsibility to inspect the CRFs at regular intervals throughout the trial 
to verify adherence to the protocol, the completeness, accuracy and consistency of the 
data, and adherence to GCP guidelines.  
The Investigator agrees to cooperate with the monitor to ensure that any problems detected 
during the course of these monitoring visits are resolved. 
14.6 
Case Report Forms and Study Records 
The investigative site will use eCRFs to record all the protocol-specified data for each 
participant enrolled in this study. Entries made in the eCRF must be verifiable against source 
documents. Data reported in the eCRF that are derived from source documents should be 
consistent with the source documents or the discrepancies should be explained.  


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The Investigator will be responsible for reviewing all data and eCRF entries and will sign 
and date the designated pages in each participant’s eCRF, verifying that the information is 
accurate. 
14.7 
Data Monitoring Committee 
A DSMB will be established to assess participant safety at predetermined intervals during the 
study, and as needed. Refer to the DSMB Charter for further details. 
 
 
 
14.8 
Data Generation and Analysis 
The investigative site will use eCRFs to record all the protocol-specified data for each 
participant enrolled in this study. Entries made in the eCRF must be verifiable against source 
documents. Data reported in the eCRF that are derived from source documents should be 
consistent with the source documents or the discrepancies should be explained.  
The Investigator will be responsible for reviewing all data and eCRF entries and will sign 
and date the designated pages in each participant’s eCRF, verifying that the information is 
accurate. 
14.9 
Retention of Data 
The Investigator must ensure that all records pertaining to the conduct of the clinical study, 
ICFs, drug accountability records, source documents, and other study documentation are 
adequately maintained for a period of 2 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 at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug.  
The Investigator must not destroy any records associated with the study without receiving 
approval from the Sponsor. The Investigator must notify the Sponsor in the event of 
accidental loss or destruction of any study records.  
Whenever possible, an original recording of an observation must be retained as the source 
document. However, a photocopy of a record is acceptable provided it is legible and is a 
verified copy of the original document.  
All eCRF data entered by the site (including audit trail), as well as computer hardware and 
software (for accessing the data), will be maintained or made available at the site in 
compliance with applicable record retention regulations. The CRO will retain the original 
eCRF data and audit trail. 
14.10 
Financial Disclosure 
Financial Disclosure statements will be handled in a separate agreement apart from the 
protocol, kept on file, and submitted as applicable with any subsequent license application.  


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14.11 
Publication and Disclosure Policy 
The data generated in this clinical study are the exclusive property of the Sponsor and are 
confidential. Any publication of the results of this study must be authorized by the Sponsor. 
The Sponsor will have the opportunity to review any publications that arise from the 
Investigators before submission for publication. Any such review and approval of 
publications related to the study shall be made pursuant to the process agreed between the 
parties in the site’s clinical trial agreement with Sponsor. Authorship on any publication of 
the results from this study will be based on contributions to study design, enrollment, data 
analysis, and interpretation of results.  


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15 
REFERENCE LIST 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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APPENDIX 1 
SCHEDULE OF EVENTS: PARTS B AND C 
 
Screening 
Treatment 
EoS / ET 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Day -28 
to Day -1 
Baseline 
Day 1 
Week 2 
Day 14 
(±2 days) 
Week 4 
Day 28 
(±2 days) 
Week 8 
Day 56 
(±3 days) 
Week 12 
Day 84 
(±3 days) 
Week 14  
Day 98  
(±3 days) 
Informed consent 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Demographics (age, sex, race) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
X 
 
 
 
 
 
 
Check inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
Complete physical examination (including height and weight) 
X 
 
 
 
 
 
 
Targeted physical examination  
 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLco 
X 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Vital signs (post 3 minutes, supine; approx 2 hrs post dose 
and around the time of the 
) 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Hematology (post 8-hour fast) 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry (post 8-hour fast)  
X 
X 
X 
X 
X 
X 
X 
Coagulation (post 8-hour fast) 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic sample plasma × 2 (predose and at least 
2 hours postdose) g 
 
X 
 
X 
 
X 
Xg 
Pharmacokinetic nintedanib/pirfenidone sample plasma x 2 
(predose and at least 2 hours post dose to PLN-74809)h 
 
X 
 
X 
 
X 
X 


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Screening 
Treatment 
EoS / ET 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Day -28 
to Day -1 
Baseline 
Day 1 
Week 2 
Day 14 
(±2 days) 
Week 4 
Day 28 
(±2 days) 
Week 8 
Day 56 
(±3 days) 
Week 12 
Day 84 
(±3 days) 
Week 14  
Day 98  
(±3 days) 
Pharmacogenomic sample  
 
X 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Urine pregnancy test (positive tests will be confirmed with a 
serum test) 
 
X 
 
X 
X 
X 
X 
Urinalysis (dipstick, followed up by micro if abnormal) 
X 
X 
 
X 
X 
 
X 
Adverse events  
 
Concomitant medications 
 
Study drug administration (
 
) 
 
X 
 
X 
 
X 
 
Study drug dispensing 
 
X 
 
X 
X 
 
 
Study drug accountability 
 
X 
 
X 
X 
X 
X 
 
; EoS = end of study; ET = early termination; 
; HRCT = high resolution computerized tomography; 
PK = pharmacokinetic; 
 
a 
A HRCT scan performed within 2 years of the screening date may be used for emphysema vs. fibrotic changes. 
 
 
 
  
c 
A historical value may be used if it has been completed within 1 month from the Baseline visit. 
 
 
 
   
 
. 
 
 
g 
 PLN-74809 levels will be measured. Actual PK sample collection time and dosing time will be recorded. If the participant discontinues 
the study early, a plasma sample for PK should be taken at the ET Visit if possible.  
h 
For participants receiving nintedanib/pirfenidone only; timed relative to PLN-74809 dosing. 


