A Phase 2b Randomized, Double-blind, Placebo-controlled, Repeat-dose, Multicenter Trial to Evaluate the Efficacy, Safety and Tolerability of HZN-825 in Subjects With Idiopathic Pulmonary Fibrosis
Phase: PHASE2
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Amgen

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) 
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Internal Use Only General and Administrative
 
 
 
CLINICAL TRIAL PROTOCOL  
FOR FIPAXALPARANT (HZN-825) 
Protocol Number:  HZNP-HZN-825-303 
IND:  154671 
EU CT Number: 2023-509784-24-00 
 
A Phase 2b Randomized, Double-blind, Placebo-controlled, Repeat-dose, 
Multicenter Trial to Evaluate the Efficacy, Safety and Tolerability of 
HZN-825 in Subjects with Idiopathic Pulmonary Fibrosis 
 
Date:  07 October 2024 
Version 5.0 
Sponsor: 
Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) 
70 St. Stephen's Green 
Dublin 2  
D02 E2X4 
Ireland 
 
 
 
 
 
This protocol is the confidential information of Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) and is intended 
solely for the guidance of the clinical investigation.  This protocol may not be disclosed to parties not associated with the clinical investigation 
or used for any purpose without the prior written consent of Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) 
CONFIDENTIAL 
 
 
 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) 
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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(A WHOLLY OWNED SUBSIDIARY OF AMGEN INC.) 
Internal Use Only General and Administrative
 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) 
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 5.0, Amendment 4 
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(A WHOLLY OWNED SUBSIDIARY OF AMGEN INC.) 
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PROTOCOL 
1 
TITLE PAGE 
Trial Title: A Phase 2b Randomized, Double-blind, 
Placebo-controlled, Repeat-dose, Multicenter 
Trial to Evaluate the Efficacy, Safety and 
Tolerability of HZN-825 in Subjects with 
Idiopathic Pulmonary Fibrosis 
Protocol Number: HZNP-HZN-825-303 
Version: 5.0 
Investigational Product: Fipaxalparant (HZN-825) 
Indication: Idiopathic pulmonary fibrosis 
Sponsor: Horizon Therapeutics Ireland DAC (a wholly 
owned subsidiary of Amgen Inc.) 
70 St. Stephen's Green 
Dublin 2  
D02 E2X4 
Ireland 
Development Phase: 2b 
Sponsor’s Responsible Medical Officer: 
, MBBS, MD 
Senior Medical Director, Clinical 
Development (Rare Disease) 
Horizon Therapeutics USA., Inc. 
1 Horizon Way 
Deerfield, IL  60015 
Approval Date: 07 October 2024 
 
 
 CONTACT IN THE EVENT OF AN EMERGENCY 
Any death, life-threatening event or other serious adverse event experienced by a subject during 
the course of the trial, whether or not judged drug-related, must be reported immediately and not 
later than 24 hours of knowledge of the event by entering the information into the electronic case 
report form (eCRF).  If unable to access the eCRF, the event must be reported by submitting the 
completed Serious Adverse Event Form via email or fax to the contacts provided below. 
US Fax: 1-888-814-8653 (toll free, within US) 
Ex-US Fax: +44 (0)207-136-1046 
Email (worldwide): svc-ags-in-us@amgen.com 
 
 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) 
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
HZNP-HZN-825-303 
Version: 
5.0 
Protocol Title: 
A Phase 2b Randomized, Double-blind, Placebo-controlled, Repeat-dose, 
Multicenter Trial to Evaluate the Efficacy, Safety and Tolerability of 
HZN-825 in Subjects with Idiopathic Pulmonary Fibrosis 
Version Date: 
07 October 2024 
I agree to conduct the trial according to the protocol named above.  I fully understand that any 
changes instituted by the Principal Investigator without previous discussion with the Sponsor 
constitute a violation of the protocol, unless necessary to eliminate an immediate hazard to the 
safety or well-being of a subject. 
I acknowledge that I have read and understand the protocol named above and agree to carry out 
all of its terms in accordance with applicable regulations and laws. 
I assure that the trial drug supplied by the Sponsor will be used only as described in the protocol 
named above. 
Signature: 
 
 
 
 
 
 
 
Name  
Trial Center 
Address 
City State Country 
 
Date 
 
 
 
 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) 
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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SUMMARY OF CHANGES 
Protocol HZNP-HZN-825-303 
Protocol Version 4.0, Amendment 3 (01 December 2022) to Protocol Version 5.0, 
Amendment 4 (07 October 2024) 
Key additions, revisions and clarifications to Version 5.0 of the protocol include: 
 Updating to align with new company structure under new sponsor throughout. 
 Updating numbers referring to safety and efficacy data to that from most recently 
completed studies. 
 Adding the non-proprietary name (fipaxalparant) throughout the document. 
 Align with European Union Clinical Trials (EU CT) submission requirements. 
 Removing the sponsor signature page to align with new sponsor processes. 
 Adding safety reporting language to align with new sponsor standard language. 
 Updating Principal Investigator responsibilities to report serious breaches. 
 Including definition of serious adverse events (SAEs), outcomes for reported adverse 
events (AEs)/SAEs/adverse events of special interest (AESIs) to align protocol 
information with revised Clinical SAE Report Form/electronic case report forms 
(eCRFs). 
 Updated to Orthostatic Hypotension Assessment Manual v3.0 14 June 2023.  The 
revisions in this manual from the prior version were previously communicated to all sites 
via memo on 12 June 2023. 
 Added 17.10 Clinical SAE Report Form, 17.11 Clinical Trial Drug Exposure During 
Conception/Pregnancy Form, and 17.12 Lactation Notification Form to the appendix 
section. 
Changes considered not key, minor wording changes, and correction of minor typographical 
errors are not detailed below. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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SUMMARY TABLE OF CHANGES 
Protocol Version 4.0, Amendment 3 (01 December 2022) to 
Protocol Version 5.0, Amendment 4 (07 October 2024) 
Text 
Version 4.0, Amendment 3 
01 December 2022 
Amended Text 
Version 5.0, Amendment 4 
07 October 2024 
Reason for Change 
Global 
HZN-825 
Global 
fipaxalparant (HZN-825) 
To incorporate non-proprietary 
name throughout document 
Cover Page and Title Page 
Horizon Therapeutics Ireland DAC 
 
EudraCT Number:  2021-001253-32 
Cover Page and Title Page 
Horizon Therapeutics Ireland DAC (a wholly owned 
subsidiary of Amgen Inc.) 
 
EU CT Number: 2023-509784-24-00 
To clarify new company 
structure 
Title Page 
Sponsor’s Responsible Medical Officer and Signatory: 
Title Page 
Sponsor’s Responsible Medical Officer: 
To change the Sponsor’s 
approver with shift to Amgen 
processes 
Title Page - Contact in the event of an emergency 
Any death, life-threatening event or other serious adverse 
event experienced by a subject during the course of the trial, 
whether or not judged drug-related, must be reported 
immediately, without undue delay, but not later than 
24 hours of knowledge of the event by entering the 
information into the electronic case report form (eCRF). 
Title Page - Contact in the event of an emergency 
Any death, life-threatening event or other serious adverse 
event experienced by a subject during the course of the trial, 
whether or not judged drug-related, must be reported 
immediately and not later than 24 hours of knowledge of the 
event by entering the information into the electronic case 
report form (eCRF). 
To align with new sponsor 
standard safety reporting 
language 
Title page 
US Fax: 800-860-7836 
Ex-US Fax: +1-224-855-5055 
Email: clinicalsafety@horizontherapeutics.com 
Title Page 
US Fax: 1-888-814-8653 (toll free, within US) 
Ex-US Fax:  +44 (0)207-136-1046 
Email (worldwide): svc-ags-in-us@amgen.com 
To update with new company 
structure 
Sponsor Signature Page 
Removed 
To change the Sponsor’s 
approver with shift to Amgen 
processes 
2 Synopsis, Part 2 (Extension Phase), Safety Objective 
The safety objective is to examine the safety and tolerability 
of 52 weeks of open-label treatment with HZN-825 based 
on: 
• Treatment-emergent adverse event (TEAE) assessment 
• Concomitant medication use 
2 Synopsis, Part 2 (Extension Phase), Safety Objective 
The safety objective is to examine the safety and tolerability 
of 52 weeks of open-label treatment with fipaxalparant 
(HZN 825) based on: 
• Treatment-emergent adverse event (TEAE) assessment 
• Concomitant medication use 
To remove repeated sentence 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Text 
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01 December 2022 
Amended Text 
Version 5.0, Amendment 4 
07 October 2024 
Reason for Change 
• Vital signs 
• 12-lead electrocardiogram (ECG) 
• Clinical safety laboratory results 
The primary safety objective is to examine the TEAEs 
during 52 weeks of open-label treatment with HZN 825. 
• Vital signs 
• 12-lead electrocardiogram (ECG) 
• Clinical safety laboratory results 
2 Synopsis, Trial Design, Paragraph 5 
An interim analysis with a futility analysis will be 
performed when
 
 
  These unblinded 
efficacy and safety data will be provided to an independent 
data monitoring committee (IDMC) and will be used to 
inform conduct of the Core Phase.   
2 Synopsis, Trial Design, Paragraph 5 
An interim analysis with a futility analysis will be 
performed when 
 
 
 These unblinded 
efficacy and safety data will be provided to an independent 
data monitoring committee (IDMC) and will be used to 
inform conduct of the current trial.   
To update the current trial. 
2 Synopsis, Exclusion Criteria, Item 5 
5. Use of any of the following therapies within 4 weeks prior 
to Screening, during the Screening Period or planned during 
the trial:  prednisone at steady dose >10 mg/day or 
equivalent or cyclosporine.  Prednisone ≤10 mg/day (or 
equivalent dosing of glucocorticoids) is allowed. 
2 Synopsis, Exclusion Criteria, Item 5 
5. Use of any of the following therapies within 4 weeks prior 
to Screening, during the Screening Period or planned during 
the trial:  prednisone at steady dose >10 mg/day or 
equivalent or cyclosporine. 
To remove the allowance of 
prednisone ≤10 mg/day (or 
equivalent dosing of 
glucocorticoids) in the study. 
2.2 Schedule of Assessments During the Extension Phase, 
Footnote 
8 The DLCO can be assessed within ±2-weeks of the 
Week 86 and Week 104/PD Visits.   
2.2 Schedule of Assessments During the Extension Phase, 
Footnote 
8 The DLCO is required for Week 80 and Week 104/PD 
Visits.   
To update the appropriate week 
and requirement diffusing 
capacity of the lungs for carbon 
monoxide (DLCO) 
7.1.3.4 Clinical Experience, Paragraphs 1 and 4 
HZN-825 has been administered to 102 healthy subjects in 
6 completed Phase 1 clinical trials and 31 subjects with 
diffuse cutaneous SSc in a Phase 2a clinical trial.  In clinical 
trials completed as of 28 February 2022, HZN-825 was 
well-tolerated and showed similar safety and PK profiles 
across healthy subjects (including elderly healthy subjects) 
and subjects with diffuse cutaneous SSc.   
7.1.3.4 Clinical Experience, Paragraphs 1 and 4 
Fipaxalparant (HZN-825) has been administered to 244 
healthy subjects in nine Phase 1 completed clinical trials and 
31 subjects with diffuse cutaneous SSc in a Phase 2a clinical 
trial.  In clinical trials completed, as provided in the current 
version of the Investigator’s Brochure, fipaxalparant (HZN-
825) was well-tolerated and showed similar safety and 
pharmacokinetic profiles across healthy subjects (including 
To update numbers 
based on most recently 
completed studies. 
 
To update information about 
elevated transaminases being 
observed in clinical studies 
with Investigational Product. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Text 
Version 4.0, Amendment 3 
01 December 2022 
Amended Text 
Version 5.0, Amendment 4 
07 October 2024 
Reason for Change 
Based on safety results to date, orthostatic hypotension is 
identified as a potential risk of HZN825 therapy that will 
continue to be monitored as an AE of special interest (AESI) 
(Section 9.5.5.1.1.4). 
elderly healthy subjects) and subjects with diffuse cutaneous 
SSc. 
Based on safety results to date, orthostatic hypotension is 
identified as a potential risk of fipaxalparant (HZN-825) 
therapy that will continue to be monitored as an AE of 
special interest (AESI) (Section 9.5.5.1.1.4).  Additionally, 
increases in hepatic transaminases have been seen in blinded 
clinical studies with fipaxalparant (HZN-825). These events 
are mostly non-serious and reversible. Liver enzyme 
elevation will be monitored per FDA guidelines (Section 
9.3.3.1) 
7.1.3.5 Benefit/Risk Assessment, Paragraph 2 
Based on the cumulative safety data available to date on 
HZN-825 orthostatic hypotension, drug-drug interactions, 
embryo-fetal toxicity and liver toxicity are considered as 
important potential risks. 
7.1.3.5 Benefit/Risk Assessment, Paragraph 2 
Based on the cumulative safety data available to date on 
fipaxalparant (HZN-825), transaminase increase has been 
evaluated as an important identified risk and orthostatic 
hypotension, drug-drug interactions, and embryo-fetal 
toxicity are considered as important potential risks. 
To update the risk of elevated 
transaminases and removal of 
liver toxicity. 
7.3 Rationale for Dose Selection, Paragraph 1 
The dose regimens to be evaluated in this trial are 300 mg 
QD and 300 mg BID with a meal using HZN-825 tablets 
manufactured by 
. 
7.3 Rationale for Dose Selection, Paragraph 1 
The dose regimens to be evaluated in this trial are 300 mg 
QD and 300 mg BID with a meal using fipaxalparant (HZN-
825) tablets manufactured by 
 
 
To add a new manufacturer of 
the HZN-825 investigational 
product that may be used 
during the conduct of the trial. 
9.3.3.1.1 Removal of Subjects from Trial Drug, Bullet 2 
Subjects who have ALT or AST levels >3 × ULN confirmed 
in a repeat test need to undergo close observation as 
prescribed by the FDA guidance on drug-induced liver 
injury.  Close observation includes repeating liver enzyme 
and serum bilirubin tests 2 or 3 times weekly.  Frequency of 
retesting can decrease to once a week or less if 
abnormalities stabilize and the subject is asymptomatic.  At 
the discretion of the Investigator the trial drug can be 
continued during this close observation. 
9.3.3.1.1 Removal of Subjects from Trial Drug, Bullet 2 
Subjects who have ALT or AST levels >3 × ULN confirmed 
in a repeat test need to undergo close observation as 
prescribed by the FDA guidance on drug-induced liver 
injury.  Close observation includes repeating liver enzyme 
and serum bilirubin tests 2 or 3 times weekly.  Frequency of 
retesting can decrease to once a week or less if 
abnormalities stabilize and the subject is asymptomatic.  
The decision to rechallenge the subject is to be discussed 
and agreed upon by the investigator, and Amgen Medical 
Monitor. 
To update the decision to 
rechallenge a subject. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Text 
Version 4.0, Amendment 3 
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Amended Text 
Version 5.0, Amendment 4 
07 October 2024 
Reason for Change 
9.4.6.1.2 Drug-induced Liver Injury 
Refer to Section 9.3.3.1 for criteria regarding trial drug 
discontinuation due to drug-induced liver injury. 
9.4.6.1.2 Drug-induced Liver Injury 
Elevated hepatic transaminases have been evaluated to be an 
important identified risk with fipaxalparant (HZN-825). The 
events are mostly non-serious and transient. Refer to 
Section 9.3.3.1 for criteria regarding trial drug 
discontinuation due to drug-induced liver injury. 
To update the information 
about elevated transaminases. 
9.5.1.6.5 Exit Interviews 
To understand what subjects perceive as meaningful in 
terms of change in some of the patient-reported outcome 
measures during the Core Phase of the trial, semi-structured 
qualitative interviews will be conducted by telephone after 
the Week 52 Visit (trial exit) at 4 to 5 sites (approximately 
20 subjects) across the US.  Subjects in the exit interviews 
will be selected in order to approximate representativeness 
of the clinical trial population of patients with IPF, with 
diversity in terms of age, gender, ethnicity, urban/rural 
practice and geographic area of residence, where possible.  
The one-on-one, semi structured, qualitative interviews will 
provide a greater understanding of the subjects’ treatment 
experience and meaningful change in select patient-reported 
endpoints.  These interviews are covered and conducted 
under a separate protocol, and are not part of the schedule of 
assessments for HZNP-HZN-825-303. 
9.5.1.6.5 Exit Interviews 
Section deleted. 
Section deleted 
9.5.5.1.1.4  Adverse Events of Special Interest, Paragraph 
s 2, 3 and 5 
The following AESI is identified for this trial: 
• Orthostatic hypotension.  The Sponsor will consider an 
event of orthostatic hypotension if the following definition 
is met:  a reduction of systolic blood pressure by ≥20 mmHg 
or reduction of diastolic blood pressure by ≥10 mmHg and 
associated with symptoms such as lightheadedness, blurred 
vision, weakness, fatigue, cognitive impairment, nausea, 
9.5.5.1.1.4 Adverse Events of Special Interest, 
Paragraphs 2, 3 and 5 
The following AESI is identified for this trial: 
• Orthostatic hypotension.  The Sponsor will consider an 
event of orthostatic hypotension if the following definition 
is met:  a reduction of systolic blood pressure by ≥20 mmHg 
or reduction of diastolic blood pressure by ≥10 mmHg and 
associated with symptoms such as lightheadedness, blurred 
vision, weakness, fatigue, cognitive impairment, nausea, 
To update the eligibility of 
Adverse Events (AE) while 
subject is going through 
Orthostatic hypotension 
assessment. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Reason for Change 
palpitations, tremulousness, headache, presyncope or 
syncope.  
Orthostatic hypotension assessment procedure will be 
performed during the Core Phase (as outlined in Section 2.1 
on Day 1 and at Weeks 4, 28 and 52/premature 
discontinuation) and the Extension Phase (as outlined in 
Section 2.2 on Day 1 [Week 52 of Core Phase] and at 
Weeks 56, 80 and 104/premature discontinuation), as is 
detailed in the Orthostatic Hypotension Assessment Manual 
in Section 17.9. 
If any symptoms occur during the assessment in 
combination with the blood pressure reductions noted 
above, they are considered as part of the orthostatic 
hypotension event and will not be recorded separately as 
individual AEs. 
If symptoms are reported by the subject throughout the 
assessment, without the blood pressure reductions noted 
above, then the symptoms will be recorded separately as 
AEs and orthostatic hypotension will not be recorded. 
palpitations, tremulousness, headache, presyncope or 
syncope.  
The symptoms i.e., lightheadedness, blurred vision, 
weakness, fatigue, cognitive impairment, nausea, 
palpitations, tremulousness, headache, presyncope or 
syncope are reported by the patient throughout the 
orthostatic hypotension assessment, without the BP 
reductions (reduction of systolic BP ≥ 20 mmHg or diastolic 
BP ≥10 mmHg), then these symptoms will be recorded as 
AE. 
Please note that the above-mentioned reported symptoms 
during orthostatic hypotension assessment should only be 
reported as adverse events separately if they meet any of the 
below criteria:  
• The symptoms are severe and/or require medical 
interventions 
• The symptoms triggered by the orthostatic hypotension 
assessment maneuver and persisted for a significantly longer 
duration beyond the orthostatic hypotension assessment 
period 
• The symptoms are assessed not due to the maneuver of 
orthostatic hypotension assessment 
If these symptoms are reported in combination with the BP 
reductions, i.e., reduction of systolic BP ≥20 mmHg or 
diastolic BP ≥10 mmHg, these symptoms will be considered 
part of the orthostatic hypotension event and will not be 
reported separately. 
Orthostatic hypotension assessment procedure will be 
performed during the Core Phase (as outlined in Section 2.1 
on Day 1 and at Weeks 4, 28, and 52/premature 
discontinuation) and the Extension Phase (as outlined in 
Section 2.2 on Day 1 [Week 52 of Core Phase] and at 
Weeks 56, 80, and 104/premature discontinuation), as is 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Reason for Change 
detailed in the Orthostatic Hypotension Assessment Manual 
in Section 17.9. 
If symptoms are reported by the subject throughout the 
assessment, without the BP reductions noted above, then the 
symptoms will be recorded separately as AEs and 
orthostatic hypotension will not be recorded. 
9.5.5.1.2 Documentation of Adverse Events 
If the Investigator observes an SAE after trial completion 
that he/she believes was possibly caused by trial drug, the 
Investigator will report this SAE using the procedures 
described in Section 9.5.5.1.5. 
Detailed information regarding all SAEs must also be 
recorded on the Serious Adverse Event Reporting Form. 
Whenever clinically appropriate, the Investigator should 
group together into a single term the signs and symptoms 
that constitute a single diagnosis. For example, cough, 
rhinitis. and sneezing might be grouped together as “upper 
respiratory infection” if the Investigator is confident of the 
diagnosis. 
9.5.5.1.2 Documentation of Adverse Events 
If the Investigator observes an SAE after trial completion 
that he/she believes was possibly caused by trial drug, the 
Investigator will report this SAE using the procedures 
described in Section 9.5.5.1.5.  The Investigator is 
responsible for collecting and documenting the outcome of 
AEs/SAEs. 
 
If specifically requested, the investigator may need to 
provide additional follow‑up information, such as discharge 
summaries, medical records, or extracts from the medical 
records.  In this case, all subject identifiers, except for the 
subject number, will be blinded on the copies of the medical 
records before submission to the Sponsor. 
To align with expected 
reporting and subject 
confidentiality 
9.5.5.1.4  Relationship or Causality to Trial Drug 
The relationship of the trial drug to each AE will be 
determined by the Investigator and the Sponsor based on the 
following definitions: 
• Not related:  There is no plausible temporal relationship or 
there is another explanation that unequivocally provides a 
more plausible explanation for the event. 
• Related:  There is evidence in favor of a causal relationship 
(i.e., there is a plausible time course) and at least one of the 
following criteria apply: 
▪ 
There is a reasonable pharmacological relationship (or 
known class effect). 
▪ 
There is no other more plausible explanation. 
▪ 
There is a positive de-challenge (without active 
treatment of the event). 
9.5.5.1.4  Relationship or Causality to Trial Drug 
The investigator is obligated to assess the relationship 
between investigational product(s) and each occurrence of 
each AE and SAE. 
Relatedness means that there are facts or reasons to support 
a relationship between investigational product and the event. 
The investigator will use clinical judgment to determine the 
relationship. 
Alternative causes, such as underlying disease(s), 
concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to study treatment 
administration will be considered and investigated. 
The investigator will also consult the Investigator’s 
Brochure and/or product information, for marketed 
products, in their assessment. 
To align with new sponsor 
standard safety reporting 
language 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Reason for Change 
▪ 
There is a positive re-challenge. 
▪ 
There is a distinguishable dose effect. 
For each AE/SAE, the investigator must document in the 
medical notes that they have reviewed the AE/SAE and has 
provided an assessment of causality. 
There may be situations in which a SAE has occurred and 
the investigator has minimal information to include in the 
initial report.  However, it is very important that the 
investigator always assess causality for every event before 
the initial transmission of the SAE data. 
The investigator may change their opinion of causality in 
light of follow-up information and send a SAE follow-up 
report with the updated causality assessment. 
The relationship of the trial drug to each AE will be 
determined by the Investigator and the Sponsor based on the 
following definitions: 
• Not related:  There is no plausible temporal relationship or 
there is another explanation that unequivocally provides a 
more plausible explanation for the event. 
• Related:  There is evidence in favor of a causal relationship 
(i.e., there is a plausible time course) and at least one of the 
following criteria apply: 
▪ 
There is a reasonable pharmacological relationship (or 
known class effect). 
▪ 
There is no other more plausible explanation. 
▪ 
There is a positive de-challenge (without active 
treatment of the event). 
▪ 
There is a positive re-challenge. 
▪ 
There is a distinguishable dose effect. 
9.5.5.1.5 Reporting and Documenting Serious Adverse 
Events 
All SAEs beginning with the time of signing of the ICF and 
continuing through 4 weeks after the last dose of trial drug 
must be reported.  The following steps will be taken to 
report promptly and document accurately any SAE, whether 
or not it appears to be related to trial drug:   
1. Report the SAE to the Sponsor by entering the 
information into the eCRF immediately, without undue 
9.5.5.1.5 Reporting and Documenting Serious Adverse 
Events 
All SAEs beginning with the time of signing of the ICF and 
continuing through 4 weeks after the last dose of trial drug 
must be reported.  The following steps will be taken to 
report promptly and document accurately any SAE, whether 
or not it appears to be related to trial drug:   
 
To align with new sponsor 
standard safety reporting 
language 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
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delay but not later than 24 hours after becoming aware 
that a subject has experienced an SAE.  If unable to access 
the eCRF, the event must be reported by submitting the 
completed SAE form immediately, without undue delay 
but not later than 24 hours after becoming aware that a 
subject has experienced an SAE (see Section 17.1 for 
contact information). 
2.  Perform appropriate diagnostic tests and therapeutic 
measures and submit all follow up substantiating data, such 
as diagnostic test reports, hospital discharge summaries and 
autopsy report to the Sponsor’s representative. 
3. Conduct appropriate consultation and follow-up 
evaluation until the SAE outcome is known or the SAE is 
resolved. 
4. Review each SAE report and evaluate the relationship of 
the SAE to trial treatment. 
1. Report the SAE to the Sponsor by entering the 
information into the eCRF immediately and not later 
than 24 hours after becoming aware that a subject has 
experienced an SAE.  If unable to access the eCRF, the 
event must be reported by submitting the completed 
SAE Reporting form immediately and not later than 
24 hours after becoming aware that a subject has 
experienced an SAE (see Section 17.1 for contact 
information). 
After the study is completed at a given site, the 
electronic data capture (EDC) system will be taken 
off-line to prevent the entry of new data or changes to 
existing data. 
If a site receives a report of a new SAE from a study 
subject or receives updated data on a previously 
reported SAE after the EDC system has been taken 
off-line, then the site can report this information on the 
paper-based SAE Form.  
 
2. Perform appropriate diagnostic tests and therapeutic 
measures and submit all follow-up substantiating data, 
such as diagnostic test reports, hospital discharge 
summaries and autopsy report to the Sponsor’s 
representative. 
 
3. 
Conduct appropriate consultation and follow-up 
evaluation until the SAE outcome is known or the SAE 
is resolved.  Outcomes for reported AEs/SAEs/AESIs 
are to be defined as follows: 
• Recovering/Resolving  
• Recovered/Resolved  
• Not Recovered/Not Resolved  
• Recovered/Resolved with sequelae  
• Fatal  
• Unknown 
 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
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4. All new information for previously reported SAEs must 
be sent to the Sponsor immediately and no later than 
24 hours after investigator’s awareness of the new 
information.  If specifically requested, the investigator 
may need to provide additional follow-up information, 
such as discharge summaries, medical records, or 
extracts from the medical records.  Information provided 
about the SAE must be consistent with that recorded on 
the Adverse Events eCRF. 
There is no requirement to actively monitor study 
subjects after the study has ended with regards to study 
subjects treated by the investigator.  However, if the 
investigator becomes aware of SAEs suspected to be 
related to investigational product, then these SAEs will 
be reported to the Sponsor immediately and no later 
than 24 hours after the investigator’s awareness of the 
event. 
Serious adverse events reported after the end of the 
study will be captured within the safety database as 
clinical study cases and handled accordingly based on 
relationship to investigational product.  
If further safety-related data is needed to fulfill any 
regulatory reporting requirements for a reportable event, 
then additional information may need to be collected 
from the subject’s records after the subject ends the 
study. 
Review each SAE report and evaluate the relationship of 
the SAE to trial treatment. 
9.5.5.1.6 Follow-up of Adverse Events 
The Investigator is obligated to follow up any reported AE, 
SAE or AESI until all relevant clinical data are known to 
allow for an outcome or the event is resolved, in addition to 
confirming the causality assessment. Any ongoing trial 
drug-related AE present at the time of trial termination, 
including a clinically significant laboratory test abnormality, 
9.5.5.1.6 Follow-up of Adverse Events 
The Investigator is obligated to follow-up any reported AE, 
SAE or AESI until all relevant clinical data are known to 
allow for an outcome or the event is resolved, in addition to 
confirming the causality assessment.  Any ongoing trial 
drug-related AE present at the time of trial termination, 
including a clinically significant laboratory test abnormality, 
To align with new sponsor 
standard safety reporting 
language 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
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will be followed until the event is resolved or until the 
outcome is known. 
will be followed until resolved or until the event stabilizes 
and the overall clinical outcome has been ascertained. 
The investigator is obligated to perform or arrange for the 
conduct of supplemental measurements and/or evaluations 
as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as 
fully as possible.  This may include additional laboratory 
tests or investigations, histopathological examinations, or 
consultation with other healthcare professionals. 
If a subject is permanently withdrawn from investigational 
product(s) and/or noninvestigational product(s)/auxiliary 
medicinal product(s) because of a SAE, this information 
must be submitted to Sponsor. 
The investigator will submit any updated SAE data to 
Sponsor immediately and no later than 24 hours of 
receipt of the information. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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9.5.5.1.10 Development Safety Update Reports 
The Sponsor will prepare and submit annual safety reports 
to the US FDA.  Drug safety update reports will also be 
submitted to countries and territories as required. 
9.5.5.1.10 Development Safety Update Reports 
The Sponsor will prepare and submit annual safety reports 
to the FDA.  Drug safety update reports will also be 
submitted to countries and territories as required. 
The Sponsor will prepare a single Development Safety 
Update Report (DSUR) (also referred to as Annual Safety 
Report in the European Union) for the Sponsor 
Investigational Product.  To ensure that consolidated safety 
information for the study is provided, this single DSUR will 
also include appropriate information on any other 
investigational products used in the clinical study, if 
applicable. 
 
9.5.5.1.11  Regulatory Reporting Requirements for Safety 
Information 
If subject is permanently withdrawn from investigational 
product(s), and/or noninvestigational product(s)/auxiliary 
medicinal product(s) because of a SAE, this information 
must be submitted to the Sponsor. 
 
Prompt notification by the investigator to the Sponsor of 
SAEs is essential so that legal obligations and ethical 
responsibilities towards the safety of subjects and the safety 
of a study treatment under clinical investigation are met. 
 
The Sponsor has a legal responsibility to notify both the 
local regulatory authority and other regulatory agencies 
about the safety of a study treatment under clinical 
investigation.  The Sponsor will comply with country-
specific regulatory requirements relating to safety reporting 
to the external review body and investigators. 
 
Individual safety reports for suspected unexpected serious 
adverse reactions will be reported by the Sponsor according 
to local regulatory requirements (e.g., electronic submission 
to the Eudravigilance database in the EU as per EU Clinical 
Trial Regulation 536/2014) as well as Sponsor policy and 
forwarded to investigators as necessary.  
To add the development safety 
update report to align with 
recommendations from 
regulatory agencies and 
additional sections to align 
with new sponsor standard 
safety reporting language 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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An investigator who receives an individual safety report 
describing a SAE or other specific safety information (e.g., 
summary or listing of SAEs) from the Sponsor will file it 
along with the Investigator’s Brochure and will notify the 
external review body, if appropriate according to local 
requirements. 
 
For studies in which the treatment assignment is blinded, to 
comply with worldwide reporting regulations for SAEs, the 
treatment assignment of subjects who develop serious, 
unexpected, and related AEs may be unblinded by the 
Sponsor before submission to regulatory authorities.  
Aggregate analyses may also be unblinded by the Safety 
Assessment Team, as appropriate.  Investigators will receive 
notification of related SAEs reports sent to regulatory 
authorities in accordance with local requirements. 
 
9.5.5.1.12 Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in the 
Sponsor’s safety surveillance and signal management 
processes. 
9.5.5.2 Pregnancy Reporting 
The Investigator should report pregnancies to the Sponsor 
within 24 hours by submitting the completed pregnancy 
report form by email to 
clinicalsafety@horizontherapeutics.com, fax or telephone 
within 24 hours after becoming aware that the 
subject/subject’s female partner has become pregnant (see 
Section 17.1 for contact information).  The Investigator 
should counsel the subject and discuss the possible risks of 
continuing the pregnancy.  If pregnancy continues and the 
subject signs the pregnancy consent form, monitoring 
should also continue to the conclusion of the pregnancy and 
the outcome of the pregnancy should be reported to the 
Sponsor.   
9.5.5.2 Pregnancy and Lactation Reporting 
Details of all pregnancies and/or lactation in female subjects 
and pregnancies in female partners of male subjects will be 
collected after the start of study treatment and until 4 weeks 
after last dose of trial drug. 
 
If a pregnancy is reported, the investigator is to inform the 
Sponsor immediately and no later than 24 hours of 
learning of the pregnancy and/or lactation.  The Investigator 
should report pregnancies to the Sponsor by submitting the 
completed PRF immediately and not later than 24 hours 
after becoming aware that the subject/subject’s female 
partner has become pregnant (see Appendix 17.1 for contact 
information).  The Investigator should counsel the subject 
and discuss the possible risks of continuing the pregnancy.  
To align with new sponsor 
standard safety reporting 
language 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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If pregnancy continues and the subject signs the pregnancy 
consent form, monitoring should also continue to the 
conclusion of the pregnancy and the outcome of the 
pregnancy should be reported to the Sponsor. 
 
Lactation information will be recorded on the Lactation 
Notification Form and submitted to Sponsor Global Patient 
Safety immediately and no later than 24 hours of the 
investigator’s awareness of the event. 
12 Trial Monitoring 
Every effort will be made to maintain the anonymity and 
confidentiality of subjects participating in this clinical trial.  
However, because of the investigational nature of this 
treatment, the Investigator agrees to allow representatives of 
the Sponsor, its designated agents and authorized employees 
of the appropriate regulatory agencies to inspect the 
facilities used in this trial and to have direct access to 
inspect, for purposes of verification, the hospital or clinical 
records of all subjects enrolled in this trial.  A statement to 
this effect should be included in the ICF. 
12 Trial Monitoring 
Every effort will be made to maintain the anonymity and 
confidentiality of subjects participating in this clinical trial.  
However, because of the investigational nature of this 
treatment, the Investigator agrees to allow representatives of 
the Sponsor, its designated agents and authorized employees 
of the appropriate regulatory agencies to inspect the 
facilities used in this trial and to have direct access to 
inspect, for purposes of verification, the hospital or clinical 
records of all subjects enrolled in this trial.  A statement to 
this effect should be included in the ICF. 
 
Serious Breach 
Suspected Serious Breaches must be reported to the study 
team (e.g., Clinical Monitor) or the Clinical Out-of-Hours 
Support Program:  
https://wwwext.amgen.com/science/clinical-trials/clinical-
out-of-hours-support-program immediately and no later than 
1 calendar day from the time of awareness. 
 
A Serious Breach is a breach of any of the following: 
• 
GCP 
• 
the clinical trial protocol 
• 
an applicable regulation 
 
That is likely to impact to a significant degree either of the 
following: 
To update requirements for 
Principal Investigator’s (PI) 
responsibilities to report 
serious breaches per regulatory 
recommendations  

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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• 
the safety, physical, or mental integrity and the rights of 
the participant 
• 
the reliability and robustness of the data and the 
scientific value of the trial 
17.9 Orthostatic Hypotension Assessment Manual 
Version 2.0 
17.9 Orthostatic Hypotension Assessment Manual 
Version 3.0 
To update the symptoms 
reported during the orthostatic 
hypotension assessment will 
only be recorded as adverse 
events if they are severe, persist 
beyond the assessment, or are 
unrelated to the assessment 
maneuver, unless accompanied 
by significant blood pressure 
reductions. 
 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) 
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
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2 
SYNOPSIS 
Protocol Title:  A Phase 2b Randomized, Double-blind, Placebo-controlled, Repeat-dose, Multicenter Trial to 
Evaluate the Efficacy, Safety and Tolerability of HZN-825 in Subjects with Idiopathic Pulmonary Fibrosis 
Protocol Number:  HZNP-HZN-825-303 
Phase:  2b 
Protocol Version:  5.0 
 
Test Drug:  Fipaxalparant (HZN-825) 
Indication:  Idiopathic pulmonary fibrosis 
Number and Geographical Regions of Trial Sites:  Approximately 85 trial sites in North America, Europe, 
South America, Africa, Asia (including Japan), and Australia  
Objectives:   
The trial will be conducted in 2 parts, Part 1 (Core Phase) followed by Part 2 (Extension Phase).  The Core Phase 
will include a 52-week, randomized, double-blind, placebo-controlled treatment period and the Extension Phase 
will include a 52-week, open-label extension (OLE). 
Part 1 (Core Phase) 
The overall objective of the Core Phase is to investigate the efficacy, safety, and tolerability of 2 dose regimens 
of fipaxalparant (HZN-825), a selective antagonist of lysophosphatidic acid receptor 1 (LPAR1), administered 
once daily (QD) or twice daily (BID) for 52 weeks in the treatment of subjects with idiopathic pulmonary fibrosis 
(IPF). 
Primary Objective 
The primary objective is to demonstrate the efficacy of 2 dose regimens of fipaxalparant (HZN-825) versus 
placebo in subjects with IPF, as determined by a comparison of change in forced vital capacity (FVC) % 
predicted after 52 weeks of treatment. 
Secondary Objectives 
1. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on the proportion of 
subjects with decline in FVC % predicted ≥10% from Baseline after 52 weeks of treatment. 
2. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on the changes from 
Baseline in the 6-Minute Walk Test (6MWT) after 52 weeks of treatment. 
3. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on the King's Brief 
Interstitial Lung Disease Questionnaire (K-BILD) after 52 weeks of treatment.  
4. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on the Living with IPF 
(L-IPF) after 52 weeks of treatment. 
5. Evaluate the effect of 2 dose regimens fipaxalparant (HZN-825) versus placebo on the Leicester Cough 
Questionnaire (LCQ) after 52 weeks of treatment. 
6. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on the rate of 
hospitalization due to respiratory distress up to 52 weeks of treatment. 
7. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on the composite endpoint 
of progression-free survival (PFS), where progression includes decline in FVC % predicted ≥10% from 
Baseline or death over 52 weeks of treatment. 
8. Assess safety and tolerability of fipaxalparant (HZN-825), inclusive of, but not limited to, adverse events 
(AEs), serious adverse events (SAEs), and adverse event of special interest (AESI). 
9. Evaluate the pharmacokinetics (PK) of fipaxalparant (HZN-825). 
Exploratory Objectives 
1. 
2. 
3. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) 
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
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4. 
 
 
5. 
 
6. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on mortality due to 
respiratory deterioration up to 52 weeks of treatment. 
7. 
 
 
8. 
 
 
 
 
  
 
  
 
  
 
  
 
 
 
Part 2 (Extension Phase) 
The overall objective of the Extension Phase is to investigate the long-term efficacy, safety, and tolerability of 
fipaxalparant (HZN-825), a selective antagonist of LPAR1, administered at a dose of 300 mg BID to subjects 
with IPF in a 52-week OLE following completion of the Core Phase of the trial.  The dose for the Extension 
Phase may be modified based on the results of the Core Phase. 
Two types of Baseline are defined for the Extension Phase: 
 
OLE Baseline, defined as the latest measurement prior to the first dose of fipaxalparant (HZN-825) in 
the Extension Phase 
 
Fipaxalparant (HZN-825) Baseline, defined as the latest measurement prior to the first dose of 
fipaxalparant (HZN-825) in either the Core Phase or the Extension Phase.  For subjects who received 
placebo in the Core Phase, OLE Baseline will be the same as fipaxalparant (HZN-825) Baseline. 
Primary Objective 
The primary efficacy objective is to assess the efficacy of fipaxalparant (HZN-825) in subjects with IPF after 
52 weeks of open-label treatment. 
Safety Objective 
The safety objective is to examine the safety and tolerability of 52 weeks of open-label treatment with 
fipaxalparant (HZN-825) based on: 
 
Treatment-emergent adverse event (TEAE) assessment 
 
Concomitant medication use 
 
Vital signs 
 
12-lead electrocardiogram (ECG) 
 
Clinical safety laboratory results 
Exploratory Objectives 
The exploratory efficacy objective is to evaluate the efficacy of 52 weeks of open-label treatment with 
fipaxalparant (HZN-825) via additional efficacy measurements: 
 
Proportion of subjects with decline in FVC % predicted ≥10% 
 
6MWT 
 
K-BILD 
 
L-IPF 
 
LCQ 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) 
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
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 
 
 
 
 
 
 
 
 
The exploratory PK objective is to evaluate the PK of fipaxalparant (HZN-825). 
Trial Design: 
HZNP-HZN-825-303 (HARBOR) comprises 2 parts.  Part 1 (Core Phase) is a randomized, double-blind, 
placebo-controlled, repeat-dose, multicenter trial to evaluate the efficacy, safety, and tolerability of fipaxalparant 
(HZN-825) in subjects with IPF.  Part 2 (Extension Phase) is an optional, open-label, repeat-dose, multicenter 
extension of the Core Phase.  The trial will include up to an 8-week Screening Period and a 52-week 
Double-blind Treatment Period in the Core Phase and 52 weeks of open-label fipaxalparant (HZN-825) treatment 
in the Extension Phase.   
During the Core Phase, subjects will be screened within 8 weeks prior to the Baseline (Day 1) Visit.  
Approximately 135 subjects who meet the trial eligibility criteria will be randomly assigned in a 1:1:1 ratio on 
Day 1 to receive fipaxalparant (HZN-825) 300 mg QD, fipaxalparant (HZN-825) 300 mg BID, or placebo for 
52 weeks using the following 2 stratification factors: 
1. Concomitant use of approved IPF therapy (i.e., nintedanib or pirfenidone):  yes or no 
2. FVC % predicted at Baseline:  ≥70% or <70% 
During the Core Phase, subjects will take their first dose of trial drug at the clinic on Day 1 (Week 0) and will 
participate in trial visits at Week 4 and every 6 weeks thereafter until Week 52.  If a subject prematurely 
discontinues trial drug, he/she will be asked to remain in the trial, participating in the scheduled trial visits 
through Week 52.  If a subject prematurely discontinues trial drug and does not wish to continue in the trial, 
he/she will be asked to return for a clinic visit and undergo the Week 52 assessments. 
An interim analysis with a futility analysis will be performed 
 
  These unblinded 
efficacy and safety data will be provided to an independent data monitoring committee (IDMC) and will be used 
to inform conduct of the current trial.  The IDMC will include at least 1 statistician and at least 2 clinicians 
experienced in clinical trials and managing IPF subjects.  The IDMC charter will include processes to unblind 
select Horizon personnel who are not directly involved with the trial conduct to assess unforeseen issues.  A 
Horizon unblinded team may also aid in dose selection and future trial design. 
Subjects who complete the 52-week Double blind Treatment Period of the Core Phase of the trial will be invited 
to extend their participation in the 52-week Extension Phase of the trial, for a total exposure to trial drug of 
104 weeks.  If the subject does not enroll into the Extension Phase, a Safety Follow-up Visit will occur 4 weeks 
after the last dose of trial drug. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) 
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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An overview of the trial design is presented below. 
Core Phase 
Screening 
Baseline 
Double-blind Treatment Period 
fipaxalparant (HZN-825) or Placebo 1, 2 
52 Weeks 
Safety  
Follow-up 
Visit 
< –––––––––––––––––––––––––––––––––––––––––––––– Trial Visits 3, 4––––––––––––––––––––—————————— > 
 
 
 
 
 
 
 
 
8 weeks 
prior to first 
dose of trial 
drug 
Day 1 
Weeks 2 4, 4, 6 4 and 10 and every 6 weeks thereafter 
Week 52 5 4 weeks after 
last dose of 
trial drug 
Randomization1 < ––––––––––––––––––––––––––––––––––––––– Trial Week –––––––––––––––––––––––––––––––––––––––– > 
 
 
BID=twice daily; QD=once daily 
1. 
Subjects will be randomized in a 1:1:1 ratio to receive fipaxalparant (HZN-825) 300 mg QD, fipaxalparant (HZN-825) 300 mg BID, or placebo.   
2. 
If a subject prematurely discontinues trial drug, he/she will be asked to remain in the trial, participating in the scheduled trial visits through 
Week 52.  If a subject prematurely discontinues trial drug and does not wish to continue in the trial, he/she will be asked to return for a clinic visit 
and undergo the Week 52 assessments.  Subjects not entering the 52-week Extension Phase will return to the clinic 4 weeks after the last dose of 
trial drug for a Safety Follow-up Visit. 
3. 
Visit windows are ±3 days for Week 4, ±7 days for Week 10 to Week 52, inclusive, and ±14 days for the Safety Follow-up Visit.   
4. 
Visits at Weeks 2 and 6 are remote (telephone) visits with a ±3-day window. 
5. 
Subjects who complete the Double-blind Treatment Period (Week 52) may be eligible to enter the 52-week Extension Phase of the trial.  
Extension Phase 
Week 52 Visit of Core Phase 
Open-label Treatment Period 
fipaxalparant (HZN-825) 300 BID 1, 2 
52 Weeks (Week 52 – Week 104) 
Safety  
Follow-up 
Visit 
< –––––––––––––––––––––––––––––––––––––––––––––– Trial Visits 3, 4––––––––––––––––––––—————————— > 
 
 
 
 
 
 
 
 
Day 1 of Extension Phase 
Weeks 56, 62, 68, 74 4, 80, 86 4, 92, and 98 4 
Week 104 4 weeks after 
last dose of 
fipaxalparant 
(HZN-825) 
BID=twice daily 
1. 
The fipaxalparant (HZN-825) dose may be modified based on the results of the Core Phase.   
2. 
If a subject prematurely discontinues open-label fipaxalparant (HZN-825), he/she will be asked to remain in the trial, participating in the scheduled 
trial visits through Week 104.  If a subject prematurely discontinues open-label fipaxalparant (HZN-825) and does not wish to continue in the trial, 
he/she will be asked to return for a clinic visit and undergo the Week 104 assessments.   
3. 
Visit windows are ±5 days for Week 56, ±7 days for Week 62 to Week 104, inclusive, and ±14 days for the Safety Follow-up Visit.   
4. 
Visits at Weeks 74, 86, and 98 are remote (telephone) visits with a ±7-day window. 
 
Subject Population: 
Approximately 135 subjects ≥18 years of age with IPF will be enrolled. 
Eligibility Criteria for the Core Phase: 
Inclusion Criteria: 
Eligible subjects must meet/provide all of the following criteria: 
1. Written informed consent. 
2. Male or female ≥18 years of age at Screening. 
3. Current diagnosis of IPF, as defined by American Thoracic Society (ATS)/European Respiratory Society 
(ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Society (ALAT) guidelines [Raghu et 
al., 2022] and determined by central review; the date of initial diagnosis of IPF should be ≤7 years prior to 
Screening.   

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) 
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
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4. No recent changes or planned changes to the dose or regimen for IPF therapy, defined as:   
 
Receiving a stable dose of IPF-approved therapy (i.e., nintedanib or pirfenidone) for a minimum of 
3 months prior to Day 1 with no plans to change the background regimen during trial participation, or 
 
Not currently receiving background IPF-approved therapy at Screening (either naïve to IPF-approved 
therapy or previously discontinued any IPF-approved therapy at least 4 weeks prior to Day 1 or 
drug-specific, 5 half-lives elimination period if longer than 4 weeks), and with no current plans to restart 
treatment during trial participation 
 
Subjects receiving any additional agent for IPF therapy must be on a stable regimen for at least 3 months 
prior to Day 1 with no current plans to change the treatment regimen during trial participation.  Any 
previously discontinued therapy used to treat IPF must have been discontinued at least 4 weeks prior to 
Day 1 or 5 half-lives for that specific therapy must have elapsed, whichever is longer, with no plans to 
restart the therapy during trial participation.  
5. Lung HRCT historically performed within 6 months prior to the Screening Visit and according to the 
minimum requirements for IPF diagnosis by central review based on subject's HRCT.  If an evaluable HRCT 
is not available within 6 months prior to Screening, an HRCT will be performed at Screening to determine 
eligibility, according to the same requirements as the historical HRCT.  The HRCT must demonstrate a usual 
interstitial pneumonia or probable usual interstitial pneumonia pattern based on central review vendor 
interpretation.  Histopathology in combination with HRCT results supportive of an IPF or IPF likely 
diagnosis according to Raghu et al., 2022 can be submitted to support subject eligibility.   
6. HRCT shows ≥10% to <50% parenchymal fibrosis (reticulation) and the extent of fibrotic changes is greater 
than the extent of emphysema on the most recent HRCT scan (central reviewer determined). 
7. Meets all of the following criteria during the Screening Period, as determined by central review:   
a. FVC ≥45% predicted of normal 
b. forced expiratory volume in 1 second /FVC ≥0.7 
c. DLCO corrected for hemoglobin is ≥25% and ≤90% predicted of normal 
8. Estimated minimum life expectancy of ≥30 months for non-IPF-related disease, in the opinion of the 
Investigator. 
9. Vaccinations are up to date, according to the Investigator’s discretion, given age, comorbidities, and local 
availability prior to trial drug dosing. 
10. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the 
trial. 
Exclusion Criteria: 
Subjects will be ineligible for trial participation if they meet any of the following criteria: 
1. Any of the following cardiovascular diseases:   
a. uncontrolled, severe hypertension (≥160/100 mmHg), within 6 months of Screening 
b. myocardial infarction within 6 months of Screening 
c. unstable cardiac angina within 6 months of Screening 
2. Interstitial lung disease (ILD) associated with known primary diseases (e.g., sarcoidosis, amyloidosis, and 
coronavirus disease 2019 [COVID-19]), connective tissue disorders (e.g., rheumatoid arthritis, systemic 
lupus erythematosus, Sjogren’s, dermatomyositis, scleroderma), exposures (e.g., radiation, silica, asbestos, 
and coal dust) or drugs (e.g., amiodarone).   
3. Known active bacterial, viral, fungal, mycobacterial, or other infection, including tuberculosis or atypical 
mycobacterial disease (fungal infections of nail beds are allowed).  The subject must be 3 months beyond any 
acute infection with COVID-19 if there has been a prior infection. 
4. Clinically significant pulmonary hypertension requiring chronic medical therapy. 
5. Use of any of the following therapies within 4 weeks prior to Screening, during the Screening Period or 
planned during the trial:  prednisone at steady dose >10 mg/day or equivalent or cyclosporine.  Change in 
regimen or dosage of any immunosuppressant during the Screening Period through the end of trial 
participation will require consultation with and approval by the trial Medical Monitor.  See Section 9.4.9 for 
full details.  Avoiding the use of listed prohibited treatments must not be considered detrimental and must be 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) 
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
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indicated by the treating physician.  Subjects must not be withdrawn from any standard-of-care treatment that 
is considered necessary for the clinical management of the subject in order to fulfill the trial eligibility 
requirements. 
6. Use of rifampin within 2 weeks prior to Day 1 or planned during the trial. 
7. Malignant condition in the past 5 years (except successfully treated basal/squamous cell carcinoma of the 
skin or cervical cancer in situ). 
8. Women of childbearing potential (WOCBP) or male subjects not agreeing to use highly effective method(s) 
of birth control throughout the trial and for 4 weeks after last dose of trial drug.  Females must refrain from 
egg/ova donation for 4 weeks after the last dose of trial drug and males must refrain from sperm donation for 
3 months after the last dose of trial drug.  Women are considered of childbearing potential if they are not 
postmenopausal and not surgically sterile (documented bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy).  A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause.  A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm 
a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy.  
However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.  Fertile 
male subjects must use a condom throughout the trial and for 4 weeks after the last dose of trial drug.  A man 
is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
9. Pregnant or lactating women and women who plan to become pregnant or breast feed during the trial and 
within 4 weeks after the last dose of trial drug. 
10. Current drug or alcohol abuse or history of either within the previous 2 years, in the opinion of the 
Investigator or as reported by the subject. 
11. Previous enrollment in this trial or participation in a prior fipaxalparant (HZN-825) or SAR100842 clinical 
trial. 
12. Known history of positive test for human immunodeficiency virus (HIV).  HIV testing is optional based on 
Investigator assessment, institutional practices or local guidelines, to rule out suspected HIV or potential for a 
positive HIV result.  Subject consent is required prior to HIV testing. 
13. Active hepatitis (any of the following at Screening): 
Hepatitis B:   
 
positive hepatitis B surface antigen 
 
positive for anti-hepatitis B core antibody (anti-HBcAb) and a positive test for hepatitis B surface 
antibody (HBsAb) and presence of hepatitis B virus DNA 
 
positive for HBcAb and a negative test for HBsAb and presence of hepatitis B virus DNA 
Hepatitis C:   
 
positive anti-hepatitis C virus (anti-HCV) and positive HCV RNA. 
14. Current alcoholic liver disease, primary biliary cirrhosis or primary sclerosing cholangitis. 
15. Previous organ transplant (including allogeneic and autologous marrow transplant). 
16. International Normalized Ratio (INR) >2, prolonged prothrombin time >1.5 × the upper limit of normal 
(ULN) or partial thromboplastin time >1.5 × ULN at Screening. 
17. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.0 × ULN. 
18. Estimated glomerular filtration rate <30 mL/min/1.73 m2 at Screening.   
19. Total bilirubin >1.5 × ULN.  Subjects with documented diagnosis of Gilbert’s syndrome may be enrolled if 
their total bilirubin is ≤3.0 mg/dL. 
20. Moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment according to the Child-Pugh scoring 
system. 
21. Any confirmed Grade 3 or higher laboratory abnormality.   
22. Any laboratory abnormality at Screening that, in the opinion of the Investigator, would preclude the subject’s 
participation in the trial. 
23. Exposure to an experimental drug or experimental vaccine within either 30 days, 5 half-lives of the test 
agent, or twice the duration of the biological effect of the test agent, whichever is the longest, prior to Day 1. 
24. Any other condition that, in the opinion of the Investigator, would preclude enrollment in the trial. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) 
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Eligibility Criteria for the Extension Phase: 
Inclusion Criteria: 
Eligible subjects must meet/provide all of the following criteria: 
1. Written informed consent. 
2. Completed the Double-blind Treatment Period (Week 52) of the Core Phase of the trial; subjects prematurely 
discontinued from trial drug in the Core Phase of the trial for reasons other than safety or tolerability may be 
included at the discretion of the Investigator after completing scheduled visits, including Week 52 
assessments. 
3. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the 
Extension Phase of the trial. 
Exclusion Criteria: 
Subjects will be ineligible for Extension Phase of the study if they meet any of the following criteria: 
1. Anticipated use of another investigational agent for any condition during the course of the trial. 
2. New diagnosis of malignant condition after enrolling in Trial HZNP-HZN-825-303 (except successfully 
treated basal/squamous cell carcinoma of the skin or cervical cancer in situ).   
3. Estimated minimum life expectancy ≤18 months, in the opinion of the Investigator. 
4. WOCBP or male subjects not agreeing to use highly effective method(s) of birth control throughout the 
Extension Phase and for 4 weeks after last dose of fipaxalparant (HZN-825). Females must refrain from 
egg/ova donation for 4 weeks after the last dose of trial drug and males must refrain from sperm donation for 
3 months after the last dose of trial drug.  Women are considered of childbearing potential if they are not 
postmenopausal and not surgically sterile (documented bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy).  A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause.  A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy.  However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.  A man is considered fertile after 
puberty unless permanently sterile by bilateral orchidectomy. 
5. Pregnant or lactating women. 
6. Any other new development of the disease/condition/significant laboratory test abnormality during the course 
of the Core Phase of the trial, in the opinion of the Investigator, that would potentially put the subject at 
unacceptable risk. 
7. In the opinion of the Investigator, unlikely to comply with the trial protocol or has a concomitant disease or 
condition that could interfere with the conduct of the trial. 
Dose Regimen/Route of Administration: 
Core Phase:  Subjects will take 2 tablets of trial drug orally in the morning and evening with a meal.   
 
