A Phase IIa, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of INS018_055 Administered Orally to Subjects With Idiopathic Pulmonary Fibrosis (IPF)
Phase: PHASE2
Conditions: Idiopathic Pulmonary Fibrosis (IPF)
Sponsor: InSilico Medicine Hong Kong Limited

 
 
 
Clinical Study Protocol 
 
 
Protocol No.: INS018-055-003 
Official Title of Study: A Phase IIa, Randomized, Double-Blind, Placebo-Controlled 
Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of 
INS018_055 Administered Orally to Subjects With Idiopathic Pulmonary Fibrosis (IPF) 
NCT Number: NCT05938920 
 

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INS018_055 Phase IIa Protocol
Protocol No. INS018-055-003
Version/Date: V4.0, 02 Feb 2024
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Investigator Protocol Agreement Page
I have carefully read this study protocol and agree that it contains all necessary information 
required to conduct this study. I agree to conduct the study according to this protocol 
(including any amendments) and in accordance with clinical sites Standard Operating 
Procedures, International Council for Harmonization Good Clinical Practice, all other 
applicable regulations, and the recommendations laid down in the most recent version of the 
Declaration of Helsinki.
Signature of Principal Investigator
Date
Printed Name of Principal Investigator

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Protocol No. INS018-055-003
Version/Date: V4.0, 02 Feb 2024
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SUMMARY OF REVISIONS
Document
Version and 
Date
Key Changes
Rationale
Amendment 
version
3.0
02Feb2024
Page 7, update the estimated total 
number of randomized patients.
To ensure approximately 60 
patients completing treatment 
during the study.
Page 74, Section 5.8. add the 
following language for 
clarification:
...only data from acceptable 
spirometry maneuvers will be 
used for eligibility confirmation 
and data analysis. For baseline 
and EOT visits, if multiple 
acceptable spirometry results are 
reported for one visit, mean values 
of the acceptable results will be 
used for data analysis. For 
detailed information, refer to the 
statistical analysis plan
Clarification of spirometry data 
management method.
Page 77-78, Section 5.12, add the 
following language:
In addition, high-throughput 
proteomic analysis will be 
performed to further explore the 
mechanism of action of 
INS018_055 in IPF patients. 
Add high-throughput proteomic 
analysis as a method for 
exploratory endpoints.
Page 103, Section 10.3, update the 
format of Borg Scale CR10 form
Update the Borg Scale CR10 form 
to be consistent with the 
purchased copyrighted version.

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CLINICAL TRIAL PROTOCOL
Protocol Number
INS018-055-003
InSilico Investigational 
Medicinal Product
INS018_055 capsule
Title
A Phase IIa, Randomized, Double-Blind, Placebo-Controlled     
Study Evaluating the Safety, Tolerability, Pharmacokinetics, and 
Efficacy of INS018_055 Administered Orally to Subjects with 
Idiopathic Pulmonary Fibrosis (IPF)
Lay Title
A study to test INS018_055 safety and how taking INS018_055  
over 12 weeks affects the lung function of adults with idiopathic 
pulmonary fibrosis 
Sponsor
InSilico Medicine Hong Kong Limited
Unit 310, F3, Building 8W, Phase 2, Hong Kong Science Park, 
Pak Shek Kok, New Territories, Hong Kong
Study Phase
IIa
Study Sites
About 30 sites in China
Indication
Idiopathic pulmonary fibrosis 
Version and Date
4.0
Date: 02Feb2024
Proprietary confidential information
© 2022 InSilico Medicine or one or more of its affiliated companies. All rights reserved. 
This document may not - in full or in part - be passed on, reproduced, published or otherwise 
used without prior written permission.

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Protocol No. INS018-055-003
Version/Date: V4.0, 02 Feb 2024
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PROTOCOL SYNOPSIS
Company Name
InSilico Medicine Hong Kong Limited
Protocol version 1.0 
Date
04Nov2022
Version 2.0 Date
28Dec2022
Version 2.2 Date
08May2023
Version 3.0 Date
18Aug2023
Version 4.0 Date
02Feb2024
Protocol Number
INS018-055-003
Study Title
A Phase IIa, Randomized, Double-Blind, Placebo-Controlled         
Study Evaluating the Safety, Tolerability, Pharmacokinetics, and 
Efficacy of INS018_055 Administered Orally to Subjects with 
Idiopathic Pulmonary Fibrosis (IPF)
Study Site(s)
Multicenter trial at an estimated 30 sites in China
Clinical Phase
IIa
Study Rationale
The purpose of this study is to demonstrate safety and proof of 
concept for clinical activity of INS018-055 on change in forced 
vital capacity (FVC) over 12 weeks in adults with idiopathic 
pulmonary fibrosis (IPF). IPF is a fatal lung disease characterized
by reduced quality of life and a median survival of 3 to 4 years. 
While current standard of care (SoC) treatments including 
pirfenidone and nintedanib slow disease progression, they are not 
curative and poorly tolerated due to their toxicity profiles. To 
address the need for new treatments in IPF, InSilico Medicine is 
developing INS018_055, a potent inhibitor of the serine/threonine 
kinase Traf2- and Nck-interacting kinase (TNIK). INS018_055 
modulates the Wnt signaling pathway and engages other          
IPF-related signaling pathways. Wnt signaling is consistently 
identified as a major signaling cascade that significantly 
contributes to the pathogenesis of lung fibrosis. Therefore, TNIK 
is a clinically meaningful therapeutic target and INS018_055 
could potentially address the unmet need in IPF for novel 
treatments.
Study Objectives
Primary Objective:
To evaluate the safety and tolerability of INS018_055 orally 
administered for up to 12 weeks in adult patients with IPF 
compared to placebo
Secondary Objectives:

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To evaluate the pharmacokinetics (PK) of INS018_055 orally 
administered to subjects with IPF 
To evaluate the efficacy of INS018_055 orally administered 
for up to 12 weeks of treatment on FVC decline in adult 
subjects with IPF compared to placebo
To evaluate the efficacy of INS018_055 orally administered 
for up to 12 weeks of treatment to improve quality of life 
(QoL) and functional measures compared to placebo 
To evaluate the impact of INS018_055 orally administered 
on acute IPF exacerbations compared to placebo
Exploratory Objective:
To explore the impact of INS018_055 on IPF disease-related 
biomarkers in the blood
To explore the potential mechanism of action of INS018_055 
in IPF patients
Study Endpoints
The primary endpoint is the percentage of patients who have at 
least 1 treatment-emergent adverse event (TEAE).  
The secondary endpoints are PK parameters, change in FVC (mL 
and % predicted), change in diffuse capacity of the lungs for 
carbon monoxide (DLCO %) predicted, change in Leicester 
Cough Questionnaire, change in 6-minute walk test (6MWD), 
number of acute IPF exacerbations, and number of hospitalization 
days for acute exacerbations.
Study Design
Randomized, double-blind, placebo-controlled, parallel-group 
design of 4 groups over 12 weeks
Total Number of 
Patients Randomized
Approximately 70 (approximately 60 to complete treatment)
Number of Patients 
on Each Treatment
Approximately 15
Diagnosis
Idiopathic pulmonary fibrosis 
Key Study Criteria
All inclusion criteria and no exclusion must be met for study 
enrollment. See detailed list in section 3.3.2 (inclusion criteria) 
and section 3.3.3 (exclusion criteria).
Key inclusion criteria:
Patients aged > 40 years at screening
Diagnosis of IPF confirmed by site investigator

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Pre-bronchodilator FEV1/FVC ratio > 0.7 (absence of 
relevant airway obstruction)
Ability to walk > 150 meters for 6MWD at Visit 1
Either stable treatment with background SoC pirfenidone or 
with SoC pirfenidone or nintedanib discontinued for > 4 
weeks prior to Visit 1
Subjects who have previously never received SoC treatment
with pirfenidone or nintedanib are eligible to participate 
provided they meet all other eligibility criteria and have 
discussed all SoC treatment options with their physician 
Compliance with study protocol
Key exclusion criteria:
Investigator-determined clinically significant airway disease 
that could impact study objectives
Acute IPF exacerbation < 4 months prior to Visit 1 and/or 
during the screening period
Upper or lower respiratory tract infection that has not fully 
resolved within 4 weeks prior to Visit 1 and/or before Visit 2 
(Day 1). (section 3.3.3)
COVID-19: RT-PCR-confirmed or rapid antigen test
confirmed infection at Visit 1or at Visit 2; vaccine within the 
last 7 days of Visit 2; severe infection requiring 
hospitalization within the last 6 months of screening; 
symptoms > 12 weeks of acute infection (Long COVID-19)
Current smoker or prior smoker with nicotine or tobacco use 
< 3 months prior to Visit 1
Unstable cardiac angina or myocardial infarction < 6 months 
prior to Visit 1
Documented active or suspected malignancy or history of 
malignancy < 5 years prior to Visit 1, except appropriately 
treated basal cell carcinoma of the skin, in situ carcinoma of 
the uterine cervix, or prostate cancer under surveillance
Significant trauma or major surgery < 3 months prior to Visit 
1
Medications: 
-Concurrent treatment with nintedanib and pirfenidone is not 
allowed during the study unless the patients have had a stable 
treatment with one of them for 8 weeks prior to visit 2
-Current oral corticosteroids > 15 mg prednisone daily (or 
equivalent) or combination of prednisone, azathioprine, and 

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N-acetylcysteine, ambrisentan, or imatinib < 30 days prior to 
Visit 2
-Current moderate or strong CYP3A4 inhibitors/inducers, 
moderate or strong CYP1A2 inhibitors/inducers, or 
medications primarily metabolized by CYP3A4 or CYP1A2
-Current enrollment or prior participation in interventional 
clinical studies < 30 days or 5 half-lives of investigational 
therapy (whichever is longer) prior to Visit 1
Investigator-determined medical or psychological condition 
that might create undue risk or interfere with study 
compliance, including but not limited to pulmonary 
hypertension, active lung transplantation registration, 
uncontrolled hypertension, laboratory values (e.g. BMI, 
AST/ALT, total bilirubin, eGFR, QTc), known 
hypersensitivity or contraindications to INS018_055 or its 
class, pregnant or lactating, substance abuse, chronic liver 
disease, HIV+ history, active HCV, active HBV, or other 
active infection 
Investigational 
product(s)
INS018_055 capsule
     Dose(s)
30 mg QD or 30 mg BID or 60 mg QD (maximum 60 mg daily):
30 mg QD INS018_055      
30 mg BID INS018_055      
60 mg QD INS018_055
  Administration
Oral
Comparator 
product(s)
Placebo
     Dose(s)
Matching placebo 
     Administration
Oral
Duration of 
Treatment
12 weeks
Statistical Methods
Safety Population: The safety population will include all subjects 
who receive > 1 dose of study treatment.
ITT Population: The intent-to-treat (ITT) population will include 
any randomized subjects.
PK Population: The PK population will include subjects who 
receive > 1 dose of study treatment and have a majority of 

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scheduled PK samples drawn that allow for PK parameters to be 
generated. 
Per Protocol (PP) Population: The PP population will exclude 
non-evaluable subjects and subjects with major protocol 
deviations thought to impact the ability to assess the effect of 
study treatment. The criteria for excluding subjects from the PP 
population will be specified in the Statistical Analysis Plan 
(SAP).
A formal sample size calculation based on statistical power 
considerations will not be performed. However, given an 
approximate sample size of 15 subjects per treatment arm, there 
exists a 90% probability of observing > 1 AE if the true 
population rate is approximately 15%, which will be sufficient to 
assess the feasibility of safety parameters.
Demographic and Baseline Characteristics:
The ITT population will be used for summary of demographic 
and baseline characteristics. Demographic characteristics (e.g.,
age, sex, ethnicity, race, etc.) and screening clinical 
characteristics (e.g., vital signs, physical examination, etc.) will 
be summarized using descriptive statistics [number of patients 
(n), mean, standard deviation (SD), median, minimum (min), and 
maximum (max)] for continuous variables, and using counts (%) 
for categorical variables. Baseline laboratory results will be 
summarized overall and by treatment arm using descriptive 
statistics. Additionally, the proportion of subjects on antifibrotic 
or not on antifibrotic therapy at the time of randomization for 
each treatment arm will be summarized.
Safety Endpoints:
All safety analyses will be performed on the safety population.
The analysis of safety endpoints, including AEs, SAEs, TEAEs 
and AEs of interest (coded using the Medical Dictionary for 
Regulatory Activities [MedDRA®]), will be summarized by 
System Organ Class, Preferred Terms, and their maximum 
severity based on CTCAE v5.0 grade for all treated subjects. 
Clinical laboratory tests, physical examination, ECGs, and vital 
signs will be summarized or tabulated by treatment arm and visit, 
and will also be presented in shift tables. 

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SCHEDULE OF STUDY ACTIVITIES 
The table below shows the overall order of procedures by visit.  See section 5.1 for details 
about order of procedures within each visit. 
Trial Period
Screeninga
Treatment Periodb
Follow-up 
Visit Number
1
2
3
4
5
6 
(EOT)
7
(EOS)
Study Week
0
2
4
8
12
13
Study Day
-30 to 0
1
15
29
57
85
92
Visit Window (days)c
-
-
± 3
± 7
± 7
± 7
+10
Informed consentd
X
Demographics
X
Medical history
X
HRCTe
X
HBV, HCV, HIV, 
syphilis testingf
X
Height
X
Spirometry (FEV1, 
FVC)g
X
X
X
DLCOh
X
X
X
6MWD
X
X
X
SARS-CoV-2 testingi
X
X
Assess eligibility 
criteria
X
X
BMI
X
X
X
12-lead ECGj
X
X
X
X
X
X
Physical examinationk
X
X
X
X
X
X
X
Vital signsl
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
Pregnancy testingm
X
X
X
X
X
X
X
Safety laboratory 
testsn,o
X
X
X
X
X
X
X
Urinalysisp
X
X
X
X
X
X
X
Adverse eventsq
X
X
X
X
X
X
X
Prior and concomitant 
medications
X
X
X
X
X
X
X
Randomization
X
LCQr
X
X
X
X
Pharmacokinetic (PK) 
samplings
X
X
X
X
X

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Trial Period
Screeninga
Treatment Periodb
Follow-up 
Visit Number
1
2
3
4
5
6 
(EOT)
7
(EOS)
Study Week
0
2
4
8
12
13
Study Day
-30 to 0
1
15
29
57
85
92
Visit Window (days)c
-
-
± 3
± 7
± 7
± 7
+10
Dispense study drug
X
X
X
X
Self-administer study 
drugt
------------------------X-----------------------
Subject study diaryu
------------------------X-----------------------
IPF biomarker (PD) 
sampling (blood, pre-
dose)v
X
X
X
X
X
PK of SoC therapyw
X
X
X
X
X
Acute IPF 
exacerbationsx
X
X
X
X
X
X
Drug accountability 
and compliancey
X
X
X
X
Completion of patient 
participation
X
a Screening (Visit 1) should be conducted up to 30 days prior to Visit 2 (randomization), with time allowed for 
central review of HRCT (performed during the screening period or within the last 12 months) or surgical 
lung biopsy to confirm eligibility (if HRCT is equivocal). This period may be extended up to 44 days in 
case of administrative issue (e.g. result from HRCT is not available). If Visit 1 cannot be performed in this 
extended timeframe, the patient will have to be considered a screen fail.
b Subjects who discontinue study medication will be asked to attend all study visits as originally planned in 
order to minimize missing data. If subject declines, all activities scheduled for the EOT visit (Visit 6) 
should be performed if possible. The last morning dose in the study is considered the last study dose. All 
subjects will be asked to return all unused medication at Visit 6/EOT.
c All efforts should be made to maintain protocol-defined visit windows. If an extenuating circumstance arises 
preventing this, the Sponsor and/or designee should be consulted. If the Sponsor and/or designee 
determines that the scientific integrity of data and patient safety would not be compromised, an out-of-
window visit may be permitted.
d Informed consent must be obtained before study-related procedures are performed, including HRCT review. 
All AEs will be recorded from the signing of the ICF. All non-serious ongoing AEs that occurred prior to 
the time of first dose will be captured as medical history.
e Central review of HRCT will be performed. A historical HRCT performed within 12 months of screening 
(Visit 1) should be evaluated for eligibility. If an HRCT performed within the last 12 months is not 
available or does not meet required image acquisition specifications and the patient meets all other 
eligibility criteria, HRCT should be performed during the screening period.
f Including HBsAg, anti-HCV, hepatitis B viral load DNA, and hepatitis C viral load RNA (if applicable), anti-
HIV-1, anti-HIV-2, and syphilis. Patients who are known to be hepatitis B surface antigen (HBsAg) 
negative, hepatitis B core antibody (HBcAb) positive will undergo hepatitis B viral load DNA by PCR. 
Patients who are known to be hepatitis C virus (HCV) antibody positive must undergo hepatitis C viral load 
RNA by PCR.

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g Spirometry results to be reviewed centrally to meet American Thoracic Society-European Respiratory Society 
criteria 2019 guideline. Order of lung function measurements: 1. Spirometry followed by patient rest; 2. 
DLCO. 
h DLCO % predicted to be corrected for hemoglobin level and conducted with equipment at each study site, 
carried out according to international guidelines. 
i SARS-CoV-2 testing to be performed at screening (Visit 1) and prior to randomization at Visit 2. Both SARS-
CoV-2 RT-PCR testing and rapid antigen test are acceptable.
j All ECGs will be performed pre-dose.
k A complete physical examination will be completed at screening and symptom-specific physical examinations 
will be completed for other visits.
l Measurements of vital signs should precede blood sampling.
m Female with childbearing potential only: urine pregnancy test at each visit, except at Screening (Visit 1). 
Serum pregnancy test will be performed at screening visit.
n For laboratory parameters that initially do not meet eligibility requirements, a single retest within the 
screening period is permitted before subject is declared a screen failure.
o Safety laboratory parameters will be evaluated at each visit, pre-dose. This will include blood and urine. 
Serum chemistry analysis includes AST, ALT, AP, GGT, CK (CK-MB only if CK is elevated), glucose, 
creatinine, total bilirubin, direct and indirect bilirubin, total protein, albumin, hsCRP, BUN or urea, uric 
acid. Electrolyte analysis includes sodium, potassium, calcium, chloride, inorganic phosphate. Hematology 
includes hematocrit, hemoglobin, RBC count, reticulocyte count, WBC with differential (automatic WBC
differential includes the relative and absolute quantification of neutrophils, eosinophils, basophils, 
monocytes and lymphocytes). If automatic WBC differential is abnormal, manual WBC differential is 
advised to include polymorphonuclear neutrophils (segs), band neutrophils (stabs), eosinophils, basophils, 
monocytes and lymphocytes, platelet count, ESR. Lipid panel to include total cholesterol, triglycerides, 
LDL cholesterol, HDL cholesterol,. Coagulation panel includes aPTT, Prothrombin time (
INR), and fibrinogen. Hormone tests include thyroid stimulating hormone (TSH), fT3, fT4. eGFR by CKD-
EPI equation.
p Urinalysis to include qualitative/semi-quantitative, appearance, color, pH, specific gravity, glucose, 
erythrocytes, leukocytes, protein, urobilinogen, urine bilirubin.
q Acute IPF exacerbation will be defined as an acute, clinically significant, respiratory deterioration 
characterized by evidence of new widespread alveolar abnormality with all of the following: Acute 
worsening or development of dyspnea typically for < 1 month duration, CT scan with new bilateral ground-
glass opacity and/or consolidation superimposed on a background pattern consistent with IPF, deterioration 
not fully explained by cardiac failure or fluid overload. [Collard 2016] Events that are clinically considered 
to meet the definition of acute exacerbation but fail to meet diagnostic criteria due to missing CT data 
sh
r The Leicester Cough Questionnaire (LCQ) is a 19-item questionnaire that assesses cough related QoL. It has 3 
domains (physical, psychological, and social). The total score range is 3-21, and domain scores range from 
1-7; a higher score indicates a better QoL. The overall score for the LCQ for each subject is calculated by 
adding the individual domain scores. The LCQ will be self-administered by subjects at the indicated visits.
s Blood samples for plasma concentrations of INS018_055 and metabolites (INS018_063 and INS018_095) will 
be collected at time points according shown in section 10.4. Date and exact clock time of drug 
administration and blood sampling must be recorded on the eCRF. 
t Subjects will self-administer study medication. Site team will explain dosing schedule, provide study 
medication, and follow up with subjects. 
u Subjects will maintain a study diary throughout study. Site team will instruct subject to record precisely the 
time of drug intake.
v Including  evaluation of levels of MMP-7, MMP-2, MMP-9, TGF-beta, IL-6, TIMP-1, IL-1beta in blood 
samples and evaluation of blood proteome. 
w Blood samples for plasma concentrations of SoC therapy will be collected pre-dose (ie, prior to pirfenidone or 
nintedanib dosing), in order to get the trough plasma concentration of SoC therapy at Visit 2, 3, 4, 5, and 6.

