A Randomized, Double-blind, Placebo-controlled, Repeat-dose, Multicenter Trial to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of HZN-825 in Patients With Diffuse Cutaneous Systemic Sclerosis
Phase: PHASE2
Conditions: Diffuse Cutaneous Systemic Sclerosis, Sclerosis, Systemic
Sponsor: Amgen

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
Version 5.0, Amendment 4 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
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CLINICAL TRIAL PROTOCOL  
FOR FIPAXALPARANT (HZN-825) 
Protocol Number:  HZNP-HZN-825-301 
IND:  112818 
EU CT Number:  2023-509782-20-00 
 
A Randomized, Double-blind, Placebo-controlled, Repeat-dose, Multicenter 
Trial to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of 
HZN-825 in Patients with Diffuse Cutaneous Systemic Sclerosis 
 
Date:  22 August 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 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. 
CONFIDENTIAL 
 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
Version 5.0, Amendment 4 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
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PROTOCOL 
1 
TITLE PAGE 
Trial Title: A Randomized, Double-blind, 
Placebo-controlled, Repeat-dose, Multicenter 
Trial to Evaluate the Efficacy, Safety, 
Tolerability and Pharmacokinetics of HZN-825 
in Patients with Diffuse Cutaneous Systemic 
Sclerosis 
Protocol Number: HZNP-HZN-825-301 
Version: 5.0 
Investigational Product: Fipaxalparant (HZN-825) 
Indication: Systemic Sclerosis 
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: 
 MD 
Medical Director, Clinical Development 
Horizon Therapeutics U.S.A., Inc. 
1 Horizon Way 
Deerfield, IL  60015 
Approval Date: 22 August 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: 
Ex-US Fax: 
1-888-814-8653 (toll free, within USA) 
+44 (0)207-136-1046 
Email (worldwide): svc-ags-in-us@amgen.com 
 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
Version 5.0, Amendment 4 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
HZNP-HZN-825-301 
Version: 
5.0 
Protocol Title: 
A Randomized, Double-blind, Placebo-controlled, Repeat-dose, 
Multicenter Trial to Evaluate the Efficacy, Safety, Tolerability and 
Pharmacokinetics of HZN-825 in Patients with Diffuse Cutaneous 
Systemic Sclerosis 
Version Date: 
22 August 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 
 
Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
Version 5.0, Amendment 4 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 4 of 157 
 
SUMMARY OF CHANGES 
Protocol Version 4.0, Amendment 3 (22 June 2023) to 
Protocol Version 5.0, Amendment 4 (22 August 2024) 
Key additions, revisions and clarifications to Version 5.0 of the protocol are: 
 Updating to align with new company structure under new sponsor throughout. 
 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. 
 Amending the order and content of the secondary objectives to enhance the ability to 
demonstrate overall improvement in the disease.  Additionally, to adapt to new updates in 
the definition of Revised Composite Response Index in Systemic Sclerosis (CRISS 25). 
 Clarifying when all assessments must be completed to ensure study completion before 
subsequent treatment if joining another study. 
 Amending language to clarify that unblinded dose selection is no longer applicable and 
other changed blinding activities. 
 Clarifying that Exclusion criteria 21 only applies to the first 110 subjects. 
 Updating Physician Global Assessment to Clinician Global Assessment throughout the 
document to align with industry standards. 
 Removing language for a separate shift table to evaluate glucose as this is no longer 
applicable to the study. 
 Updating numbers referring to safety and efficacy data to that from most recently 
completed studies. 
 Amending description of risks to align with current available data on risks associated 
with use of the investigational product. 
 Introducing the revised CRISS (CRISS 25) into the endpoints and associated definitions 
to align throughout the protocol. 
 Adjusting language surrounding exit interviews and number of subjects participating in 
the interviews and align with CRISS 25. 
 Updating language to ensure subject safety and confidentiality if medical records need to 
be shared. 
 Adding safety reporting language to align with new sponsor standard language. 
 Amending statistical language to align with changes in unblinding, simplify descriptions 
of analyses to be performed, and clarify that the independent data monitoring committee 
(IDMC) will review futility data. 
 Updating principal investigator (PI) responsibilities to report serious breaches. 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
Version 5.0, Amendment 4 
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 Including definition of serious adverse events (SAE) Outcomes for reported adverse 
events (AEs)/SAEs/adverse events of special interest (AESIs) to align protocol 
information with revised Clinical SAE Report Form/case report forms (CRFs). 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
Version 5.0, Amendment 4 
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SUMMARY TABLE OF CHANGES 
Protocol Version 4.0 (22 June 2023) to 
Protocol Version 5.0, Amendment 4 (22 August 2024) 
Text 
Version 4.0, Amendment 3 
22 June 2023 
Amended Text 
Version 5.0, Amendment 4 
22 August 2024 
Reason for Change 
Global 
HZN-825 
Global 
fipaxalparant (HZN-825) 
To incorporate non-
proprietary name 
throughout document 
Cover Page 
EudraCT Number:  2020-005764-62 
Cover Page 
EU CT Number:  2023-509782-20-00 
To update in alignment 
with EU CT submission 
Cover Page and Title Page 
Horizon Therapeutics Ireland DAC 
Cover Page and Title Page 
Horizon Therapeutics Ireland DAC (a wholly owned subsidiary 
of Amgen Inc.) 
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 USA) 
Ex-US Fax: +44 (0)207-136-1046 
Email (worldwide):svc-ags-in-us@amgen.com 
To update with new 
company structure 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
Version 5.0, Amendment 4 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 7 of 157 
 
Text 
Version 4.0, Amendment 3 
22 June 2023 
Amended Text 
Version 5.0, Amendment 4 
22 August 2024 
Reason for Change 
Sponsor Signature Page 
Removed 
To change the Sponsor’s 
approver with shift to 
Amgen processes 
Synopsis – Secondary Objectives and Section 8.2 Secondary 
Objectives 
1. Evaluate the effect of 2 dose regimens of HZN-825 versus 
placebo on Health Assessment Questionnaire Disability Index 
[HAQ-DI] after 52 weeks of treatment. 
2. Evaluate the effect of 2 dose regimens of HZN-825 versus 
placebo on Physician Global Assessment (MDGA) after 52 
weeks of treatment. 
3. Evaluate the effect of 2 dose regimens of HZN-825 versus 
placebo on Patient Global Assessment (PTGA) after 52 weeks of 
treatment. 
4. Evaluate the effect of 2 dose regimens of HZN-825 versus 
placebo on the Physical Effects subscale of the scleroderma skin 
patient-reported outcome (SSPRO-18) after 52 weeks of 
treatment. 
5. Evaluate the effect of 2 dose regimens of HZN-825 versus 
placebo on the Physical Limitations subscale of the SSPRO-18 
after 52 weeks of treatment. 
6. Evaluate the effect of 2 dose regimens of HZN-825 versus 
placebo on the modified Rodnan skin score (mRSS), after 52 
weeks of treatment. 
7. Evaluate the effect of 2 dose regimens of HZN-825 versus 
placebo on American College of Rheumatology Composite 
Response Index in Systemic Sclerosis (ACR-CRISS), defined as 
improvement from Baseline in mRSS, HAQ-DI, PTGA, MDGA 
and FVC % predicted after 52 weeks of treatment. 
Synopsis – Secondary Objectives and Section 8.2 Secondary 
Objectives 
1. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-
825) versus placebo on the modified Rodnan skin score (mRSS), 
after 52 weeks of treatment. 
2. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-
825) versus placebo on the Revised Composite Response Index 
in Systemic Sclerosis (Revised CRISS [CRISS 25]) after 
52 weeks of treatment. 
3. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-
825) versus placebo on Health Assessment Questionnaire-
Disability Index [HAQ-DI] after 52 weeks of treatment. 
4. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-
825) versus placebo on Clinician Global Assessment (CGA) 
after 52 weeks of treatment. 
5. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-
825) versus placebo on Patient Global Assessment (PTGA) after 
52 weeks of treatment. 
6. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-
825) versus placebo on the Physical Effects subscale of the 
scleroderma skin patient-reported outcome (SSPRO-18) after 52 
weeks of treatment. 
7. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-
825) versus placebo on the Physical Limitations subscale of the 
SSPRO-18 after 52 weeks of treatment. 
To enhance the ability to 
demonstrate overall 
improvement in the 
disease-Improvement in 
mRSS score is 
associated with 
favorable outcomes 
including better survival 
in patients with dcSSc.  
Composite endpoint like 
CRISS 25 will help in 
global evaluation of 
likelihood of 
improvement.  The 
hierarchical testing 
approach will allow 
evaluation of the 
primary and secondary 
endpoints in the order of 
statistical and clinical 
significance. 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
Version 5.0, Amendment 4 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
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Text 
Version 4.0, Amendment 3 
22 June 2023 
Amended Text 
Version 5.0, Amendment 4 
22 August 2024 
Reason for Change 
8. Evaluate the effect of 2 dose regimens of HZN-825 versus 
placebo on ACR-CRISS-20, defined as improvement in ≥3 core 
set measures from Baseline of ≥20% in mRSS, ≥20% in HAQ-
DI, ≥20% in PTGA, ≥20% in MDGA and ≥5% in FVC % 
predicted after 52 weeks of treatment. 
9. Assess safety and tolerability of HZN-825 based on adverse 
events (AEs), the adverse event of special interest (AESI) 
 concomitant medication use, vital 
signs, 12-lead electrocardiogram (ECG) and clinical safety 
laboratory evaluations (hematology, chemistry, inflammatory 
parameters, coagulation panel and urinalysis). 
10. Evaluate the pharmacokinetics (PK) of HZN-825. 
8. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-
825) versus placebo on proportion of subjects with clinically 
important change in the mRSS, after 52 weeks of treatment. 
9. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-
825) versus placebo on American College of Rheumatology-
Composite Response Index in Systemic Sclerosis (ACR-CRISS), 
defined as improvement from Baseline in mRSS, HAQ-DI, 
PTGA, CGA and FVC % predicted after 52 weeks of treatment. 
10. Assess safety and tolerability of fipaxalparant (HZN-825) 
based on adverse events (AEs), the adverse event of special 
interest (AESI) 
, concomitant 
medication use, vital signs, 12-lead electrocardiogram (ECG) 
and clinical safety laboratory evaluations (hematology, 
chemistry, inflammatory parameters, coagulation panel and 
urinalysis). 
11. Evaluate the pharmacokinetics (PK) of fipaxalparant (HZN-
825). 
Synopsis – Trial Design 
The trial will include up to a 42-day Screening Period and a 52-
week Double-blind Treatment Period.  Subjects will take their 
first dose of trial drug at the clinic and will participate in trial 
visits at Week 4 and every 6 weeks thereafter until Week 52.  All 
subjects who complete the Double-blind Treatment Period 
(Week 52) will be eligible to enter a 52-week extension trial 
(HZNP-HZN-825-302).  Subjects not entering the extension trial 
will participate in a Safety Follow-up Visit 4 weeks after the last 
dose of trial drug.   
Synopsis – Trial Design 
The trial will include up to a 42-day Screening Period and a 
52-week Double-blind Treatment Period.  Subjects will take their 
first dose of trial drug at the clinic and will participate in trial 
visits at Week 4 and every 6 weeks thereafter until Week 52.  All 
subjects who complete the Double-blind Treatment Period 
(Week 52) will be eligible to enter a 52-week extension trial 
(HZNP-HZN-825-302).  All Week 52 assessments should be 
performed before the first dose of the extension trial drug is 
administered.  Subjects not entering the extension trial will 
participate in a Safety Follow-up Visit 4 weeks after the last dose 
of trial drug.   
To ensure subjects 
complete the current 
study in its entirety 
before starting the next 
treatment 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
Version 5.0, Amendment 4 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 9 of 157 
 