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APPENDIX 2 
SCHEDULE OF EVENTS: PART D 
The Schedule of Events for Part D is presented in 2 sections: Screening through the Week 12 Visit and the Week 14 Visit through End 
of Study. 
Screening through Week 12 Visit 
 
Screening 
Treatment   
(continued) 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Day -28 
to Day -1 
Baseline 
Day 1 
Week 2 
Day 14 
(±2 days) 
Week 4 
Day 28 
(±2 days) 
Week 8 
Day 56 
(±3 days) 
Week 12 
Day 84 
(±3 days) 
Informed consent 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Demographics (age, sex, race) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
X 
 
 
 
 
 
Check inclusion and exclusion criteria 
X 
X 
 
 
 
 
Complete physical examination (including height and weight) 
X 
 
 
 
 
 
Targeted physical examination  
 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLco 
X 
 
 
 
 
 
  
 
 
 
 
 
 
Vital signs (post 3 minutes, supine; approx 2 hrs post dose and 
around the time of the 
) 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Hematology (post 8-hour fast) 
X 
X 
X 
X 
X 
X 
Clinical chemistry (post 8-hour fast)  
X 
X 
X 
X 
X 
X 
Coagulation (post 8-hour fast) 
X 
X 
X 
X 
X 
X 


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Screening 
Treatment   
(continued) 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Day -28 
to Day -1 
Baseline 
Day 1 
Week 2 
Day 14 
(±2 days) 
Week 4 
Day 28 
(±2 days) 
Week 8 
Day 56 
(±3 days) 
Week 12 
Day 84 
(±3 days) 
Pharmacokinetic sample plasma × 2 (predose and at least 
2 hours postdose) g 
 
X 
 
X 
 
X 
Pharmacokinetic nintedanib/pirfenidone sample plasma x 2 
(predose and at least 2 hours post dose to PLN-74809)h 
 
X 
 
X 
 
X 
Pharmacogenomic sample  
 
X 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
Urine pregnancy test (positive tests will be confirmed with a 
serum test) 
 
X 
 
X 
X 
X 
Urinalysis (dipstick, followed up by micro if abnormal) 
X 
X 
 
X 
X 
 
Adverse events  
 
Concomitant medications 
 
Study drug administration (
 
) 
 
X 
 
X 
 
X 
Study drug dispensing 
 
X 
 
X 
X 
X 
Study drug accountability 
 
X 
 
X 
X 
X 
 
; ET = early termination; 
; HRCT = high resolution computerized tomography; PK = pharmacokinetic; 
 
a 
A HRCT scan performed within 2 years of the screening date may be used for emphysema vs. fibrotic changes. 
 
 
 
  
c 
A historical value may be used if it has been completed within 1 month from the Baseline visit. 
 
 
 
   
 
 


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g 
 PLN-74809 levels will be measured. Actual PK sample collection time and dosing time will be recorded. If the participant discontinues 
the study early, a plasma sample for PK should be taken at the ET Visit if possible.  
h 
For participants receiving nintedanib/pirfenidone only; timed relative to PLN-74809 dosing. 
 


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Week 14 Visit through End of Study 
 (continued) 
Treatment 
EoS / ET 
 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11a 
Visit 12a 
Week 48 / 
Unscheduled / 
End of 
Treatment Visit 
EoTa,b 
End of 
Study Visit  
EoS 
Week 14 
Day 98 
(±3 days) 
Week 20 
Day 140 
(±3 days) 
Week 24 
Day 168 
(±3 days) 
Week 26 
Day 182 
(±3 days) 
Week 32 
Day 224 
(±5 days) 
Week 40 
Day 280 
(±5 days) 
Final On-
Treatment Visit 
Final On-
Treatment 
Visit 
+ 2 weeks  
(±3 days) 
 
 
 
 
 
 
 
 
 
Targeted physical examination  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Vital signs (post 3 minutes, supine; approx 2 hrs 
post dose and around the time of the 
) 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
  
 
 
 
 
 
 
 
 
Hematology (post 8-hour fast) 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry (post 8-hour fast)  
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation (post 8-hour fast) 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic sample plasma × 2 (predose and 
at least 2 hours postdose)f, h  
 
 
X 
 
 
 
 
 
Pharmacokinetic nintedanib/pirfenidone sample 
plasma x 2 (predose and at least 2 hours post dose 
to PLN-74809)g,h  
 
 
X 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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 (continued) 
Treatment 
EoS / ET 
 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11a 
Visit 12a 
Week 48 / 
Unscheduled / 
End of 
Treatment Visit 
EoTa,b 
End of 
Study Visit  
EoS 
Week 14 
Day 98 
(±3 days) 
Week 20 
Day 140 
(±3 days) 
Week 24 
Day 168 
(±3 days) 
Week 26 
Day 182 
(±3 days) 
Week 32 
Day 224 
(±5 days) 
Week 40 
Day 280 
(±5 days) 
Final On-
Treatment Visit 
Final On-
Treatment 
Visit 
+ 2 weeks  
(±3 days) 
Urine pregnancy test (positive tests will be 
confirmed with a serum test) 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis (dipstick, followed up by micro if 
abnormal) 
 
 
X 
X 
 
 
 
X 
Adverse events  
 
Concomitant medications 
 
Study drug administration (
 
) 
 
 
X 
 
 
 
 
 
Study drug dispensing 
 
X 
X 
 
X 
X 
 
 
Study drug accountability 
X 
X 
X 
X 
X 
X 
X 
 
 
; EoS = end of study; ET = early termination; 
; HRCT = high resolution computerized tomography; 
PK = pharmacokinetic; 
 
a 
All participants will complete visits every 8 weeks after the Week 24 visit until such time as the last participant enrolled has completed the Week 24 visit. At 
this time, all participants will be contacted to return and complete the Final On-Treatment Visit. 
b 
EoT Visit not required for the last participant to complete the Week 24 Visit; the Week 26 visit will be considered the EoT visit for this participant. This 
participant will then be required to complete a final EoS visit. 
 
 
 
   
 
 
 
 
f 
 PLN-74809 levels will be measured. Actual PK sample collection time and dosing time will be recorded.  


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g 
For participants receiving nintedanib/pirfenidone only; timed relative to PLN-74809 dosing.  
h 
If the participant discontinues the study early, a plasma sample for PK should be taken at the ET Visit if possible (PK at ET visit can be collected at any 
point in visit). 
 
 
 


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APPENDIX 3 
SPONSOR SIGNATURE 
 
Study Title: 
A randomized, double-blind, dose-ranging, placebo-controlled Phase 2a 
evaluation of the safety, tolerability and pharmacokinetics of PLN-74809 
in participants with idiopathic pulmonary fibrosis (IPF)   
Study Number: 
PLN-74809-IPF-202 (INTEGRIS-IPF) 
Version 
Protocol Amendment 3 (v3.0) 
Final Date: 
19 October 2021 
 
This clinical study protocol was subject to critical review and has been approved by the 
Sponsor.  
 