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x Investigator-reported acute IPF exacerbations to be reported in the eCRF.
y Collect unused previously dispensed study drug at each visit

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Table of Contents
SUMMARY OF REVISIONS................................................................................................. 4
CLINICAL TRIAL PROTOCOL............................................................................................... 5
PROTOCOL SYNOPSIS ....................................................................................................... 6
SCHEDULE OF STUDY ACTIVITIES .................................................................................... 11
LIST OF TABLES............................................................................................................... 19
LIST OF FIGURES............................................................................................................. 20
ABBREVIATIONS............................................................................................................. 21
1
  INTRODUCTION .................................................................................................... 24
1.1
MEDICAL BACKGROUND ............................................................................................24
1.2
DRUG PROFILE...........................................................................................................24
1.2.1 Mode of Action ..................................................................................................................................24
1.2.2 Key Pharmacokinetic Characteristics .................................................................................................25
1.2.3 Drug Drug Interactions.......................................................................................................................27
1.2.4 Data From Non-Clinical Studies .........................................................................................................27
1.2.5 Data From Clinical Studies .................................................................................................................28
1.3
RATIONALE FOR PERFORMING THE STUDY .................................................................34
1.4
BENEFIT-RISK ASSESSMENT ........................................................................................35
1.4.1 Potential Benefits...............................................................................................................................35
1.4.2 Potential Risks....................................................................................................................................37
1.4.3 Discussion ..........................................................................................................................................39
2
STUDY OBJECTIVES AND ENDPOINTS...................................................................... 41
2.1 
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........................................41
2.1.1 
Primary Objective .........................................................................................................................41
2.1.2
Secondary Objectives ...................................................................................................................41
2.1.3
Primary Endpoint..........................................................................................................................41
2.1.4
Secondary Endpoints ....................................................................................................................41
2.2 
EXPLORATORY OBJECTIVES AND EXPLORATORY ENDPOINTS.......................................42
2.2.1 
Exploratory Objective ...................................................................................................................42
2.2.2
Exploratory Endpoint....................................................................................................................42
3
DESCRIPTION OF STUDY DESIGN AND STUDY POPULATION .................................... 43
3.1 
OVERALL STUDY DESIGN ............................................................................................43
3.2 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF CONTROL GROUP............44
3.3 
SELECTION OF STUDY POPULATION............................................................................45
3.3.1
Main Diagnosis for Study Entry ....................................................................................................46
3.3.2
Inclusion Criteria...........................................................................................................................47
3.3.3
Exclusion Criteria ..........................................................................................................................48
3.3.4
Withdrawal of Subjects From Treatment or Assessments ...........................................................51

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4
TREATMENTS ......................................................................................................... 54
4.1
INVESTIGATIONAL TREATMENTS ................................................................................54
4.1.1
Identity of Investigational Medicinal Products.............................................................................54
4.1.2
Selection of Doses in the Study and Dose Modifications .............................................................54
4.1.3
Method of Assigning Patients to Treatment Arms .......................................................................56
4.1.4
Drug Assignment and Administration of Doses for Each Patient .................................................56
4.1.5
Blinding and Procedures for Unblinding.......................................................................................58
4.1.6
Packaging, Labeling, and Re-supply of the Study Treatment .......................................................59
4.1.7
Storage Conditions .......................................................................................................................59
4.1.8
Drug Accountability ......................................................................................................................59
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES,  AND RESTRICTIONS .......................61
4.2.1
Other Treatments and Emergency Procedures ............................................................................61
4.2.2
Restrictions...................................................................................................................................61
4.3
TREATMENT COMPLIANCE ........................................................................................63
5
ASSESSMENTS ........................................................................................................ 64
5.1
OVERVIEW OF PROCEDURES AT STUDY VISITS ............................................................64
5.2.
SAFETY LABORATORY PARAMETERS...........................................................................64
5.3
PATIENT-REPORTED OUTCOMES ................................................................................67
5.3.1
Leicester Cough Questionnaire.....................................................................................................67
5.4
PHYSICAL EXAMINATION............................................................................................67
5.5
VITAL SIGNS...............................................................................................................68
5.6
ADVERSE EVENTS.......................................................................................................68
5.6.1
Definitions of Adverse Event .......................................................................................................68
5.6.2
Intensity (severity) of Adverse Events .........................................................................................71
5.6.3
Causal Relationship of Adverse Events ........................................................................................71
5.6.4
Collecting and Reporting of Adverse Events................................................................................71
5.7
ELECTROCARDIOGRAM RECORDING ...........................................................................73
5.7.1
ECG Procedure..............................................................................................................................73
5.7.2
ECG Evaluation..............................................................................................................................73
5.8
SPIROMETRY..............................................................................................................73
5.9
DLCO .........................................................................................................................74
5.10
6MWD.......................................................................................................................75
5.11
DRUG CONCENTRATION OF MEASUREMENTS AND PHARMACOKINETICS ....................75
5.11.1
Assessment of Pharmacokinetics .................................................................................................75
5.11.2
Monitoring of Concentrations of Background SoC Therapy.........................................................76
5.11.3
Methods of Sample Collection......................................................................................................76
5.11.4
Analytical Determinations ............................................................................................................77
5.12
ASSESSMENT OF BIOMARKER(S).................................................................................77
5.12.1
Blood Biomarkers .........................................................................................................................78
5.12.2
Methods of Sample Collection......................................................................................................78
5.12.3
Analytical Determinations ............................................................................................................78

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5.12.4 
Appropriateness of Measurements .........................................................................................78
6
INVESTIGATIONAL PLAN ......................................................................................... 79
6.1
VISIT SCHEDULE ........................................................................................................79
6.2
SCREENING PERIOD...................................................................................................79
6.3
TREATMENT PERIOD .................................................................................................80
6.4
FOLLOW UP PERIOD AND STUDY COMPLETION..........................................................81
7
STATISTICAL ANALYSIS PLAN................................................................................... 83
7.1
NULL AND ALTERNATIVE HYPOTHESES........................................................................83
7.2 
PLANNED ANALYSES ..................................................................................................83
7.2.1
General Considerations ................................................................................................................83
7.2.2
Primary Endpoint Analyses...........................................................................................................84
7.2.3
Secondary Endpoint Analyses.......................................................................................................85
7.2.4
Exploratory Endpoint Analyses.....................................................................................................86
7.3 
HANDLING MISSING DATA .........................................................................................86
7.4 
RANDOMIZATION ......................................................................................................87
7.5 
DETERMINATION OF SAMPLE SIZE..............................................................................87
8
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, PUBLICATION POLICY, 
AND ADMINISTRATIVE STRUCTURE................................................................................ 88
8.1
STUDY APPROVAL, PATIENT INFORMATION, INFORMED CONSENT .............................88
8.2 
DATA QUALITY ASSURANCE .......................................................................................89
8.3 
RECORDS ...................................................................................................................90
8.3.1
Source Documents........................................................................................................................90
8.3.2
Direct Access to Source Data and Documents..............................................................................92
8.3.3
Storage Period of Records ............................................................................................................92
8.4 
EXPEDITED REPORTING OF ADVERSE EVENTS..............................................................92
8.5 
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY ..........................................93
8.5.1
Collection, storage, and future use of biological samples and corresponding data.....................93
8.6 
STUDY MILESTONES...................................................................................................93
8.7 
ADMINISTRATIVE STRUCTURE OF THE STUDY .............................................................94
9
REFERENCES ........................................................................................................... 96
10
APPENDICES ......................................................................................................... 100
10.1 
LCQ PRO TOOL.........................................................................................................100
10.2 
DLCO .......................................................................................................................101
10.3 
6MWD.....................................................................................................................103
10.4 
TIME SCHEDULING FOR PK BLOOD SAMPLING ..........................................................104

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10.5 
ELIGIBILITY CONFIRMATION OF IPF DIAGNOSIS.........................................................105
10.6 
CREATINE CLEARANCE..............................................................................................106
10.7 
EQUIVALENT DOSES OF CORTICOSTEROIDS...............................................................107
10.8 
RESTRICTED MEDICATIONS.......................................................................................108

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LIST OF TABLES
Table 1. Plasma PK Parameters of INS018_055 in SAD Cohorts in Study in New Zealand ..............................26
Table 2. Plasma PK Parameters of INS018_055 in MAD Cohorts in Study in New Zealand.............................26
Table 3. Risks of Clinical Relevance ...............................................................................................................37
Table 4. Characteristics of Treatments..........................................................................................................54
Table 5. Dosage and Treatment Schedule .....................................................................................................57
Table 6. Restricted Medications During the Study.........................................................................................61
Table 7. Order of Procedures During Study Visit ...........................................................................................64
Table 8. Safety Laboratory Tests ...................................................................................................................65
Table 9. Guidance on Transaminase Laboratory Values and Treatment Management ..................................66
Table 10. The Borg Scale CR10..................................................................................................................... 103
Table 11. Time Schedule for PK Blood Sampling.......................................................................................... 104
Table 12. Calculation of GFR CKD-EPI .......................................................................................................... 106
Table 13. Equivalent Doses of Corticosteroids............................................................................................. 107
Table 14. Examples of Clinical Inhibitors and Inducers for CYP-Mediated Metabolism ............................... 108

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LIST OF FIGURES
Figure 1. Study Schema.................................................................................................................................44
Figure 2. IPF Diagnosis on the Basis of HRCT and Biopsy Patterns (2022 ATS/ERS/JRS/ALAT Clinical Practice 
Guideline) .......................................................................................................................................... 106

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ABBREVIATIONS
%CV
Percent Coefficient of Variation 
                                   
aPTT
Activated Partial Thromboplastin Time 
                
ADL
Activities of Daily Living
   
ADME
Absorption, Distribution, Metabolism, and Elimination                                                             
AE 
Adverse Event
           
AESI 
Adverse Event of Special Interest
ALCOA 
Attributable, Legible, Contemporaneous, Original, Accurate         
                              
ALK       
Anaplastic Lymphoma Kinase              
ALT 
Alanine Aminotransferase
ANCOVA
Analysis of Covariance 
                             
AP 
Alkaline phosphatase
                
AST 
Aspartate Aminotransferase
                  
ATS
American Thoracic Society 
            
AUC 
Area Under the Curve
BALF
Broncho-Alveolar Lavage Fluid
             
BID
bis in die (twice daily dosing)
BLM
Bleomycin
                  
BMI 
Body Mass Index
                   
   
BUN
Blood Urea Nitrogen
CA 
Competent Authority
CI
Confidence interval
                  
CK
Creatine kinase 
           
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum Plasma Concentration
                         
COPD 
Chronic Obstructive Pulmonary Disease
CRA 
Clinical Research Associate
CRF
Case Report Form
                          
CRO 
Contract Research Organization
                 
CRP
C-Reactive Protein 
               
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
               
CTP 
Clinical Trial Protocol
CYP 
Cytochrome P450
DDI
Drug Drug Interaction     
             
DDR1
Discoidin Domain Receptor 1                                                                              
DLCO 
Diffusion Capacity of the Lung for Carbon Monoxide 
DSMB
Data Safety Monitoring Board 
ECG 
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
                
ERS
European Respiratory Society 
                
ESR
Erythrocyte Sedimentation Rate 
                
eCRF 
electronic Case Report Form

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EDC 
Electronic Data Capture
eGFR 
estimated Glomerular Filtration Rate
EOS
End of Study
EOT 
End of Treatment
FDA
Federal Drug Administration
                           
FEV1 
Forced Expiratory Volume in one second
FOBT
Fecal Occult Blood Testing
FSH 
Follicle Stimulating Hormone
FVC 
Forced Vital Capacity
GCP 
Good Clinical Practice
GCV
Geometric Coefficients of Variation 
             
GGT
Gamma-glutamyl transferase 
                  
GI 
Gastro Intestinal
GMP 
Good Manufacturing Practice
HA 
Health Authority
HR 
Heart Rate
HRCT 
High Resolution Computed Tomography Scan
HBcAb 
Hepatitis B core Antibody 
HBsAg 
Hepatitis B surface Antigen
HBV
Hepatitis B 
             
HCV 
Hepatitis C 
                 
HDL
High-Density Lipoprotein
HIV 
Human Immunodeficiency Virus
   
hsCRP
high sensitivity C-Reactive Protein
HV 
Healthy Volunteers
IC50 
Half maximal Inhibitory Concentration
ICH 
International Council on Harmonization
IEC 
Independent Ethics Committee
IL
Interleukin
  
IPF 
Idiopathic Pulmonary Fibrosis
IRB 
Institutional Review Board
IRT 
Interactive Response Technology
ISF 
Investigator Site File
                         
ITT
Intention to treat
LCQ 
Leicester Cough Questionnaire
LDH
Lactate dehydrogenase 
                 
LDL
Low-Density Lipoprotein
LFT
Liver Function Test
             
LMM 
Linear Mixed Effect Model 
                          
LPLT
Last Patient Last Treatment
LPS
lipopolysaccharides 
                      
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
                    
  
MMRM
Mixed Model Repeated Measures
          
MNAR
Missing Not At Random 
           
NOAEL
No Observed Adverse Effect Level 
    

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NZ
New Zealand 
                           
PBPK 
Physiologically-based Pharmacokinetic
PFT
Pulmonary Function Test
               
PCR
Polymerase Chain Reaction
PFT
Pulmonary Function Test 
PK 
Pharmacokinetics
PoC 
Proof of Concept
PP 
Per Protocol 
PRO 
Patient Reported Outcome
PV
Pharmacovigilance
  
PY
Person-Year
                                   
QD 
every day
                                         
QoL 
Quality of Life
RA 
Regulatory Authority
                
RBC
Red Blood Cell
                 
RNA
Ribonucleic acid
SAE 
Serious Adverse Event
SAP 
Statistical Analysis Plan 
              
SD
Standard Deviation
                             
SoC 
Standard of Care
SOP 
Standard Operating Procedure
SUSAR 
Suspected Unexpected Serious Adverse Reactions                                                   
Tmax 
Time to reach Maximum Plasma Concentration     
          
TEAE 
Treatment Emergent Adverse Event
TGF
Transforming Growth Factor
        
TSH
Thyroid Stimulating Hormone 
           
ULN 
Upper Level of Normal
UIP 
Usual Interstitial Pneumonia
                     
WBC
White Blood Cell
WHO
World Health Organization
          
WOCBP 
Woman Of Childbearing Potential 
6MWD
6-Minute Walk Distance

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1
INTRODUCTION
INS018_055 is a potent inhibitor of the serine/threonine kinase Traf2- and Nck-interacting 
kinase (TNIK) that can manipulate the aberrant Wnt signaling pathway and engage other 
IPF-related signaling pathways, including NF-
-
It is under development for the 
treatment of idiopathic pulmonary fibrosis (IPF). 
1.1
MEDICAL BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease, characterized by distorted lung 
architecture and loss of respiratory function as a result of alveolar epithelial cell injury and 
hyperplasia, enhanced extracellular matrix deposition, and myofibroblast activation. IPF 
carries a poor prognosis with a median survival of 3 to 4 years. [Fernández Pérez 2010] 
[Strongman 2018]. 
IPF occurs worldwide. The prevalence of IPF appears to be increasing, although it is unclear 
whether this reflects increased recognition or a true increase in incidence. The incidence of 
IPF appears to be higher in North America and Europe [3 to 9 cases per 100,000 person-
years (PY)] than in South America and East Asia (fewer than 4 cases per 100,000 PYs).
[Hutchinson 2015] In the U.S., the prevalence of IPF has been reported to range from 10 to 
60 cases per 100,000. [Esposito 2015] [Raghu 2016] [Raghu 2014] Increasing rates of 
hospital admissions and deaths due to IPF also suggest an increasing burden of disease.
[Hutchinson 2015] [Hutchinson 2014] [Lee 2014]
Pirfenidone and nintedanib are antifibrotic therapies approved for the treatment of IPF and 
can slow disease progression. [Richeldi 2014] [Flaherty 2019] However, currently available 
therapies are not curative and are associated with side effects, including gastrointestinal (GI) 
side effects, liver injury, photosensitivity rash, change in taste and smell perception 
(pirfenidone only), bleeding risk (nintedanib only). [Richeldi 2014] [Flaherty 2019] 
[Proesmans 2019] [
020] Real world data suggests that 20 to 27% of patients 
discontinue treatment with approved therapy due to adverse effects or poor tolerability. [Galli 
2017] [Strens 2021] New treatments that further slow disease progression and expand 
treatment options for patients unable to tolerate currently approved treatments are needed.
[Chambers 2022] [Somogyi 2019]
1.2
DRUG PROFILE
1.2.1 Mode of Action
INS018_055 is a potent inhibitor of the serine/threonine kinase Traf2- and Nck-interacting 
kinase (TNIK) that can reduce idiopathic pulmonary fibrosis in adults. The serine/threonine 

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kinase TNIK, first identified as a regulatory kinase in cell spreading or migration through 
cytoskeleton organization, is a member of germinal center kinases (GCKs) possessing the N-
terminal kinase domain, an intermediate domain, and a C-terminal germinal center kinase 
homology (GCKH) region and interacts with important signal transduction cascades where 
its mechanisms of action include: 
Modulation of Wnt-induced gene expression program together with Transcription 
Factor 7 Like 2 (TCF7L2)
Co-operation within c-Jun N-terminal kinase (JNK) and mitogen-activated protein 
kinase (MAPK) pathway 
Other interactions and cross-talks with nuclear factor kappa B (NF-
-
pathways
Of all the signaling pathways where TNIK acts, Wnt signaling is consistently identified as a 
major activated signaling cascade that significantly contributes to the pathogenesis of lung 
fibrosis. [Morrisey 2003] [Baarsma 2018] Therefore, TNIK is a feasible target of 
pharmacologic intervention in IPF.
1.2.2 Key Pharmacokinetic Characteristics
Two phase 1, randomized, double-blind, placebo-controlled, parallel-group, single ascending 
dose (SAD) and multiple ascending dose (MAD) studies were conducted to evaluate the 
safety, tolerability, pharmacokinetic (PK), food effects, and drug-drug interaction (DDI)
potential of INS018_055 in healthy subjects in New Zealand (NZ) (NCT05154240) and 
China (CTR20221542). 
PK summary for phase 1 study in New Zealand (NCT05154240)
The PK data of INS018_055 for all SAD and MAD cohorts showed a dose-proportional 
increase of the plasma exposure over the single-dose range of 10 to 120 mg and no 
significant accumulation after 7-day every day (QD) oral administrations when the steady 
state was reached. Food effect on the PK of INS018_055 was assessed at the single dose of 
90 mg. Compared to fasted conditions, food decreased Cmax and AUC0-t by approximately 
38% and 14%, respectively, and prolonged Tmax from 1 to 3 hours. The PK parameters of 
INS018_055 for SAD cohorts in the NZ study are shown Table 1. Three MAD cohorts were 
also completed and the PK parameters are shown in below Table 2.