Text 
Version 4.0, Amendment 3 
22 June 2023 
Amended Text 
Version 5.0, Amendment 4 
22 August 2024 
Reason for Change 
Synopsis – Trial Design 
An independent data monitoring committee (IDMC) will review 
unblinded safety and efficacy data on a scheduled basis.  A 
futility analysis will be performed when approximately 50% of 
the subjects reach Week 52 or discontinue the trial before Week 
52 and will include comparative unblinded efficacy and safety 
data.  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. 
Synopsis – Trial Design 
An independent data monitoring committee (IDMC) will review 
unblinded safety and efficacy data on a scheduled basis.  A 
futility analysis will be performed when approximately 50% of 
the subjects reach Week 52 or discontinue the trial before Week 
52 and will include comparative unblinded efficacy and safety 
data. 
Removed as dose 
selection is no longer 
applicable. 
Synopsis – Study Schema, Synopsis - Duration of Treatment 
and Follow-up, 9.1 Overall Trial Design and Plan, and 
Figure 9.1 Schematic of Trial Design 
Subjects who complete the Double-blind Treatment Period 
(Week 52) will be eligible to enter a 52-week extension trial 
(HZNP-HZN-825-302). 
Synopsis – Study Schema, Synopsis - Duration of Treatment 
and Follow-up, 9.1 Overall Trial Design and Plan, and 
Figure 9.1 Schematic of Trial Design 
Subjects who complete the Double-blind Treatment Period 
(Week 52) will be eligible to enter a 52-week extension trial  
(HZNP-HZN-825-302).  All Week 52 assessments should be 
performed before the first dose of the extension trial drug is 
administered. 
To ensure subjects 
complete the current 
study in its entirety 
before starting the next 
treatment 
Synopsis – Exclusion Criteria and 9.3.2 Exclusion Criteria 
21. International normalized ratio >2, prolonged prothrombin 
time >1.5 × the upper limit of normal (ULN) or partial 
thromboplastin time >1.5 × ULN at Screening. 
Synopsis – Exclusion Criteria and 9.3.2 Exclusion Criteria 
21. International normalized ratio >2, prolonged prothrombin 
time >1.5 × the upper limit of normal (ULN) or partial 
thromboplastin time >1.5 × ULN at Screening (only applicable 
to the first 110 subjects for whom biopsy will be performed). 
To clarify this is 
applicable to the first 
110 subjects 
Global 
MDGA 
Global 
CGA 
To align with industry-
standard language 
Synopsis – Statistical Analysis and Section 9.6.1.2 Secondary 
Efficacy Endpoints 
Secondary Efficacy Endpoints 
Synopsis – Statistical Analysis and Section 9.6.1.2 Secondary 
Efficacy Endpoints 
1. Change from Baseline in the mRSS at Week 52. 
To enhance the ability to 
demonstrate overall 
improvement in the 
disease-Improvement in 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
Version 5.0, Amendment 4 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 10 of 157 
 
Text 
Version 4.0, Amendment 3 
22 June 2023 
Amended Text 
Version 5.0, Amendment 4 
22 August 2024 
Reason for Change 
1. Change from Baseline in HAQ-DI at Week 52. 
2. Change from Baseline in MDGA at Week 52. 
3. Change from Baseline in PTGA at Week 52. 
4. Change from Baseline in the Physical Effects subscale of the 
SSPRO 18 at Week 52.  
5. Change from Baseline in the Physical Limitations subscale of 
the SSPRO 18 at Week 52. 
6. Proportion of subjects with an mRSS decrease of ≥5 points 
and 25% from Baseline at Week 52. 
7. Responder rate (defined as ACR-CRISS [predicted probability] 
of at least 0.6) at Week 52. 
8. Proportion of subjects with an improvement in ≥3 of 5 core 
measures from Baseline:  ≥20% in mRSS, ≥20% in HAQ DI, 
≥20% in PTGA, ≥20% in MDGA and ≥5% for FVC % 
predicted at Week 52 (ACR CRISS 20). 
2. Proportion of subjects responding to treatment based on 
CRISS 25 at Week 52.  
3. Change from Baseline in HAQ-DI at Week 52. 
4. Change from Baseline in CGA at Week 52. 
5. Change from Baseline in PTGA at Week 52. 
6. Change from Baseline in the Physical Effects subscale of the 
SSPRO-18 at Week 52. 
7. Change from Baseline in the Physical Limitations subscale of 
the SSPRO-18 at Week 52. 
8. Proportion of subjects with an mRSS decrease of ≥5 points 
and 25% from Baseline at Week 52. 
9. Responder rate (defined as ACR-CRISS [predicted probability] 
of at least 0.6) at Week 52. 
mRSS score is 
associated with 
favorable outcomes 
including better survival 
in patients with dcSSc.  
Composite endpoint like 
CRISS 25 will help in 
global evaluation of 
likelihood of 
improvement.  The 
hierarchical testing 
approach will allow 
evaluation of the 
primary and secondary 
endpoints in the order of 
statistical and clinical 
significance. 
 