Signed: 
 
 
Date:  
 
 
 
  
 
 
 


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APPENDIX 4 
INVESTIGATOR’S SIGNATURE 
 
Study Title: 
A randomized, double-blind, dose-ranging, placebo-controlled Phase 2a 
evaluation of the safety, tolerability and pharmacokinetics of PLN-74809 
in participants with idiopathic pulmonary fibrosis (IPF)   
Study Number: 
PLN-74809-IPF-202 (INTEGRIS-IPF) 
Version 
Protocol Amendment 3 (v3.0) 
Final Date: 
19 October 2021 
I have read the protocol described above. I agree to comply with all applicable regulations, 
Good Clinical Practices, and to conduct the study as described in the protocol.  
 
 
 
 
Signed: 
 
 
Date:  
 
 
 
Name: 
 
 
 
 
Affiliation: 
 
 
 
Site Number: 
 
 

SAP_001.pdf: 
ontrolled Quality Management Document 
Sponsor: 
Pliant Therapeutics Inc. 
Protocol Number: 
PLN-74809-IPF-202 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
Confidentiality Statement 
This document is the property of 
. and may not be duplicated, copied, altered or removed from company without 
prior approval from 
 or in compliance with 
. 
 
 
Page 1 of 43 
Statistical Analysis Plan 
A randomized, double-blind, dose-ranging, placebo-controlled Phase 2a evaluation 
of the safety, tolerability, and pharmacokinetics of PLN-74809 in participants with 
idiopathic pulmonary fibrosis (IPF) (INTEGRIS-IPF) 
Protocol Number: PLN-74809-IPF-202 
Protocol Version: 3.0, 
 
SAP Version 2.0, 
 
Addendum 1.0, 
 
Addendum 2.0, 
 
Addendum 3.0, 
 
Addendum 4.0, 
 
Addendum 5.0, 
 
 
Post Final database lock Addendum, 
  
 
Previous SAP Versions 
SAP Version 1.0, 
 
 


 Controlled Quality Management Document 
Sponsor: 
Pliant Therapeutics Inc. 
Protocol Number: 
PLN-74809-IPF-202 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
Confidentiality Statement 
This document is the property of 
. and may not be duplicated, copied, altered or removed from company without 
prior approval from 
 or in compliance with 
. 
 
 
Page 2 of 43 
SAP Amendments Before Database Lock for Parts A/B/C Week 12 
Version  Issue Date 
Section 
Revision / Addition 
2.0 
17 June 2022 
6.1.7 
Definition of Efficacy Per Protocol Population was 
amended.  
6.2.4 
Procedure for early termination assessments was 
defined.  
6.2.5 
Handling of spirometry assessments was clarified. 
6.2.13 
Compliance calculation was refined.  
6.2.17 
Definition of electrocardiogram abnormalities was 
amended and clarified.  
6.6 
Handling of DLCO lung function assessment at 
screening was clarified.  
6.6 
Duration Since Diagnosis at Screening and Duration 
of Standard of Care at Randomization was defined 
and will be summarized in Participant Disposition.  
 
 
6.11.1 
Clarification added. FVC in mL will be analyzed.  
6.13 
Clarification added. Result adjusted for dilution 
factor will be used.  
 
 
 
 
 
 
 
 
   
6.15.1 
Tabulations and listings for serious adverse events 
were added.  
6.15.2 
Clarification added. Système International (SI) units 
will be used to report laboratory results.  
6.15.4 
Definition of ‘Confirmed Abnormality’ was clarified.  
9 
Changes to Planned Protocol Analyses was updated.   
11 
List of Tables, Figures and Listings was updated.  
 
 
 
 


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SAP Amendments Post Database Lock for Parts A/B/C Week 12 and pre 
database lock for Part D Week 12 
Version  
Issue Date 
Section 
Revision / Addition 
Addendum 
1.0 
02 Dec 2022 
6.15.2 
CTCAE grading for laboratory test parameters 
removed 
6.11.1 
Added new pooled placebo groups and Wilcoxon 
rank sum test for FVC at Week 12 
7 
Added text to clarify data cut off day for Part D 
interim 
11 
List of Tables, Figures and Listings was updated.  
Addendum 
2.0 
06 Dec 2022 
11 
List of Tables, Figures and Listings was updated.  
Addendum 
3.0 
12 Dec 2022 
11 
List of Tables, Figures and Listings was updated.  
SAP Amendments Post Database Lock for Parts A/B/C/D Week 12 and pre 
database lock for Part D Week 24 
Version  
Issue Date 
Section 
Revision / Addition 
Addendum 
4.0 
31 Jan 2023 
 
 
 
6.2.20 
Addition of SAS code to determine outliers 
11 
List of Tables, Figures and Listings was updated. 
Addendum 
5.0 
30 Mar 2023 
6.6 
Added summary of pulmonary function at baseline 
 
 
 
11 
List of Tables, Figures and Listings was updated. 
SAP Amendments Post Final Database Lock 
Version  
Issue Date 
Section 
Revision / Addition 
Post 
database 
lock 
09 May 2023 
6.6 
Added baseline summaries by study part 
 
 
 
11 
List of Tables, Figures and Listings was updated. 
 
 


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Table of Contents 
1 
INTRODUCTION ............................................................................................... 7 
2 
STUDY OBJECTIVES ....................................................................................... 7 
2.1 
Primary Objective ........................................................................................................... 7 
2.2 
Secondary Objective ....................................................................................................... 7 
2.3 
Exploratory Objectives ................................................................................................... 7 
3 
ENDPOINTS ....................................................................................................... 8 
3.1 
Primary Safety Endpoint ................................................................................................. 8 
3.2 
Secondary Pharmacokinetic Endpoints........................................................................... 8 
3.3 
Secondary Pharmacodynamic Endpoints ........................................................................ 8 
3.4 
Exploratory Endpoints .................................................................................................... 8 
3.4.1 
Exploratory Efficacy Endpoints ................................................................................ 8 
3.4.2 
Other Assessments or Analyses ................................................................................ 9 
4 
SAMPLE SIZE .................................................................................................... 9 
5 
RANDOMIZATION ........................................................................................... 9 
6 
PLANNED ANALYSES ...................................................................................10 
6.1 
Analysis Populations ..................................................................................................... 10 
6.1.1 
Screened Participants .............................................................................................. 10 
6.1.2 
Randomized Participants ........................................................................................ 10 
6.1.3 
Safety Population .................................................................................................... 10 
6.1.4 
PK Analysis Population .......................................................................................... 10 
6.1.5 
PD Analysis Population .......................................................................................... 11 
6.1.6 
Efficacy Intent-to-Treat Population ........................................................................ 11 
6.1.7 
Efficacy Per Protocol Population ............................................................................ 11 
6.1.8 
Efficacy Modified Intent-to-Treat Population ........................................................ 11 
6.2 
Derived Data ................................................................................................................. 11 
6.2.1 
Race......................................................................................................................... 11 
6.2.2 
Body Mass Index .................................................................................................... 11 
6.2.3 
Baseline ................................................................................................................... 12 
6.2.4 
Early Termination Assessments .............................................................................. 12 
6.2.5 
Spirometry Assessments ......................................................................................... 12 
6.2.6 
GAP Index and Staging System .............................................................................. 12 
6.2.7 
Study Day................................................................................................................ 13 