Fipaxalparant (HZN-825) 300 mg QD regimen:   2 fipaxalparant (HZN-825) tablets in the morning and 
2 placebo tablets in the evening. 
 
Fipaxalparant (HZN-825) 300 mg BID regimen:   2 fipaxalparant (HZN-825) tablets in the morning and 
2 fipaxalparant (HZN-825) tablets in the evening. 
 
Placebo regimen:   2 placebo tablets in the morning and 2 placebo tablets in the evening. 
Extension Phase:  The dose regimen for all subjects will be fipaxalparant (HZN-825) 300 mg BID.  Subjects will 
take 2 fipaxalparant (HZN-825) 150 mg tablets orally in the morning and evening with a meal.  The dose for the 
Extension Phase may be modified based on the results of the Core Phase. 
Dosage Form, Strength Formulation and Storage: 
Fipaxalparant (HZN-825) 150 mg tablets and matching placebo tablets will be used in this trial.  Fipaxalparant 
(HZN-825) 150 mg and placebo tablets will be packaged in blinded blister packs according to the dose regimens 
indicated (blister packs will be blinded for the Core Phase).  The film-coated tablets are stored at controlled room 
temperature (20ºC to 25Cº, 68ºF to 77Fº). 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) 
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Duration of Treatment and Follow-up: 
The planned duration of the Double-blind Treatment Period of the Core Phase is 52 weeks.  All subjects who 
complete the Double-blind Treatment Period may be eligible to enter into the Extension Phase of the trial and 
receive 52 weeks of open-label fipaxalparant (HZN-825).  The total maximum exposure to trial drug during the 
trial is 104 weeks.  Subjects not entering the Extension Phase of the trial will return to the clinic 4 weeks after the 
last dose of trial drug for a Safety Follow-up Visit. 
Criteria for Evaluation: 
Details of time points for trial activities and assessments are provided in Section 2.1 (Core Phase) and Section 2.2 
(Extension Phase). 
Efficacy will be assessed by FVC, 6MWT, PFS, patient-reported outcomes (K-BILD, L-IPF, LCQ, and SF-12), 
respiratory-related hospitalization, TOR, DLCO, IPF-related acute exacerbation, all-cause mortality, mortality 
due to respiratory deterioration, mortality due to IPF-related events and lung HRCT. 
Blood samples for fipaxalparant (HZN-825) PK assessment, pharmacodynamic markers, and optional 
pharmacogenetic assessment (for drug metabolizing enzymes and/or transporters) will be collected. 
Safety will be assessed via AEs, concomitant medication use, physical examinations, vital signs, orthostatic 
hypotension assessment, laboratory evaluations, 12-lead ECG, and echocardiogram.   
Statistical Analyses: 
Core Phase: 
Primary Efficacy Endpoint 
Change in FVC % predicted from Baseline to Week 52. 
Key Secondary Efficacy Endpoint 
Proportion of subjects with decline in FVC % predicted ≥10% from Baseline at Week 52. 
Other Secondary Efficacy Endpoints 
1. Change from Baseline in the 6MWT results to Week 52. 
2. Change from Baseline in K-BILD scores to Week 52.  
3. Change from Baseline in L-IPF scores to Week 52.  
4. Change from Baseline in LCQ scores to Week 52. 
5. Time to first hospitalization due to respiratory distress from Baseline up to Week 52. 
6. Time to first onset of the composite endpoint of PFS from Baseline up to Week 52, where progression 
includes decline in FVC % predicted ≥10% or death. 
Exploratory Endpoints 
6. Time to death due to respiratory deterioration from Baseline up to Week 52. 
 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) 
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Safety and Tolerability Endpoints 
1. Incidence of TEAEs, SAEs and the AESI (orthostatic hypotension). 
2. Concomitant medication use. 
3. Vital signs. 
4. 12-lead ECGs and echocardiograms. 
5. Laboratory evaluations. 
Pharmacokinetic Endpoint 
Pre- and post-dose concentrations of fipaxalparant (HZN-825). 
Statistical Analysis of Efficacy and Safety Endpoints 
Efficacy analyses will be performed on the full analysis set (FAS), consisting of all subjects who are randomized 
to treatment and take at least 1 dose of trial drug; subjects will be analyzed according to the treatment group to 
which they were randomized.  Safety analyses will be performed on the safety analysis set, consisting of all 
subjects who receive at least 1 dose or partial dose of trial drug.   
Efficacy 
The estimand for the primary efficacy analyses will be constructed to compare the primary endpoint between 
each dose regimen of fipaxalparant (HZN-825) and placebo using the treatment policy strategy approach to 
intercurrent events.  All subjects who are randomized and take at least 1 dose of trial drug will be included in the 
primary efficacy analyses (FAS).   
The primary efficacy endpoint will be change from Baseline in FVC % predicted to Week 52.  A mixed model 
for repeated measures (MMRM) analysis of covariance model will be fit to the data using observed change in 
FVC % predicted values from all planned post-Baseline assessments (i.e., Weeks 4, 16, 28, 40, and 52) with 
covariates of stratification factors (concomitant use of IPF therapy [yes, no] and FVC % predicted at Baseline 
[≥70%, <70%]), treatment group, visit and visit-by-treatment group interaction.  The unstructured variance-
covariance matrix will be used in the model.  Treatment group least squares means, associated standard error 
(SE) and their differences (each fipaxalparant [HZN-825] group minus placebo separately), SE of the difference, 
90% confidence intervals (CIs) and p-value overall and for each visit will be provided.   
For subjects with missing data at 1 or more time points, the available data will be included in the analysis. 
One sensitivity analysis will consider whether data missing not at random may change the conclusion.  A tipping 
point analysis will estimate the difference in true values among unobserved data that must occur to change the 
conclusion for each dose (i.e., change the result for each dose from p≤0.10 to p>0.10).  Intercurrent events will be 
addressed in the primary analysis by using treatment policy strategy with all available data.  
Sensitivity/supplemental analyses will assess the impact of missing data, as needed.  
The key secondary endpoint will be the proportion of subjects with decline in FVC % predicted ≥10% from 
Baseline at Week 52 and will be analyzed using a logistic regression model with treatment group and stratified by 
factors used for stratifying the randomization.  The logistic model will provide odds ratio, its 90% CI and p-value 
for comparing each fipaxalparant (HZN-825) group with the placebo group.  Statistical significance for the key 
secondary endpoint will only be concluded if statistical significance is achieved for the primary efficacy 
endpoint.   

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) 
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
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  This analysis will have 2 potential 
outcomes: 
 
If neither dose regimen of fipaxalparant (HZN-825) shows better efficacy compared to placebo with an 
acceptable safety profile, the trial will be discontinued for futility. 
 
If 1 or both dose regimens of fipaxalparant (HZN-825) show better efficacy compared to placebo with an 
acceptable safety profile, the trial will continue with no changes. 
The futility analysis will not be used to make a positive determination of efficacy to stop the trial. 
Conditional power will be used to determine which of the options is chosen, with a conditional power of 
≥10% required for at least 1 dose regimen to continue the trial.  Other statistics, such as Bayesian statistics, may 
also be used for the futility analysis and dose selection. 
To support the dose selection and as part of the Week 28 unblinded interim analysis, the FVC % predicted 
change from Baseline at Week 28 will be evaluated in subjects who were randomized with concomitant standard-
of-care treatment at Baseline.  Approximately 60 subjects in the standard-of-care stratum with 28 weeks of data 
(approximately 20 subjects per arm) will be included.  The positive signal in the FVC % predicted change from 
Baseline at Week 28 and related results in standard-of-care subjects will support the dose selection and future 
trial design. 
Additionally, safety will be assessed, and an fipaxalparant (HZN-825) dose regimen that has an unacceptable 
safety profile will be discontinued and subjects assigned to that dose regimen will be assigned to the other dose 
regimen for the remainder of the trial, if the other dose regimen continues. 
At the interim analysis, the IDMC will provide recommendation to select Horizon personnel not involved in the 
oversight of the trial to facilitate trial continuation and dose selection for future trials.  To support decisions on 
future dose selection and future trial design, a Horizon unblinded team may be established and receive unblinded  
data and perform ad hoc analyses, as needed.  All unblinded data and analysis results made available to Horizon 
unblinded team will be archived to allow for any potential post hoc assessments of bias.  For additional details, 
please refer to the IDMC charter and Blinding Maintenance Plan for this trial. 
The overall statistical level is α=0.10 (2-sided).  Because 2 dose regimens of fipaxalparant (HZN-825) will be 
compared to placebo, a hierarchical testing procedure will be used for multiple comparisons.  Therefore, α=0.10 
(2-sided) will be used in the final analysis.  The hierarchical testing procedure will be used for the primary and 
key secondary endpoint.  For the primary endpoint, the BID dose will be tested versus placebo first; if significant, 
the QD dose will then be tested.  If 1 or 2 dose regimens of the primary endpoint are not rejected after completing 
testing, no further testing will occur.  If both fipaxalparant (HZN-825) doses are statistically significantly better 
than placebo for primary efficacy endpoint, the testing procedure will continue for the key secondary endpoint 
and will be similar to that performed for the primary endpoint.   
Although p-values will be provided for the other secondary and exploratory endpoints, they will not be used for 
inferential purposes. 
Safety and Tolerability 
All subjects who receive at least 1 dose or partial dose of trial drug will be included in safety and tolerability 
analyses.  Subjects who receive treatment other than that to which they were randomized will be included in 
summaries based on treatment received.  Subjects who receive more than 1 treatment will be listed separately and 
included in summaries with the treatment received most frequently. 
Safety analyses will be summarized by treatment group.  The incidence of TEAEs, treatment-related TEAEs, 
TEAEs Grade 3 and above, AESI, SAEs, and TEAEs leading to trial drug discontinuation by Preferred Term and 
System Organ Class will be summarized.  AE rates (events per patient-year of follow-up during the Double-blind 
Treatment Period) will also be summarized to account for different treatment durations.  Orthostatic hypotension 
is prospectively defined as an AESI and will be summarized separately. 
Summary statistics will be used for laboratory values, vital signs, ECG results, and use of concomitant 
medications.  

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) 
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Statistical Analyses: 
Extension Phase: 
Primary Efficacy Endpoint 
Change from both Baselines in FVC % predicted at Week 104. 
Safety and Tolerability Endpoints 
 
Incidence of TEAEs and the AESI (orthostatic hypotension) in the Extension Phase. 
 
Concomitant medication use in the Extension Phase 
 
Change from OLE Baseline in vital signs in the Extension Phase 
 
Change from OLE Baseline in 12-lead ECG measurements in the Extension Phase 
 
Change from OLE Baseline in clinical safety laboratory test results in the Extension Phase 
Exploratory Endpoints 
 
Change from both Baselines in proportion of subjects with decline in FVC % predicted ≥10% at Week 52 of 
the Extension Phase (Trial Week 104). 
 
Change from both Baselines in the 6MWT results to Week 104 
 
Change from both Baselines in K-BILD scores to Week 104 
 
Change from both Baselines in L-IPF scores to Week 104 
 
Change from both Baselines in LCQ scores to Week 104 
 
 
 
Time to first onset of the composite endpoint of PFS from fipaxalparant (HZN-825) Baseline up to Week 
104, where progression includes decline in FVC % predicted ≥10% from Baseline or death 
 
 
 
 
 
Time to death due to respiratory deterioration from fipaxalparant (HZN-825) Baseline up to Week 104 
 
 
Exploratory PK Endpoints 
 
Pre- and post-dose concentrations of fipaxalparant (HZN-825) in the Extension Phase 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.) 
Fipaxalparant (HZN-825) 
Date:  07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Statistical Analysis of Efficacy and Safety Endpoints  
Efficacy analyses will be performed on the FAS, consisting of all subjects who entered and received at least 
1 dose or partial dose of fipaxalparant (HZN-825) in the Extension Phase.  Subjects will be analyzed according to 
the treatment group to which they were randomized in the Core Phase and combined into an ‘overall’ group. 
Safety analyses will be performed on the safety analysis set, consisting of all subjects who receive at least 1 dose 
or partial dose of fipaxalparant (HZN-825) in the Extension Phase.  This analysis set will be analyzed according 
to the group determined by the treatment the subject received in the Core Phase and combined into an ‘overall’ 
group.  
All efficacy and safety endpoints will be summarized using descriptive statistics. 
Sample Size Estimate: 
Approximately 135 subjects (45 subjects per treatment group) will be enrolled in the trial.  Based on a prior trial 
of pirfenidone [Nathan et al., 2019] in a similar subject population, change in FVC % predicted is expected to 
have a standard deviation of 6% to 9% after 52 weeks of treatment.  Assuming a clinically important difference 
between fipaxalparant (HZN-825) and placebo is 3% and a common standard deviation is 9%, a sample size of 
45 subjects per treatment group in the Core Phase will provide 85% probability to detect a positive signal (FVC 
% predicted difference for each dose vs. placebo at Week 52 >1%) and 70% probability to detect a positive signal 
(FVC % predicted difference for each dose vs. placebo at Week 52 >2%).  If the true FVC % predicted difference 
for each dose versus placebo at Week 52 is 0%, then there is only 15% probability to detect a positive signal 
(FVC % predicted difference for each dose vs. placebo at Week 52 >2%). 
The sample size for the Extension Phase is based on the number of subjects who complete the Core Phase. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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2.1 
Schedule of Assessments During the Core Phase 
 
Screening 1 
Double-blind Treatment Period 
Safety  
Follow-up 
Visit 
Trial Visit 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
4 weeks after 
last dose of 
trial drug 
Trial Week (W) -56 days -35 days Day 1 2, 3 
W2 4 
W4 
W6 4 
W10 
W16 
W22 5 W28 3 W34 5 W40 
W46 5 W52/PD 3, 6 
W56 
Visit Window (±days) 
 
 
(±3) 
(±3) 
(±3) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±14) 
Informed consent 7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lung HRCT (assessed by 
central review) 8 
X 
 
 
 
 
 
 
 
 
 
 
 
X 9 
 
Histopathology central review 
(assessed by central review, if 
available, but not required) 10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review eligibility criteria 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, IPF, and substance use 
history 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight  
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 11 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Trial drug dispensing 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 12 
 
Treatment compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
FVC % predicted/spirometry 
 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Titrated oxygen requirement  
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
6MWT 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
DLCO 13 
 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Patient-reported Outcome Assessments  
L-IPF, K-BILD, LCQ, SF-12 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Anchor Questions 
FVC (last week) 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
FVC (change since start of 
trial) 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Pregnancy test 14 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Physical examination 15 
 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
Vital signs, including pulse 
oximetry 16 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 5.0, Amendment 4 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 33 of 153 
(A WHOLLY OWNED SUBSIDIARY OF AMGEN INC.) 
Internal Use Only General and Administrative
 
Screening 1 
Double-blind Treatment Period 
Safety  
Follow-up 
Visit 
Trial Visit 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
4 weeks after 
last dose of 
trial drug 
Trial Week (W) -56 days -35 days Day 1 2, 3 
W2 4 
W4 
W6 4 
W10 
W16 
W22 5 W28 3 W34 5 W40 
W46 5 W52/PD 3, 6 
W56 
Visit Window (±days) 
 
 
(±3) 
(±3) 
(±3) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±14) 
Orthostatic hypotension 
assessment 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
12-lead electrocardiogram 17 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Echocardiogram 17 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Laboratory Evaluations  
Chemistry and hematology 18, 
19 
 
X  
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting glucose and lipids 20 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
hsCRP 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Urinalysis 18 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV and HCV serology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV test 21 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event assessment 22 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concom. medications 23 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samples 24 
 
 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
Pharmacodynamic serum 
sample (collect pre-dose) 25 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
Pharmacogenetic sample 
(optional) 26 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PBMC sample 27 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
6MWT=6-minute Walk Test; BID=twice daily; concom.=concomitant; CYP=cytochrome P450; DLCO=diffusing capacity of the lungs for carbon monoxide; FVC=forced vital 
capacity; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; HRCT=high-resolution computed tomography; hsCRP=high-sensitivity 
C-reactive protein; IPF=idiopathic pulmonary fibrosis; LCQ=Leicester Cough Questionnaire; L-IPF=Living with IPF; K-BILD= King's Brief Interstitial Lung Disease 
Questionnaire; LPAR1=lysophosphatidic acid receptor 1; PBMC=peripheral blood mononuclear cell; PD=premature discontinuation; PK=pharmacokinetic; QD=once daily; 
SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SF-12=SF-12® Health Survey; SLCO=solute carrier organic anion transporter family member; W=Week; 
WOCBP=women of childbearing potential 
1. Screening procedures can take place over more than 1 day/clinic visit provided consent is obtained first and all assessments are completed within the designated window.  An 
abnormal test or assessment during Screening may be repeated once during the Screening Period. 
2. On Day 1 (Baseline), subjects will be randomized and receive the first dose of trial drug in the clinic.  All Day 1 assessments should be performed before the first dose of trial 
drug is administered in the clinic except for the PK sample collected 2-4 hours post dose. 
3. Subjects should fast at least 8 hours prior to clinic visits on Day 1, Week 28, and Week 52 due to the need for fasting glucose, total cholesterol, high-density lipoprotein 
cholesterol, low density lipoprotein cholesterol, and triglycerides. 
4. Remote (telephone) visit. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 5.0, Amendment 4 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 34 of 153 
(A WHOLLY OWNED SUBSIDIARY OF AMGEN INC.) 
Internal Use Only General and Administrative
5. Visits may be conducted as home health visits, as available within local regions. 
6. If a subject prematurely discontinues trial drug, he/she will be asked to remain in the trial, participating in the scheduled trial visits through Week 52.  If a subject prematurely 
discontinues trial drug and does not wish to continue in the trial, he/she will be asked to return for a clinic visit and undergo the Week 52 assessments.  Subjects not entering 
the 52-week OLE will return to the clinic 4 weeks after the last dose of trial drug for a Safety Follow-up Visit. 
7. Informed consent is required prior to performing any assessments, including submission of medical information for central review.  Record date and time informed consent was 
given and who conducted the process on the appropriate source documentation and per required regulations. 
8. Baseline lung HRCT will be performed only if no previous lung HRCT is available within the last 6 months prior to Screening date.  This can be performed any time between 
the start of the initial 56 days of Screening and must be completed with results from central review vendor prior to Day 1.  Confirm enough time for results to be made 
available from the central review vendor with turnaround time being up to 5 business days for results.  Results are required from central review vendor. 
9. The lung HRCT scan will be performed for all subjects within ±2 weeks of the Week 52/PD Visit.  Central review will be performed. 
10. Histopathology reports used towards IPF diagnosis (if available, but these are not required) will be submitted for central review. 
11. Subjects will be randomized in a 1:1:1 ratio to receive fipaxalparant (HZN-825) 300 mg QD, fipaxalparant (HZN-825) 300 mg BID, or placebo. 
12. For subjects who are entering the OLE Phase. 
13. If SARS-CoV-2 exposure is of clinical concern for any subject, consider using a DLCO up to 6 months before the Screening Visit. 
14. Perform for WOCBP.  Serum pregnancy test at Screening and Week 52 (or as needed).  Urine pregnancy tests should also be done every 4 weeks after randomization, which 
includes both in-clinic testing at scheduled visits prior to dosing (Weeks 1, 4, 16, 28, and 40) and at home (also a ±5-day window) by the subject and reported to the site 
(Weeks 8, 12, 20, 24, 32, 36, 44, and 48).    
15. A complete physical examination will be performed, including, but not limited to, cardiac, pulmonary and neurologic assessments. 
16. Vital signs (blood pressure, heart rate, respiratory rate, temperature, pulse oximetry) will be measured at each visit.   
17. Additional electrocardiograms or echocardiograms will be conducted, if clinically indicated.  An echocardiogram that has been performed within 3 months prior to Day 1 can 
serve as the Baseline echocardiogram if the subject has been clinically stable. 
18. See Section 9.5.5.9 for details. 
19. For subjects taking warfarin, physicians should monitor their INR, as needed. 
20. Includes fasting glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides.   
21. HIV testing is optional based on Investigator assessment, institutional practices or local guidelines to rule out suspected HIV or potential for a positive HIV result.  Subject 
consent is required prior to HIV testing. 
22. Adverse events that occur after signing the informed consent form and prior to dosing on Day 1 will be considered medical history.  Adverse events occurring or worsening 
after the first dose of trial drug through the Safety Follow-up Visit will be considered treatment-emergent adverse events.  All adverse events that occur from the signing of 
informed consent through the Safety Follow-up Visit will be recorded.   
23. Includes recording of herb/supplement use.  See Table 9.1 for restrictions regarding medications. 
24. PK samples will be collected at each of the following visits:  Day 1 (at 2 to 4 hours after the first dose of trial drug), Week 4 (pre-dose), Week 10 (anytime during the visit), 
Weeks 16 and 28 (pre-dose and 2 to 4 hours post-dose), and Weeks 40 and 52 (pre-dose for subjects entering the 52-week open-label Extension Phase).  For the Day 1, 
Week 16 and Week 28 Visits with post-dose PK samples, the morning dose regimen will be taken in the clinic.  Note:  all pre-dose samples will be collected prior to any trial 
drug administration during the clinic visit; record date and time of last dose prior to visit.  For subjects not entering the 52-week open-label Extension Phase, a sample will be 
collected anytime during the Week 52 Visit.  Record date/time of all samples. 
25. To be stored for future analysis.  Use of stored serum sample for pharmacodynamic endpoints will be limited to understanding the trial drug as related to investigation of the 
LPAR1 pathway or disease for the current trial. 
26. This optional sample will be used to explore the impact of polymorphisms in genes encoding drug metabolizing enzymes and transporters (e.g., CYP2C9, CYP2D6, SLCO1B1, 
and SLCO1B3) on fipaxalparant (HZN-825) PK. 
27. A blood sample for PBMCs will be collected on Day 1 (pre-dose), Week 28 (pre-dose) and Week 52 (pre-dose) for transcriptomic analysis. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 5.0, Amendment 4 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 35 of 153 
(A WHOLLY OWNED SUBSIDIARY OF AMGEN INC.) 
Internal Use Only General and Administrative
2.2 
Schedule of Assessments During the Extension Phase 
  
Open-label Treatment Period 
Safety Follow-up 
Visit  
 
Trial Visit 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
4 weeks after last 
dose of 
fipaxalparant 
(HZN-825) 
23  
Trial Week (W) 
W52 1  
W56 
W62 
W68 
W74 2  
W80 
W86 2 
W92 
W98 2 
W104/PD 3 
  
Visit Window (±days) 
(±7)  
(±5)  
(±7)  
(±7)  
(±7)  
(±7)  
(±7)  
(±7)  
(±7)  
(±7)  
(±14)  
Informed consent 4 
X 
 
 
 
Review eligibility criteria  
X 
 
 
 
Weight  
X 5 
 
X 
 
 
X 
Fipaxalparant (HZN-825) dispensing  
X 
X 
X 
X 
 
X 
 
X 
 
Compliance  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy Assessments 
FVC % predicted/spirometry 6  
X 5 
X 
 
X 
 
X 
 
X 
Titrated oxygen requirement 
X 5 
 
X 
 
 
X 
6MWT 
X 5 
 
 
 
 
X 
 
 
 
X 
 
Lung HRCT   
X 5 
 
 
 
X 7 
DLCO  
X 5, 8 
 
X 8 
 
 
X 8 
Patient-reported Outcome Assessments  
L-IPF, K-BILD, LCQ, SF-12 
X 5 
 
X 
 
 
X 
Anchor questions  
FVC (last week)  
X 5 
 
X 
 
 
 
X 
FVC (change since start of trial)  
 
X 
 
 
X 
Clinical Safety Assessments 
Pregnancy test 9  
X 5 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Physical examination 10 
X 5 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Vital signs, including pulse oximetry 11 
X 5 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Orthostatic hypotension assessment  
X 5 
X 
 
 
 
X 
 
 
 
X 
 
12-lead electrocardiogram 12 
X 5 
X 
 
 
 
X 
 
 
 
X 
 
Echocardiogram 12  
X 5 
 
 
 
Clinical Laboratory Safety Tests 
Chemistry and hematology 13, 14  
X 5 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Fasting glucose and lipids 15  
X 5 
 
 
 
 
X 
 
 
 
X 
 
hsCRP   
X 5 
 
X 
 
 
X 
 
Urinalysis 16 
X 5 
X 
X 
X 
 
X 
 
X 
 
X 
X 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 5.0, Amendment 4 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 36 of 153 
(A WHOLLY OWNED SUBSIDIARY OF AMGEN INC.) 
Internal Use Only General and Administrative
  
Open-label Treatment Period 
Safety Follow-up 
Visit  
 
Trial Visit 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
4 weeks after last 
dose of 
fipaxalparant 
(HZN-825) 
23  
Trial Week (W) 
W52 1  
W56 
W62 
W68 
W74 2  
W80 
W86 2 
W92 
W98 2 
W104/PD 3 
  
Visit Window (±days) 
(±7)  
(±5)  
(±7)  
(±7)  
(±7)  
(±7)  
(±7)  
(±7)  
(±7)  
(±7)  
(±14)  
PK samples 17 
X 5 
X 
X 
 
X 
 
X 
 
Pharmacodynamic serum sample 
(collect pre-dose) 18 
X 5 
 
 
 
 
X 
 
 
 
X 
 
PBMC samples (collect pre-dose) 19 
X 5 
 
 
 
 
X 
 
 
 
X 
 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant medications 20  
X 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6MWT=6-minute Walk Test; DLCO=diffusing capacity of the lungs for carbon monoxide; FVC=forced vital capacity; HRCT=high-resolution computed tomography; 
hsCRP=high-sensitivity C-reactive protein; K-BILD=King's Brief Interstitial Lung Disease Questionnaire; LCQ=Leicester Cough Questionnaire; L-IPF=Living with IPF; 
LPAR1=lysophosphatidic acid receptor 1; PBMC=peripheral blood mononuclear cell; PD=premature discontinuation; PK=pharmacokinetic; SF-12=SF-12® Health Survey; 
W=Week; WOCBP=women of childbearing potential 
1. Subjects will receive the first dose of open-label fipaxalparant (HZN-825) in the Extension Phase in the clinic.  Baseline assessments will be performed prior to dosing.  
2. Remote (telephone) visit. 
3. If a subject prematurely discontinues fipaxalparant (HZN-825), he/she will be asked to remain in the trial, participating in the scheduled trial visits through Week 104.  If a 
subject prematurely discontinues fipaxalparant (HZN-825) and does not wish to continue in the trial, he/she will be asked to return for a clinic visit and undergo the Week 104 
assessments.  Subjects will return to the clinic 4 weeks after the last dose of fipaxalparant (HZN-825) for a Safety Follow-up Visit.  
4. Informed consent is required prior to performing any assessments in the Extension Phase.  Record date and time informed consent was given and who conducted the process on 
the appropriate source documentation and per required regulations. 
5. The result will be considered a Baseline value for this Extension Phase.  
6. Except when strictly unavoidable, the same person should perform the assessment at each evaluation during the trial.   
7. The HRCT scan should be performed within ±2 weeks of the Week 104/PD Visit.  
8. The DLCO is required for Week 80 and Week 104/PD Visits.   
9. Perform for WOCBP.  Serum pregnancy test at Week 104 (or as needed).  Urine pregnancy tests should also be done every 4 weeks after the Week 52 Visit, which includes 
both in-clinic testing at scheduled visits prior to dosing (Weeks 52, 56, 68, 80, and 92) and at home (also a ±7-day window) by the subject and reported to the site (Weeks 60, 
64, 72, 76, 84, 88, 96, and 100). 
10. A complete physical examination will be performed, including, but not limited to, cardiac, pulmonary and neurologic assessments. 
11. Vital signs (blood pressure, heart rate, respiratory rate, temperature, pulse oximetry) will be measured at each clinic visit.  The Week 52 vital sign assessment should be 
performed before the first dose of open-label fipaxalparant (HZN-825) is administered in the clinic. 
12. Additional electrocardiograms or echocardiograms will be conducted, if clinically indicated.  The Week 52 electrocardiogram should be performed before the first dose of 
open-label fipaxalparant (HZN-825) is administered in the clinic.   
13. See Section 9.5.5.9 for details.  Samples collected at the Week 52 Visit should be collected before the first dose of open-label fipaxalparant (HZN-825) is administered in the 
clinic. 
14. For subjects taking warfarin, physicians should monitor their INR, as needed.  

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 5.0, Amendment 4 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 37 of 153 
(A WHOLLY OWNED SUBSIDIARY OF AMGEN INC.) 
Internal Use Only General and Administrative
15. Includes fasting glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides.   
16. See Section 9.5.5.9 for details. 
17. PK samples will be collected at each of the following visits:  Week 52 (pre-dose), Week 56 (pre-dose and 2 to 4 hours post-dose) and Week 68, 80, 92 (pre-dose).  Note:  all 
pre-dose samples will be collected prior to any fipaxalparant (HZN-825) administration for the day.  
18. To be stored for future analysis.  Use of stored serum sample for pharmacodynamic endpoints will be limited to understanding the trial drug as related to investigation of the 
LPAR1 pathway or disease for the current trial. 
19. A blood sample for PBMCs will be collected for transcriptomic analysis. 
20. Includes recording of herb/supplement use.  See Table 9.1 for restrictions regarding medications.

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 5.0, Amendment 4 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 38 of 153 
(A WHOLLY OWNED SUBSIDIARY OF AMGEN INC.) 
Internal Use Only General and Administrative
3 
TABLE OF CONTENTS 
1 
TITLE PAGE .......................................................................................................................... 2 
2 
SYNOPSIS ............................................................................................................................ 19 
2.1 
Schedule of Assessments During the Core Phase .......................................................... 31 
2.2 
Schedule of Assessments During the Extension Phase .................................................. 34 
3 
TABLE OF CONTENTS ...................................................................................................... 37 
4 
LIST OF ABBREVIATIONS ............................................................................................... 43 
5 
ETHICS ................................................................................................................................. 46 
5.1 
Institutional Review Board/Independent Ethics Committee .......................................... 46 
5.2 
Ethical Conduct of the Trial ........................................................................................... 46 
5.3 
Subject Information and Consent ................................................................................... 46 
5.4 
Compensation for Health Damage of Subjects/Insurance .............................................. 47 
5.5 
Confidentiality ................................................................................................................ 47 
6 
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE ............................. 48 
7 
INTRODUCTION ................................................................................................................ 49 
7.1 
Background .................................................................................................................... 49 
7.1.1 
Idiopathic Pulmonary Fibrosis ................................................................................ 49 
7.1.2 
Lysophosphatidic Acid Receptor 1 (LPAR1) and Related Mechanism .................. 50 
7.1.2.1 Autotaxin ............................................................................................................. 50 
7.1.2.2 Lysophosphatidic Acid ........................................................................................ 51 
7.1.2.3 Lysophosphatidic Acid Receptor 1 ..................................................................... 52 
7.1.3 
Fipaxalparant (HZN-825) ....................................................................................... 52 
7.1.3.1 Pharmacology Related to Potential Therapeutic Activity ................................... 52 
7.1.3.2 Nonclinical Safety ............................................................................................... 53 
7.1.3.3 Nonclinical Pharmacokinetics ............................................................................. 53 
7.1.3.4 Clinical Experience ............................................................................................. 54 
7.1.3.5 Benefit/Risk Assessment ..................................................................................... 54 
7.2 
Rationale for this Trial ................................................................................................... 55 
7.3 
Rationale for Dose Selection .......................................................................................... 56 
8 
TRIAL OBJECTIVES .......................................................................................................... 58 
8.1 
Part 1 (Core Phase) ......................................................................................................... 58 
8.1.1 
Primary Objective ................................................................................................... 58 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 5.0, Amendment 4 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 39 of 153 
(A WHOLLY OWNED SUBSIDIARY OF AMGEN INC.) 
Internal Use Only General and Administrative
8.1.2 
Secondary Objectives.............................................................................................. 58 
8.1.3 
Exploratory Objectives ........................................................................................... 59 
8.2 
Part 2 (Extension Phase) ................................................................................................ 59 
8.2.1 
Primary Objective ................................................................................................... 60 
8.2.2 
Safety Objective ...................................................................................................... 60 
8.2.3 
Exploratory Objectives ........................................................................................... 60 
9 
INVESTIGATIONAL PLAN ............................................................................................... 62 
9.1 
Overall Trial Design and Plan ........................................................................................ 62 
9.1.1 
Adjudication Committee ......................................................................................... 64 
9.2 
Discussion of Trial Design ............................................................................................. 64 
9.3 
Selection of Trial Population ......................................................................................... 64 
9.3.1 
Eligibility Criteria for the Core Phase .................................................................... 64 
9.3.1.1 Inclusion Criteria ................................................................................................. 64 
9.3.1.2 Exclusion Criteria ................................................................................................ 66 
9.3.2 
Eligibility Criteria for the Extension Phase ............................................................ 68 
9.3.2.1 Inclusion Criteria ................................................................................................. 68 
9.3.2.2 Exclusion Criteria ................................................................................................ 68 
9.3.3 
Removal of Subjects from Treatment or the Trial .................................................. 68 
9.3.3.1 Removal of Subjects from Treatment ................................................................. 69 
9.3.3.1.1 
Removal of Subjects from Trial Drug ....................................................... 69 
9.3.3.1.2 
Changes to Background Therapy for IPF .................................................. 70 
9.3.3.2 Removal of Subjects from the Trial .................................................................... 71 
9.3.4 
Discontinuation of a Treatment Group or the Trial ................................................ 71 
9.3.5 
Replacement Policy ................................................................................................ 71 
9.3.5.1 Subjects ............................................................................................................... 71 
9.3.5.2 Centers ................................................................................................................. 72 
9.3.5.3 Screen Failures .................................................................................................... 72 
9.4 
Treatments ...................................................................................................................... 72 
9.4.1 
Treatments Administered ........................................................................................ 72 
9.4.2 
Identity of Investigational Products ........................................................................ 72 
9.4.2.1 Fipaxalparant (HZN-825) .................................................................................... 72 
9.4.2.2 Placebo ................................................................................................................ 72 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 5.0, Amendment 4 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 40 of 153 
(A WHOLLY OWNED SUBSIDIARY OF AMGEN INC.) 
Internal Use Only General and Administrative
9.4.3 
Labeling .................................................................................................................. 73 
9.4.4 
Storage .................................................................................................................... 73 
9.4.5 
Drug Accountability................................................................................................ 73 
9.4.6 
Trial Drug Administration and Timing of Dose for Each Subject .......................... 73 
9.4.6.1 Dose Modifications, Interruptions and Delays .................................................... 73 
9.4.6.1.1 
Orthostatic Hypotension ............................................................................ 74 
9.4.6.1.2 
Drug-induced Liver Injury ......................................................................... 74 
9.4.7 
Method of Assigning Subjects to Treatment Groups .............................................. 74 
9.4.8 
Blinding and Unblinding......................................................................................... 74 
9.4.9 
Concomitant Therapy and Restricted Medications ................................................. 75 
9.4.10 Treatment Compliance ............................................................................................ 77 
9.5 
Efficacy and Safety Variables ........................................................................................ 77 
9.5.1 
Efficacy Variables ................................................................................................... 77 
9.5.1.1 Spirometry ........................................................................................................... 77 
9.5.1.2 6-minute Walk Test ............................................................................................. 78 
9.5.1.3 Titrated Oxygen Requirement ............................................................................. 78 
9.5.1.4 Diffusing Capacity of the Lungs for Carbon Monoxide ..................................... 79 
9.5.1.5 Lung High-resolution Computed Tomography ................................................... 79 
9.5.1.6 Patient-reported Outcome Assessments .............................................................. 79 
9.5.1.6.1 
Living with IPF .......................................................................................... 79 
9.5.1.6.2 
King's Brief Interstitial Lung Disease Questionnaire ................................ 80 
9.5.1.6.3 
Leicester Cough Questionnaire ................................................................. 80 
9.5.1.6.4 
SF-12 Health Survey ................................................................................. 80 
9.5.2 
Pharmacokinetic Measurements ............................................................................. 80 
9.5.3 
Pharmacogenetic Assessments................................................................................ 81 
9.5.4 
Pharmacodynamic Assessments ............................................................................. 82 
9.5.5 
Safety Variables ...................................................................................................... 82 
9.5.5.1 Adverse Events .................................................................................................... 82 
9.5.5.1.1 
Definitions ................................................................................................. 82 
9.5.5.1.2 
Documentation of Adverse Events ............................................................ 85 
9.5.5.1.3 
Intensity or Severity of Adverse Events .................................................... 85 
9.5.5.1.4 
Relationship or Causality to Trial Drug .................................................... 86 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
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9.5.5.1.5 
Reporting and Documenting Serious Adverse Events .............................. 87 
9.5.5.1.6 
Follow-up of Adverse Events .................................................................... 88 
9.5.5.1.7 
Medication Errors ...................................................................................... 89 
9.5.5.1.8 
Review of Adverse Events and Emerging New Safety Information ......... 89 
9.5.5.1.9 
Reporting of Investigational New Drug Safety Reports ............................ 89 
9.5.5.1.10 Development Safety Update Reports ........................................................ 89 
9.5.5.1.11 Regulatory Reporting Requirements for Safety Information .................... 90 
9.5.5.1.12 Safety Monitoring Plan .............................................................................. 90 
9.5.5.2 Pregnancy and Lactation Reporting .................................................................... 90 
9.5.5.3 Medical History ................................................................................................... 92 
9.5.5.4 Vital Signs, Weight and Height........................................................................... 92 
9.5.5.5 Orthostatic Hypotension Assessment .................................................................. 92 
9.5.5.6 Physical Examination .......................................................................................... 92 
9.5.5.7 Electrocardiogram ............................................................................................... 92 
9.5.5.8 Echocardiogram .................................................................................................. 93 
9.5.5.9 Laboratory Tests for Evaluation .......................................................................... 93 
9.5.6 
Appropriateness of Measurements .......................................................................... 94 
9.5.7 
Trial Procedures ...................................................................................................... 94 
9.5.8 
Effect of a Pandemic on Trial Procedures .............................................................. 94 
9.6 
Statistical Methods and Determination of Sample Size ................................................. 95 
9.6.1 
Core Phase .............................................................................................................. 95 
9.6.1.1 Endpoints ............................................................................................................. 95 
9.6.1.1.1 
Primary Efficacy Endpoint ........................................................................ 95 
9.6.1.1.2 
Key Secondary Efficacy Endpoint ............................................................ 95 
9.6.1.1.3 
Other Secondary Efficacy Endpoints ........................................................ 95 
9.6.1.1.4 
Exploratory Endpoints ............................................................................... 95 
9.6.1.1.5 
Safety and Tolerability Endpoints ............................................................. 96 
9.6.1.1.6 
Pharmacokinetic Endpoint ......................................................................... 96 
9.6.1.2 Analysis Sets ....................................................................................................... 96 
9.6.1.3 Primary Efficacy Endpoint Analysis ................................................................... 96 
9.6.1.4 Secondary Efficacy Endpoint Analyses .............................................................. 97 
9.6.1.5 Exploratory Endpoint Analyses .......................................................................... 98 

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9.6.1.6 Safety and Tolerability Analyses ........................................................................ 98 
9.6.1.7 Pharmacokinetic Analyses .................................................................................. 98 
9.6.1.8 Interim Analysis .................................................................................................. 98 
9.6.1.9 Multiple Comparisons ......................................................................................... 99 
9.6.2 
Extension Phase ...................................................................................................... 99 
9.6.2.1 Endpoints ............................................................................................................. 99 
9.6.2.1.1 
Primary Efficacy Endpoint ...................................................................... 100 
9.6.2.1.2 
Safety and Tolerability Endpoints ........................................................... 100 
9.6.2.1.3 
Exploratory Endpoints ............................................................................. 100 
9.6.2.1.4 
Exploratory PK Endpoints ....................................................................... 101 
9.6.2.2 Analysis Sets ..................................................................................................... 101 
9.6.2.3 Efficacy Endpoint Analysis ............................................................................... 102 
9.6.2.4 Safety and Tolerability Analyses ...................................................................... 102 
9.6.2.5 Pharmacokinetic Analyses ................................................................................ 103 
9.6.3 
Sample Size and Power Considerations ................................................................ 103 
9.7 
Changes in the Conduct of the Trial............................................................................. 103 
10 SOURCE DOCUMENTATION AND INVESTIGATOR FILES ..................................... 104 
11 CASE REPORT FORMS ................................................................................................... 105 
12 TRIAL MONITORING ...................................................................................................... 106 
13 DATA MANAGEMENT .................................................................................................... 108 
14 RETENTION OF RECORDS ............................................................................................. 109 
15 PUBLICATION .................................................................................................................. 110 
16 REFERENCES ................................................................................................................... 111 
17 APPENDICES .................................................................................................................... 117 
17.1 Administrative Appendix ............................................................................................. 117 
17.2 Hospitalization Due to Respiratory Distress ................................................................ 118 
17.3 IPF-related Acute Exacerbation ................................................................................... 119 
17.4 Living with IPF ............................................................................................................ 122 
17.5 King’s Brief Interstitial Lung Disease Questionnaire .................................................. 130 
17.6 Leicester Cough Questionnaire .................................................................................... 131 
17.7 SF-12® Health Survey (SF-12) ..................................................................................... 132 
17.8 Serious Adverse Events Anticipated in the Trial Population ....................................... 133 

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17.9 Orthostatic Hypotension Assessment Manual.............................................................. 134 
17.10 Clinical SAE Report Form ........................................................................................... 137 
17.11 Clinical Trial Drug Exposure During Conception/Pregnancy Form ............................ 148 
17.12 Lactation Notification Form ......................................................................................... 152 
LIST OF TABLES 
Table 6.1 Table of Non-Sponsor Trial Responsibilities ............................................................ 48 
Table 9.1 Restricted Medications .............................................................................................. 76 
Table 9.2 Schedule of Pharmacokinetic Sample Collection ...................................................... 81 
Table 17.1 Proposed Revised Definition and Diagnostic Criteria for Acute Exacerbation of 
IPF............................................................................................................................ 121 
LIST OF FIGURES 
Figure 9.1 Schematic of Trial Design – Core Phase ................................................................... 63 
Figure 9.2 Schematic of Trial Design – Extension Phase ........................................................... 64 
Figure 17.1 Algorithm for Adjudication of Respiratory-related Hospitalization in Idiopathic 
Pulmonary Fibrosis .................................................................................................. 119 
Figure 17.2 Conceptual Framework for Evaluation of Acute Respiratory Deterioration in IPF 120 
 

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4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
6MWT 
6-Minute Walk Test 
AE 
adverse event 
AESI 
adverse event of special interest 
ALAT 
Latin American Thoracic Society 
ALT  
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
ATX 
autotaxin 
AUC 
area under the (plasma) concentration-time curve 
AUC 
area under the concentration-time curve from 0 to 12 hours  
BAL 
bronchoalveolar lavage 
BID 
twice daily 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum observed concentration 
COVID-19 
coronavirus disease 2019 
Ctrough 
minimum total trough concentration  
CYP 
cytochrome P450  
DLCO 
diffusing capacity of the lungs for carbon monoxide  
DOCA 
deoxycorticosterone acetate 
DSUR 
Development Safety Update Report 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ERS 
European Respiratory Society 
EU 
European Union 
EU CT 
European Union Clinical Trials 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
FVC 
forced vital capacity 

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Abbreviation 
Definition 
GCP 
Good Clinical Practice 
HAQ-DI 
Health Assessment Questionnaire – Disability Index 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HCV 
hepatitis C virus 
HRCT 
high-resolution computed tomography 
IC50 
half-maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
INR 
international normalized ratio 
IDMC 
independent data monitoring committee 
ILD 
interstitial lung disease 
IND 
Investigational New Drug 
IPF 
idiopathic pulmonary fibrosis 
IRT 
interactive response technology 
JRS 
Japanese Respiratory Society 
K-BILD 
King's Brief Interstitial Lung Disease Questionnaire 
LCQ 
Leicester Cough Questionnaire 
L-IPF 
Living with IPF 
LPA 
lysophosphatidic acid 
LPAR1 
lysophosphatidic acid receptor 1 
MMRM 
mixed model for repeated measures 
mRSS 
modified Rodnan skin score 
OAT 
organic anion transporter 
OLE 
open-label extension 
PFS 
progression-free survival 
PK 
pharmacokinetic 
QD 
once daily 
SAE 
serious adverse event 
SE 
standard error 
SF-12 
SF-12® Health Survey 
SLCO 
solute carrier organic anion transporter family member 
SOC 
System Organ Class 

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Abbreviation 
Definition 
Sp,O2 
oxygen saturation 
SSc 
systemic sclerosis 
TEAE 
treatment-emergent adverse event 
TOR 
titrated oxygen requirement 
ULN 
upper limit of normal 
US 
United States 
WOCBP 
women of childbearing potential 
Abbreviations that appear only in figures and tables or in a single paragraph are defined with the relevant figures, 
tables and paragraphs. 

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5 
ETHICS 
5.1 
Institutional Review Board/Independent Ethics Committee 
The Principal Investigator (Investigator), the Sponsor and/or contract research organization 
authorized by the Sponsor will submit this protocol, any protocol modifications, the informed 
consent form (ICF) and all applicable trial documentation to be used in this trial to the 
appropriate external review bodies for review and approval/favorable opinion.  A letter 
confirming the external review bodies’ approval/favorable opinion of the protocol, the subject 
ICF and applicable trial documentation, a list of the external review bodies’ members involved in 
the vote, as well as a statement that the external review body is organized and operates according 
to Good Clinical Practice (GCP) and the applicable laws and regulations, must be forwarded to 
the Sponsor or its designee prior to the enrollment of subjects into the trial.  A copy of the 
approved ICF will also be forwarded to the Sponsor or its designee.  Appropriate reports on the 
progress of the trial will be made to the external review bodies and the Sponsor or its designee by 
the Investigator in accordance with applicable governmental regulations and in agreement with 
the policy established by the Sponsor. 
5.2 
Ethical Conduct of the Trial 
The Investigators will ensure that this trial is conducted in a manner that fully conforms with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the individual.  The 
trial must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) Tripartite Guideline or with local law if it affords greater protection to the 
subject.  For trials conducted in the United States (US) or under a US Investigational New Drug 
(IND) program, the Investigator will additionally ensure adherence to the basic principles of 
“Good Clinical Practice” as outlined in the current version of 21 Code of Federal Regulations 
(CFR), subchapter D, part 312, “Responsibilities of Sponsors and Investigators”, part 50, 
“Protection of Human Subjects” and part 56, “Institutional Review Boards.” 
5.3 
Subject Information and Consent 
It is the responsibility of the Investigator, or a person designated by the Investigator (if 
acceptable by local regulations) to obtain signed informed consent from each subject prior to 
participating in this trial after adequate explanation of the aims, methods, anticipated benefits 
and potential hazards of the trial.  Both the Core Phase and the optional open-label extension 
(OLE) Phase will require separate ICFs to be signed by subjects. 
The Investigator or designee must also explain that the subjects are completely free to refuse to 
enter the trial or to withdraw from it at any time, for any reason.  
The ICF and any other written information provided to subjects will be revised whenever 
important new information becomes available that may be relevant to the subject’s consent, or 
there is an amendment to the protocol that necessitates a change to the content of the subject 
information and/or the written ICF.  The Investigator will inform the subject of changes in a 

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timely manner and will ask the subject to confirm his/her participation in the trial by signing the 
revised ICF.  Any revised written ICF and written information must receive the external review 
bodies’ approval/favorable opinion in advance of use. 
All signed ICFs are to remain in the Investigator’s site file or, if locally required, in the subjects’ 
notes/files of the medical institution. 
The electronic case report forms (eCRFs) for this trial contain a section for documenting all 
subject informed consent(s) and this must be completed appropriately.  If new safety information 
results in significant changes in the risk/benefit assessment, the ICF should be reviewed and 
updated if necessary.  All subjects (including those already being treated) should be informed of 
the new information, given a copy of the revised form and give their consent to continue in the 
trial. 
5.4 
Compensation for Health Damage of Subjects/Insurance 
The Sponsor maintains clinical trial insurance coverage for this trial in accordance with the laws 
and regulations of the country in which the trial is performed. 
5.5 
Confidentiality  
All records identifying the subject will be kept confidential and to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
Subject names will not be supplied to the Sponsor.  Only the subject number will be recorded in 
the eCRF and if the subject name appears on any other document, it must be obliterated before a 
copy of the document is supplied to the Sponsor.  Trial findings stored on a computer will be 
stored in accordance with local data protection laws.  As part of the informed consent process, 
the subjects will be informed in writing that representatives of the Sponsor, external review 
bodies, or regulatory authorities may inspect their medical records to verify the information 
collected and that all personal information made available for inspection will be handled in 
strictest confidence and in accordance with local data protection laws. 
If the results of the trial are published, the subject’s identity will remain confidential. 
The Investigator will maintain a list to enable subjects to be identified. 