10. Change from Baseline to Week 52 in the mRSS. 
To align with updated 
secondary endpoints.  
“Change from Baseline 
to Week 52 in the 
mRSS” is moved from 
exploratory to the 
secondary endpoints. 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
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Text 
Version 4.0, Amendment 3 
22 June 2023 
Amended Text 
Version 5.0, Amendment 4 
22 August 2024 
Reason for Change 
Synopsis – Statistical Analyses – Efficacy and Section 9.6.3 
Primary Efficacy Endpoint Analyses 
Then adjustments for each treatment group (placebo and HZN-
825 dose selected for Phase 3) will be added to the imputed data 
and vary to find conditions with non-significant treatment effect. 
Synopsis – Statistical Analyses – Efficacy and Section 9.6.3 
Primary Efficacy Endpoint Analyses 
Then adjustments for each treatment group (placebo and 
fipaxalparant [HZN-825]) will be added to the imputed data and 
vary to find conditions with non-significant treatment effect. 
Updated to remove 
specific mention of dose 
selection. 
Synopsis – Statistical Analyses – Efficacy and Section 9.6.4 
Secondary Efficacy Endpoint Analyses 
The key secondary endpoint for the trial will be change in HAQ-
DI from Baseline to Week 52.  Analysis will follow that of the 
primary efficacy endpoint.  Statistical significance on change in 
HAQ-DI will only be concluded if statistical significance was 
achieved for the primary endpoint.   
Synopsis – Statistical Analyses – Efficacy and Section 9.6.4 
Secondary Efficacy Endpoint Analyses 
The key secondary endpoint for the trial will be change in mRSS 
from Baseline to Week 52.  Analysis will follow that of the 
primary efficacy endpoint.  Statistical significance on change in 
mRSS will only be concluded if statistical significance was 
achieved for the primary endpoint.   
Updated to align with 
updated key secondary 
endpoint. 
Synopsis – Statistical Analyses and Section 9.6.10 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 (0.001) 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 secondary endpoints as specified. 
Synopsis – Statistical Analyses and Section 9.6.10 Multiple 
Comparisons 
The overall statistical level is α=0.05 (2-sided). 
Unblinded data review 
is no longer used in this 
protocol 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
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Text 
Version 4.0, Amendment 3 
22 June 2023 
Amended Text 
Version 5.0, Amendment 4 
22 August 2024 
Reason for Change 
Synopsis – Statistical Analyses and Section 9.6.10 Multiple 
Comparisons 
The resulting p-values will be ranked, and the larger p-value will 
be evaluated at the α = 0.049 (2-sided) threshold. If statistically 
significant, then both comparisons will be considered significant. 
If the larger of the two P-values is not statistically significant at α 
= 0.049 (2-sided), then the smaller P-value will be compared to 
an α = 0.0245 (2 sided). If 1 or both dose regimens of the 
primary endpoint are not rejected after completing testing, no 
further testing will occur due to exhaustion of alpha. If both 
HZN-825 doses are statistically significantly better than the 
placebo for the primary efficacy endpoint at α = 0.049 (2-sided), 
the same Hochberg testing procedure will subsequently be used 
to evaluate the key secondary endpoint. 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 in the order presented above, using 
α = 0.0245 (2-sided) in a sequential testing procedure. If all 
preceding sequentially tested hypotheses are rejected at α = 
0.0245 (2-sided) the next hypothesis will be tested. Once a 
hypothesis is not rejected, all subsequent endpoints within the 
same dose will not be tested due to alpha exhaustion. Although 
p-values will be provided for exploratory endpoints, they will not 
be used for inferential purposes. 
Synopsis – Statistical Analyses and Section 9.6.10 Multiple 
Comparisons 
The resulting p-values will be ranked, and the larger p-value will 
be evaluated at the α = 0.05 (2-sided) threshold. If statistically 
significant, then both comparisons will be considered significant. 
If the larger of the two P-values is not statistically significant at α 
= 0.05 (2-sided), then the smaller P-value will be compared to an 
α = 0.025 (2-sided). If 1 or both dose regimens of the primary 
endpoint are not rejected after completing testing, no further 
testing will occur due to exhaustion of alpha. If both 
fipaxalparant (HZN-825) doses are statistically significantly 
better than the placebo for the primary efficacy endpoint at α = 
0.05 (2-sided), the same Hochberg testing procedure will 
subsequently be used to evaluate the key secondary endpoint. If 
both dose regimens of fipaxalparant (HZN-825) for the key 
secondary endpoint are considered significant, subsequent 
secondary endpoints will be tested sequentially within each dose 
in the order presented above, using α = 0.025 (2-sided) in a 
sequential testing procedure. If all preceding sequentially tested 
hypotheses are rejected at α = 0.025 (2-sided) the next 
hypothesis will be tested. Once a hypothesis is not rejected, all 
subsequent endpoints within the same dose will not be tested due 
to alpha exhaustion. 
To align with removal of 
unblinded review 
Synopsis – Statistical Analyses -Safety and Tolerability 
Laboratory values and vital signs will be summarized by 
treatment received with change from Baseline and with shift 
tables.  Additionally, a shift table for glucose by Common 
Terminology Criteria for Adverse Events grade and visit will be 
summarized.  Summaries will be provided separately for 
hyperglycemia. 
Synopsis – Statistical Analyses -Safety and Tolerability 
Laboratory values and vital signs will be summarized by 
treatment received with change from Baseline and with shift 
tables. 
Removed as no longer 
applicable 

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Synopsis – Sample Size Estimate 
Assuming a clinically important difference between HZN-825 
and placebo of 4 percentage points and a standard deviation of 
8.5, a sample size of 100 subjects per treatment group will 
provide 85% power to demonstrate an improvement between a 
dose regimen of HZN-825 and placebo using α=0.024, 2-sided. 
Synopsis – Sample Size Estimate 
Assuming a clinically important difference between 
fipaxalparant (HZN-825) and placebo of 4 percentage points and 
a standard deviation of 8.5, a sample size of 100 subjects per 
treatment group will provide 85% power to demonstrate an 
improvement between a dose regimen of fipaxalparant 
(HZN-825) and placebo using α=0.025, 2-sided. 
To align with removal of 
unblinded review 
List of Abbreviations 
 
List of Abbreviations 
CGA Clinician Global Assessment 
DSUR Development Safety Update Report 
EU European Union 
For defining new 
abbreviations used in 
body of document 
Section 6 Investigators and Trial Administrative Structure 
The Sponsor of this trial is Horizon Therapeutics Ireland DAC 
(Horizon).   
Section 6 Investigators and Trial Administrative Structure 
The Sponsor of this trial is Horizon Therapeutics Ireland DAC 
(Horizon, a wholly owned subsidiary of Amgen Inc.).   
To clarify new company 
structure 
Section 7.1.3.4 Clinical Experience 
HZN-825 has been administered to 186 healthy subjects in 8 
completed Phase 1 clinical trials and 31 subjects with diffuse 
cutaneous SSc in a Phase 2a clinical trial.  In clinical trials 
completed as of 03 March 2023, 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.   
Section 7.1.3.4 Clinical Experience 
Fipaxalparant (HZN-825) has been administered to 244 healthy 
subjects in 9 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. 
To update numbers 
based on most recently 
completed studies 
Section 7.1.3.4 Clinical Experience 
 
that will 
continue to be monitored as an AE of special interest (AESI) 
(Section 9.5.4.1.1.4). 
Section 7.1.3.4 Clinical Experience 
 
therapy that will 
continue to be monitored as an AE of special interest (AESI) 
(Section 9.5.4.1.1.4).  Additionally, increases in 
 
 have been seen in blinded clinical studies with 
To update in alignment 
with additional risks 
observed with use of 
investigational product 

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fipaxalparant.  These events are mostly non-serious and 
reversible.  Liver enzyme elevation will be monitored per FDA 
guidelines (Section 9.3.3.1). 
Section 7.1.3.5 Benefit/Risk Assessment 
Based on the cumulative safety data available to date on HZN-
825, 
, drug-drug interactions, embryo-
fetal toxicity and liver toxicity are considered as important 
potential risks.   
Section 7.1.3.5 Benefit/Risk Assessment 
Based on the cumulative safety data available to date on 
fipaxalparant (HZN-825), transaminase increase has been 
evaluated as an important identified risk and 
 
, drug-drug interactions, and embryo-fetal toxicity 
are considered as important potential risks. 
To update in alignment 
with additional risks 
observed with use of 
investigational product 
Section 7.3  Rationale for Dose Selection 
Based on preliminary PK results from Trial HZNP-HZN-825-
101, 300 mg BID dosing with a meal using HZN-825 
 
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.   
Section 7.3  Rationale for Dose Selection 
Based on PK results from Trial HZNP-HZN-825-101, 300 mg 
BID dosing with a meal using fipaxalparant (HZN-825)
 
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.   
To remove 
“preliminary” as results 
are no longer 
preliminary 
Section 9.1 Overall Trial Design and Plan 
A futility analysis will be conducted after approximately 50% of 
the subjects reach Week 52 or discontinue the trial before Week 
52 and these unblinded efficacy and safety data will be provided 
to an independent data monitoring committee (IDMC).  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. 
Section 9.1 Overall Trial Design and Plan 
A futility analysis will be conducted after approximately 50% of 
the subjects reach Week 52 or discontinue the trial before Week 
52 and these unblinded efficacy and safety data will be provided 
to an independent data monitoring committee (IDMC).  The 
IDMC will also review accumulating safety data to ensure 
subject safety. 
To align with change in 
blinding procedures 
Section 9.3.3.1 Removal of Subjects from Treatment 
Subjects who have ALT or AST levels >3 × ULN confirmed in a 
repeat test need to undergo close observation as prescribed by 
Section 9.3.3.1 Removal of Subjects from Treatment 
Subjects who have ALT or AST levels >3 × ULN confirmed in a 
repeat test need to undergo close observation as prescribed by 
To remove option for 
continued dosage and 
promote subject safety 

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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. 
the FDA guidance on drug-induced liver injury (refer to 
Appendix 17.15).  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. 
Section 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. 
Section 9.4.6.1.2 Drug-induced Liver Injury 
Elevated 
 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 in alignment 
with additional risks 
observed with use of 
investigational product 
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 
approximately 50% of the subjects reach Week 52 or discontinue 
the trial before Week 52 and will include comparative unblinded 
efficacy and safety data.  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. 
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 
approximately 50% of the subjects reach Week 52 or discontinue 
the trial before Week 52 and will include comparative unblinded 
efficacy and safety data. 
To align with change in 
blinding procedures 
Section 9.5.1.2 Clinician Global Assessment 
9.5.1.2 Physician Global Assessment 
The MDGA is an 11-point Likert scale ranging from 0 to 10 
(0=excellent to 10=extremely poor) on which the physician rates 
the subject’s overall health over the past week.   
Section 9.5.1.2 Clinician Global Assessment 
9.5.1.2 Clinician Global Assessment  
The CGA is also known as Physician Global Assessment 
(MDGA).  The CGA is an 11-point Likert scale ranging from 0 
to 10 (0=excellent to 10=extremely poor) on which the physician 
rates the subject’s overall health over the past week.   
To align with industry-
standard language 