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6.2.8 
Unscheduled Visits ................................................................................................. 13 
6.2.9 
Conventions for Missing and Partial Dates ............................................................ 14 
6.2.10 
Missing / Partial Start / Stop Date of Adverse Events, Medical History and 
Concomitant Medications ...................................................................................................... 14 
6.2.11 
Date of Last Dose of Study Drug ............................................................................ 15 
6.2.12 
Exposure to Study Drug .......................................................................................... 15 
6.2.13 
Study Drug Compliance .......................................................................................... 15 
6.2.14 
Imperial to Metric Unit Conversion ........................................................................ 16 
6.2.15 
Inexact Values ......................................................................................................... 17 
6.2.16 
 
6.2.17 
 
6.2.18 
 
6.2.19 
 
6.2.20 
Determination of FVC outliers ............................................................................... 19 
6.3 
Conventions .................................................................................................................. 20 
6.3.1 
Medical Coding ....................................................................................................... 20 
6.3.2 
Data Handling ......................................................................................................... 20 
6.3.3 
Validation Methods ................................................................................................. 20 
6.3.4 
Summary Statistics.................................................................................................. 20 
6.3.5 
Decimal Places ........................................................................................................ 21 
6.3.6 
Data Displays .......................................................................................................... 21 
6.4 
Participant Disposition .................................................................................................. 22 
6.5 
Protocol Deviations ....................................................................................................... 22 
6.6 
Baseline Comparability ................................................................................................. 22 
6.7 
Medical History ............................................................................................................ 23 
6.8 
Prior and Concomitant Medications ............................................................................. 24 
6.9 
Exposure to Study Drug ................................................................................................ 24 
6.10 
Study Drug Compliance ................................................................................................ 24 
6.11 
Efficacy Analyses ......................................................................................................... 24 
6.11.1 
Spirometry............................................................................................................... 24 
6.11.1 
Patient-Reported Cough .......................................................................................... 27 
6.11.2 
Quantitative Lung Fibrosis ..................................................................................... 27 
6.12 
Pharmacokinetic Analyses ............................................................................................ 27 
6.12.1 
Concentration-Time Data ........................................................................................ 27 


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6.12.2 
PK Parameters ......................................................................................................... 28 
6.13 
Pharmacodynamic Analyses ......................................................................................... 28 
6.14 
Pharmacogenomic Analyses ......................................................................................... 29 
6.15 
Safety Analyses ............................................................................................................. 29 
6.15.1 
Adverse Events ....................................................................................................... 29 
6.15.2 
Laboratory Data ...................................................................................................... 31 
6.15.3 
Vital Signs ............................................................................................................... 31 
6.15.4 
 
6.15.5 
Physical Examination.............................................................................................. 32 
7 
INTERIM ANALYSIS ......................................................................................33 
8 
DATA SAFETY MONITORING BOARD ANALYSIS .................................33 
9 
CHANGES TO PLANNED PROTOCOL ANALYSIS ...................................33 
10 REFERENCES ..................................................................................................34 
11 LIST OF TABLES, FIGURES AND LISTINGS .............................................35 
 


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1 
INTRODUCTION 
This document details the planned statistical analyses for Pliant Therapeutics Inc., protocol number 
“PLN-74809-IPF-202” study titled “A randomized, double-blind, dose-ranging, placebo-
controlled Phase 2a evaluation of the safety, tolerability, and pharmacokinetics of PLN-74809 in 
participants with idiopathic pulmonary fibrosis (IPF) (INTEGRIS-IPF)”.   
The proposed analyses are based on the contents of Protocol Amendment 3, dated 19 
October 2021.     
This is a Phase 2a, multicenter, 4-part, randomized, double-blind, dose-ranging, placebo-
controlled study to evaluate the safety, tolerability, and pharmacokinetics (PK) of once-daily (QD) 
treatment with PLN-74809 in participants with idiopathic pulmonary fibrosis (IPF).  
Each study part consists of an up to 28-day screening period, a 4-week (Part A), 12-week (Parts B 
and C), or at least 24-week (Part D) treatment period, and a 2-week (±3 days) post-treatment 
follow-up period.  
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
• Assessment of the safety and tolerability of PLN-74809.  
2.2 
Secondary Objective 
• Assessment of PK of PLN-74809.  
2.3 
Exploratory Objectives 
The exploratory objectives of this study are as follows: 
• Assessment of change from baseline in Forced Vital Capacity (FVC) 
• Assessment of change from baseline in Quantitative Lung Fibrosis (QLF) score 
• Assessment of change from baseline in a visual analog scale (VAS) for cough 
• Assessment of changes in selected biomarkers.  


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3 
ENDPOINTS 
3.1 
Primary Safety Endpoint 
The primary safety endpoint is the nature and proportion of AEs between PLN-74809 and placebo 
groups (descriptive).  
Other safety endpoints include clinical laboratory tests (including hematology, serum chemistry, 
coagulation, and urinalysis), 
, vital sign measurements, changes in physical 
examination and concomitant medications.  
3.2 
Secondary Pharmacokinetic Endpoints 
Plasma PLN-74809 concentrations (
) at each sampling timepoint 
will be presented in listings and descriptive summary statistics by dose and visit. The data will also 
be presented graphically.  
3.3 
Secondary Pharmacodynamic Endpoints 
• Presence or actual concentration of biomarkers in urine, plasma, or serum samples.   
• Levels of biomarkers markers as well as relative (and/or absolute) change in levels for each 
participant and the relationship between these markers.  
• Relationships between PK and PD may be evaluated in an exploratory fashion and 
presented in graphical manner.  
3.4 
Exploratory Endpoints 
3.4.1 Exploratory Efficacy Endpoints 
• FVC including percent of predicted and absolute volume (mL). 
• QLF score assessed by high-resolution computerized tomography (HRCT). 
• Patient-reported outcome (PRO) measured by visual analog scale (VAS) for cough. 