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6 
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE 
The Sponsor of this trial is Horizon Therapeutics Ireland DAC (Horizon, a wholly owned 
subsidiary of Amgen Inc.).  Horizon and/or designee personnel will serve as the Medical Monitor 
(see Section 17.1 for details).  The Sponsor will be responsible for timely reporting of serious 
adverse events (SAEs) to regulatory authorities as required.  The Sponsor will be responsible for 
timely reporting of SAEs and any other new pertinent safety information to all Investigators as 
required. 
The trial will be conducted at approximately 85 trial sites in North America, Europe, South 
America, Africa, Asia (including Japan), and Australia.  Prior to initiation of the trial, each 
Principal Investigator in the US will provide the Sponsor or its designee with a fully executed 
and signed Food and Drug Administration (FDA) Form 1572 and a Financial Disclosure Form.  
Financial Disclosure Forms will also be completed by all Sub-Investigators listed on Form 1572.  
It is the responsibility of the Investigators or Sub-Investigators to advise the Sponsor of any 
change in the relevant financial interests that occur during the trial and the 1-year period 
following its completion. 
Table 6.1 lists other organizations that are critical to the conduct of the trial, with a brief 
description of their roles: 
Table 6.1 
Table of Non-Sponsor Trial Responsibilities 
Trial Responsibility 
Organization 
Contract research organization 
PPD (subsidiary of Thermo Fisher Scientific) Biotech 
929 North Front Street 
Wilmington, NC  28401 
Central safety laboratory 
PPD Laboratories – North and South America 
2 Tesseneer Drive  
Highland Heights, KY  41076 
PPD Laboratories – Middle East and Africa 
Clusterpark, Kleine Kloosterstraat 19 
1932 Zaventem, Belgium 
PPD Laboratories – Asia Pacific 
61, Science Park Road 
#02-11/14, The Galen, Singapore Science 
Park II 
Singapore  117525 
 

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7 
INTRODUCTION 
7.1 
Background 
7.1.1 Idiopathic Pulmonary Fibrosis 
The interstitial lung diseases (ILDs) are a heterogeneous group of parenchymal lung diseases 
characterized by both fibrosis and inflammation.  The etiology of ILDs involve known causes, 
such as autoimmune connective tissue disease, hypersensitivity to inhaled organic antigens, drug 
exposure or sarcoidosis, while the idiopathic interstitial pneumonias have no identifiable cause 
[International consensus statement, 2000].  Idiopathic pulmonary fibrosis (IPF) is defined as a 
specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause and is 
associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia in 
the lungs.  
In 2018, the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese 
Respiratory Society (JRS) and the Latin American Thoracic Society (ALAT) jointly updated 
recommendations to reach a consensus for the diagnosis of IPF and provided additional updates 
to the guidance in 2022 [Raghu et al., 2018; Raghu et al., 2022].  IPF is one of the most common 
types of ILD, estimated to affect 132,000 to 200,000 people in the US.  In the US, approximately 
50,000 new cases are diagnosed each year, and as many as 40,000 patients die from IPF each 
year according to the Pulmonary Fibrosis Foundation.  IPF is diagnosed more frequently in men 
than women, usually occurs in adults over 50 years of age and is characterized by progressive 
dyspnea, non-productive cough and progressive pulmonary insufficiency consistent with 
increasing fibrosis. 
The reported incidence rates of IPF vary considerably, which is likely due to differences between 
diagnostic approaches and definitions used for IPF.  A systematic review of the global incidence 
of IPF estimated a rate of 2.8 to 9.3 per 100,000 per year in North America and Europe 
[Barratt et al., 2018].  Regional variation within countries has also been observed, possibly 
reflecting exposure to environmental or occupational risk factors [Gribbin et al., 2006; 
Navaratnam et al., 2011; Raghu et al., 2014; Hopkins et al., 2016; Strongman et al., 2018].  
Evidence suggests that the incidence of IPF is rising [Hutchinson et al., 2015].  A recent analysis 
of a United Kingdom-based, primary care database calculated a rise in incidence of 78% between 
2000 and 2012, as well as a doubling of prevalence, estimated at 38.8 per 100,000 
[Strongman et al., 2018], with the consequential growing economic burden on global health care 
[Diamantopoulos et al., 2018].  Mortality following diagnosis of IPF is high, with a median 
survival of 2 to 3 years from time of diagnosis [Raghu et al., 2011].  
The antifibrotic drugs nintedanib and pirfenidone were first approved in 2014 by the US FDA.  
Nintedanib and pirfenidone are approved for the treatment of IPF and nintedanib is also 
approved for treatment of chronic fibrosing ILDs with a progressive phenotype and slowing the 
rate of decline in pulmonary function in patients with systemic sclerosis (SSc)-associated ILD 
[OFEV™ Full Prescribing Information; ESBRIET™ Full Prescribing Information].  Nintedanib 
has also been approved in multiple regions and countries, including Europe, Canada, Japan, and 
Brazil.  Pirfenidone has also been approved in multiple regions and countries, including Europe, 
Canada, Japan, Brazil, Norway, Iceland, India, South Korea, Argentina, and Mexico. 

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Important warnings and precautions for use of nintedanib and pirfenidone include elevated liver 
enzymes and drug-induced liver injury as well as gastrointestinal disorders.  Although these 
treatments offer substantial improvement over previously available therapy options, additional 
opportunities remain for novel or add-on treatments that will further arrest disease progression 
and potentially improve lung function over time.   
7.1.2 Lysophosphatidic Acid Receptor 1 (LPAR1) and Related Mechanism 
The signal transduction cascades initiated by lysophosphatidic acid (LPA) (1-oleoyl-sn-glycerol 
3-phosphate and derivatives) binding to LPA receptor 1 (LPAR1) are of interest in the 
therapeutic treatment of a several diseases due to involvement of the LPAR1 pathway in 
inflammation and fibrosis.  Extracellularly, LPA can be produced by 2 different mechanisms 
from phospholipids.  Autotaxin (ATX) is the enzyme that generates the majority of serum LPA.  
There is also an ATX-independent mechanism whereby LPA is generated from phospholipids 
via a 2-step process.  Phospholipase D1 or phospholipase D2 converts phospholipids to 
phosphatidic acid, which is then converted to LPA by phospholipase A1 or phospholipase A2 
[Geraldo et al., 2021].  Below is a review of the background of ATX, LPA and LPAR1, as well 
as the key information linking their activities to diseases characterized by inflammation and 
fibrosis. 
7.1.2.1 Autotaxin 
ATX is an ecto-enzyme that hydrolyzes the phosphodiester bonds in lysophospholipids 
ultimately leading to the production of LPA [Knowlden and Georas, 2014; 
Valdes-Rives and González-Arenas, 2017].  ATX is thought to be the primary enzyme 
responsible for the production of LPA, the ligand for the LPAR family of receptors, including 
LPAR1, in serum [Nakanaga et al., 2010; Knowlden and Georas, 2014].  The evidence for this 
includes:  1) levels of LPA and ATX correlate in human serum samples, 2) mice heterozygous 
for ATX showed ~50% reduction in LPA levels, 3) depletion of ATX from serum abrogates 
lysophospholipidase activity and LPA levels are non-detectable, and 4) administration of an 
ATX inhibitor to healthy humans in a clinical trial resulted in human decreases of serum LPA 
levels by ~80% [Tanaka et al., 2006; Tsuda et al., 2006; van Meeteren et al., 2006; 
Nakamura et al., 2008; Maher et al., 2018; van der Aar et al., 2020].  
Inhibition of ATX has been evaluated in a mouse model of lung fibrosis induced by 
administration of bleomycin, with conflicting results regarding efficacy.  Several studies have 
demonstrated that blockade of the ATX enzyme leads to reduction in LPA levels, histological 
disease score of lung and/or lung collagen levels [Oikonomou et al., 2012; Desroy et al., 2017; 
van der Aar et al., 2020].  Additionally, deletion of ATX in the bronchial epithelial cells or 
macrophages in mice reduces pulmonary fibrosis-induced by bleomycin 
[Oikonomou et al., 2012].  However, there is also evidence that the LPA species induced in lungs 
by bleomycin in the mouse model is produced by an ATX-independent mechanism 
[Black et al., 2016].  Further, inhibition with a specific inhibitor of ATX led to reduction in ATX 
activity systemically and in the lung of mice with pulmonary fibrosis induced by bleomycin 
without reduction in pulmonary LPA levels or fibrosis, suggesting the ATX-independent 
mechanisms were responsible for local generation of LPA in the injury lung [Black et al., 2016].  
In a mouse model of smoke inhalation, ATX inhibition reduced immune cell infiltration into the 

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bronchoalveolar lavage (BAL) fluid and lung gene expression of tobacco smoke-induced genes 
[Blanqué et al., 2015].  
Immunohistochemistry analysis of lung tissue isolated from patients with ILDs, including IPF, 
interstitial pneumonia and the fibrosing form of nonspecific interstitial pneumonia, showed 
increased protein levels of ATX levels in patients with IPF and fibrotic nonspecific interstitial 
pneumonia [Oikonomou et al., 2012]. 
In summary, ATX is upregulated in several forms of fibrosing ILDs, but animal data show 
fibrosis induced by bleomycin in lungs of mice might be through an ATX-independent 
mechanism and that inhibition of ATX might not be effective in lung fibrosis.  LPA signals 
through at least 6 type I rhodopsin-like receptors (LPARs) that exhibit widespread, but 
differential, tissue distribution, as well as overlapping specificities [Yung et al., 2014].  LPARs 
couple with G-proteins, crucial molecular switches activating numerous signal transduction 
pathways [Oldham and Hamm, 2008].  Overall, any LPA effect in each cell type depends on its 
local concentration, regulated by both ATX-dependent and -independent pathways, the levels of 
possible agonists and antagonists and the relative abundance of the different receptor subtypes 
[Ninou et al., 2018].  These complexities associated with ATX inhibition as a potential 
therapeutic approach are distinct from the mechanism of action of fipaxalparant (HZN-825), 
which acts as a selective, small molecule antagonist of LPAR1 that antagonizes the pathway of 
LPA production.  Fipaxalparant (HZN-825) will inhibit LPA produced by ATX-dependent 
and -independent pathways from signaling through LPAR1 (see Sections 7.1.2.3 and 7.1.3). 
7.1.2.2 Lysophosphatidic Acid 
LPA is a small bioactive glycerophospholipid present in all eukaryotic tissues and produced from 
membrane phospholipids via different enzymatic pathways.  LPA is also generated at sites of 
inflammation or cell injury [Zhao and Natarajan, 2013].  LPA accumulates in the serum of 
patients with SSc, in BAL fluid of patients suffering from IPF and in human atherosclerotic 
plaques [Tager et al., 2008; Tokumura et al., 2009; Schober and Siess, 2012].  
LPA can activate 6 distinct G protein-coupled receptors that differ in their tissue distribution and 
coupling to downstream signaling pathways enabling LPA to elicit a variety of cellular responses 
including mitogenic effects, differentiation, survival, cytoskeletal reorganization, and cell 
migration [Fukushima et al., 2001; Chun et al., 2002; Takuma et al., 2002].  LPA has been 
shown to promote the differentiation, proliferation and migration of cells from a mesenchymal 
origin, including lung and dermal fibroblasts, and also induce the de-differentiation of vascular 
smooth muscle cells [Kim et al., 2006; Yin et al., 2008].  
LPA has direct effects on inflammatory cells of both the innate and adaptive immune systems 
including being a powerful stimulator of human neutrophil motility, causing an increase in 
binding of monocytes and neutrophils to human aortic endothelial cells, activating human 
eosinophils.  The effects on eosinophils are mediated by LPAR1 and/or LPAR3 as they are 
antagonized by an LPAR1/LPAR3 antagonist [Idzko et al., 2004].  LPA increases the 
allostimulatory function of mature dendritic cells, inhibits their capacity to induce T helper 1 cell 
differentiation and increases the ability of dendritic cells to polarize T cells to a Th2 phenotype 
[Panther et al., 2002]. 

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7.1.2.3 Lysophosphatidic Acid Receptor 1 
In nonclinical studies, LPAR1 antagonism decreased organ fibrosis in several experimental 
settings, including models of skin [Cabello-Verrugio et al., 2011], lung [Tager et al., 2008] and 
kidney [Pradère et al., 2007] fibrosis.  LPAR1 knockout mice were also protected from 
developing skin and lung fibrosis [Tager et al., 2008; Cabello-Verrugio et al., 2011].  
Additionally, LPA-induced cardiac fibroblast proliferation and extracellular matrix production 
are mediated by LPAR1 [Cabello-Verrugio et al., 2011].  LPAR1 has also been implicated in the 
development of IPF given its role in mediation of ﬁbroblast recruitment, differentiation of cells 
into myofibroblasts, inflammation, extracellular matrix deposition, vascular leak, and endothelial 
barrier dysfunction in animal models [Tager et al., 2008; Ninou et al., 2018; Swaney et al., 
2010].  In the bleomycin mouse model of pulmonary ﬁbrosis, LPAR1-deﬁcient mice showed 
reduced levels of ﬁbroblast recruitment and decreased vascular permeability, indicating a 
protective role for decreased LPA signaling.  Additionally, LPAR1 knockout mice showed 
reduction in bronchial epithelial cells apoptosis following bleomycin administration 
[Funke et al., 2012].   
LPAR1 receptor antagonism has also been shown to block LPA induced differentiation of bone 
marrow-derived mesenchymal stem cells into myofibroblasts and LPA-induced proliferation of 
normal human lung fibroblasts [Tang et al., 2014; Qian et al., 2012].  LPA signaling through 
LPAR1 promoted the resistance of lung fibroblasts to apoptosis, which has also been implicated 
in IPF [Funke et al., 2012]. 
In a Phase 2 clinical trial of IPF, LPAR1 antagonism significantly slowed the rate of decline in 
forced vital capacity (FVC) compared with placebo [Palmer et al., 2018].  These findings suggest 
a role for antagonists of LPAR1 as therapeutic treatments for a variety of fibrotic conditions. 
7.1.3 Fipaxalparant (HZN-825) 
7.1.3.1 Pharmacology Related to Potential Therapeutic Activity 
The activity of fipaxalparant (HZN-825), an LPAR1-specific antagonist, was evaluated in vitro in 
lung fibroblasts isolated from patients with IPF and in dermal fibroblasts isolated from patients 
with SSc.  LPA-induced signaling in IPF or diffuse cutaneous SSc patient-derived fibroblasts 
was blocked by fipaxalparant (HZN-825) in a concentration-dependent manner, confirming that 
LPA signaling in these cells is a result of LPAR1 [Ledein et al., 2020].  Fipaxalparant (HZN-825) 
was also able to block LPA-induced differentiation of IPF patient-derived fibroblasts into 
myofibroblasts in a dose-dependent manner, reduced the secretion of inflammatory markers and 
activated Wnt family members [Ledein et al., 2020]. 
The activity of fipaxalparant (HZN-825) was also evaluated in vivo in models of skin, kidney 
and heart fibrosis.  Two models of dermal fibrosis were used to evaluate the effect of 
fipaxalparant (HZN-825) treatment in comparison with the positive control Gleevec® (imatinib 
mesylate).  In a mouse model of bleomycin-induced skin fibrosis, therapeutic dosing of 
fipaxalparant (HZN-825) prevented progression of fibrosis, as indicated by reductions in dermal 
thickness, myofibroblast numbers, and hydroxyproline content of the bleomycin-injected skin.  
Treatment of tight-skin 1 (Tsk-1) mice with fipaxalparant (HZN-825) prevented the progression 
of skin fibrosis, with significant reductions in hypodermal thickness, myofibroblast numbers and 
hydroxyproline content; the anti-fibrotic effects were comparable to those of imatinib. 

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The role of LPA and LPAR1 signaling was also evaluated in an experimental model of lung 
irritation to study the impact on inflammation that can lead to airway remodeling (Study report 
GVV0148).  Fipaxalparant (HZN-825) dose dependently reduced the total cells and eosinophils 
in the BAL fluid, with 91% reduction in total cellularity of BAL and 99% reduction in eosinophil 
number at 24 hours. 
In addition, fipaxalparant (HZN-825) treatment improved kidney function in models of 
hypertension- or nephrotoxicity-induced renal injury and showed beneficial effects on cardiac 
function and hypertrophy in models of hypertension or diabetes-related cardiac injury, fibrosis 
and heart failure.  In parallel, fipaxalparant (HZN-825) showed moderate but significant 
antithrombotic activity in acute models of coagulation and arterial thrombosis.  
7.1.3.2 Nonclinical Safety 
In animal studies, single oral administration of fipaxalparant (HZN-825) at up to 2000 mg/kg to 
rats and up to 1000 mg/kg to dogs resulted in no adverse findings in safety pharmacology and 
single-dose toxicity studies.  The no-observed-adverse-effect level values in the 6-month rat and 
9-month dog toxicology studies were 2000 and 1000 mg/kg/day, respectively, which were the 
highest dose levels evaluated in each species.  Fipaxalparant (HZN-825) and M4 were neither 
mutagenic nor clastogenic/aneugenic in a standard battery of genetic toxicology studies.  No 
compound-related effects on fertility and/or early embryonic development were noted in either 
male or female rats administered fipaxalparant (HZN-825) at dosages up to 2000 mg/kg/day.  
There was no evidence of developmental toxicity in embryo-fetal toxicity studies conducted in 
both rats and rabbits at dose levels up to 2000 mg/kg/day.  Additional information regarding the 
nonclinical safety pharmacology studies is provided in the current version of the Investigator’s 
Brochure. 
7.1.3.3 Nonclinical Pharmacokinetics 
Following single oral administration of [14C]-fipaxalparant (HZN-825) to rats, maximum 
observed concentration (Cmax) was observed at 1 to 2 hours post dose and oral bioavailability was 
estimated to be 17.8%.  In general, increases in exposure were less than dose-proportional in 
both species, and negligible accumulation in Cmax or area under the plasma concentration-time 
curve (AUC) was observed after repeated dosing.  Plasma elimination half-lives in rats, rabbits, 
and dogs ranged from 1.4 to 3.6 hours and plasma clearance was 0.226 to 1.46 L/h/kg.  The 
excretion of [14C]-fipaxalparant (HZN-825) and/or its metabolites in rats and dogs occurred 
almost exclusively via feces, regardless of the route of administration.  The main in vitro 
metabolic pathways of [14C]-fipaxalparant (HZN-825) were identified as single hydroxylation 
followed by glucuronidation and direct acylglucuronidation of parent drug.  After oral 
administration of [14C]-fipaxalparant (HZN-825) to rats, unchanged fipaxalparant (HZN-825) 
was found to be the predominant peak in plasma, amounting to 80% to 89% of total radioactivity 
in plasma. 
In protein binding studies, [14C]-fipaxalparant (HZN-825) was found to be highly protein bound 
in all species, with fraction bound ranging from 98.94% to 99.97%.  Human serum albumin was 
found to be the major binding protein in human plasma.  Additional information regarding the 

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nonclinical pharmacokinetics (PK) studies is provided in the current version of the Investigator’s 
Brochure. 
7.1.3.4 Clinical Experience 
Fipaxalparant (HZN-825) has been administered to 244 healthy subjects in nine Phase 1 
completed clinical trials and 31 subjects with diffuse cutaneous SSc in a Phase 2a clinical trial.  
In clinical trials completed, as provided in the current version of the Investigator’s Brochure, 
fipaxalparant (HZN-825) was well-tolerated and showed similar safety and pharmacokinetic 
profiles across healthy subjects (including elderly healthy subjects) and subjects with diffuse 
cutaneous SSc.  In the Phase 2a trial, treatment with fipaxalparant (HZN-825) 300 mg twice 
daily (BID) resulted in numerical improvement from baseline compared with placebo at the end 
of the 8-week double-blind period and at the end of the 16-week, open-label period based on 
clinical outcomes, including the modified Rodnan skin score (mRSS), Health Assessment 
Questionnaire – Disability Index (HAQ-DI) and other components of the Scleroderma Health 
Assessment Questionnaire, overall disease severity and pruritus [Allanore et al., 2018].  
In Phase 1 Trial HZNP-HZN-825-104 in healthy subjects, preliminary data suggested there are 
no relevant mutual drug-drug interactions between fipaxalparant (HZN-825) and 
pirfenidone/nintedanib at clinical doses.  The 90% confidence interval (CI) of the geometric least 
squares mean ratio for both AUC and Cmax (test vs reference) was within the predefined no-effect 
bound of (0.70, 1.43). 
No SAEs or severe adverse events (AEs) occurred in Phase 1 trials.  One subject experienced 
AEs leading to permanent trial drug discontinuation (Nausea and Abdominal pain) on 
fipaxalparant (HZN-825) 300 mg BID and midazolam.  In the Phase 2a trial, fipaxalparant 
(HZN-825) 300 mg BID given up to 24 weeks was well-tolerated.  During the 8-week 
double-blind period, the most frequent treatment-emergent adverse events (TEAEs) in the 
fipaxalparant (HZN-825) group were headache, diarrhea, nausea and fall. 
Based on safety results to date, orthostatic hypotension is identified as a potential risk of 
fipaxalparant (HZN-825) therapy that will continue to be monitored as an AE of special interest 
(AESI) (Section 9.5.5.1.1.4). Additionally, increases in hepatic transaminases have been seen in 
blinded clinical studies with fipaxalparant (HZN-825). These events are mostly non-serious and 
reversible. Liver enzyme elevation will be monitored per FDA guidelines (Section 9.3.3.1) 
Additional and current information regarding the safety of fipaxalparant (HZN-825) is provided 
in the current Investigator’s Brochure.  
7.1.3.5 Benefit/Risk Assessment 
Fipaxalparant (HZN-825) is a new therapeutic agent under development for treating fibrotic 
diseases, including SSc.  The anti-inflammatory and anti-fibrotic properties of LPAR1 
antagonism have been demonstrated in both animal models and in a Phase 2 clinical trial.  
Positive changes in mRSS, HAQ-DI and LPAR1 pathway genes were detected in the completed 
Phase 2a trial in diffuse cutaneous SSc.  Results of trials to date support the safety and potential 

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efficacy of 300 mg BID for up to 24 weeks of treatment.  The exposure, PK and safety profiles 
of fipaxalparant (HZN-825) were similar across the completed trials. 
Based on the cumulative safety data available to date on fipaxalparant (HZN-825), transaminase 
increase has been evaluated as an important identified risk and orthostatic hypotension, 
drug-drug interactions, and embryo-fetal toxicity are considered as important potential risks.  No 
severe AEs or SAEs were reported in healthy subjects in Phase 1 trials.  TEAEs of orthostatic 
hypotension, postural dizziness, flatulence, and abdominal pain were slightly more frequent in 
fipaxalparant (HZN-825)-treated than in placebo-treated subjects.  Orthostatic hypotension was 
mainly observed in healthy subjects and tended to be less marked in subjects with diffuse 
cutaneous SSc treated with fipaxalparant (HZN-825).  The potential safety risk of fipaxalparant 
(HZN-825) due to drug-drug interactions is considered low as medications that may have 
potential interactions with fipaxalparant (HZN-825) are restricted in this protocol (Section 9.4.9).   
Participants with IPF receiving fipaxalparant (HZN-825) may benefit from the LPAR1 
antagonism by slowing the decline of lung function due to progressive fibrotic disease.  Subjects 
in the trial will also benefit from receiving trial-related medical examinations, imaging and 
laboratory tests at no cost. 
AESIs are considered monitorable.  Taking into account mitigation measures to minimize risk to 
subjects in this trial, the potential risks identified in association with fipaxalparant (HZN-825) 
treatment and the trial as a whole are justified by the anticipated benefits that may be afforded to 
patients with IPF. 
Additional information regarding the benefit and risks of fipaxalparant (HZN-825) are located in 
the current Investigator’s Brochure Section 6.2 and Section 12. 
7.2 
Rationale for this Trial 
IPF is an advancing and fatal lung disease with significant morbidity and reported increasing 
incidence and prevalence.  Pirfenidone and nintedanib were approved by the FDA in 2014 for the 
treatment of IPF based on positive results in Phase 3 trials, and both of these antifibrotic drugs 
are conditionally recommended in the 2015 ATS/ERS/JRS/ALAT Clinical Practice Guideline 
[Raghu et al., 2015].  Although an improvement over previously suggested therapies, their 
capacity to reduce but not completely arrest progression of lung fibrosis or improve lung 
function over time presents an opportunity for novel or add-on pharmacologic agents.  
Pirfenidone should be taken 3 times daily with food at a target dose that is generally achieved 
over 14 days [Lancaster et al., 2017].  Nintedanib recommended dosage includes BID dosing 
with food.  In randomized, double-blind, placebo-controlled trials, gastrointestinal adverse 
reactions occurring in ≥10% of treated subjects that may require temporary dosage reductions or 
discontinuations for pirfenidone and nintedanib included diarrhea, nausea, abdominal pain, and 
vomiting [ESBRIET Full Prescribing Information; OFEV Full Prescribing Information].  While 
significant advances have been made in the past decade using pharmacological therapy, there 
remains a substantial unmet clinical need for treatment regimens with improved efficacy, 
tolerability and dosing convenience for patients with IPF.   

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Fipaxalparant (HZN-825) is under investigation as a novel therapy for IPF because it selectively 
antagonizes LPAR1, which has been shown to be associated with skin, pulmonary, cardiac, 
peritoneal, and tubulointerstitial fibrosis and has potential as a new therapeutic for treating 
fibrotic diseases, including IPF.  Details are provided in the current version of the Investigator’s 
Brochure. 
This trial is designed to evaluate the efficacy and safety of fipaxalparant (HZN-825) in subjects 
with IPF. The trial will be conducted in 2 parts, Part 1 (Core Phase) and Part 2 (Extension 
Phase).  In the Core Phase of the trial, subjects will receive fipaxalparant (HZN-825) 300 mg 
once daily (QD), fipaxalparant (HZN-825) 300 mg BID, or placebo during the 52-week 
Double-blind Treatment Period.  Subjects who complete the Double-blind Treatment Period 
(Week 52) in the Core Phase may be eligible for the Extension Phase and will receive open-label 
fipaxalparant (HZN-825) 300 mg BID for 52 weeks (up to Week 104).  This Extension Phase 
will allow subjects to have up to 24 months of treatment with fipaxalparant (HZN-825), as well 
as limit the duration subjects are exposed to placebo.  The trial is designed with the Extension 
Phase to allow examination of long-term safety and tolerability of fipaxalparant (HZN-825), 
assessment of the durability of response and/or improved response in subjects who received 
fipaxalparant (HZN-825) in the Core Phase and evaluation of efficacy in subjects who received 
placebo in the Core Phase. 
7.3 
Rationale for Dose Selection 
The dose regimens to be evaluated in this trial are 300 mg QD and 300 mg BID with a meal 
using fipaxalparant (HZN-825) tablets manufactured by 
 
.  These regimens are selected based on a comprehensive review of preclinical data 
assessing in vitro LPAR1 inhibitory activity, information from rodent fibrosis models, Phase 1 
PK data and information from a Phase 2a trial in subjects with diffuse cutaneous SSc.   
The completed Phase 2a trial in diffuse cutaneous SSc supports the safety and potential efficacy 
of 300 mg BID for up to 24 weeks of treatment.  The exposures and safety profiles of 
fipaxalparant (HZN-825) in this trial were similar to those previously observed in healthy 
subjects, and positive changes in mRSS, HAQ-DI and LPAR1 pathway genes were detected.  
 
in the Phase 2a trial is thus considered a relevant target exposure of fipaxalparant (HZN-825) for 
IPF, as by blocking LPAR1 signaling, fipaxalparant (HZN-825) has the potential to specifically 
and efficaciously resolve the underlying pathologies of IPF, thereby reducing the severity and 
progression of the disease. 
Preclinical data also support the fipaxalparant (HZN-825) exposures targeted for this trial.  The 
minimum total Ctrough in humans needed for inhibition of LPAR1 activity was between 
25.3 ng/mL and 1536 ng/mL based on in vitro potency evaluations.  The half-maximal inhibitory 
concentration (IC50) of fipaxalparant (HZN-825) against LPAR1 activity ranged from 1.1 ng/mL 
to 66.8 ng/mL without presence of albumin, corresponding to 25.3 ng/mL to 1536 ng/mL after 
adjusting for the 23-fold shift in IC50 in the presence of 3.5% albumin in the range of human 
plasma albumin level of 3.5 g/dL to 4.5 g/dL [Human Albumin, 2009].  In a rat 
deoxycorticosterone acetate (DOCA) salt model, fipaxalparant (HZN-825) reduced cardiac 

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hypertrophy, hydroxyproline levels, and kidney damage at 10 mg/kg BID, with a steady-state 
area under the concentration-time curve from 0 to 12 hours (AUC0-12h) of 12000 ng*h/mL.   
Based on preliminary PK results from Trial HZNP-HZN-825-101, 300 mg BID dosing with a 
meal using fipaxalparant (HZN-825) Aptuit and Siegfried Barbera S.L. tablets are expected to 
achieve similar steady-state Ctrough as observed in the Phase 2a trial in subjects with SSc and is 
selected as the higher dose in this trial.  Additionally, there was less than dose-proportional 
increase in systemic exposures of fipaxalparant (HZN-825) from 150 mg to 300 mg (about 
30% and 40% increase in Cmax and AUC, respectively) and no exposure increase from 300 mg to 
450 mg with Aptuit tablets; also, food intake increased fipaxalparant (HZN-825) exposures.  
Therefore, a second, less-frequent dose regimen, 300 mg QD with a meal, is selected to provide a 
broad range of fipaxalparant (HZN-825) exposures (2-fold different for AUC and ~6-fold 
different for steady-state Ctrough) for evaluation in this trial, a dose that is still expected to achieve 
pharmacologically active steady-state Ctrough above the concentrations needed for in vitro 
inhibition of LPAR1 activity.  Additionally, after adjusting for plasma protein binding of 
fipaxalparant (HZN-825) between humans and rats (99.97% and 99.92%, respectively), both 
300 mg QD and 300 mg BID are also expected to achieve AUC0-12h above the AUC0-12h that 
showed efficacy in the rat DOCA model.   
In summary, the plasma exposures associated with both fipaxalparant (HZN-825) 300 mg QD 
and 300 mg BID are anticipated to be well-tolerated and have clinical efficacy.  The range of 
exposures achieved with these dose regimens will support efficient dose-range exploration and 
allow exposure-response evaluation of fipaxalparant (HZN-825) in subjects with IPF.  

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8 
TRIAL OBJECTIVES 
The trial will be conducted in 2 parts, Part 1 (Core Phase) followed by Part 2 (Extension Phase).  
The Core Phase will include a 52-week, randomized, double-blind, placebo-controlled treatment 
period and the Extension Phase will include a 52-week, OLE. 
8.1 
Part 1 (Core Phase) 
The overall objective of the Core Phase is to investigate the efficacy, safety, and tolerability of 
2 dose regimens of fipaxalparant (HZN-825), a selective antagonist of LPAR1, administered QD 
or BID for 52 weeks in the treatment of subjects with IPF. 
8.1.1 Primary Objective 
The primary objective is to demonstrate the efficacy of 2 dose regimens of fipaxalparant 
(HZN-825) versus placebo in subjects with IPF, as determined by a comparison of change in 
FVC % predicted after 52 weeks of treatment. 
8.1.2 Secondary Objectives 
1. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on the 
proportion of subjects with decline in FVC % predicted ≥10% from Baseline after 
52 weeks of treatment. 
2. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on the 
changes from Baseline in the 6-Minute Walk Test (6MWT) after 52 weeks of treatment. 
3. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on the 
King's Brief Interstitial Lung Disease Questionnaire (K-BILD) after 52 weeks of 
treatment.  
4. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on the 
living with IPF (L-IPF) after 52 weeks of treatment. 
5. Evaluate the effect of 2 dose regimens fipaxalparant (HZN-825) versus placebo on the 
Leicester Cough Questionnaire (LCQ) after 52 weeks of treatment. 
6. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on the 
rate of hospitalization due to respiratory distress up to 52 weeks of treatment. 
7. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on the 
composite endpoint of progression-free survival (PFS), where progression includes 
decline in FVC % predicted ≥10% from Baseline or death over 52 weeks of treatment. 
8. Assess safety and tolerability of fipaxalparant (HZN-825), inclusive of, but not limited to, 
AEs, SAEs, and AESI. 
9. Evaluate the PK of fipaxalparant (HZN-825). 

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8.1.3 Exploratory Objectives 
1. 
2. 
3. 
4. 
5. 
6. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on 
mortality due to respiratory deterioration up to 52 weeks of treatment. 
7.
8.
8.2 
Part 2 (Extension Phase) 
The overall objective of the Extension Phase is to investigate the long-term efficacy, safety, and 
tolerability of fipaxalparant (HZN-825), a selective antagonist of LPAR1, administered at a dose 
of 300 mg BID to subjects with IPF in a 52-week OLE following completion of the Core Phase 
of the trial.  The dose for the Extension Phase may be modified based on the results of the Core 
Phase. 
Two types of Baseline are defined for the Extension Phase: 
 OLE Baseline, defined as the latest measurement prior to the first dose of fipaxalparant 
(HZN-825) in Extension Phase 

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 Fipaxalparant (HZN-825) Baseline, defined as the latest measurement prior to the first 
dose of fipaxalparant (HZN-825) in either the Core Phase or the Extension Phase.  For 
subjects who received placebo in the Core Phase, OLE Baseline will be the same as 
fipaxalparant (HZN-825) Baseline. 
8.2.1 Primary Objective 
The primary efficacy objective is to assess the efficacy of fipaxalparant (HZN-825) in subjects 
with IPF after 52 weeks of open-label treatment. 
8.2.2 Safety Objective 
The safety objective is to examine the safety and tolerability of 52 weeks of open-label treatment 
with fipaxalparant (HZN-825) based on: 
 TEAE assessment 
 Concomitant medication use 
 Vital signs 
 12-lead electrocardiogram (ECG) 
 Clinical safety laboratory results 
8.2.3 Exploratory Objectives 
The exploratory efficacy objective is to evaluate the efficacy of 52 weeks of open-label treatment 
with fipaxalparant (HZN-825) via additional efficacy measurements: 
 Proportion of subjects with decline in FVC % predicted ≥10% 
 6MWT 
 K-BILD 
 L-IPF 
 LCQ 
 
  
 Hospitalization due to respiratory distress  
 Composite endpoint of PFS, where progression includes decline in FVC % predicted 
≥10% or death 
 
 
 
 
 
  
 
 
 
  

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 
 
 
The exploratory PK objective is to evaluate the PK of fipaxalparant (HZN-825). 

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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Trial Design and Plan 
HZNP-HZN-825-303 (HARBOR) will be conducted at approximately 85 trial sites in North 
America, Europe, South America, Africa, Asia (including Japan), and Australia.  The trial 
comprises 2 parts.  Part 1 (Core Phase) is a randomized, double-blind, placebo-controlled, 
repeat-dose, multicenter trial to evaluate the efficacy, safety, and tolerability of fipaxalparant 
(HZN-825) in subjects with IPF.  Part 2 (Extension Phase) is an optional, open-label, 
repeat-dose, multicenter extension of the Core Phase.   
Design of the Core Phase of the Trial 
This is a randomized, double-blind, placebo-controlled, repeat-dose, multicenter trial to evaluate 
the efficacy, safety, and tolerability of fipaxalparant (HZN-825) in subjects with IPF.  Subjects 
will be screened within 8 weeks prior to the Baseline (Day 1) Visit.  Approximately 135 subjects 
who meet the trial eligibility criteria will be randomly assigned in a 1:1:1 ratio on Day 1 to 
receive fipaxalparant (HZN-825) 300 mg QD, fipaxalparant (HZN-825) 300 mg BID, or placebo 
for 52 weeks using the following 2 stratification factors: 
1. Concomitant use of approved IPF therapy (i.e., nintedanib or pirfenidone):  yes or no 
2. FVC % predicted at Baseline:  ≥70% or <70% 
The Core Phase will include up to an 8-week Screening Period and a 52-week Double-blind 
Treatment Period.  Subjects will take their first dose of trial drug at the clinic on Day 1 (Week 0) 
and will participate in trial visits at Week 4 and every 6 weeks thereafter until Week 52.  
Subjects who complete the 52-week Double-blind Treatment Period may be eligible to enroll 
into the Extension Phase of the trial.  If the subject does not enroll into the Extension Phase, a 
Safety Follow-up Visit will occur 4 weeks after the last dose of trial drug.   
If a subject prematurely discontinues trial drug, he/she will be asked to remain in the trial, 
participating in the scheduled trial visits through Week 52.  If a subject prematurely discontinues 
trial drug and does not wish to continue in the trial, he/she will be asked to return for a clinic 
visit and undergo the Week 52 assessments. 
An interim analysis with a futility analysis will be performed
 
 
  These unblinded efficacy and safety data will be provided to an independent 
data monitoring committee (IDMC) and will be used to inform conduct of the current trial.  The 
IDMC will include at least 1 statistician and at least 2 clinicians experienced in clinical trials and 
managing IPF subjects.  The IDMC charter will include processes to unblind select Horizon 
personnel who are not directly involved with the trial conduct to assess unforeseen issues.   
At the interim analysis, the IDMC will provide recommendation to select Horizon personnel not 
involved in the oversight of the trial to facilitate trial continuation and dose selection for future 
trials.  To support decisions on future dose selection and future trial design, a Horizon unblinded 
team may be established and receive unblinded data and perform ad hoc analyses, as needed.  All 

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unblinded data and analysis results made available to the Horizon unblinded team will be 
archived to allow for any potential post hoc assessments of bias.  For additional details, please 
refer to the IDMC charter and Blinding Maintenance Plan for this trial.  
An overview of the Core Phase trial design is presented in Figure 9.1 and details of trial activities 
during the Core Phase are provided in Section 2.1, Schedule of Assessments During the Core 
Phase. 
Figure 9.1 
Schematic of Trial Design – Core Phase 
Screening 
Baseline 
Double-blind Treatment Period 
fipaxalparant (HZN-825) or Placebo 1, 2 
52 Weeks 
Safety Follow-up 
Visit 
< –––––––––––––––––––––––––––––––––––––––––––– Trial Visits 3, 4 ––––––––––––––––––––––—————————–– > 
 
 
 
 
 
 
 
8 weeks 
prior to first 
dose of trial 
drug 
Day 1 
Weeks 2 4, 4, 6 4 and 10 and every 6 weeks thereafter 
Week 52 5 4 weeks after 
last dose of trial 
drug 
Randomization1 < –––––––––––––––––––––––––––––––––––––– Trial Week –––––––––––––––––––––––––––––––––––––––––– > 
 
 
BID=twice daily; QD=once daily 
1. 
Subjects will be randomized in a 1:1:1 ratio to receive fipaxalparant (HZN-825) 300 mg QD, fipaxalparant (HZN-825) 300 mg BID, or placebo.   
2. 
If a subject prematurely discontinues trial drug, he/she will be asked to remain in the trial, participating in the scheduled trial visits through 
Week 52.  If a subject prematurely discontinues trial drug and does not wish to continue in the trial, he/she will be asked to return for a clinic visit 
and undergo the Week 52 assessments.  Subjects not entering the 52-week Extension Phase will return to the clinic 4 weeks after the last dose of 
trial drug for a Safety Follow-up Visit. 
3. 
Visit windows are ±3 days for Week 4, ±7 days for Week 10 to Week 52, inclusive, and ±14 days for the Safety Follow-up Visit.  
4. 
Visits at Weeks 2 and 6 are remote (telephone) visits with a ±3-day window. 
5. 
Subjects who complete the Double-blind Treatment Period (Week 52) may be eligible to enter the 52-week Extension Phase of the trial. 
 
Design of the Extension Phase of the Trial 
The Extension Phase of the trial is an optional, open-label, repeat-dose, multicenter extension of 
the Core Phase.  Subjects who complete the Double-blind Treatment Period (Week 52) in the 
Core Phase of the trial may be eligible to enter this 52-week Extension Phase.  Subjects entering 
the Extension Phase will complete the Week 52 Visit, which will be considered Day 1 of the 
Extension Phase, and will receive their first dose of open-label fipaxalparant (HZN-825) in the 
Extension Phase at the clinic and return to the clinic for trial visits at Weeks 56, 62, and 68, then 
every 12 weeks through Week 104.  The Week 52 Visit activities will serve as Baseline for the 
Extension Phase.  Subjects will return to the clinic for a Safety Follow-up Visit 4 weeks after the 
last dose of fipaxalparant (HZN-825).   
If a subject prematurely discontinues fipaxalparant (HZN-825), he/she will be asked to remain in 
the trial, participating in the scheduled trial visits through Week 104.  If a subject prematurely 
discontinues fipaxalparant (HZN-825) and does not wish to continue in the trial, he/she will be 
asked to return for a clinic visit and undergo the Week 104 assessments. 
An overview of the Extension Phase trial design is presented in Figure 9.2 and details of trial 
activities during the Extension Phase are provided in Section 2.2, Schedule of Assessments 
During the Extension Phase. 

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Figure 9.2 
Schematic of Trial Design – Extension Phase 
Week 52 Visit of Core Phase 
Open-label Treatment Period 
fipaxalparant (HZN-825) 300 BID 1, 2 
52 Weeks (Week 52 – Week 104) 
Safety  
Follow-up 
Visit 
< –––––––––––––––––––––––––––––––––––––––––––––– Clinic Visits 3, 4––––––––––––––––––––—————————— > 
 
 
 
 
 
 
 
 
Day 1 of Extension Phase 
Weeks 56, 62, 68, 74 4, 80, 86 4, 92, and 98 4 
Week 104 4 weeks after 
last dose of 
fipaxalparant 
(HZN-825) 
BID=twice daily 
1. 
The fipaxalparant (HZN-825) dose may be modified based on the results of the Core Phase.   
2. 
If a subject prematurely discontinues open-label fipaxalparant (HZN-825), he/she will be asked to remain in the trial, participating in the scheduled 
trial visits through Week 104.  If a subject prematurely discontinues open-label fipaxalparant (HZN-825) and does not wish to continue in the trial, 
he/she will be asked to return for a clinic visit and undergo the Week 104 assessments.   
3. 
Visit windows are ±5 days for Week 56, ±7 days for Week 62 to Week 104, inclusive, and ±14 days for the Safety Follow-up Visit.   
4. 
Visits at Weeks 74, 86, and 98 are remote (telephone) visits with a ±7-day window. 
 
9.1.1 Adjudication Committee 
Cases of respiratory hospitalizations and acute exacerbations will each be reviewed by an 
independent adjudication committee in a blinded manner before database lock for the Core Phase 
of the trial.  Details outlining the responsibilities of the adjudication committee and the 
parameters related to these events of interest will be included in the adjudication committee 
charter. 
9.2 
Discussion of Trial Design 
This trial is a randomized, double-blind, placebo-controlled, repeat-dose, multicenter trial in 
subjects with IPF that was designed according to standard principles.  The measurements used in 
this trial to assess safety and efficacy are established and well-defined. 
A treatment duration of 12 months was the length of exposure to trial drug in randomized, 
double-blind, placebo-controlled registrational clinical trials of IPF for pirfenidone 
[King et al., 2014] and nintedanib [Richeldi et al., 2014] and was sufficient to observe separation 
from placebo with respect to change in FVC % predicted.  Receipt of placebo longer than 
12 months would not be ethical in subjects with IPF, a progressive, debilitating and fatal disease.  
The Extension Phase of this clinical trial will allow subjects to receive up to 24 months of 
treatment with fipaxalparant (HZN-825), as well as limit the duration subjects are exposed to 
placebo.  Subjects will be allowed to continue standard-of-care treatments, within guidelines 
outlined in the protocol, as well as protocol-permissible rescue therapy. 
9.3 
Selection of Trial Population 
9.3.1 Eligibility Criteria for the Core Phase 
9.3.1.1 Inclusion Criteria 
Eligible subjects must meet/provide all of the following criteria: 

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1. Written informed consent. 
2. Male or female ≥18 years of age at Screening. 
3. Current diagnosis of IPF, as defined by ATS/ERS/JRS/ALAT guidelines 
[Raghu et al., 2022] and determined by central review; the date of initial diagnosis of IPF 
should be ≤7 years prior to Screening.   
4. No recent changes or planned changes to the dose or regimen for IPF therapy, defined as:   
 Receiving a stable dose of IPF-approved therapy (i.e., nintedanib or pirfenidone) for a 
minimum of 3 months prior to Day 1 with no plans to change the background 
regimen during trial participation, or 
 Not currently receiving background IPF-approved therapy at Screening (either naïve 
to IPF-approved therapy or previously discontinued any IPF-approved therapy at least 
4 weeks prior to Day 1 or drug-specific, 5 half-lives elimination period if longer than 
4 weeks), and with no current plans to restart treatment during trial participation 
 Subjects receiving any additional agent for IPF therapy must be on a stable regimen 
for at least 3 months prior to Day 1 with no current plans to change the treatment 
regimen during trial participation.  Any previously discontinued therapy used to treat 
IPF must have been discontinued at least 4 weeks prior to Day 1 or 5 half-lives for 
that specific therapy must have elapsed, whichever is longer, with no plans to restart 
the therapy during trial participation.  
5. Lung HRCT historically performed within 6 months prior to the Screening Visit and 
according to the minimum requirements for IPF diagnosis by central review based on 
subject's HRCT.  If an evaluable HRCT is not available within 6 months prior to 
Screening, an HRCT will be performed at Screening to determine eligibility, according to 
the same requirements as the historical HRCT.  The HRCT must demonstrate a usual 
interstitial pneumonia or probable usual interstitial pneumonia pattern based on central 
review vendor interpretation.  Histopathology in combination with HRCT results 
supportive of an IPF or IPF likely diagnosis according to Raghu et al., 2022 can be 
submitted to support subject eligibility.  
6. HRCT shows ≥10% to <50% parenchymal fibrosis (reticulation) and the extent of fibrotic 
changes is greater than the extent of emphysema on the most recent HRCT scan (central 
reviewer determined). 
7. Meets all of the following criteria during the Screening Period, as determined by central 
review:   
a. FVC ≥45% predicted of normal 
b. forced expiratory volume in 1 second /FVC ≥0.7 
c. DLCO corrected for hemoglobin is ≥25% and ≤90% predicted of normal 
8. Estimated minimum life expectancy of ≥30 months for non-IPF-related disease, in the 
opinion of the Investigator. 
9. Vaccinations are up to date, according to the Investigator’s discretion, given age, 
comorbidities, and local availability prior to trial drug dosing. 
10. Willing and able to comply with the prescribed treatment protocol and evaluations for the 
duration of the trial. 

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9.3.1.2 Exclusion Criteria 
Subjects will be ineligible for trial participation if they meet any of the following criteria: 
1. Any of the following cardiovascular diseases:   
a. uncontrolled, severe hypertension (≥160/100 mmHg), within 6 months of Screening 
b. myocardial infarction within 6 months of Screening 
c. unstable cardiac angina within 6 months of Screening 
2. ILD associated with known primary diseases (e.g., sarcoidosis, amyloidosis, and 
coronavirus disease 2019 [COVID-19]), connective tissue disorders (e.g., rheumatoid 
arthritis, systemic lupus erythematosus, Sjogren’s, dermatomyositis, scleroderma), 
exposures (e.g., radiation, silica, asbestos, and coal dust) or drugs (e.g., amiodarone).   
3. Known active bacterial, viral, fungal, mycobacterial, or other infection, including 
tuberculosis or atypical mycobacterial disease (fungal infections of nail beds are 
allowed).  The subject must be 3 months beyond any acute infection with COVID-19 if 
there has been a prior infection. 
4. Clinically significant pulmonary hypertension requiring chronic medical therapy. 
5. Use of any of the following therapies within 4 weeks prior to Screening, during the 
Screening Period or planned during the trial:  prednisone at steady dose >10 mg/day or 
equivalent or cyclosporine.  Change in regimen or dosage of any immunosuppressant 
during the Screening Period through the end of trial participation will require consultation 
with and approval by the trial Medical Monitor.  See Section 9.4.9 for full details.  
Avoiding the use of listed prohibited treatments must not be considered detrimental and 
must be indicated by the treating physician.  Subjects must not be withdrawn from any 
standard-of-care treatment that is considered necessary for the clinical management of the 
subject in order to fulfill the trial eligibility requirements. 
6. Use of rifampin within 2 weeks prior to Day 1 or planned during the trial. 
7. Malignant condition in the past 5 years (except successfully treated basal/squamous cell 
carcinoma of the skin or cervical cancer in situ). 
8. Women of childbearing potential (WOCBP) or male subjects not agreeing to use highly 
effective method(s) of birth control throughout the trial and for 4 weeks after last dose of 
trial drug.  Females must refrain from egg/ova donation for 4 weeks after the last dose of 
trial drug and males must refrain from sperm donation for 3 months after the last dose of 
trial drug.  Women are considered of childbearing potential if they are not 
postmenopausal and not surgically sterile (documented bilateral salpingectomy, bilateral 
oophorectomy, or hysterectomy).  A postmenopausal state is defined as no menses for 
12 months without an alternative medical cause.  A high follicle-stimulating hormone 
(FSH) level in the postmenopausal range may be used to confirm a postmenopausal state 
in women not using hormonal contraception or hormonal replacement therapy.  However, 
in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.  
Fertile male subjects must use a condom throughout the trial and for 4 weeks after the last 

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dose of trial drug.  A man is considered fertile after puberty unless permanently sterile by 
bilateral orchidectomy. 
9. Pregnant or lactating women and women who plan to become pregnant or breast feed 
during the trial and within 4 weeks after the last dose of trial drug. 
10. Current drug or alcohol abuse or history of either within the previous 2 years, in the 
opinion of the Investigator or as reported by the subject. 
11. Previous enrollment in this trial or participation in a prior fipaxalparant (HZN-825) or 
SAR100842 clinical trial. 
12. Known history of positive test for human immunodeficiency virus (HIV).  HIV testing is 
optional based on Investigator assessment, institutional practices or local guidelines, to 
rule out suspected HIV or potential for a positive HIV result.  Subject consent is required 
prior to HIV testing. 
13. Active hepatitis (any of the following at Screening): 
Hepatitis B:   
 positive hepatitis B surface antigen 
 positive for anti-hepatitis B core antibody (anti-HBcAb) and a positive test for 
hepatitis B surface antibody (HBsAb) and presence of hepatitis B virus DNA 
 positive for HBcAb and a negative test for HBsAb and presence of hepatitis B virus 
DNA 
Hepatitis C:   
 positive anti-hepatitis C virus (anti-HCV) and positive HCV RNA. 
14. Current alcoholic liver disease, primary biliary cirrhosis or primary sclerosing 
cholangitis. 
15. Previous organ transplant (including allogeneic and autologous marrow transplant). 
16. INR >2, prolonged prothrombin time >1.5 × the upper limit of normal (ULN) or partial 
thromboplastin time >1.5 × ULN at Screening. 
17. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.0 × ULN. 
18. Estimated glomerular filtration rate <30 mL/min/1.73 m2 at Screening.   
19. Total bilirubin >1.5 × ULN.  Subjects with documented diagnosis of Gilbert’s syndrome 
may be enrolled if their total bilirubin is ≤3.0 mg/dL. 
20. Moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment according to the 
Child-Pugh scoring system. 
21. Any confirmed Grade 3 or higher laboratory abnormality.   
22. Any laboratory abnormality at Screening that, in the opinion of the Investigator, would 
preclude the subject’s participation in the trial. 
23. Exposure to an experimental drug or experimental vaccine within either 30 days, 
5 half-lives of the test agent, or twice the duration of the biological effect of the test 
agent, whichever is the longest, prior to Day 1. 
24. Any other condition that, in the opinion of the Investigator, would preclude enrollment in 
the trial. 

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9.3.2 Eligibility Criteria for the Extension Phase 
9.3.2.1 Inclusion Criteria 
Eligible subjects must meet/provide all of the following criteria: 
1. Written informed consent. 
2. Completed the Double-blind Treatment Period (Week 52) of the Core Phase of the trial; 
subjects prematurely discontinued from trial drug in the Core Phase of the trial for 
reasons other than safety or tolerability may be included at the discretion of the 
Investigator after completing scheduled visits, including Week 52 assessments. 
3. Willing and able to comply with the prescribed treatment protocol and evaluations for the 
duration of the Extension Phase of the trial.   
9.3.2.2 Exclusion Criteria 
Subjects will be ineligible for trial participation if they meet any of the following criteria: 
1. Anticipated use of another investigational agent for any condition during the course of 
the trial.   
2. New diagnosis of malignant condition after enrolling in Trial HZNP-HZN-825-303 
(except successfully treated basal/squamous cell carcinoma of the skin or cervical cancer 
in situ).   
3. Estimated minimum life expectancy ≤18 months, in the opinion of the Investigator. 
4. WOCBP or male subjects not agreeing to use highly effective method(s) of birth control 
throughout the trial and for 1 month after last dose of fipaxalparant (HZN-825).  Male 
subjects must refrain from sperm donation and females from egg/ova donation for this 
same time period.  Women are considered of childbearing potential if they are not 
postmenopausal and not surgically sterile (documented bilateral salpingectomy, bilateral 
oophorectomy, or hysterectomy).  A postmenopausal state is defined as no menses for 
12 months without an alternative medical cause.  A high FSH level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy.  However, in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.  A man 
is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
5. Pregnant or lactating women.   
6. Any other new development of the disease/condition/significant laboratory test 
abnormality during the course of the Core Phase of the trial, in the opinion of the 
Investigator, that would potentially put the subject at unacceptable risk. 
7. In the opinion of the Investigator, unlikely to comply with the trial protocol or has a 
concomitant disease or condition that could interfere with the conduct of the trial. 
9.3.3 Removal of Subjects from Treatment or the Trial 
All subjects are free to withdraw from trial participation at any time, for any reason and without 
prejudice to their further medical care.  In addition, the Investigator may terminate a subject from 
treatment at any time, if further treatment in the trial is not in the best interest of the subject. 