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Section 9.5.1.5 Revised Composite Response Index in 
Systemic Sclerosis (CRISS 25) 
New section, subsequent sections re-numbered with this 
insertion 
9.5.1.5  Revised Composite Response Index in Systemic 
Sclerosis (CRISS 25) 
The Revised CRISS (CRISS 25) is defined as improvement in at 
least 2 components: ≥5% increase for FVCpp and/or ≥25% 
decrease for mRSS, HAQ-DI, PTGA, CGA and worsening in no 
more than one component: ≥5% decrease percent predicted FVC 
and/or ≥25% increase for mRSS, HAQ-DI, PTGA, CGA, at 52 
weeks.  Revised CRISS (CRISS 25) is also a 2-step process.  If 
the subject meets Step 1 (as defined in Section 9.5.1.4), they are 
considered not improved, given a percentage change of 0% for 
each core set item.  In Step 2, the five core set measures are 
individually collected and scored. 
To define the CRISS 25 
as has been added to 
study objectives 
Section 9.5.1.9.7 Exit Interviews 
To understand what patients 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 approximately 4 
to 5 sites, and with approximately 20 subjects across the US.  
Participants in the exit interviews will be selected in order to 
approximate representativeness of the clinical trial population of 
patients with SSc, 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, including the global questions of the 
 
and the SSPRO overall score and domain scores. 
Section 9.5.1.10.7 Exit Interviews 
To understand what patients 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) in a subset of 
subjects.  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 and some of the core set measures of the Revised 
CRISS (CRISS 25). 
To provide flexibility on 
number of exit 
interviews, number of 
sites and countries, and 
align with CRISS 25 
Section 9.5.4.1.2 Documentation of Adverse Events 
If the Investigator observes an SAE after trial completion that 
he/she believes was possibly caused by trial drug, the 
Section 9.5.4.1.2 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 
To align with expected 
reporting and subject 
confidentiality 

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Investigator will report this SAE using the procedures described 
in Section 9.5.4.1.5. 
in Section 9.5.4.1.5.  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. 
Section 9.5.4.1.4 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: 
Section 9.5.4.1.4 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. 
To align with new 
sponsor standard safety 
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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: 
Section 9.5.4.1.5 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 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 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. 
Section 9.5.4.1.5 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 form immediately and not later 
than 24 hours after becoming aware that a subject has 
experienced an SAE.  
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. 
To align with new 
sponsor standard safety 
reporting language 

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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 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 

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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. 
Section 9.5.4.1.6 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 resolved or 
until the event stabilizes and the overall clinical outcome has 
been ascertained. 
Section 9.5.4.1.6 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 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. 
To align with new 
sponsor standard safety 
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Section 9.5.4.1.10 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. 
Section 9.5.4.1.10 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. 
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. 
9.5.4.1.11  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 (eg, 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 (eg, 
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 

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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. 
9.5.4.1.12 Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in the 
Sponsor’s safety surveillance and signal management processes. 
Section 9.5.4.2 Pregnancy Reporting 
Section 9.5.4.2 Pregnancy and Lactation Reporting 
To better encompass 
content of this section 
Section 9.5.4.2 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 
Appendix 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.   
Section 9.5.4.2 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 
pregnancy report form 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.  If 
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sponsor standard safety 
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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. 
Section 9.5.6.1 Screening 
• Enter visit data in the electronic data capture (EDC) system. 
Section 9.5.6.1 Screening 
• Enter visit data in the EDC system. 
To align with 
abbreviation now 
presented previously. 
Section 9.5.6.2.10  Week 52 (End of Treatment) 
Subjects who complete the Double-blind Treatment Period 
(Week 52) will be eligible enter an extension trial, HZNP-HZN-
825-302. 
Section 9.5.6.2.10  Week 52 (End of Treatment) 
Subjects who complete the Double-blind Treatment Period 
(Week 52) will be eligible enter an extension trial, HZNP-HZN-
825-302.  All Week 52 assessments should be performed before 
the first dose of the extension trial drug is administered. 
To ensure subjects 
complete the current 
study in its entirety 
before starting the next 
treatment 
Section 9.6.4 Secondary Efficacy Endpoint Analyses 
The key secondary endpoint for the trial will be change in HAQ-
DI from Baseline to Week 52.  Analysis will follow that of the 
primary efficacy endpoint.  Statistical significance on change in 
HAQ-DI will only be concluded if statistical significance was 
achieved for the primary endpoint. 
The MDGA, PTGA and Physical Effects and Physical 
Limitations subscales of the SSPRO-18 will be analyzed 
analogously to the primary efficacy endpoint. 
Section 9.6.4 Secondary Efficacy Endpoint Analyses 
The key secondary endpoint for the trial will be change in mRSS 
from Baseline to Week 52.  Analysis will follow that of the 
primary efficacy endpoint.  Statistical significance on change in 
mRSS will only be concluded if statistical significance was 
achieved for the primary endpoint. 
The proportion of subjects responding to treatment based on   
CRISS 25 will be evaluated using logistic model.  The Revised 
CRISS (CRISS 25) is defined as improvement in at least 2 
components: ≥5% increase for FVCpp and/or ≥25% decrease 
for mRSS, HAQ-DI, PTGA, CGA and worsening in no more 
than one component: ≥5% decrease percent predicted FVC 
and/or ≥25% increase for mRSS, HAQ-DI, PTGA, CGA, at 52 
weeks.  Revised CRISS (CRISS 25) is also a 2-step process.  If 
To align with updated 
secondary endpoints. 

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the subject meets Step 1 (as defined in Section 9.5.1.4), they are 
considered not improved, given a percentage change of 0% for 
each core set item.  In Step 2, the five core set measures are 
individually collected and scored. 
The CGA, PTGA and Physical Effects and Physical Limitations 
subscales of the SSPRO-18 will be analyzed analogously to the 
primary efficacy endpoint. 
Section 9.6.4 Secondary Efficacy Endpoint Analyses 
Analysis of ACR-CRISS response rate and proportion of 
subjects with an improvement in ≥3 of 5 core measures from 
Baseline will be analogous to that of the mRSS.  
We will use NRI-MI (Non-Responder Imputation in conjunction 
with Multiple Imputation) for missing values observed in 
calculations of mRSS and ACR-CRISS responders at Week 52; 
and patients who died before Week 52 will be categorized as 
non-responders. 
Section 9.6.4 Secondary Efficacy Endpoint Analyses 
Analyses of ACR-CRISS and Revised CRISS (CRISS 25) 
response rates will be done using summary statistics and logistic 
models. 
We will use NRI-MI (Non-Responder Imputation in conjunction 
with Multiple Imputation) for missing values observed in 
calculations of mRSS and ACR-CRISS responders at Week 52; 
and patients who died before Week 52 will be categorized as 
non-responders.  This same rule will be applied to Revised 
CRISS (CRISS 25) analysis. 
To provide details for 
statistical analyses for 
CRISS 25. 
Section 9.6.9  Interim Analyses and Synopsis - Efficacy 
The futility analysis will not be used to make a positive 
determination of efficacy to stop the trial. 
Section 9.6.9  Interim Analyses and Synopsis - Efficacy 
The futility data will be reviewed by the IDMC.  But the futility 
analysis will not be used to make a positive determination of 
efficacy to stop the trial. 
To clarify that the IDMC 
will review futility data 

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Figure 9.2 Schematic of Hochberg Testing Procedure 
Throughout: 0.0245 and 0.049 
Figure 9.2 Schematic of Hochberg Testing Procedure 
Throughout: 0.025 and 0.05 
To align with removal of 
unblinded review 
Section 9.6.11 Sample Size and Power Considerations 
Assuming a clinically important difference between HZN-825 
and placebo of 4 percentage points and a standard deviation of 
8.5, a sample size of 100 subjects per treatment group will 
provide 85% power to demonstrate an improvement between a 
dose regimen of HZN-825 and placebo using α=0.024, 2-sided. 
Section 9.6.11 Sample Size and Power Considerations 
Assuming a clinically important difference between 
fipaxalparant (HZN-825) and placebo of 4 percentage points and 
a standard deviation of 8.5, a sample size of 100 subjects per 
treatment group will provide 85% power to demonstrate an 
improvement between a dose regimen of fipaxalparant (HZN-
825) and placebo using α=0.025, 2-sided. 
To align with removal of 
unblinded review 
Section 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. 
Section 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 
(eg 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: 
• Good Clinical Practice (GCP) 
• the clinical trial protocol 
To update requirements 
for PI responsibilities to 
report serious breaches 
per regulatory 
recommendations  

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• 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 
Section 17.1 Administrative Appendix 
Sponsor Contact for Horizon Therapeutics U.S.A., Inc. 
Serious Adverse Event Reporting US Fax:   800-860-7836 
 Ex US Fax:  +1-224-855-5055 
 Email:  clinicalsafety@horizontherapeutics.com 
Section 17.1 Administrative Appendix 
 
To align with new 
sponsor where this 
information is reported 
within the associated 
forms themselves 
Section 17.2  Physician Global Assessment (MDGA) 
Section 17.2 Clinician Global Assessment (CGA) 
To align with industry-
standard language 
Section 17.15  Detailed Requirements for the Evaluation of 
Patients Detected with Abnormal Liver Function Test (new) 
Section 17.15  Detailed Requirements for the Evaluation of 
Patients Detected with Abnormal Liver Function Test (new) 
Per protocol Section 9.3.3.1, 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. 
An increase of serum aminotransferases to >3 × ULN and/or 
total bilirubin (TBL) >2 × ULN should be followed by repeat 
testing (ALT, AST, ALP, and TBL at minimum) within 48 to 72 
hours to confirm the abnormality*. 
A confirmed ALT/AST >3 × ULN and/or TBL >2 × ULN should 
be considered to record as AE.  Please reach out to the Medical 
Monitor via Electronic Protocol Inquiry Platform to inform such 
events. 
To align with guidance 
from regulatory 
agencies and sponsor. 