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Table 1. Plasma PK Parameters of INS018_055 in SAD Cohorts in Study in New 
Zealand
PK 
Parameter 
INS018_055
10 mg
(N=6) 
INS018_055
30 mg
(N=6) 
INS018_055
60 mg
(N=6) 
INS018_055
90 mg 
Fasted
(N=6) 
INS018_055
90 mg 
Fed
(N=6) 
INS018_055 
120 mg 
(N=6) 
Cmax (ng/mL) 
25.4 (66.8) 
105 (44.4) 
273 (47.5) 
270 (44.1) 
169 (42.8) 
339 (32.1) 
Tmax (h) 
1.0 (1.0-2.0) 
1.53 (1.0-4.0) 
1.0 (0.5-2.0) 
1.01 (0.5-
2.0) 
3.0 (2.0-4.0) 
1.5 (1.0-2.0) 
AUC0-t
(ng*h/mL) 
124 (69.3) 
552 (46.0) 
1210 (61.0) 
1620 (40.5) 
1390 (44.9) 
1980 (35.1) 
T1/2 (h) 
9.72 (23.8) 
7.42 (9.30) 
7.96 (23.6) 
8.61 (48.9) 
9.71 (35.0) 
9.74 (39.2) 
CL/F (L/h)
74.2 (63.3) 
53.7 (45.7) 
49.1 (61.0) 
55.2 (40.4) 
64.1 (44.6) 
60.0 (35.1) 
Vd/F (L)
1040 (68.7) 
575 (39.2) 
563 (39.9) 
685 (29.2) 
898 (22.9) 
843 (61.0) 
Table 2. Plasma PK Parameters of INS018_055 in MAD Cohorts in Study in New 
Zealand
PK 
Parametera
INS018_055 
30 mg QD
(N=6 for Day 1, N=5 for 
Day 7)
INS018_055 
60 mg QD
(N=6)
INS018_055 
120 mg QD
(N=6)
Day
Day 1
Day 7
Day 1
Day 7
Day 1
Day 7
Cmax (ng/mL) 
106 (28.1) 
79.4 (50.1) 
226 (24.1) 
191 (36.5) 
511 (13.5)
463 (26.5)
Tmax (h) 
1.0 (1.0-1.0) 
1.0 (1.0-
1.98) 
1.0 (1.0-2.0) 
1.5 (0.52-
2.0) 
1.5 (1.0-4.0)
2.0 (1.0-2.0)
AUC0-
(ng*h/mL) 
404 (34.8) 
439 (39.8) 
1150 (25.3) 
1210 (29.9) 
3050 (24.9)
3040 (25.3)
T1/2 (h) 
5.80 (8.32) 
9.36 (24.4) 
-
11.9 (13.9) 
-
10.2 (11.4)
ARCmaxb
-
0.739 (25.9) 
-
0.843 (33.0) 
-
0.905 (21.7)
ARAUCc
-
1.02 (20.0) 
-
1.05 (5.81) 
-
0.996 (3.66)
a Values are presented as the geometric mean (geometric CV%), except for Tmax shown as the median (min-
max). 
b ARCmax derived as Cmax Day 7 / Cmax Day 1.
c ARAUC derived as AUC0- Day 7 / AUC0- Day 1.
PK summary for phase 1 study in China (CTR20221542)
The other phase I, randomized, double-blind, placebo-controlled, parallel-group, SAD and 
MAD study to evaluate the safety, tolerability, and pharmacokinetics of INS018_055 in 
healthy subjects in China (CTR20221542) has also been completed. In the SAD part, 24 
subjects were given a single dose of INS018-055 30 mg, 60 mg, 120 mg or placebo control 
(8 subjects/cohort with a INS018-055 treatment to placebo ratio of 3 to 1). In the MAD part, 
32 subjects were given multiple doses of INS018-055 30 mg twice daily (BID), 60 mg BID, 
90 mg BID or placebo control for 7 days (8 subjects/cohort with a treatment to placebo ratio 

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of 3 to 1). The study objectives (primary, secondary, exploratory) and analysis plan are 
similar to the SAD part and the MAD part of the NZ study (NCT05154240). 
After healthy subjects received INS018_055 capsule administration, PK exposure of 
INS018_055, INS018_063, and INS018_095 in the SAD and MAD phases increased with 
dose but did not show a complete dose-linear relationship. After 7 consecutive days of BID 
oral administration of INS018_055 capsules, INS018_055 and INS018_095 were essentially 
stabilized, whereas the trough concentrations of INS018_063 tended to increase at D2-D7. 
No significant accumulation was observed for INS018_055 and INS018_095, except for 
INS018_063, which had an accumulation ratio of >1 and <5 for systemic exposure. In 
addition, the PK profile of INS018-055 in this study was similar to those in the New Zealand 
study with no significant differences.
1.2.3 Drug Drug Interactions
The CYP3A4 pathway will significantly affect INS018_055, which is primarily metabolized 
by CYP3A4 based on in vitro data. The DDI potential of INS018_055 to induce CYP1A2 
expression is currently being studied (NCT05154240). 
Given the potential CYP3A4- and CYP1A2-mediated DDIs with permitted SoC antifibrotic 
treatments (pirfenidone, nintedanib), including with INS018_055, concurrent 
moderate/strong CYP3A4 inhibitors/inducers or medications primarily metabolized by 
CYP3A4 are not permitted. Moderate/strong CYP1A2 inhibitors/inducers or medications 
primarily metabolized by CYP1A2 are also not permitted.
Pirfenidone in vitro profiling studies in hepatocytes and liver microsomes indicate it is 
primarily metabolized in the liver by CYP1A2 with minor contributions from other CYP
isozymes (CYP2C9, 2C19, 2D6, and 2E1). Concomitant use of pirfenidone and a
moderate/strong CYP1A2 inhibitor/inducer could change the exposure of pirfenidone. 
Nintedanib is mainly metabolized by esterases. In vitro, CYP-dependent metabolism 
accounted for about 5% (CYP 3A4 predominant enzyme) compared to about 25% ester 
cleavage. The major CYP-dependent metabolite could not be detected in plasma in the 
human ADME study. Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4. 
Concomitant use of nintedanib and a CPY3A4 inhibitor/inducer may change the exposure of 
nintedanib.
1.2.4 Data From Non-Clinical Studies
The biological activities of INS018_055, a potent inhibitor of the serine/threonine kinase 
TNIK, has been fully characterized. INS018_055 showed potent inhibition of TNIK in a 
biochemical enzymatic assay with an IC50 value of 23 nmol/L. INS018_055 inhibited a few 

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other kinases that are known to be involved in pro-fibrotic pathways, i.e., ALK4, DDR1, 
FMS, TGFBR1. INS018_055 potently inhibited TGF- -
-SMA, 
fibronectin and PAI-1 in MRC-5 cells (a lung fibroblast cell line). INS018_055 showed 
concentration-dependent inhibition of TGF-
-
-SMA expression in primary lung 
fibroblasts (FMT assay) and fibronectin expression in primary bronchial epithelial cells 
(EMT assay) derived from IPF patients.
INS018_055 (3 mg/kg BID, 10 mg/kg BID, 30 mg/kg BID) exerted anti-inflammatory and 
anti-fibrotic effects in bleomycin (BLM)-induced lung fibrosis mouse model and 
significantly improved the lung function impaired by BLM. In a combination therapy study 
using a BLM-induced lung fibrosis mouse model, INS018_055 3 mg/kg BID exerted additive 
effect when combined with the suboptimal dose of pirfenidone 60 mg/kg BID. 
 
 
 In a second combination therapy study, the group treated with 
INS018_055 10 mg/kg BID and optimal dose of pirfenidone 200 mg/kg BID showed the best 
improvement in body weight loss recovery and lung function. 
 
In a study conducted in a lipopolysaccharides (LPS)-induced acute lung 
injury mouse model, INS018_055 suppressed proinflammatory cytokines, which were 
elevated post-LPS challenge; INS018_055 increased anti-inflammatory cytokine levels, 
which were decreased post-LPS challenge. The antifibrotic effect of INS018_055 was also 
validated in a widely used kidney fibrosis model, i.e., mouse unilateral ureteral obstruction
model, which has the pathological features of chronic kidney disease including interstitial 
fibrosis.
Overall, INS018_055 pre-clinical studies showed potent anti-fibrotic and anti-inflammatory 
activities in lung and rescued loss of lung function.
1.2.5 Data From Clinical Studies
Two phase 1 trials in New Zealand (NCT05154240) and China (CTR20221542) have been 
completed and the clinical study reports are available. 
Safety summary for phase 1 study in New Zealand (NCT05154240)
For the phase 1 study in New Zealand,  78 healthy volunteer subjects were dosed with 
INS018_055 or placebo. This included 40 subjects in SAD cohorts (Part A) who received the 
single dose of 10 mg, 30 mg, 60 mg, 90 mg, or 120 mg (8 subjects in each cohort: 2 from the 
sentinel group and 6 from the rest of cohort group), and 24 subjects in MAD cohorts (Part B) 
 
 
 
 

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who received the multiple doses of 30 mg QD, 60 mg QD or 120 mg QD, respectively for up 
to 7 days (8 subjects in each cohort). For DDI (Part C) study, 14 healthy participants  
received a single oral dose of caffeine 200 mg on Day one, followed by a washout from Day 
two to four, and subsequently received multiple oral doses of INS018_055 120 mg QD for 14 
days (Day five through 18) with a single oral dose of caffeine 200 mg on Day 18.
SAD Part (Part A)
Administration of a single dose of INS018_055 (10 mg, 30 mg, 60 mg, 90 mg, or 120 mg) 
under fasted conditions and a single dose of INS018_055 (90 mg) under fed conditions was 
safe and generally well tolerated by the healthy subjects in this study.
There were no deaths or SAEs during the study, and no subject discontinued the study 
treatment due to TEAEs. No dose-related trends were observed.
Overall, 11 of 30 subjects (36.7%) who received INS018_055 and 4 of 10 subjects (40.0%) 
who received placebo experienced at least 1 TEAE. A total of 21 TEAEs (14 TEAEs in 
subjects who received INS018_055 and 7 TEAEs in subjects who received placebo) were 
reported. All TEAEs were of mild severity and resolved.
Most reported TEAEs in subjects who received INS018_055 were phlebitis reported in 3 
subjects (10.0%), fecal occult blood positive and medical device site irritation reported in 2 
subjects (6.7%) each, and all remaining TEAEs were reported in 1 subject (3.3%) each.
Four subjects (13.3%) who received INS018_055 and 4 subjects (40.0%) who received 
placebo experienced TEAEs that were considered related to the study treatment.
No clinically significant results were observed for clinical laboratory evaluations; however, 
positive test results were noted for fecal occult blood and reported as mild TEAEs.
No treatment-related trends were observed in 12-lead ECG measurements. No abnormal 
ECG finding was clinically significant. None of the individual hematology, serum chemistry, 
urinalysis values, vital signs, or 12-lead ECG measurements were considered clinically 
significant or were reported as a TEAE by the investigator.
MAD part (Part B)
Administration of INS018_055 QD for 7 days under fasted conditions (30 mg, 60 mg, or 120 
mg) was safe and generally well tolerated by the healthy subjects in this study.
There were no deaths or SAEs during the study. One subject discontinued the study treatment 
due to a moderate TEAE of influenza-like illness. No dose-related trends were observed in 
TEAEs.

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Overall, 16 of 18 subjects (88.9%) who received INS018_055 and 5 of 6 subjects (83.3%) 
who received placebo experienced at least 1 TEAE. A total of 55 TEAEs (46 TEAEs in 
subjects who received INS018_055 and 9 TEAEs in subjects who received placebo) were 
reported. Most reported TEAEs in subjects who received INS018_055 were headache 
reported in 10 subjects (55.6%), fecal occult blood positive in 7 subjects (38.9%), upper 
respiratory tract infection in 3 subjects (16.7%), and all remaining TEAEs were reported in 
1 subject (5.6%) each.
One subject was reported with a moderate TEAE; all other TEAEs were mild. All TEAEs 
resolved, except for a mild TEAE of seasonal allergy reported in INS018_055 60 mg cohort 
that did not resolve and a mild TEAE of COVID-19 in INS018_055 30 mg cohort which was 
resolving by end of the study. The TEAEs of seasonal allergy and COVID-19 were not 
related to the study treatment.
Thirteen subjects (72.2%) who received INS018_055 and 1 subject (16.7%) who received 
placebo experienced TEAEs that were considered related to the study treatment.
Changes observed in serum chemistry were mild. Positive test results were noted for fecal 
occult blood and reported as mild TEAEs. All changes were transient and resolved within the 
study duration.
No treatment-related trends were observed in 12-lead ECG measurements. None of the 
individual hematology, urinalysis values, vital signs, or 12-lead ECG measurements were 
considered clinically significant or were reported as a TEAE by the investigator.
DDI part (Part C)
Administration of a single dose of caffeine (200 mg) with INS018_055 (120 mg) was 
generally safe and well tolerated by the healthy subjects in this study.
There were no deaths, SAEs or TEAEs leading to early discontinuation in Part C of the study 
with the exception of 1 subject who discontinued treatment due to a moderate TEAE of ALT 
increase. 
Overall, 8 of 14 subjects (57.1%) in Period 1 (caffeine) and 14 of 14 subjects (100.0%) in 
Period 2 (caffeine+INS018_055 120mg) experienced at least 1 TEAE, in which 2 subjects 
(14.3%) in Period 1 (caffeine) and 14 subjects (100.0%) in Period 2 (caffeine+INS018_055 
120mg) experienced TEAEs that were considered related to the study treatment. In total 99 

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TEAEs (9 TEAEs in subjects in Period 1 [caffeine] and 90 TEAEs in subjects in Period 2 
[caffeine+INS018_055 120mg]) were reported, in which 2 TEAEs in Period 1 (caffeine) and 
61 TEAEs in Period 2 (caffeine+INS018_055 120mg) were considered related to the study 
treatment. Most reported TEAEs in subjects during Period 1 (caffeine) were headache and 
catheter site phlebitis in 3 subjects (21.4%) each; In Period 2 (caffeine+INS018_055 120mg), 
the most reported TEAEs were headache in 13 subjects (92.9%). TEAEs were reported in 3 
subjects (21.4%) for the following: nausea, fatigue, increased ALT, increased AST and fecal 
occult blood positive. All other TEAEs were reported in 
2 subjects.
All TEAEs were mild in severity with the exception of one subject with moderate elevation 
of ALT in Period 2 (caffeine+INS018_055 120 mg) that retuned to baseline. All other 
TEAEs resolved, except for mild TEAEs of mouth ulceration and rash (non-erythematous) 
reported in one subject and a mild TEAE of erythematous rash reported in another subject in 
Period 2 (caffeine+INS018_055 120 mg). The TEAEs of mouth ulceration and rash 
erythematous were related to the study treatment and the TEAE of rash (non-erythematous) 
was not related to the study treatment.
Mild to moderate changes were observed for serum chemistry, and positive test results were 
noted for fecal occult blood and reported as mild TEAEs. None of the individual hematology, 
quantitative urinalysis, coagulation test values were considered clinically significant.
None of the individual vital signs were considered clinically significant or were reported as a 
TEAE by the investigator. No treatment-related trends were observed in 12 lead ECG 
measurements. One subject was reported with a mild TEAE of tachycardia that was 
considered clinically significant and resolved on the same day. This TEAE was considered 
related to the study treatment.
Phase 1 study in China (CTR20221542)
Part A (SAD)
In this study, single doses of INS018_055 (30 mg, 60 mg, 120 mg) given under fasting 
conditions to healthy subjects were safe and well tolerated. During the study, there were no 
severe adverse events, serious adverse events, adverse events leading to withdrawal from the 
study, or TEAEs leading to death.
A total of 24 (100.0%) subjects were included in SS, and a total of 23 TEAEs occurred to 14 
(58.3%) subjects; among them, 9 TEAEs occurred to 5 (83.3%) subjects in 30 mg dose 
group; 2 TEAEs occurred to 2 (33.3%) subjects in 60 mg dose group; 6 TEAEs occurred to 3

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(50.0%) subjects in 120 mg dose group; 6 TEAEs occurred to 4 (66.7%) subjects in placebo 
group.
Among subjects treated with INS018_055, the most common TEAEs were occult blood, 
hypertriglyceridaemia (5 subjects each, 27.8%), sinus bradycardia (2 subjects, 11.1%), and 
the incidences of other TEAEs were 5.6% (1 subject each). Among subjects treated with 
placebo, the most common TEAE was occult blood (2 subjects, 33.3%); and the incidences 
of other TEAEs were 16.7% (1 subject each). All TEAEs were mild in severity and 
recovered.
Eight (44.4%) subjects who received INS018_055 treatments had TEAEs related to the study 
drug, the most common TEAEs were occult blood and hypertriglyceridaemia (5 subjects 
each, 27.8%), and the incidence of other TEAEs was 5.6% (1 subject each); 3 (50.0%) 
subjects who received placebo treatment had TEAEs related to the study drug, the most 
common TEAE was occult blood (2 subjects, 33.3%), and the incidences of other TEAEs 
were 16.7% (1 subject each).
The change of any laboratory test indicator from normal/abnormal without clinical 
significance at baseline to abnormal with clinical significance post-dose occurred in at least 2 
subjects includes: abnormally elevated triglycerides in 2 (33.3%) subjects and 
positive/weakly positive fecal occult blood in 3 (50.0%) subjects in the 30 mg dose group; 
abnormally elevated triglycerides in 2 (33.3%) subjects and positive/weakly positive fecal 
occult blood in 2 (33.3%) subjects in the 120 mg dose group, all were judged to be abnormal 
with clinical significance, and reported as TEAEs related to the study drug, these TEAEs 
were all recovered.
The incidence of change of any vital sign examination indicator from normal value with no 
clinically significant abnormality at baseline to abnormal value with clinically significance 
post-dose was low in each dose group, with no more than 1 (16.7%) subject. Among them, 1 
(16.7%) subject in the 30 mg dose group reported diastolic blood pressure decreased as a 
TEAE related to the study drug, which returned to normal before the end of the study.
ECG results showed that 1 (16.7%) subject in the 30 mg dose group developed sinus 
bradycardia after dosing; 1 (16.7%) subject in the 60 mg dose group developed sinus 
bradycardia with cardiac dysrhythmias. All were judged to be abnormal with clinical 
significance, but not related to the study drug, and returned to normal before the end of the 
study.
Part B (MAD)