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If a subject prematurely discontinues trial drug, he/she will be asked to remain in the trial, 
participating in the scheduled trial visits through Week 52 (if discontinuation occurs during the 
Core Phase) or Week 104 (if discontinuation occurs during the Extension Phase).  If a subject 
prematurely discontinues trial drug and does not wish to continue in the trial, he/she will be 
asked to return for a clinic visit and undergo the Week 52 (if discontinuation occurs during the 
Core Phase) or Week 104 (if discontinuation occurs during the Extension Phase) assessments.  
Subjects will be asked to return to the clinic for a Safety Follow-up Visit 4 weeks after the last 
dose of fipaxalparant (HZN-825). 
9.3.3.1 Removal of Subjects from Treatment 
9.3.3.1.1 Removal of Subjects from Trial Drug 
The primary reason for discontinuation from trial drug should be recorded on the eCRF using 
one of the following categories: 
 AE or clinically significant laboratory/ECG abnormality.  The subject experiences an AE 
or clinically significant laboratory/ECG abnormality that imposes an unacceptable risk to 
the subject’s health, or the subject is unwilling to continue receiving treatment because of 
an AE or clinically significant laboratory/ECG abnormality.  Subjects who discontinue 
trial drug due to an AE or clinically significant laboratory/ECG abnormality will remain 
in the trial unless they withdraw from the trial for another reason.  In such cases, if 
situation is not an immediate emergency, the Investigator should contact the trial Medical 
Monitor.   
 Drug-induced liver injury.  Trial drug discontinuation should be considered if: 
o ALT or AST >8 × ULN 
o ALT or AST >5 × ULN for more than 2 weeks  
o ALT or AST >3 × ULN and (total bilirubin >2 × ULN or INR >1.5) 
o ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%) 
Subjects who have ALT or AST levels >3 × ULN confirmed in a repeat test need to 
undergo close observation as prescribed by the FDA guidance on drug-induced liver 
injury.  Close observation includes repeating liver enzyme and serum bilirubin tests 2 or 
3 times weekly.  Frequency of retesting can decrease to once a week or less if 
abnormalities stabilize and the subject is asymptomatic.  The decision to rechallenge the 
subject is to be discussed and agreed upon by the Investigator, and Amgen Medical 
Monitor. 
 Lack of efficacy.  Discontinuation of trial drug due to lack of efficacy is at the discretion 
of the Investigator or subject and may occur if the Investigator determines that trial drug 
administration is not benefiting the subject.  Subjects who discontinue trial drug due to 
lack of efficacy during the Core Phase will remain in the trial for scheduled safety and 
efficacy assessments through Week 52 unless they also withdraw from the trial for 
another reason.  Subjects who discontinue trial drug due to lack of efficacy during the 

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Extension Phase will remain in the trial for scheduled safety and efficacy assessments 
through Week 104 unless they also withdraw from the trial for another reason. 
 Restricted medications.  Initiation of any therapy prohibited in the trial per Table 9.1 or 
use of any rescue medications prior to Week 28 may lead to subject discontinuation from 
treatment (see Section 9.4.9).  The Investigator may consult with the trial Medical 
Monitor before initiation of the restricted medications. 
 Withdrawal by subject.  The subject wishes to withdraw from trial treatment.  The 
clinical site should attempt to determine the underlying reason for the voluntary 
withdrawal and document it on the eCRF. 
 Investigator’s decision.   
 Trial terminated by Sponsor.  The Sponsor, external review bodies or regulatory agency 
terminates the trial. 
 Pregnancy.  The subject is removed from trial drug but not the trial; the subject continues 
with protocol-specified visits. 
 Death. 
 Completed.  The subject completed treatment. 
 Lost to follow-up.  The subject does not participate in scheduled assessments and does 
not respond to the site’s attempts to contact the subject.  Before the subject is deemed 
‘lost to follow-up,’ the Investigator or designee must make every effort to regain contact 
with the subject (where possible, 3 telephone calls and, if necessary, a certified letter to 
the subject’s last known mailing address or local equivalent methods).  These contact 
attempts should be documented in the subject’s medical record. 
Subjects who prematurely discontinue trial drug during the Core Phase will be encouraged to 
continue trial participation in all planned visits, particularly returning for the Week 52/premature 
discontinuation assessments.   Subjects who prematurely discontinue trial drug during the 
Extension Phase will be encouraged to continue trial participation in all planned visits, 
particularly returning for the Week 104/premature discontinuation assessments.   Subjects who 
discontinue trial drug due to an AE should be followed until resolution or stabilization of the AE, 
or an adequate explanation for the event is obtained, in addition to being encouraged to continue 
participation in all planned assessments. 
9.3.3.1.2 Changes to Background Therapy for IPF 
Subjects who change or discontinue standard of care therapy for IPF and/or another agent used to 
treat IPF should continue treatment with randomized investigational product for the planned 
duration of the trial unless removal of trial drug is also required due to meeting requirements 
listed in Section 9.3.3.1.1.  The primary reason for change in background therapy should be 
recorded within the eCRF. 

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9.3.3.2 Removal of Subjects from the Trial 
The primary reason for discontinuation from the trial should be recorded on the eCRF using one 
of the following categories: 
 Lost to follow-up.  The subject does not participate in scheduled assessments and does 
not respond to the site’s attempts to contact the subject.  Before the subject is deemed 
‘lost to follow-up,’ the Investigator or designee must make every effort to regain contact 
with the subject (where possible, 3 telephone calls and, if necessary, a certified letter to 
the subject’s last known mailing address or local equivalent methods).  These contact 
attempts should be documented in the subject’s medical record. 
 Withdrawal by subject/guardian.  The subject wishes to withdraw from the trial.  The 
clinical site should attempt to determine the underlying reason for the voluntary 
withdrawal and document it on the eCRF. 
 Death. 
 Completed.  The subject completed the Core Phase, including the Safety Follow-up Visit 
(if the subject does not enroll into the Extension Phase) or the subject completed the 
Extension Phase, including the Safety Follow-up Visit. 
 Trial terminated by Sponsor. 
9.3.4 Discontinuation of a Treatment Group or the Trial 
The following events, if applicable, may cause premature termination of the clinical trial or trial 
arms:  unjustifiable risk and/or toxicity in risk-benefit analysis (decision taken by Sponsor or 
representative), e.g., when AEs occur, unknown to date in respect of their nature, severity, 
duration or frequency in relation to the current established safety profile (substantial changes in 
risk-benefit considerations), and, therefore, medical and/or ethical reasons affect the continued 
performance of the trial; new scientific evidence becomes available during the trial that could 
affect the subject’s safety (benefit-risk analysis no longer positive), e.g., new insights from other 
clinical trials; request of the Sponsor with or without recommendation from a data safety 
monitoring board, or of a regulatory agency, e.g., as a consequence of inspection; favorable 
opinion withdrawn by the ethics commission; in case of difficulties in the recruitment of the 
planned number of subjects in the indicated time (insufficient recruitment rate); and withdrawal 
of the license to manufacture (and/or of the permission to import). 
9.3.5 Replacement Policy 
9.3.5.1 Subjects 
In general, no subject prematurely discontinued from the trial for any reason will be replaced.  
An exception may be made for subjects who are unevaluable due to the impact of an external 
event, for example, a pandemic or a natural disaster and associated restrictions on movement and 
work.  Subjects unable to receive treatment or be evaluated due to restrictions during the event 
may be replaced, at the discretion of the Sponsor.  This may result in more subjects being 
enrolled into the trial to allow for the planned number to be evaluable for the efficacy and safety 
analyses. 

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9.3.5.2 Centers 
Prior to a site being recommended for closure, the site Principal Investigator, Medical Monitor, 
Trial Manager and possibly the Site Monitor will discuss the decision for closure. 
A center may be closed and/or replaced for the following administrative reasons:   
 Excessively slow recruitment. 
 Unacceptable protocol adherence. 
9.3.5.3 Screen Failures 
Subjects who do not meet all of the inclusion criteria or meet any of the exclusion criteria will be 
considered screen failures.  An abnormal test during Screening may be repeated once during the 
Screening Period.   
Screen failures may be allowed to rescreen for the trial if both the Investigator and Sponsor are 
in agreement regarding rescreening and if the Investigator determines that the subject can satisfy 
all of the eligibility criteria.   
9.4 
Treatments 
9.4.1 Treatments Administered 
During the Core Phase of the trial, on Day 1 of the Double-blind Treatment Period, subjects will 
be randomized in a 1:1:1 ratio to receive for 52 weeks: 
1. 
Fipaxalparant (HZN-825) 300 mg QD, or  
2. 
Fipaxalparant (HZN-825) 300 mg BID, or 
3. 
Placebo. 
During the Extension Phase, all subjects will receive open-label fipaxalparant (HZN-825) 
300 mg BID for 52 weeks.  The dose for the Extension Phase may be modified based on the 
results of the Core Phase. 
9.4.2 Identity of Investigational Products 
9.4.2.1 Fipaxalparant (HZN-825) 
Fipaxalparant (HZN-825) is a selective antagonist of LPAR1.  Fipaxalparant (HZN-825) will be 
provided as film-coated tablets for oral administration.  The oblong, white tablets contain 
fipaxalparant (HZN-825) 150 mg and the following excipients: 
 
  
9.4.2.2 Placebo 
Placebo tablets match the appearance of active tablets and include the following excipients:  
 
 

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9.4.3 Labeling 
Fipaxalparant (HZN-825) 150 mg and placebo tablets will be packaged in blister packs (blister 
packs will be blinded for the Core Phase) according to the dose regimens identified in 
Section 9.4.1.  Trial drug packaging will be in compliance with Sponsor/contract research 
organization standard procedures and will meet all local requirements.  Each blister pack label 
will be labeled with a unique number.   
Upon arrival of investigational products at the site, the Investigator (or designee in accordance 
with institutional policies and local regulations) should inspect them for damage and verify 
proper identity, quantity, integrity of seals and temperature conditions and report any deviations 
or product complaints to the monitor/Sponsor upon discovery. 
9.4.4 Storage 
Fipaxalparant (HZN-825) tablets should be stored at controlled room temperature, per US 
Pharmacopeia, between 20°C and 25°C (68°F to 77°F), with excursions permitted between 15°C 
and 30°C (59°F to 86°F).   
9.4.5 Drug Accountability 
The Principal Investigator at each site is responsible for the control of all trial drug and must 
maintain adequate records of the receipt and disposition of all trial drug shipped to the trial 
center.  Records will include receipt dates, condition at time of receipt, quantities received, 
quantities dispensed, quantities returned or destroyed and the identification numbers of the 
subjects who received trial drug. 
Investigational clinical supplies will be received by a designated person(s) at the trial site, 
handled and stored safely and properly and kept in a secured location to which only the 
Investigator and designated assistants have access. 
At the end of the trial or if the subject prematurely discontinues the trial, the subjects should 
return any unused or partially used trial drugs to the site. 
9.4.6 Trial Drug Administration and Timing of Dose for Each Subject 
Subjects will take 2 tablets of fipaxalparant (HZN-825) 150 mg and/or placebo orally in the 
morning and evening with a meal in the Core Phase. Subject will take 2 tablets of fipaxalparant 
(HZN-825) 150 mg orally in the morning and evening with a meal in the Extension Phase.  In the 
event a subject misses a dose, the dose should be taken along with the next planned dose 
(evening or morning) with a meal such that 4 tablets (up to 600 mg) in total will be taken.  Due 
to a less than dose-proportional increase in fipaxalparant (HZN-825) systemic exposure, the 
600 mg dose taken in the event of a prior missed dose will be considered part of the planned 
dosing for this trial. 
9.4.6.1 Dose Modifications, Interruptions and Delays 
All dosing instructions are applicable for fipaxalparant (HZN-825) and placebo administration.  
Any completely missed dose should be recorded on the Dosing Interruptions eCRF. 

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9.4.6.1.1 Orthostatic Hypotension 
Orthostatic hypotension is considered the AESI for this trial.  Trial drug should be temporarily 
discontinued in the case of trial drug-related, newly developed and clinically significant 
orthostatic hypotension associated with clinical symptoms requiring medical intervention.  Trial 
drug may be restarted at the discretion of the Investigator after the clinical symptoms have 
resolved and following consultation with the Sponsor trial medical monitor.  Subjects should 
have normal blood pressure (BP) and heart rate with absence of symptoms related to orthostatic 
hypotension for at least 5 days prior to restarting. 
See Section 9.5.5.5 for details of orthostatic hypotension assessment. 
9.4.6.1.2 Drug-induced Liver Injury 
Elevated hepatic transaminases have been evaluated to be an important identified risk with 
fipaxalparant (HZN-825). The events are mostly non-serious and transient. Refer to 
Section 9.3.3.1 for criteria regarding trial drug discontinuation due to drug-induced liver injury. 
9.4.7 Method of Assigning Subjects to Treatment Groups 
For the Core Phase of the study, a randomization schedule will be generated by an unblinded 
statistician not otherwise associated with the trial prior to shipment of any trial drug to the 
clinical sites.  On Day 1 of the Double-blind Treatment Period, once all Baseline procedures 
other than administration of trial drug have been completed, authorized site personnel will use 
the interactive response technology (IRT) system to randomize the subject.  The Investigator or 
designee will then use the IRT system to obtain dosing information and dispense the appropriate 
trial drug. 
All subjects in the Extension Phase will receive open-label fipaxalparant (HZN-825). 
9.4.8 Blinding and Unblinding 
The subject, Investigator and all other trial site personnel, including Sponsor or designee 
monitors, will be blinded to the trial drug being administered during the Core Phase. 
The trial blind should be broken only if the safety of a subject is at risk and the treatment plan 
depends on which trial drug he or she received.  Unless the subject is at immediate risk, the 
Investigator must make diligent attempts to contact the Sponsor or Sponsor’s designee before 
unblinding the subject’s data.  If a subject’s data are unblinded without prior knowledge of the 
Sponsor, the Investigator must notify the Sponsor as soon as possible and no later than the next 
business day.  All circumstances surrounding the event must be clearly documented.  Please refer 
to the instructions in the eCRF guidelines for unblinding a subject.  
The Sponsor or designee will unblind the identity of the trial drug for a drug-related SAE for 
submission to health authorities and external review bodies according to applicable regulatory 
requirements.  However, the results will not be shared with other Sponsor representatives or staff 
at trial sites.  Details of subjects who are unblinded during the trial will be included in the 
clinical study report. 

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Unblinding for independent pharmacological analysis of biological samples or SAE reporting 
will be performed according to procedures in place to ensure integrity of the data.  
All investigative site staff directly involved in this trial will remain blinded from Screening 
through analysis of the follow-up data and all site close-out visits.  The Sponsor and its designees 
will be unblinded after the database lock following completion of all subjects in the Double-blind 
Treatment Period. 
An IDMC will review unblinded safety and efficacy data on a scheduled basis during the Core 
Phase of the trial.  An interim analysis with a futility analysis will be performed
 
 
 At the interim analysis, the 
IDMC will provide recommendation to select Horizon personnel not involved in the oversight of 
the trial to facilitate trial continuation and dose selection for future trials.  To support decisions 
on future dose selection and future trial design, a Horizon unblinded team may be established 
and receive unblinded data and perform ad hoc analyses, as needed.  All unblinded data and 
analysis results made available to the Horizon unblinded team will be archived to allow for any 
potential post hoc assessments of bias.  For additional details, please refer to the IDMC charter 
and Blinding Maintenance Plan for this trial.  
The Extension Phase is open-label, and all subjects will receive fipaxalparant (HZN-825). 
9.4.9 Concomitant Therapy and Restricted Medications 
All concomitant treatment, including herbs and supplements, must be documented in the eCRF. 
Medication use restricted during the trial is presented in Table 9.1. 

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Table 9.1 
Restricted Medications 
Medication 
Restricted Time Period 
Prednisone at steady dose >10 mg/day or equivalent or 
cyclosporine 1  
 
4 weeks prior to Screening through trial completion 
Topical steroids for dermatological conditions and 
inhaled/intranasal/intra-articular steroids are allowed 
during the trial.   
Short bursts for acute illnesses (asthma, allergic 
reaction) are permitted. 
Other immunosuppressant agents 
Change in treatment regimen or dosage with any other 
immunosuppressant during the Screening Period 
through the end of trial participation will require 
consultation and approval by the trial Medical Monitor. 
An investigational agent for any condition 
4 weeks or 5 half-lives, whichever is longer, prior to 
Screening through trial completion 
Drug/alcohol abuse 
History of abuse within the past 2 years or abuse 
during trial 
Rifampin 2  
2 weeks prior to dosing through trial completion 
OATP inhibitors:  clarithromycin and gemfibrozil 
BCRP inhibitor 3:  eltrombopag 
3 days prior to dosing through trial completion 
BCRP=breast cancer resistance protein; CYP=cytochrome P450; OATP=organic anion transporter polypeptide 
1. Cyclosporine is also an OATP and BCRP inhibitor. 
2. Rifampin is a CYP enzyme inducer and an OATP inhibitor. 
3. Known clinical OATP and BCRP inhibitors include, but are not limited to, the drugs included in this table. 
The INR may need to be monitored more frequently for subjects taking warfarin.  Fipaxalparant 
(HZN-825) is a weak inhibitor of cytochrome P450 (CYP)2C9, increasing S-warfarin AUC by 
23% and R-warfarin AUC by 13% in healthy subjects, with minimal impact on INR (the mean 
increase in INR at 24 hours post warfarin administration from Baseline was 14.2% without 
fipaxalparant (HZN-825) and 16.8% with fipaxalparant (HZN-825) treatment). 
Caution should be exercised when co-administering fipaxalparant (HZN-825) with other 
substrates of CYP2C9 or organic anion transporter (OAT)1/OAT3 that have narrow therapeutic 
windows. 
Caution should be observed when co-administering fipaxalparant (HZN-825) with strong 
inhibitors of CYP2C9 or CYP2D6. 
Fipaxalparant (HZN-825) and background therapy drugs (pirfenidone/nintedanib) are not 
expected to affect each other’s exposure (see Section 7.1.3.4). 
In case of a clinically significant deterioration in lung function, initiation of additional therapy or 
change in dose of background therapy or immunosuppressant therapy for IPF is allowed after 
Week 28 following consultation with the trial Medical Monitor.  The addition or change of 

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background therapy for IPF treatment due to clinical deterioration will be labeled as “rescue 
therapy.”  Detailed (S)AE information following such events should be recorded in the eCRF. 
Clinically significant deterioration includes: 
 An absolute decline since Baseline in FVC % predicted ≥10% or an absolute decline 
since Baseline in FVC % predicted ≥5% to 9% with associated decline in DLCO 
≥15% since Baseline, or  
 Clinically significant deterioration in other organ systems, per Investigator assessment. 
Other causes for FVC decline (i.e., respiratory tract infection) should be excluded.  Repeat 
FVC/spirometry should be performed and confirmed prior to initiation of rescue medication if, to 
the Investigator’s clinical judgment, well-founded doubts in the test’s quality and the subject’s 
good condition justify the associated delay in subject care, and the increase in risk for the 
subject. 
9.4.10 Treatment Compliance 
The Investigator is responsible for ensuring that dosing is administered in compliance with the 
protocol.  Delegation of this task must be clearly documented and approved by the Investigator. 
Subjects who are not compliant with trial drug dosing should be counseled about the importance 
of taking trial drug on time and regularly. 
An inventory of the trial drug supplies will be performed by the site or authorized trial designee 
and recorded onto the Drug Accountability Log in the subject’s source document records or 
equivalent.  
9.5 
Efficacy and Safety Variables 
Refer to the Schedules of Assessments (Section 2.1 and Section 2.2) for timing of all assessments. 
9.5.1 Efficacy Variables 
9.5.1.1 Spirometry 
Spirometry, including FVC % predicted, will be assessed using a device provided by the 
Sponsor.  Spirometry should only be performed by a trained assessor and the same assessor 
should complete the procedure for a given subject throughout the duration of the trial, unless it is 
not possible.  For spirometry at Screening, the central review results are required for 
determination of eligibility. 
Spirometry measurements must be performed according to ATS/ERS 2019 guidelines 
[Graham et al., 2019] whenever possible.  The test will be done in triplicate (3 curves to be 
provided) and the best result selected according to the guidelines.  The best of 3 efforts will be 
defined as the highest FVC, obtained on any of the 3 blows meeting the ATS/ERS criteria with a 
maximum of 8 maneuvers.   

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Spirometry measurements should be attempted at approximately the same time of day from 
Baseline onwards.  On days of clinic visits, subjects must refrain from strenuous activity at least 
12 hours prior to pulmonary function testing.  Smoking should be discouraged throughout the 
visit days and will not be permitted in the 30-minute period prior to spirometry.  Subjects should 
also avoid cold temperatures, environmental smoke, dust or areas with strong odors 
(e.g., perfumes).  If treated with bronchodilators, washout of 24 hours for long-acting and 
8 hours for short-acting bronchodilators should be observed before spirometry. 
Spirometry results will be electronically transmitted.  To ensure the quality of primary endpoint 
measurement, a central spirometry review will occur.  Results will be over-read by a central 
reader, confirmed by the clinical site and data will be transferred into the clinical database.  
In addition, the subject will be asked the following anchor (additional) questions at the time 
points indicated in Section 2.1 and Section 2.2. 
Rate the severity of your breathing problems over the last week: 
 0:  no breathing problems 
 1:  mild breathing problems 
 2:  moderate breathing problems 
 3:  severe breathing problems 
 4:  very severe breathing problems 
How have your breathing problems changed since the start of the trial?   
 +3:  very much better 
 +2:  much better 
 +1:  a little better 
▪   0:  no change  
 -1:  a little worse 
 -2:  much worse 
 -3:  very much worse 
9.5.1.2 6-minute Walk Test 
The 6MWT measures the distance a subject can quickly walk on a flat, hard surface in 6 minutes 
(6-minute walk distance).  This test evaluates the global and integrated responses of all the 
systems involved during exercise, including the pulmonary and cardiovascular systems, systemic 
circulation, peripheral circulation, blood, neuromuscular units and muscle metabolism.  The 
6MWT will be performed according to ATS guidelines for the 6MWT [Lancaster, 2018; ATS 
Guidelines, 2002].   
9.5.1.3 Titrated Oxygen Requirement 
Oxygen titration will be performed to determine the lowest oxygen flow rate required to maintain 
an oxygen saturation (Sp,O2) of ≥96% in the standing position (TOR).  Titration will begin with 
the subject breathing room air.  Sp,O2 will be monitored for 1 minute.  If the Sp,O2 is ≥96%, the test 

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will conclude.  If Sp,O2 is <96%, the oxygen flow rate will be increased each minute to achieve a 
target Sp,O2 of ≥96% using the following titration steps:  1, 2, 3, 4, 5, 6, 8, 12, and 15 L·min−1.   
9.5.1.4 Diffusing Capacity of the Lungs for Carbon Monoxide 
The site will use its own DLCO equipment and conduct all measurements with the same DLCO 
equipment in case that several devices are available at the site.  Single-breath DLCO 
measurement will be performed according to the ATS guideline on DLCO measurements, when 
possible [Graham et al., 2017].  Refer to the DLCO procedural manual for details.  Sites may 
request, but will not be required, to have subjects attend unscheduled visits for repeat DLCO 
measurements when the initial measurement has not passed according to DLCO central review 
quality control criteria.  DLCO assessments for determining subject eligibility for the trial can be 
repeated once during the 35-day Screening window.  During the treatment period, repeat 
measurements should be attempted within 1 week, if possible.  DLCO results that do not pass 
quality control and for which it is not practical to recall the subject to the trial site for a repeat 
test, Investigators should assess and record within the subject’s source documents whether the 
DLCO performed was valid per the site’s standard practices and correlates well with the 
subject’s clinical conditions and previous DLCO results.  
DLCO values will be adjusted for altitude when necessary, and the most recent hemoglobin 
value.  An adjustment for carboxyhemoglobin will be made if the Investigator determines that 
the subject may have elevated carboxyhemoglobin.  The DLCO assessment should always be 
performed after the FVC measurement and should always be started approximately the same 
time each day.  
9.5.1.5 Lung High-resolution Computed Tomography 
Lung HRCT will be reviewed by a central reader.  These results must be available prior to 
randomization.   
If HRCT has been performed for clinical care in the 6 months prior to Screening and has been 
reviewed and deemed acceptable per central reader, then HRCT need not be performed at 
Screening. 
9.5.1.6 Patient-reported Outcome Assessments 
Health outcomes assessments are recommended to be administered at the beginning of the visit 
prior to collection of blood for analysis and other scheduled assessments.  
A copy of each assessment is provided in the Appendix (Section 17). 
9.5.1.6.1 Living with IPF 
The L-IPF is a validated questionnaire that assesses symptoms, disease impacts and 
health-related quality of life in subjects with IPF [Swigris et al., 2020].  This questionnaire was 
developed with input from the FDA and comprises 2 modules:  a 15-item symptom module with 
3 domains (dyspnea, cough, and energy), all with a 24-hour recall, and a 20-item impacts module 

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with 1-week recall.  All items in both modules have response options in a 5-point (0-4) 
numerical rating scale format.   
9.5.1.6.2 King's Brief Interstitial Lung Disease Questionnaire 
The K-BILD is a self-completed health status questionnaire comprising 15 items and a 7-point 
Likert response scale that was developed and validated specifically for patients with IPF 
[Patel et al., 2012].  This questionnaire has 3 domains:  psychological, breathlessness and 
activities and chest symptoms.  The K-BILD domains and total score range from 0 to 100; 100 
represents best health status.  The K-BILD scoring has recently changed with the introduction of 
a logit transformation step.  The minimal clinically important difference for the K-BILD total 
score (logit version), as determined by both anchor and distribution-based methods, is a change 
of 5 units [Sinha et al., 2019].  
9.5.1.6.3 Leicester Cough Questionnaire 
The LCQ is a patient-reported questionnaire evaluating the impact of cough on quality of life.  
This questionnaire was originally developed for use in people with idiopathic chronic cough and 
has since been validated for use in people with bronchiectasis and chronic obstructive pulmonary 
disease [Birring et al., 2003]. 
The LCQ comprises 19 items and takes 5 to 10 minutes to complete.  Each item assesses 
symptoms or the impact of symptoms over the last 2 weeks on a 7-point Likert scale.  Scores in 
3 domains (physical, psychological, and social) are calculated as a mean for each domain (range:  
1 to 7).  A total score (range:  3 to 21) is also calculated by summing the domain scores.  Higher 
scores indicate better quality of life. 
9.5.1.6.4 SF-12 Health Survey 
The SF-12 [Ware et al., 1996] is a 12-item survey used to assess general health-related quality of 
life.  The SF-12 items are scored to generate a physical component score and mental component 
score (from the subject’s perspective.  The SF-12 examines 8 domains of health outcomes, 
including physical functioning, role-physical, bodily pain, general health, vitality, social 
functioning, role-emotional, and mental health.  The SF-12 is a shorter version of the SF-36, 
which has accepted validity for use in subjects with IPF [Swigris et al., 2010; 
Tomioka et al., 2007] and is 1 of 4 questionnaires used in the IPF Prospective Outcomes, an 
ongoing observational US registry of patients with confirmed IPF that records patient-reported 
outcomes. 
9.5.2 Pharmacokinetic Measurements 
Blood samples will be collected from all subjects to evaluate the PK of fipaxalparant (HZN-825) 
at the time points shown in Table 9.2.  For visits with post-dose PK samples, the morning dose 
regimen will be taken in the clinic.  Note that all pre-dose samples will be collected prior to any 
trial drug administration during the clinic visit.  For subjects not entering the 52-week Extension 
Phase, a sample will be collected anytime during the Week 52 Visit.  PK sample collection time 

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and the most recent dosing time prior to PK sample collection will be recorded for all PK 
samples.   
If the clinic visit is in the morning, on days when a pre-dose PK sample will be collected, 
subjects will be instructed to withhold taking trial drug before the visit, and drug and a meal will 
be administered in the clinic after the pre-dose PK samples are taken.  Time of drug 
administration in the clinic as well as the most recent dosing time prior to the visit will be 
recorded; 1 additional PK sample will be collected 2 to 4 hours after dosing in the clinic during 
the Week 16, Week 28, and Week 56 Visits. 
If the clinic visit is in the afternoon, on days when a pre-dose PK sample will be collected, 
subjects will be instructed to take trial drug before 8 a.m. with a meal and record dosing time; 
1 PK sample will be collected anytime during the clinic.  For the Week 16, Week 28, and 
Week 56 Visits, subjects will receive the evening dose during the visit (dosing time to be 
recorded) if it is at least 8 hours from the morning dosing.  An additional PK sample will be 
collected 2 to 4 hours post-dose; otherwise, subjects will be instructed to take the evening dose at 
regular dosing time and no post-dose PK sample will be collected. 
Instructions for collection, processing, handling, storing and shipping of PK samples will be 
detailed in a laboratory manual that will be provided to each site prior to site initiation.  
Table 9.2 
Schedule of Pharmacokinetic Sample Collection 
Time point 
Pre-dose 
2 to 4 Hours Post-dose 
Anytime During Visit 
Core Phase 
Day 1 
 
X 
Week 4 
X 
 
 
Week 10 
 
 
X 
Weeks 16 and 28 
X 
X 
 
Weeks 40 and 52 
X 
 
 
Extension Phase 
Day 1 (Week 52 of Core Phase) 
X 
 
 
Week 56 
X 
X 
 
Week 68 
X 
 
 
Week 80 
X 
 
 
Week 92 
X 
 
 
9.5.3 Pharmacogenetic Assessments 
An optional blood sample will be collected from all subjects providing consent and may be 
analyzed to explore the impact of polymorphisms in genes encoding drug metabolizing enzymes 
and/or transporters (e.g., cytochrome P450 CYP2C9, CYP2D6, solute carrier organic anion 

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transporter family member [SLCO] 1B1 and SLCO1B3) on fipaxalparant (HZN-825) PK.  These 
samples will be stored no longer than 5 years. 
Instructions for collection, processing, handling, storing and shipping of samples will be detailed 
in a laboratory manual that will be provided to each site prior to site initiation. 
9.5.4 Pharmacodynamic Assessments 
Blood samples will be taken during the trial to evaluate the pharmacodynamic effect of 
fipaxalparant (HZN-825).  Serum samples will be taken at the following visits:  Day 1 (pre-
dose), Week 16 (pre-dose), Week 28 (pre-dose), Week 52 (pre-dose), Week 80 (pre-dose) and 
Week 104 (pre-dose).  Samples will be stored frozen for potential analysis of biomarkers of the 
LPAR1 pathway or IPF disease.  All samples will be destroyed after potential biomarkers have 
been tested or 5 years after the trial is complete, whichever comes first. 
A blood sample will be taken at Day 1 (pre-dose), Week 28 (pre-dose), Week 52 (pre-dose), 
Week 80 (pre-dose) and Week 104 (pre-dose) for gene expression profiling of peripheral blood 
mononuclear cells as it relates to disease biology.  Instructions for collection, processing, 
handling, storing and shipping of samples will be detailed in a laboratory manual that will be 
provided to each site prior to site initiation. 
9.5.5 Safety Variables 
Safety will be assessed via AEs, concomitant medication use, physical examinations, vital signs, 
orthostatic hypotension assessment, laboratory evaluations, 12-lead ECG, and echocardiogram. 
9.5.5.1 Adverse Events 
9.5.5.1.1 Definitions 
9.5.5.1.1.1 Adverse Event Definition 
According to ICH, an AE is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 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 (investigational) product, whether or not considered 
related to the medicinal (investigational) product.  
A suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE.  Reasonable possibility means there is evidence to suggest a causal 
relationship between the drug and the AE. 
Exacerbation of a chronic or intermittent pre-existing condition that worsens in intensity or 
increases in frequency during a trial is to be reported as an AE.   
Unchanged, chronic conditions are NOT considered AEs and should not be recorded on the AE 
pages of the eCRF unless there is a clear exacerbation of a chronic condition.  

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Disease progression can be considered as a worsening of a subject’s condition attributable to the 
disease for which the trial drug is being studied (i.e., IPF).  It may be an increase in the severity 
of the disease under study and/or increases in the symptoms of the disease.  Events that are 
unequivocally due to disease progression should only be reported as AEs if they fulfill any of the 
SAE criteria or are the reason for discontinuation of trial drug. 
9.5.5.1.1.2 Serious Adverse Event Definition 
A TEAE, baseline event or suspected adverse reaction is considered serious if, in the view of 
either the Investigator or Sponsor, it results in any of the following: 
 Death.  This includes any death that occurs during the conduct of a clinical trial, 
including deaths that appear to be completely unrelated to the trial drug (e.g., car 
accidents). 
 Life-threatening adverse experience.  An AE or suspected adverse reaction is considered 
life-threatening if, in the view of either the Investigator or the Sponsor, its occurrence 
places the subject at immediate risk of death.  It does not include an AE or suspected 
adverse reaction that, had it occurred in a more severe form, might have caused death. 
 Persistent or significant disability or incapacity. 
 Inpatient hospitalization or prolongation of an existing hospitalization. 
 Congenital anomaly or birth defect. 
 Other medically important event that, according to appropriate medical judgment, may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Surgical procedures or other therapeutic interventions themselves are not AEs, but the condition 
for which the surgery/intervention is required is an AE and should be documented accordingly.  
Elective surgeries that require hospitalization and treatment received at an emergency room or 
similar facility will not be considered as SAEs unless one of the definitions of an SAE listed 
above is met. 
In addition, hospitalizations for planned procedures are not considered an AE, unless they are 
prolonged hospitalizations and emergency room visits <24 hours in duration are not considered 
hospitalizations. 
9.5.5.1.1.3 Non-serious Adverse Event Definition 
A non-serious AE includes any AE that is not described in the previous SAE category. 
9.5.5.1.1.4 Adverse Events of Special Interest 
An AESI is an AE (serious or non-serious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and rapid communication by the 
Investigator to the Sponsor may be appropriate.  Such events may require further investigation in 

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order to characterize and understand them.  AESIs may be added or removed during a trial by 
protocol amendment. 
The following AESI is identified for this trial: 
 
Orthostatic hypotension:  The Sponsor will consider an event of orthostatic hypotension 
if the following definition is met:  a reduction of systolic BP by ≥20 mmHg or reduction 
of diastolic BP by ≥10 mmHg and associated with symptoms such as lightheadedness, 
blurred vision, weakness, fatigue, cognitive impairment, nausea, palpitations, 
tremulousness, headache, presyncope or syncope.  
The symptoms i.e., lightheadedness, blurred vision, weakness, fatigue, cognitive 
impairment, nausea, palpitations, tremulousness, headache, presyncope, or syncope are 
reported by the patient throughout the orthostatic hypotension assessment, without the BP 
reductions (reduction of systolic BP ≥ 20 mmHg or diastolic BP ≥10 mmHg), then these 
symptoms will be recorded as AE. 
Please note that the above-mentioned reported symptoms during orthostatic hypotension 
assessment should only be reported as adverse events separately if they meet any of the below 
criteria:  
 The symptoms are severe and/or require medical interventions 
 The symptoms were triggered by the orthostatic hypotension assessment maneuver and 
persisted for a significantly longer duration beyond the orthostatic hypotension 
assessment period 
 The symptoms are assessed not due to the maneuver of orthostatic hypotension 
assessment 
If these symptoms are reported in combination with the BP reductions, i.e., reduction of systolic 
BP ≥20 mmHg or diastolic BP ≥10 mmHg, these symptoms will be considered part of the 
orthostatic hypotension event and will not be reported separately. 
Orthostatic hypotension assessment procedure will be performed during the Core Phase (as 
outlined in Section 2.1 on Day 1 and at Weeks 4, 28, and 52/premature discontinuation) and the 
Extension Phase (as outlined in Section 2.2 on Day 1 [Week 52 of Core Phase] and at Weeks 56, 
80 and 104/premature discontinuation), as is detailed in the Orthostatic Hypotension Assessment 
Manual in Section 17.9. 
If symptoms are reported by the subject throughout the assessment, without the BP reductions 
noted above, then the symptoms will be recorded separately as AEs and orthostatic hypotension 
will not be recorded.  
Signs and symptoms associated with orthostatic hypotension reported outside of the assessment 
will be captured as part of spontaneously reported AEs at each visit.  

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Depending on the timing, nature and severity of these spontaneous AEs, additional investigations 
will be conducted at the next scheduled visit or at an unscheduled visit, as clinically indicated per 
the Investigator’s judgment.  Whenever possible, the following data should be collected:  
concomitant medications, and BP and heart rate measurements in supine and standing positions.  
Depending on the severity, plasma glucose level and ECG should be obtained per Investigator’s 
clinical judgment. 
9.5.5.1.2 Documentation of Adverse Events 
Any AEs that occur after signing the ICF and prior to dosing on Day 1 will be considered 
medical history.  The TEAE reporting period begins with administration of the first dose of trial 
drug on Day 1 and continues until 4 weeks after the last dose of trial drug or premature 
discontinuation.  All medical history, TEAEs and AEs must be recorded in the source documents 
and on the subject’s eCRF.  All AEs and SAEs with onset after signing of informed consent 
through 4 weeks after the last dose of trial drug will be recorded.  If a subject discontinues due to 
an SAE, that subject will be followed as per Section 9.5.5.1.5. 
If the Investigator observes an SAE after trial completion that he/she believes was possibly 
caused by trial drug, the Investigator will report this SAE using the procedures described in 
Section 9.5.5.1.5.  The Investigator is responsible for collecting and documenting the outcome of 
AEs/SAEs. 
If specifically requested, the investigator may need to provide additional follow‑up information, 
such as discharge summaries, medical records, or extracts from the medical records.  In this case, 
all subject identifiers, except for the subject number, will be blinded on the copies of the medical 
records before submission to the Sponsor. 
Detailed information regarding all SAEs must also be recorded on the SAE Reporting Form.  
Whenever clinically appropriate, the Investigator should group together into a single term the 
signs and symptoms that constitute a single diagnosis.  For example, cough, rhinitis and sneezing 
might be grouped together as “upper respiratory infection” if the Investigator is confident of the 
diagnosis. 
9.5.5.1.3 Intensity or Severity of Adverse Events 
All AEs, both serious and non-serious, will be assessed for severity using the Rheumatology 
Common Toxicity Criteria v2.0 [Woodworth et al., 2007].  The scale displays Grades 1 through 
4 with unique clinical descriptions of severity for each AE (including abnormal laboratory 
values) based on this general guideline.  
 Grade 1 (mild) – asymptomatic or transient, short duration (<1 week), no change in 
lifestyle, no medication or over-the-counter drugs 
 Grade 2 (moderate) – symptomatic, duration 1 to 2 weeks, alter lifestyle occasionally, 
medications give relief (may be prescription), trial drug continued 

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 Grade 3 (severe) – prolonged symptoms, reversible, major functional impairment, 
prescription medications/partial relief, hospitalized <24 hours, temporary trial drug 
discontinuation or/and dose reduced 
 Grade 4 (includes life-threatening) – at risk of death, substantial disability, especially if 
permanent, hospitalized >24 hours, permanent trial drug discontinuation 
9.5.5.1.4 Relationship or Causality to Trial Drug 
The investigator is obligated to assess the relationship between investigational product(s) and 
each occurrence of each AE and SAE. 
Relatedness means that there are facts or reasons to support a relationship between 
investigational product and the event. 
The investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study treatment administration will be 
considered and investigated. 
The investigator will also consult the Investigator’s Brochure and/or product information, for 
marketed products, in their assessment. 
For each AE/SAE, the investigator must document in the medical notes that they have reviewed 
the AE/SAE and has provided an assessment of causality. 
There may be situations in which a SAE has occurred and the investigator has minimal 
information to include in the initial report.  However, it is very important that the investigator 
always assess causality for every event before the initial transmission of the SAE data. 
The investigator may change their opinion of causality in light of follow-up information and send 
a SAE follow-up report with the updated causality assessment. 
The relationship of the trial drug to each AE will be determined by the Investigator and the 
Sponsor based on the following definitions: 
 Not related:  There is no plausible temporal relationship or there is another explanation 
that unequivocally provides a more plausible explanation for the event. 
 Related:  There is evidence in favor of a causal relationship (i.e., there is a plausible time 
course) and at least one of the following criteria apply: 
▪ There is a reasonable pharmacological relationship (or known class effect). 
▪ There is no other more plausible explanation. 

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▪ There is a positive de-challenge (without active treatment of the event). 
▪ There is a positive re-challenge. 
▪ There is a distinguishable dose effect. 
9.5.5.1.5 Reporting and Documenting Serious Adverse Events 
All SAEs beginning with the time of signing of the ICF and continuing through 4 weeks after the 
last dose of trial drug must be reported.  The following steps will be taken to report promptly and 
document accurately any SAE, whether or not it appears to be related to trial drug:   
1. Report the SAE to the Sponsor by entering the information into the eCRF 
immediately and not later than 24 hours after becoming aware that a subject has 
experienced an SAE.  If unable to access the eCRF, the event must be reported by 
submitting the completed SAE Reporting form immediately and not later than 
24 hours after becoming aware that a subject has experienced an SAE (see 
Section 17.1 for contact information).  
After the study is completed at a given site, the electronic data capture (EDC) system 
will be taken off-line to prevent the entry of new data or changes to existing data.  
If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the EDC system has been taken off-line, then the 
site can report this information on the paper-based SAE Reporting Form. 
2. Perform appropriate diagnostic tests and therapeutic measures and submit all 
follow-up substantiating data, such as diagnostic test reports, hospital discharge 
summaries and autopsy report to the Sponsor’s representative. 
3. Conduct appropriate consultation and follow-up evaluation until the SAE outcome is 
known or the SAE is resolved.  Outcomes for reported AEs/SAEs/AESIs are to be 
defined as follows: 
 Recovering/Resolving  
 Recovered/Resolved  
 Not Recovered/Not Resolved  
 Recovered/Resolved with sequelae  
 Fatal  
 Unknown 
4. All new information for previously reported SAEs must be sent to the Sponsor 
immediately and no later than 24 hours after Investigator’s awareness of the new 
information.  If specifically requested, the investigator may need to provide additional 
follow-up information, such as discharge summaries, medical records, or extracts 

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from the medical records.  Information provided about the SAE must be consistent 
with that recorded on the Adverse Events eCRF. 
There is no requirement to actively monitor study subjects after the study has ended 
with regards to study subjects treated by the investigator.  However, if the 
investigator becomes aware of SAEs suspected to be related to investigational 
product, then these SAEs will be reported to the Sponsor immediately and no later 
than 24 hours after the investigator’s awareness of the event. SAEs reported after the 
end of the study will be captured within the safety database as clinical study cases and 
handled accordingly based on relationship to investigational product.  
If further safety-related data is needed to fulfill any regulatory reporting requirements 
for a reportable event, then additional information may need to be collected from the 
subject’s records after the subject ends the study. 
Review each SAE report and evaluate the relationship of the SAE to trial treatment. 
9.5.5.1.5.1 Monitoring of Serious Adverse Events Anticipated in the Trial Population 
SAEs are anticipated to occur in the trial population independent of the subject’s exposure to 
trial drug.  These anticipated SAEs are provided in Section 17.8 (Serious Adverse Events 
Anticipated in the Trial Population) for reference.  The list does NOT change the Investigator’s 
reporting obligations or prevent the need to report an AE meeting the definition of an SAE, as 
detailed above.  The purpose of this list is to alert the Investigator that some events reported as 
SAEs that are anticipated to occur in the trial population due to underlying disease, may not 
require expedited reporting to the regulatory authorities in every country/region.  The Sponsor 
will monitor these events throughout the course of the trial for any change in frequency. 
9.5.5.1.6 Follow-up of Adverse Events 
The Investigator is obligated to follow up any reported AE, SAE, or AESI until all relevant 
clinical data are known to allow for an outcome or the event is resolved, in addition to 
confirming the causality assessment.  Any ongoing trial drug-related AE present at the time of 
trial termination, including a clinically significant laboratory test abnormality, will be followed 
until the event is resolved or until the event stabilizes and the overall clinical outcome has been 
ascertained.  
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to elucidate 
the nature and/or causality of the AE or SAE as fully as possible.  This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other 
healthcare professionals. 
If a subject is permanently withdrawn from investigational product(s) and/or noninvestigational 
product(s)/auxiliary medicinal product(s) because of a SAE, this information must be submitted 
to Sponsor. 

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The investigator will submit any updated SAE data to Sponsor immediately and no later than 
24 hours of receipt of the information. 
9.5.5.1.7 Medication Errors 
A medication error is any unintended failure in the drug treatment process, such as a mistake in 
the prescribing, dispensing, storing, preparation or administration of a medicine that leads to, or 
has the potential to lead to harm to the subject.   
An overdose is defined as a known deliberate or accidental administration of investigational drug 
to a subject.  For this trial, any dose of fipaxalparant (HZN-825) that is more than the dose that 
has been assigned will be considered an overdose.   
An AE or SAE that is associated with a medication error, such as an overdose, is to be reported 
according to the procedures outlined in Sections 9.5.5.1.2 and 9.5.5.1.5, respectively.  All 
medication errors or overdoses, with or without an AE or SAE, should be recorded as a protocol 
deviation and reported to the trial Medical Monitor in a timely manner.  AEs or SAEs may not 
occur immediately after the medication error or overdose.  
There is no clinical experience with overdose with fipaxalparant (HZN-825).  No specific 
antidote or detoxification measures can be recommended to date.  If accidental overdose is 
suspected, the subject should be treated symptomatically.   
9.5.5.1.8 Review of Adverse Events and Emerging New Safety Information 
The Sponsor will perform an ongoing review of all AEs and all other emerging new information 
relevant to the safety of the drug, including periodic review and analyses of cumulative safety 
data for the trial. 
9.5.5.1.9 Reporting of Investigational New Drug Safety Reports 
The Sponsor will report SAEs associated with fipaxalparant (HZN-825) to the appropriate 
regulatory authorities and all Investigators in accordance with the local and regional regulatory 
authorities laws and regulations. 
9.5.5.1.10  Development Safety Update Reports 
The Sponsor will prepare and submit annual safety reports to the FDA.  Drug safety update 
reports will also be submitted to countries and territories as required. 
The Sponsor will prepare a single Development Safety Update Report (DSUR) (also referred to 
as Annual Safety Report in the European Union [EU]) for the Sponsor investigational product.  
To ensure that consolidated safety information for the study is provided, this single DSUR will 
also include appropriate information on any other investigational products used in the clinical 
study, if applicable. 

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9.5.5.1.11 Regulatory Reporting Requirements for Safety Information 
If subject is permanently withdrawn from investigational product(s), and/or noninvestigational 
product(s)/auxiliary medicinal product(s) because of a SAE, this information must be submitted 
to the Sponsor. 
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a study 
treatment under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation.  The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the external review body and investigators. 
Individual safety reports for suspected unexpected serious adverse reactions will be reported by 
the Sponsor according to local regulatory requirements (e.g., electronic submission to the 
Eudravigilance database in the EU as per EU Clinical Trial Regulation 536/2014) as well as 
Sponsor policy and forwarded to investigators as necessary. 
An investigator who receives an individual safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will file it along with the 
Investigator’s Brochure and will notify the external review body, if appropriate according to 
local requirements. 
For studies in which the treatment assignment is blinded, to comply with worldwide reporting 
regulations for SAEs, the treatment assignment of subjects who develop serious, unexpected, and 
related AEs may be unblinded by the Sponsor before submission to regulatory authorities.  
Aggregate analyses may also be unblinded by the Safety Assessment Team, as appropriate.  
Investigators will receive notification of related SAEs reports sent to regulatory authorities in 
accordance with local requirements. 
9.5.5.1.12 Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in the Sponsor’s safety surveillance and 
signal management processes. 
9.5.5.2 Pregnancy and Lactation Reporting 
Pregnancy testing will be performed for WOCBP.  Serum pregnancy tests will be analyzed at a 
central trial laboratory and the urine pregnancy tests will be performed locally.  In addition, 
at-home pregnancy tests will be completed by WOCBP at Weeks 8, 12, 20, 24, 32, 36, 44, and 
48 during the Core Phase and at Weeks 60, 64, 72, 76, 84, 88, 96 and 100 during the Extension 
Phase, and results will be reported to the site. 

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If a female subject becomes pregnant during the Double-blind Treatment Period, she should 
immediately notify the Investigator and trial drug dosing should be permanently discontinued but 
the subject will be asked to continue in the trial for evaluations.  
Pregnancy occurring in the partner of a male subject participating in the trial should be reported 
to the Investigator and the Sponsor immediately upon awareness of pregnancy.  Monitoring of 
the subject’s partner should continue until conclusion of the pregnancy.  
Subjects should be instructed to continue contraception for 4 weeks after their last dose of trial 
drug.  Pregnancies occurring up to 4 weeks after the last dose of trial drug must also be reported 
to the Investigator. 
Some examples of highly effective contraceptive methods that have a failure rate of <1% per 
year when used consistently and correctly are: 
 Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation  
o Oral  
o Intravaginal 
o Transdermal 
 Progestogen-only hormonal contraception associated with inhibition of ovulation 
o Oral  
o Injectable 
o Implantable 
 Intrauterine device  
 Intrauterine hormone-releasing system  
 Bilateral tubal ligation 
 Vasectomized partner 
 Sexual abstinence from heterosexual intercourse 
There are no expected drug interactions between fipaxalparant (HZN-825) and hormonal 
contraceptives. 
Abstinence should only be used as a contraceptive method if it is in line with the subject’s usual 
and preferred lifestyle.  Periodic abstinence (calendar, symptothermal, postovulation methods) is 
not an acceptable method of contraception. 
Details of all pregnancies and/or lactation in female subjects and pregnancies in female partners 
of male subjects will be collected after the start of study treatment and until 4 weeks after last 
dose of trial drug. 
If a pregnancy is reported, the investigator is to inform the Sponsor immediately and no later 
than 24 hours of learning of the pregnancy and/or lactation.  The Investigator should report 
pregnancies to the Sponsor by submitting the completed Pregnancy Report Form immediately 

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and not later than 24 hours after becoming aware that the subject/subject’s female partner has 
become pregnant (see Section 17.1 for contact information).  The Investigator should counsel the 
subject and discuss the possible risks of continuing the pregnancy.  If pregnancy continues and 
the subject signs the pregnancy consent form, monitoring should also continue to the conclusion 
of the pregnancy and the outcome of the pregnancy should be reported to the Sponsor. 
Lactation information will be recorded on the Lactation Notification Form and submitted to 
Sponsor Global Patient Safety immediately and no later than 24 hours of the investigator’s 
awareness of the event. 
9.5.5.3 Medical History 
Medical history, including IPF history and treatment and substance use history, will be recorded.   
9.5.5.4 Vital Signs, Weight and Height 
BP and pulse measurements will be obtained with the subject’s arm unconstrained by clothing or 
other material and while the subject is sitting up.  When possible, the same arm will be used for 
measurements for all trial visits.  
Weight and height measurements will be obtained.  To limit the potential for variability in 
weight collection, the subject should wear lightweight clothing and no shoes during weighing.   
9.5.5.5 Orthostatic Hypotension Assessment 
Due to a potential role of LPA in vascular tone (Section 7.1.2), orthostatic hypotension will be 
assessed at the time points indicated in Section 2.1 and Section 2.2. 
BP and heart rate will be measured after the subject has rested ≥5 minutes in the supine position 
and after 1 minute and 3 minutes in the standing position, as per the Orthostatic Hypotension 
Assessment Manual provided by the Sponsor.  See Section 9.5.5.1.1.4 for more information on 
orthostatic hypotension assessment. 
A copy of the Orthostatic Hypotension Assessment Manual is provided in Section 17.9. 
9.5.5.6 Physical Examination 
A complete physical examination, including but not limited to, cardiac, pulmonary and 
neurologic assessments, will be performed per the Schedules of Assessments (Section 2.1 and 
Section 2.2).  
9.5.5.7 Electrocardiogram 
ECG results will be recorded as normal or abnormal on the eCRF and all abnormal results will 
be evaluated by the Investigator as clinically significant or not clinically significant.  Any 
clinically significant abnormal ECG, including a QT interval corrected for heart rate >450 ms, 
should be confirmed by a repeat resting ECG at the same visit.  The site personnel should ensure 
that ECGs are collected after the subject is supine for at least 10 minutes.   
A copy of the ECG tracing will remain with the source documents 

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9.5.5.8 Echocardiogram 
A standard transthoracic echocardiogram will be conducted according to the Schedules of 
Assessments (Section 2.1 and Section 2.2).  Echocardiogram results will be recorded on the 
eCRF as normal or abnormal and all abnormal results will be evaluated by the Investigator as 
clinically significant or not clinically significant.  A copy of the echocardiogram results will 
remain with the source documents. 
9.5.5.9 Laboratory Tests for Evaluation 
A central trial laboratory will be used for all protocol-specified laboratory evaluations, with the 
exception of urine pregnancy tests that will be performed locally at each site or at-home, as 
applicable, in order to maintain monthly pregnancy testing. 
Chemistry parameters to be evaluated include total protein, albumin, sodium, phosphate, 
potassium, calcium, chloride, bicarbonate, blood urea nitrogen, creatinine, creatine kinase, uric 
acid, glucose, lactate dehydrogenase; liver function tests (ALT, AST, gamma 
glutamyltransferase, alkaline phosphatase, total bile acid, total bilirubin, conjugated, and 
unconjugated bilirubin, if applicable).   
Fasting glucose and fasting lipid profile (total cholesterol, high-density lipoprotein cholesterol, 
low-density lipoprotein cholesterol, triglycerides) will also be evaluated (see Sections 2.1 and 
2.2).   
Hematology parameters to be evaluated include hemoglobin, hematocrit, red blood cell count 
(with morphology if blood cell count is abnormal), mean corpuscular volume (MCV), mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, red blood cell distribution 
width, reticulocyte count, white blood cell count with differential (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes) and platelet count.   
Urinalysis parameters to be evaluated include macroscopic panel (i.e., appearance, bilirubin, 
blood, color, glucose, ketones, leukocyte esterase, nitrites, pH, protein, specific gravity and 
urobilinogen) and microscopic panel (i.e., amorphous crystals, bacteria, calcium carbonate 
crystals, calcium oxalate crystals, calcium phosphate crystals, cysteine crystals, granular casts, 
hyaline casts, leucine crystals, mucus, red blood cells, renal epithelial cells, squamous epithelial 
cells, transitional epithelial cells, triple phosphate crystals, tyrosine crystals, uric acid crystals, 
waxy casts, white blood cells, white blood cell casts and yeast). 
Samples for clinical inflammatory laboratory evaluation of high-sensitivity C-reactive protein 
will also be collected.  
The total blood volume for planned visits through the final safety follow-up visit in the Core 
Phase is approximately 305 mL.  Extension Phase, repeat or unscheduled blood tests performed 
in individual subjects may add to the total blood volume.  Instructions for the collection, 
handling and analysis of clinical laboratory samples will be provided to the site prior to trial site 
initiation. 