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It is critical to exclude the other possible causes of increased 
liver enzymes.  If needed, please consider 
hepatologist/gastroenterologist consultation early in the 
evaluation.  Additional imaging and laboratory tests (e.g., 
abdominal ultrasound, Hepatitis panel testing, etc.), as deemed 
necessary, should be performed to ascertain the etiology. 
Below are the requirements which need to be followed to ensure 
the close observation of patients who have confirmed ALT or 
AST levels >3 × ULN and/or TBL >2 × ULN: 
• Repeating liver enzyme and serum bilirubin tests two or three 
times weekly.  Frequency of retesting can decrease to once a 
week or less if abnormalities stabilize or the trial drug has been 
discontinued and the subject is asymptomatic. 
• Obtaining a more detailed history of symptoms and prior or 
concurrent diseases. 
• Obtaining a history of concomitant drug use (including 
nonprescription medications and herbal and dietary supplement 
preparations), alcohol use, recreational drug use, and special 
diets. 
• Ruling out acute viral hepatitis types A, B, C, D, and E; 
autoimmune or alcoholic hepatitis; nonalcoholic steatohepatitis; 
hypoxic/ischemic hepatopathy; and biliary tract disease. 
• Obtaining a history of exposure to environmental chemical 
agents. 
• Obtaining additional tests to evaluate liver function, as 
appropriate (e.g., INR, direct bilirubin). 
• Considering gastroenterology or hepatology consultations. 
*If it is difficult for the subjects to return to the trial site 
promptly, the repeat test can be analyzed locally, but normal 
laboratory ranges should be recorded.  Results should be made 

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available to trial investigators immediately and the data should 
be included in the case report forms. 
The subject should return to the site for the lab testing as soon as 
possible. 

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2 
SYNOPSIS 
Protocol Title:  A Randomized, Double-blind, Placebo-controlled, Repeat-dose, Multicenter Trial to Evaluate 
the Efficacy, Safety, Tolerability and Pharmacokinetics of HZN-825 in Patients with Diffuse Cutaneous 
Systemic Sclerosis 
Protocol Number:  HZNP-HZN-825-301 
Phase:  2b 
Protocol Version:  5.0 
 
Test Drug:  Fipaxalparant (HZN-825) 
Indication:  Systemic Sclerosis 
Number and Country of Trial Sites:  Up to 135 sites globally 
Objectives:   
The overall objective 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 diffuse cutaneous systemic sclerosis (diffuse 
cutaneous SSc). 
Primary Objective 
The primary objective is to demonstrate the efficacy of 1 or 2 dose regimens of fipaxalparant (HZN-825) versus 
placebo in subjects with diffuse cutaneous SSc, 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 modified Rodnan 
skin score (mRSS), after 52 weeks of treatment. 
2. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on the Revised 
Composite Response Index in Systemic Sclerosis (Revised CRISS [CRISS 25]) after 52 weeks of treatment. 
3. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on Health Assessment 
Questionnaire-Disability Index [HAQ-DI] after 52 weeks of treatment. 
4. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on Clinician Global 
Assessment (CGA) after 52 weeks of treatment. 
5. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on Patient Global 
Assessment (PTGA) after 52 weeks of treatment. 
6. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on the Physical Effects 
subscale of the scleroderma skin patient-reported outcome (SSPRO-18) after 52 weeks of treatment. 
7. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on the Physical 
Limitations subscale of the SSPRO-18 after 52 weeks of treatment. 
8. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on proportion of subjects 
with clinically important change in the mRSS, after 52 weeks of treatment. 
9. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on American College of 
Rheumatology-Composite Response Index in Systemic Sclerosis (ACR-CRISS), defined as improvement 
from Baseline in mRSS, HAQ-DI, PTGA, CGA and FVC % predicted after 52 weeks of treatment. 
10. Assess safety and tolerability of fipaxalparant (HZN-825) based on adverse events (AEs), the adverse event 
of special interest (AESI) 
, concomitant medication use, vital signs, 12-lead 
electrocardiogram (ECG) and clinical safety laboratory evaluations (hematology, chemistry, inflammatory 
parameters, coagulation panel and urinalysis). 
11. Evaluate the pharmacokinetics (PK) of fipaxalparant (HZN-825). 

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Trial Design: 
This is a randomized, double-blind, placebo-controlled, repeat-dose, multicenter trial.  Subjects will be screened 
within 6 weeks prior to the Baseline (Day 1) Visit.  Approximately 300 subjects who meet the trial eligibility 
criteria will be randomized on Day 1 in a 1:1:1 ratio to receive fipaxalparant (HZN-825) 300 mg QD, 
fipaxalparant (HZN-825) 300 mg BID or placebo for 52 weeks.  Randomization will be stratified according to 
Screening use of mycophenolate mofetil (yes/no) and presence of interstitial lung disease (ILD) (yes/no) based 
on a Screening 
 scan. 
The trial will include up to a 42-day Screening Period and a 52-week Double-blind Treatment Period.  Subjects 
will take their first dose of trial drug at the clinic and will participate in trial visits at Week 4 and every 6 weeks 
thereafter until Week 52.  All subjects who complete the Double-blind Treatment Period (Week 52) will be 
eligible to enter a 52-week extension trial (HZNP-HZN-825-302).  All Week 52 assessments should be 
performed before the first dose of the extension trial drug is administered.  Subjects not entering the extension 
trial will participate in a Safety Follow-up Visit 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 

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continue in the trial, he/she will be asked to return for a clinic visit and undergo the Week 52 assessments. 
Subjects will participate in a Safety Follow-up Visit 4 weeks after the last dose of trial drug. 
An independent data monitoring committee (IDMC) will review unblinded safety and efficacy data on a 
scheduled basis.  A futility analysis will be performed when approximately 50% of the subjects reach Week 52 
or discontinue the trial before Week 52 and will include comparative unblinded efficacy and safety data. 
An overview of the trial design is presented in the schematic below. 
Screening 
Baseline 
Double-blind Treatment Period 
Fipaxalparant (HZN-825) or Placebo 1,2 
52 Weeks 
Safety  
Follow-up 
Visit 
< –––––––––––––––––––––––––––––––––––––––––––––– Trial Visits 3––––––––––––––––––––—————————— > 
 
 
 
 
 
 
 
 
42 days 
prior to first 
dose of trial 
drug 
Day 1 
Week 4 and every 6 weeks thereafter 
Week 52 4 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 trial (HZNP-HZN-825-302) will participate in a Safety 
Follow-up Visit 4 weeks after the last dose of trial drug. 
3. 
Visit windows are ±3 days for Week 4, ±5 days for Week 10 to Week 52, inclusive, and ±14 days for the Safety Follow-up Visit. 
4. 
Subjects who complete the Double-blind Treatment Period (Week 52) will be eligible to enter a 52-week extension trial  
(HZNP-HZN-825-302).  All Week 52 assessments should be performed before the first dose of the extension trial drug is administered. 
Subject Population: 
Approximately 300 male and non-pregnant female subjects between the ages of 18 and 75 years, inclusive, with 
diffuse cutaneous SSc will be enrolled. 
Inclusion Criteria: 
Eligible subjects must meet/provide all of the following criteria: 
1. Written informed consent. 
2. Male or female between the ages of 18 and 75 years, inclusive, at Screening. 
3. Meets the 2013 American College of Rheumatology/European League Against Rheumatism classification 
criteria for SSc with a total score of ≥9 (Van den Hoogen et al., 2013).   
4. Classified as having skin involvement proximal to the elbow and/or knee (diffuse cutaneous SSc subset by 
LeRoy and Medsger, 2001). 
5. At the time of enrollment, less than or equal to 72 months (6 years) since the onset of the first SSc 
manifestation, other than Raynaud’s phenomenon. 
6. Skin in the forearm suitable for repeat biopsy (only applicable to the first 110 subjects for whom biopsy will 
be performed). 
7. mRSS units ≥15 at Screening.   
8. FVC ≥45% predicted at Screening, as determined by spirometry. 
9. 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. Positive for anti-centromere antibodies with the exception that subjects who are positive for both 
anti-centromere and anti-topoisomerase 1 antibodies may be enrolled. 
2. Diagnosed with sine scleroderma or limited cutaneous SSc. 