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In this study, INS018_055 (30 mg, 60 mg, 90 mg) given twice daily for 7 days under fasting 
conditions to healthy subjects was safe and well tolerated. During the study, there were no 
severe adverse events, serious adverse events, adverse events leading to withdrawal from the 
study, or TEAEs leading to death.
A total of 24 (100.0%) subjects were enrolled in SS, and a total of 92 TEAEs occurred to 21 
(87.5%) subjects at MAD stage; among them, 10 TEAEs occurred to 4 (66.7%) subjects in 
30 mg dose group; 24 TEAEs occurred to 6 (100.0%) subjects in 60 mg dose group; 39 
TEAEs occurred to 6 (100.0%) subjects in 90 mg dose group; 19 TEAEs occurred to 5 
(83.3%) subjects in placebo group.
Among subjects treated with INS018_055, the most common TEAEs were occult blood (10 
subjects, 55.6%), hypertriglyceridaemia (9 subjects, 50.0%), influenza like illness, pain in 
limb (5 subjects each, 27.8%), dizziness (4 subjects, 22.2%), rash, headache, haematuria (3 
subjects each, 16.7%), blood fibrinogen decreased, white blood cells urine positive, 
ulceration mouth, epistaxis, fever and anaemia (2 subjects each, 11.1%), and the incidences 
of other TEAEs were 5.6% (1 subject each); among subjects treated with placebo, the most 
common TEAE were occult blood (3 subjects, 50.0%), hypertriglyceridaemia, influenza like 
illness and rash (2 subjects each, 33.3%), and the incidences of other TEAEs were 16.7% (1 
subject each).
Except for 5 (27.8%) subjects in the INS018_055 dosing group and 2 (33.2%) subjects in the 
placebo group, the severity of TEAEs of influenza like illness was moderate, and the severity 
of other TEAEs were mild, and all TEAEs were recovered. All moderate TEAEs were not 
related to the study drug.
Sixteen (88.9%) subjects treated with INS018_055 had TEAEs related to the study drug, the 
most common TEAEs were occult blood (10 subjects, 55.6%), hypertriglyceridaemia (9 
subjects, 50.0%), pain in limb (5 subjects, 27.8%), dizziness (4 subjects, 22.2%), rash, 
headache, haematuria (3 subjects each, 16.7%), blood fibrinogen decreased, white blood cells 
urine positive, ulceration mouth, epistaxis, fever and anaemia (2 subjects each, 11.1%), and 
the incidences of other TEAEs were 5.6% (1 subject each); 5 (83.3%) subjects treated with 
placebo had TEAEs related to the study drug, the most common TEAE were occult blood (3 
subjects, 50.0%), hypertriglyceridaemia and rash (2 subjects each, 33.3%), and the 
incidences of other TEAEs were 16.7% (1 subject each).
In each dose group, the changes of laboratory test indicators from normal/abnormal without 
clinical significance at baseline to abnormal with clinical significance post-dose occurred in 
at least 2 subjects, including abnormally elevated triglycerides in 3 (50.0%) subjects in the 30 
mg dose group; abnormally elevated triglycerides in 4 (66.7%) subjects and positive/weakly 

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positive fecal occult blood in 4 (66.7%) subjects in the 60 mg dose group; abnormally 
decreased haematocrit, hemoglobin, red blood cell count, and serum sodium in 2 (33.3%) 
subjects, abnormally decreased lymphocyte percentage and lymphocyte count in 4 (66.7%) 
subjects, abnormally elevated triglycerides in 2 (33.3%) subjects and positive/weakly 
positive fecal occult blood in 5 (83.3%) subjects in the 90 mg dose group; abnormally 
elevated triglycerides in 2 (33.3%) subjects and positive/weakly positive fecal occult blood in 
3 (50.0%) subjects in the placebo group, all were judged to be abnormal with clinical 
significance. Except for 1 subject (01-175) with abnormally decreased serum sodium in the 
90 mg dose group, the rest of the abnormal changes were reported as TEAEs related to the 
study drug, and all these TEAEs were recovered.
In each dose group, the changes of vital sign examination from normal/abnormal without 
clinical significance at baseline to abnormal with clinical significance post-dose occurred in 
at least 2 subjects, including body temperature increased in 6 (100.0%) subjects, diastolic 
blood pressure decreased in 3 (50.0%) subjects, and pulse increased in 2 (33.3%) subjects in 
the 90 mg dose group, all were judged to be abnormal with clinical significance. One 
(16.7%) subject in each of the 30 mg, 60 mg, 90 mg and placebo groups reported 1 TEAE 
related to the study drug, which returned to normal before the end of the study.
Physical examination results showed that 1 (16.7%) subject in each of the 30 mg dose group, 
60 mg dose group, and placebo group and 4 (66.7%) subjects in the 90 mg dose group had 
abnormal change with clinical significance, all of which were reported as TEAEs related to 
the study drug and returned to normal/abnormal without clinical significance before the end 
of the study.
ECG test results showed that 1 (16.7%) subject in the 30 mg dose group developed sinus 
bradycardia; 2 (33.3%) subjects in the 90 mg dose group developed sinus tachycardia; 1 
(16.7%) subject in the placebo group developed sinus bradycardia with cardiac dysrhythmias, 
all were judged to be abnormal with clinical significance. Among them, 1 (16.7%) subject 
each in the 30 mg and placebo groups reported a TEAE related to the study drug, which 
returned to normal before the end of the study.
In summary, in this Phase 1 study conducted in healthy subjects, no severe adverse events or 
serious adverse events were observed after single oral-route dose of INS018_055 Capsules at 
30-120 mg or multiple oral-route doses of INS018_055 Capsules at 30-90 mg for 7 consecutive 
days (Q12 h), indicating good safety and tolerability of INS018_055 Capsules.
1.3
RATIONALE FOR PERFORMING THE STUDY
There is an unmet need in IPF for novel treatments that further slow disease progression and 
expand treatment options for patients unable to tolerate currently approved treatments. New 

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strong/moderate CYP1A2 
inhibitor/inducer may
change the exposure of 
pirfenidone.
High Resolution Computed 
Tomography Scan (HRCT)
HRCT is required to 
confirm diagnosis of IPF 
-HRCT is needed in the 
absence of a historical 
HRCT performed within 12 
months before Screening 
(Visit 1) or if the historical 
HRCT is of inadequate 
quality
-When HRCT is needed, 
there will be close 
monitoring of AEs, selection 
of site based on ability to 
perform HRCT and ability 
of staff to conduct correct 
procedure
Administration of Placebo
No treatment benefit
-Thorough informed consent
-Inclusion in protocol that 
subjects not on SoC 
treatments are eligible if 
they have discussed with 
their physician all available 
SoC therapies prior to 
enrollment
*See Abbreviations as needed
1.4.3 Discussion
Current understanding of the mode of action of INS018_055 specifically, its TNIK 
inhibitory activity affecting the Wnt signaling pathway, which has been shown to 
significantly contribute to the pathogenesis of lung fibrosis suggests that INS018_055 has 
the potential to yield meaningful benefit to patients with IPF by slowing decline of lung 
function as well as improving symptoms and quality of life (QoL). INS018_055 has potential 
to be a new therapy for patients with IPF, particularly those with limited treatment options, 
i.e., intolerance to currently available therapies.
Overall, the preliminary results from the phase 1 study in NZ (NCT05154240) showed that
INS018_055 orally administered at a single dose of 10 mg, 30 mg, 60 mg, 90 mg, or 120 mg 

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(SAD) and dosed at 30 mg QD, 60 mg QD, or 120 mg QD for up to 7 days (MAD) appears 
to have a manageable safety profile. 
The currently available PK data of INS018_055 showed a dose-proportional increase in 
plasma exposure from 10 mg to 120 mg in SAD cohorts and no significant accumulation 
after 7-day once daily oral administrations when the steady state was reached. Food effect led 
to approximately 38% of decrease in Cmax and 14% of decrease in AUC under fed conditions 
compared to fasted conditions based on data with the same dose level in the same set of 
subjects. Median Tmax shifted from 1 hour to 3 hours post-dose. These studies support the 
initiation of this randomized, parallel-group study to evaluate the safety, tolerability, PK, and 
PoC for efficacy of INS018_055 administered orally to patients with IPF. In this phase IIa
study, INS018_055 administered at three doses, 30 mg QD or 30 mg BID or 60 mg QD 
(maximum 60 mg daily), is considered appropriate from both a pre-clinical and clinical point 
of view. 

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2 
 STUDY OBJECTIVES AND ENDPOINTS 
2.1  
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS  
2.1.1  
Primary Objective  
The primary objective is to evaluate the safety and tolerability of INS018_055 orally 
administered for up to 12 weeks in adult subjects with IPF compared to placebo. 
2.1.2 
Secondary Objectives 
The secondary objectives are:  
 
To evaluate the pharmacokinetics of INS018_055 orally administered to subjects with 
IPF  
 
To evaluate the efficacy of INS018_055 orally administered for up to12 weeks of 
treatment on FVC decline in adult subjects with IPF compared to placebo 
 
To evaluate the efficacy of INS018_055 orally administered for up to12 weeks of 
treatment to improve quality of life (QoL) and functional measures compared to placebo  
 
To evaluate the impact of INS018_055 orally administered on acute IPF exacerbations 
compared to placebo 
2.1.3 
Primary Endpoint 
The primary endpoint is the percentage of patients who have at least 1 treatment-emergent 
adverse event (TEAE).  An AE will be counted irrespective of treatment compliance, early 
treatment discontinuation, or use of antifibrotic or prohibited therapies. Similar estimates for 
specific serious AEs (SAEs), TRAEs, AEs of special interest (AESIs) and abnormal clinical 
findings may be specified in the statistical analysis plan (SAP). 
2.1.4 
Secondary Endpoints 
The secondary endpoints are:  
 PK parameters of INS018_055 and metabolites (INS018_063 and INS018_095) 
following the first dose on Day 1 (Visit 2) and the last dose during Week 12 (Visit 6, 
EOT):  
o Maximum plasma concentration (Cmax) 
o Time at which the maximum plasma concentration occurred (tmax) 
o Area under the plasma concentration-time curve from time zero to: 
 
Dosing interval  (AUC0- ) 
 
Time with last measurable concentration t (AUC0-t) 
 
Infinity 
-
 
 

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o Terminal elimination half-life (t1/2) 
o 
 
o Apparent clearance (CL/F) 
o Apparent volume of distribution (Vz/F) 
o Accumulation ratio (Rac) for Cmax and AUC  
o Trough plasma concentration (Ctrough).  
 Relative change in FVC in mL from Week 0/Visit 2 up to Week 12  
 Percentage change in FVC in mL from Week 0/Visit 2  up to Week 12  
 Absolute and relative change in FVC % predicted from Week 0/Visit 2  up to Week 12  
 Change in Diffusion Capacity of the lung for Carbon Monoxide (DLCO) % predicted 
from Week 0/Visit 2 to Week 12 
 Change in Leicester Cough Questionnaire (LCQ) from Week 0 to Week 4, 8 and 12 
 Change in 6-Minute Walk Distance (6MWD) in meters, from Week 0 to Week 12 
 Number of acute IPF exacerbations from Week 0  up to Week 12 
 Number of days hospitalized for acute IPF exacerbations from Week 0 to up Week 12 
 
2.2  
EXPLORATORY OBJECTIVES AND EXPLORATORY ENDPOINTS  
2.2.1  
Exploratory Objective 
The exploratory objective is:  
 To explore the impact of oral INS018_055 on IPF disease-related biomarkers in the blood 
 To explore the potential mechanism of action of INS018_055 in IPF patients by high-
throughput proteomic analysis on blood proteome 
2.2.2 
Exploratory Endpoint 
The exploratory endpoint is: 
 Change in IPF blood biomarkers upon INS018_055 treatment from Week 0 to Weeks 2, 
4, 8 and 12. 
 Change in blood proteome in IPF patients upon INS018_055 treatment from Week 0 to 
Weeks 2, 4, 8 and 12. 
  
 
 

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3 
 DESCRIPTION OF STUDY DESIGN AND STUDY POPULATION  
3.1  
OVERALL STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, parallel-group, PoC phase IIa study 
evaluating safety/tolerability, PK, and efficacy of INS018_055 orally administered at three 
doses, 30 mg QD or 30 mg BID or 60 mg QD (maximum 60 mg daily). Patients randomized 
into the study will be treated for 12 weeks.  
 
After providing informed consent, subjects will undergo a screening visit (Visit 1) up to 30 
days prior to the first day of the treatment period (Day 1, Visit 2). Subjects on SoC treatment 
for IPF with nintedanib or pirfenidone will be eligible for study enrollment and to continue 
receiving their nintedanib or pirfenidone throughout the study. Eligible subjects who meet all 
inclusion criteria and no exclusion criteria will be assigned in a 1:1:1:1 ratio to 1 of 4 
treatment arms: 
 INS018_055 30 mg QD  
 INS018_055 30 mg BID  
 INS018_055 60 mg QD  
 Placebo 
 
A target of 15 subjects will be assigned to each treatment arm. Approximately 70 patients 
will be enrolled to ensure approximately 60 patients complete treatment of 12 weeks. 
Subjects being treated with background SoC antifibrotic therapy (nintedanib or pirfenidone) 
at the time of randomization will be maintained on their therapy throughout the study.  
 
The duration of the study will be approximately 17 weeks for each subject from Visit 1 
through the Visit 7 (EOS). The treatment period will include 5 visits: Study Day 1, 15 ± 3 
(Week 2), 29 ± 7 (Week 4), 57 ± 7 (Week 8), and 85 ± 7 (Week 12, EOT). Subjects will 
return for an EOS visit approximately 1 week after completing the treatment period (Visit 7).  
 
Following the Schedule of Study Activities, all visits [Visit 1-7 (EOS)] will include a 
physical exam, vital signs, weight, laboratory tests, urinalysis, medication review, assessment 
for AEs, and pregnancy testing (WOCBP). During the treatment period, subjects will also be 
assessed for COVID-19, BMI, ECG, study drug compliance, blood sampling [PK (study 
drug, SOC antifibrotic therapy), biomarker, LCQ, spirometry, DLCO, 6MWD, and acute IPF 
exacerbations. Safety will be assessed from Visit 1 through the follow-up visit at Week 13 
(Visit 7, EOS). Efficacy assessments will occur through Week 12 (Visit 6). 

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relationship. A double-blind design minimizes bias, and a parallel-group design is best for 
efficiency and cost effectiveness.  
 
In this study, subjects not on SoC treatments are eligible if they have discussed with their 
physician all available SoC therapies prior to enrollment. The use of placebo may raise 
ethical concerns since SoC treatment includes antifibrotic treatment. [Richeldi 2014] 
[Flaherty 2019] [Temple 2000] [Krishna 2022. However, the response to antifibrotic 
treatment may be limited by side effects and intolerance. [Galli 2017] [Strens 2021] 
Moreover, SoC antifibrotics such as nintedanib and pirfenidone can slow progression of IPF 
but do not significantly impact mortality. [Somogyi 2019] [Maher 2019] 
 
A treatment duration of 12 weeks will inform the safety and tolerability of INS018_055 
overall and at 3 different doses in patients with IPF. This treatment period approximates or 
exceeds that of treatment periods in related studies. [Oguro 2015] [Richeldi 2014] In 
addition, a 12-week treatment duration will provide insight into the PK profile of 
INS018_055, potential early efficacy for FVC decline, and improvement in QoL. 
 
A DSMB will assess safety and tolerability during the study by evaluating entire safety data 
on an ongoing basis. FVC was chosen as a clinical endpoint, since it is a reliable, valid, and 
responsive measure of clinical status of IPF. [du Bois 2011] Lung function and respiratory 
symptoms are also clinically meaningful outcomes [Raghu 2022], thus 6MWD, number of 
acute IPF exacerbations, number of days hospitalized for IPF exacerbations, and patient-
reported QoL (LCQ) are also included as clinical endpoints. [Raghu 2022] 
 
In this PoC study, the testing of selected doses for INS018_055 orally administered is guided 
by phase 1 studies (NCT05154240, CTR20221542). The selected doses of 30 mg QD, 30 mg 
BID, or 60 mg QD will provide insight into comparative safety and efficacy across different 
doses and versus placebo. 
 
A formal sample size calculation based on statistical power considerations will not be 
performed. Further details about the statistical approach, including rationale for sample size, 
is described in the Statistical Analysis Plan. 
3.3  
SELECTION OF STUDY POPULATION 
This Phase IIa study will include patients with IPF with and without background SoC 
antifibrotic therapy (nintedanib or pirfenidone). Determination of study criteria was guided 

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by studies of other therapies studied in IPF [Oguro 2015] [Richeldi 2014] and consultation 
with pulmonologists.  
This study will aim to assign15 patients in each treatment arm. Approximately 70 patients 
will be enrolled to ensure approximately 60 patients complete treatment of 12 weeks. All 
patients enrolled into the study must meet all inclusion criteria (section 3.3.2) and no 
exclusion criteria (section 3.3.3) as outlined, respectively.  
Subjects being treated with nintedanib or pirfenidone at the time of randomization will be 
maintained on their respective therapy throughout the study. The 1:1:1:1 randomization 
scheme will eliminate selection bias, allow for balanced allocation, and contribute to internal 
study validity.  
The screening period will be 30 days during which subject eligibility will be evaluated. If a 
patient is unable to complete the necessary study procedures due to unforeseen circumstances 
or because of the need for retesting, the screening period can be extended by a maximum of 2 
weeks for a total allowed screening time of 44 days. 
A sufficient number of male and female patients with a confirmed diagnosis of IPF will be 
screened to meet the study enrollment goal. Screening for this study is competitive. 
Screening will simultaneously cease at all study sites once a sufficient number of patients has 
been screened. At the time of this notice, subjects who are currently in screening will be 
permitted to continue to study enrollment if they are determined to be eligible. 
Documentation of screening results, including number of subjects screened, number of 
subjects who meet study criteria, number of subjects who do not meet study criteria, and 
reason for screen failure, will be captured in the Investigator Site File (ISF). A log of all 
subjects enrolled into the study, defined as having signed and dated informed consent, will be 
maintained regardless of the 
. If a patient is enrolled in 
error, such as not meeting all inclusion criteria or meets any exclusion criteria on the day of 
enrollment, the sponsor should be contacted immediately.  
3.3.1 
Main Diagnosis for Study Entry 
Subjects who have a diagnosis of IPF, meet all inclusion (section 3.3.2) and no exclusion 
criteria (section 3.3.3) are eligible to be enrolled in the study.  Please refer to Source 
Documents (section 8.3.1) for the documentation requirements pertaining to the inclusion 
criteria and exclusion criteria.  