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9.5.6 Appropriateness of Measurements 
All safety and efficacy variables, as well as the methods to measure them, are standard 
variables/methods in clinical trials and/or clinical practice and are widely used and generally 
recognized as reliable, accurate and relevant. 
The L-IPF [Swigris et al., 2020], K-BILD [Patel et al., 2012], LCQ [Birring et al., 2003] and 
SF-12 [Swigris et al., 2010; Tomioka et al., 2007] have been validated for use in subjects with 
IPF. 
9.5.7 Trial Procedures 
Trial procedures and timing are detailed in the Schedules of Assessments (Section 2.1 and 
Section 2.2).   
Visits at Weeks 22, 34 and 46 during the Core Phase and at Weeks 74, 86, and 98 during the 
Extension Phase may be completed at an alternative remote location, e.g., a subject’s home, by a 
visiting home healthcare professional and will be based on local availability and as allowable 
based on local laws and regulations.  Remote locations will be discussed during the consent 
process per subject’s preference and as approved by the Investigator.  Site Investigators will have 
direct awareness and oversight of remote subject visits.   
The end of the trial is defined as the date of the last visit of the last subject undergoing the trial. 
9.5.8 Effect of a Pandemic on Trial Procedures 
In rare situations due directly to COVID-19 where trial subjects cannot attend scheduled clinic 
visits, the following modifications may be considered:   
 For efficacy assessments, a home visit or a subject-collected FVC may be used.  For 
patient-reported outcomes or other questionnaires, a telephone visit, virtual visit or home 
visit may be used to collect information.  
 For safety assessments, a local laboratory or a home visit may be used to collect 
laboratory-related assessments to monitor safety and results will be communicated to the 
Medical Monitor.  A telephone visit, virtual visit or home visit may be used to collect 
information on AEs and drug compliance.  Investigators may also consider shipping trial 
drug to a subject’s home via appropriate courier, if necessary.   
 If data are captured in an irregular manner (e.g., patient-reported outcomes via telephone 
or FVC in-home) this should be captured via source documentation.  If possible, these 
protocol modifications should be discussed with the Sponsor and contract research 
organization prior to implementation, but deviations to immediately address subject 
safety are possible per the Investigator’s discretion. 

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9.6 
Statistical Methods and Determination of Sample Size  
9.6.1 Core Phase 
9.6.1.1 Endpoints 
9.6.1.1.1 Primary Efficacy Endpoint 
The primary endpoint is the change in FVC % predicted from Baseline to Week 52. 
9.6.1.1.2 Key Secondary Efficacy Endpoint 
Proportion of subjects with decline in FVC % predicted ≥10% from Baseline at Week 52. 
9.6.1.1.3 Other Secondary Efficacy Endpoints  
1. Change from Baseline in the 6MWT results to Week 52. 
2. Change from Baseline in K-BILD scores to Week 52.  
3. Change from Baseline in L-IPF scores to Week 52.  
4. Change from Baseline in LCQ scores to Week 52. 
5. Time to first hospitalization due to respiratory distress from Baseline up to Week 52. 
6. Time to first onset of the composite endpoint of PFS from Baseline up to Week 52, where 
progression includes decline in FVC % predicted ≥10% or death. 
9.6.1.1.4 Exploratory Endpoints  
1. 
2. 
3. 
4. 
5. 
6. Time to death due to respiratory deterioration from Baseline up to Week 52. 
7. 
8. 

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9.6.1.1.5 Safety and Tolerability Endpoints 
1. Incidence of TEAEs, SAEs and the AESI (orthostatic hypotension). 
2. Concomitant medication use. 
3. Vital signs.  
4. 12-lead ECGs and echocardiograms. 
5. Laboratory evaluations.  
9.6.1.1.6 Pharmacokinetic Endpoint 
1. Pre- and post-dose concentrations of fipaxalparant (HZN-825). 
9.6.1.2 Analysis Sets 
Three analysis sets will be defined for the Core Phase of the trial.  The full analysis set (FAS) 
will include all subjects who are randomized to treatment and take at least 1 dose of trial drug.  
This will be the analysis set used for efficacy data analyses and subjects will be analyzed 
according to the treatment to which they were randomized.  The safety analysis set will include 
all subjects who receive at least 1 dose or partial dose of trial drug.  The PK analysis set will 
include all subjects who receive at least 1 dose or partial dose of fipaxalparant (HZN-825) and 
have at least 1 PK sample post fipaxalparant (HZN-825) treatment.  
9.6.1.3 Primary Efficacy Endpoint Analysis 
The estimand for the primary efficacy analyses will be constructed to compare the primary 
endpoint between each dose regimen of fipaxalparant (HZN-825) and placebo using the 
treatment policy strategy approach to intercurrent events.  All subjects who are randomized and 
take at least 1 dose of trial drug will be included in the primary efficacy analyses (FAS).   
The primary efficacy endpoint will be change from Baseline in FVC % predicted to Week 52.  A 
mixed model for repeated measures (MMRM) analysis of covariance model will be fit to the data 
using observed change in FVC % predicted values from all planned post-Baseline assessments 
(i.e., Weeks 4, 16, 28, 40, and 52) with covariates of stratification factors (concomitant use of 
IPF therapy [yes, no] and FVC % predicted at Baseline [≥70%, <70%]), treatment group, visit 
and visit-by-treatment group interaction.  The unstructured variance-covariance matrix will be 
used in the model.  Treatment group least squares means, associated standard error (SE) and their 
differences (each fipaxalparant [HZN-825] group minus placebo separately), SE of the 
difference, 90% CIs and p-value overall and for each visit will be provided.  
For subjects with missing data at 1 or more time points, the available data will be included in the 
analysis.   
As a supplemental analysis to assess the robustness of the efficacy analysis results, the effect of 
each dose regimen of fipaxalparant (HZN-825) will be compared to placebo using the following 
measurements and methods: 

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 Change in FVC (in mL) from Baseline to Week 52 using a similar MMRM analysis 
method as described for the primary efficacy endpoint 
 Cumulative response curve comparison using the Kolmogorov-Smirnov test on: 
o The range of improvement (≥0% to ≥15% with a 5% increment) and worsening 
(< -15% to <0% with a 5% increment) based on the change in FVC % predicted 
value from Baseline at Week 52 
o The range cut-off values from less than -300 mL to greater 100 mL with a 
100-mL increment based on the change in FVC (in mL) from Baseline at 
Week 52 
One sensitivity analysis will consider whether data missing not at random may change the 
conclusion.  A tipping point analysis will estimate the difference in true values among 
unobserved data that must occur to change the conclusion for each dose (i.e., change the result 
for each dose from p≤0.10 to p>0.10).   
Potential intercurrent events such as discontinuing from the treatment, early discontinuing from 
the trial, initiating rescue therapy, death, lung transplant or potentially COVID-19, may occur 
during the trial.  Intercurrent events will be addressed in the primary analysis by using treatment 
policy strategy with all available data.  Supplemental analyses will assess the use of rescue 
medication.  The proportion of subjects who qualify for and who receive rescue medication at 
each potential time point will be summarized for each treatment group to determine whether 
there are different use rates between treatment groups.  A supplemental analysis will repeat the 
primary analysis except that it will ignore all FVC data collected after the initiation of rescue 
medication; the result will be a sensitivity analysis that uses a hypothetical strategy approach to 
the intercurrent even of initiation of rescue medication.  A detailed plan for sensitivity/ 
supplemental analyses regarding potential intercurrent events including how to handle the data 
impacted by COVID19, will be provided in the statistical analysis plan. 
9.6.1.4 Secondary Efficacy Endpoint Analyses 
The key secondary endpoint will be the proportion of subjects with decline in FVC % predicted 
≥10% from Baseline at Week 52 and will be analyzed using a logistic regression model with 
treatment group and stratified by factors used for stratifying the randomization.  The logistic 
model will provide odds ratio, its 90% CI and p-value for comparing each fipaxalparant 
(HZN-825) group with the placebo group.  Statistical significance for the key secondary endpoint 
will only be concluded if statistical significance is achieved for the primary efficacy endpoint. 
Changes from Baseline in 6MWT, K-BILD, L-IPF, and LCQ scores will be analyzed 
analogously to the primary efficacy endpoints.  Survival analysis will be used for the time-to-
event endpoints, including time to the first onset of the composite endpoint and the time to the 
first hospitalization due to respiratory distress.  A Cox proportional hazard model stratified like 
the previous logistic model with treatment group will provide hazard ratio, its 90% CI and 
p-value to compare each fipaxalparant (HZN-825) group with the placebo group. 

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9.6.1.5 Exploratory Endpoint Analyses 
Exploratory endpoints will be summarized at each time point.  The statistical methods for 
comparisons of each dose regimen of fipaxalparant (HZN-825) to placebo will be analogous to 
the methods for comparisons of primary and secondary efficacy endpoints.  Correlation analysis 
will be used to assess the relationship between the percent change from Baseline in FVC % 
predicted and the percent change from Baseline in lung fibrosis scores at Week 52.    
9.6.1.6 Safety and Tolerability Analyses 
All subjects who receive at least 1 dose or partial dose of trial drug will be included in safety and 
tolerability analyses.  Subjects who receive treatment other than that to which they were 
randomized will be included in summaries with the treatment received.  Subjects who receive 
more than 1 treatment will be listed separately and included in summaries with the treatment 
received most frequently. 
The number and percentage of subjects reporting at least 1 TEAE, SAE, AESI, and TEAE 
resulting in premature discontinuation of trial drug for each unique System Organ Class (SOC) 
and Preferred Term will be summarized.  AE rates (events per patient-year of follow-up during 
dosing) will also be summarized to account for the different treatment durations.  TEAEs and 
SAEs will also be summarized by severity and relationship to trial drug as assessed by the 
Investigator.  Grade 3 and above TEAEs will also be summarized for each unique SOC and 
Preferred Term.  Orthostatic hypotension is prospectively defined as an AESI and will be 
summarized separately. 
Summary statistics will be used for laboratory values, vital signs, ECG results, and use of 
concomitant medications.  
No inferential statistics are planned for any safety endpoint. 
9.6.1.7 Pharmacokinetic Analyses 
PK data will be analyzed using the PK analysis set.  Plasma concentrations of fipaxalparant 
(HZN-825) will be summarized descriptively, including arithmetic means, standard deviations, 
geometric means, coefficients of variation, medians, first and third quartiles and ranges by 
treatment group and by time point.  Population PK analysis may be performed.   
9.6.1.8 Interim Analysis 
An interim analysis of the primary efficacy endpoint will be conducted using unblinded data 
after 
  
This analysis will have 2 potential outcomes: 
 If neither dose regimen of fipaxalparant (HZN-825) shows better efficacy compared to 
placebo with an acceptable safety profile, the trial will be discontinued for futility. 
 If 1 or both dose regimens of fipaxalparant (HZN-825) show better efficacy compared to 
placebo with an acceptable safety profile, the trial will continue with no changes. 

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The futility analysis will not be used to make a positive determination of efficacy to stop the 
trial. 
Conditional power will be used to determine which of the options is chosen, with a conditional 
power of ≥10% required for at least 1 dose regimen to continue the trial.  Other statistics, such as 
Bayesian statistics, may also be used for the futility analysis and dose selection. 
To support the dose selection and as part of the Week 28 unblinded interim analysis, the FVC % 
predicted change from Baseline at Week 28 will be evaluated in subjects who were randomized 
with concomitant standard-of-care treatment at Baseline.  Approximately 60 subjects in the 
standard-of-care stratum with 28 weeks of data (approximately 20 subjects per arm) will be 
included.  The positive signal in the FVC % predicted change from Baseline at Week 28 and 
related results in standard-of-care subjects will support the dose selection and future trial design. 
Additionally, safety will be assessed, and an fipaxalparant (HZN-825) dose regimen that has an 
unacceptable safety profile will be discontinued and subjects assigned to that dose regimen 
would be assigned to the other dose regimen for the remainder of the trial, if the other dose 
regimen continues. 
At the interim analysis, the IDMC will provide recommendation to select Horizon personnel not 
involved in the oversight of the trial to facilitate trial continuation and dose selection for future 
trials.  To support decisions on future dose selection and future trial design, a Horizon unblinded 
team may be established and receive unblinded data and perform ad hoc analyses, as needed.  All 
unblinded data and analysis results made available to the Horizon unblinded team will be 
archived to allow for any potential post hoc assessments of bias.  For additional details, please 
refer to the IDMC charter and Blinding Maintenance Plan for this trial.  
9.6.1.9 Multiple Comparisons 
The overall statistical level is α=0.10 (2-sided).  Because 2 dose regimens of fipaxalparant 
(HZN-825) will be compared to placebo, a hierarchical testing procedure will be used for 
multiple comparisons.  Therefore, α=0.10 (2-sided) will be used in the final analysis.  The 
hierarchical testing procedure will be used for the primary and key secondary endpoint.  For the 
primary endpoint, the BID dose will be tested versus placebo first; if significant, the QD dose 
will then be tested.  If 1 or 2 dose regimens of the primary endpoint are not rejected after 
completing testing, no further testing will occur.  If both fipaxalparant (HZN-825) doses are 
statistically significantly better than placebo for primary efficacy endpoint, the testing procedure 
will continue for the key secondary endpoint and will be similar to that performed for the 
primary endpoint.   
Although p-values will be provided for the other secondary and exploratory endpoints, they will 
not be used for inferential purposes. 
9.6.2 Extension Phase 
9.6.2.1 Endpoints 
Two types of Baseline are defined for the Extension Phase: 

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 OLE Baseline, defined as the latest measurement prior to the first dose of fipaxalparant 
(HZN-825) in Extension Phase 
 Fipaxalparant (HZN-825) Baseline, defined as the latest measurement prior to the first 
dose of fipaxalparant (HZN-825) in either the Core Phase or the Extension Phase.  For 
subjects who received placebo in the Core Phase, OLE Baseline will be the same as 
fipaxalparant (HZN-825) Baseline. 
9.6.2.1.1 Primary Efficacy Endpoint 
The primary endpoint is the change from both Baselines in FVC % predicted at Week 104. 
9.6.2.1.2 Safety and Tolerability Endpoints 
 Incidence of TEAEs and the AESI (orthostatic hypotension) in the Extension Phase 
 Concomitant medication use in the Extension Phase 
 Change from Trial Baseline in vital signs in the Extension Phase 
 Change from Trial Baseline in 12-lead ECG measurements in the Extension Phase 
 Change from Trial Baseline in clinical safety laboratory test results in the Extension 
Phase 
9.6.2.1.3 Exploratory Endpoints  
 Change from both Baselines in proportion of subjects with decline in FVC % 
predicted ≥10% at Week 104 
 Change from both Baselines in the 6MWT results to Week 104 
 Change from both Baselines in K-BILD scores to Week 104 
 Change from both Baselines in L-IPF scores to Week 104 
 Change from both Baselines in LCQ scores to Week 104 
 
 
 Time to first hospitalization due to respiratory distress from fipaxalparant 
(HZN-825) Baseline up to Week 104 
 Time to first onset of the composite endpoint of PFS from fipaxalparant (HZN-825) 
Baseline up to Week 104, where progression includes decline in FVC % predicted 
≥10% from Baseline or death 
 
 
 
 
 
 
 

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 
 
 Time to death due to respiratory deterioration from fipaxalparant (HZN-825) Baseline up 
to Week 104 
 
 
9.6.2.1.4 Exploratory PK Endpoints 
 Pre- and post-dose concentrations of fipaxalparant (HZN-825) in the Extension Phase 
9.6.2.2 Analysis Sets 
Three analysis sets will be defined for the Extension Phase of the trial.   
 The FAS will include all subjects who entered and received at least 1 dose or partial dose 
of fipaxalparant (HZN-825) in the Extension Phase.  This will be the analysis set used for 
efficacy data analyses; subjects will be analyzed according to the treatment group to 
which they were randomized in the Core Phase and combined into an ‘overall’ group.   
 The safety analysis set will include all subjects who receive at least 1 dose or partial dose 
of fipaxalparant (HZN-825) in the Extension Phase.  Subjects in this analysis set will be 

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analyzed according to the group determined by the treatment the subject received in the 
Core Phase and combined into an ‘overall’ group. 
 The PK analysis set will include all subjects who received at least 1 dose or partial dose 
of fipaxalparant (HZN-825) and have at least 1 PK sample post fipaxalparant (HZN-825) 
treatment in the Extension Phase.  
9.6.2.3 Efficacy Endpoint Analysis 
All efficacy endpoints will be summarized for the FAS using descriptive statistics, presented by 
the treatment group subjects were randomly assigned to in the Core Phase and overall. 
A MMRM will be fit to the data for descriptive purposes using observed change in FVC % 
predicted values from all planned post-Trial OLE Baseline assessments (Weeks 68, 80, 92, and 
104).  A similar model that was used in the Core Phase may be used for the Extension Phase.  An 
unstructured covariance matrix will be used for the primary analysis; if the model does not 
converge, other covariance matrices will be considered.  The least squares mean (LS mean) 
difference in change from OLE Baseline to Week 52 from MMRM will be estimated from this 
model.  For subjects with missing data at 1 or more time points, the available data will be 
included in the analysis. 
Exploratory endpoints will be summarized at each time point.  Change from Baseline will be 
evaluated separately for each of the defined Baselines.   
9.6.2.4 Safety and Tolerability Analyses 
All safety endpoints will be summarized for the safety analysis set in the Extension Phase using 
descriptive statistics. 
The number and percentage of subjects reporting at least 1 TEAE, SAE, AESI and TEAE 
resulting in premature discontinuation of fipaxalparant (HZN-825) will be summarized by each 
unique SOC and Preferred Term.  AE rates (events per patient-year of follow-up during dosing) 
will also be summarized to account for the different treatment durations.  TEAEs and SAEs will 
also be summarized by maximum severity and relationship to fipaxalparant (HZN-825), as 
assessed by the Investigator.  Grade 3 and above TEAEs will also be summarized for each 
unique SOC and Preferred Term.  
The number and percentage of subjects using concomitant medications will be summarized by 
Anatomical Therapeutic Chemical Level 4 term and Preferred Term. 
Laboratory values and change from OLE Baseline and fipaxalparant (HZN-825) Baseline will be 
summarized by visit using descriptive statistics.  The laboratory assessment will be categorized 
as low, normal or high based on normal ranges.  Shift tables using categories of low, normal and 
high from each Baseline to each visit in the Extension Phase will be summarized.  If toxicity 
grading is available, then those grades will also be used for shift table summaries.   

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Descriptive summaries of observed and change from OLE Baseline and fipaxalparant (HZN-
825) Baseline will be presented for each vital sign parameter by visit.  A shift table for vital signs 
by visit will be provided. 
ECG results will be summarized for each visit in the Extension Phase. 
9.6.2.5 Pharmacokinetic Analyses 
PK data will be analyzed using the PK analysis set.  Plasma concentrations of fipaxalparant 
(HZN-825) will be summarized descriptively, including arithmetic means, standard deviations, 
geometric means, coefficients of variation, medians, first and third quartiles and ranges by 
treatment group in the Core Phase and by time point.  Population PK analysis may be performed.   
9.6.3 Sample Size and Power Considerations 
Approximately 135 subjects (45 subjects per treatment group) will be enrolled in the trial.  Based 
on a prior trial of pirfenidone [Nathan et al., 2019] in a similar subject population, change in 
FVC % predicted is expected to have a standard deviation of 6% to 9% after 52 weeks of 
treatment.  Assuming a clinically important difference between fipaxalparant (HZN-825) and 
placebo is 3% and a common standard deviation is 9%, a sample size of 45 subjects per 
treatment group in the Core Phase will provide 85% probability to detect a positive signal (FVC 
% predicted difference for each dose vs. placebo at Week 52 >1%) and 70% probability to detect 
a positive signal (FVC % predicted difference for each dose vs. placebo at Week 52 >2%).  If the 
true FVC % predicted difference for each dose versus placebo at Week 52 is 0%, then there is 
only 15% probability to detect a positive signal (FVC % predicted difference for each dose vs. 
placebo at Week 52 >2%). 
The sample size for the Extension Phase is based on the number of subjects who complete the 
Core Phase. 
9.7 
Changes in the Conduct of the Trial 
If any modifications in the experimental design, dosages, parameters, subject selection or any 
other sections of the protocol are indicated or required, the Investigator will consult with the 
Sponsor before any such changes are instituted.  Modifications will be accomplished through 
formal amendments to this protocol by the Sponsor and approved from the appropriate external 
review bodies. 
The Investigator or other health professional in attendance must contact the Sponsor as soon as 
possible.  All protocol deviations and the reasons for such deviations must be documented into 
the electronic database.  In the event of a protocol deviation, the Investigator and Sponsor’s 
Medical Monitor will determine whether the subject should continue to participate in the trial. 
The Sponsor has a legal responsibility to report fully to regulatory authorities all results of 
administration of investigational drugs to humans.  No investigational procedures other than 
those described in this protocol will be undertaken on the enrolled subjects without the 
agreement of the external review bodies and Sponsor. 

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10 SOURCE DOCUMENTATION AND INVESTIGATOR FILES 
The Investigator must maintain adequate and accurate records to document fully the conduct of 
the trial and to ensure that trial data can be subsequently verified.  These documents should be 
classified in 2 separate categories:  (1) Investigator trial file and (2) subject clinical source 
documents that corroborate data collected in the eCRFs.  Subject clinical source documents 
would include, as applicable, original hospital/clinic subject records; physicians and nurses’ 
notes; appointment book; original laboratory, ECG, echocardiogram, electroencephalogram, 
radiology, pathology, and special assessment reports; dispensing records; signed ICFs; consultant 
letters; and subject Screening and enrollment logs. 
In order to comply with regulatory requirements, it is the policy of the Sponsor that, at a 
minimum, the following be documented in source documents at the trial center: 
 Medical history/physical condition and diagnosis of the subject before involvement in the 
trial sufficient to verify that the subject meets protocol entry criteria.  
 Trial number, assigned subject number and verification that written informed consent was 
obtained (each recorded in dated and signed progress notes). 
 Progress notes or for each subject visit (each dated and signed). 
 Records of each trial visit including each trial assessment and the identity of the staff 
member performing the assessment. 
 Trial drug dispensing and return. 
 Review by the Investigator or qualified personnel on the 1572 of laboratory test results. 
 AEs (start and stop date, description, relationship to trial drug, action taken and 
resolution). 
 Investigator or Sub-Investigator’s signed assessment of each AE. 
 Concomitant medications (start and stop dates, reason for use). 
 Condition of subject upon completion of, or premature discontinuation from, the trial. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
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11 CASE REPORT FORMS 
An eCRF is required for every subject who signs the ICF.  Required data must be entered on the 
eCRF within the required time period, which will be outlined within each site agreement, after 
data collection or the availability of test results.  Separate source records are required to support 
all eCRF entries.   
The Investigator will ensure that the eCRFs are accurate, complete, legible and timely and will 
review and provide an electronic signature for the eCRF according to the standard operating 
procedure of the Data Management System.  Final eCRFs will be provided to the Investigator 
and Sponsor by Data Management. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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12 TRIAL MONITORING 
The Investigator will ensure that the trial is conducted in accordance with all regulations 
governing the protection of human subjects and will adhere to the basic principles of GCP as 
outlined in Title 21 of the CFR, Part 312, Subpart D, “Responsibilities of Sponsors and 
Investigators”; 21 CFR, Part 50, “Protection of Human Subjects”; 21 CFR, Part 56, “Institutional 
Review Boards”; 21 CFR, Part 54 “Financial Disclosure by Clinical Investigators”; and the ICH 
guideline entitled “Good Clinical Practice:  Consolidated Guidance.”  Additionally, this trial will 
be conducted in compliance with the Declaration of Helsinki and with all local laws and 
regulations. 
The Investigator will ensure that all work and services described in or associated with this 
protocol are conducted in accordance with the investigational plan, applicable regulations and 
the highest standards of medical and clinical research practice.  The Investigator will provide 
copies of the trial protocol and Investigator's Brochure to all Sub-Investigators, pharmacists and 
other staff responsible for trial conduct. 
All aspects of the trial will be monitored by qualified individuals designated by the Sponsor.  
The Sponsor will ensure that the trial is monitored adequately in accordance with GCP 
guidelines. 
Prior to initiation of the trial, the Sponsor’s representatives will review with trial center 
personnel information regarding the investigational drug, protocol requirements, monitoring 
requirements, and reporting of SAEs. 
At intervals during the trial, as well as after the completion of subject enrollment, the trial center 
will be monitored by the Sponsor or designee for compliance.  During these visits, the monitor 
will discuss trial progress, verify adherence to the protocol and the completeness, consistency 
and accuracy of the data being entered on the eCRF (source data verification); oversee the 
resolution of outstanding data discrepancies; and check on various aspects of trial conduct 
(e.g., drug accountability, sample storage).  The Investigator agrees to allow unblinded monitors 
access to the clinical supplies, dispensing and storage areas and clinical records of the trial 
subjects and, if requested, agrees to assist the monitors.  The Investigator must cooperate with 
the monitors to ensure that any problems detected in the course of these monitoring visits are 
resolved. 
A secondary audit may be conducted by Quality Assurance designated by the Sponsor.  The 
Investigator will be informed if this is to take place and advised as to the nature of the audit.  
Representatives of the FDA and/or representatives of other regulatory authorities may also 
conduct an inspection of the trial at the investigative site.  If informed of such an inspection, the 
Investigator should notify the Sponsor immediately. 
Every effort will be made to maintain the anonymity and confidentiality of subjects participating 
in this clinical trial.  However, because of the investigational nature of this treatment, the 
Investigator agrees to allow representatives of the Sponsor, its designated agents and authorized 
employees of the appropriate regulatory agencies to inspect the facilities used in this trial and to 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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have direct access to inspect, for purposes of verification, the hospital or clinical records of all 
subjects enrolled in this trial.  A statement to this effect should be included in the ICF. 
Serious Breach 
Suspected Serious Breaches must be reported to the study team (e.g., Clinical Monitor) or the 
Clinical Out-of-Hours Support Program:  https://wwwext.amgen.com/science/clinical-
trials/clinical-out-of-hours-support-program immediately and no later than 1 calendar day from 
the time of awareness. 
A Serious Breach is a breach of any of the following: 
 GCP 
 the clinical trial protocol 
 an applicable regulation 
That is likely to impact to a significant degree either of the following: 
 the safety, physical, or mental integrity and the rights of the participant 
 the reliability and robustness of the data and the scientific value of the trial 
 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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13 DATA MANAGEMENT 
Data will be entered into a clinical database as specified in the Data Management Plan.  Quality 
control and data validation procedures will be applied to ensure the validity and accuracy of the 
clinical database.  Data will be reviewed and checked for omissions, apparent errors, and values 
requiring further clarification using computerized and manual procedures.  Data queries 
requiring clarification will be communicated to the investigational site for resolution.  Only 
authorized personnel will make corrections to the clinical database and all corrections will be 
documented in an audit trail. 
The coding of an AE, medical history and concomitant medication terms will be performed by a 
qualified medical coder and reviewed and approved by the Sponsor.  Concomitant medications 
will be coded using the World Health Organization Drug Dictionary and AE/medical 
history/surgery/non-drug therapy terms will be coded using the Medical Dictionary for 
Regulatory Activities. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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14 RETENTION OF RECORDS 
No trial documents at the trial site should be destroyed without prior written agreement between 
the Sponsor and the Investigator.  All subjects’ medical records, the Investigator’s copy of the 
eCRF, other supporting data, records of drug dispensing and accountability, signed ICFs, 
external review bodies correspondence and correspondence with the Sponsor must be kept by the 
Investigator for at least 2 years and as required by the local law following the date of the last 
approval of a marketing application in an ICH region (including the US) and until there are no 
pending or contemplated marketing applications in any other ICH region.  If an application is not 
filed or not approved for the indication under study, all trial-related files must be retained for at 
least 2 years following the date of discontinuation of the clinical development program for 
fipaxalparant (HZN-825) and for a period in compliance with all federal, state and local 
regulations.  The Sponsor must be notified prior to the disposal of any trial-related files.  If the 
Investigator leaves the practice or institution during the required retention period, it is important 
that arrangements be made for continued record retention.  In that event, the records generally 
will be retained at the institution at which the trial was conducted. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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15 PUBLICATION 
To avoid disclosures that could jeopardize proprietary rights, the institution and/or the 
Investigator agree to certain restrictions on publications (e.g., abstracts, speeches, posters, 
manuscripts and electronic communications) as detailed in the Clinical Trial Agreement. 
Independent publications of results, including unfavorable results, will be submitted to 
applicable databases within the required timeframe. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
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16 REFERENCES  
Allanore Y, Distler O, Jagerschmidt A, et al. Lysophosphatidic acid receptor 1 antagonist 
SAR100842 for patients with diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 
2018;70:1634-43. 
American Thoracic Society. Idiopathic pulmonary fibrosis: Diagnosis and treatment. 
International consensus statement. American Thoracic Society (ATS), and the European 
Respiratory Society (ERS). Am J Respir Crit Care Med. 2000;161:646-64. 
ATS Guidelines. ATS Committee on Proficiency Standards for Clinical Pulmonary Function 
Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care 
Med. 2002;166(1):111-7. Erratum in: Am J Respir Crit Care Med. 2016;193(10):1185.  
Barratt SL, Creamer A, Hayton C, Chaudhuri N. Idiopathic pulmonary fibrosis (IPF):  an 
overview. J Clin Med. 2018;7(8):201. 
Birring SS, Prudon B, Carr AJ, Singh SJ, Morgan MDL, Pavord DI. Development of a symptom 
specific health status measure for patients with chronic cough: Leicester Cough Questionnaire 
(LCQ). Thorax. 2003;58:339-43. 
Black KE, Berdyshev E, Bain G, et al. Autotaxin activity increases locally following lung injury, 
but is not required for pulmonary lysophosphatidic acid production or fibrosis. FASEB J. 
2016;30:2435-50. 
Blanqué R, Desroy N, Dupont S, et al. Pharmacological profile and efficacy of GLPG1690, a 
novel ATX inhibitor for COPD treatment. Eur Res Society Poster 2015. Available online at 
www.glpg.com. 
Cabello-Verrugio C, Cordova G, Vial C, Zuniga LM, Brandan E. Connective tissue growth 
factor induction by lysophosphatidic acid requires transactivation of transforming growth factor 
type beta receptors and the JNK pathway. Cell Signal. 2011;23(2):449-57. 
Chun J, Goetzl EJ, Hla T, et al. International Union of Pharmacology. XXXIV. 
Lysophospholipid receptor nomenclature. Pharmacol Rev. 2002;54(2):265-9. 
Collard HR, Ryerson CJ, Corte TJ, et al. Acute exacerbation of idiopathic pulmonary fibrosis. an 
international working group report. Am J Respir Crit Care Med. 2016;194(3):265-75. 
Desroy N, Housseman C, Bock X, et al. Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-
yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-
fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a first-in-class autotaxin inhibitor undergoing 
clinical evaluation for the treatment of idiopathic pulmonary fibrosis. J Med Chem. 
2017;60(9):3580-90.  
Diamantopoulos A, Wright E, Vlahopoulou K, Cornic L, Schoof N, Maher TM. The burden of 
illness of idiopathic pulmonary fibrosis: a comprehensive evidence review. Pharmacoeconomics. 
2018;36:779-807. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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ESBRIET® (pirfenidone). Full Prescribing Information. Revision date: 7/2019. 
Fukushima N, Ishii I, Contos JJ, Weiner JA, Chun J. Lysophospholipid receptors. Annu Rev 
Pharmacol Toxicol. 2001;41:507-34. 
Funke M, Zhao Z, Xu Y, Chun K, Tager M. The lysophosphatidic acid receptor LPA1 promotes 
epithelial cell apoptosis after lung injury. Am J Respir Cell Mol Biol. 2012;46(3):355-64. 
Geraldo LHM, de Sampaio Spohr TCL, do Amaral RF, et al. Role of lysophosphatidic acid and 
its receptors in health and disease: novel therapeutic strategies. Signal Transduct Target Ther. 
2021;6:45. 
Graham BL, Brusasco V, Burgos F, et al. Executive Summary: 2017 ERS/ATS standards for 
single-breath carbon monoxide uptake in the lung. Eur Respir J. 2017;49:16E0016. 
Graham BL, Steenbruggen I, Miller MR, et al. Standardization of Spirometry 2019 Update. An 
Official American Thoracic Society and European Respiratory Society Technical Statement. Am 
J Respir Crit Care Med. 2019;200:e70-e88. 
Gribbin J, Hubbard RB, le Jeune I, Smith CJ, West J, Tata LJ. Incidence and mortality of 
idiopathic pulmonary fibrosis and sarcoidosis in the UK. Thorax. 2006;61:980-5. 
Hopkins RB, Burke N, Fell C, Dion G, Kolb M. Epidemiology and survival of idiopathic 
pulmonary fibrosis from national data in Canada. Eur Respir J. 2016;48:187-95. 
Human Albumin. Transfus Med Hemother. 2009;36:399-407. 
Hutchinson J, Fogarty A, Hubbard R, McKeever T. Global incidence and mortality of idiopathic 
pulmonary fibrosis: A systematic review. Eur Respir J. 2015;46:795-806. 
Idzko M, Laut M, Panther E, et al. Lysophosphatidic acid induces chemotaxis, oxygen radical 
production, CD11b up-regulation, Ca2+ mobilization, and actin reorganization in human 
oesinophils via pertussis toxin-sensitive G proteins. J Immunol. 2004;172(7):4480-5. 
Kim J, Keys JR, Eckhart AD. Vascular smooth muscle migration and proliferation in response to 
lysophosphatidic acid (LPA) is mediated by LPA receptors coupling to Gq. Cell Signal. 
2006;18(10):1695-701. 
King TE, Bradford WZ, Castro-Bernardini S, et al.  A phase 3 trial of pirfenidone in patients 
with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083-92. 
Knowlden S, Georas SN. The autotaxin-LPA axis emerges as a novel regulator of lymphocyte 
homing and inflammation. J Immunol. 2014;192(3):851-7. 
Kreuter M, Polke M, Walsh SLF, et al. Acute exacerbation of idiopathic pulmonary fibrosis: 
international survey and call for harmonisation. Eur Respir J. 2020;55(4):1901760. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Lancaster LH. Utility of the six-minute walk test in patients with idiopathic pulmonary fibrosis. 
Multidiscip Respir Med. 2018;13;13:45. 
Lancaster LH, de Andrade JA, Zibrak JD, et al. Pirfenidone safety and adverse event 
management in idiopathic pulmonary fibrosis. Eur Respir Rev. 2017;26:170057. 
Ledein L, Léger B, Dees C, et al. Translational engagement of LPA1 receptor in skin fibrosis:  
from dermal fibroblasts of patients with scleroderma to Tsk1 mouse. Br J Pharmacol. 
2020;177:4296-309. 
Maher TM, van der Aar EM, Van de Steen O, et al. Safety, tolerability, pharmacokinetics, and 
pharmacodynamics of GLPG1690, a novel autotaxin inhibitor, to treat idiopathic pulmonary 
fibrosis (FLORA): a phase 2a randomised placebo-controlled trial. Lancet Respir Med. 
2018;6(8):627-35. 
Nakamura K, Igarashi K, Ide K, et al. Validation of an autotaxin enzyme immunoassay in human 
serum samples and its application to hypoalbuminemia differentiation. Clin Chim Acta. 
2008;388(1-2):51-8. 
Nakanaga K, Hama K, Aoki J. Autotaxin—an LPA producing enzyme with diverse functions. 
J Biochem. 2010;148(1):13-24. 
Nathan SD, Costabel U, Albera C, et al. Pirfenidone in patients with idiopathic pulmonary 
fibrosis and more advanced lung function impairment. Respir Med. 2019;153:44-51. 
Navaratnam V, Fleming KM, West J, et al. The rising incidence of idiopathic pulmonary fibrosis 
in the U.K. Thorax. 2011;66:462-7. 
Ninou I, Magkrioti C, Aidinis V. Autotaxin in pathophysiology and pulmonary fibrosis. Front 
Med (Lausanne). 2018;5:180. 
OFEV® (nintedanib capsules). Full Prescribing Information. Revision date: 10/2020. 
Oikonomou N, Mouratis M-A, Tzouvelekis A, et al. Pulmonary autotaxin expression contributes 
to the pathogenesis of pulmonary fibrosis. Am J Respir Cell Mol Biol. 2012;47(5):566-74. 
Oldham WM, Hamm HE. Heterotrimeric G protein activation by G-protein-couples receptors. 
Nat Rev Mol Cell Biol. 2008;9:60-71. 
Palmer SM, Synder L, Todd JL, et al. Randomized, double-blind, placebo-controlled, phase 2 
trial of BMS-986020, a lysophosphatidic acid receptor antagonist for the treatment of idiopathic 
pulmonary fibrosis. Chest. 2018;154:1061-9. 
Panther E, Idzko M, Corinti S, et al. The influence of lysophosphatidic acid on the functions of 
human dendritic cells. J Immunol. 2002;169:4129-35. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Patel AS, Siegert RJ, Brignall K, et al. The development and validation of the King's Brief 
Interstitial Lung Disease (K-BILD) health status questionnaire. Thorax. 2012;67:804-10. 
Pradère JP, Klein J, Grès S, et al. LPA1 receptor activation promotes renal interstitial fibrosis. 
J Am Soc Nephrol. 2007;18:3110-8. 
Qian Y, Hamilton M, Sidduri A, et al. discovery of highly selective and orally active 
lysophosphatidic acid receptor‑1 antagonists with potent activity on human lung fibroblasts. 
J Med Chem. 2012;55(17):7920-39.  
Raghu G, Chen SY, Yeh WS, et al. Idiopathic pulmonary fibrosis in US Medicare beneficiaries 
aged 65 years and older: incidence, prevalence, and survival, 2001–11. Lancet Respir Med. 
2014;2:566-72. 
Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: Idiopathic 
pulmonary fibrosis: Evidence-based guidelines for diagnosis and management. Am J Respir Crit 
Care Med. 2011;183:788-824. 
Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of idiopathic pulmonary fibrosis. An 
official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Car Med. 
2018;198:e44-68. 
Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic pulmonary fibrosis (an update) and 
progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT Clinical Practice 
Guideline. Am J Respir Crit Care Med. 2022;205(9):e18-47. 
Raghu G, Rochwerg B, Zhang Y, et al. An official ATS/ERS/JRS/ALAT clinical practice 
guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice 
guideline. Am J Respir Crit Car Med. 2015;192:e3-19. 
Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic 
pulmonary fibrosis. N Engl J Med. 2014;370:2071-82. 
Schober A, Siess W. Lysophosphatidic acid in atherosclerotic diseases. Br J Pharmacol. 
2012;167(3):465-82. 
Sinha A, Patel AS, Siegert RJ, et al. The King's Brief Interstitial Lung Disease (KBILD) 
questionnaire:  an updated minimal clinically important difference. BMJ Open Respir Res. 
2019;6:e000363. 
Strongman H, Kausar I, Maher TM. Incidence, prevalence, and survival of patients with 
idiopathic pulmonary fibrosis in the UK. Adv Ther. 2018;35:724-36. 
Swaney JS, Chapman C, Correa LD, et al. A novel, orally active LPA1 receptor antagonist 
inhibits lung fibrosis in the mouse bleomycin model. Br J Pharmacol. 2010;160:1699-713. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
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Swigris JJ, Andrae DA, Churney T, et al. Development and initial validation analyses of the 
Living with Idiopathic Pulmonary Fibrosis Questionnaire. Am J Respir Crit Care Med. 
2020;202:1689-97. 
Swigris JJ, Broan KK, Behr J, et al. The SF-36 and SGRQ: validity and first look at minimum 
important differences in IPF. Respir Med. 2010;104:296-304. 
Tager AM, LaCamera P, Shea BS, et al. The lysophosphatidic acid receptor LPA1 links 
pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat 
Med. 2008;14(1):45-54. 
Takuma Y, Takuma N, Sugimoto N. The Edg family G protein-coupled receptors for 
lysophospholipids:  their signaling properties and biological activities. J Biochem. 
2002;131(6):767-71. 
Tanaka M, Okudaira S, Kishi Y, et al. Autotaxin stabilizes blood vessels and is required for 
embryonic vasculature by producing lysophosphatidic acid. J Biol Chem. 
2006;281(35):25822-30. 
Tang N, Zhao Y, Feng R, et al. Lysophosphatidic acid accelerates lung fibrosis by inducing 
differentiation of mesenchymal stem cells into myofibroblasts. J Cell Mol Med. 
2014;18(1):156-69. 
Tokumura A, Carbone LD, Yoshioka Y, et al. Elevated serum levels of 
arachidonoyl-lysophosphatidic acid and sphingosine 1-phosphate in systemic sclerosis. Int J Med 
Sci. 2009;6:168-76. 
Tomioka H, Imanaka K, Hashimoto K, Iwasaki H. Health-related quality of life in patients with 
idiopathic pulmonary fibrosis--cross-sectional and longitudinal study. Intern Med. 
2007;46:1533-42. 
Tsuda S, Okudaira S, Moriya-Ito K, et al. Cyclic phosphatidic acid is produced by autotaxin in 
blood. J Biol Chem. 2006;281(36):26081-8. 
US Department of Health and Human Services, Food and Drug Administration. Drug-induced 
liver injury:  premarketing clinical evaluation. July 2009. 
Valdes-Rives SA, González-Arenas A. Autotaxin-lysophosphatidic acid: from inflammation to 
cancer development. Mediators Inflamm. 2017:9173090. 
van der Aar EM, Heckmann B, Blanque R, et al. Pharmacological profile and efficacy of 
GLPG1690, a novel autotaxin inhibitor for the treatment of idiopathic pulmonary fibrosis. 
Am J Respir Crit Care Med. 2020;201:A4532. 
van Meeteren LA, Ruurs P, Stortelers C, et al. Autotaxin, a secreted lysophospholipase D, is 
essential for blood vessel formation during development. Mol Cell Biol. 2006;26:5015-22. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
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Ware J, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and 
preliminary tests of reliability and validity. Med Care. 1996;34:220-33. 
Woodworth T, Furst DE, Alten R, et al. Standardizing assessment and reporting of adverse 
effects in rheumatology clinical trials II: the Rheumatology Common Toxicity Criteria v2.0. 
J Rheumatol. 2007;34(6):1401-14. 
Yin Z, Tong Y, Zhu H, Watsky MA. CLC-3 is required for LPA-activated Cl- current activity 
and fibroblasts to myofibroblasts differentiation. Am J Physiol Cell Physiol. 2008;294(2):535-
42. 
Yung YC, Stoddard NC, Chun J. LPA receptor signaling:  pharmacology, physiology, and 
pathophysiology. J Lipid Res. 2014;55:1192-214. 
Zhao Y, Natarajan V. Lysophosphatidic acid (LPA) and its receptors: role in airway 
inflammation and remodeling. Biochim Biophys Acta. 2013;1831(1):86-92. 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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17 APPENDICES 
Versions of the assessment instruments are provided in the appendices as examples based on the 
versions available at the time of protocol publication and may differ from the assessment 
instruments actually administered in the trial in the event that additional validated versions 
become available. 
17.1 
Administrative Appendix 
This appendix provides names and contact information for the trial administrative structure.  The 
external review bodies must be notified of changes that are made to this section, but external 
review bodies review or approval of these changes is not required.  Changes made in this section 
will be dated but will not be assigned a protocol amendment number. 
Medical Monitor 
 MBBS, MD 
 Senior Medical Director, Clinical Development (Rare Disease) 
 
Horizon Therapeutics USA., Inc. 
 
1 Horizon Way 
 
Deerfield, IL  60015 
 
Mobile telephone number:  
 
 
Email:  
 
 
Sponsor 
 
Representative 
Associate Director, Clinical Operations 
 
Horizon Therapeutics U.S.A., Inc. 
 
1 Horizon Way 
 
Deerfield, IL  60015 
 
Business telephone number:  
 
 
 Email:  
  
 
 
 

Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
Fipaxalparant (HZN-825) 
Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
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17.2 
Hospitalization Due to Respiratory Distress 
Hospitalization due to respiratory distress is defined as a non-elective hospitalization lasting 
more than 24 hours in a hospital, emergency room or observation unit, due to respiratory causes 
that occur after randomization.  
Clinical information for potential hospitalization due to respiratory distress will be collected on a 
dedicated questionnaire.  In addition, all relevant clinical data (summary on clinical course, signs 
and symptoms; laboratory, lung function and imaging results; and treatment provided) relating to 
the hospitalization will be collected and provided to an independent adjudication committee for 
review.  
Clinical information related to potential respiratory related hospitalizations will be provided to an 
independent adjudication committee for review in accordance with the standardized algorithm 
proposed by Kreuter et al., 2020 (Figure 17.1).  For additional details, refer to the adjudication 
committee charter. 

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Figure 17.1 
Algorithm for Adjudication of Respiratory-related Hospitalization in 
Idiopathic Pulmonary Fibrosis 
 
17.3 
IPF-related Acute Exacerbation 
Clinical information for potential IPF-related acute exacerbations will be collected on a 
dedicated questionnaire.  In addition, all relevant clinical data (summary on clinical course, signs 
and symptoms; laboratory, lung function and imaging results; and treatment provided) relating to 
the exacerbation will be collected and provided to an independent adjudication committee for 
review.  The conceptual framework for evaluation of acute respiratory deterioration in IPF, as 
defined by Collard et al., 2016, is shown in Figure 17.2.  Acute respiratory deterioration of IPF 
(defined as “typically, 1 month in duration”) can be categorized as extraparenchymal 
(e.g., pulmonary embolism, pneumothorax, pleural effusion) or parenchymal.  Parenchymal 

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causes that demonstrate new bilateral ground-glass opacification/consolidation on computed 
tomography that is not fully explained by cardiac failure or fluid overload are categorized as 
acute exacerbations of IPF, regardless of the presence or absence of a known trigger 
(e.g., infection).  Acute exacerbations are further categorized as triggered acute exacerbation or 
idiopathic acute exacerbation, depending on whether an underlying trigger for acute exacerbation 
is found.  For additional details, refer to the adjudication committee charter. 
Figure 17.2 
Conceptual Framework for Evaluation of Acute Respiratory Deterioration in 
IPF 
 
 
Source:  [Collard et al., 2016] 
CT=computed tomography; GGO=ground-glass opacification; IPF=idiopathic pulmonary fibrosis 
The revised definition and diagnostic criteria for acute exacerbation of IPF are shown in 
Table 17.1. 

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Table 17.1 
Proposed Revised Definition and Diagnostic Criteria for Acute Exacerbation 
of IPF 
Revised definition 
An acute, clinically significant respiratory deterioration characterized by evidence of new widespread alveolar 
abnormality 
Revised diagnostic criteria 
 
Previous or concurrent diagnosis of IPF* 
 
Acute worsening or development of dyspnea typically <1 month in duration 
 
Computed tomography with new bilateral ground-glass opacity and/or consolidation superimposed on a 
background pattern consistent with usual interstitial pneumonia pattern† 
 
Deterioration not fully explained by cardiac failure or fluid overload 
Source:  [Collard et al., 2016] 
IPF=idiopathic pulmonary fibrosis 
Events that are clinically considered to meet the definition of acute exacerbation of IPF but fail to meet all 
4 diagnostic criteria owing to missing computed tomography data should be termed “suspected acute exacerbations.” 
*If the diagnosis of IPF is not previously established, this criterion can be met by the presence of radiologic and/or 
histopathologic changes consistent with usual interstitial pneumonia pattern on the current evaluation. 
†If no previous computed tomography is available, the qualifier “new” can be dropped. 