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3. Diagnosed with other autoimmune connective tissue diseases, except for fibromyalgia, 
scleroderma-associated myopathy and secondary Sjogren’s syndrome.   
4. Scleroderma renal crisis diagnosed within 6 months of the Screening Visit (see Section 9.5.1.4). 
5. Any of the following cardiovascular diseases: 
a. 
uncontrolled, severe hypertension (≥160/100 mmHg) or persistent low blood pressure (systolic 
blood pressure <90 mmHg) within 6 months of Screening, 
b. myocardial infarction within 6 months of Screening,  
c. 
unstable cardiac angina within 6 months of Screening. 
6. DLCO <40% predicted (corrected for hemoglobin).  If severe acute respiratory syndrome coronavirus 
2 (SARS-CoV-2) exposure is of clinical concern for any subject, consider using a DLCO up to 6 months 
before the Screening Visit.   
7. Pulmonary arterial hypertension (PAH) by right heart catheterization requiring treatment with more than 
1 oral PAH-approved therapy or any parenteral therapy.  Treatment is allowed for erectile dysfunction 
and/or Raynaud’s phenomenon/digital ulcers. 
8. Corticosteroid use for conditions other than SSc within 4 weeks prior to Screening (topical steroids for 
dermatological conditions and inhaled/intranasal/intra-articular steroids are allowed). 
9. Use of any other non-steroid immunosuppressive agent, small biologic molecule, cytotoxic or anti-fibrotic 
drug within 4 weeks prior to Screening, including cyclophosphamide, azathioprine (Imuran®) or other 
immunosuppressive or cytotoxic medication.  Avoiding the use of listed prohibited treatments must not be 
considered detrimental and must be indicated by the treating physician.  Exceptions include mycophenolate 
mofetil (CellCept®), mycophenolic acid (Myfortic®), methotrexate and low-dose prednisone, as follows:  
use of CellCept ≤3 g/day, Myfortic ≤2.14 g/day, methotrexate ≤20 mg/week and prednisone ≤10 mg/day (or 
equivalent dosing of glucocorticoids) is allowed.  See Table 9.1 for full details.  Subjects taking CellCept, 
Myfortic or methotrexate must have been doing so for ≥6 months and the dose must have been stable for 
≥4 weeks prior to the Day 1 Visit.  Prednisone must have been at a stable dose for ≥8 weeks prior to the 
Day 1 Visit.  It is acceptable to be on background low-dose prednisone and anti-malarial drug along with 
CellCept, Myfortic or methotrexate.  Rituximab must not have been used within 6 months of the Day 1 
Visit.  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. 
10. Known active bacterial, viral, fungal, mycobacterial or other infection, including tuberculosis or atypical 
mycobacterial disease (fungal infections of nail beds are allowed) at the time of randomization. 
11. Use of a United States Food and Drug Administration-approved agent for SSc or an investigational agent 
for any condition within 90 days or 5 half-lives, whichever is longer, prior to Screening or anticipated use 
during the course of the trial. 
12. Malignant condition in the past 5 years (except successfully treated basal/squamous cell carcinoma of the 
skin or cervical cancer in situ). 
13. 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.  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.  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. 
14. Pregnant or lactating women. 
15. 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. 

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16. Previous enrollment in this trial or participation in a prior fipaxalparant (HZN-825) or SAR100842 clinical 
trial. 
17. 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. 
18. 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. Current alcoholic liver disease, primary biliary cirrhosis or primary sclerosing cholangitis or moderate 
(Child-Pugh B) to severe (Child-Pugh C) hepatic impairment by Child-Pugh scoring system. 
20. Previous organ transplant (including allogeneic and autologous marrow transplant). 
21. International normalized ratio >2, prolonged prothrombin time >1.5 × the upper limit of normal (ULN) or 
partial thromboplastin time >1.5 × ULN at Screening (only applicable to the first 110 subjects for whom 
biopsy will be performed). 
22. Alanine aminotransferase or aspartate aminotransferase >2 × ULN. 
23. Estimated glomerular filtration rate <30 mL/min/1.73 m2 at Screening. 
24. Total bilirubin >2 × ULN.  Subjects with documented diagnosis of Gilbert’s syndrome may be enrolled if 
their total bilirubin is ≤3.0 mg/dL. 
25. Any other condition that, in the opinion of the Investigator, would preclude enrollment in the trial. 
Dose Regimen/Route of Administration: 
Subjects will take 2 tablets of trial drug orally in the morning and evening with a meal.   
Fipaxalparant (HZN-825) 300 mg QD regimen: One set of 2 fipaxalparant (HZN-825) 150 mg tablets in the 
morning and one set of 2 placebo tablets in the evening.  
Fipaxalparant (HZN-825) 300 mg BID regimen: One set of 2 fipaxalparant (HZN-825) 150 mg tablets in the 
morning and one set of 2 fipaxalparant (HZN-825) 150 mg tablets in the evening. 
Placebo regimen: One set of 2 placebo tablets in the morning and these same tablets again in the evening. 
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.  The film-coated tablets are stored at controlled room temperature (20ºC to 25Cº, 68ºF to 77Fº). 
Duration of Treatment and Follow-up: 
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 extension trial (HZNP-HZN-825-302).  
All Week 52 assessments should be performed before the first dose of the extension trial drug is administered.  
Subjects not entering the extension trial will participate in a Safety Follow-up Visit 4 weeks after the last dose of 
trial drug. 
Criteria for Evaluation:  Details of time points for trial activities and assessments are provided in Section 2.1. 
Efficacy will be assessed by FVC % predicted, CGA, mRSS, ACR-CRISS, patient-reported outcomes 
(HAQ-DI, 
, PTGA, SSPRO-18, 
, 
quality-of-life, 
 
   

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Blood samples for fipaxalparant (HZN-825) PK assessment, 
 
 
 
   
Safety will be assessed via AEs, concomitant medication use, physical examinations, vital signs, 
 
 laboratory evaluations and 12-lead ECG.   
Statistical Analyses: 
Primary Efficacy Endpoint 
Change in FVC % predicted from Baseline to Week 52. 
Secondary Efficacy Endpoints 
1. Change from Baseline in the mRSS at Week 52. 
2. Proportion of subjects responding to treatment based on CRISS 25 at Week 52. 
3. Change from Baseline in HAQ-DI at Week 52. 
4. Change from Baseline in CGA at Week 52. 
5. Change from Baseline in PTGA at Week 52. 
6. Change from Baseline in the Physical Effects subscale of the SSPRO-18 at Week 52. 
7. Change from Baseline in the Physical Limitations subscale of the SSPRO-18 at Week 52. 
8. Proportion of subjects with an mRSS decrease of ≥5 points and 25% from Baseline at Week 52. 
9. Responder rate (defined as ACR-CRISS [predicted probability] of at least 0.6) at Week 52. 
Safety and Tolerability Endpoints 
1. Incidence of treatment-emergent adverse events (TEAEs) and the AESI 
. 
2. Concomitant medication use. 
3. Vital signs. 
4. 12-lead ECGs. 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
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5. Clinical safety laboratory evaluations. 
 