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3.4.2 Other Assessments or Analyses 
 concentrations of PLN-74809 will be determined in plasma samples. Exploratory 
metabolite evaluation may be performed in plasma samples.  
4 
SAMPLE SIZE 
Recruitment for Part A is complete with 1 participant enrolled. 
For Parts B, C and D, the sample size of approximately 21 participants receiving PLN-74809 per 
treatment group is expected to provide a meaningful evaluation of PLN-74809 safety, tolerability 
and PK in the target population.  
Approximately 112 participants may be enrolled in study Parts B (n = 28), C (n = 56), and D 
(n=28).  
5 
RANDOMIZATION 
In Part A, participants were randomized 1:1:1 to receive PLN-74809 (20 mg), PLN-74809 (40 mg) 
or Placebo.  Recruitment for Part A is complete with 1 participant enrolled.  
In Part B, 28 eligible participants were randomized 3:1 on Day 1 (Visit 2) to receive 
PLN-74809 (40 mg) or Placebo. 
In Part C, 56 eligible participants per cohort will be randomized 3:3:2 on Day 1 (Visit 2) to receive 
PLN-74809 (80 mg), PLN 74809 (160 mg) or Placebo.  
In Part D, 28 eligible participants will be randomized 3:1 on Day 1 (Visit 2) to receive PLN-74809 
(320 mg) or Placebo. 
Randomization will be stratified by use of Standard of Care (SoC) IPF therapy (pirfenidone or 
nintedanib) (SoC use; yes or no).   
Assignment will be performed in a blinded manner using interactive response technology (IRT) 
based on a previously generated randomization code. Randomization will occur immediately prior 
to dosing on the morning of the first dose (Day 1).  


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6 
PLANNED ANALYSES 
Any statistical analysis plan (SAP) prepared in advance of final participant data cannot be 
definitive, therefore the Clinical Study Report (CSR) may contain additional tables or statistical 
tests if warranted by the data obtained. The justification for any such additional analyses will be 
fully documented in the final CSR.  
Please note: Since study Part A is considered complete, data from the one enrolled participant in 
Part A will be listed only. Analyses described herein refer to analysis of data from participants 
taking part in study parts B, C, and D only.  
6.1 
Analysis Populations 
Participants excluded from the analysis populations and the reason for their exclusion will be listed 
in Appendix 16.2 of the CSR. 
6.1.1 Screened Participants 
Screened Participants are any participants who gave informed consent to participate in the study.   
6.1.2 Randomized Participants 
Randomized Participants are any participants who were assigned a randomization number.   
6.1.3 Safety Population 
The Safety Population includes all randomized participants who receive at least one dose of study 
drug.   
6.1.4 PK Analysis Population 
The PK Analysis Population includes all randomized participants who have concentration data 
(including below the limit of quantification (BLQ)) for PLN-74809, nintedanib or pirfenidone.   


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6.1.5 PD Analysis Population 
The PD Analysis Population includes all randomized participants who receive any amount of study 
drug and who have results from baseline and from at least one post-baseline PD assessment.    
6.1.6 Efficacy Intent-to-Treat Population 
The Efficacy Intent-to-Treat (ITT) Population includes all randomized participants.   
6.1.7 Efficacy Per Protocol Population  
The Efficacy Per Protocol Population will include the subset of the ITT Population who complete 
the study without any protocol deviations that may significantly impact the interpretation of safety 
and/or efficacy analyses. 
6.1.8 Efficacy Modified Intent-to-Treat Population 
The Efficacy modified Intent-to-Treat (mITT) Population includes all randomized participants 
who do not have FVC values that meet outlier criteria. 
 
. 
6.2 
Derived Data 
This section describes the derivations required for statistical analysis. Unless otherwise stated, 
variables derived in the source data will not be re-calculated. 
6.2.1 Race 
Where more than one race category has been selected for a participant, these race categories will 
be combined into a single category labeled “Multiple Race” in the summary tables. The listings 
will reflect the original selected categories.  
6.2.2 Body Mass Index 
Body mass index (BMI) will be calculated as follows: 
BMI (kg/m2) = Weight at Screening (kg) / [Height at Screening (m)2] 


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6.2.3 Baseline 
In general, baseline is defined as the last non-missing value (either scheduled, unscheduled or 
repeat) before the participant receives the first dose of study drug, unless otherwise specified.  
6.2.4 Early Termination Assessments 
Early termination assessments will not be summarized. Early termination assessments will appear 
in the listings as recorded.  
6.2.5 Spirometry Assessments 
Raw spirometry data will be provided by an external data vendor and this data will be used for 
analyses. The vendor will identify the best value out of 5 attempts at each visit and the best value 
will be taken for summary and analysis.  
 
 
    
 
  
 
   
 
 
 
 
   
6.2.6 GAP Index and Staging System 
The GAP index and staging system is a multidimensional prognostic staging system derived from 
four commonly measured clinical and physiologic variables (Gender, Age and two lung 
physiology variables (FVC and DLCO)2. Points are allocated to each clinical or physiological 
variable and points are summed to provide a total score (from 0-8).  The total score is then used to 
assign a stage (I, II, or III) as follows:  


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GAP Scoring 
Predictor 
Points Allocated 
Gender 
Female =  0 
Male =  1 
Age 
≤60 =  0 
61 −65 =  1 
> 65 =  2 
Physiology - FVC, % Predicted 
> 75 =  0 
50 −75 =  1 
<  50 =  2 
Physiology - DLCO, % Predicted 
> 55 =  0 
36 −55 =  1 
 ≤35 =  2 
*Cannot perform =  3 
Total Point Score 
0-8 
*’Cannot perform’ is only assigned if symptoms or lung function prohibited performance of the DLCO 
maneuver. If DLCO is unavailable for a non-respiratory reason (e.g., an operational reason), the GAP 
index and staging system cannot be applied.   
Staging System 
Stage 
I 
II 
III 
Points 
0-3 
4-5 
6-8 
6.2.7 Study Day 
Study day will be calculated as the number of days from first dose of study drug.  
• date of event – date of first dose of study drug + 1, for events on or after first dose  
• date of event – date of first dose of study drug, for events before first dose  
6.2.8 Unscheduled Visits 
Only scheduled post-baseline values will be tabulated. Post-baseline repeat / unscheduled 
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6.2.9 Conventions for Missing and Partial Dates 
All rules explained below for partial / missing dates will be followed unless contradicted by any 
other data recorded on the electronic Case Report Form (eCRF). 
All dates presented in the individual participant listings will be as recorded on the eCRF (i.e., not 
completed as per the below rules). 
6.2.10 Missing / Partial Start / Stop Date of Adverse Events, Medical History 
and Concomitant Medications 
Missing and partial start dates will be imputed solely for the purpose of determining whether an 
AE is treatment-emergent, medical history is ongoing at Screening, or a medication is concomitant 
to study treatment.   
Partial or missing stop date will be imputed as follows: 
If the stop date is completely missing and the event has resolved, or the participant has stopped 
taking the concomitant medication, the stop date will be imputed as the date of the participant’s 
last clinic visit in the study. 
• If only the year is known, the stop date will be imputed as “31-Dec” of that year or as the 
date of the participant’s last clinic visit in the study if in the same year. 
• If the month and year are known, the stop date will be imputed as the last day of that month 
unless the stop date corresponds to the same month as the participant’s last clinic visit in 
which case the date of participant’s last clinic visit in the study will be used instead. 
Missing start date will be imputed as follows: 
• If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, the start date will be imputed as the date of the first dose of study 
drug.  
• If the stop date occurs before the start of study drug, the start date of the event / concomitant 
medication will be imputed as the participant’s screening date or the stop date of the event 
/ concomitant medication whichever the earlier. 
Partial start date (year present, but month and day missing) 
• If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, and the year is the same as the year of first dosing the start date will 
be imputed as “01-Jan” of the same year or the date of the first dose of study drug 