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17.4 
Living with IPF 
Symptoms Module 
 

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Date: 07 October 2024 
 
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Date: 07 October 2024 
 
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Date: 07 October 2024 
 
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Impacts Module 

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17.5 
King’s Brief Interstitial Lung Disease Questionnaire 
 
Source:  [Patel et al., 2012] 

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17.6 
Leicester Cough Questionnaire 
 

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17.7 
SF-12® Health Survey (SF-12) 
 

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17.8 
Serious Adverse Events Anticipated in the Trial Population 
The following is a list of SAEs by organ system that the Sponsor considers to be associated with 
the disease state being studied.  Please note some of the listed events may need to present with 
severe intensity to meet the seriousness criteria (e.g., nausea and vomiting).  The list does NOT 
change the reporting obligations or prevent the need to report an AE meeting the definition of an 
SAE as detailed in Section 9.5.5.1.1.2 (Serious Adverse Event Definition).  The Investigator is 
required to follow the requirements detailed in Section 9.5.5.1.5 (Reporting and Documentation 
of Serious Adverse Events).   
For IND safety reporting, single occurrences of the following events may be excluded from 
expedited reporting to the FDA.  If aggregate analysis of these events indicates they occur more 
frequently with trial drug compared with placebo, an expedited IND safety report may be 
submitted to the FDA. 
Cardiovascular system:   
 cardiac failure (including acute, chronic and congestive) 
 ventricular failure (including ejection fraction decreased) 
 pericardial effusion 
 pericarditis 
 supraventricular tachyarrhythmia 
 hypotension  
Pulmonary system:   
 pulmonary arterial hypertension 
 pulmonary hypertension 
 FVC decreased 
 respiratory-related hospitalizations 
 acute exacerbations 
 

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17.9 
Orthostatic Hypotension Assessment Manual 
 

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Date: 07 October 2024 
 
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Date: 07 October 2024 
 
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IND 154671 
 
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Date: 07 October 2024 
 
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17.10 Clinical SAE Report Form 
 

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Date: 07 October 2024 
 
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Date: 07 October 2024 
 
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Date: 07 October 2024 
 
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Date: 07 October 2024 
 
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Date: 07 October 2024 
 
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Date: 07 October 2024 
 
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Date: 07 October 2024 
 
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IND 154671 
 
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Date: 07 October 2024 
 
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Date: 07 October 2024 
 
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Date: 07 October 2024 
 
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IND 154671 
 
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Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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17.11 Clinical Trial Drug Exposure During Conception/Pregnancy Form 
 

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Date: 07 October 2024 
 
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IND 154671 
 
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Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Horizon Therapeutics Ireland DAC (a wholly owned subsidiary of Amgen Inc.)  
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Date: 07 October 2024 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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17.12 Lactation Notification Form 
 

Approval Signatures
Document Name:
Protocol Amendment fipaxalparant 20230132 4
Document Description:
Document Number:
CLIN-000353549
Approval Date:
11 Oct 2024
Type of Study Protocol:
Amendment
Protocol Amendment No.: 4
Document Approvals
Reason for Signing: Management
Name: 
Date of Signature: 11-Oct-2024 17:02:39 GMT+0000

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 5 of 156 
 
SUMMARY OF CHANGES 
Protocol HZNP-HZN-825-303 
Version 4.0 Amendment 3, incorporating Protocol Version 3.0 
Key additions, revisions and clarifications to Version 3.0 of the protocol include: 
• Updating the Sponsor’s address. 
• Revising the geographical regions and approximate number of sites in which the trial will 
be conducted. 
• Making this a 2-part study by adding an optional, 52-week open-label extension to the 
trial (i.e., the Extension Phase [Part 2]).  The Core Phase (Part 1) refers to the 
randomized, double-blind, placebo-controlled part of the trial. 
• Clarifying the secondary objective pertaining to safety. 
• Removing evaluation of metabolite(s) of HZN-825 in the 9th secondary objective, as this 
was deemed not necessary by communication with the United States Food and Drug 
Administration. 
• Modifying one of the stratification factors to be concomitant use of approved IPF therapy 
rather than prior use and revising statistical analysis accordingly. 
• Removing baseline FVC % predicted from statistical models due to the high collinearity 
with one of the stratification factors in the model. 
• Specifying that the first secondary efficacy endpoint is the key secondary efficacy 
endpoint. 
• Updating the p-values in the description of the tipping point analysis. 
• Specifying that there will be an interim analysis
 
 
• Deleting mention of adjustment to account for the futility analysis.  Since there will be a 
futility analysis during the interim analysis, with no intention to stop the trial due to 
efficacy evaluation, there is no need to adjust the significant value for multiple 
comparisons at interim analysis. 
• Updating p-values due to updated overall significance level (alpha = 0.10, 2-sided). 
• Changing the testing procedure for multiple comparisons from a Hochberg testing 
procedure to a hierarchical testing procedure. 
• Specifying that p-values for other secondary endpoints will not be used for inferential 
purposes. 
• Updating description of the sample size estimate; the target enrollment was reduced to 
135 subjects from 360 subjects. 
• Modifying inclusion criteria with respect to age, current and initial diagnosis of 
idiopathic pulmonary fibrosis (IPF), current IPF therapy and diffusing capacity of the 
lungs for carbon monoxide (DLCO); clarifying inclusion criteria pertaining to lung 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
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 Page 6 of 156 
 
high-resolution computed tomography (HRCT) and removing mention of honeycombing; 
clarifying that vaccination status is to be determined according to the Investigator’s 
discretion; and removing examples of vaccines. 
• Including further guidance about acceptable use of restricted medications as part of the 
entry criteria evaluation in exclusion criterion 5. 
• Clarifying that subjects who complete the Double-blind Treatment Period in the Core 
Phase may be eligible for the Extension Phase. 
• Changing the primary analysis set from the intent-to-treat analysis set to the full analysis 
set. 
• Adding new requirements around condom use, aligning text with Section 9.5.5.2 in 
exclusion criterion 8 and adding clarification around abstinence as a contraceptive 
method. 
• Specifying restrictions in exclusion criterion 8 regarding egg/ova donation and sperm 
donation. 
• Making human immunodeficiency virus (HIV) testing optional (with subject consent) at 
Visit 1.  
• Modifying the exclusion criteria pertaining to total bilirubin and confirmed grade of 
laboratory abnormality. 
• Removing the exception of previous HZN-825 exposure from an exclusion criterion. 
• Clarifying the definition of active hepatitis B and reformatting exclusion criterion 13 for 
clarity. 
• Allowing subject visits at Weeks 22, 34 and 46 to be performed at locations other than 
the trial site. 
• Indicating that histopathology is not required to determine subject eligibility. 
• Adding detail around the baseline lung HRCT. 
• Adding a citation (Raghu et al., 2022) pertaining to updates to the consensus for the 
diagnosis of IPF. 
• Updating the protocol with information from the current Investigator’s Brochure 
(Version 8) and a Phase 1 drug-drug interaction trial with respect to clinical experience 
with HZN-825. 
• Including a section on the benefit/risk assessment for HZN-825. 
• Clarifying that the adjudication committee will only pertain to the Core Phase. 
• Providing description regarding Horizon unblinded personnel involvement in decisions 
on future dose selection and future trial design during the interim analysis. 
• Specifying that a clinically significant laboratory or electrocardiogram (ECG) 
abnormality may lead to removal of subjects from treatment. 
• Including restricted medication use as a specific reason for discontinuation from trial 
treatment. 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 7 of 156 
 
• Specifying that attempts should be made to contact subjects who are initially lost to 
follow-up. 
• Adding a section on changes to background therapy for IPF. 
• Adding rationale to support the safety of up to a 600 mg dose of HZN-825. 
• Specifying that any completely missed dose should be recorded on the electronic case 
report form (eCRF). 
• Updating restrictions regarding concomitant medications and removing P-glycoprotein 
(P-gp) inhibitors from the list of restricted medications because the strong P-gp 
transporter inhibitor itraconazole had no impact on HZN-825 exposure at clinically 
relevant doses in a Phase 1 trial. 
• Deleting the table that delineated specific rescue therapy, as such therapy will be 
determined in consultation with the trial Medical Monitor. 
• Including some additional cautions around use of specific concomitant medications and 
information regarding concomitant therapy.  
• Stressing the importance of compliance with trial drug. 
• Adding a reference to American Thoracic Society (ATS) guidelines for the 6-minute 
walk test (6MWT). 
• Clarifying language for obtaining DLCO measurement. 
• Deleting mention of collection of data on paper, as all data will be collected 
electronically for the trial. 
• Clarifying that subject exit interviews will be covered by a separate protocol. 
• Providing detail regarding taking trial drug with a meal. 
• Adding the definition of a suspected adverse reaction. 
• Clarifying when pre-existing conditions should be reported as AEs. 
• Aligning language throughout the protocol with that in the updated Orthostatic 
Hypotension Assessment Manual. 
• Clarifying documentation and reporting for medication errors. 
• Specifying that a repeat resting ECG should be conducted if a clinically significant ECG 
result is obtained. 
• Specifying the urinalysis parameters. 
• Including the estimated amount of total blood volume that will be collected from each 
subject. 
• Alerting trial personnel that the actual assessment instruments used may differ from those 
in Section 17 of the protocol. 
• Changing the Medical Monitor. 
• Updating the SF-12® Health Survey to the most current version. 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 8 of 156 
 
• Updating the Orthostatic Hypotension Assessment Manual and protocol language to align 
the process of assessing orthostatic hypotension with current guidelines, to clarify the 
manual to make the process more understandable and improve the method of data 
collection for orthostatic hypotension. 
Changes considered not key, minor wording changes and correction of minor typographical 
errors are not detailed below. 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 9 of 156 
 
SUMMARY TABLE OF CHANGES 
Protocol Version 3.0 (11 October 2021) to 
Protocol Version 4.0, Amendment 3 (01 December 2022) 
Text 
Version 3.0, Amendment 2 
11 October 2021 
Amended Text 
Version 4.0, Amendment 3 
01 December 2022 
Reason for 
Change 
First Page and Title Page 
Horizon Therapeutics Ireland DAC 
Connaught House, 1st Floor 
1 Burlington Road 
Dublin D04 C5Y6 
Ireland 
First Page and Title Page 
Horizon Therapeutics Ireland DAC 
70 St. Stephen's Green 
Dublin 2  
D02 E2X4 
Ireland 
To update the 
Sponsor’s 
address 
Synopsis – Number and Country of Trial Sites, 
Section 6 Investigators and Trial Administrative Structure and 
Section 9.1 Overall Trial Design and Plan 
Approximately 100 sites in the United States, Europe, Asia, 
Australia and New Zealand 
Synopsis – Number and Geographical Regions of Trial Sites, 
Section 6 Investigators and Trial Administrative Structure and 
Section 9.1 Overall Trial Design and Plan 
Approximately 85 sites in North America, Europe, South America, 
Africa, Asia (including Japan) and Australia.  
To revise the 
geographical 
regions and 
approximate 
number of sites 
in which the trial 
will be 
conducted 
Synopsis – Objectives 
Not applicable; text added to v4.0 of the protocol. 
Synopsis – Objectives and Section 8 
The trial will be conducted in 2 parts, Part 1 (Core Phase) followed 
by Part 2 (Extension Phase).  The Core Phase will include a 
52-week, randomized, double-blind, placebo-controlled treatment 
period and the Extension Phase will include a 52-week, open-label 
extension (OLE). 
To add an 
optional OLE to 
the trial 
Synopsis – Secondary Objectives and Section 8.2 Secondary 
Objectives  
8. Assess safety and tolerability of HZN-825 based on adverse 
events (AEs), serious adverse events (SAEs) and adverse event 
of special interest (AESI). 
Synopsis – Secondary Objectives and Section 8.1.2 Secondary 
Objectives  
8. Assess safety and tolerability of HZN-825, inclusive of, but not 
limited to, adverse events (AEs), SAEs and AESI. 
To clarify the 
secondary 
objective 
pertaining to 
safety 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 10 of 156 
 
Synopsis – Secondary Objectives and Section 8.2 Secondary 
Objectives  
9. Evaluate the pharmacokinetics (PK) of HZN-825 and 
metabolite(s). 
Synopsis – Secondary Objectives and Section 8.1.2 Secondary 
Objectives  
9. Evaluate the pharmacokinetics (PK) of HZN-825. 
To remove 
evaluation of 
metabolite(s) of 
HZN-825 
Synopsis – Criteria for Evaluation and Pharmacokinetic 
Endpoint, Section 9.5.2 Pharmacokinetic Measurements, 
Section 9.6.1.5 Pharmacokinetic Endpoint and 
Section 9.6.7 Pharmacokinetic Analyses  
The phrase:  “HZN-825 and metabolite(s)” 
Synopsis – Criteria for Evaluation and Pharmacokinetic 
Endpoint, Section 9.5.2 Pharmacokinetic Measurements, 
Section 9.6.1.1.6 Pharmacokinetic Endpoint and 
Section 9.6.1.7 Pharmacokinetic Analyses  
This phrase was changed to:  “HZN-825” 
To remove 
evaluation of 
metabolite(s) of 
HZN-825 
Synopsis – Objectives 
Not applicable; text added to v4.0 of the protocol. 
Synopsis – Objectives and Section 8.2 Part 2 (Extension Phase) 
Objectives were added for Part 2 (Extension Phase); see Part 2 
(Extension Phase) in the synopsis and Section 8.2. 
To add an 
optional OLE to 
the trial 
Synopsis – Trial Design 
This is a randomized, double-blind, placebo-controlled, 
repeat-dose, multicenter trial to evaluate the efficacy, safety and 
tolerability of HZN-825 in subjects with IPF.  Subjects will be 
screened within 8 weeks prior to the Baseline (Day 1) Visit.  
Approximately 360 subjects who meet the trial eligibility criteria 
will be randomly assigned in a 1:1:1 ratio on Day 1 to receive 
HZN-825 300 mg QD, HZN-825 300 mg BID or placebo for 
52 weeks using the following 2 stratification factors: 
1. Prior use of approved IPF therapy (i.e., nintedanib or 
pirfenidone):  yes or no 
2. FVC % predicted at Baseline:  ≥70% or <70% 
The trial will include up to an 8-week Screening Period and a 52-
week Double-blind Treatment Period.  Subjects will take their first 
dose of trial drug at the clinic on Day 1 (Week 0) and will return to 
the clinic for trial visits at Week 4 and every 6 weeks thereafter 
until Week 52.   
Synopsis – Trial Design 
HZNP-HZN-825-303 (HARBOR) comprises 2 parts.  Part 1 (Core 
Phase) is a randomized, double-blind, placebo-controlled, 
repeat-dose, multicenter trial to evaluate the efficacy, safety and 
tolerability of HZN-825 in subjects with IPF.  Part 2 (Extension 
Phase) is an optional, open-label, repeat-dose, multicenter extension 
of the Core Phase.  The trial will include up to an 8-week Screening 
Period and a 52-week Double-blind Treatment Period in the Core 
Phase and 52 weeks of open-label HZN-825 treatment in the 
Extension Phase.   
During the Core Phase, subjects will be screened within 8 weeks 
prior to the Baseline (Day 1) Visit.  Approximately 135 subjects 
who meet the trial eligibility criteria will be randomly assigned in a 
1:1:1 ratio on Day 1 to receive HZN-825 300 mg QD, HZN-825 
300 mg BID or placebo for 52 weeks using the following 2 
stratification factors: 
1. Concomitant use of approved IPF therapy (i.e., nintedanib or 
pirfenidone):  yes or no 
2. FVC % predicted at Baseline:  ≥70% or <70% 
During the Core Phase, subjects will take their first dose of trial 
drug at the clinic on Day 1 (Week 0) and will participate in trial 
visits at Week 4 and every 6 weeks thereafter until Week 52.   
To add an 
optional OLE to 
the trial, reduce 
the targeted 
enrollment and 
modify one of the 
stratification 
factors as 
concomitant use 
of approved IPF 
therapy is now 
allowed 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 11 of 156 
 
Synopsis – Trial Design, Section 9.1 Overall Trial Design and 
Plan 
A futility analysis will be performed when 
 
Synopsis – Trial Design, Section 9.1 Overall Trial Design and 
Plan 
An interim analysis with a futility analysis will be performed when 
 
To specify that 
there will be an 
interim analysis 
at Week 28 
Synopsis – Trial Design 
The IDMC will include at least 1 statistician and at least 
2 clinicians experienced in clinical trials and managing IPF 
subjects.  The IDMC charter will include processes to unblind 
select Horizon personnel who are not directly involved with the 
trial conduct to assess unforeseen issues that may involve subject 
safety or dose selection; otherwise, unblinded information will be 
restricted from Horizon trial team members who are involved in all 
aspects of trial conduct and management.  The IDMC will also 
review accumulating safety data to ensure subject safety.   
Synopsis – Trial Design 
The IDMC will include at least 1 statistician and at least 
2 clinicians experienced in clinical trials and managing IPF 
subjects.  The IDMC charter will include processes to unblind 
select Horizon personnel who are not directly involved with the 
trial conduct to assess unforeseen issues.  A Horizon unblinded 
team may also aid in dose selection and future trial design. 
To mention that 
Horizon 
unblinded 
personnel not 
involved directly 
in trial conduct 
may be involved 
in decisions on 
dose selection 
Synopsis – Trial Design 
Not applicable; figure added to v4.0 of the protocol. 
Synopsis – Trial Design and Figure 9.1 
A trial design figure for the Extension Phase was added; see 
Extension Phase figure and Figure 9.2. 
To add an 
optional OLE to 
the trial 
Synopsis – Subject Population 
Approximately 360 subjects between the ages of 18 and 80 years, 
inclusive, with IPF will be enrolled.  
Synopsis – Subject Population 
Approximately 135 subjects ≥18 years of age with IPF will be 
enrolled. 
To reduce the 
targeted 
enrollment and 
modify the 
inclusion criteria 
with respect to 
age 
Synopsis – Inclusion Criteria and Section 9.3.1 Inclusion 
Criteria 
2. Male or female between the ages of 18 and 80 years, inclusive, 
at Screening. 
3. Current diagnosis of IPF, as defined by American Thoracic 
Society (ATS)/European Respiratory Society (ERS)/Japanese 
Respiratory Society (JRS)/Latin American Thoracic Society 
(ALAT) guidelines [Raghu et al., 2018] and determined by 
Synopsis – Inclusion Criteria and Section 9.3.1 Inclusion 
Criteria 
2. Male or female ≥18 years of age at Screening. 
3. Current diagnosis of IPF, as defined by ATS/ERS/JRS/ALAT 
guidelines [Raghu et al., 2022] and determined by central 
review; the date of initial diagnosis of IPF should be ≤7 years 
prior to Screening.   
To modify the 
inclusion criteria 
with respect to 
age, current and 
initial diagnosis 
of IPF, current 
IPF therapy and 
DLCO; to clarify 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 12 of 156 
 
central review; the date of initial diagnosis of IPF should be 
≥1 year to ≤7 years prior to Screening.   
4. Not currently being treated with specific IPF therapy for the 
reasons below:   
a. intolerant or not responsive to approved IPF therapies 
b. ineligible to receive approved IPF therapies 
c. declines approved IPF therapies 
5. Lung HRCT historically performed within 6 months prior to 
the Screening Visit and according to the minimum 
requirements for IPF diagnosis by central review based on 
subject's HRCT.  If an evaluable HRCT is not available within 
6 months prior to Screening, an HRCT will be performed at 
Screening to determine eligibility, according to the same 
requirements as the historical HRCT.  
6. HRCT shows ≥10% to <50% parenchymal fibrosis 
(reticulation) and <25% honeycombing and the extent of 
fibrotic changes is greater than the extent of emphysema on the 
most recent HRCT scan (central reviewer determined). 
7. Meets all of the following criteria during the Screening Period:   
a. FVC ≥45% and ≤80% predicted of normal 
b. forced expiratory volume in 1 second (FEV1)/FVC ≥0.7 
c. DLCO corrected for hemoglobin is ≥30% and ≤90% 
predicted of normal 
9. Vaccinations are up to date given age, comorbidities (e.g., 
severe acute respiratory syndrome coronavirus 2 [SARS-CoV-
2]), pneumococcal pneumonia, herpes zoster, tetanus) and local 
availability prior to trial drug dosing. 
4. No recent changes or planned changes to the dose or regimen 
for IPF therapy, defined as:   
• 
Receiving a stable dose of IPF-approved therapy 
(i.e., nintedanib or pirfenidone) for a minimum of 
3 months prior to Day 1 with no plans to change the 
background regimen during trial participation, or 
• 
Not currently receiving background IPF-approved therapy 
at Screening (either naïve to IPF-approved therapy or 
previously discontinued any IPF-approved therapy at least 
4 weeks prior to Day 1 or drug-specific, 5 half-lives 
elimination period if longer than 4 weeks), and with no 
current plans to restart treatment during trial participation 
• 
Subjects receiving any additional agent for IPF therapy 
must be on a stable regimen for at least 3 months prior to 
Day 1 with no current plans to change the treatment 
regimen during trial participation.  Any previously 
discontinued therapy used to treat IPF must have been 
discontinued at least 4 weeks prior to Day 1 or 5 half-lives 
for that specific therapy must have elapsed, whichever is 
longer, with no plans to restart the therapy during trial 
participation.  
5. Lung HRCT historically performed within 6 months prior to 
the Screening Visit and according to the minimum 
requirements for IPF diagnosis by central review based on 
subject's HRCT.  If an evaluable HRCT is not available within 
6 months prior to Screening, an HRCT will be performed at 
Screening to determine eligibility, according to the same 
requirements as the historical HRCT.  The HRCT must 
demonstrate an usual interstitial pneumonia or probable usual 
interstitial pneumonia pattern based on central review vendor 
interpretation.  Histopathology in combination with HRCT 
results supportive of an IPF or IPF likely diagnosis according to 
Raghu et al., 2022 can be submitted to support subject 
eligibility.   
6. HRCT shows ≥10% to <50% parenchymal fibrosis 
(reticulation) and the extent of fibrotic changes is greater than 
inclusion criteria 
pertaining to 
lung HRCT and 
remove mention 
of 
honeycombing; 
clarify that 
vaccination 
status is to be 
determined 
according to the 
Investigator’s 
discretion and 
remove examples 
of vaccines 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 13 of 156 
 
the extent of emphysema on the most recent HRCT scan 
(central reviewer determined). 
7. Meets all of the following criteria during the Screening Period, 
as determined by central review:   
a. FVC ≥45% predicted of normal 
b. forced expiratory volume in 1 second (FEV1)/FVC ≥0.7 
c. DLCO corrected for hemoglobin is ≥25% and ≤90% 
predicted of normal 
9. Vaccinations are up to date, according to the Investigator’s 
discretion, given age, comorbidities and local availability prior 
to trial drug dosing. 
Synopsis – Exclusion Criteria and Section 9.3.2 Exclusion 
Criteria 
5. Use of any of the following therapies within 4 weeks prior to 
Screening, during the Screening Period or planned during the 
trial:  prednisone at steady dose >10 mg/day or equivalent or 
cyclosporine A.  Prednisone ≤10 mg/day (or equivalent dosing 
of glucocorticoids) is allowed.  Treatment with any other 
immunosuppressant during the Screening Period through the 
end of trial participation will require consultation with and 
approval by the trial Medical Monitor.  See Table 9.1 and 
Table 9.2 for full details.  
8. Women of childbearing potential (WOCBP) or male subjects 
not agreeing to use highly effective method(s) of birth control 
throughout the trial and for 1 month after last dose of trial drug.  
Male subjects must refrain from sperm donation and females 
from egg/ova donation for this same time period.  Women are 
considered of childbearing potential if they are not 
postmenopausal and not surgically sterile (documented bilateral 
salpingectomy, bilateral oophorectomy or hysterectomy).  A 
postmenopausal state is defined as no menses for 12 months 
without an alternative medical cause.  A high follicle-
stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement 
therapy.  However, in the absence of 12 months of amenorrhea, 
Synopsis – Exclusion Criteria and Section 9.3.2 Exclusion 
Criteria 
5. Use of any of the following therapies within 4 weeks prior to 
Screening, during the Screening Period or planned during the 
trial:  prednisone at steady dose >10 mg/day or equivalent or 
cyclosporine.  Change in regimen or dosage of any 
immunosuppressant during the Screening Period through the 
end of trial participation will require consultation with and 
approval by the trial Medical Monitor.  See Section 9.4.9 for 
full details.  Avoiding the use of listed prohibited treatments 
must not be considered detrimental and must be indicated by 
the treating physician.  Subjects must not be withdrawn from 
any standard-of-care treatment that is considered necessary for 
the clinical management of the subject in order to fulfill the 
trial eligibility requirements. 
8. Women of childbearing potential (WOCBP) or male subjects 
not agreeing to use highly effective method(s) of birth control 
throughout the trial and for 4 weeks after last dose of trial drug.  
Females must refrain from egg/ova donation for 4 weeks after 
the last dose of trial drug and males must refrain from sperm 
donation for 3 months after the last dose of trial drug.  Women 
are considered of childbearing potential if they are not 
postmenopausal and not surgically sterile (documented bilateral 
salpingectomy, bilateral oophorectomy or hysterectomy).  A 
postmenopausal state is defined as no menses for 12 months 
To change 
restrictions 
regarding 
concomitant 
medications and 
add language to 
clarify that 
avoiding the use 
of the prohibited 
medications must 
not be 
detrimental and 
the subjects must 
not be deprived 
of the standard 
of care if deemed 
necessary for the 
clinical 
management of 
the subject, 
include 
requirement for 
condom use and 
for consistency 
with language in 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 14 of 156 
 
a single FSH measurement is insufficient.  A man is considered 
fertile after puberty unless permanently sterile by bilateral 
orchidectomy. 
9. Pregnant or lactating women and women who plan to become 
pregnant or breast feed during the trial and within 1 month after 
the last dose of trial drug. 
12. Known history of positive test for human immunodeficiency 
virus. 
13. Active hepatitis (hepatitis B:  positive hepatitis B surface 
antigen and positive anti-hepatitis B core antibody [anti-
HBcAb] and negative hepatitis B surface antibody [HBsAb] or 
positive for HBcAb with a positive test for HBsAb and with 
presence of hepatitis B virus DNA at Screening; hepatitis C:  
positive anti-hepatitis C virus [anti-HCV] and positive RNA 
HCV). 
19. Total bilirubin >2 × ULN.  Subjects with documented diagnosis 
of Gilbert’s syndrome may be enrolled if their total bilirubin is 
≤3.0 mg/dL. 
21. Any verified Grade 4 laboratory abnormality. 
23. Exposure to an experimental drug (with the exception of 
HZN-825) or experimental vaccine within either 30 days, 
5 half-lives of the test agent, or twice the duration of the 
biological effect of the test agent, whichever is the longest, 
prior to Day 1. 
without an alternative medical cause.  A high follicle-
stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement 
therapy.  However, in the absence of 12 months of amenorrhea, 
a single FSH measurement is insufficient.  Fertile male subjects 
must use a condom throughout the trial and for 4 weeks after 
the last dose of trial drug.  A man is considered fertile after 
puberty unless permanently sterile by bilateral orchidectomy. 
9. Pregnant or lactating women and women who plan to become 
pregnant or breast feed during the trial and within 4 weeks after 
the last dose of trial drug. 
12. Known history of positive test for human immunodeficiency 
virus (HIV).  HIV testing is optional based on Investigator 
assessment, institutional practices or local guidelines to rule out 
suspected HIV or potential for a positive HIV result.  Subject 
consent is required prior to HIV testing. 
13. Active hepatitis (any of the following at Screening): 
Hepatitis B:   
• 
positive hepatitis B surface antigen 
• 
positive for anti-hepatitis B core antibody 
(anti-HBcAb) and a positive test for hepatitis B 
surface antibody (HBsAb) and presence of hepatitis B 
virus DNA 
• 
positive for HBcAb and a negative test for HBsAb 
and presence of hepatitis B virus DNA 
Hepatitis C:   
• 
positive anti-hepatitis C virus (anti-HCV) and positive 
HCV RNA. 
19. Total bilirubin >1.5 × ULN.  Subjects with documented 
diagnosis of Gilbert’s syndrome may be enrolled if their total 
bilirubin is ≤3.0 mg/dL. 
21. Any confirmed Grade 3 or higher laboratory abnormality. 
23. Exposure to an experimental drug or experimental vaccine 
within either 30 days, 5 half-lives of the test agent, or twice the 
Section 9.5.5.2, 
specify 
restrictions 
regarding 
egg/ova and 
sperm donation, 
make HIV testing 
optional (with 
subject consent), 
clarify the 
definition of 
active hepatitis B 
and reformat for 
clarity, modify 
exclusion 
criterion 
pertaining to 
total bilirubin 
and confirmed 
grade of 
laboratory 
abnormality and 
remove the 
exception of 
previous 
HZN-825 
exposure from 
criterion 23 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 15 of 156 
 
duration of the biological effect of the test agent, whichever is 
the longest, prior to Day 1. 
Synopsis 
Not applicable; text added to v4.0 of the protocol. 
Synopsis and Section 9.3.2 Eligibility Criteria for the Extension 
Phase 
Eligibility criteria were added for the Extension Phase; see 
Eligibility Criteria for the Extension Phase in the synopsis and 
Section 9.3.2. 
To add an 
optional OLE to 
the trial 
Synopsis – Dose Regimen/Route of Administration 
Not applicable; text added to v4.0 of the protocol. 
Synopsis – Dose Regimen/Route of Administration 
Extension Phase:  The dose regimen for all subjects will be 
HZN-825 300 mg BID.  Subjects will take 2 HZN-825 150 mg 
tablets orally in the morning and evening with a meal.  The dose for 
the Extension Phase may be modified based on the results of the 
Core Phase. 
To add an 
optional OLE to 
the trial 
Synopsis – Duration of Treatment and Follow-up and 
Schematic of Trial Design 
The planned duration of the Double-blind Treatment Period is 
52 weeks.  All subjects who complete the Double-blind Treatment 
Period will be eligible to enter into a 52-week open-label extension 
trial (HZNP-HZN-825-304).  Subjects not entering the open-label 
extension trial will return to the clinic 4 weeks after the last dose of 
trial drug for a Safety Follow-up Visit. 
Synopsis – Duration of Treatment and Follow-up and 
Schematic of Trial Design (Core Phase) 
The planned duration of the Double-blind Treatment Period of the 
Core Phase is 52 weeks.  All subjects who complete the 
Double-blind Treatment Period may be eligible to enter into the 
Extension Phase of the trial and receive 52 weeks of open-label 
HZN-825.  The total maximum exposure to trial drug during the 
trial is 104 weeks.  Subjects not entering the Extension Phase of the 
trial will return to the clinic 4 weeks after the last dose of trial drug 
for a Safety Follow-up Visit. 
To clarify that 
subjects who 
complete the 
Double-blind 
Treatment 
Period may be 
eligible for the 
Extension Phase 
of the trial 
Synopsis – Statistical Analyses 
Secondary Efficacy Endpoints 
1. Proportion of subjects with decline in FVC % predicted ≥10% 
from Baseline at Week 52. 
Synopsis – Statistical Analyses 
Key Secondary Efficacy Endpoint 
Proportion of subjects with decline in FVC % predicted ≥10% from 
Baseline at Week 52. 
To specify a key 
secondary 
efficacy endpoint 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 16 of 156 
 
Synopsis – Statistical Analyses 
Statistical Analysis of Efficacy and Safety Endpoints 
Efficacy analyses will be performed on the intent-to-treat (ITT) 
analysis set, consisting of all subjects who are randomized to 
treatment; subjects will be analyzed according to the treatment 
group to which they were randomized.  Safety analyses will be 
performed on the safety analysis set, consisting of all subjects who 
receive at least 1 dose or partial dose of trial drug.   
Efficacy 
The estimand for the primary efficacy analyses will be constructed 
to compare the primary endpoint between each dose regimen of 
HZN-825 and placebo using the treatment policy strategy approach 
to intercurrent events.  All subjects who are randomized will be 
included in the primary efficacy analyses (ITT analysis set).   
Synopsis – Statistical Analyses 
Statistical Analysis of Efficacy and Safety Endpoints 
Efficacy analyses will be performed on the full analysis set (FAS), 
consisting of all subjects who are randomized to treatment and take 
at least 1 dose of trial drug; subjects will be analyzed according to 
the treatment group to which they were randomized.  Safety 
analyses will be performed on the safety analysis set, consisting of 
all subjects who receive at least 1 dose or partial dose of trial drug.   
Efficacy 
The estimand for the primary efficacy analyses will be constructed 
to compare the primary endpoint between each dose regimen of 
HZN-825 and placebo using the treatment policy strategy approach 
to intercurrent events.  All subjects who are randomized and take at 
least 1 dose of trial drug will be included in the primary efficacy 
analyses (FAS).  
To change the 
primary analysis 
set from the 
intent-to-treat 
analysis set to 
the full analysis 
set 
Synopsis – Statistical Analyses and Section 9.6.3 Primary 
Efficacy Endpoint Analysis 
A mixed model for repeated measures (MMRM) analysis of 
covariance (ANCOVA) model will be fit to the data using observed 
change in FVC % predicted values from all planned post-Baseline 
assessments (i.e., Weeks 4, 16, 28, 40 and 52) with covariates of 
Baseline FVC % predicted value, stratification factors (prior use of 
IPF therapy [yes, no] and FVC % predicted at Baseline [≥70%, 
<70%]), treatment group, visit and visit-by-treatment group 
interaction.  The unstructured variance-covariance matrix will be 
used in the model.  Treatment group least squares means, 
associated standard error (SE) and their differences (each HZN-825 
group minus placebo separately), SE of the difference, 95% 
confidence intervals (CIs) and p-value overall and for each visit 
will be provided.   
Synopsis – Statistical Analyses and Section 9.6.1.3 Primary 
Efficacy Endpoint Analysis 
A mixed model for repeated measures (MMRM) analysis of 
covariance (ANCOVA) model will be fit to the data using observed 
change in FVC % predicted values from all planned post-Baseline 
assessments (i.e., Weeks 4, 16, 28, 40 and 52) with covariates of 
stratification factors (concomitant use of IPF therapy [yes, no] and 
FVC % predicted at Baseline [≥70%, <70%]), treatment group, visit 
and visit-by-treatment group interaction.  The unstructured 
variance-covariance matrix will be used in the model.  Treatment 
group least squares means, associated standard error (SE) and their 
differences (each HZN-825 group minus placebo separately), SE of 
the difference, 90% confidence intervals (CIs) and p-value overall 
and for each visit will be provided.   
To modify 
statistical 
analysis as 
concomitant use 
of approved IPF 
therapy is now 
allowed and 
change the CI 
from 95% to 
90% and remove 
baseline FVC % 
predicted from 
the model 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 17 of 156 
 
Synopsis – Statistical Analyses and 9.6.3 Primary Efficacy 
Endpoint Analysis 
A tipping point analysis will estimate the difference in true values 
among unobserved data that must occur to change the conclusion 
for each dose (i.e., change the result for each dose from p≤0.025 to 
p>0.025).   
Synopsis – Statistical Analyses and 9.6.1.3 Primary Efficacy 
Endpoint Analysis 
A tipping point analysis will estimate the difference in true values 
among unobserved data that must occur to change the conclusion 
for each dose (i.e., change the result for each dose from p≤0.10 to 
p>0.10).   
To update the 
p-values in the 
description of 
the tipping point 
analysis 
Synopsis – Statistical Analyses and 9.6.4 Secondary Efficacy 
Endpoint Analyses 
The logistic model will provide odds ratio, its 95% CI and p-value 
for comparing each HZN-825 group with the placebo group.   
Synopsis – Statistical Analyses and 9.6.1.4 Secondary Efficacy 
Endpoint Analyses 
The logistic model will provide odds ratio, its 90% CI and p-value 
for comparing each HZN-825 group with the placebo group.   
To change the CI 
from 95% to 
90% 
Synopsis – Statistical Analyses and Section 9.6.8 Interim 
Analyses 
After approximately
 
an analysis of the primary 
efficacy endpoint will be conducted using unblinded, comparative 
data.  This analysis will have 2 potential outcomes: 
• 
If neither dose regimen of HZN-825 shows better efficacy 
compared to placebo with an acceptable safety profile, the 
trial will be discontinued for futility. 
• 
If 1 or both dose regimens of HZN-825 show better 
efficacy compared to placebo with an acceptable safety 
profile, the trial will continue with no changes. 
The futility analysis will not be used to make a positive 
determination of efficacy to stop the trial. 
Conditional power will be used to determine which of the options is 
chosen, with a conditional power of ≥10% required for at least 
1 dose regimen to continue the trial.  
Synopsis – Statistical Analyses and 9.6.1.8 Interim Analysis 
An interim analysis of the primary efficacy endpoint will be 
conducted
 
 
This analysis will have 2 potential outcomes: 
• 
If neither dose regimen of HZN-825 shows better efficacy 
compared to placebo with an acceptable safety profile, the 
trial will be discontinued for futility. 
• 
If 1 or both dose regimens of HZN-825 show better 
efficacy compared to placebo with an acceptable safety 
profile, the trial will continue with no changes. 
The futility analysis will not be used to make a positive 
determination of efficacy to stop the trial. 
Conditional power will be used to determine which of the options is 
chosen, with a conditional power of ≥10% required for at least 
1 dose regimen to continue the trial.  Other statistics, such as 
Bayesian statistics, may also be used for the futility analysis and 
dose selection. 
To specify that 
there will be an 
interim analysis 
at Week 28 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Synopsis – Statistical Analyses and Section 9.6.8 Interim 
Analyses 
Not applicable; text added to v4.0 of the protocol. 
Synopsis – Statistical Analyses and Section 9.6.1.8 Interim 
Analysis 
To support the dose selection and as part of the Week 28 unblinded 
interim analysis, the FVC % predicted change from Baseline at 
Week 28 will be evaluated in subjects who were randomized with 
concomitant standard-of-care treatment at Baseline.  Approximately 
60 subjects in the standard-of-care stratum with 28 weeks of data 
(approximately 20 subjects per arm) will be included.  The positive 
signal in the FVC % predicted change from Baseline at Week 28 
and related results in standard-of-care subjects will support the dose 
selection and future trial design. 
To add statistical 
analysis for data 
from standard-
of-care subjects 
to support dose 
selection at the 
interim analysis 
at Week 28 
Synopsis – Statistical Analyses, Section 9.1 Overall Trial Design 
and Plan, Section 9.4.8 Blinding and Unblinding and 
Section 9.6.8 Interim Analyses 
The IDMC will provide recommendation to select Horizon 
personnel not involved in the oversight of the trial to facilitate trial 
continuation and dose selection for future studies.  For additional 
details, please refer to the IDMC charter for this study. 
Synopsis – Statistical Analyses, Section 9.1 Overall Trial Design 
and Plan, Section 9.4.8 Blinding and Unblinding and 
Section 9.6.1.8 Interim Analysis 
At the interim analysis, the IDMC will provide recommendation to 
select Horizon personnel not involved in the oversight of the trial to 
facilitate trial continuation and dose selection for future trials.  To 
support decisions on future dose selection and future trial design, a 
Horizon unblinded team may be established and receive unblinded 
data and perform ad hoc analyses, as needed.  All unblinded data 
and analysis results made available to the Horizon unblinded team 
will be archived to allow for any potential post hoc assessments of 
bias.  For additional details, please refer to the IDMC charter and 
Blinding Maintenance Plan for this trial. 
To provide 
description 
regarding 
Horizon 
unblinded 
personnel 
involvement in 
decisions on 
future dose 
selection and 
future trial 
design at the 
interim analysis 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Synopsis – Statistical Analyses 
The overall statistical level is α=0.05 (2-sided).  Because 2 dose 
regimens of HZN-825 will be compared to placebo, a Hochberg 
testing procedure will be used for multiple comparison [Hochberg, 
1988].  An additional adjustment will be made to account for the 
futility analysis. Even though there is no chance to stop the trial at 
the futility analysis for conclusion of benefit, a small adjustment to 
the type I error rate (0.001, 2-sided) will be made to account for the 
unblinded, comparative summary.  Therefore, we will use α=0.049 
(2-sided) in the final analysis. The Hochberg testing procedure will 
be used for the primary endpoint first. If one or two dose regimens 
of the primary endpoint are not rejected after completing testing, no 
further testing will occur. If both HZN-825 are statistically 
significantly better than the placebo for primary efficacy endpoint, 
the Hochberg testing procedure will be used for the key secondary 
endpoint similar as the primary endpoint was performed. If both 
dose regimens of HZN-825 for the key secondary endpoint are 
considered significant, subsequent secondary endpoints will be 
tested sequentially within each dose regimen in the order as above, 
using α=0.0245 (2-sided) in a sequential testing procedure.  
Although p-values will be provided for exploratory endpoints, they 
will not be used for inferential purposes. 
Synopsis – Statistical Analyses 
The overall statistical level is α=0.10 (2-sided).  Because 2 dose 
regimens of HZN-825 will be compared to placebo, a hierarchical 
testing procedure will be used for multiple comparisons.  Therefore, 
α=0.10 (2-sided) will be used in the final analysis.  The hierarchical 
testing procedure will be used for the primary and key secondary 
endpoint.  For the primary endpoint, the BID dose will be tested 
versus placebo first; if significant, the QD dose will then be tested.  
If 1 or 2 dose regimens of the primary endpoint are not rejected 
after completing testing, no further testing will occur.  If both HZN-
825 doses are statistically significantly better than placebo for 
primary efficacy endpoint, the testing procedure will continue for 
the key secondary endpoint and will be similar to that performed 
for the primary endpoint.    
Although p-values will be provided for the other secondary and 
exploratory endpoints, they will not be used for inferential 
purposes. 
Since there will 
be a futility 
analysis during 
the interim 
analysis with no 
intention to stop 
the trial due to 
efficacy 
evaluation, there 
is no need to 
adjust the 
significant value 
for multiple 
comparisons at 
interim analysis; 
to update the 
overall statistical 
level of the trial; 
to replace the 
Hochberg 
procedure with a 
hierarchical 
procedure and 
specify that 
p-values for 
other secondary 
endpoints will 
not be used for 
inferential 
purposes 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Synopsis – Statistical Analyses and Section 9.6.4 Secondary 
Efficacy Endpoint Analyses 
The key secondary endpoint will be the proportion of subjects with 
decline in FVC % predicted ≥10% from Baseline at Week 52 and 
will be analyzed using a logistic regression model with baseline 
FVC % predicted, treatment group and stratified by factors used for 
stratifying the randomization.   
Synopsis – Statistical Analyses and Section 9.6.1.4 Secondary 
Efficacy Endpoint Analyses 
The key secondary endpoint will be the proportion of subjects with 
decline in FVC % predicted ≥10% from Baseline at Week 52 and 
will be analyzed using a logistic regression model with treatment 
group and stratified by factors used for stratifying the 
randomization.   
To remove 
baseline FVC % 
predicted from 
the model 
Synopsis – Sample Size Estimate and Section 9.6.10 Sample 
Size and Power Considerations 
A total of 360 subjects (120 subjects per treatment group) will be 
enrolled in the trial.  Based on a prior trial of pirfenidone [Nathan et 
al., 2019] in a similar subject population, change in FVC % 
predicted is expected to have a standard deviation of 6% to 9% 
after 52 weeks of treatment.  Assuming a clinically important 
difference between HZN-825 and placebo is 4% and a common 
standard deviation is 9%, a sample size of 120 subjects per 
treatment group will provide 88% power to detect a clinically 
important difference between each posology of HZN-825 and 
placebo at a significance level of 0.0245, 2-sided. 
Synopsis – Sample Size Estimate and Section 9.6.3 Sample Size 
and Power Considerations 
Approximately 135 subjects (45 subjects per treatment group) will 
be enrolled in the trial.  Based on a prior trial of pirfenidone 
[Nathan et al., 2019] in a similar subject population, change in FVC 
% predicted is expected to have a standard deviation of 6% to 9% 
after 52 weeks of treatment.  Assuming a clinically important 
difference between HZN-825 and placebo is 3% and a common 
standard deviation is 9%, a sample size of 45 subjects per treatment 
group in the Core Phase will provide 85% probability to detect a 
positive signal (FVC % predicted difference for each dose vs. 
placebo at Week 52 >1%) and 70% probability to detect a positive 
signal (FVC % predicted difference for each dose vs. placebo at 
Week 52 >2%).  If the true FVC % predicted difference for each 
dose versus placebo at Week 52 is 0%, then there is only 15% 
probability to detect a positive signal (FVC % predicted difference 
for each dose vs. placebo at Week 52 >2%). 
The sample size for the Extension Phase is based on the number of 
subjects who complete the Core Phase. 
To reduce target 
enrollment, 
update values for 
significance level 
due to updated 
overall 
significance level 
(alpha = 0.10, 
2-sided) and 
update 
description of 
the sample size 
estimate 
Synopsis and Section 9.6 Statistical Methods and Determination 
of Sample Size 
No applicable; text added to v4.0 of the protocol. 
Synopsis and Section 9.6.2 
Statistical analyses were added for the Extension Phase; see 
statistical analyses for the Extension Phase in the synopsis 
(Extension Phase) and Section 9.6.2. 
To add an 
optional OLE to 
the trial 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
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Section 2.1 Schedule of Assessments 
 
Section 2.1 Schedule of Assessments During the Core Phase 
 
To combine rows 
in the Schedule 
of Assessments 
for the Core 
Phase pertaining 
to lung HRCT 
and allow 
subject visits at 
Weeks 22, 34 
and 46 to be 
performed at 
locations other 
than the 
investigational 
site  
Section 2.1 Schedule of Assessments 
Not applicable; footnote added to v4.0 of the protocol. 
Section 2.1 Schedule of Assessments During the Core Phase 
5. Visits may be conducted as home health visits, as available 
within local regions. 
To allow visits at 
Weeks 22, 34 
and 46 to be 
conducted at 
locations other 
than the 
investigational 
site 
Section 2.1 Schedule of Assessments 
 
Footnote 8: Histopathology samples used towards IPF diagnosis (if 
required) will be submitted for central review. 
Section 2.1 Schedule of Assessments During the Core Phase 
 
Footnote 9: Histopathology samples used towards IPF diagnosis (if 
available, but these are not required) will be submitted for central 
review. 
To indicate that 
histopathology is 
not required to 
determine 
subject eligibility 
for the Core 
Phase 
Section 2.1 Schedule of Assessments 
Footnote 11: The lung HRCT scan will be performed for all 
subjects within ±2 weeks of the Week 52/PD Visit. 
Section 2.1 Schedule of Assessments During the Core Phase 
Footnote 9: The lung HRCT scan will be performed for all subjects 
within ±2 weeks of the Week 52/PD Visit.  Central review will be 
performed. 
To emphasize 
that lung HRCT 
at Week 52 will 
include central 
review. 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
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Section 2.1 Schedule of Assessments 
Not applicable; information added to v4.0 of the protocol. 
Section 2.1 Schedule of Assessments During the Core Phase 
 
Footnote 21: HIV testing is optional based on Investigator 
assessment, institutional practices or local guidelines to rule out 
suspected HIV or potential for a positive HIV result.  Subject 
consent is required prior to HIV testing. 
To indicate that 
HIV testing is 
optional at 
Visit 1 
Section 2.1 Schedule of Assessments 
7. Baseline lung HRCT will be performed only if no lung HRCT 
is available within the last 6 months prior to Screening date and 
can be performed any time between Screening and Day 1.  
Results are required to be sent for central review. 
Section 2.1 Schedule of Assessments During the Core Phase 
8. Baseline lung HRCT will be performed only if no previous 
lung HRCT is available within the last 6 months prior to 
Screening date.  This can be performed any time between the 
start of the initial 56 days of Screening and must be completed 
with results from central review vendor prior to Day 1.  
Confirm enough time for results to be made available from the 
central review vendor with turnaround time being up to 5 
business days for results.  Results are required from central 
review vendor. 
To add detail 
around the 
baseline lung 
HRCT 
Not applicable; section added to v4.0 of the protocol. 
Section 2.2 Schedule of Assessments During the Extension 
Phase 
See Section 2.2. 
To add an 
optional OLE to 
the trial 
Section 5.3 Subject Information and Consent 
Not applicable; text added to v4.0 of the protocol. 
Section 5.3 Subject Information and Consent 
Both the Core Phase and the optional open-label Extension Phase 
will require separate ICFs to be signed by subjects. 
To add an 
optional OLE to 
the trial 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
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Section 7.1.1 Idiopathic Pulmonary Fibrosis 
In 2018, the American Thoracic Society (ATS), European 
Respiratory Society (ERS), Japanese Respiratory Society (JRS) and 
the Latin American Thoracic Society (ALAT) jointly updated 
recommendations to reach a consensus for the diagnosis of IPF 
[Raghu et al., 2018].   
Section 7.1.1 Idiopathic Pulmonary Fibrosis 
In 2018, the American Thoracic Society (ATS), European 
Respiratory Society (ERS), Japanese Respiratory Society (JRS) and 
the Latin American Thoracic Society (ALAT) jointly updated 
recommendations to reach a consensus for the diagnosis of IPF and 
provided additional updates to the guidance in 2022 [Raghu et al., 
2018; Raghu et al., 2022].   
To add a citation 
pertaining to 
updates to the 
consensus for the 
diagnosis of IPF 
Section 7.1.3.4 Clinical Experience 
As of 10 January 2021, HZN-825 has been studied in humans in a 
series of 5 Phase 1 clinical trials in healthy subjects and 1 Phase 2a 
trial in subjects with diffuse cutaneous SSc.  Across all trials, HZN-
825 was administered to 94 healthy subjects, including 8 elderly 
subjects, at single doses of up to 1000 mg (i.e., 30, 100, 250, 500 
and 1000 mg) and multiple doses of up to 300 mg twice daily 
(BID) or 600 mg once daily (QD) for 14 days.  Overall, HZN-825 
was well tolerated and showed similar safety and PK profiles across 
healthy subjects (including elderly healthy subjects) and subjects 
with diffuse cutaneous SSc.  No gender differences have been 
observed in systemic exposure or the safety profile.  
As of 10 January 2021, 47 subjects in Phase 1 trials had received a 
600 mg daily dose (38 subjects as 300 mg BID and 9 as 600 mg 
QD).  No SAEs or severe adverse events occurred in Phase 1 
studies.  One subject experienced adverse events leading to 
permanent trial drug discontinuation (Nausea and Abdominal pain) 
on HZN-825 300 mg BID and midazolam. 
In a Phase 2a trial that evaluated 32 subjects with diffuse cutaneous 
SSc, HZN-825 300 mg BID or matching placebo with a 
randomization ratio of 1:1 was given to subjects in an 8-week 
double-blind trial, followed by a 16-week open-label extension, to 
evaluate HZN-825 safety and tolerability, characterize plasma PK, 
assess potential activity on a series of biomarkers hypothesized to 
correlate with clinical severity of scleroderma and assess potential 
clinical benefit.  A signal of therapeutic activity was observed in 
this Phase 2a trial.  Treatment with HZN-825 300 mg BID resulted 
in numerical improvement from Baseline compared with placebo at 
the end of the 8-week double-blind period and at the end of the 
Section 7.1.3.4 Clinical Experience 
HZN-825 has been administered to 102 healthy subjects in 
6 completed Phase 1 clinical trials and 31 subjects with diffuse 
cutaneous SSc in a Phase 2a clinical trial.  In clinical trials 
completed as of 28 February 2022, HZN-825 was well-tolerated 
and showed similar safety and pharmacokinetic profiles across 
healthy subjects (including elderly healthy subjects) and subjects 
with diffuse cutaneous SSc.  In the Phase 2a trial, treatment with 
HZN-825 300 mg twice daily (BID) resulted in numerical 
improvement from baseline compared with placebo at the end of 
the 8-week double-blind period and at the end of the 16-week, 
open-label period based on clinical outcomes, including the 
modified Rodnan skin score (mRSS), Health Assessment 
Questionnaire – Disability Index (HAQ-DI) and other components 
of the Scleroderma Health Assessment Questionnaire (SHAQ), 
overall disease severity and pruritus [Allanore et al., 2018].  
In Phase 1 Trial HZNP-HZN-825-104 in healthy subjects, 
preliminary data suggested there are no relevant mutual drug-drug 
interactions between HZN-825 and pirfenidone/nintedanib at 
clinical doses.  The 90% confidence interval (CI) of the geometric 
least squares mean (GLSM) ratio for both area under the 
concentration-time curve (AUC) and Cmax (test vs reference) was 
within the predefined no-effect bound of (0.70, 1.43). 
No SAEs or severe adverse events (AEs) occurred in Phase 1 trials.  
One subject experienced AEs leading to permanent trial drug 
discontinuation (Nausea and Abdominal pain) on HZN-825 300 mg 
BID and midazolam.  In the Phase 2a trial, HZN-825 300 mg BID 
given up to 24 weeks was well-tolerated.  During the 8-week 
double-blind period, the most frequent treatment-emergent adverse 
To update with 
information from 
the current 
Investigator’s 
Brochure 
(Version 8) and 
report 
preliminary 
results from a 
Phase 1 
drug-drug 
interaction trial 
between 
HZN-825 and 
pirfenidone or 
nintedanib to 
enable the 
addition of 
standard-of-care 
therapy to the 
current trial 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
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16-week open-label period based on clinical outcomes, including 
the modified Rodnan skin score (mRSS), Health Assessment 
Questionnaire – Disability Index (HAQ-DI) and other components 
of Scleroderma Health Assessment Questionnaire (SHAQ), overall 
disease severity (visual analog scale [VAS]) and pruritus (VAS) 
[Allanore et al., 2018].  In this trial, HZN-825 300 mg BID given 
up to 24 weeks was well tolerated.  During the 8-week double-blind 
period, the most frequent treatment-emergent adverse events 
(TEAEs) in the HZN-825 group were headache, diarrhea, nausea 
and fall. 
events (TEAEs) in the HZN-825 group were headache, diarrhea, 
nausea and fall. 
Based on safety results to date, orthostatic hypotension is identified 
as a potential risk of HZN-825 therapy that will continue to be 
monitored as an AE of special interest (AESI) (Section 9.5.5.1.1.4). 
Additional and current information regarding the safety of 
HZN-825 is provided in the current Investigator’s Brochure.  
Not applicable; section added to v4.0 of the protocol. 
Section 7.1.3.5 Benefit/Risk Assessment 
See Section 7.1.3.5. 
To include 
information on 
the potential 
benefits and 
risks of HZN-825 
Section 7.2 Rationale for this Trial 
Not applicable; text added to v4.0 of the protocol. 
Section 7.2 Rationale for this Trial 
See last paragraph in Section 7.2. 
To add an 
optional OLE to 
the trial 
Section 9.1 Overall Trial Design and Plan 
This trial will be conducted at approximately 100 sites in the US, 
Europe, Asia, Australia and New Zealand. 
Section 9.1 Overall Trial Design and Plan 
HZNP-HZN-825-303 (HARBOR) will be conducted at 
approximately 85 trial sites in North America, Europe, South 
America, Africa, Asia (including Japan) and Australia.  The trial 
comprises 2 parts.  Part 1 (Core Phase) is a randomized, double-
blind, placebo-controlled, repeat-dose, multicenter trial to evaluate 
the efficacy, safety and tolerability of HZN-825 in subjects with 
IPF.  Part 2 (Extension Phase) is an optional, open-label, repeat-
dose, multicenter extension of the Core Phase.   
To revise the 
geographical 
regions and 
approximate 
number of sites 
in which the trial 
will be 
conducted and 
add an optional 
OLE to the trial 
Section 9.1 Overall Trial Design and Plan 
Not applicable; text added to v4.0 of the protocol. 
Section 9.1 Overall Trial Design and Plan 
A description of the design of the Extension Phase was added; see 
Design of the Extension Phase of the Trial. 
To add an 
optional OLE to 
the trial 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
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Section 9.1.1 Adjudication Committee 
Cases of respiratory hospitalizations and acute exacerbations will 
each be reviewed by an independent adjudication committee in a 
blinded manner before database lock.  Details outlining the 
responsibilities of the adjudication committee and the parameters 
related to these events of interest will be included in the 
adjudication committee charter. 
Section 9.1.1 Adjudication Committee 
Cases of respiratory hospitalizations and acute exacerbations will 
each be reviewed by an independent adjudication committee in a 
blinded manner before database lock.  Details outlining the 
responsibilities of the adjudication committee and the parameters 
related to these events of interest will be included in the 
adjudication committee charter. 
To clarify that 
the adjudication 
committee will 
only pertain to 
the Core Phase 
Section 9.3.3 Removal of Subjects from Treatment or the Trial 
If a subject prematurely discontinues trial drug, he/she will be 
asked to remain in the trial, participating in the scheduled trial visits 
through Week 52.  If a subject prematurely discontinues trial drug 
and does not wish to continue in the trial, he/she will be asked to 
return for a clinic visit and undergo the Week 52 assessments. 
Section 9.3.3 Removal of Subjects from Treatment or the Trial 
If a subject prematurely discontinues trial drug, he/she will be 
asked to remain in the trial, participating in the scheduled trial visits 
through Week 52 (if discontinuation occurs during the Core Phase) 
or Week 104 (if discontinuation occurs during the Extension 
Phase).  If a subject prematurely discontinues trial drug and does 
not wish to continue in the trial, he/she will be asked to return for a 
clinic visit and undergo the Week 52 (if discontinuation occurs 
during the Core Phase) or Week 104 (if discontinuation occurs 
during the Extension Phase) assessments.  Subjects will be asked to 
return to the clinic for a Safety Follow-up Visit 4 weeks after the 
last dose of HZN-825. 
To add text 
pertaining to the 
Extension Phase 
Section 9.3.3.1 Removal of Subjects from Treatment 
• 
AE.  The subject experiences an AE that imposes an 
unacceptable risk to the subject’s health, or the subject is 
unwilling to continue receiving treatment because of an AE.  
Subjects who discontinue trial drug due to an AE will remain in 
the trial unless they withdraw from the trial for another reason.   
Section 9.3.3.1.1 Removal of Subjects from Trial Drug 
• 
AE or clinically significant laboratory/electrocardiogram 
(ECG) abnormality.  The subject experiences an AE or 
clinically significant laboratory/ECG abnormality that 
imposes an unacceptable risk to the subject’s health, or the 
subject is unwilling to continue receiving treatment because of 
an AE or clinically significant laboratory/ECG abnormality.  
Subjects who discontinue trial drug due to an AE or clinically 
significant laboratory/ECG abnormality will remain in the 
trial unless they withdraw from the trial for another reason.  In 
such cases, if situation is not an immediate emergency, the 
Investigator should contact the trial Medical Monitor. 
To specify that a 
clinically 
significant 
laboratory or 
ECG 
abnormality may 
lead to removal 
of subjects from 
treatment 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
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Section 9.3.3.1 Removal of Subjects from Treatment 
• 
Lack of efficacy.  Discontinuation of trial drug due to lack of 
efficacy is at the discretion of the Investigator or subject and 
may occur if the Investigator determines that trial drug 
administration is not benefitting the subject.  Subjects who 
discontinue trial drug due to lack of efficacy will remain in the 
trial for scheduled safety and efficacy assessments through 
Week 52 unless they also withdraw from the trial for another 
reason 
Section 9.3.3.1.1 Removal of Subjects from Trial Drug 
• 
Lack of efficacy.  Discontinuation of trial drug due to lack of 
efficacy is at the discretion of the Investigator or subject and 
may occur if the Investigator determines that trial drug 
administration is not benefitting the subject.  Subjects who 
discontinue trial drug due to lack of efficacy during the Core 
Phase will remain in the trial for scheduled safety and efficacy 
assessments through Week 52 unless they also withdraw from 
the trial for another reason.  Subjects who discontinue trial 
drug due to lack of efficacy during the Extension Phase will 
remain in the trial for scheduled safety and efficacy 
assessments through Week 104 unless they also withdraw 
from the trial for another reason.  
To add text 
pertaining to the 
Extension Phase 
Section 9.3.3.1 Removal of Subjects from Treatment 
Not applicable; text added to v4.0 of the protocol. 
Section 9.3.3.1.1 Removal of Subjects from Trial Drug 
• 
Restricted medications.  Initiation of any therapy prohibited 
in the trial per Table 9.1 or use of any rescue medications  
prior to Week 28 may lead to subject discontinuation from 
treatment (see Section 9.4.9).  The Investigator may consult 
with the trial Medical Monitor before initiation of the 
restricted medications. 
To add a reason 
for 
discontinuation 
from treatment 
Section 9.3.3.1 Removal of Subjects from Treatment and 
Section 9.3.3.2 Removal of Subjects from the Trial 
• 
Lost to follow-up.  The subject does not return to the clinic for 
scheduled assessments and does not respond to the site’s 
attempts to contact the subject. 
Subjects who prematurely discontinue trial drug during the Double-
blind Treatment Period will be encouraged to continue trial 
participation in all planned visits, particularly returning for the 
Week 52/premature discontinuation assessments.   Subjects who 
discontinue trial drug due to an AE should be followed until 
resolution or stabilization of the AE, or an adequate explanation for 
the event is obtained, in addition to being encouraged to continue 
participation in all planned assessments. 
Section 9.3.3.1.1 Removal of Subjects from Trial Drug and 
Section 9.3.3.2 Removal of Subjects from the Trial 
• 
Lost to follow-up.  The subject does not participate in 
scheduled assessments and does not respond to the site’s 
attempts to contact the subject.  Before the subject is deemed 
‘lost to follow up,’ the Investigator or designee must make 
every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the 
subject’s last known mailing address or local equivalent 
methods).  These contact attempts should be documented in the 
subject’s medical record. 
Subjects who prematurely discontinue trial drug during the Core 
Phase will be encouraged to continue trial participation in all 
planned visits, particularly returning for the Week 52/premature 
discontinuation assessments.   Subjects who prematurely 
To specify that 
attempts should 
be made to 
contact subjects 
who are initially 
lost to follow-up 
and to add text 
pertaining to the 
Extension Phase 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
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discontinue trial drug during the Extension Phase will be 
encouraged to continue trial participation in all planned visits, 
particularly returning for the Week 104/premature discontinuation 
assessments.   Subjects who discontinue trial drug due to an AE 
should be followed until resolution or stabilization of the AE, or an 
adequate explanation for the event is obtained, in addition to being 
encouraged to continue participation in all planned assessments. 
Not applicable; section added to v4.0 of the protocol. 
Section 9.3.3.1.2 Changes to Background Therapy for IPF 
Subjects who change or discontinue standard of care therapy for 
IPF and/or another agent used to treat IPF should continue 
treatment with randomized investigational product for the planned 
duration of the trial unless removal of trial drug is also required due 
to meeting requirements listed in Section 9.3.3.1.1.  The primary 
reason for change in background therapy should be recorded within 
the eCRF. 
To provide 
guidelines for 
subjects who 
change or 
discontinue 
standard of care 
therapy for IPF 
Section 9.3.3.2 Removal of Subjects from the Trial 
• 
Completed.  The subject completed the trial, including the 
Safety Follow-up Visit (if the subject does not enroll into the 
extension trial). 
Section 9.3.3.2 Removal of Subjects from the Trial 
• 
Completed.  The subject completed the Core Phase, including 
the Safety Follow-up Visit (if the subject does not enroll into 
the Extension Phase) or the subject completed the Extension 
Phase, including the Safety Follow-up Visit. 
To add text 
pertaining to the 
Extension Phase 
Section 9.4.1 Treatments Administered 
On Day 1 of the Double-blind Treatment Period, subjects will be 
randomized in a 1:1:1 ratio to receive: 
1. 
HZN-825 300 mg QD, or  
2. 
HZN-825 300 mg BID, or 
3. 
Placebo. 
Section 9.4.1 Treatments Administered 
During the Core Phase of the trial, on Day 1 of the Double-blind 
Treatment Period, subjects will be randomized in a 1:1:1 ratio to 
receive for 52 weeks: 
1. 
HZN-825 300 mg QD, or  
2. 
HZN-825 300 mg BID, or 
3. 
Placebo. 
During the Extension Phase, all subjects will receive open-label 
HZN-825 300 mg BID for 52 weeks.  The dose for the Extension 
Phase may be modified based on the results of the Core Phase. 
To add text 
pertaining to the 
Extension Phase 