Pharmacokinetic Endpoint 
1. Pre- and post-dose concentrations of fipaxalparant (HZN-825). 
Statistical Analysis of Efficacy and Safety Parameters 
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 fipaxalparant (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). 
The primary efficacy endpoint will be change from Baseline in FVC % predicted to Week 52.  A mixed model 
for repeated measures (MMRM) will be fit to the data using observed change in FVC % predicted values from 
all planned post-Baseline assessments (i.e., Weeks 16, 28, 40 and 52) and including factors used for stratifying 
randomization as covariates (use of mycophenolate mofetil [yes/no] and presence of ILD [yes/no]).  The least 
squares mean (LS mean) difference in change from 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.  
In the tipping point analysis, data from fipaxalparant (HZN-825) and placebo groups will be imputed under an 
Missing Not at Random (MNAR) assumption. The missing values in each treatment group will be imputed 
separately based on observed values in each group, respectively. Then adjustments for each treatment group 
(placebo and fipaxalparant [HZN-825]) will be added to the imputed data and vary to find conditions with non-
significant treatment effect.  
The key secondary endpoint for the trial will be change in mRSS from Baseline to Week 52.  Analysis will 
follow that of the primary efficacy endpoint.  Statistical significance on change in mRSS will only be concluded 
if statistical significance was achieved for the primary endpoint.   
After approximately 50% of the subjects reach Week 52 or discontinue the trial before Week 52, a futility 
analysis on the primary efficacy endpoint will be conducted using unblinded, comparative data.  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 data will be reviewed by the IDMC.  But 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.  
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. 
The overall statistical level is α=0.05 (2-sided). 
Since 2 dose regimens of fipaxalparant (HZN-825) will be compared to placebo in the final analysis, adjustment 
for multiplicity will be used to preserve the family-wise error rate for multiple comparisons in the primary 
analysis. For the primary endpoint change from Baseline in FVC % predicted at Week 52, a Hochberg testing 
procedure will be used for the comparisons of fipaxalparant (HZN-825) BID vs. placebo and fipaxalparant 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
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(HZN-825) QD vs placebo. The resulting p-values will be ranked, and the larger p-value will be evaluated at the 
α = 0.05 (2-sided) threshold. If statistically significant, then both comparisons will be considered significant. If 
the larger of the two P-values is not statistically significant at α = 0.05 (2-sided), then the smaller P-value will be 
compared to an α = 0.025 (2-sided). If 1 or both dose regimens of the primary endpoint are not rejected after 
completing testing, no further testing will occur due to exhaustion of alpha. If both fipaxalparant (HZN-825) 
doses are statistically significantly better than the placebo for the primary efficacy endpoint at α = 0.05 
(2-sided), the same Hochberg testing procedure will subsequently be used to evaluate the key secondary 
endpoint. If both dose regimens of fipaxalparant (HZN-825) for the key secondary endpoint are considered 
significant, subsequent secondary endpoints will be tested sequentially within each dose in the order presented 
above, using α = 0.025 (2-sided) in a sequential testing procedure. If all preceding sequentially tested hypotheses 
are rejected at α = 0.025 (2-sided) the next hypothesis will be tested. Once a hypothesis is not rejected, all 
subsequent endpoints within the same dose will not be tested due to alpha exhaustion. 
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 highest dose received. Supplemental analyses based on randomized dose 
groups for key safety analysis parameters if there are more than 5% patients with dose error in the trial. 
AEs will be summarized for all subjects who receive at least 1 dose or partial dose of trial drug, according to 
treatment received.  The number and percentage of subjects who report at least 1 AE, at least 1 AE of 
Rheumatology Common Toxicity Criteria (RCTC) Grade 3 or higher, at least 1 serious AE and at least 1 AE 
related to trial drug will be summarized by System Organ Class and Preferred Term, along with the number who 
discontinue treatment due to an AE.  AE rates (events per patient-year of follow-up during dosing) will also be 
summarized to account for the different treatment durations.  
 is prospectively defined as 
an AESI and will be summarized separately. The exact methods may be used to evaluate AE/SAE risks for 
individual groups (i.e., QD, BID, and placebo) and difference between 2 groups (QD vs placebo, BID vs 
placebo). 
Laboratory values and vital signs will be summarized by treatment received with change from Baseline and with 
shift tables. 
Concomitant medications will be summarized by treatment received by Anatomical Therapeutic Chemical 
Level 4 term and Preferred Term.   
Sample Size Estimate: 
Based on prior trials of tocilizumab [Khanna and Denton et al., 2016; Khanna and Lin et al., 2020] and 
abatacept [Khanna and Spino et al., 2020] in a similar subject population, change in FVC % predicted is 
expected to have a standard deviation of 8 to 8.5 percentage points after 52 weeks of treatment.  Assuming a 
clinically important difference between fipaxalparant (HZN-825) and placebo of 4 percentage points and a 
standard deviation of 8.5, a sample size of 100 subjects per treatment group will provide 85% power to 
demonstrate an improvement between a dose regimen of fipaxalparant (HZN-825) and placebo using α=0.025, 
2-sided. 
 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
 
 
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2.1 
Schedule of Assessments 
 
SCR 1 
Double-blind Treatment Period 2 
Safety Follow-
up Visit 3 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
4 weeks after 
last dose of trial 
drug 
                                               Trial Visit  
Trial Week (W) -42 days 
Day 1 4 
W4 
W10 3 
W16 
W22 3 
W28 
W34 3 
W40 
W46 3 W52/PD 5 
 
Visit Window (±days)
 
 
(±3) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±14) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Review eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 6 
X  
X 
 
 
 
 
 
 
 
 
 
 
Weight  
X 
X 
 
 
 
 
X 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 7 
 
X  
 
 
 
 
 
 
 
 
 
 
Trial drug dispensing 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 8 
 
Compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
mRSS 9 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
FVC % predicted/spirometry 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
CGA 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Patient-reported outcome assessments 
 
 
 
 
 
 
 
 
 
 
 
 
PTGA  
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
SSPRO-18 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
 
 
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SCR 1 
Double-blind Treatment Period 2 
Safety Follow-
up Visit 3 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
4 weeks after 
last dose of trial 
drug 
                                               Trial Visit  
Trial Week (W) -42 days 
Day 1 4 
W4 
W10 3 
W16 
W22 3 
W28 
W34 3 
W40 
W46 3 W52/PD 5 
 
Visit Window (±days)
 
 
(±3) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±14) 
Anchor questions 
 
 
 
 
 
 
 
 
 
 
 
 
ACR-CRISS (last week) 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
ACR-CRISS (overall health and 
change since start of trial) 
 
 
 
 
 
 
X 
 
 
 
X 
 
FVC (last week) 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
FVC (change since start of trial) 
 
 
 
 
 
 
X 
 
 
 
X 
 
HAQ-DI (last week) 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
HAQ-DI (change since start of trial) 
 
 
 
 
 
 
X 
 
 
 
X 
 
SSPRO-18 ( last week) 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
SSPRO-18 (change since start of 
trial) 
 
 
 
 
 
 
X 
 
 
 
X 
 
Pregnancy test 15 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Physical examination 16 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
Vital signs 17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogram 18 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
 
Echocardiogram 18 
X 
 
 
 
 
 
 
 
 
 
 
 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
 
 
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SCR 1 
Double-blind Treatment Period 2 
Safety Follow-
up Visit 3 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
4 weeks after 
last dose of trial 
drug 
                                               Trial Visit  
Trial Week (W) -42 days 
Day 1 4 
W4 
W10 3 
W16 
W22 3 
W28 
W34 3 
W40 
W46 3 W52/PD 5 
 
Visit Window (±days)
 
 
(±3) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±14) 
Clinical laboratory safety tests  
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry 19 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lipids 20 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
Hematology 21 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 22 
X 
 
 
X 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV and HCV serology 
X 
 
 
 
 
 
 
 
 
 
 
 
PK samples 25 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
Adverse event assessment 28 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant medications 29 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ACR-CRISS=American College of Rheumatology-Composite Response Index in Systemic Sclerosis; BID=twice daily; CGA=Clinician Global Assessment; 
 
FVC=forced vital capacity; HAQ-DI=Health Assessment Questionnaire – Disability Index; HBV=hepatitis B virus; HCV=hepatitis C virus; 
 
; hsCRP=high-sensitivity C-reactive protein; mRSS=modified Rodnan skin score; PD=premature discontinuation; PK=pharmacokinetic; 
PTGA=Patient Global Assessment; QD=once daily; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SCR=Screening; 
 
; SSc=systemic sclerosis;
 
 
SSPRO=scleroderma skin patient-reported outcome; VAS=visual analog scale; 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 during Screening may be repeated once during the Screening Period. 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
 
 
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2. Subjects will take fipaxalparant (HZN-825) 300 mg QD, fipaxalparant (HZN-825) 300 mg BID or placebo depending upon randomization.   
3. Visits may be conducted as home health visits, as available within local regions. 
4. 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. 
5. 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 trial will participate in a Safety Follow-up Visit 4 weeks after the last dose of trial drug. 
6. Medical history, including SSc history and treatment, as well as substance use history.   
7. 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. 
8. For subjects who are entering the extension trial. 
9. The assessment should be performed by the Investigator (or designee) who is trained in skin scoring.  Except when strictly unavoidable, the same person should 
perform the assessment at each evaluation during the trial. 
15. 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). A urine pregnancy test will also be done at the Safety Follow-up Visit.   
16. A complete physical examination, including but not limited to cardiac, pulmonary, neurologic and skin assessments, as well as directed rheumatology assessments 
 
17. Vital signs (blood pressure, heart rate, respiratory rate, temperature) will be measured at each trial visit.   
18. Additional electrocardiograms or echocardiograms will be conducted, if clinically indicated.  An echocardiogram that has been performed within the 3 months prior to 
Screening can serve as the Baseline echocardiogram if the subject has been clinically stable. 
19. Includes total protein, albumin, sodium, glucose, phosphate, potassium, calcium, chloride, bicarbonate, blood urea nitrogen, creatinine, creatine kinase, uric acid, 
lactate dehydrogenase, hsCRP and liver function tests (alanine aminotransferase, aspartate aminotransferase, gamma glutamyltransferase, alkaline phosphatase, total 
bile acid, total bilirubin and conjugated and unconjugated bilirubin, if applicable).  Samples collected at the Day 1 Visit should be collected before the dose of trial 
drug is administered in the clinic.  Subjects should be fasting for Day 1, Week 28 and Week 52/PD. 
20. Includes total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides.  Samples collected at the Day 1 Visit should be 
collected before the dose of trial drug is administered in the clinic.  Subjects should be fasting for Day 1, Week 28 and Week 52/PD. 
21. Includes hemoglobin, hematocrit, red blood cell count (with morphology if blood cell count is abnormal), mean corpuscular volume, 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), platelet count and erythrocyte sedimentation rate (must be processed within 1 hour of blood draw).  Samples collected at the 
Day 1 Visit should be collected before the dose of trial drug is administered in the clinic. 
22. To determine risk of bleeding for 
; includes prothrombin time, partial thromboplastin time, international normalized ratio and fibrinogen. Only the first 110 
consenting subjects will have these assessments completed.  For subjects taking warfarin or for evaluation of suspected drug-induced liver injury, physicians should 
monitor the international normalized ratio or other coagulation parameters, as needed. 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
 
 
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25. 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).  Note: all pre-dose samples will be collected prior to any trial drug 
administration for the day.  For subjects not entering the 52-week extension, a sample will be collected anytime during the Week 52 Visit. 
28. 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.  The subject should be assessed for the development of new onset of 
scleroderma renal crisis, new onset or worsening of lung fibrosis, new onset of pulmonary arterial hypertension requiring treatment or right heart catheterization or 
new onset of left ventricular failure. 
29. Includes recording of herb/supplement use.  See Table 9.1 for restrictions regarding medications. 