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3.3.2 
Inclusion Criteria 
1. Informed consent signed and dated at screening visit, prior to initiation of any study 
related procedures, and in accordance with ICH-GCP and local legislation 
2. 
 time of signing informed consent 
3. Diagnosis of IPF confirmed by investigator and according ATS/ERS/JRS/ALAT Clinical 
Practice Guideline. The current ATS/ERS/JRS/ALAT Clinical Practice Guideline at the 
time of diagnosis should be referenced, i.e., 2022  
a. Diagnosis must be confirmed by HRCT scan. HCRT scan must be performed 
within 12 months prior to screening and, if available, surgical lung biopsy. If an 
HRCT scan within 12 months prior to screening is not available, a scan to qualify 
for study eligibility may be performed during the screening period. If HRCT is 
equivocal, surgical lung biopsy results may be used.  
4. Maintenance of ADL with supplemental oxygen up to a maximum of 6 L/min is allowed 
5. Ability to walk > 150 meters during the 6MWD at Visit 1. Supplemental oxygen up to 6 
L/min may be added 
6. 
 40% predicted normal at Visit 1 as confirmed through central review 
7. Absence of relevant airway obstruction defined as prebronchodilator FEV1/FVC ratio > 
0.7 (Tiffeneau-Pinelli index) at Visit 1 as confirmed through central review 
8. Diffusing capacity of lung for carbon monoxide (DLCO) corrected for hemoglobin  
25% and < 80% predicted normal at Visit 1  
9. Subjects with background pirfenidone or nintedanib may be enrolled if their regimen of 
antifibrotic therapy has been stable for > 8 weeks prior to Visit 1 
10. Subjects who were previously treated with pirfenidone or nintedanib and discontinued 
this treatment may be enrolled if it has been > 4 weeks since they discontinued this 
treatment and there is no plan for them to restart this treatment during the study 
11. Subjects who have never received SoC treatment pirfenidone or nintedanib are eligible to 
participate if they meet all other study eligibility criteria and have discussed all SoC 
treatment options with their physician 
 

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12. Subjects must agree to use acceptable contraceptive methods during the study to avoid 
pregnancy, from first dosing day (Visit 2, Day 1) until 3 months after study completion 
(Visit 7, EOS):  
a. Female subjects of childbearing potential must have a negative pregnancy test 
result at Visit 1 
b. Female subjects not of childbearing potential, defined as > 6 weeks after 
hysterectomy with or without surgical bilateral oophorectomy, or postmenopausal 
(> 12 months since natural amenorrhea) are not required to have a negative 
pregnancy test at Visit 1. In questionable cases, a blood sample with simultaneous 
levels of follicle-stimulating hormone (FSH) > 40 U/L and estradiol < 30 ng/L is 
confirmatory 
c. Male subjects with partners of childbearing potential must agree to use acceptable 
contraceptive methods during the study to avoid pregnancy in their female 
partners from first dosing day (Visit 2, Day 1) until 3 months after study 
completion (Visit 7, EOS)  
d. Acceptable methods of contraception include: barrier contraception and a 
medically accepted contraceptive method for the female partner (intrauterine 
device with spermicide, hormonal contraceptive used for > 2 months prior); true 
sexual abstinence (when this is in line with the preferred and usual lifestyle of the 
subject); or surgically sterilized, including vasectomy for men. Women not of 
childbearing potential do not need to follow any contraceptive method 
3.3.3 
Exclusion Criteria 
1. Presence of other clinically significant airway disease that may, in the opinion of the 
investigator, impact the study safety or efficacy objectives, such as cystic fibrosis, active 
aspergillosis, active tuberculosis, or other serious concomitant respiratory disorder other 
than pulmonary fibrosis. Investigators are encouraged to discuss eligibility of subjects 
with respiratory diagnoses other than IPF with the medical monitor before study 
enrollment if there is uncertainty over the potential to impact study outcomes 
a. Subjects with emphysema or asthma may be included if fibrosis is the major 
contributing factor to the subject's respiratory disorder upon HRCT central 
overread. 
b. Subjects with comorbid emphysema or asthma may be eligible if all the following 
are true: 

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i. Receiving < 2 controller therapies (2 different mechanisms of action) and 
no changes to their controller regimen within 3 months before dosing (Day 
1)  
ii. No disease exacerbation that required systemic corticosteroids or 
hospitalization within the past 12 months before dosing (Day 1) 
iii. Stable comorbid disease in the opinion of the investigator 
iv. Extent of emphysema on CT scan does not exceed the extent of fibrotic 
changes as assessed by investigator review of HRCT and all other entry 
criteria (e.g., FEV1/FVC > 0.7) are met upon central overread 
2. Subjects with contraindications for forced expiratory maneuvers during  pulmonary 
function testing 
3. Coronavirus disease (COVID-19): 
a. Confirmed COVID-19 infection at Visit 1 or at Visit 2, either by reverse 
transcription polymerase chain reaction test or by rapid antigen test 
i. Subjects who previously had a positive COVID-19 test result at Visit 1 or 
Visit 2 may be reconsidered for study enrollment after they recover from 
the infection as confirmed by a negative retest before enrollment 
b. History of severe COVID-19 infection requiring hospitalization within the last 6 
months prior to Visit 1 
c. History of Long COVID-19, defined as symptoms beyond 12 weeks of acute 
infection, that has not fully resolved prior to Visit 1 
d. COVID-19 vaccine within 7 days before Visit 2 (Dosing day 1). Any systemic 
symptoms, e.g., myalgia, fever, chills, fatigue, after COVID-19 vaccine should 
have subsided < 2 days before Visit 2  
4. Pulmonary hypertension that is clinically relevant or severe as deemed by the investigator 
5. Acute IPF exacerbation within 4 months prior to Visit 1 and/or during the screening 
period, as determined by the investigator 
6. Upper or lower respiratory tract infection that has not fully resolved within 4 weeks prior 
to Visit 1 and/or before Visit 2 (Day 1). Patients who have had an upper or lower 
respiratory tract infection within 4 weeks prior to Visit 1 and/or before Visit 2 (Day 1) 
may be rescreened once they have recovered in the opinion of the investigator 
7. Subject is active on the lung transplantation register or expected to become active on the 
lung transplant register within 6 months prior to Visit 1 based on the opinion of the 
investigator. Patients who were previously assessed for lung transplantation are eligible if 
they are not actively waiting for a transplant  
8. Subject has a history of lung volume reduction surgery or lung transplant 

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9. Current smoker. All inhaled products, including cigarettes, pipes, cigars, e-cigarettes/ 
vaping, and marijuana, are prohibited throughout the study. Prior smokers are eligible if 
they have not used any nicotine- or tobacco-containing products for > 3 months prior to 
Visit 1 
10. BMI > 40 kg/m2 
11. Subjects with AST or ALT  1.5 times ULN or total Bilirubin  1.5 times ULN at Visit 1 
12. 
 60 mL/min/1.73m2 (CKD-EPI formula) at Visit 1 
13. Subjects with uncontrolled hypertension (systolic pressure > 160 mmHg or diastolic 
pressure > 95 mmHg despite treatment with anti-hypertensive treatments) at Visit 1. Sites 
may repeat the blood pressure measurement once after > 10 minutes and use the lower 
values to determine eligibility 
14. Subjects with unstable cardiac angina or myocardial infarction within 6 months prior to 
Visit 1 
15. Subjects taking oral corticosteroids at a daily dose of >15 mg prednisone or equivalent, 
combination of prednisone, azathioprine, and N-acetylcysteine, ambrisentan, or imatinib 
within 30 days prior to Visit 2 
16. Subjects with any documented active or suspected malignancy or history of malignancy 
within 5 years prior to Visit 1, except appropriately treated basal cell carcinoma of the 
skin, in situ carcinoma of the uterine cervix, or prostate cancer under surveillance that are 
considered cured, inactive, and/or not currently under treatment. 
17. Subjects with known hypersensitivity or contraindications to serine/threonine kinase 
inhibitors (including but not limited to the following FDA-approved kinase inhibitors 
such as Abemaciclib, Belumosudil, Dabrafenib, Encorafenib, Everolimus, Netarsudil, 
Palbociclib, Ribociclib, Sirolimus, Temsirolimus, Trilaciclib and Vemurafenib, etc) 
[Roskoski 2023].  
18. Subjects with any condition or treatment possibly affecting drug absorption, e.g., 
gastrectomy, metoclopramide 
19. Significant trauma or major surgery within 3 months prior to Visit 1, or planned major 
surgery during the study 
20. Subjects taking restricted medications, e.g., moderate/strong CYP3A4/CYP1A2 
inhibitors/inducers or medications primarily metabolized by CYP3A4/CYP1A2, or who 
have consumed grapefruit or grapefruit juice, pomelo, Seville orange or Seville orange-
containing products juice within 48 hrs before Day 1 [
before Day 1 (Imai 2008)], all of which are considered likely to interfere with safe 
conduct of the study 

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21. Subjects who are currently enrolled or have previously participated in interventional 
clinical studies within 30 days or 5 half-lives of investigational therapy (whichever is 
longer) prior to Visit 1 
22. Subjects with other medical or psychological condition, which in the opinion of the 
investigator and/or medical monitor, might create undue risk to the subject, interfere with 
protocol requirements, or 
the study  
23. Subjects who are pregnant or lactating 
24. Subjects with active alcohol or drug abuse, in the opinion of the investigator 
25. Subjects with underlying chronic liver disease (Child Pugh A, B or C) 
26. Subjects with positive human immunodeficiency virus (HIV) or positive for hepatitis B 
surface antigen (HBsAg) or positive for HCV antibody (HCVAb) or positive for specific 
treponema pallidum antibody or positive for syphilis will be excluded  
a. HBV positive is defined as HBsAg positive or HBcAb positive
HBV DNA 
positive. HBcAb positive
HBV DNA negative is allowed  
b. HCV positive is defined as HCV antibody positive
HCV RNA positive. HCV 
antibody positive
HCV RNA negative is allowed  
c. HIV positive is defined as HIV antibody positive. 
27. Subjects with evidence of active infection (chronic or acute) based on clinical exam or 
laboratory findings at Visit 1 or Visit 2  
28. The subject has 12-lead ECG demonstrating corrected QT interval by Fridericia (QTcF) > 
450 msec for males and > 470 msec for females, or a QRS interval > 120 msec at Visit 1. 
If these parameters are met at first take, the ECG should be repeated 2 more times. The 
average of the 3 QTcF (or QRS interval) values should be used in that case to determine 
the sub
 
29. Subjects with a significant disease or condition (other than IPF) which, in the opinion of 
the investigator, may put the subject at risk because of participation, interfere with study 
 ability to participate in the study 
30. Subjects with any medical condition that leads to a life expectancy < 12 months 
31. Previous randomization in this study 
 
3.3.4 
Withdrawal of Subjects From Treatment or Assessments 
Patients may discontinue study treatment or withdraw consent to study participation as a 
section 3.3.4.1 and section 3.3.4.2. 

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Every effort should be made to keep the subjects enrolled in the study. If possible, subjects  
will stay on study treatment, or at least continue to collect important study data. Subjects who 
choose to withdraw from the study will have an EOT visit within 7 days according to the 
Schedule of Assessments. Strategies to control the withdrawal rate include careful subject 
selection, clear informed consent including appropriate and thorough explanation of study 
requirements and procedures prior to study enrolment, as well as explanation of the 
consequences of study withdrawal. Investigators are encouraged to discuss a subject s 
withdrawal with the medical monitor prior to deciding to discontinue. 
 
The decision to discontinue trial treatment or withdraw consent to study participation and the 
reason for either of these decisions must be documented in the patient files and eCRF. If 
applicable, consider the requirements for Adverse Event collection reporting (5.6.4) 
3.3.4.1 
Discontinuation of Study Treatment 
A subject enrolled in the study will be considered to discontinue study treatment if: 
 The subject indicates wanting to discontinue study treatment, without the need to 
justify this decision 
 The subject is shown to be repeatedly non-compliant with important study 
procedures. In addition, the investigator and sponsor representative determine that the 
subject is not willing or unable to adhere to future study requirements  
 The subject experiences unacceptable adverse events in the opinion of the 
investigator 
 The subject needs to take concomitant medication(s) that interfere with the 
investigational medicinal product or other study treatment (4.2.2) and would 
constitute a safety hazard 
 The subject can no longer receive study treatment for medical reasons, such as 
surgery, adverse events, other diseases, or pregnancy.  
 For subject with BMI < 18.5 kg/m2 at Visit 2 only: unexplained and clinically 
significant weight loss (> 10%) 
 The subject has clinically relevant changes in ECG requiring intervention 
 The subject has QTcF > 500 ms in ECG 
In case of a temporary reason, trial treatment should be restarted if medically justified. 
Investigator should consult with the medical monitor. If new efficacy/safety information 
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warranted, there may be pausing or stopping of study treatment or taking other appropriate 
action to guarantee the safety of study patients. If study treatment is discontinued, if possible, 
subjects should follow the study schedule as outlined in the Schedule of Study Activities to 
complete the subsequent visits. 
3.3.4.2 
Withdrawal of Consent to Study Participation 
Subjects may withdraw their consent to study participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the patient and explain the difference between study 
treatment discontinuation and withdrawal of consent to study participation. In addition, the 
investigator should explain the options for continued follow-up after study treatment 
discontinuation as described in section 6.4. 
3.3.4.3 
Discontinuation of Study by the Sponsor 
InSilico Medicine reserves the right at any time to discontinue the study overall or at a 
specific study site for the following reasons: 
1. Failure to meet expected enrollment goals 
2. New efficacy or safety information about INS018_055 invalidating the earlier 
positive benefit-risk-assessment (section 1.4) 
3. Deviations from GCP, study protocol, or the contract impairing the appropriate 
conduct of the study 
In the case of sponsor-determined study termination, further follow up of subjects will occur 
as described in section 6.4. InSilico Medicine will work with the investigator and study site 
to reimburse for reasonable expenses incurred and related to reasons 1 and 2 above. 
 

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INS018_055 has a manageable side effect profile; the majority of TEAEs are mild and 
transient. The phase 1 studies are background, and final results are pending.  
 
This proposed Phase IIa study will test 2 active doses of INS018_055 (30 mg and 60 mg) 
orally administered as 30 mg QD, 30 mg BID, or 60 mg QD for a period of 12 weeks. 
Nonclinical efficacy and safety studies have shown that pharmacological effects start at a 
24-hour exposure level [area under the concentration-time curve (AUC0-24)] of approximately 
300 h*ng/mL and reach a plateau at levels greater than 900 h*ng/mL. The no observed 
adverse effect level (NOAEL) exposures (AUC0-24) in the 28-day toxicity studies in mice 
(3820 h*ng/mL for female, 4440 h*ng/mL for male) and dogs (2010 h*ng/mL for female, 
2600 h*ng/mL for male) were clearly higher than the anticipated exposures associated with a 
pharmacologically active dose. The NOAEL exposure levels (AUC0-24) in the 3-month 
toxicity in mice (4300 h*ng/mL for males and 5250 h*ng/mL for females) and dog (1000 
h*ng/mL for males and 1030 h*ng/mL for females) were close to the exposure required for a 
maximum pharmacological effect. Thus, the therapeutic exposure levels (AUC0-24) should be 
greater than 300 h*ng/mL and not markedly exceed 1000 h*ng/mL. 
 
Based on these data and supported by physiologically based pharmacokinetic (PBPK) 
analysis (GastroPlus) of the available phase 1 data, the following dose levels and dosing 
schemes of INS018_055 have been selected for the planned phase IIa study: INS018_055 
30 mg QD or 60 mg QD either as a single daily dose or in 2 divided doses  alone or adjunct 
to SoC pirfenidone or nintedanib according to their respective labels. The doses of 30 mg QD 
and 60 mg QD in healthy volunteers after 7-day oral administrations led to exposure levels 
(AUC0-24 in plasma) of 438 and 1210 h*ng/mL on Day 7 when the steady state was reached, 
respectively (section 1.2.2). Thus, the selected doses are expected to be in the 
pharmacological range from half maximum efficacy to maximum efficacy and not 
anticipated to markedly exceed the NOAEL exposures in nonclinical species. Additionally, 
there was mean bound fraction (%) of 97.2% in human plasma and 93% in Beagle dog 
plasma, with about a 2-fold lower free fraction in human plasma. Therefore, from the free 
exposure perspective, 60 mg QD with the total exposure of 1210 h*ng/mL in humans will not 
exceed the free exposure at the dog NOAEL. 
 
The dose of 60 mg/day will be given either as a single daily dose (60 mg QD) or in 2 divided 
doses per day (30 mg BID). This is based on the results of PBPK modeling of clinical plasma 
concentrations, which showed that the 60 mg QD dose will achieve plasma concentrations 
above the TNIK half maximal inhibitory concentration (IC50) value for approximately 16 

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hours per day, while the BID dose may result in plasma concentrations above the TNIK IC50 
value throughout the whole 24-hour period. By comparison of these 2 dosing schemes, it can 
be clarified whether a permanent inhibition of TNIK is required for maximum therapeutic 
efficacy. 
 
In this phase IIa study, the exposure in patients with IPF at the doses of INS018_055 30 mg 
QD, INS018_055 30 mg BID, or INS018_055 60 mg QD (maximum 60 mg daily) is 
expected to fall within estimated therapeutic range and below the human systemic exposure 
limit of INS018_055 based on animal toxicology studies. In addition, based on the current 
knowledge on pharmacodynamics of INS018_055, nintedanib, and pirfenidone, we do not 
anticipate DDIs among these treatments.  
4.1.3 
Method of Assigning Patients to Treatment Arms 
After the investigator and/or study staff confirm that a subject has met all eligibility criteria 
(meet all inclusion criteria and none of the exclusion criteria), each eligible subject will be 
randomized to a treatment group according to a 1:1:1:1 ratio randomization plan. 
Randomization will occur at Visit 2 via Interactive Response Technology (IRT). The 
treatment arms are: 
 INS018_055 30 mg QD  
 INS018_055 30 mg BID  
 INS018_055 60 mg QD  
 Placebo  
4.1.4 
Drug Assignment and Administration of Doses for Each Patient 
The 12-week treatment period begins and ends with Visit 2 and Visit 6, respectively. 
Subjects being treated with background SoC antifibrotic therapy (nintedanib, pirfenidone) at 
the time of randomization will maintain their therapy throughout the study. Subjects will 
orally self-administer their assigned treatment for 12 weeks [until Visit 6 (EOT)].   
 
 
Subjects will be given medicine kits at each visit starting with Day 1 (Visit 2). 
INS018_055 will be supplied as solid, acetate salt drug substance, no excipients, in 
hypromellose capsules, 30 mg of INS018_055 per capsule (calculated as the free base 
form). 
 