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whichever is latest. If the year is different from the year of first dosing “01-Jan” will be 
used. 
• If the stop date occurs before the start of study drug, the start date of the event / concomitant 
medication will be imputed as the “01-Jan” of the same year. 
Partial start date (month and year present, but day missing) 
• If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, the start date will be imputed as the first day of the same month and 
year unless this partial start date is in same month as the first dose of study drug in which 
case the date of first dose of study drug will be used.  
• If the stop date occurs before the start of study drug, the start date will be imputed as the 
first day of the month and year of the partial stop date. 
If the start time is missing it will be imputed only in the case where the start date of the concomitant 
medication / event corresponds to the date of the first dose of study drug. The time will be imputed 
as the same time as the first dose of study drug. In all other cases the time will not be imputed. 
6.2.11 Date of Last Dose of Study Drug 
Date of Last Dose will be recorded at the Study Completion/Termination visit, if different from 
the from Date of Completion/Termination.  If Date of Last Dose is not present, the Date of 
Completion/Termination will be taken as Date of Last Dose for calculation of study drug exposure.   
6.2.12 Exposure to Study Drug  
Exposure to study drug will be calculated as follows from the date of last dose (or the date of 
completion/termination if not present) minus the date of first dose + 1. The exposure calculation 
will not take into account breaks in therapy. 
Duration of exposure (in days) will be calculated as follows:  
• Date of Last Dose (or the Date of Completion/Termination if not present) of study drug 
(irrespective of dose) – Date of First Dose of study drug + 1 
6.2.13 Study Drug Compliance 
Study drug compliance will be calculated by comparing the amount of drug dispensed and drug 
returned for each participant as follows:   




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6.2.15 Inexact Values 
In the case where a variable is recorded as “> x”, “≥ x”, “< x” or “≤ x”, a value of x will be taken 
for analysis purposes.  
 
 
 
.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
   


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6.2.20 Determination of FVC outliers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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6.3 
Conventions 
6.3.1 Medical Coding 
Adverse events and medical history will be coded using the Medical Dictionary of Regulated 
Activities (MedDRA) Version 24.1 (or higher). Conditions will be assigned to a System organ 
class (SOC) and preferred term (PT) based on the Investigator-reported verbatim term.  
Any medications taken (other than study drug) will be coded using the World Health Organization 
Drug Dictionary (
) September 2021 Version (or higher).  Medications (both prior and 
concomitant) will be assigned to an Anatomical Therapeutic Chemical (ATC) Level 4 drug 
classification and Preferred Name based on the medication name reported on the eCRF.  
6.3.2 Data Handling 
All clinical data programming will be performed using 
 
 
 and based on Clinical Data Interchange 
Standards Consortium (CDISC) data standards.   
Study Data Tabulation Model (SDTM) programming will follow SDTM version 1.7 together with 
SDTM implementation guide 3.3. Analytical Data Model (ADaM) programming will follow 
ADaM implementation guide 1.1. Specifications for SDTM and ADaM datasets are described in 
a separate document. 
6.3.3 Validation Methods 
All programming of datasets and outputs will be validated by fully independent double 
programming of values and manual review of format compared to the SAP and agreed shell 
template.   Figures will be validated by manual review of format and visual inspection of graphical 
display compared to tabulated data. All tables, figures and listings will be reviewed by a statistician 
prior to each milestone delivery.   
6.3.4 Summary Statistics 
Continuous variables will be summarized by the number of non-missing observations, mean, 
median, standard deviation, and minimum and maximum.  


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Categorical variables will be summarized by presenting the frequency and percent. Percentages 
will be based on the number of non-missing observations or the participant population unless 
otherwise specified. For each variable, all categories will be shown. Zero frequencies (but not the 
percent) within a category will be presented.  
Incidences of adverse events, medical history and concomitant medications will be reported at the 
participant level. Participants can only be counted once within each PT and SOC under the highest 
severity and most related.  Percentages will be calculated using the number of participants in the 
treatment group for the Safety Population. 
6.3.5 Decimal Places 
For summary statistics, n will be reported as a whole number. Means, medians and percentiles will 
be displayed to one more decimal place than the data, dispersion statistics (e.g., standard deviation) 
will have two more decimal places, and the minimum and maximum will be displayed to the same 
number of decimal places as reported in the raw data. Percentages will be displayed with one 
decimal place. All data presented in the individual participant listings will be as recorded on the 
eCRF.  
6.3.6 Data Displays 
All clinical data tabulations, figures and listings will be generated as individual Rich Text Format 
(.rtf) files using 
)1. Data summaries and graphical analyses will be 
reported within Section 14 of the CSR and individual participant data listings within 
Appendix 16.2 of the CSR.  
Participant disposition, baseline characteristics, demographic, compliance, concomitant 
medication, and adverse event data will be presented by treatment group and overall.  Other safety 
data will be presented by treatment group only.   
Please note: Data from study Part A will be listed only.  
Treatment group labels will be displayed as follows:  
PLN-74809  
(40 mg) 
(N=XX) 
PLN-74809  
(80 mg) 
(N=XX) 
PLN-74809  
(160 mg) 
(N=XX) 
PLN-74809  
(320 mg) 
(N=XX) 
All  
PLN-74809  
(N=XX) 
 
Placebo 
(N=XX) 