Horizon Therapeutics Ireland DAC 
 
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Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
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Section 9.4.6 Trial Drug Administration and Timing of Dose for 
Each Subject 
Subjects will take 2 tablets of trial drug (HZN-825 150 mg and/or 
placebo) orally in the morning and evening with a meal.  In the 
event a subject misses a dose, the dose should be taken along with 
the next planned dose (evening or morning) with a meal. 
Section 9.4.6 Trial Drug Administration and Timing of Dose for 
Each Subject 
Subjects will take 2 tablets of HZN-825 150 mg and/or placebo 
orally in the morning and evening with a meal in the Core Phase. 
Subject will take 2 tablets of HZN-825 150 mg orally in the 
morning and evening with a meal in the Extension Phase.  In the 
event a subject misses a dose, the dose should be taken along with 
the next planned dose (evening or morning) with a meal such that 
4 tablets (up to 600 mg) in total will be taken.  Due to a less than 
dose-proportional increase in HZN-825 systemic exposure, the 
600 mg dose taken in the event of a prior missed dose will be 
considered part of the planned dosing for this trial. 
To add rationale 
to support the 
safety of up to a 
600 mg dose of 
HZN-825 and 
text pertaining to 
the Extension 
Phase 
Section 9.4.6.1 Dose Modifications, Interruptions and Delays 
All dosing instructions are applicable for HZN-825 and placebo 
administration.  
Section 9.4.6.1 Dose Modifications, Interruptions and Delays 
All dosing instructions are applicable for HZN-825 and placebo 
administration.  Any completely missed dose should be recorded on 
the Dosing Interruptions eCRF. 
To specify that 
any completely 
missed dose 
should be 
recorded on the 
eCRF 
Section 9.4.7 Method of Assigning Subjects to Treatment 
Groups 
A randomization schedule will be generated by an unblinded 
statistician not otherwise associated with the trial prior to shipment 
of any trial drug to the clinical sites.  On Day 1 of the Double-blind 
Treatment Period, once all Baseline procedures other than 
administration of trial drug have been completed, authorized site 
personnel will use the interactive response technology (IRT) system 
to randomize the subject.  The Investigator or designee will then 
use the IRT system to obtain dosing information and dispense the 
appropriate trial drug. 
Section 9.4.7 Method of Assigning Subjects to Treatment 
Groups 
For the Core Phase of the study, a randomization schedule will be 
generated by an unblinded statistician not otherwise associated with 
the trial prior to shipment of any trial drug to the clinical sites.  On 
Day 1 of the Double-blind Treatment Period, once all Baseline 
procedures other than administration of trial drug have been 
completed, authorized site personnel will use the interactive 
response technology (IRT) system to randomize the subject.  The 
Investigator or designee will then use the IRT system to obtain 
dosing information and dispense the appropriate trial drug. 
All subjects in the Extension Phase will receive open-label 
HZN-825. 
To add text 
pertaining to the 
Extension Phase 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
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Section 9.4.8 Blinding and Unblinding 
An IDMC will review unblinded safety and efficacy data on a 
scheduled basis.  A futility analysis will be performed when 
 
   
Section 9.4.8 Blinding and Unblinding 
An IDMC will review unblinded safety and efficacy data on a 
scheduled basis during the Core Phase of the trial.  An interim 
analysis with a futility analysis will be performed when 
 
 
  
To specify that 
there will be an 
interim analysis 
at Week 28 and 
that the IDMC 
will review Core 
Phase data only 
Section 9.4.8 Blinding and Unblinding 
Not applicable; text added to v4.0 of the protocol.   
Section 9.4.8 Blinding and Unblinding 
The Extension Phase is open-label, and all subjects will receive 
HZN-825.   
To add text 
pertaining to the 
Extension Phase 
Section 9.4.9 Concomitant Therapy and Restricted Medications 
 
Section 9.4.9 Concomitant Therapy and Restricted Medications 
 
To update 
restrictions 
regarding 
concomitant 
medications and 
remove P-gp 
inhibitors from 
the list of 
restricted 
medications 
because the 
strong P-gp 
transporter 
inhibitor 
itraconazole had 
no impact on 
HZN-825 
exposure at 
clinically 
relevant doses in 
a Phase 1 trial 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Section 9.4.9 Concomitant Therapy and Restricted Medications 
Not applicable; text added in v4.0 of the protocol. 
Section 9.4.9 Concomitant Therapy and Restricted Medications 
Caution should be exercised when coadministering HZN-825 with 
other substrates of CYP2C9 or organic anion transporter 
(OAT)1/OAT3 that have narrow therapeutic windows. 
Caution should be observed when coadministering HZN-825 with 
strong inhibitors of CYP2C9 or CYP2D6. 
HZN-825 and background therapy drugs (pirfenidone/nintedanib) 
are not expected to affect each other’s exposure (see 
Section 7.1.3.4). 
To include some 
additional 
concomitant 
medication 
cautions and 
information 
regarding 
concomitant 
therapy  
Section 9.4.9 Concomitant Therapy and Restricted Medications 
In case of a clinically significant deterioration in lung function, 
initiation of additional therapy is allowed, as described in Table 
9.2, after Week 28.  Detailed (S)AE information following such 
events should be recorded in the eCRF. 
Section 9.4.9 Concomitant Therapy and Restricted Medications 
In case of a clinically significant deterioration in lung function, 
initiation of additional therapy or change in dose of background 
immunosuppressant therapy is allowed after Week 28 following 
consultation with the trial Medical Monitor.  The addition or 
change of background therapy for IPF treatment due to clinical 
deterioration will be labeled as “rescue therapy.”  Detailed (S)AE 
information following such events should be recorded in the eCRF. 
To delete the 
table that 
delineated 
specific rescue 
therapy, as such 
therapy will be 
determined in 
consultation with 
the trial Medical 
Monitor 
Section 9.4.10 Treatment Compliance 
Not applicable; text added in v4.0 of the protocol. 
Section 9.4.10 Treatment Compliance 
Subjects who are not compliant with trial drug dosing should be 
counseled about the importance of taking trial drug on time and 
regularly. 
To stress the 
importance of 
compliance with 
trial drug 
Section 9.5.1.2 6-minute Walk Test 
The 6MWT measures the distance a subject can quickly walk on a 
flat, hard surface in 6 minutes (6-minute walk distance).  This test 
evaluates the global and integrated responses of all the systems 
involved during exercise, including the pulmonary and 
cardiovascular systems, systemic circulation, peripheral circulation, 
blood, neuromuscular units and muscle metabolism.  The 6MWT 
will be performed according to ATS guidelines for the 6MWT 
[Lancaster, 2018].   
Section 9.5.1.2 6-minute Walk Test 
The 6MWT measures the distance a subject can quickly walk on a 
flat, hard surface in 6 minutes (6-minute walk distance).  This test 
evaluates the global and integrated responses of all the systems 
involved during exercise, including the pulmonary and 
cardiovascular systems, systemic circulation, peripheral circulation, 
blood, neuromuscular units and muscle metabolism.  The 6MWT 
will be performed according to ATS guidelines for the 6MWT 
[Lancaster, 2018; ATS Guidelines, 2002].   
To add a 
reference to ATS 
guidelines for 
the 6MWT 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
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Section 9.5.1.4 Diffusing Capacity of the Lungs for Carbon 
Monoxide 
The site will use its own DLCO equipment and conduct all 
measurements with the same DLCO equipment in case that several 
devices are available at the site.  Single-breath DLCO measurement 
will be carried out according to the ATS guideline on DLCO 
measurements [Graham et al., 2017].  
DLCO values will be adjusted for altitude, carboxyhemoglobin and 
the most recent hemoglobin value.  The DLCO assessment should 
always be performed after the FVC measurement and should 
always be started approximately the same time each day.  
Section 9.5.1.4 Diffusing Capacity of the Lungs for Carbon 
Monoxide 
The site will use its own DLCO equipment and conduct all 
measurements with the same DLCO equipment in case that several 
devices are available at the site.  Single-breath DLCO measurement 
will be performed according to the ATS guideline on DLCO 
measurements, when possible [Graham et al., 2017].  Refer to the 
DLCO procedural manual for details.  Sites may request, but will 
not be required, to have subjects attend unscheduled visits for 
repeat DLCO measurements when the initial measurement has not 
passed according to DLCO central review quality control criteria.  
DLCO assessments for determining subject eligibility for the trial 
can be repeated once during the 35-day Screening window.  During 
the treatment period, repeat measurements should be attempted 
within 1 week, if possible.  DLCO results that do not pass quality 
control and for which it is not practical to recall the subject to the 
trial site for a repeat test, Investigators should assess and record 
within the subject’s source documents whether the DLCO 
performed was valid per the site’s standard practices and correlates 
well with the subject’s clinical conditions and previous DLCO 
results.  
DLCO values will be adjusted for altitude when necessary, and the 
most recent hemoglobin value.  An adjustment for 
carboxyhemoglobin will be made if the Investigator determines that 
the subject may have elevated carboxyhemoglobin.  The DLCO 
assessment should always be performed after the FVC 
measurement and should always be started approximately the same 
time each day. 
To clarify 
language for 
obtaining DLCO 
measurement 
Section 9.5.1.6 Patient-reported Outcome Assessments 
Health outcomes assessments are recommended to be administered 
with a paper instrument at the beginning of the visit prior to 
collection of blood for analysis and other scheduled assessments.  
Section 9.5.1.6 Patient-reported Outcome Assessments 
Health outcomes assessments are recommended to be administered 
at the beginning of the visit prior to collection of blood for analysis 
and other scheduled assessments.  
To delete 
mention of paper 
as all data will 
be collected 
electronically for 
the trial 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
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Section 9.5.1.6.5 Exit Interviews 
To understand what subjects perceive as meaningful in terms of 
change in some of the patient-reported outcome measures, semi-
structured qualitative interviews will be conducted by telephone 
after the Week 52 Visit (trial exit) at 4 to 5 sites (n=20 subjects) 
across the US.  Subjects in the exit interviews will be selected in 
order to approximate representativeness of the clinical trial 
population of patients with IPF, with diversity in terms of age, 
gender, ethnicity, urban/rural practice and geographic area of 
residence, where possible.  The one-on-one, semi-structured, 
qualitative interviews will provide a greater understanding of the 
subjects’ treatment experience and meaningful change in select 
patient-reported endpoints. 
Section 9.5.1.6.5 Exit Interviews 
To understand what subjects perceive as meaningful in terms of 
change in some of the patient-reported outcome measures during 
the Core Phase of the trial, semi-structured qualitative interviews 
will be conducted by telephone after the Week 52 Visit (trial exit) 
at 4 to 5 sites (approximately 20 subjects) across the US.  Subjects 
in the exit interviews will be selected in order to approximate 
representativeness of the clinical trial population of patients with 
IPF, with diversity in terms of age, gender, ethnicity, urban/rural 
practice and geographic area of residence, where possible.  The 
one-on-one, semi-structured, qualitative interviews will provide a 
greater understanding of the subjects’ treatment experience and 
meaningful change in select patient-reported endpoints.  These 
interviews are covered and conducted under a separate protocol, 
and are not part of the schedule of assessments for HZNP-HZN-
825-303. 
To clarify that 
exit interviews 
pertain only to 
the Core Phase 
and will be 
covered by a 
separate 
protocol 
Section 9.5.2 Pharmacokinetic Measurements 
If the clinic visit is in the morning, on days when a pre-dose PK 
sample will be collected (i.e., Weeks 4, 16, 28, 40 and 52), subjects 
will be instructed to withhold taking trial drug before the visit and 
drug will be administered in the clinic after the pre-dose PK 
samples are taken.  Time of drug administration in the clinic as well 
as the most recent dosing time prior to the visit will be recorded; 1 
additional PK sample will be collected 2 to 4 hours after dosing in 
the clinic for during the Week16 and Week 28 Visits. 
If the clinic visit is in the afternoon, on days when a pre-dose PK 
sample will be collected (i.e., Weeks 4, 16, 28, 40 and 52), subjects 
will be instructed to take trial drug before 8 a.m. and record dosing 
time; 1 PK sample will be collected anytime during the clinic.  For 
the Week 16 and Week 28 Visits, subjects will receive the evening 
dose during the visit (dosing time to be recorded) if it’s at least 8 
hours from the morning dosing.  An additional PK sample will be 
collected 2 to 4 hours post-dose; otherwise, subjects will be 
instructed to take the evening dose at regular dosing time and no 
post-dose PK sample will be collected. 
Section 9.5.2 Pharmacokinetic Measurements 
If the clinic visit is in the morning, on days when a pre-dose PK 
sample will be collected, subjects will be instructed to withhold 
taking trial drug before the visit, and drug and a meal will be 
administered in the clinic after the pre-dose PK samples are taken.  
Time of drug administration in the clinic as well as the most recent 
dosing time prior to the visit will be recorded; 1 additional PK 
sample will be collected 2 to 4 hours after dosing in the clinic 
during the Week 16, Week 28 and Week 56 Visits. 
If the clinic visit is in the afternoon, on days when a pre-dose PK 
sample will be collected, subjects will be instructed to take trial 
drug before 8 a.m. with a meal and record dosing time; 1 PK 
sample will be collected anytime during the clinic.  For the 
Week 16, Week 28 and Week 56 Visits, subjects, subjects will 
receive the evening dose during the visit (dosing time to be 
recorded) if it is at least 8 hours from the morning dosing.  An 
additional PK sample will be collected 2 to 4 hours post-dose; 
otherwise, subjects will be instructed to take the evening dose at 
regular dosing time and no post-dose PK sample will be collected. 
To provide detail 
regarding taking 
trial drug with a 
meal and add 
Extension Phase 
time points 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Section 9.5.2 Pharmacokinetic Measurements 
Not applicable; table added to v4.0 of the protocol. 
Section 9.5.2 Pharmacokinetic Measurements 
Table 9.2 was added to show the schedule of pharmacokinetic 
sample collection. 
To make 
pharmacokinetic 
sample 
collection 
schedule more 
reader friendly 
Section 9.5.4 Pharmacodynamic Assessments 
Blood samples will be taken during the study to evaluate the 
pharmacodynamic effect of HZN-825.  Serum samples will be 
taken at the following visits:  Day 1 (pre-dose), Week 16 
(pre-dose), Week 28 (pre-dose) and Week 52 (pre-dose).  Samples 
will be stored frozen for potential analysis of biomarkers of the 
LPAR1 pathway or IPF disease.  All samples will be destroyed after 
potential biomarkers have been tested or 5 years after the study is 
complete, whichever comes first. 
A blood sample will be taken at Day 1 (pre-dose), Week 28 (pre-
dose) and Week 52 (pre-dose) for gene expression profiling of 
peripheral blood mononuclear cells (PBMCs) as it relates to disease 
biology.  Instructions for collection, processing, handling, storing 
and shipping of samples will be detailed in a laboratory manual that 
will be provided to each site prior to site initiation. 
Section 9.5.4 Pharmacodynamic Assessments 
Blood samples will be taken during the trial to evaluate the 
pharmacodynamic effect of HZN-825.  Serum samples will be 
taken at the following visits:  Day 1 (pre-dose), Week 16 
(pre-dose), Week 28 (pre-dose), Week 52 (pre-dose), Week 80 
(pre dose) and Week 104 (pre-dose).  Samples will be stored frozen 
for potential analysis of biomarkers of the LPAR1 pathway or IPF 
disease.  All samples will be destroyed after potential biomarkers 
have been tested or 5 years after the trial is complete, whichever 
comes first. 
A blood sample will be taken at Day 1 (pre-dose), Week 28 
(pre dose), Week 52 (pre-dose), Week 80 (pre-dose) and Week 104 
(pre-dose) for gene expression profiling of peripheral blood 
mononuclear cells (PBMCs) as it relates to disease biology.  
Instructions for collection, processing, handling, storing and 
shipping of samples will be detailed in a laboratory manual that will 
be provided to each site prior to site initiation. 
To add 
Extension Phase 
time points 
Section 9.5.5.1.1.1 Adverse Event Definition 
Not applicable; text added in v4.0 of the protocol. 
Section 9.5.5.1.1.1 Adverse Event Definition 
A suspected adverse reaction means any AE for which there is a 
reasonable possibility that the drug caused the AE. Reasonable 
possibility means there is evidence to suggest a causal relationship 
between the drug and the AE. 
To add the 
definition of a 
suspected 
adverse reaction 
and clarify  
Section 9.5.5.1.1.1 Adverse Event Definition 
Pre-existing conditions that worsen during a trial are to be reported 
as AEs.   
Section 9.5.5.1.1.1 Adverse Event Definition 
Exacerbation of a chronic or intermittent pre-existing condition that 
worsens in intensity or increases in frequency during a trial is to be 
reported as an AE. 
To clarify when 
pre-existing 
conditions 
should be 
reported as AEs 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
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Section 9.5.5.1.1.4 Adverse Events of Special Interest 
The following AESI is identified for this trial: 
• 
Orthostatic hypotension.  The Sponsor will consider an 
event of orthostatic hypotension if the following definition 
is met:  a reduction of systolic blood pressure by 
≥20 mmHg or reduction of diastolic blood pressure by 
≥10 mmHg at 1, 5 or 10 minutes in the standing position 
and associated with symptoms such as lightheadedness, 
blurred vision, weakness, fatigue, cognitive impairment, 
nausea, palpitations, tremulousness, headache, presyncope 
and syncope.  
Any spontaneously reported signs or symptoms possibly associated 
with orthostatic hypotension should be reported as AEs.  
Depending on the timing, nature and severity of these spontaneous 
AEs, additional investigations will be conducted at the next 
scheduled visit or at an unscheduled visit, as clinically indicated per 
the Investigator’s judgment.  Whenever possible, the following data 
should be collected:  concomitant medications, and blood pressure 
and heart rate measurements in supine and standing positions.  
Depending on the severity, plasma glucose level and ECG should 
be obtained per Investigator’s clinical judgment. 
The protocol-defined orthostatic hypotension assessment procedure 
(performed as outlined in Section 2.1 on Day 1 and at Weeks 4, 28 
and 52/premature discontinuation and is detailed in the Orthostatic 
Hypotension Assessment Manual in Section 17.9). 
Section 9.5.5.1.1.4 Adverse Events of Special Interest 
The following AESI is identified for this trial: 
• 
Orthostatic hypotension.  The Sponsor will consider an 
event of orthostatic hypotension if the following definition 
is met:  a reduction of systolic blood pressure by 
≥20 mmHg or reduction of diastolic blood pressure by 
≥10 mmHg and associated with symptoms such as 
lightheadedness, blurred vision, weakness, fatigue, 
cognitive impairment, nausea, palpitations, tremulousness, 
headache, presyncope or syncope.  
Orthostatic hypotension assessment procedure will be performed 
during the Core Phase (as outlined in Section 2.1 on Day 1 and at 
Weeks 4, 28 and 52/premature discontinuation) and the Extension 
Phase (as outlined in Section 2.2 on Day 1 [Week 52 of Core 
Phase] and at Weeks 56, 80 and 104/premature discontinuation), as 
is detailed in the Orthostatic Hypotension Assessment Manual in 
Section 17.9. 
If any symptoms occur during the assessment in combination with 
the blood pressure reductions noted above, they are considered as 
part of the orthostatic hypotension event and will not be recorded 
separately as individual AEs. 
If symptoms are reported by the subject throughout the assessment, 
without the blood pressure reductions noted above, then the 
symptoms will be recorded separately as AEs and orthostatic 
hypotension will not be recorded.  
Signs and symptoms associated with orthostatic hypotension 
reported outside of the assessment will be captured as part of 
spontaneously reported AEs at each visit.  
Depending on the timing, nature and severity of these spontaneous 
AEs, additional investigations will be conducted at the next 
scheduled visit or at an unscheduled visit, as clinically indicated per 
the Investigator’s judgment.  Whenever possible, the following data 
should be collected:  concomitant medications, and blood pressure 
and heart rate measurements in supine and standing positions.  
Depending on the severity, plasma glucose level and ECG should 
be obtained per Investigator’s clinical judgment. 
To align with 
language in the 
updated 
Orthostatic 
Hypotension 
Assessment 
Manual and add 
Extension Phase 
time points 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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Section 9.5.5.1.7 Medication Errors 
All cases of medication errors, which include overdose, will be 
documented on the AE eCRF in order to capture this important 
safety information consistently in the database.  An AE that leads to 
or is associated with a medication error, such as an overdose, or an 
SAE of overdose is to be reported according to the procedures 
outlined in Sections 9.5.5.1.2 and 9.5.5.1.5, respectively. 
Section 9.5.5.1.7 Medication Errors 
An AE or SAE that is associated with a medication error, such as an 
overdose, is to be reported according to the procedures outlined in 
Sections 9.5.5.1.2 and 9.5.5.1.5, respectively.  All medication errors 
or overdoses, with or without an AE or SAE, should be recorded as 
a protocol deviation and reported to the trial Medical Monitor in a 
timely manner.  AEs or SAEs may not occur immediately after the 
medication error or overdose.  
Clarifying 
documentation 
and reporting for 
medication 
errors 
Section 9.5.5.2 Pregnancy Reporting 
Pregnancy testing will be performed for WOCBP.  Serum 
pregnancy tests will be analyzed at a central trial laboratory and the 
urine pregnancy tests will be performed locally.  In addition, 
at-home pregnancy tests will be completed by WOCBP at Weeks 8, 
12, 20, 24, 32, 36, 44 and 48, and results will be reported to the site. 
Section 9.5.5.2 Pregnancy Reporting 
Pregnancy testing will be performed for WOCBP.  Serum 
pregnancy tests will be analyzed at a central trial laboratory and the 
urine pregnancy tests will be performed locally.  In addition, 
at-home pregnancy tests will be completed by WOCBP at Weeks 8, 
12, 20, 24, 32, 36, 44 and 48 during the Core Phase and at Weeks 
60, 64, 72, 76, 84, 88, 96 and 100 during the Extension Phase, and 
results will be reported to the site. 
To add 
Extension Phase 
time points 
Section 9.5.5.2 Pregnancy Reporting 
Not applicable; text added in v4.0 of the protocol. 
Section 9.5.5.2 Pregnancy Reporting 
Abstinence should only be used as a contraceptive method if it is in 
line with the subject’s usual and preferred lifestyle.  Periodic 
abstinence (calendar, symptothermal, postovulation methods) is not 
an acceptable method of contraception. 
To include 
additional 
clarifications 
around 
abstinence 
Section 9.5.5.5 Orthostatic Hypotension Assessment 
Blood pressure and heart rate will be measured after the subject has 
rested ≥10 minutes in the supine position and after 1 minute, 5 
minutes and 10 minutes in the standing position.   
Orthostatic hypotension is defined as a reduction of systolic blood 
pressure by ≥20 mmHg or reduction of diastolic blood pressure by 
≥10 mmHg within 10 minutes of standing after being supine, as per 
orthostatic hypotension assessment document provided by the 
Sponsor. 
Symptoms commonly associated with orthostatic hypotension 
include positional nausea, headache, neck ache, lightheadedness, 
dizziness, blurred vision, fatigue, palpitations and impaired 
cognition.  Signs and symptoms associated with orthostatic 
Section 9.5.5.5 Orthostatic Hypotension Assessment 
Blood pressure and heart rate will be measured after the subject has 
rested ≥5 minutes in the supine position and after 1 minute and 3 
minutes in the standing position, as per the Orthostatic Hypotension 
Assessment Manual provided by the Sponsor.  See 
Section 9.5.5.1.1.4 for more information on orthostatic hypotension 
assessment.  
To align with 
language in the 
updated 
Orthostatic 
Hypotension 
Assessment 
Manual and 
minimize 
repetition in the 
protocol 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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hypotension will be captured as part of spontaneously reported AEs 
at each visit. 
Section 9.5.5.7 Electrocardiogram 
ECG results will be recorded as normal or abnormal on the eCRF 
and all abnormal results will be evaluated by the Investigator as 
clinically significant or not clinically significant.  A copy of the 
ECG tracing will remain with the source documents. 
Section 9.5.5.7 Electrocardiogram 
ECG results will be recorded as normal or abnormal on the eCRF 
and all abnormal results will be evaluated by the Investigator as 
clinically significant or not clinically significant.  Any clinically 
significant abnormal ECG, including a QT interval corrected for 
heart rate (QTc) >450 ms, should be confirmed by a repeat resting 
ECG at the same visit.  The site personnel should ensure that ECGs 
are collected after the subject is supine for at least 10 minutes.   
A copy of the ECG tracing will remain with the source documents. 
To specify that a 
repeat resting 
ECG should be 
conducted if a 
clinically 
significant ECG 
result is obtained 
Section 9.5.5.9 Laboratory Tests for Evaluation 
Not applicable; text added to v2.0 of the protocol. 
Section 9.5.5.9 Laboratory Tests for Evaluation 
Urinalysis test parameters were added (see Section 9.5.5.9). 
To specify the 
urinalysis 
laboratory 
parameters 
Section 9.5.5.9 Laboratory Tests for Evaluation 
Not applicable; text added in v4.0 of the protocol. 
Section 9.5.5.9 Laboratory Tests for Evaluation 
The total blood volume for planned visits through the final safety 
follow-up visit in the Core Phase is approximately 305 mL.  
Extension Phase, repeat or unscheduled blood tests performed in 
individual subjects may add to the total blood volume.  Instructions 
for the collection, handling and analysis of clinical laboratory 
samples will be provided to the site prior to trial site initiation. 
To include the 
estimated 
amount of total 
blood volume 
that will be 
collected from 
each subject and 
add text 
pertaining to the 
Extension Phase 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 37 of 156 
 
Section 9.5.7 Trial Procedures 
Not applicable; text added in v4.0 of the protocol. 
Section 9.5.7 Trial Procedures 
Visits at Weeks 22, 34 and 46 during the Core Phase and at 
Weeks 74, 86 and 98 during the Extension Phase may be completed 
at an alternative remote location, e.g., a subject’s home, by a 
visiting home healthcare professional and will be based on local 
availability and as allowable based on local laws and regulations.  
Remote locations will be discussed during the consent process per 
subject’s preference and as approved by the Investigator.  Site 
Investigators will have direct awareness and oversight of remote 
subject visits. 
To allow subject 
visits to be 
performed at 
locations other 
than the trial site 
at Weeks 22, 34 
and 46 during 
the Core Phase 
and at Weeks 74, 
86 and 98 during 
the Extension 
Phase  
Section 9.6.2 Analysis Sets 
Three analysis sets will be defined for this trial.  The intent-to-treat 
(ITT) analysis set will include all subjects who are randomized to 
treatment.  This will be the analysis set used for efficacy data 
analyses and subjects will be analyzed according to the treatment to 
which they were randomized.  The safety analysis set will include 
all subjects who receive at least 1 dose or partial dose of trial drug.  
The PK analysis set will include all subjects who receive at least 
1 dose or partial dose of HZN-825 and have at least 1 PK sample 
post HZN-825 treatment. 
Section 9.6.1.2 Analysis Sets 
Three analysis sets will be defined for this trial.  The full analysis 
set (FAS) will include all subjects who are randomized to treatment 
and take at least 1 dose of trial drug.  This will be the analysis set 
used for efficacy data analyses and subjects will be analyzed 
according to the treatment to which they were randomized.  The 
safety analysis set will include all subjects who receive at least 
1 dose or partial dose of trial drug.  The PK analysis set will include 
all subjects who receive at least 1 dose or partial dose of HZN-825 
and have at least 1 PK sample post HZN-825 treatment. 
To change the 
primary analysis 
set from the 
intent-to-treat 
analysis set to 
the full analysis 
set 
Section 9.6.3 Primary Efficacy Endpoint Analysis 
The estimand for the primary efficacy analyses will be constructed 
to compare the primary endpoint between each dose regimen of 
HZN-825 and placebo using the treatment policy strategy approach 
to intercurrent events.  All subjects who are randomized will be 
included in the primary efficacy analyses (ITT analysis set).  
Section 9.6.1.3 Primary Efficacy Endpoint Analysis 
The estimand for the primary efficacy analyses will be constructed 
to compare the primary endpoint between each dose regimen of 
HZN-825 and placebo using the treatment policy strategy approach 
to intercurrent events.  All subjects who are randomized and take at 
least 1 dose of trial drug will be included in the primary efficacy 
analyses (FAS).  
To change the 
primary analysis 
set from the 
intent-to-treat 
analysis set to 
the full analysis 
set 
Section 9.6.4 Secondary Efficacy Endpoint Analyses 
A Cox proportional hazard model stratified like the previous 
logistic model with baseline FVC % predicted and treatment group 
will provide hazard ratio, its 95% CI and p-value to compare each 
HZN-825 group with the placebo group. 
Section 9.6.1.4 Secondary Efficacy Endpoint Analyses 
A Cox proportional hazard model stratified like the previous 
logistic model with treatment group will provide hazard ratio, its 
90% CI and p-value to compare each HZN-825 group with the 
placebo group. 
To change the CI 
from 95% to 
90% and remove 
baseline FVC % 
predicted from 
the model 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 38 of 156 
 
Section 9.6.9 Multiple Comparisons 
The overall statistical level is α=0.05 (2-sided).  An adjustment will 
be made to account for the futility analysis at the interim analysis.  
Even though there is no chance to stop the trial at the futility 
analysis for conclusion of benefit, a small adjustment to the type I 
error rate with α = 0.001 (2-sided) will be made to account for the 
unblinded, comparative summary.  Therefore, we will use α=0.049 
(2-sided) in the final analysis to evaluate the primary and the key 
secondary endpoints. Because 2 dose regimens of HZN-825 will be 
compared to placebo in the final analysis, the adjustment for 
multiplicity will be used for the primary analysis to preserve the 
family-wise error rate. For the primary endpoint change from 
Baseline in FVC % predicted at Week 52, a Hochberg testing 
procedure [Hochberg, 1988] will be used where the larger P-value 
will be compared at α = 0.049 (2-sided) for the comparisons of 
HZN-825 BID vs. placebo and HZN-825 QD vs placebo. If 
statistically significant, then both comparisons will be considered 
significant. If the larger P-value is not statistically significant, then 
the smaller P-value will be compared at α = 0.0245 (2-sided). If one 
or two dose regimens of the primary endpoint are not rejected after 
completing testing, no further testing will occur. If both HZN-825 
are statistically significantly better than the placebo for primary 
efficacy endpoint, the Hochberg testing procedure will be used for 
the key secondary endpoint with the procedure similar as primary 
endpoint was performed. If both dose regimens of HZN-825 for the 
key secondary endpoint are considered significant, subsequent 
secondary endpoints will be tested sequentially within each dose 
regimen in the order shown in Section 9.6.1.2, using α=0.0245 
(2-sided) in a sequential testing procedure.  
Although p-values will be provided for exploratory endpoints, they 
will not be used for inferential purposes. 
Section 9.6.1.9 Multiple Comparisons 
The overall statistical level is α=0.10 (2-sided).  Because 2 dose 
regimens of HZN-825 will be compared to placebo, a hierarchical 
testing procedure will be used for multiple comparisons.  Therefore, 
α=0.10 (2-sided) will be used in the final analysis.  The hierarchical 
testing procedure will be used for the primary and key secondary 
endpoint.  For the primary endpoint, the BID dose will be tested 
versus placebo first; if significant, the QD dose will then be tested.  
If 1 or 2 dose regimens of the primary endpoint are not rejected 
after completing testing, no further testing will occur.  If both 
HZN-825 doses are statistically significantly better than placebo for 
primary efficacy endpoint, the testing procedure will continue for 
the key secondary endpoint and will be similar to that performed 
for the primary endpoint.   
Although p-values will be provided for the other secondary and 
exploratory endpoints, they will not be used for inferential 
purposes. 
To update values 
for significance 
level due to 
updated overall 
significance level 
(alpha = 
0.10,2-sided) 
and specify that 
p-values for 
other secondary 
endpoints will 
not be used for 
inferential 
purposes 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 39 of 156 
 
Section 16 References 
Not applicable; reference added to v4.0 of the protocol. 
Section 16 References 
ATS Guidelines. ATS Committee on Proficiency Standards for 
Clinical Pulmonary Function Laboratories. ATS statement: 
guidelines for the six-minute walk test. Am J Respir Crit Care Med. 
2002;166(1):111-7. Erratum in: Am J Respir Crit Care Med. 
2016;193(10):1185.  
Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic pulmonary 
fibrosis (an update) and progressive pulmonary fibrosis in adults: 
an official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am 
J Respir Crit Care Med. 2022;205(9):e18-47. 
To add a 
reference to ATS 
guidelines for 
the 6MWT and 
the citation 
pertaining to 
updates to the 
consensus for the 
diagnosis of IPF 
Section 16 References 
Hochberg Y. A Sharper Bonferroni Procedure for Multiple Test of 
Significance. Biometrika 75 (4), 1988;800-802. 
Section 16 References 
This reference was deleted in v4.0 of the protocol. 
To delete a 
reference 
because of the 
change in testing 
procedure for 
multiple 
comparisons 
Section 17 APPENDICES 
Not applicable; text added in v4.0 of the protocol. 
Section 17 APPENDICES 
Versions of the assessment instruments are provided in the 
appendices as examples based on the versions available at the time 
of protocol publication and may differ from the assessment 
instruments actually administered in the trial in the event that 
additional validated versions become available. 
To alert trial 
personnel to the 
fact that the 
actual 
assessment 
instruments used 
may differ from 
those in the 
protocol 
Appendix 17.1 Administrative Appendix 
 
Appendix 17.1 Administrative Appendix 
 
To change the 
Medical Monitor 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  01 December 2022 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 4.0, Amendment 3 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 40 of 156 
 
Appendix 17.1 Administrative Appendix 
 
Appendix 17.1 Administrative Appendix 
 
To add an ex US 
fax number 
Appendix 17.7 SF-12® Health Survey (SF-12) 
This appendix included an old sample of this instrument. 
Appendix 17.7 SF-12® Health Survey (SF-12) 
This appendix was updated with a sample US Version 2.0. 
To update to the 
most current 
version of the 
SF-12 
Appendix 17.9 Orthostatic Hypotension Assessment Manual 
This appendix included Version 1.0, Dated 07 Dec 2020. 
Appendix 17.9 Orthostatic Hypotension Assessment Manual 
This appendix was updated with Version 2.0, Dated 28 Feb 2022, 
that changed the timing and frequency of blood pressure and heart 
rate recordings and removed the Valsalva provocation test and 
patient-reported outcome assessment. 
To align process 
with current 
guidelines, to 
make the process 
more 
understandable 
and improve the 
method of data 
collection 
 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  11 October 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 3.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 5 of 136 
 
SUMMARY OF CHANGES 
Protocol HZNP-HZN-825-303 
Version 3.0 Amendment 2, incorporating Protocol Version 2.0 
Key additions, revisions and clarifications to Version 2.0 of the protocol include: 
• Changing the timing of interim (futility) analyses to occur 
 
 
• Further clarifying in the Schedule of Assessment table that pharmacogenetic assessment 
and sampling is optional. 
• Providing details on the IDMC’s role in recommending dose selection and trial 
continuation. 
• Modifying the statistical analysis to reduce nominal alpha spending at interim (futility) 
analysis and increase power for final analysis. The Hochberg testing procedure will be 
used. 
• Changing the screening period to 35 days to allow additional flexibility. 
• Clarifying that unfasted glucose testing is included in the planned standard chemistry 
panel utilized by the central lab. 
• Clarifying the methods of contact the Investigator can use to report pregnancies to the 
Sponsor. 
• Clarifying that monitoring should continue to the conclusion of pregnancy. 
Changes considered not key, minor wording changes and correction of minor typographical 
errors are not detailed below. 
 
 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  11 October 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 3.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 8 of 136 
 
SUMMARY TABLE OF CHANGES 
Protocol Version 2.0 (02 August 2021) to 
Protocol Version 3.0, Amendment 2 (11 October 2021) 
Text 
Version 2.0, Amendment 1 
02 August 2021 
Amended Text 
Version 3.0, Amendment 2 
11 October 2021 
Reason for 
Change 
Synopsis– Trial Design, Section 9.1 Overall Trial Design and 
Plan,  
 
A futility analysis will be performed 
 
and these unblinded efficacy and safety data will be provided to an 
independent data monitoring committee (IDMC).   
Synopsis– Trial Design, Section 9.1 Overall Trial Design and 
Plan,  
 
A futility analysis will be performed 
 
and these unblinded efficacy and safety data will be 
provided to an independent data monitoring committee (IDMC).   
 
To ensure 
sufficient safety 
and efficacy data 
are available to 
the IDMC to 
inform dose 
selection and 
trial 
continuation 
Synopsis– Criteria for Evaluation 
 
Blood samples for HZN-825 and metabolite(s) PK assessment, 
pharmacodynamic markers and pharmacogenetic assessment (for 
drug metabolizing enzymes and/or transporters) will be collected. 
Synopsis– Criteria for Evaluation 
 
Blood samples for HZN-825 and metabolite(s) PK assessment, 
pharmacodynamic markers and optional pharmacogenetic 
assessment (for drug metabolizing enzymes and/or transporters) 
will be collected. 
To further clarify 
that a blood 
sample for 
pharmacogenetic 
assessment is 
optional 
Synopsis– Efficacy, Section 9.6.8 Interim Analyses 
 
 
 
Synopsis– Efficacy, Section 9.6.8 Interim Analyses 
 
 
To ensure  
sufficient safety 
and efficacy data 
are available to 
the IDMC to 
inform dose 
selection and 
trial 
continuation 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  11 October 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 3.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 9 of 136 
 
Synopsis– Efficacy, Section 9.6.8 Interim Analyses 
 
Not applicable (new addition in Amendment 2) 
 
Synopsis– Efficacy, Section 9.6.8 Interim Analyses 
 
The IDMC will provide recommendation to select Horizon 
personnel not involved in the oversight of the trial to facilitate 
trial continuation and dose selection for future studies.  For 
additional details, please refer to the IDMC charter for this study. 
To provide 
details regarding 
IDMC process 
per IDMC 
charter 
Synopsis– Efficacy 
 
Because 2 dose regimens of HZN-825 will be compared to placebo, 
an adjustment for multiple comparisons will be made and the primary 
DQDO\VLVZLOOEHLQWHUSUHWHGXVLQJĮ -sided, for each 
comparison.  An additional adjustment will be made to account for 
the futility analysis.  Even though there is no chance to stop the trial 
at the futility analysis for conclusion of benefit, a small adjustment to 
the Type I error rate will be made to account for the unblinded, 
comparative summary.  Adjusting the Type I error rate by 0.001 for 
each comparison of an HZN-825 dose regimen to placebo results in 
WKHILQDODQDO\VLVXVLQJĮ WRFRPSDUHHDFK+=1-825 dose 
regimen to placebo. 
Secondary endpoints for comparing each HZN-825 dose regimen to 
placebo will be tested in the order presented above.  Each endpoint 
will be compared to placebo within a dose regimen only if the 
primary and all prior secondary endpoints first show statistical 
significance.  
 
Synopsis– Efficacy 
 
7KHRYHUDOOVWDWLVWLFDOOHYHOLVĮ -sided).  Because 2 dose 
regimens of HZN-825 will be compared to placebo, a Hochberg 
testing procedure will be used for multiple comparison 
[Hochberg, 1988].  An additional adjustment will be made to 
account for the futility analysis. Even though there is no chance to 
stop the trial at the futility analysis for conclusion of benefit, a 
small adjustment to the type I error rate (0.001, 2-sided) will be 
made to account for the unblinded, comparative summary.  
Therefore, ZHZLOOXVHĮ -sided) in the final analysis. 
The Hochberg testing procedure will be used for the primary 
endpoint first. If one or two dose regimens of the primary 
endpoint are not rejected after completing testing, no further 
testing will occur. If both HZN-825 are statistically significantly 
better than the placebo for primary efficacy endpoint, the 
Hochberg testing procedure will be used for the key secondary 
endpoint similar as the primary endpoint was performed. If both 
dose regimens of HZN-825 for the key secondary endpoint are 
considered significant, subsequent secondary endpoints will be 
tested sequentially within each dose regimen in the order as 
DERYHXVLQJĮ -sided) in a sequential testing procedure.   
To reduce the 
nominal alpha 
spending at 
interim (futility) 
analyses and 
increase the 
power for the 
final analysis 
 
The Hochberg 
method, which is 
a more powerful 
test for the 
primary 
endpoint, is used 
in lieu of 
Graphic method. 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  11 October 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 3.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 10 of 136 
 
Synopsis– Sample Size Estimate 
 
Assuming a clinically important difference between HZN-825 and 
placebo is 4% and a common standard deviation is 9%, a sample size 
of 120 subjects per treatment group will provide 88% power to detect 
a clinically important difference between each posology of HZN-825 
and placebo at a significance level of 0.024, 2-sided. 
Synopsis– Sample Size Estimate 
 
Assuming a clinically important difference between HZN-825 
and placebo is 4% and a common standard deviation is 9%, a 
sample size of 120 subjects per treatment group will provide 88% 
power to detect a clinically important difference between each 
posology of HZN-825 and placebo at a significance level of 
0.0245, 2-sided. 
To reduce the 
nominal alpha 
spending at 
interim (futility) 
analyses and 
increase the 
power for the 
final analysis 
Section 2.1 Schedule of Assessments 
 
Screening period is 28 days. 
Section 2.1 Schedule of Assessments 
 
Screening period is 35 days. 
To provide 
additional 
flexibility in the 
screening period 
Section 2.1 Schedule of Assessments 
 
Pharmacogenetic sample24 
Section 2.1 Schedule of Assessments 
 
Pharmacogenetic sample (optional)24 
To further clarify 
that a blood 
sample for 
pharmacogenetic 
assessment is 
optional 
Section 2.1 Schedule of Assessments, Section 9.5.5.9 Laboratory 
Test for Evaluation 
 
Chemistry parameters to be evaluated include total protein, albumin, 
sodium, phosphate, potassium, calcium, chloride, bicarbonate, blood 
urea nitrogen, creatinine, creatine kinase, uric acid, lactate 
dehydrogenase; liver function tests (alanine aminotransferase, 
aspartate aminotransferase, gamma glutamyltransferase, alkaline 
phosphatase, total bile acid, total bilirubin, conjugated and 
unconjugated bilirubin, if applicable).   
 
Section 2.1 Schedule of Assessments, Section 9.5.5.9 
Laboratory Test for Evaluation 
 
Chemistry parameters to be evaluated include total protein, 
albumin, sodium, phosphate, potassium, calcium, chloride, 
bicarbonate, blood urea nitrogen, creatinine, creatine kinase, uric 
acid, glucose, lactate dehydrogenase; liver function tests (alanine 
aminotransferase, aspartate aminotransferase, gamma 
glutamyltransferase, alkaline phosphatase, total bile acid, total 
bilirubin, conjugated and unconjugated bilirubin, if applicable).   
 