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Subjects will be instructed to maintain a consistent treatment schedule for taking their 
assigned treatments. Regardless of treatment arm, subjects will take 3 capsules (two in 
the morning and one in the evening) every day:  
 INS018_055 30 mg QD treatment arm: one INS018_055 capsule + one placebo 
together in the morning; and one placebo in the evening. Subjects should take their 
treatment at the same time every day +/- 30 min with interval of 12 hours between 
doses (+/- 1 hour) and maintain the same schedule for their other medications 
 INS018_055 30 mg BID treatment arm: one INS018_055 30 mg + one placebo 
together in the morning; and one INS018_055 30 mg in the evening. Subjects should 
take their treatment at the same time every day +/- 30 min with interval of 12 hours 
between doses (+/- 1 hour) and maintain the same schedule for their other 
medications 
 INS018_055 60 mg QD treatment arm: two INS018_055 together in the morning and 
one placebo in the evening. Subjects should take their treatment at the same time 
every day +/- 30 min with interval of 12 hours between doses (+/- 1 hour) and 
maintain the same schedule for their other medications. 
 Placebo arm: two placebo together in the morning and one placebo in the evening. 
Subjects should take their treatment at the same time every day +/- 30 min with 
interval of 12 hours (+/- 1 hour) between doses and maintain the same schedule for 
their other medications. 
Table 5. Dosage and Treatment Schedule 
Regardless of treatment arm, subjects will take 3 capsules (two in the morning and one 
in the evening) every day 

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4.1.5.2 
Unblinding and Breaking the Code 
Emergency unblinding will be available to the investigator via IRT. It must only be used in 
an emergency situation when the identity of the study drug must be revealed in order to 
provide appropriate medical treatment or otherwise assure the safety of study participants. 
Investigators are encouraged to discuss the need for unblinding with the medical monitor as 
warranted before unblinding the subject. The reason for unblinding must be documented in 
the source documents and/or appropriate case report form (CRF). 
 
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for InSilico Medicine to access the randomization code for 
individual subjects during the course of the study. Access to the code will only be given to 
authorized InSilico Medicine Pharmacovigilance (PV) team members for processing in the 
PV database system and not be shared further.  
4.1.6 
Packaging, Labeling, and Re-supply of the Study Treatment  
The study treatment INS018_055 will be provided by InSilico Medicine or a designated 
CRO. The INS018_055 capsules will be packaged in high-density polyethylene bottles sealed 
with polypropylene continuous-thread child-resistant caps with an induction sealed and 
aluminum-faced liner. Each bottle is filled with 30 capsules.  
INS018_055 will be packaged and labelled in accordance with the principles of Good 
Manufacturing Practice (GMP). Re-supply to the sites will be managed via an IRT system, 
which will also monitor expiry dates of supplies available at the sites. For details of 
packaging and the description of the label, refer to the ISF.  
4.1.7 
Storage Conditions  
Study treatments, including INS018_055 and placebo, will be kept in their original packaging 
in a secure limited access storage area according to the recommended storage conditions on 
the provided medication label. A temperature log must be maintained for documentation. The 
products will be stored at 15-25 C. If the storage conditions are found to be outside the 
specified range, the investigator should contact InSilico Medicine immediately. 
4.1.8 
Drug Accountability  
The investigator or designee will receive the investigational drugs delivered by InSilico 
Medicine (or designated CRO) when the following requirements are fulfilled: 

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 Approval of the clinical study protocol by local IRB / ethics committee, HA/RA 
approval 
 Availability of a signed and dated clinical study contract between InSilico Medicine 
and the investigational site 
 Approval/notification of the regulatory authority, e.g., competent authority 
 Availability of the curriculum vitae of the Site Principal Investigator 
 Availability of a signed and dated clinical study protocol 
 Availability of the proof of a medical license for the Site Principal Investigator 
 Availability of signed and dated FDA Form 1572 (if applicable) 
Investigational drugs are not allowed to be used outside the context of this study protocol. 
Investigational drugs must not be forwarded to other investigators, clinicians, or clinics 
internal or external to the study site. Subjects should be instructed to return unused 
investigational drug directly to site study staff.  
The investigator or designee must maintain records of the delivery of study treatments, 
including INS018_055 and placebo, to the study site, current inventory at the site, use by 
each subject, and return of products to InSilico Medicine (or designated CRO) or warehouse / 
drug distribution center. The investigator should contact InSilico Medicine about questions 
related to disposal of unused products. InSilico Medicine (or designated CRO) or warehouse 
/ drug distribution center will maintain records of the disposal.  
Documentation of study treatments will include dates, quantities, batch/serial numbers, 
-
medicinal product and study subjects. The investigator or designee will maintain records that 
adequately document that the subjects were provided the doses specified by the Clinical Trial 
Protocol (CTP) and reconcile all investigational medicinal products received from the 
sponsor. At the time of return to InSilico Medicine (or designated CRO), the investigator or 
designee must verify that all unused or partially used study treatments have been returned by 
the clinical study subject and that no remaining study treatments 
possession.  

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Oral corticosteroids 
at daily dose >15 
mg prednisone or 
equivalentc 
Not allowed  
Not allowed 
Not allowedd 
Allowed 
Combination of 
prednisone, 
azathioprine, and N-
acetylcysteine, 
ambrisentan, or 
imatinibe 
Not allowed 
Not allowed  
Not allowed 
Not allowed 
Controller therapies 
for patients with 
COPDf 
Allowed 
Allowed 
Allowed  
Allowed 
Moderate/strong 
CYP3A4 
inhibitors/inducers h 
Allowed  
Not allowed 
Not allowed 
Allowed 
Moderate/strong 
CYP1A2 
inhibitors/inducersg,h 
Allowed  
Not allowed 
Not allowed 
Allowed 
 
a Only allowed for subjects with baseline background SoC pirfenidone or nintedanib as monotherapy that has 
been stable > 8 weeks prior to Visit 1. Subjects will continue to take their own supply of respective therapy 
throughout the study. In no other circumstances will subjects be allowed to take pirfenidone or nintedanib. 
Section 3.3.2 lists the study inclusion criteria. 
b Subjects who enroll into the study and are not currently taking SoC pirfenidone or nintedanib or subjects who 
have never been treated with pirfenidone or nintedanib will not be allowed to take pirfenidone or nintedanib 
during the study. Section 3.3.2 lists the study inclusion criteria  
c Oral corticosteroids at daily dose of >15 mg prednisone or equivalent is not allowed during the 30 days prior 
to randomization (Visit 2).  A table of equivalent doses of corticosteroids can be found in section 10.7 
d Prednisone >15 mg/day or equivalent can be prescribed during the treatment period in case of acute 
exacerbation as described in section 5.6.1.3. A table of equivalent doses of corticosteroids can be found in 
section 10.7 
e Combination of prednisone, azathioprine, and N-acetylcysteine, ambrisentan, or imatinib within 30 days prior 
to Visit 2 is not allowed. Section 3.3.3 lists the study exclusion criteria 
f Controller therapies for subjects with comorbid COPD are allowed if subjects are receiving < 2 controller 
therapies (2 different mechanisms of action) and there have been no changes to their controller regimen within 3 
months prior to Day 1. Section 3.3.3 lists the study exclusion criteria 
g Applies to subjects who are taking SoC pirfenidone 
h Also include Chinese herbal medicine that have DDI potentials. 
 
4.2.2.2 
Restrictions on Diet and Lifestyle 
All inhaled products, including cigarettes, pipes, cigars, e-cigarettes/ vaping, and marijuana, 
are prohibited throughout the study. 

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Subjects should refrain from consuming grapefruit or grapefruit juice, pomelo, Seville orange 
or Seville orange-
during the entire study. These 
are considered likely to interfere with safe conduct of the study. 
Patients should refrain from consuming methylxanthine-containing drinks or foods (such as 
coffee, tea, cola, energy drinks, and chocolate) in the 24 h preceding each on site visit.  
4.2.2.3 
Contraception Requirements 
Subjects must agree to use acceptable contraceptive methods during the study to avoid 
pregnancy, from first dosing day (Visit 2, Day 1) until 3 months after study completion (Visit 
7, EOS). This applies to female subjects of childbearing potential and male subjects with 
partners of childbearing potential. Acceptable methods of contraception include: barrier 
contraception and a medically accepted contraceptive method for the female partner (intra-
uterine device with spermicide, hormonal contraceptive used for > 2 months prior); true 
sexual abstinence (when this is in line with the preferred and usual lifestyle of the subject); or 
surgically sterilized, including vasectomy for men.  
 
4.3 
 TREATMENT COMPLIANCE 
Subjects will be asked to bring remaining study medication, including INS018_055 and 
placebo, as well as empty package material with them to the study visits. Based on capsule 
counts, treatment compliance will be calculated as shown in the formula below. Compliance 
will be verified by the CRA authorized by the sponsor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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phosphatase (AP), Gamma-glutamyl 
transferase (GGT), Creatine kinase (CK),  
CK-MB only if CK is elevated 
Hormones  
 
Thyroid stimulating hormone (TSH), fT3, 
fT4  
Substrates  
 
Plasma glucose, Creatinine, Total bilirubin, 
Direct and indirect bilirubin, Total protein, 
High sensitivity C-Reactive Protein (hs 
CRP), blood urea nitrogen (BUN) or urea, 
Uric acid, Total cholesterol, Triglycerides, 
low density lipoprotein (LDL), high density 
lipoprotein (HDL), Albumin 
Electrolytes  
 
Sodium, Potassium, Chloride, Calcium, 
Inorganic phosphate  
Urine analysis  
 
Qualitative/semi-quantitative, appearance, 
color, pH, specific gravity, glucose, 
erythrocytes, leukocytes, protein, 
urobilinogen, urine bilirubin. 
Guidance on transaminase values and treatment management are shown below. Site 
investigators should follow Table 9, and refer to the package insert for nintedanib and 
pirfenidone where relevant. LFT assessments should be performed prior to starting treatment 
for INS018_055, nintedanib, and pirfenidone. Adjustments to treatment should be made 
according to the AST and ALT laboratory values as outlined below. 
 
Table 9. Guidance on Transaminase Laboratory Values and Treatment Management 
Criteria 
INS018_055 
Nintedanib or Pirfenidone 
LFT assessment schedule 
 Conduct LFT prior to start 
of treatment 
 
 Conduct LFT prior to 
start of treatment 
 Follow package insert 
AST/ALT  < 3x ULN 
 Continue treatment  
 Follow package insert 
AST/ALT  > 3x ULN  
5x ULN without liver 
damage  
 Interrupt treatment until 
return to 1.5x ULN and 
normal bilirubin  
 Follow package insert 

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AST/ALT  > 3x ULN  
5x ULN with signs of 
liver damage  
 Discontinue treatment 
 Follow package insert 
AST/ALT  > 5x ULN 
 Discontinue treatment  
 Perform hepatic 
serologies, ultrasound of 
the liver, and other tests 
per investigator discretion  
 Follow package insert 
 
5.3 
PATIENT-REPORTED OUTCOMES 
Subjects should complete the patient reported outcome questionnaire on his/her own as 
defined in the Schedule of Study Activities. Ideally, the subject should complete the 
questionnaire in a quiet area/room prior to any other study-related examination. Study site 
personnel will check the questionnaires for completeness prior to the subject leaving the site, 
but the response to each item should not be scrutinized. In instances where a patient cannot 
give or decide upon a response, no response should be recorded. The scores will be 
transcribed into the eCRF by designated site personnel.  
5.3.1 
Leicester Cough Questionnaire 
The LCQ (section 10.1) will be self-administered by the subject at study visits according to 
the Schedule of Study Activities. The LCQ is a 19-item questionnaire that assesses cough 
related QoL (Birring 2003). It examines 3 domains: physical, psychological and social. The 
24-
hour time frame. The range for the total score on the LCQ is 3-21, and each domain score 
ranges from 1-7. The overall score for the LCQ for each patient is calculated by adding the 
individual domain scores. A higher score indicates a better QoL.  
 
5.4 
PHYSICAL EXAMINATION 
A complete physical examination will be performed at the time points specified in the 
Schedule of Study Activities. Physical examination includes, at a minimum, assessment of a 
 extremities, and 
skin. All abnormal findings at baseline will be recorded on the Baseline Condition eCRF 
page. New abnormal findings or worsening of baseline conditions detected at subsequent 

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physical examinations, if judged clinically relevant, will be recorded as adverse events on 
the appropriate eCRF page.  
Measurement of height will be performed at the screening visit only. 
Body weight will also be evaluated at each visit. Body weight should be measured with the 
patient wearing indoor clothing and without shoes. For each subject, weight should be 
measured consistently in the morning at all visits after emptying the bladder. The results 
must be included in the source documents available at the site.  
5.5 
VITAL SIGNS 
Vital signs will be evaluated at the time points specified in the Schedule of Study Activities 
and prior to blood sampling. This includes body temperature, systolic and diastolic blood 
pressure and pulse rate (electronically or by palpation count for 1 minute). Subjects should 
be in a seated position after 5 minutes of rest. The results must be included in the source 
documents available at the site.  
5.6 
ADVERSE EVENTS 
Safety will be assessed through the collection and evaluation of AEs, including TEAEs, 
SAEs and AESIs. Safety will also be assessed based on physical examinations, vital sign 
measurements, clinical laboratory assessments and ECGs. Common Terminology Criteria 
for AEs (CTCAE) v5.0 grading scale will be used for grading of AEs. A DSMB will oversee 
the safety of the study and will have scheduled meetings. 
 
5.6.1 
 Definitions of Adverse Event 
5.6.1.1 
 Adverse Event 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. The following should also be recorded as an AE in the EDC: 

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 Worsening of the underlying disease or of other pre-existing conditions 
 Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator 
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the EDC. 
5.6.1.2 
 Serious Adverse Event 
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria listed below. All SAEs should be recorded in the EDC. 
 Results in death 
 Life-threatening, defined as an event in which the patient was at risk of death at the 
time of the event. It does not refer to an event that hypothetically might have caused 
death if it were more severe 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Congenital anomaly / birth defect 
 Deemed serious for any other reason if it is an important medical event based on 
appropriate medical judgement which may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias, convulsions that do 
not result in hospitalization, or development of dependency or abuse 
 
5.6.1.3 
 Acute IPF Exacerbation 
The most recent definition of acute IPF exacerbation will be used. [Collard 2016] The AEs 
will not be adjudicated. Acute IPF exacerbation will be defined as an acute, clinically 
significant, respiratory deterioration characterized by evidence of new widespread alveolar 
abnormality with all of the following: 
 Acute worsening or development of dyspnea typically of < 1 month duration 

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 Computed tomography scan with new bilateral ground-glass opacity and/or 
consolidation superimposed on a background pattern consistent with IPF 
 Deterioration not fully explained by cardiac failure or fluid overload. 
Events that are clinically considered to meet the definition of acute IPF exacerbation but fail 
 (as long as this assessment persists).  
5.6.1.4 
 AEs of Special Interest 
 
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this study, e.g., the potential for AEs based on knowledge from 
other compounds in the same class.  
The following are considered potential  AESIs:  
Gastrointestinal: diarrhea, nausea, vomiting, clinical bleeding 
Hepatic injury. A hepatic injury is defined by the following alterations of hepatic 
laboratory parameters:  
 An elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
-
-
fold ULN measured in the same blood draw sample, or  
 
-fold ULN  
These lab findings constitute a hepatic injury alert. Subjects with these lab abnormalities 
need to be followed up. In case of clinical symptoms of hepatic injury, i.e., icterus, 
unexplained encephalopathy, unexplained coagulopathy, right upper quadrant abdominal 
pain, etc., without available laboratory results (ALT, AST, total bilirubin), the investigator 
should make sure these parameters are analyzed. If necessary, these parameters can be 
analyzed in an unscheduled blood test. Should the results meet the criteria of hepatic injury 
alert, the investigator should contact the medical monitor. 

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5.6.2 
 Intensity (severity) of Adverse Events 
The intensity (severity) of the AE should be judged based on the CTCAE v5.0. 
5.6.3 
 Causal Relationship of Adverse Events 
Medical judgement should be used to determine whether there is a reasonable possibility of 
a causal relationship between an AE and the given study treatment. All relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history should be considered. 
Site investigator should assess the AE based on 5 scales for the causality/ relatedness: 
 
 Definite: The AE is clearly related to the investigational drug or study treatment  
 Probable: The AE is likely related to the investigational drug or study treatment  
 Possible: The AE may be related to the investigational drug or study treatment  
 Unlikely: The AE is doubtfully related to the investigational drug or study treatment  
 Unrelated: The AE is clearly NOT related to the investigational drug or study 
treatment 
 
5.6.4 
 Collecting and Reporting of Adverse Events 
5.6.4.1 
 Collection of AEs 
The investigator shall maintain and keep detailed records of all AEs in the study subject 
files. The following must be collected and documented in the eCRF by the investigator:  
 
From the signing of the informed consent 
all AEs (serious and non-serious) and all AESIs must be collected and documented in 
the eCRF. All non-serious ongoing AEs that occurred prior to the time of first dose 
will be captured as medical history. 
 
S visit, the investigator does not need to actively monitor 
the patient for new AEs. However, the investigator should report any study 
treatment-related SAEs and study treatment-related AESIs of which the investigator 
may become aware of by any means of communication, e.g., phone call. These AEs 
should be reported in the eCRF. 

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5.6.4.2 
 Reporting AEs to the Sponsor and Timelines 
The investigator must report SAEs on the SAE form within 24 hours to the InSilico 
 (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions, 
the investigator could inform the InSilico Medicine upfront via telephone and or via email. 
This does not replace the requirement to complete the SAE report (in the EDC).  
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. 
information can be obtained. 
5.6.4.3 
 Pregnancy 
In rare cases, pregnancy might occur in a clinical study. Once a patient has been enrolled in 
the study and has taken study medication, the investigator must report any drug exposure 
during pregnancy in a study subject within 24 hours. This can be done by means of Part A of 
 
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
study subject becomes pregnant. This requires written consent of the pregnant partner. 
Reporting and consenting must be in line with local regulations. The ISF will contain the 
trial specific information and consent for the pregnant partner.  
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed and reported to the InSilico 
Monitoring Form for Clinical Studies (Part B). As pregnancy itself is not to be reported as an 
AE, in the absence of an accompanying SAE and/or AESI, only the Pregnancy Monitoring 
Form for Clinical Studies and not the SAE form is to be completed. The ISF will contain the 
Pregnancy Monitoring Form for Clinical Studies (Part A and B). If there is an SAE and/or 
AESI associated with the pregnancy an SAE and/or AESI form must be completed in 
addition.  