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Listings will be sorted in the following order, study part (Parts B/C/D/A), treatment group, 
participant number, parameter, and visit unless otherwise stated. All data will be listed, participants 
who were not randomized will be displayed after the randomized treatment groups.  
6.4 
Participant Disposition 
Participant disposition will be summarized by treatment group and overall, for the Safety 
Population as follows:  
• The number of participants entering the study. 
• The number of participants in each analysis population. 
• The number of participants completing study treatment.  
• The number of participants not completing study treatment and reason for non-completion 
of study treatment.  
• The number of participants completing the study.  
• The number of participants with early termination and the reasons for early termination.  
• The reasons for exclusion from the Efficacy Per-Protocol Population will be listed.  
6.5 
Protocol Deviations 
All reported protocol deviations (PD) will be summarized by treatment group, PD category and 
PD classification (Major, Minor, and total) as well as listed.    
6.6 
Baseline Comparability 
Comparability of treatment groups with respect to participant demographics and baseline 
characteristics will be assessed in a descriptive manner, but no formal statistical testing will be 
performed.  
Baseline summaries will be presented by treatment group and overall, for the following variables 
based on the Safety Population:  
Demographic Data 
• Age at Informed Consent (years) 
• Sex 
• Ethnicity 


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• Race, where more than one race is selected the participant will be presented under the 
‘Multiple races’ category in the summary but each selected race will be identified in the 
listing.  
Baseline Characteristics 
• Weight at Screening (kg) 
• Height at Screening (cm) 
• BMI at Screening (kg/m2) 
• Fertility Status (Childbearing Potential, Postmenopausal, Surgically Sterile) 
• Participant taking nintedanib or pirfenidone at Screening 
Clinical Characteristics 
• Pulmonary Function at Screening 
• Pulmonary Function at Baseline 
• DLCO Lung Function Assessment at Screening (if repeated, the last non-missing value 
before first dose will be taken) 
• GAP Index Score and Staging 
• Duration Since Diagnosis at Screening (first date reported for Idiopathic Pulmonary 
Fibrosis, Pulmonary Fibrosis or Interstitial Lung Disease) 
• Duration of Standard of Care at Randomization (defined as the number of months from 
start date of nintedanib or pirfenidone to date of randomization) 
Additional summaries will be completed for Part D only participants as well as placebo 
participants by study part.  
6.7 
Medical History 
Separate tabulations of prior and ongoing conditions at screening will be presented by treatment 
group and overall, for the Safety Population. All reported medical history data will be listed.  Non-
pharmacological procedures will be provided as a separate listing.  




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The number and percent of participants showing a relative decline in FVC (% Predicted) of ≥5% 
and ≥10% over the first 12 weeks will also be provided for each treatment group. 
A categorical summary of participants by FVC change relative to baseline (increase/ decrease) will 
be provided for Part D participants at Weeks 12 and 24. 
A mixed model for repeated measures (MMRM) will also be utilized to analyze the change from 
baseline to each post-baseline visit in FVC (mL).   
The MMRM model will 
 
 
 
 
 
  
The LS means, corresponding SEs, and 95% CI for each treatment group at each visit will be 
obtained from the model.  An estimate for the LS mean difference (PLN-74809 vs. placebo), 
corresponding SE, 95% CI, and p-value for each dose group at each visit will also be presented. 
Separate MMRM analyses 
 
 
 will be provided showing all available data (scheduled and unscheduled) for each 
individual participant over the study for the parameters listed below.  One panel will be displayed 
per treatment group.   
Plots will also be provided showing mean (± SD) for all treatment groups at each scheduled visit 
for all parameters.  Each treatment group will be identified using different plot symbols. Plots will 
be shown for actual values, change from baseline and percent change from baseline.  Baseline will 
be set to zero for change from baseline plots.   
Spirometry parameters to be summarized by treatment group and visit include: 
• FVC (mL) Actual 
• % FVC Predicted 
• 
 
• 
 


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All spirometry data will be listed.    
Sensitivity Analyses: 
The MMRM will be repeated in the 
 
 as sensitivity analyses.  In addition, a sensitivity analysis will be conducted 
using the 
 
 
A trimmed mean analysis trimming the participants 
 
 will also be conducted for Part D participants. 
In addition, FVC will be summarized using descriptive statistics by the following treatment groups 
at baseline and Week 12 for the Efficacy Intent-to-Treat Population: 
• 
 
 
 
  
 
 
 
Actual values, the changes from baseline and the percent changes from baseline will be presented 
along with 95% confidence intervals (CI) for the mean changes and mean percent change from 
baseline.  
The two comparisons below will be performed via the MMRM on (a) FVC change from baseline 
at each visit, and (b) FVC percent change from baseline at each visit. Additionally, 
 
 
 will test  (a) FVC Week 12 change from baseline endpoint, and (b) FVC week 12 
percent change from baseline :  
 
 
 
 
As a further exploratory analysis, 
 will be utilized to analyze the change 
from baseline to Week 12 in FVC between subjects in each of the treatment group selections above, 
as well as in Part D alone (not pooled). 


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6.11.1 Patient-Reported Cough 
Descriptive statistics for the patient-reported VAS for cough and change from baseline will be 
summarized by treatment group and visit for the Safety Population.  The number and percent of 
participants with VAS ≥ 40 at Baseline and reduction in VAS of ≥ 30 at Week 12 (as described in 
3) will also be provided by treatment group.  Mean (± SD) change from 
baseline will also be presented graphically by treatment group.  All collected VAS data will be 
listed.   
6.11.2 Quantitative Lung Fibrosis 
Collection data for HRCT scans performed will be listed. Analysis of QLF (assessed by HRCT) 
will be described in a separate analysis plan.   
6.12 Pharmacokinetic Analyses 
6.12.1 Concentration-Time Data 
In study Parts B and C, plasma samples will be taken 
 
relative to PLN-74809 dosing on 
 In study Part D, plasma 
samples will be taken 
 relative to PLN-74809 dosing on 
  
Concentration data will be obtained for PLN-74809 
 
   
 PLN-74809 concentration 
 will be calculated as follows: 
 
  
 
 
 
PLN-74809 concentration data (
) will be summarized by dose 
level and visit at each scheduled sample time (nominal time) using descriptive statistics: number 
of non-missing observations (n), arithmetic mean (mean), standard deviation (SD), median, 
minimum (min), maximum (max), and coefficient of variation (CV%). Scatter plots will also be 
provided showing mean (SD). Similarly, 
 will be 


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Page 28 of 43 
summarized. Concentrations that are below the limit of quantification (BLQ) will be set to zero 
for summary statistics. BLQ concentrations will be retained as BLQ in listings. The data will be 
reported to 3 significant figures.  
Individual PLN-74809 
 