To clarify that 
unfasted glucose 
testing is 
included in the 
planned 
standard 
chemistry panel 
utilized by the 
central lab  

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  11 October 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 3.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 11 of 136 
 
Section 9.4.8 Blinding and Unblinding, Section 9.6.8 Interim 
Analyses 
 
A futility analysis will be performed when 
 
 
 
Section 9.4.8 Blinding and Unblinding, Section 9.6.8 Interim 
Analyses 
 
A futility analysis will be performed when 
 
To ensure 
sufficient safety 
and efficacy data 
are available to 
the IDMC to 
inform dose 
selection and 
trial 
continuation 
Section 9.5.5.2 Pregnancy Reporting 
 
The Investigator should report pregnancies to the Sponsor within 24 
hours by submitting the completed pregnancy report form within 24 
hours after becoming aware that the subject/subject’s female partner 
has become pregnant (see Section 17.1 for contact information).  The 
Investigator should counsel the subject and discuss the possible risks 
of continuing the pregnancy.  
Section 9.5.5.2 Pregnancy Reporting 
 
The Investigator should report pregnancies to the Sponsor within 
24 hours by submitting the completed pregnancy report form by 
email to clinicalsafety@horizontherapeutics.com, fax or telephone 
within 24 hours after becoming aware that the subject/subject’s 
female partner has become pregnant (see Section 17.1 for contact 
information).  The Investigator should counsel the subject and 
discuss the possible risks of continuing the pregnancy.   
To clarify the 
contact methods 
the Investigator 
can use to report 
pregnancies to 
the Sponsor 
 
Section 9.5.5.2 Pregnancy Reporting 
 
If pregnancy continues and the subject signs the pregnancy consent 
form, the subject will be contacted 2 weeks after her calculated 
delivery time to provide information about the outcome of the 
pregnancy and the well-being of the child. A final contact will be 
made 8 weeks after delivery, when the subject will again be asked 
about the well-being of the child. 
Section 9.5.5.2 Pregnancy Reporting 
 
If pregnancy continues and the subject signs the pregnancy 
consent form, monitoring should also continue to the conclusion 
of the pregnancy. 
To provide 
clarity for 
pregnancy 
reporting to 
ensure 
monitoring 
continues 
throughout the 
pregnancy 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  11 October 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 3.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 12 of 136 
 
Section 9.6.9 Multiple Comparisons 
 
Because 2 dose regimens of HZN-825 will be compared to placebo, 
an adjustment for multiple comparisons will be made, and the 
SULPDU\DQDO\VLVZLOOEHLQWHUSUHWHGXVLQJĮ -sided, for each 
comparison.  An additional adjustment will be made to account for 
the futility analysis.  Even though there is no chance to stop the trial 
at the futility analysis for conclusion of benefit, a small adjustment to 
the Type I error rate will be made to account for the unblinded, 
comparative summary.  Adjusting the Type I error rate by 0.001 for 
each comparison of a dose regimen of HZN-825 to placebo results in 
WKHILQDODQDO\VLVXVLQJĮ WRFRPSDUHHDFKGRVHUHJLPHQRI
HZN-825 to placebo.  
Secondary endpoints for comparing each dose to placebo will be 
tested in the order presented in Section 9.6.1.2.  Each endpoint will 
be compared to placebo within a dose regimen only if the primary 
and all prior secondary endpoints first show statistical significance.  
The primary and first secondary endpoints for comparing the 2 dose 
regimens will be tested as follows: 
• 
If the primary endpoint is not significant comparing either of 
the 2 dose regimens of HZN-825 to placebo, no further 
alpha-protected testing will be reported. 
• 
If the primary endpoint is significant comparing each of the 
2 dose regimens of HZN-825 to placebo, the first secondary 
endpoint will be tested, comparing each dose regimen to 
placebo, using the Holm procedure with equal weighting, 
first rejecting the null hypothesis associated with the smaller 
p-value if that p-YDOXHLVDQGWKHQUHMHFWLQJWKHQXOO
hypothesis associated with the larger p-value if that p-value 
LV 
o If statistical significance is shown for both dose 
regimens, subsequent secondary endpoints will be 
Section 9.6.9 Multiple Comparisons 
 
The overall statistical level LVĮ -sided).  An adjustment 
will be made to account for the futility analysis at the interim 
analysis.  Even though there is no chance to stop the trial at the 
futility analysis for conclusion of benefit, a small adjustment to 
the type I error rate ZLWKĮ -sided) will be made to 
account for the unblinded, comparative summary.  Therefore, we 
ZLOOXVHĮ -sided) in the final analysis to evaluate the 
primary and the key secondary endpoints. Because 2 dose 
regimens of HZN-825 will be compared to placebo in the final 
analysis, the adjustment for multiplicity will be used for the 
primary analysis to preserve the family-wise error rate. For the 
primary endpoint change from Baseline in FVC % predicted at 
Week 52, a Hochberg testing procedure [Hochberg, 1988] will be 
used where the larger P-YDOXHZLOOEHFRPSDUHGDWĮ -
sided) for the comparisons of HZN-825 BID vs. placebo and 
HZN-825 QD vs placebo. If statistically significant, then both 
comparisons will be considered significant. If the larger P-value 
is not statistically significant, then the smaller P-value will be 
FRPSDUHGDWĮ -sided). If one or two dose regimens of 
the primary endpoint are not rejected after completing testing, no 
further testing will occur . If both HZN-825 are statistically 
significantly better than the placebo for primary efficacy 
endpoint, the Hochberg testing procedure will be used for the key 
secondary endpoint with the procedure similar as primary 
endpoint was performed. If both dose regimens of HZN-825 for 
the key secondary endpoint are considered significant, subsequent 
secondary endpoints will be tested sequentially within each dose 
regimen in the order shown in Section 9.6.1.2, XVLQJĮ 0245 (2-
sided) in a sequential testing procedure.  
To reduce the 
nominal alpha 
spending at 
interim (futility) 
analyses and 
increase the 
power for the 
final analysis 
 
The Hochberg 
method, which is 
a more powerful 
test for the 
primary 
endpoint, is used 
in lieu of 
Graphic method. 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  11 October 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 3.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 13 of 136 
 
tested sequentially within each dose regimen in the 
RUGHUVKRZQDERYHXVLQJĮ LQDVHTXHQWLDO
testing procedure. 
• 
If the primary endpoint is significant comparing exactly 1 of 
the 2 dose regimens of HZN-825 to placebo, the secondary 
HQGSRLQWIRUWKDWGRVHZLOOWKHQEHWHVWHGDWĮ  
o If the comparison of that secondary endpoint is 
VLJQLILFDQWDWĮ WKHSULPDU\HQGSRLQWIRU
comparing the other dose regimen to placebo will 
WKHQEHWHVWHGDWĮ  
o If that comparison also shows significance, the 
secondary endpoint for comparing the other dose 
UHJLPHQWRSODFHERZLOOEHWHVWHGDWĮ  
o If this comparison also shows significance, 
subsequent secondary endpoints will be tested 
sequentially within each dose regimen in the order 
VKRZQDERYHXVLQJĮ LQDVHTXHQWLDOWHVWLQJ
procedure. 
The multiple comparisons procedure described above can be written 
as a graphical procedure [Bretz et al., 2009] and, therefore, controls 
the Type I error rate in the strong sense for the family of all primary 
and secondary endpoints, comparing both dose regimens of HZN-825 
to placebo. 
 
 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  02 August 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 2.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 5 of 130 
 
SUMMARY OF CHANGES 
Protocol HZNP-HZN-825-303 
Version 2.0 Amendment 1, incorporating Protocol Version 1.0 
Key additions, revisions and clarifications to Version 1.0 of the protocol include: 
x Updating the development phase of the trial from 2b/3 to 2b. 
x Specifying evaluation of the proportion of subjects with decline in FVC % predicted 
≥10% from Baseline after 52 weeks of treatment as the first secondary objective. 
x Changing the definition of progression-free survival (PFS) to exclude lung transplant and 
moving the PFS objective to be the last secondary objective pertaining to efficacy. 
x Changing some secondary and exploratory endpoints from analysis of rate to analysis of 
time to event and updating the description of the statistical analyses of these endpoints 
accordingly. 
x Updating the order of trial endpoints to be consistent with changes to the objectives. 
x To minimize the amount of missing data, emphasizing that subjects who prematurely 
discontinue trial drug will be asked to remain in the trial, participating in the scheduled 
trial visits through Week 52. 
x Removing the specification that the 6-Minute Walk Test (6MWT) will be performed at 
selected sites, as it will be performed at all sites. 
x Clarifying the assessments (cardiac, pulmonary and neurologic assessments) to be 
included as part of the physical examination. 
x Changing fasting glucose to be analyzed at the same time points as lipid profile and that 
subjects should fast at least 8 hours before collection of samples for glucose and lipids. 
x Deleting erythrocyte sedimentation rate. 
x Specifying that an independent adjudication committee will review cases of respiratory 
hospitalizations and acute exacerbations. 
x Excluding subjects with moderate to severe hepatic impairment based on Child-Pugh 
score. 
x Specifying that trial drug should be taken with a meal to achieve sufficient targeted drug 
exposure. 
x Allowing for an echocardiogram that has been performed within the 3 months prior to 
Baseline to serve as the Baseline echocardiogram if the subject has been clinically stable 
because some countries have annual echocardiograms as standard of care. 
x Adding organic anion transporter polypeptide (OATP) inhibitors, P-glycoprotein (P-gp) 
inhibitors and a breast cancer resistance protein (BRCP) inhibitor as restricted 
medications. 
x Adding definitions of women of childbearing potential (WOCBP), postmenopausal 
women and fertile men to exclusion criterion 8. 

Horizon Therapeutics Ireland DAC 
HZN-825 
Date:  02 August 2021 
Protocol:  HZNP-HZN-825-303 
IND 154671 
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x Changing pregnancy testing to every 4 weeks, adding specifics regarding pregnancy 
outcome follow-up and adding examples of highly effective contraceptive methods. 
x Adding a statement that development safety update reports will be submitted to countries 
and territories as required. 
x Adding the definition of “end-of-trial.” 
x Clarifying that unblinded information will be restricted from Horizon trial team members 
who are involved in all aspects of trial conduct and management unless other select 
Horizon personnel need to be unblinded. 
x Providing guidance regarding restarting trial drug after a subject experiences clinically 
significant orthostatic hypotension. 
x Providing regional addresses for the central safety laboratory. 
x Removing long-term survival follow-up. 
x Clarifying serious adverse event (SAE) reporting requirements. 
x Adding reasons that a treatment group or the trial may be discontinued. 
x Indicating Investigator discretion in repeat of spirometry prior to rescue medication. 
x Clarifying that, during the Screening Period, cyclophosphamide and prednisone 
>10 mg/day are not permitted for 4 weeks prior to Screening and throughout Screening.
x Clarifying that an abnormal test during Screening may be repeated once during the 
Screening Period. 
x Adding an appendix regarding hospitalization due to respiratory distress. 
Changes considered not key, minor wording changes and correction of minor typographical 
errors are not detailed below. 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  02 August 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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SUMMARY TABLE OF CHANGES 
Protocol Version 1.0 (17 March 2021) to 
Protocol Version 2.0, Amendment 1 (02 August 2021) 
Text 
Version 1.0 
17 March 2021 
Amended Text 
Version 2.0, Amendment 1 
02 August 2021 
Reason for 
Change 
Title Page 
Any death, life-threatening event or other serious adverse event 
experienced by a subject during the course of the trial, whether or not 
judged drug-related, must be reported within 24 hours of knowledge 
of the event by entering the information into the electronic case 
report form (eCRF).  If unable to access the eCRF, the event must be 
reported by submitting the completed Serious Adverse Event Form 
via email or fax to the contacts provided below. 
Title Page 
Any death, life-threatening event or other serious adverse event 
experienced by a subject during the course of the trial, whether or not 
judged drug-related, must be reported immediately, without undue 
delay but not later than 24 hours of knowledge of the event by 
entering the information into the electronic case report form (eCRF).  
If unable to access the eCRF, the event must be reported by 
submitting the completed Serious Adverse Event Form via email or 
fax to the contacts provided below. 
To clarify 
SAE 
reporting 
requirements 
Title Page and Synopsis 
Phase:  2b/3 
Title Page and Synopsis 
Phase:  2b 
To update the 
development 
phase of the 
trial 
Synopsis – Secondary Objectives and Section 8.2 Secondary 
Objectives 
Secondary Objectives 
1. Evaluate the effect of 2 dose regimens of HZN-825 versus 
placebo on the composite endpoint of progression-free survival 
(PFS), where progression includes death, lung transplant or 
decline in FVC ≥10% from Baseline after 52 weeks of treatment. 
2. Evaluate the effect of 2 dose regimens of HZN-825 versus 
placebo on the changes from Baseline in the 6-Minute Walk Test 
(6MWT) after 52 weeks of treatment. 
3. Evaluate the effect of 2 dose regimens of HZN-825 versus 
placebo on the King's Brief Interstitial Lung Disease 
Questionnaire (K-BILD) after 52 weeks of treatment.  
Synopsis – Secondary Objectives and Section 8.2 Secondary 
Objectives 
Secondary Objectives 
1. 
Evaluate the effect of 2 dose regimens of HZN-825 versus 
placebo on the proportion of subjects with decline in FVC % 
predicted ≥10% from Baseline after 52 weeks of treatment. 
2. Evaluate the effect of 2 dose regimens of HZN-825 versus 
placebo on the changes from Baseline in the 6-Minute Walk Test 
(6MWT) after 52 weeks of treatment. 
3. Evaluate the effect of 2 dose regimens of HZN-825 versus 
placebo on the King's Brief Interstitial Lung Disease 
Questionnaire (K-BILD) after 52 weeks of treatment.  
To specify 
the 
proportion of 
subjects with 
decline in 
FVC % 
predicted 
≥10% from 
Baseline 
after 52 
weeks of 
treatment as 
the first 
secondary 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  02 August 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
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4. Evaluate the effect of 2 dose regimens of HZN-825 versus 
placebo on the Living with IPF (L-IPF) after 52 weeks of 
treatment. 
5. Evaluate the effect of 2 dose regimens HZN-825 versus placebo 
on the Leicester Cough Questionnaire (LCQ) after 52 weeks of 
treatment. 
6. Evaluate the effect of 2 dose regimens of HZN-825 versus 
placebo on the rate of hospitalization due to respiratory distress 
up to 52 weeks of treatment. 
7. Assess safety and tolerability of HZN-825 based on adverse 
events (AEs), serious adverse events (SAEs) and adverse event of 
special interest (AESI). 
8. Evaluate the pharmacokinetics (PK) of HZN-825 and 
metabolite(s). 
4. Evaluate the effect of 2 dose regimens of HZN-825 versus 
placebo on the Living with IPF (L-IPF) after 52 weeks of 
treatment. 
5. Evaluate the effect of 2 dose regimens HZN-825 versus placebo 
on the Leicester Cough Questionnaire (LCQ) after 52 weeks of 
treatment. 
6. Evaluate the effect of 2 dose regimens of HZN-825 versus 
placebo on the rate of hospitalization due to respiratory distress 
up to 52 weeks of treatment. 
7. Evaluate the effect of 2 dose regimens of HZN-825 versus 
placebo on the composite endpoint of progression-free survival 
(PFS), where progression includes decline in FVC % predicted 
≥10% from Baseline or death over 52 weeks of treatment. 
8. Assess safety and tolerability of HZN-825 based on adverse 
events (AEs), serious adverse events (SAEs) and adverse event of 
special interest (AESI). 
9. Evaluate the pharmacokinetics (PK) of HZN-825 and 
metabolite(s). 
objective, 
change the 
definition of 
PFS to 
exclude lung 
transplant 
and move the 
PFS 
objective to 
be the last 
secondary 
objective 
pertaining to 
efficacy 
Synopsis – Trial Design and Section 9.1 Overall Trial Design and 
Plan 
The trial will include up to an 8-week Screening Period and a 
52-week Double-blind Treatment Period.  Subjects will take their 
first dose of trial drug at the clinic on Day 1 (Week 0) and will return 
to the clinic for trial visits at Week 4 and every 6 weeks thereafter 
until Week 52.  There will be remote (telephone) visits at Weeks 2 
and 6 to monitor safety.  Subjects who complete the 52-week Double-
blind Treatment Period may be eligible to enter a 52-week extension 
trial (HZNP-HZN-825-304).  If the subject does not enroll into the 
extension trial, a Safety Follow-up Visit will occur 4 weeks after the 
last dose of trial drug. 
Synopsis – Trial Design and Section 9.1 Overall Trial Design and 
Plan 
The trial will include up to an 8-week Screening Period and a 
52-week Double-blind Treatment Period.  Subjects will take their 
first dose of trial drug at the clinic on Day 1 (Week 0) and will return 
to the clinic for trial visits at Week 4 and every 6 weeks thereafter 
until Week 52.  Subjects who complete the 52-week Double-blind 
Treatment Period may be eligible to enter a 52-week extension trial 
(HZNP-HZN-825-304).  If the subject does not enroll into the 
extension trial, a Safety Follow-up Visit will occur 4 weeks after the 
last dose of trial drug. 
If a subject prematurely discontinues trial drug, he/she will be asked 
to remain in the trial, participating in the scheduled trial visits 
through Week 52.  If a subject prematurely discontinues trial drug 
and does not wish to continue in the trial, he/she will be asked to 
return for a clinic visit and undergo the Week 52 assessments. 
To minimize 
the amount of 
missing data, 
emphasizing 
that subjects 
who 
prematurely 
discontinue 
trial drug 
will be asked 
to remain in 
the trial, 
participating 
in the 
scheduled 
trial visits 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  02 August 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 2.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 9 of 130 
 
through 
Week 52 
Synopsis – Trial Design, Section 9.1 Overall Trial Design and 
Plan and Section 9.4.8 Blinding and Unblinding 
The IDMC charter will include processes to unblind select Horizon 
personnel who are not directly involved with the trial conduct to 
assess unforeseen issues that may involve subject safety or dose 
selection; otherwise, unblinded information will be restricted to 
IDMC members who are not involved in other aspects of the trial.   
Synopsis – Trial Design, Section 9.1 Overall Trial Design and 
Plan and Section 9.4.8 Blinding and Unblinding 
The IDMC charter will include processes to unblind select Horizon 
personnel who are not directly involved with the trial conduct to 
assess unforeseen issues that may involve subject safety or dose 
selection; otherwise, unblinded information will be restricted from 
Horizon trial team members who are involved in all aspects of trial 
conduct and management.   
 
To clarify 
that 
unblinded 
information 
will be 
restricted 
from Horizon 
trial team 
members 
who are 
involved in 
all aspects of 
trial conduct 
and 
management 
unless other 
select 
Horizon 
personnel 
need to be 
unblinded 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  02 August 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 2.0 
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 Page 10 of 130 
 
Synopsis – Exclusion Criteria and Section 9.3.2 Exclusion 
Criteria 
8.  Women of childbearing potential or male subjects not agreeing to 
use highly effective method(s) of birth control throughout the 
trial and for 1 month after last dose of trial drug.  Male subjects 
must refrain from sperm donation and females from egg/ova 
donation for this same time period. 
Synopsis – Exclusion Criteria and Section 9.3.2 Exclusion 
Criteria 
8. Women of childbearing potential (WOCBP) or male subjects not 
agreeing to use highly effective method(s) of birth control 
throughout the trial and for 1 month after last dose of trial drug.  
Male subjects must refrain from sperm donation and females from 
egg/ova donation for this same time period.  Women are 
considered of childbearing potential if they are not 
postmenopausal and not surgically sterile (documented bilateral 
salpingectomy, bilateral oophorectomy or hysterectomy).  A 
postmenopausal state is defined as no menses for 12 months 
without an alternative medical cause.  A high follicle-stimulating 
hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy.  However, in the 
absence of 12 months of amenorrhea, a single FSH measurement 
is insufficient.  A man is considered fertile after puberty unless 
permanently sterile by bilateral orchidectomy. 
To define 
WOCBP, 
post-
menopausal 
women and 
fertile men 
Synopsis  
Not applicable (criterion added to v2.0 of the protocol) 
Synopsis – Exclusion Criteria and Section 9.3.2 Exclusion 
Criteria 
20. Moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic 
impairment according to the Child-Pugh scoring system. 
To exclude 
subjects with 
moderate to 
severe 
hepatic 
impairment 
Synopsis– Dose Regimen/Route of Administration  
Subjects will take 2 tablets of trial drug orally in the morning and 
evening with food. 
Synopsis– Dose Regimen/Route of Administration 
Subjects will take 2 tablets of trial drug orally in the morning and 
evening with a meal. 
“With food” 
could be 
interpreted 
as dosing 
with a snack, 
which is not 
sufficient for 
targeted drug 
exposure 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  02 August 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 2.0 
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Synopsis – Statistical Analyses and Section 9.6.1.2 Secondary 
Efficacy Endpoints and Section 9.6.1.3 Exploratory Endpoints 
Secondary Efficacy Endpoints 
1. Proportion of subjects meeting the composite endpoint of PFS at 
Week 52, where progression includes death, lung transplant or 
decline in FVC ≥10%. 
2. Change from Baseline in the 6MWT results to Week 52. 
3. Change from Baseline in K-BILD scores to Week 52.  
4. Change from Baseline in L-IPF scores to Week 52.  
5. Change from Baseline in LCQ scores to Week 52. 
6. Rate of hospitalization due to respiratory distress up to Week 52. 
Exploratory Endpoints 
1. 
2. 
3. 
4. 
5. 
6. Rate of mortality due to respiratory deterioration up to Week 52. 
7. 
(Remaining exploratory endpoints are not shown because no change 
from v1.0 to v2.0 of the protocol.) 
Synopsis – Statistical Analyses and Section 9.6.1.2 Secondary 
Efficacy Endpoints and Section 9.6.1.3 Exploratory Endpoints 
Secondary Efficacy Endpoints 
1. 
Proportion of subjects with decline in FVC % predicted 
≥10% from Baseline at Week 52. 
2. Change from Baseline in the 6MWT results to Week 52. 
3. Change from Baseline in K-BILD scores to Week 52.  
4. Change from Baseline in L-IPF scores to Week 52.  
5. Change from Baseline in LCQ scores to Week 52. 
6. Time to first hospitalization due to respiratory distress from 
Baseline up to Week 52. 
7. Time to first onset of the composite endpoint of PFS from 
Baseline up to Week 52, where progression includes decline in 
FVC % predicted ≥10% or death. 
Exploratory Endpoints 
1. 
2. 
3. 
4. 
5. 
6. Time to death due to respiratory deterioration from Baseline up 
to Week 52. 
7. 
To specify 
the 
proportion of 
subjects with 
decline in 
FVC % 
predicted 
≥10% from 
Baseline 
after 
52 weeks of 
treatment as 
the first 
secondary 
endpoint, 
change the 
definition of 
PFS to 
exclude lung 
transplant, 
move the 
PFS endpoint 
to be the last 
secondary 
efficacy 
endpoint and 
change some 
secondary 
and 
 
 
 
 
 
 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  02 August 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 2.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 12 of 130 
 
Synopsis – Statistical Analyses and Section 9.6.4 Secondary 
Efficacy Endpoint Analyses 
The first ranked secondary endpoint will be the proportion of subjects 
meeting the composite endpoint of PFS (including death, lung 
transplant or decline in FVC ≥10%).  The PFS endpoint will be 
analyzed using a stratified analysis, with stratification by factors used 
for stratifying the randomization.  Within each of the 4 resulting 
strata, data will be summarized and the strata will be combined into a 
single test statistic using Cochran-Mantel-Haenszel weighting.  
Statistical significance for the PFS endpoint will only be concluded if 
statistical significance is achieved for the primary efficacy endpoint.   
Synopsis – Statistical Analyses and Section 9.6.4 Secondary 
Efficacy Endpoint Analyses 
The key secondary endpoint will be the proportion of subjects with 
decline in FVC % predicted ≥10% from Baseline at Week 52 and will 
be analyzed using a logistic regression model with baseline FVC % 
predicted, treatment group and stratified by factors used for 
stratifying the randomization. The logistic model will provide odds 
ratio, its 95% CI and p-value for comparing each HZN-825 group 
with the placebo group.  Statistical significance for the key secondary 
endpoint will only be concluded if statistical significance is achieved 
for the primary efficacy endpoint.   
To specify 
the 
proportion of 
subjects with 
decline in 
FVC % 
predicted 
≥10% from 
Baseline 
after 
52 weeks of 
treatment as 
the first 
secondary 
endpoint 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  02 August 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 2.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 13 of 130 
 
Section 2.1 Schedule of Assessments 
 
Section 2.1 Schedule of Assessments (continued) 
 
 
Section 2.1 Schedule of Assessments 
 
Section 2.1 Schedule of Assessments (continued) 
 
 
 
To: 
clarify that an 
abnormal test 
during 
Screening 
may be 
repeated once 
during the 
Screening 
Period; 
change 
pregnancy 
testing to 
every 4 weeks 
and fasting 
glucose to be 
analyzed at 
the same time 
points as lipid 
profile and 
that subjects 
should fast at 
least 8 hours 
before 
collection of 
samples for 
glucose and 
lipids; delete 
erythrocyte 
sedimenta-
tion rate from 
the protocol; 
allow for an 
echocardiogr
am that has 
been 
performed 
within the 3 
months prior 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  02 August 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 2.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 14 of 130 
 
Section 2.1 Schedule of Assessments (continued) 
 
Section 2.1 Schedule of Assessments (continued) 
 
Section 2.1 Schedule of Assessments (continued) 
 
Section 2.1 Schedule of Assessments (continued) 
 
to Baseline to 
serve as the 
Baseline 
echocardiogr
am if the 
subject has 
been 
clinically 
stable; 
remove the 
specification 
that the 
6MWT will be 
performed at 
selected sites, 
as it will be 
performed at 
all sites; 
clarify the 
assessments 
to be included 
as part of the 
examination 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  02 August 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 2.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 15 of 130 
 
Section 6 Investigators and Trial Administrative Structure 
 
Section 6 Investigators and Trial Administrative Structure 
 
To provide 
regional 
addresses for 
the central 
safety 
laboratory 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  02 August 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 2.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 16 of 130 
 
Section 7.3 Rational for Dose Selection 
The dose regimens to be evaluated in this trial are 300 mg QD and 
300 mg BID with food using HZN-825 tablets manufactured by 
.  These regimens are selected based on a 
comprehensive review of preclinical data assessing in vitro LPAR1 
inhibitory activity, information from rodent fibrosis models, Phase 1 
PK data and information from a Phase 2a trial in SSc subjects.   
The completed Phase 2a trial in diffuse cutaneous SSc supports the 
safety and potential efficacy of 300 mg BID for up to 24 weeks of 
treatment.  The exposures and safety profiles of HZN-825 in this trial 
were similar to those previously observed in healthy subjects, and 
positive changes in mRSS, HAQ-DI and LPAR1 pathway genes were 
detected.  The observed mean steady-state trough concentration 
(
) in the Phase 2a trial is 
thus considered a relevant target exposure of HZN-825 for IPF, as by 
blocking LPAR1 signaling, HZN-825 has the potential to specifically 
and efficaciously resolve the underlying pathologies of IPF, thereby 
reducing the severity and progression of the disease. 
Preclinical data also support the HZN-825 exposures targeted for this 
trial.  The minimum total Ctrough in humans needed for inhibition of 
LPAR1 activity was between 25.3 and 1536 ng/mL based on in vitro 
potency evaluations.  The half-maximal inhibitory concentration 
(IC50) of HZN-825 against LPAR1 activity ranged from 1.1 to 
66.8 ng/mL without presence of albumin, corresponding to 25.3 to 
1536 ng/mL after adjusting for the 23-fold shift in IC50 in the 
presence of 3.5% albumin (in the range of human plasma albumin 
level of 3.5 to 4.5 g/dL [Human Albumin 2009].  In a rat 
deoxycorticosterone acetate (DOCA) salt model, HZN-825 reduced 
cardiac hypertrophy, hydroxyproline levels and kidney damage at 
10 mg/kg BID, with a steady-state area under the concentration-time 
curve from 0 to 12 hours (AUC0-12h) of 12000 ng*h/mL.   
Based on preliminary PK results from Trial HZNP-HZN-825-101, 
300 mg BID dosing with food using HZN-825 Aptuit tablets is 
expected to achieve similar steady-state Ctrough as observed in the 
Phase 2a trial in subjects with SSc and is selected as the higher dose 
in this trial.  Additionally, there was less than dose-proportional 
Section 7.3 Rational for Dose Selection 
The dose regimens to be evaluated in this trial are 300 mg QD and 
300 mg BID with a meal using HZN-825 tablets manufactured by 
.  These regimens are selected based on a 
comprehensive review of preclinical data assessing in vitro LPAR1 
inhibitory activity, information from rodent fibrosis models, Phase 1 
PK data and information from a Phase 2a trial in subjects with diffuse 
cutaneous SSc.   
The completed Phase 2a trial in diffuse cutaneous SSc supports the 
safety and potential efficacy of 300 mg BID for up to 24 weeks of 
treatment.  The exposures and safety profiles of HZN-825 in this trial 
were similar to those previously observed in healthy subjects, and 
positive changes in mRSS, HAQ-DI and LPAR1 pathway genes were 
detected.  The observed mean steady-state trough concentration 
(
) in the Phase 2a trial is 
thus considered a relevant target exposure of HZN-825 for IPF, as by 
blocking LPAR1 signaling, HZN-825 has the potential to specifically 
and efficaciously resolve the underlying pathologies of IPF, thereby 
reducing the severity and progression of the disease. 
Preclinical data also support the HZN-825 exposures targeted for this 
trial.  The minimum total Ctrough in humans needed for inhibition of 
LPAR1 activity was between 25.3 and 1536 ng/mL based on in vitro 
potency evaluations.  The half-maximal inhibitory concentration 
(IC50) of HZN-825 against LPAR1 activity ranged from 1.1 to 
66.8 ng/mL without presence of albumin, corresponding to 25.3 to 
1536 ng/mL after adjusting for the 23-fold shift in IC50 in the 
presence of 3.5% albumin (in the range of human plasma albumin 
level of 3.5 to 4.5 g/dL [Human Albumin 2009].  In a rat 
deoxycorticosterone acetate (DOCA) salt model, HZN-825 reduced 
cardiac hypertrophy, hydroxyproline levels and kidney damage at 
10 mg/kg BID, with a steady-state area under the concentration-time 
curve from 0 to 12 hours (AUC0-12h) of 12000 ng*h/mL.   
Based on preliminary PK results from Trial HZNP-HZN-825-101, 
300 mg BID dosing with a meal using HZN-825 Aptuit tablets is 
expected to achieve similar steady-state Ctrough as observed in the 
Phase 2a trial in subjects with SSc and is selected as the higher dose 
“With food” 
could be 
interpreted 
as dosing 
with a snack, 
which is not 
sufficient for 
targeted drug 
exposure 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  02 August 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 2.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 17 of 130 
 
increase in systemic exposures of HZN-825 from 150 mg to 300 mg 
(about 30% and 40% increase in Cmax and area under the 
concentration-time curve [AUC], respectively) and no exposure 
increase from 300 mg to 450 mg with Aptuit tablets; also, food intake 
increased HZN-825 exposures.  Therefore, a second, less-frequent 
dose regimen, 300 mg QD with food, is selected to provide a broad 
range of HZN-825 exposures (2-fold different for AUC and ~6-fold 
different for steady-state Ctrough) for evaluation in this trial, a dose that 
is still expected to achieve pharmacologically active steady-state 
Ctrough above the concentrations needed for in vitro inhibition of 
LPAR1 activity.  Additionally, after adjusting for plasma protein 
binding of HZN-825 between humans and rats (99.97% and 99.92%, 
respectively), both 300 mg QD and 300 mg BID are also expected to 
achieve AUC0-12h above the AUC0-12h that showed efficacy in the rat 
DOCA model.   
In summary, the plasma exposures associated with both HZN-825 
300 mg QD and 300 mg BID are anticipated to be well tolerated and 
have clinical efficacy.  The range of exposures achieved with these 
dose regimens will support efficient dose-range exploration and allow 
exposure-response evaluation of HZN-825 in subjects with IPF 
in this trial.  Additionally, there was less than dose-proportional 
increase in systemic exposures of HZN-825 from 150 mg to 300 mg 
(about 30% and 40% increase in Cmax and area under the 
concentration-time curve [AUC], respectively) and no exposure 
increase from 300 mg to 450 mg with Aptuit tablets; also, food intake 
increased HZN-825 exposures.  Therefore, a second, less-frequent 
dose regimen, 300 mg QD with a meal, is selected to provide a broad 
range of HZN-825 exposures (2-fold different for AUC and ~6-fold 
different for steady-state Ctrough) for evaluation in this trial, a dose that 
is still expected to achieve pharmacologically active steady-state 
Ctrough above the concentrations needed for in vitro inhibition of 
LPAR1 activity.  Additionally, after adjusting for plasma protein 
binding of HZN-825 between humans and rats (99.97% and 99.92%, 
respectively), both 300 mg QD and 300 mg BID are also expected to 
achieve AUC0-12h above the AUC0-12h that showed efficacy in the rat 
DOCA model.   
In summary, the plasma exposures associated with both HZN-825 
300 mg QD and 300 mg BID are anticipated to be well tolerated and 
have clinical efficacy.  The range of exposures achieved with these 
dose regimens will support efficient dose-range exploration and allow 
exposure-response evaluation of HZN-825 in subjects with IPF. 
Not applicable (section added to v2.0 of the protocol) 
Section 9.1.1 Adjudication Committee 
Cases of respiratory hospitalizations and acute exacerbations will 
each be reviewed by an independent adjudication committee in a 
blinded manner before database lock.  Details outlining the 
responsibilities of the adjudication committee and the parameters 
related to these events of interest will be included in the adjudication 
committee charter. 
To specify 
that an 
independent 
adjudication 
committee 
will review 
cases of 
respiratory 
hospitalizatio
ns and acute 
exacerba-
tions 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  02 August 2021 
 
Protocol:  HZNP-HZN-825-303 
IND 154671 
 
Version 2.0 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 18 of 130 
 
Section 9.3.3 Removal of Subjects from Treatment or the Trial 
All subjects are free to withdraw from trial participation at any time, 
for any reason and without prejudice to their further medical care.  In 
addition, the Investigator may terminate a subject from treatment at 
any time, if further participation in the trial is not in the best interest 
of the subject. 
Section 9.3.3 Removal of Subjects from Treatment or the Trial 
All subjects are free to withdraw from trial participation at any time, 
for any reason and without prejudice to their further medical care.  In 
addition, the Investigator may terminate a subject from treatment at 
any time, if further treatment in the trial is not in the best interest of 
the subject. 
If a subject prematurely discontinues trial drug, he/she will be asked 
to remain in the trial, participating in the scheduled trial visits 
through Week 52.  If a subject prematurely discontinues trial drug 
and does not wish to continue in the trial, he/she will be asked to 
return for a clinic visit and undergo the Week 52 assessments. 
To minimize 
the amount of 
missing data, 
emphasizing 
that subjects 
who 
prematurely 
discontinue 
trial drug 
will be asked 
to remain in 
the trial, 
participating 
in the 
scheduled 
trial visits 
through 
Week 52 
Not applicable (section added to v2.0 of the protocol) 
Section 9.3.4 Discontinuation of a Treatment Group or the Trial 
The following events, if applicable, may cause premature termination 
of the clinical trial or trial arms:  unjustifiable risk and/or toxicity in 
risk-benefit analysis (decision taken by Sponsor or representative), 
e.g., when adverse events occur, unknown to date in respect of their 
nature, severity, duration or frequency in relation to the current 
established safety profile (substantial changes in risk-benefit 
considerations), and, therefore, medical and/or ethical reasons affect 
the continued performance of the trial; new scientific evidence 
becomes available during the trial that could affect the subject’s 
safety (benefit-risk analysis no longer positive), e.g., new insights 
from other clinical trials; request of the Sponsor with or without 
recommendation from a data safety monitoring board, or of a 
regulatory agency, e.g., as a consequence of inspection; favorable 
opinion withdrawn by the ethics commission; in case of difficulties in 
the recruitment of the planned number of subjects in the indicated 
time (insufficient recruitment rate); and withdrawal of the license to 
manufacture (and/or of the permission to import). 
To add 
reasons that 
a treatment 
group or the 
trial may be 
discontinued  

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Section 9.3.4.3 Screen Failures 
Subjects who do not meet all of the inclusion criteria or meet any of 
the exclusion criteria will be considered screen failures.  An 
abnormal test during Screening may be repeated during the Screening 
Period.  Screen failures may be allowed to rescreen for the trial if 
both the Investigator and Sponsor are in agreement regarding 
rescreening and if the Investigator determines that the subject can 
satisfy all of the eligibility criteria.   
Section 9.3.5.3 Screen Failures 
Subjects who do not meet all of the inclusion criteria or meet any of 
the exclusion criteria will be considered screen failures.  An 
abnormal test during Screening may be repeated once during the 
Screening Period.  Screen failures may be allowed to rescreen for the 
trial if both the Investigator and Sponsor are in agreement regarding 
rescreening and if the Investigator determines that the subject can 
satisfy all of the eligibility criteria.   
To clarify 
that an 
abnormal 
test during 
Screening 
may be 
repeated 
once during 
the Screening 
Period   
Section 9.4.6 Trial Drug Administration and Timing of Dose for 
Each Subject 
Subjects will take 2 tablets of trial drug (HZN-825 150 mg and/or 
placebo) orally in the morning and evening with food.  In the event a 
subject misses a dose, the dose should be taken along with the next 
planned dose (evening or morning) with food. 
Section 9.4.6 Trial Drug Administration and Timing of Dose for 
Each Subject 
Subjects will take 2 tablets of trial drug (HZN-825 150 mg and/or 
placebo) orally in the morning and evening with a meal.  In the event 
a subject misses a dose, the dose should be taken along with the next 
planned dose (evening or morning) with a meal. 
“With food” 
could be 
interpreted 
as dosing 
with a snack, 
which is not 
sufficient for 
targeted drug 
exposure 
Section 9.4.6.1.1 Orthostatic Hypotension 
Orthostatic hypotension is considered the AESI for this trial.  Trial 
drug should be temporarily discontinued in the case of trial drug-
related, newly developed and clinically significant orthostatic 
hypotension associated with clinical symptoms requiring medical 
intervention.  Trial drug may be restarted at the discretion of the 
Investigator after the clinical symptoms have resolved. 
Section 9.4.6.1.1 Orthostatic Hypotension 
Orthostatic hypotension is considered the AESI for this trial.  Trial 
drug should be temporarily discontinued in the case of trial drug-
related, newly developed and clinically significant orthostatic 
hypotension associated with clinical symptoms requiring medical 
intervention.  Trial drug may be restarted at the discretion of the 
Investigator after the clinical symptoms have resolved and following 
consultation with the Sponsor trial medical monitor.  Subjects should 
have normal blood pressure and heart rate with absence of symptoms 
related to orthostatic hypotension for at least 5 days prior to 
restarting. 
To provide 
guidance 
regarding 
restarting 
trial drug 
after a 
subject 
experiences 
clinically 
significant 
orthostatic 
hypotension 

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Section 9.4.8 Blinding and Unblinding 
An IDMC will review unblinded safety and efficacy data on a 
scheduled basis.  A futility analysis will be performed when 
 
 The IDMC charter will include processes to unblind 
select Horizon personnel to assess unforeseen issues that may affect 
dose selection; otherwise, unblinded information will be restricted to 
IDMC members who are not involved in other aspects of the trial. 
Section 9.4.8 Blinding and Unblinding 
An IDMC will review unblinded safety and efficacy data on a 
scheduled basis.  A futility analysis will be performed when 
 
 
 The IDMC charter will include processes to unblind 
select Horizon personnel to assess unforeseen issues that may affect 
dose selection; otherwise, unblinded information will be restricted 
from Horizon trial team members who are involved in all aspects of 
trial conduct and management. 
To clarify 
that 
unblinded 
information 
will be 
restricted 
from Horizon 
trial team 
members 
who are 
involved in 
all aspects of 
trial conduct 
and 
management 
unless other 
select 
Horizon 
personnel 
need to be 
unblinded 

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Section 9.4.9 Concomitant Therapy and Restricted Medications 
Other causes for FVC decline (i.e., respiratory tract infection) should 
be excluded.  Repeat FVC/spirometry should be performed and 
confirmed prior to initiation of rescue medication. 
 
Section 9.4.9 Concomitant Therapy and Restricted Medications 
Other causes for FVC decline (i.e., respiratory tract infection) should 
be excluded.  Repeat FVC/spirometry should be performed and 
confirmed prior to initiation of rescue medication if, to the 
Investigator’s clinical judgment, well-founded doubts in the test’s 
quality and the subject’s good condition justify the associated delay 
in subject care, and the increase in risk for the subject. 
 
To add 
OATP 
inhibitors, 
P-gp 
inhibitors 
and a BRCP 
inhibitor as 
restricted 
medications 

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Section 9.4.9 Concomitant Therapy and Restricted Medications 
Section 9.4.9 Concomitant Therapy and Restricted Medications 
 
To indicate 
Investigator 
discretion in 
repeat of 
spirometry 
prior to 
rescue 
medication 
and clarify 
that 
cyclophos-
phamide and 
prednisone 
>10 mg/day 
are not 
permitted for 
4 weeks prior 
to Screening 
and 
throughout 
Screening 
Section 9.5.4.1.5 Reporting and Documenting Serious Adverse 
Events 
1. Report the SAE to the Sponsor by entering the information into 
the eCRF within 24 hours after becoming aware that a subject 
has experienced an SAE.  If unable to access the eCRF, the event 
must be reported by submitting the completed SAE form within 
24 hours after becoming aware that a subject has experienced an 
SAE (see Section 17.1 for contact information). 
Section 9.5.5.1.5 Reporting and Documenting Serious Adverse 
Events 
1. Report the SAE to the Sponsor by entering the information into 
the eCRF immediately, without undue delay but not later 
than 24 hours after becoming aware that a subject has 
experienced an SAE.  If unable to access the eCRF, the event 
must be reported by submitting the completed SAE form 
immediately, without undue delay but not later than 
24 hours after becoming aware that a subject has experienced an 
SAE (see Section 17.1 for contact information). 
To clarify 
SAE 
reporting 
requirements 

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Section 9.5.4.1.5.1 Monitoring of Serious Adverse Events 
Anticipated in the Trial Population 
SAEs are anticipated to occur in the trial population independent of 
the subject’s exposure to trial drug.  These anticipated SAEs are 
provided in Section 17.7 (Serious Adverse Events Anticipated in the 
Trial Population) for reference.  The list does NOT change the 
Investigator’s reporting obligations or prevent the need to report an 
AE meeting the definition of an SAE, as detailed above.  The purpose 
of this list is to alert the Investigator that some events reported as 
SAEs may not require expedited reporting to the regulatory 
authorities if they are on this list.  The Sponsor will monitor these 
events throughout the course of the trial for any change in frequency. 
Section 9.5.5.1.5.1 Monitoring of Serious Adverse Events 
Anticipated in the Trial Population 
SAEs are anticipated to occur in the trial population independent of 
the subject’s exposure to trial drug.  These anticipated SAEs are 
provided in Section 17.8 (Serious Adverse Events Anticipated in the 
Trial Population) for reference.  The list does NOT change the 
Investigator’s reporting obligations or prevent the need to report an 
AE meeting the definition of an SAE, as detailed above.  The purpose 
of this list is to alert the Investigator that some events reported as 
SAEs that are anticipated to occur in the trial population due to 
underlying disease, may not require expedited reporting to the 
regulatory authorities in every country/region.  The Sponsor will 
monitor these events throughout the course of the trial for any change 
in frequency. 
To clarify 
local 
reporting 
obligations 
for SAEs 
Section 9.5.4.1.10 Development Safety Update Reports 
The Sponsor will prepare and submit annual safety reports to the US 
FDA.   
Section 9.5.5.1.10 Development Safety Update Reports 
The Sponsor will prepare and submit annual safety reports to the US 
FDA.  Drug safety update reports will also be submitted to countries 
and territories as required. 
To include a 
statement 
that 
development 
safety update 
reports will 
be submitted 
to countries 
and 
territories as 
required 

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Section 9.5.4.2 Pregnancy Reporting 
Pregnancy testing will be performed for women of childbearing 
potential.  Serum pregnancy tests will be analyzed at a central trial 
laboratory and the urine pregnancy tests will be performed locally. 
If a female subject becomes pregnant during the Double-blind 
Treatment Period, she should immediately notify the Investigator and 
trial drug dosing should be permanently discontinued but the subject 
will be asked to continue in the trial for evaluations.  
Pregnancy occurring in the partner of a male subject participating in 
the trial should be reported to the Investigator and the Sponsor 
immediately upon awareness of pregnancy.  Monitoring of the 
subject’s partner should continue until conclusion of the pregnancy.  
Subjects should be instructed to continue contraception for 4 weeks 
after their last dose of trial drug.  Pregnancies occurring up to 4 
weeks after the last dose of trial drug must also be reported to the 
Investigator. 
The Investigator should report pregnancies to the Sponsor within 
24 hours by submitting the completed pregnancy report form within 
24 hours after becoming aware that the subject/subject’s female 
partner has become pregnant (see Section 17.1 for contact 
information).  The Investigator should counsel the subject and discuss 
the possible risks of continuing the pregnancy.  If pregnancy 
continues and the subject signs the pregnancy consent form, 
monitoring should also continue to the conclusion of the pregnancy. 
 
Section 9.5.5.2 Pregnancy Reporting 
Pregnancy testing will be performed for WOCBP.  Serum pregnancy 
tests will be analyzed at a central trial laboratory and the urine 
pregnancy tests will be performed locally.  In addition, at-home 
pregnancy tests will be completed by WOCBP at Weeks 8, 12, 20, 
24, 32, 36, 44 and 48, and results will be reported to the site. 
If a female subject becomes pregnant during the Double-blind 
Treatment Period, she should immediately notify the Investigator and 
trial drug dosing should be permanently discontinued but the subject 
will be asked to continue in the trial for evaluations.  
Pregnancy occurring in the partner of a male subject participating in 
the trial should be reported to the Investigator and the Sponsor 
immediately upon awareness of pregnancy.  Monitoring of the 
subject’s partner should continue until conclusion of the pregnancy.  
Subjects should be instructed to continue contraception for 4 weeks 
after their last dose of trial drug.  Pregnancies occurring up to 4 
weeks after the last dose of trial drug must also be reported to the 
Investigator. 
Some examples of highly effective contraceptive methods that have a 
failure rate of <1% per year when used consistently and correctly are: 
x 
Combined (estrogen- and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation  
o 
Oral  
o 
Intravaginal 
o 
Transdermal 
x 
Progestogen-only hormonal contraception associated with 
inhibition of ovulation 
o 
Oral  
o 
Injectable 
o 
Implantable 
x 
Intrauterine device (IUD) 
x 
Intrauterine hormone-releasing system (IUS)  
x 
Bilateral tubal ligation 
To change 
pregnancy 
testing to 
every 
4 weeks and 
add specifics 
regarding 
pregnancy 
outcome 
follow-up 
and examples 
of highly 
effective 
contraceptive 
methods 

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x 
Vasectomized partner 
x 
Sexual abstinence from heterosexual intercourse 
There are no expected drug interactions between HZN-825 and 
hormonal contraceptives. 
The Investigator should report pregnancies to the Sponsor within 
24 hours by submitting the completed pregnancy report form within 
24 hours after becoming aware that the subject/subject’s female 
partner has become pregnant (see Section 17.1 for contact 
information).  The Investigator should counsel the subject and discuss 
the possible risks of continuing the pregnancy.  If pregnancy 
continues and the subject signs the pregnancy consent form, the 
subject will be contacted 2 weeks after her calculated delivery time to 
provide information about the outcome of the pregnancy and the 
well-being of the child.  A final contact will be made 8 weeks after 
delivery, when the subject will again be asked about the well-being of 
the child.  
Section 9.5.4.6 Physical Examination 
A physical examination will be performed per the Schedule of 
Assessments (Section 2.1). 
Section 9.5.5.6 Physical Examination 
A complete physical examination, including but not limited to, 
cardiac, pulmonary and neurologic assessments, will be performed 
per the Schedule of Assessments (Section 2.1). 
To clarify the 
assessments 
to be 
included as 
part of the 
physical 
examination 

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Section 9.5.4.9 Laboratory Tests for Evaluation 
A central trial laboratory will be used for all protocol-specified 
laboratory evaluations, with the exception of urine pregnancy tests 
that will be performed locally at each site. 
Chemistry parameters to be evaluated include total protein, albumin, 
sodium, phosphate, potassium, calcium, chloride, bicarbonate, blood 
urea nitrogen, creatinine, creatine kinase, uric acid, glucose (fasting), 
lactate dehydrogenase; liver function tests (alanine aminotransferase, 
aspartate aminotransferase, gamma glutamyltransferase, alkaline 
phosphatase, total bile acid, total bilirubin, conjugated and 
unconjugated bilirubin, if applicable); lipid profile (total cholesterol, 
high-density lipoprotein cholesterol, low-density lipoprotein 
cholesterol, fasting triglycerides).   
Hematology parameters to be evaluated include hemoglobin, 
hematocrit, red blood cell count (with morphology if blood cell count 
is abnormal), mean corpuscular volume (MCV), mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration 
(MCHC), red blood cell distribution width (RDW), reticulocyte 
count, white blood cell count with differential (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes) and platelet count.   
Section 9.5.5.9 Laboratory Tests for Evaluation 
A central trial laboratory will be used for all protocol-specified 
laboratory evaluations, with the exception of urine pregnancy tests 
that will be performed locally at each site or at-home, as applicable, 
in order to maintain monthly pregnancy testing. 
Chemistry parameters to be evaluated include total protein, albumin, 
sodium, phosphate, potassium, calcium, chloride, bicarbonate, blood 
urea nitrogen, creatinine, creatine kinase, uric acid, lactate 
dehydrogenase; liver function tests (alanine aminotransferase, 
aspartate aminotransferase, gamma glutamyltransferase, alkaline 
phosphatase, total bile acid, total bilirubin, conjugated and 
unconjugated bilirubin, if applicable).   
Fasting glucose and fasting lipid profile (total cholesterol, high-
density lipoprotein cholesterol, low-density lipoprotein cholesterol, 
triglycerides) will also be evaluated (see Section 2.1).   
Hematology parameters to be evaluated include hemoglobin, 
hematocrit, red blood cell count (with morphology if blood cell count 
is abnormal), mean corpuscular volume (MCV), mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration 
(MCHC), red blood cell distribution width (RDW), reticulocyte 
count, white blood cell count with differential (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes) and platelet count.   
To change 
pregnancy 
testing to 
every 
4 weeks and 
fasting 
glucose to be 
analyzed at 
the same time 
points as 
lipid profile 
Section 9.5.6 Trial Procedures 
Trial procedures and timing are detailed in the Schedule of 
Assessments (Section 2.1) and operations manual. 
Section 9.5.7 Trial Procedures 
Trial procedures and timing are detailed in the Schedule of 
Assessments (Section 2.1).   
The end of the trial is defined as the date of the last visit of the last 
subject undergoing the trial. 
To define end 
of trial 
Section 9.5.8 Long-term Survival Follow-up 
Following the end of the trial or after premature withdrawal, the 
Investigator or designee may follow the long-term health of subjects 
for up to 5 years via inspection of hospital records or publicly 
available sources.   
Section deleted from v2.0 of the protocol 
To remove 
long-term 
survival 
follow-up 

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Section 9.6.1.6 Pharmacodynamic Endpoint 
1. Pharmacodynamic effects of HZN-825 on biomarkers 
Section deleted from v2.0 of the protocol. 
To correct an 
error in the 
original 
protocol 
because 
evaluation of 
pharmaco-
dynamics is 
exploratory 
and not an 
objective of 
the trial 
Section 9.6.4 Secondary Efficacy Endpoint Analyses 
Changes from Baseline in 6MWT, K-BILD, L-IPF and LCQ scores 
will be analyzed analogously to the primary efficacy endpoints.  The 
rate of hospitalization due to respiratory distress will be analyzed 
analogously to the PFS endpoint described above. 
Section 9.6.4 Secondary Efficacy Endpoint Analyses 
Changes from Baseline in 6MWT, K-BILD, L-IPF and LCQ scores 
will be analyzed analogously to the primary efficacy endpoints.  
Survival analysis will be used for the time-to-event endpoints, 
including time to the first onset of the composite endpoint and the 
time to the first hospitalization due to respiratory distress.  A Cox 
proportional hazard model stratified like the previous logistic model 
with baseline FVC % predicted and treatment group will provide 
hazard ratio, its 95% CI and p-value to compare each HZN-825 group 
with the placebo group. 
To update the 
description 
of the 
secondary 
efficacy 
endpoint 
analyses 
Not applicable (section added to v2.0 of the protocol) 
Section 17.2 Hospitalization Due to Respiratory Distress 
See Section 17.2. 
To add an 
appendix 
pertaining to 

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hospitaliza-
tion due to 
respiratory 
distress 
Section 17.2 IPF-related Acute Exacerbation 
The conceptual framework for evaluation of acute respiratory 
deterioration in IPF, as defined by Collard et al., 2016, is shown in 
Figure 17.1.  Acute respiratory deterioration of IPF (defined as 
“typically, 1 month in duration”) can be categorized as 
extraparenchymal (e.g., pulmonary embolism, pneumothorax, pleural 
effusion) or parenchymal.  Parenchymal causes that demonstrate new 
bilateral ground-glass opacification/consolidation on computed 
tomography that is not fully explained by cardiac failure or fluid 
overload are categorized as acute exacerbations of IPF, regardless of 
the presence or absence of a known trigger (e.g., infection).  Acute 
exacerbations are further categorized as triggered acute exacerbation 
or idiopathic acute exacerbation, depending on whether an underlying 
trigger for acute exacerbation is found. 
Section 17.3 IPF-related Acute Exacerbation 
Clinical information for potential IPF-related acute exacerbations will 
be collected on a dedicated questionnaire.  In addition, all relevant 
clinical data (summary on clinical course, signs and symptoms; 
laboratory, lung function and imaging results; and treatment 
provided) relating to the exacerbation will be collected and provided 
to an independent adjudication committee for review.  The 
conceptual framework for evaluation of acute respiratory 
deterioration in IPF, as defined by Collard et al., 2016, is shown in 
Figure 17.2.  Acute respiratory deterioration of IPF (defined as 
“typically, 1 month in duration”) can be categorized as 
extraparenchymal (e.g., pulmonary embolism, pneumothorax, pleural 
effusion) or parenchymal.  Parenchymal causes that demonstrate new 
bilateral ground-glass opacification/consolidation on computed 
tomography that is not fully explained by cardiac failure or fluid 
overload are categorized as acute exacerbations of IPF, regardless of 
the presence or absence of a known trigger (e.g., infection).  Acute 
exacerbations are further categorized as triggered acute exacerbation 
or idiopathic acute exacerbation, depending on whether an underlying 
trigger for acute exacerbation is found.  For additional details, refer to 
the adjudication committee charter. 
To specify 
that clinical 
information 
for potential 
IPF-related 
acute exacer-
bations will 
be collected 
on a 
dedicated 
questionnaire 
and that all 
relevant data 
will be 
provided to 
an 
independent 
adjudication 
committee 
for review