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5.7 
ELECTROCARDIOGRAM RECORDING 
5.7.1 
ECG Procedure 
In order to achieve a stable heart rate (HR) at rest and to assure high-quality recordings at 
comparable resting phases, all ECGs will be recorded for 10-sec duration after the subjects 
have rested for  10 min in a supine position. Study site staff will be instructed to assure for 
the subject a relaxed and quiet environment to optimize complete rest conditions during the 
recordings. Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded 
using a computerized electrocardiograph, at the time points given in the Schedule of Study 
Activities. Electrode placement will be performed according to the method of Wilson, 
Goldberger and Einthoven or limb leads modified by Mason and Likar (hips and shoulders 
instead of ankles and wrists). For patient eligibility at screening, if the ECG parameters are 
not met at first take, the ECG should be repeated 2 more times, in which case the average of 
the 3 QTcF (or QRS interval) values s
. 
Additional (unscheduled) ECGs may be recorded for safety reasons.  
5.7.2 
ECG Evaluation 
This will include the determination of cardiac QRS-
algorithm as well as the intervals RR, PR, QRS and QT measured semi- automatically. Heart 
rate (HR) and the QT interval corrected for HR (QTcF) will be determined by the site 
equipment. All ECGs will be evaluated by the investigator or a designee. For the inclusion 
(section 3.3.2) or exclusion (section 3.3.3) of a subject and for the assessment of cardiac 
safety during the study, the QT and QTcF values generated by the ECG machines will be 
used. If the ECG machines cannot provide QTcF values directly, QTcF can be calculated 
using the Fridericia (QTcF) formula: QTcF = QT/RR1/3, where RR represents RR interval 
and RR=60/HR. 
5.8 
SPIROMETRY 
FVC and FEV1 will be assessed using standardised spirometry equipment which will be 
provided centrally with supplies of pre-calibrated disposable flow sensors.These sensors 
demonstrate variability within the required standards of +/-3% determined by the American 
Thoracic Society (ATS)/European Respiratory Society (ERS) 2019 guidelines. [Graham 
2019]. The single use Pneumotach (PT) including a mouthpiece that is pre-calibrated as part 
of the manufacturing process and is tested within the range of +/-1.5% of the expected value.  
  

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Efforts should be made to schedule spirometric measurements at approximately the same 
time of the day at each visit ± 90 min. Baseline measurement (Visit 2) will be the reference 
visit.  On days of study visits, subjects must refrain from strenuous activity at least 12 hours 
prior to pulmonary function testing. Subjects should also avoid cold temperatures, 
environmental smoke, dust, or areas with strong odors, e.g., perfumes. If treated with 
bronchodilators, the wash-out period for short-acting bronchodilators, long-acting twice-
daily bronchodilators, and long-acting once-daily bronchodilators is 4 hours, 12 hours, and 
24 hours, respectively. Subjects should be instructed to do their best to adhere to this. 
Spirometry will be conducted while the patient is in a seated position. It is preferable that the 
same trained individual performs the PFTs for a given subject. The best of three efforts will 
be defined as the highest FEV1 and the highest FVC each obtained on any of three blows 
meeting the 2019 ATS/ERS guideline criteria (maximum of eight attempts) [Graham 2019]. 
Spirometry results captured by spirometers provided by the sponsor will be electronically 
transmitted and confirmed by central reading. Only data from acceptable spirometry 
maneuvers will be used for eligibility confirmation and data analysis. For baseline and EOT 
visits, if multiple acceptable spirometry results are reported for one visit, mean values of the 
acceptable results will be used for data analysis. For detailed information, refer to the 
statistical analysis plan 
For each subject, spirometry testing and DLCO should always start at approximately the 
same time of day. DLCO should always be performed after spirometry after subjects are 
well-rested. 
5.9 
DLCO 
Each study site will use its own equipment to assess carbon monoxide diffusion capacity 
during the single breath diffusion test and conduct all measurements using with the same 
equipment. Single breath diffusion test will be carried out according to the ATS/ERS 
guidelines. [Graham 2017] Before the test, site staff should thoroughly demonstrate the 
maneuvers and be certain that subject understands the instructions. The mean value 
between > 2 acceptable tests should be reported. Sites will enter the absolute DLCO results 
using data from their own equipment software. The predicted DLCO, % predicted DLCO, 
and corrected % predicted DLCO will be calculated by statistician programmer using the 
GLI equation. Please refer to section 10.2 for additional information.  

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Only data from acceptable DLCO maneuvers will be used for eligibility confirmation. No 
more than three DLCO sessions should be performed during the screening period. Baseline 
measurement (Visit 2) will be the reference visit.   
 
5.10 
6MWD 
Subjects should rest for 30 minutes prior to performing the 6-minute walk test. Instruct the 
subject to walk on a flat, hard surface. Time the walk for 6 minutes. After 6 minutes have 
passed, measure the distance the patient has walked. [Solway 2001] For subjects who require 
supplemental oxygen to maintain their ADL (SpO2<88% at resting state), up to a maximum 
of oxygen 6 L/min is allowed so that patients should maintain SpO2 
 83%. [du Bois 2011] 
[ATS 2002] [Lama 2003] [Hu 2022] 
 
Before and after the 6MWD, subjects will complete the Borg scale. Subjects will grade their 
level of dyspnea on a scale of 0 (no dyspnea) to 10 (maximal dyspnea) before walking.  
After walking, subjects will be reminded of the level they selected pre-walk and then asked 
to grade again their level of dyspnea. [Borg 1982] [ATS 2002] 
 
5.11 
DRUG CONCENTRATION OF MEASUREMENTS AND 
PHARMACOKINETICS 
 
5.11.1 
Assessment of Pharmacokinetics 
Blood samples for plasma concentrations of INS018_055 and metabolites (INS018_063 and 
INS018_095) will be collected at specific time points: 
 
Visit 2: pre-dose and post-dose  
 
Visits 3, 4 and 5: pre-dose  
 
Visit 6 (EOT): pre-dose and post-dose   
 

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Blood samples for serum or plasma concentrations of biomarkers will also be collected: 
 
Visit 2: pre-dose 
 
Visits 3, 4 and 5: pre-dose 
 
Visit 6 (EOT): pre-dose 
 
See section 10.4 for further details. Date and clock time of drug administration and PK 
sampling will be recorded in the CRFs. The actual sampling will be used for determination 
of PK parameters.  
 
5.11.2 
Monitoring of Concentrations of Background SoC Therapy 
Blood samples for plasma concentrations of pirfenidone and nintedanib will be collected at 
the following time points (section 10.4) 
 Visit 2: pre-dose (i.e., prior to pirfenidone or nintedanib and INS018_055 dosing, in 
order to get the baseline trough plasma concentration of pirfenidone or nintedanib) 
 Visits 3, 4, 5, and 6: pre-dose 
 
5.11.3 
Methods of Sample Collection 
During the treatment period, at Visits 2 through 6 subjects will receive a study diary to 
precisely record the time of drug intake for the days preceding the next visit.  
For quantification of drug plasma concentrations of INS018_055, venous blood will be 
collected using a pre-labeled ethylenediaminetetraacetic acid (EDTA) containing blood 
drawing tube at the times indicated in the and section 10.4. Blood will be withdrawn by 
means of either an indwelling venous catheter or by venipuncture with a metal needle. A 
detailed description of sample collection and handling is provided in the Lab Manual in the 
ISF.  
After completion of the trial the plasma samples may be used for further methodological 
investigations, e.g., for stability testing, assessment of metabolites. However, only data 
related to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) 
will be generated by these additional investigations. The study samples will be discarded 

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after completion of the additional investigations but not later than 5 years after the final 
study report has been signed. 
5.11.4 
Analytical Determinations 
5.11.4.1 
Analytical Determination of Plasma Concentrations 
All samples from patients on active study treatment will be analyzed. For subjects on 
placebo, only one time point (one hour post-dose) will be analyzed in order to demonstrate 
absence of drug. If there is a quantifiable drug concentration in question, then all PK 
samples from the subject on placebo would be analyzed.  
INS018_055 concentrations in plasma will be determined by a validated high performance 
liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) assay. The analysis 
will be performed under the responsibility of InSilico Medicine.  
As described in section 4.1.5 the bioanalyst will be unblinded during sample analysis.  
5.12 
ASSESSMENT OF BIOMARKER(S) 
Serum samples will be used for explorative endpoint assessment. A part of the serum will be 
used for the detection of biomarkers associated with IPF pathology. These include levels of 
MMP-7, MMP-2, MMP-9, TGF-beta, IL-6, TIMP-1, IL-1beta in blood samples. In addition, 
part of serum sample will be used to perform high-throughput proteomic analysis on blood 
proteome to further explore the mechanism of action of INS018_055 in patients with written 
informed consent obtained. Remaining samples will be stored for a maximum of 3 years 
after approval of the clinical trial report. 
Correct, complete, and legible documentation of drug administration and blood sampling 
times is mandatory to obtain data of adequate quality for biomarker analysis. A detailed 
overview of biomarker sample collection visits and time points are outlined in the Schedule 
of Study Activities and respective footnotes. High-throughput proteomic analysis will be 
managed through a sponsor designated laboratory. Details about sample collection and 
sample handling will be provided in the lab manual. 

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5.12.1 
Blood Biomarkers 
Effects of INS018_055 treatment on several protein biomarkers, including MMP-7, MMP-2, 
MMP-9, TGF- , IL-6, TIMP-1, IL-1  as well as the mechanism of action of INS018_055 in 
blood proteome will be evaluated.   
5.12.2 
Methods of Sample Collection 
Whole blood will be collected for the preparation of serum or plasma. Collection time points 
are outlined in the Schedule of Study Activities. Correct, complete and legible 
documentation of drug administration and blood sampling times is mandatory to obtain data 
of adequate quality for biomarker analysis. A detailed description of biomarker sample 
collection and sample handling is provided in the ISF. 
 
5.12.3 
Analytical Determinations 
All biomarkers assessed in this trial are considered exploratory and qualified assays will be 
analysis of plasma or serum biomarkers will be given in detail in the analytical report.  
 
Changes in serum or plasma biomarkers will be analyzed over time pre and post treatment 
with INS018_055. All assessed biomarkers will either be analyzed at the sponsor or at a 
CRO. The results of biomarker analyses may be included into the clinical trial report, or 
reported separately. Refer to laboratory manual.  
 
5.12.4  
Appropriateness of Measurements 
 
All measurements conducted for primary and secondary endpoints are using standard 
methods. Refer to section 3.2 for the discussion of the choice of FVC as primary endpoint.  
The pharmacokinetic parameters and measurements outlined in section 5.11 generally used 
as measurements to assess drug exposure. Measures conducted for exploratory endpoints 
might be new methodologies already used in clinical trials but not yet validated for IPF. 
 

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6 
INVESTIGATIONAL PLAN 
6.1 
 VISIT SCHEDULE  
 
 
This phase IIa study will follow the measurements and assessments scheduled to occur 
 Day 1 (Schedule of Study Activities). The aim 
is to complete these procedures within a 2 h-period prior to study drug administration 
(including pre-dose values for PK and biomarkers). For planned individual plasma 
concentration sampling times refer to the section 10.4. These nominal times should be 
adhered to as closely as possible, and the actual sampling times will be recorded and used 
for determination of PK parameters.  
If a patient misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the 
Report Planning Meeting.  
For the details of the modifications refer to section 6.2. 
6.2 
 SCREENING PERIOD 
 
After having been informed about the trial, subjects will be required to give written informed 
consent in accordance with ICH-GCP and local legislation prior to study enrollment. After 
informed consent is obtained (signed and dated), study eligibility criteria (inclusion and 
exclusion) should be checked according to Schedule of Study Activities. 
For information regarding laboratory tests, ECG, vital signs, body weight and physical 
examination, refer to section 5.2 and section 5.4, respectively. For information on spirometry 
(FEV1 and FVC) and DLCO refer to section 5.8 and section 5.9, respectively.   
An historical HRCT scan can be used to determine eligibility, provided that the scan was 
performed within the past 12 months prior to Visit 1. If the historical scan is not available or 
an available scan fails to meet the required image acquisition specifications, an HRCT may 
be performed after consent to determine eligibility. Central review of all HRCT scans will be 
performed to confirm diagnosis of IPF, prior to randomization. Confirmation of diagnosis 
must be available prior to Visit 2. HRCT should not be repeated for eligibility if previous 
scan was taken within the past 3 months. To perform an HRCT within the trial, all local 
regulatory requirements to perform an HRCT have to be met. If required, the HRCT scan 

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should be performed as close to screening date as possible, preferably once eligibility is 
confirmed based on other parameters, to avoid unnecessary scans for patients who are found 
ineligible based on other criteria.  
Screening period may be extended up to 14 days for administrative reasons. Approval 
should be obtained from the sponsor who will also determine if any tests specified in the 
protocol must be repeated before the randomization visit (Visit 2).  
6.3 
 TREATMENT PERIOD 
 
Subjects who meet all inclusion criteria and none of the exclusion criteria, including positive 
HRCT review, will be randomized at Visit 2 in a 1:1:1:1 ratio to 1 of 4 treatment arms: 
 INS018_055 30 mg QD  
 INS018_055 30 mg BID  
 INS018_055 60 mg QD  
 Placebo 
Subjects already taking SoC antifibrotic therapy (pirfenidone or nintedanib) at study 
enrollment should maintain their therapy at a stable dose as much as possible during the 
study. Subjects already taking pirfenidone or nintedanib will continue to use their own 
supply.  
Subjects who are not taking pirfenidone or nintedanib at Visit 1 are not allowed to start these 
therapies while enrolled in the study. Subjects who have never been treated with pirfenidone 
or nintedanib are not allowed to start these therapies while enrolled in the study.   
At the beginning of each study visit during treatment phase, investigator and site personnel 
should check the well-being of the subject as well as prepare all requirements for conduct of 
the visit. Patients will complete the LCQ PRO described in section 5.3.1.  
Safety laboratory tests will be performed as described in section 5.2. 
FVC has to be measured at the same time ± 90 min (use Visit 1 as reference time). DLCO 
should be done after FVC measurements. Patients should rest between FVC and DLCO.  

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Subjects will self-administer INS018_055 30 mg QD, 30 mg BID, 60 mg QD, or placebo 
from Day 1 onwards according to their assigned treatment arm. All study medication will be 
taken orally. The patient will bring back all study medication, used and unused, at each at 
each study visit.   
Pre-dose PK samples will be collected at Visits 2 through 6. At Visits 2 and 6 post-dose 
samples will also be taken. Samples will be obtained at time points shown below. Refer to 
section 10.4 for additional details. 
 
Week 0 (Day 1) 
 
Pre-dose: within 45 minutes prior to morning dosing 
 
Post-dose (after morning dosing): 0.25 (± 5 min), 0.5 (± 5 min), 1 (± 5 min), 2 (± 5 
min), 4 (± 5 min), 6 (± 10 min), and 24 hours (± 30 min) (prior to Day 2 dosing)  
 
Weeks 2, 4, and 8 
 
Pre-dose: within 45 minutes prior to morning dosing 
 
Week 12 
 
Pre-dose: within 45 minutes prior to morning dosing 
 
Post-dose (after morning dosing): and 0.25 (± 5 min), 0.5 (± 5 min), 1 (± 5 min), 2 (± 
5 min), 4 (± 5 min), 6 (± 10 min), 24 (± 30 min), and 48 hours (± 60 min)  
Blood samples for serum or plasma concentrations of biomarkers will be collected pre-dose 
at Visits 2 through 6.  
At Visits 2 through 5, subjects will receive a study diary and will be instructed to record 
precisely the day and time that they take study treatment (INS018_055, placebo). Subjects 
will bring the study diary to the next study visit. Visit 6 will be the End of Treatment visit. A 
follow up EOS visit (Visit 7) will take place ~1 week after Visit 6. 
6.4 
 FOLLOW UP PERIOD AND STUDY COMPLETION 
A follow up period of a minimum of 7 days (+3 days) will be required. All patients will 
complete an end of trial visit (Visit 7). For AE assessment, laboratory tests, recording of 
ECG and vital signs, and physical examination during the end of trial period, see section 5. 
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 

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of trial must 
further information can be obtained.  
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
 

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7 
STATISTICAL ANALYSIS PLAN 
The primary objective is to evaluate the safety and tolerability of INS018_055 orally 
administered for up to 12 weeks in adult subjects with IPF compared to placebo. This study 
also aims to demonstrate proof of concept of efficacy of INS018_055 on lung function.  
 
7.1 
NULL AND ALTERNATIVE HYPOTHESES 
No hypothesis testing will be performed in the confirmatory sense. All the analyses will be 
performed in an exploratory fashion to better understand the efficacy and safety profile of 
INS018_055 in patients with IPF. 
7.2  
PLANNED ANALYSES 
7.2.1 
General Considerations 
The following subject populations are defined: 
 
Safety Population: The safety population will include all subjects who receive at least 1 dose 
of study treatment. 
 
ITT Population: The intent-to-treat (ITT) population will include any randomized subjects. 
 
PK Population: The PK population will include subjects who receive at least1 dose of study 
treatment and have a majority of scheduled PK samples drawn that allow for PK parameters 
to be generated.  
 
Per Protocol (PP) Population: The PP population will exclude non -evaluable subjects and 
subjects with major protocol deviations thought to impact the ability to assess the effect of 
study treatment. The criteria for excluding subjects from the PP population will be specified 
in the Statistical Analysis Plan (SAP). All statistical tests will be conducted at the 2-sided, 

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0.05 level of significance and the point estimate of treatment differences and the associated 
95% confidence interval (CI) will be derived. 
 
The ITT population will be used for summary of demographic and baseline characteristics.  
Demographic characteristics (age, sex, ethnicity, race, etc.) and screening clinical 
characteristics (vital signs, physical examination, etc.) will be summarized using descriptive 
statistics (number of patients [n], mean, standard deviation [SD], median, minimum [min], 
and maximum [max]) for continuous variables and using counts and associated percentages 
for categorical variables. Baseline laboratory results will be summarized overall and by 
treatment arm using descriptive statistics. Additionally, the proportion of subjects on 
antifibrotic or not on antifibrotic therapy at the time of randomization for each treatment arm 
will be summarized. 
7.2.2 
Primary Endpoint Analyses 
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature. No hypothesis testing is planned.  
 
All safety analyses will be performed on the safety population. The analysis of safety 
endpoints, including TEAEs, AEs, SAEs, TRAEs and AEs of interest (coded using the 
Medical Dictionary for Regulatory Activities [MedDRA®]), will be summarized by System 
Organ Class, Preferred Terms, and their maximum severity based on CTCAE v5.0 grade for 
all treated subjects.  
 
Laboratory data will be analyzed both quantitatively and qualitatively. The latter will be 
done via comparison of laboratory data to standard reference ranges. Values outside the 
reference range and values considered to be clinically relevant will be summarized. Clinical 
laboratory tests, physical examination, ECGs, and vital signs will be summarized or 
tabulated by treatment arm and visit and will also be presented in shift tables. Treatment 
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regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values. 
 
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.  
 
Clinical laboratory tests, physical examination, ECGs, and vital signs will be summarized or 
tabulated by treatment arm and visit and will also be presented in shift tables.  
 
7.2.3 
Secondary Endpoint Analyses 
PK analysis will be performed for PK Population and no formal statistical analysis of PK 
data is planned. For all other endpoints, analysis will be performed on the ITT population. 
 
Pharmacokinetic parameters will be summarized using arithmetic mean, percent coefficient 
of variation (%CV), standard deviation (SD), median, minimum, and maximum values, and 
number of observations. 
 