), nintedanib, and pirfenidone 
concentration data will be provided in listings. Data may be pooled with data from other studies 
for population PK and reported outside of the clinical study report. 
6.12.2 PK Parameters 
Not applicable.    
6.13 Pharmacodynamic Analyses 
Biomarker results obtained from urine, plasma or serum samples will be summarized using 
descriptive statistics by treatment group and visit for each parameter. Actual biomarker 
concentration at each visit, the change from baseline and percentage change from baseline will be 
presented. The result adjusted for dilution factor will be used in summaries and listings. Samples 
hemolyzed, received ambient or with a note indicating improper storage will be excluded from 
summaries and listed only. If a sample has been excluded, then the change from baseline for that 
sample will also not be calculated.  
Actual biomarker concentrations will be presented as a line plot showing the mean (± SD) 
concentration at each visit by treatment group for each parameter.   
For biomarkers with at least 2 post-baseline scheduled assessments, absolute change from baseline 
and percentage change from baseline will be presented as a line plot showing baseline (0) and the 
mean (± SD) concentration at each post-dose visit by treatment group for each parameter.   
For biomarkers with only one post-dose scheduled assessment, absolute change from baseline and 
percentage change from baseline will be presented by box and whisker plot for each treatment 
group.    
Change from baseline to each visit will also be analyzed for all biomarkers using an MMRM 
 
 
 LS means (±SE) for each treatment group and estimate for treatment difference 
compared to placebo, with corresponding SE, 95% CI and p-value will be provided .   


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6.14 Pharmacogenomic Analyses 
Pharmacogenomic sampling data will be listed only. Future cross-study pharmacogenomic 
analyses will be described in a separate analysis plan.   
6.15 Safety Analyses 
Safety analyses will be presented by the treatment received for the Safety Population. 
6.15.1 Adverse Events 
AE analyses will be presented by the treatment received for the Safety Population. Tabulations 
will be presented overall and by SoC (Yes, No).   
AEs will be collected from the time of informed consent through completion of the participant's 
last study visit.   
A treatment emergent adverse event (TEAE) is defined as: 
• Any AE that has an onset on or after the first dose of study drug through completion of the 
last study visit.  
• Any pre-existing AE that has worsened in severity on or after the first dose of study drug 
through completion of the last study visit.  
AEs occurring prior to first dose are considered non-treatment emergent and will be listed only.   
The Investigator will determine the relationship of the AE to treatment (Related, Not Related). If 
an AE has missing relationship it is assumed to be related to the study drug for analysis purposes.  
Severity of the AE will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) grading system (Version 5.0): Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe), 
Grade 4 (Life-Threatening), Grade 5 (Fatal).  Grade 3 (Severe) will be assumed for an AE with 
missing grade.  
An overall summary of AEs (incidence and number of events) will be presented by treatment group 
and overall, for the following:   
• Any AE 
• TEAE 
• TEAE Related to Study Drug 


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• TEAE Related to a Study Procedure 
• Serious TEAE 
• Serious TEAE Related to Study Drug 
• TEAE of CTCAE Grade 3 or Higher 
• TEAE of CTCAE Grade 3 or Higher Related to Study Drug 
• TEAE Leading to Interruption of Study Drug 
• TEAE Leading to Withdrawal of Study Drug 
• TEAE Leading to Early Termination from Study 
• TEAE Leading to Death  
Summaries of TEAEs (incidence and number of events) will be presented by SOC and PT, by 
treatment group and overall, for the following:   
• TEAE 
• TEAE Related to Study Drug 
• Serious TEAE 
• Serious TEAE Related to Study Drug 
• TEAE Related to a Study Procedure 
• TEAE of CTCAE Grade 3 or Higher 
• TEAE of CTCAE Grade 3 or Higher Related to Study Drug 
• TEAE Leading to Interruption of Study Drug 
• TEAE by SOC, PT and Maximum Grade (incidence only) 
• 
 
 
The following listings of TEAEs will be presented in Section 14.3.2 of the CSR.  
• TEAE Leading to Withdrawal of Study Drug 
• TEAE Leading to Early Termination from Study 
• TEAE Leading to Death  
• Serious TEAE 
In addition, listings of all reported AEs and SAEs will be provided in Appendix 16.2.7 of the CSR.  
 
 
   




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• Pulse oximetry (%) 
 
All vital sign data will be listed.  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
6.15.5 Physical Examination 
Shift tables for the observed change in status of each of the body systems, i.e., Normal, Abnormal 
NCS (Not Clinically Significant), and Abnormal CS (Clinically Significant) from baseline to each 


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follow-up visit will be tabulated by treatment group.  All data, including details of clinically 
significant findings will be listed.  
7 
INTERIM ANALYSIS 
Interim analyses will be conducted at the following milestones:  
• Upon completion of Parts B and C (following full enrollment and 12-week treatment 
duration with 40, 80, or 160 mg PLN-74809).  
• Upon completion of 12-week treatment duration with 320 mg PLN-74809 in Part D.  
A database freeze will occur upon completion of study Part C by the last participant. All data for 
study part A, B and C will be 100% cleaned and signed off by the investigators. After database 
freeze, participants will be unblinded and these data will be used for the statistical analysis and 
reporting of Parts A, B and C.  
Blinding measures for interim analyses performed on data up to Week 12 for all participants in 
Part D will be described in a separate blinding plan.  
Interim data from Part D will include all assessments up to the Week 12 assessments, 
 
  Adverse events or concomitant medications started/initiated post Day 
will 
not be summarized in the in the interim analysis and will be presented in the final analysis.   
Participants who discontinue treatment or the study post the Week 12 assessment date up to Day 
 will be summarized as on treatment/on study for the purposes of the interim analyses. 
8 
DATA SAFETY MONITORING BOARD ANALYSIS 
Data Safety Monitoring Board (DSMB) analyses 
 will be performed by an external 
vendor.    
9 
CHANGES TO PLANNED PROTOCOL ANALYSIS 
1. Adverse event summaries and efficacy assessments will be presented overall and 
 
   
2. Change from Baseline at Week 12 in efficacy assessments will also be presented by 
 
   


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3. 
 
   
4. A mixed model for repeated measures 
 
.   
5. Definition of Efficacy Per Protocol Population was revised from:  
 
 
 
  
6. Removed CTCAE grading summaries for laboratory test parameters. 
 
 
8. Added additional pooled placebo groups for comparison purposes. 
10 REFERENCES 
1.