Trough concentrations will be summarized by geometric means and geometric coefficients 
of variation (GCV) and will be plotted across time by treatment arm. A separate analysis 
plan and a separate analysis report will be prepared for the PK analyses, if applicable. 
 
Some of the endpoints, such as FVC, DLCO and 6MWD will be analyzed by analysis of 
covariance (ANCOVA) with study treatment without the assumption on linearity, and 
baseline values as covariates.  Missing data not due to indicators of acute IPF exacerbation 
or death will be imputed based on a multiple imputation method assuming missing not at 
random (MNAR) framework. Continuous secondary efficacy endpoints such as LCQ will be 
analyzed using a mixed model repeated measures (MMRM) with a random coefficient 
regression model. Fixed effects in the model will include treatment, time, and baseline 
values as covariates and random effects allowing for subject-specific intercepts and slopes. 
 
Analysis will be performed to evaluate the efficacy of INS018_055 orally administered for 
up to 12 weeks of treatment  on FVC decline in adult subjects with IPF compared to 

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placebo. The analysis will include the fixed, categorical effect of treatment at each visit, and 
the fixed continuous effects of baseline FVC at each visit. Visit will be treated as the 
repeated measure with an unstructured covariance structure used to model the within-patient 
measurements. 
 
All statistical tests will be conducted at the 2-sided, 0.05 level of significance and the point 
estimate of treatment differences and the associated 95% confidence interval (CI) will be 
derived. 
 
To evaluate the impact of INS018_055 orally administered on acute IPF exacerbations 
compared to placebo, analysis will be performed. Number of acute IPF exacerbations and 
hospitalizations from baseline up to Week 12 will be tabulated by treatment arm. 
 
To evaluate the efficacy of INS018_055 orally administered for up to12 weeks of treatment  
to improve QoL and functional measures compared to placebo, the LCQ tool domain-
specific scores and total score summed across the domains will  be analyzed overall and by 
treatment arm. No adjustment of multiplicity for testing is performed for this study. 
Subgroup analysis may be performed for other medications for IPF. 
 
7.2.4 
Exploratory Endpoint Analyses 
No formal statistical analysis is planned to evaluate change in IPF blood biomarkers of 
INS018_055 activity from baseline to Weeks 2, 4, 8 and 12. For biomarker population (with 
pre-dose baseline value, and at least one value after treatment initiated) , biomarker levels, 
change from baseline, percentage change from baselinewill be summarized using descriptive 
statistics including arithmetic mean, percent coefficient of variation (%CV), standard 
deviation (SD), median, minimum, and maximum values, and number of observations. 
 
7.3  
HANDLING MISSING DATA 
In the primary analysis of all continuous endpoints, missing data will not be imputed. The 
mixed model will handle missing data based on a likelihood method under the "missing at 
random assumption". This means that patients with missing data would have behaved 
similarly to patients with observed data.  

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Missing or incomplete AE dates will be imputed. For example, missing data not due to 
indicators of acute IPF exacerbation or death may be imputed based on a multiple 
imputation method. Handling of missing data for secondary endpoints as well as for 
sensitivity analysis will be described in the SAP.  
7.4  
RANDOMIZATION 
Patients will be randomized to one of the 4 treatment arms in a 1:1:1:1 ratio (INS018_055 30 
mg QD, INS018_055 30 mg BID, INS018_055 60 mg QD, or placebo), with 
approximately15 subjects in each treatment arm to ensure a total of about 60 subjects 
completing the 12-week treatment period.  
Randomization of patients to the treatment groups will be performed via IRT. This system 
will not have a cap on patients taking SoC antifibrotic treatment. 
InSilico Medicine will arrange for the randomization and the packaging and labelling of 
study medication (INS018_055, placebo). Access to the codes will be controlled and 
documented.  
7.5  
DETERMINATION OF SAMPLE SIZE 
A sample size calculation based on statistical power considerations will not be performed. 
However, given an approximate sample size of 15 subjects per treatment arm, there exists a 
90% probability of observing at least 1 AE if the true population rate is approximately 15%, 
which will be sufficient to assess the feasibility of safety parameters.  
 
 

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8 
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE 
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP) for both China and the U.S., relevant InSilico Medicine Standard 
Operating Procedures (SOPs), and other relevant regulations. Investigators and site staff 
must adhere to these principles. Deviation from the protocol, the principles of ICH GCP or 
 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.  
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.  
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in the investigator contract. As a rule, no trial results should be 
published prior to finalization of the Clinical Trial Report.  
The certificate of insurance cover is made available to the investigator and the patients, and 
is stored in the ISF.  
8.1 
STUDY APPROVAL, PATIENT INFORMATION, INFORMED CONSENT 
This study will be initiated only after all required legal documentation has been reviewed 
and approved by the respective Institutional Review Board (IRB / Independent Ethics 
Committee (IEC and competent authority (CA) according to national and international 
regulations. The same applies for the implementation of changes introduced by amendments.  
Prior to patient participation in the study, written informed consent must be obtained from 
esentative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient- 
information form retained by the investigator as part of the trial records. A signed copy of 

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the informed consent and any additional patient information must be given to each patient or 
 
The investigator or delegate must give a full explanation to study patients based on the 
patient information form. A language understandable to the patient should be chosen, 
technical terms and expressions avoided, if possible. Translation will be provided where 
needed. 
The patient must be given sufficient time to consider participation in the study. The 
informed consent form after confirming that the patient understands the contents. The 
investigator or his delegate must sign (or place a seal on) and date the informed consent 
form. If a study collaborator has given a supplementary explanation, the study collaborator 
also signs (or places a seal on) and dates the informed consent. 
Re-consenting may become necessary when new relevant information becomes available 
-
consenting process should be properly documented in the source documentation. 
8.2  
DATA QUALITY ASSURANCE 
A risk-based approach is used for study quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well 
as identification and assessment of associated risks.  Continuous risk review and assessment 
may lead to adjustments in study conduct, study design or monitoring approaches. 
 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
-related files and correspondence, 
and the informed consent documentation of this clinical trial. 
 

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8.3  
RECORDS 
8.3.1 
Source Documents 
For adverse events, an end date may not always be available (e.g., due to hospital discharge 
and later recovery, or change in treating physician), but should be recorded in the source if 
known. 
For eCRF all data need to be derived from source documents, which need to be available on- 
 
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
original and accurate. Changes to the data should be traceable (audit trail). Data reported on 
the CRF must be consistent with the source data or the discrepancies must be explained. 
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.  
 
Medical history, including number of years since IPF diagnosis, family history of IPF, 
clinically significant diseases, surgeries, cancer history (including prior cancer therapies and 
procedures), reproductive status, smoking history, and alcohol and substance use, 
that occurred prior to time of first dose of study drug should be reported as medical history 
on the General History and Baseline Conditions eCRF, including: 
 Pulmonary hypertension 
 Chronic obstructive pulmonary disease, i.e., COPD/emphysema 
 Lung cancer 
 Obstructive sleep apnea 
 Pulmonary embolism  
 Respiratory infections, including tuberculosis  

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 Cardiovascular disease and risk factors, including arrhythmias, cardiac failure or 
congestive heart failure, ischemic heart disease, cerebrovascular disease and stroke, 
peripheral artery disease systemic arterial hypertension, 
hypercholesterolemia/hyperlipidemia 
 Participation in supervised pulmonary or cardiac rehabilitation programs 
 Past surgical history 
 
All medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by a subject within 30 days prior to 
initiation of study treatment will be recorded on the eCRF. At the time of each follow-up 
physical examination, an interval medical history should be obtained and any changes in 
medications and allergies should be recorded. History of anti-fibrotic therapy should also be 
documented since IPF was diagnosed (i.e., pirfenidone and nintedanib treatment, dose, 
duration of therapy, reasons for discontinuation, if applicable). Additionally, history of all 
COVID-19 vaccinations received in the past should be documented. 
 
If it is determined that there will be central reading, copies of necessary source files will be 
provided to a vendor. Before sending or uploading those copies, the investigator must ensure 
that all patient identifiers (e.g., 
security number) have properly been re
source documents. 
If the patient is not compliant with the protocol, any corrective action e.g., re-training must 
be documented in the patient file.  
For the eCRF, data must be derived from source documents, for example:  
 Patient identification: gender, year of birth (in accordance with local laws and 
regulations) 
 Patient participation in the trial (substance, trial number, patient number, date patient 
was informed) 
 
sing of trial medication  
 Medical history (including trial indication and concomitant diseases, if applicable)  
 Adverse events and outcome events [onset date (mandatory), and end date (if available)] 
 Serious adverse events [onset date (mandatory), and end date (if available)] 

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 Concomitant therapy (start date, changes)  
 Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)  
 Patient related outcome worksheet completed by the patient and reviewed by the site.  
 
discontinuation document the reason for it).  
 Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g., medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.  
8.3.2 
Direct Access to Source Data and Documents 
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, 
which must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g., FDA). They may review all CRFs and informed consents. The accuracy of the data 
will be verified by direct comparison with the source documents described in section 8.3.1. 
The sponsor will also monitor compliance with the protocol and GCP. 
8.3.3 
Storage Period of Records 
Study sites must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is 
 
8.4  
EXPEDITED REPORTING OF ADVERSE EVENTS 
InSilico Medicine is responsible to fulfill their legal and regulatory reporting obligation in 
accordance with regulatory requirements.  

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8.5  
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook. Individual patient data obtained as a result of this trial is considered confidential 
and disclosure to third parties is prohibited with the following exceptions:  
site as a result of the trial need to be available for inspection on request by the participating 
 
8.5.1 
Collection, storage, and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, and future use 
of biological samples and clinical data, in particular: 
 The facilities storing biological samples from clinical trial participants as well as the 
external banking facility are qualified for the storage of biological samples collected in 
clinical trials  
 An appropriate sample and data management system, incl. audit trail for clinical data and 
samples to identify and destroy such samples according to ICF is in place  
 A fit for the purpose documentation (biomarker analysis plan and report) ensures 
compliant usage  
 A fit for purpose approach will be used for assay/equipment validation depending on the 
intended use of the biomarker data  
8.6  
STUDY MILESTONES 
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent. The end of the trial is defined as the date of the last visit of the last 
Last Patient Last Treatment
(LPLT) date is defined as the date on which the last patient in the whole trial is administered 
the last dose of trial treatment (as scheduled per protocol or prematurely). Individual 
investigators will be notified of SUSARs occurring with the trial medication until 30 days 

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after LPLT at their site. Early termination of the trial is defined as the premature termination 
of the trial due to any reason before the end of the trial as specified in this protocol. 
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it. Suspension of the trial is defined as an interruption 
of the trial based on a Health Authority request. The IEC/competent authority will be 
notified about the trial milestones according to the respective laws. 
A final report of the clinical trial data will be written only after all patients have completed 
the trial to incorporate and consider all data in the report. The sponsor will submit China 
database a summary of the final trial results within one year from the end of a clinical trial as 
a whole.  
8.7  
ADMINISTRATIVE STRUCTURE OF THE STUDY 
This study is sponsored by InSilico Medicine.   
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract.  
A DSMB will be established. Members of the DSMB are physicians experienced in the 
treatment of the disease under investigation. The DSMB will evaluate the entire safety data 
and will meet on an ongoing basis during the course of the trial. The DSMB can receive 
urgent significant safety concerns for immediate evaluation. While DSMB members may be 
unblinded, measures are in place to ensure the blinding for everyone else involved in the 
trial. Regular DSMB meetings will be held at specified intervals. The DSMB will 
recommend continuation, modification or termination of the trial as detailed in the DSMB 
charter. DSMB recommendations as well as the final InSilico Medicine decision will be 
reported to the appropriate Regulatory Authorities (RAs)/Health Authorities (HAs), 
IRBs/ECs, and to investigators as requested by local law. The tasks and responsibilities of 
the DSMB are specified in a charter.  
Relevant documentation on the participating (Principal) Investigators (e.g., their curricula 
vitae) will be filed in the ISF.  
The investigators will have access to the InSilico Medicine portal to access documents 
provided by the sponsor.  

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InSilico Medicine has appointed a Clinical Trial Leader (CT Leader), responsible for 
coordinating all required activities, in order to: 
 Manage the trial in accordance with applicable regulations and internal SOPs 
 Direct the clinical trial team in the preparation, conduct, and reporting of the trial,  
 Ensure appropriate training and information of Clinical Trial Managers (CT Managers), 
Clinical Research Associates (CRAs), and investigators of participating countries. 
The organization of the trial in the participating countries will be performed by the 
respective local or regional InSilico Medicine in accordance with applicable regulations and 
InSilico Medicine SOPs, or by a Contract Research Organization (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.  
Data Management and Statistical Evaluation will be done by InSilico Medicine according to 
InSilico Medicine SOPs. Bioanalysis of INS018_055 is done by sponsor or a delegated 
laboratory.  
Tasks and functions assigned in order to organize, manage, and evaluate the trial are defined 
according to InSilico Medicine SOPs. A list of responsible persons and relevant local 
information can be found in the ISF. 
An IRT vendor will be used in this trial. Details will be provided in the IRT Manual 
available in the ISF.  

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9 
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10.2  DLCO 
At Visit 1, DLCO must fulfil the following criteria: Within range 25% - 80% predicted of 
normal; corrected for Hb  
For predicted normal values, different sites may use different prediction formulas, based on 
the method used to measure DLCO. In any case, the method used must be in compliance 
with the ATS/ERS guideline on DLCO measurements [Graham 2017], and the prediction 
formula appropriate for that method. Raw data (gas mixture, equation for the prediction of 
normal, further adjustments made if so), must be traced.  
Predicted DLCO corrected for haemoglobin (Hb) expressed in g x dL-1 [Graham 2017], can 
be calculated as: 
Males: Predicted DLCO corrected for Hb = Predicted DLCO x [1.7Hb/(10.22+Hb)] 
Females: Predicted DLCO corrected for Hb= Predicted DLCO x [1.7Hb/(9.38+Hb)] 
For decision on inclusion/exclusion, DLCO results from visit 1 will be corrected for 
hemoglobin by the site.  
For analysis of the trial data, DLCO results will be corrected for hemoglobin by central data 
management. This means that the site has to enter the DLCO results without hemoglobin 
correction in the eCRF, at Visit 2 and Visit 6.   
16. In the last 2 weeks, have you worried that your cough may indicate a serious illness? 
 
1 
2 
3 
4 
5 
6 
7 
 
All of the time 
Most of the time 
A lot of the time 
Some of the time 
A little of the time 
Hardly any of the time 
None of the time
17. In the last 2 weeks, have you been concerned that other people think something is wrong with you because of your cough? 
 
1 
2 
3 
4 
5 
6 
7 
 
All of the time 
Most of the time 
A lot of the time 
Some of the time 
A little of the time 
Hardly any of the time 
None of the time
18. In the last 2 weeks, my cough has interrupted conversations or telephone calls 
 
1 
2 
3 
4 
5 
6 
7 
 
Every time 
Most times 
A lot of the time 
Some of the time 
A little of the time 
Hardly any of the time 
None of the time
19. In the last 2 weeks, I feel that my cough has annoyed my partner, family or friends 
 
1 
2 
3 
4 
5 
6 
7 
 
Every time I cough 
Most times when I cough 
Several times when 
I cough 
Sometimes when I cough 
Occasionally when I cough Rarely 
Never 
Thank you for completing this questionnaire. 

InSilico Medicine Hong Kong Limited 
INS018_055 Phase IIa Protocol 
Protocol No. INS018-055-003 
Version/Date: V4.0,02Aug2024 
 
 
 
102 
The average of DLCOs will be calculated in the EDC. The predicted DLCO, % predicted 
DLCO, and corrected % predicted DLCO will be calculated by statistician programmer 
using an equation to be confirmed, e.g. CRAPO or GLI. 
There should be > 2 acceptable tests that meet the repeatability requirement of either being 
within 3 mL CO (Standard Temperature and Pressure, Dry - 
-
-1 (or 1 
-
-1) of each other or within 10% of the highest value.  

InSilico Medicine Hong Kong Limited 
INS018_055 Phase IIa Protocol 
Protocol No. INS018-055-003 
Version/Date: V4.0,02Aug2024 
 
 
 
103 
10.3  6MWD 
Table 10. The Borg Scale CR10 
 
Borg CR10 Scale® 
© Gunnar Borg, 1982, 1998, 2004 
English 

InSilico Medicine Hong Kong Limited 
INS018_055 Phase IIa Protocol 
Protocol No. INS018-055-003 
Version/Date: V4.0,02Aug2024 
 
 
 
105 
+2:00 ± 5 min 
+4:00 ± 5 min 
+6:00 ± 10 min 
+24:00 ± 30 min 
+48:00 ± 60 min 
10.5  ELIGIBILITY CONFIRMATION OF IPF DIAGNOSIS 
Eligible refers to subjects with a clinical diagnosis of IPF based on the 2022 
ATS/ERS/JRS/ALAT Clinical Practice Guideline on the diagnosis of IPF as confirmed by 
central review on chest HRCT scan taken within 12 month of Visit 1 and if available 
surgical lung biopsy. If HRCT is equivocal, surgical lung biopsy results may be used. 
All chest HRCTs will be confirmed by central review based on the recent 2022 
ATS/ERS/JRS/ALAT Clinical Practice Guideline on the diagnosis of IPF. Patients with a 
confirmed HRCT pattern qualifying as UIP or probable UIP are eligible for participation and 
are not required to have a surgical lung biopsy in the appropriate clinical context for the 
diagnosis of IPF.  
Patients clinically suspected to have IPF with an HRCT pattern indeterminate for UIP, or 
suggesting an alternative diagnosis require historical (i.e., not taken for the purpose of this 
trial) surgical lung biopsy which will be reviewed locally (by the investigator/local 
histopathologist). In these patients, specific combinations of HRCT patterns and 
histopathology patterns may still allow a diagnosis of IPF based on the 2022 
ATS/ERS/JRS/ALAT Clinical Practice Guideline on the diagnosis of IPF. E.g., An HRCT 
pattern of "indeterminate for UIP" in combination with a surgical lung biopsy with a 
 
Appropriate documentation at site for these cases is required. Copies of the original, 
histopathological assessments and resulting diagnosis are required in patient files.  

InSilico Medicine Hong Kong Limited 
INS018_055 Phase IIa Protocol 
Protocol No. INS018-055-003 
Version/Date: V4.0,02Feb2024 
 
 
 
109
Insilico Medicine Restricted (Level 3) 
Protocol Errata 
 
Protocol No.: 
INS018-055-003 
Version of Protocol: 
4.0 (Amendment Version: 3.0) 
Date of Protocol:  
02Feb2024 
 
The following error has been identified in the protocol document.  
 
 
Item 
Location 
Incorrect 
Correct 
Header Date 
Pages 41 - 108 
02Aug2024 
02Feb2024 
 
 
This erratum is for record-keeping purposes only and does not impact on the study's scientific 
integrity or results. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
InSilico Medicine Hong Kong Limited Unit 310, F3, Building 8W, Phase 2, Hong Kong 
Science Park, Pak Shek Kok, New Territories, Hong Kong 
 
Date:  06 Nov 2025