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Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .......................................................................................................................... 2 
2 
SYNOPSIS ............................................................................................................................ 29 
2.1 
Schedule of Assessments ............................................................................................... 37 
3 
TABLE OF CONTENTS ...................................................................................................... 42 
4 
LIST OF ABBREVIATIONS ............................................................................................... 49 
5 
ETHICS ................................................................................................................................. 52 
5.1 
Institutional Review Board/Independent Ethics Committee .......................................... 52 
5.2 
Ethical Conduct of the Trial ........................................................................................... 52 
5.3 
Subject Information and Consent ................................................................................... 52 
5.4 
Compensation for Health Damage of Subjects/Insurance .............................................. 53 
5.5 
Confidentiality ................................................................................................................ 53 
6 
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE ............................. 54 
7 
INTRODUCTION ................................................................................................................ 55 
7.1 
Background .................................................................................................................... 55 
7.1.1 
Diffuse Cutaneous Systemic Sclerosis.................................................................... 55 
7.1.2 
Lysophosphatidic Acid Receptor 1 (LPAR1) .......................................................... 56 
7.1.3 
Fipaxalparant (HZN-825) ....................................................................................... 56 
7.1.3.1 Pharmacology Related to Potential Therapeutic Activity ................................... 56 
7.1.3.2 Nonclinical Safety ............................................................................................... 57 
7.1.3.3 Nonclinical Pharmacokinetics ............................................................................. 57 
7.1.3.4 Clinical Experience ............................................................................................. 58 
7.1.3.5 Benefit/Risk Assessment ..................................................................................... 58 
7.2 
Rationale for this Trial ................................................................................................... 59 
7.3 
Rationale for Dose Selection .......................................................................................... 59 
8 
TRIAL OBJECTIVES .......................................................................................................... 61 
8.1 
Primary Objective .......................................................................................................... 61 
8.2 
Secondary Objectives ..................................................................................................... 61 
9 
INVESTIGATIONAL PLAN ............................................................................................... 64 
9.1 
Overall Trial Design and Plan ........................................................................................ 64 

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Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
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9.1.1 
Independent Data Monitoring Committee (IDMC) ................................................ 65 
9.1.2 
Adjudication Committee ......................................................................................... 65 
9.2 
Discussion of Trial Design ............................................................................................. 65 
9.3 
Selection of Trial Population ......................................................................................... 66 
9.3.1 
Inclusion Criteria .................................................................................................... 66 
9.3.2 
Exclusion Criteria ................................................................................................... 66 
9.3.3 
Removal of Subjects from Treatment or the Trial .................................................. 69 
9.3.3.1 Removal of Subjects from Treatment ................................................................. 69 
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 
9.4.3 
Labeling .................................................................................................................. 72 
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 .................................................... 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 ............................................................................................ 79 
9.5 
Efficacy, Pharmacokinetic and Safety Variables ........................................................... 79 

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Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
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9.5.1 
Efficacy Variables ................................................................................................... 79 
9.5.1.1 Spirometry ........................................................................................................... 79 
9.5.1.2 Clinician Global Assessment .............................................................................. 80 
9.5.1.3 Modified Rodnan Skin Score .............................................................................. 80 
9.5.1.4 American College of Rheumatology-Composite Response Index in Systemic 
Sclerosis ............................................................................................................................ 80 
9.5.1.5 Revised Composite Response Index in Systemic Sclerosis (CRISS 25) ............ 83 
9.5.1.10 Patient-reported Outcome Assessments .............................................................. 85 
9.5.1.10.1 Health Assessment Questionnaire – Disability Index ............................... 85 
9.5.1.10.2 Patient Global Assessment ........................................................................ 85 
9.5.1.10.3 Scleroderma Skin Patient-reported Outcome Instrument .......................... 86 
9.5.1.10.7 Exit Interviews ........................................................................................... 88 
9.5.1.11 Health Status and Systemic Sclerosis-Specific Quality of Life Measures .......... 88 
9.5.2 
Pharmacokinetic Measurements ............................................................................. 89 
9.5.4 
Safety Variables ...................................................................................................... 90 
9.5.4.1 Adverse Events .................................................................................................... 90 
9.5.4.1.1 
Definitions ................................................................................................. 90 
9.5.4.1.2 
Documentation of Adverse Events ............................................................ 92 
9.5.4.1.3 
Intensity or Severity of Adverse Events .................................................... 93 

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Fipaxalparant (HZN-825) 
Date:  22 August 2024 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
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9.5.4.1.4 
Relationship or Causality to Trial Drug .................................................... 93 
9.5.4.1.5 
Reporting and Documenting Serious Adverse Events .............................. 94 
9.5.4.1.6 
Follow-up of Adverse Events .................................................................... 95 
9.5.4.1.7 
Medication Errors ...................................................................................... 96 
9.5.4.1.8 
Review of Adverse Events and Emerging New Safety Information ......... 96 
9.5.4.1.9 
Reporting of Investigational New Drug Safety Reports ............................ 97 
9.5.4.1.10 Development Safety Update Reports ........................................................ 97 
9.5.4.1.11 Regulatory Reporting Requirements for Safety Information .................... 97 
9.5.4.1.12 Safety Monitoring Plan .............................................................................. 98 
9.5.4.2 Pregnancy and Lactation Reporting .................................................................... 98 
9.5.4.3 Medical History ................................................................................................... 99 
9.5.4.4 Vital Signs, Weight and Height........................................................................... 99 
9.5.4.6 Physical Examination ........................................................................................ 100 
9.5.4.7 Electrocardiogram ............................................................................................. 100 
9.5.4.8 Echocardiogram ................................................................................................ 100 
9.5.4.9 Laboratory Tests for Evaluation ........................................................................ 100 
9.5.5 
Appropriateness of Measurements ........................................................................ 101 
9.5.6 
Trial Procedures .................................................................................................... 101 
9.5.6.1 Screening ........................................................................................................... 102 
9.5.6.2 Double-blind Treatment Period ......................................................................... 103 
9.5.6.2.1 
Day 1/Baseline ......................................................................................... 104 
9.5.6.2.2 
Week 4 ..................................................................................................... 105 
9.5.6.2.3 
Week 10 ................................................................................................... 106 
9.5.6.2.4 
Week 16 ................................................................................................... 106 
9.5.6.2.5 
Week 22 ................................................................................................... 107 
9.5.6.2.6 
Week 28 ................................................................................................... 108 
9.5.6.2.7 
Week 34 ................................................................................................... 109 
9.5.6.2.8 
Week 40 ................................................................................................... 110 
9.5.6.2.9 
Week 46 ................................................................................................... 111 
9.5.6.2.10 Week 52 (End of Treatment) ................................................................... 111 

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9.5.6.3 Safety Follow-up Visit ...................................................................................... 113 
9.5.6.4 Effect of a Pandemic on Trial Procedures ......................................................... 113 
9.6 
Statistical Methods and Determination of Sample Size ............................................... 114 
9.6.1 
Endpoints .............................................................................................................. 114 
9.6.1.1 Primary Efficacy Endpoint ................................................................................ 114 
9.6.1.2 Secondary Efficacy Endpoints .......................................................................... 114 
9.6.1.4 Safety and Tolerability Endpoints ..................................................................... 115 
9.6.1.5 Pharmacokinetic Endpoint ................................................................................ 115 
9.6.2 
Analysis Sets ......................................................................................................... 115 
9.6.3 
Primary Efficacy Endpoint Analysis .................................................................... 115 
9.6.4 
Secondary Efficacy Endpoint Analyses ................................................................ 116 
9.6.6 
Safety and Tolerability Analyses .......................................................................... 117 
9.6.7 
Pharmacokinetic Analyses .................................................................................... 118 
9.6.9 
Interim Analyses ................................................................................................... 118 
9.6.10 Multiple Comparisons ........................................................................................... 118 
9.6.11 Sample Size and Power Considerations ................................................................ 121 
9.7 
Changes in the Conduct of the Trial............................................................................. 121 
10 SOURCE DOCUMENTATION AND INVESTIGATOR FILES ..................................... 122 
11 CASE REPORT FORMS ................................................................................................... 123 
12 TRIAL MONITORING ...................................................................................................... 124 
13 DATA MANAGEMENT .................................................................................................... 126 
14 RETENTION OF RECORDS ............................................................................................. 127 
15 PUBLICATION .................................................................................................................. 128 
16 REFERENCES ................................................................................................................... 129 
17 APPENDICES .................................................................................................................... 134 
17.1 Administrative Appendix ............................................................................................. 134 
17.2 Clinician Global Assessment (CGA) ........................................................................... 135 
17.3 Modified Rodnan Skin Score (mRSS) ......................................................................... 136 

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17.5 Patient Global Assessment (PTGA) ............................................................................. 140 
17.6 Scleroderma Skin Patient-reported Outcome (SSPRO-18) .......................................... 141 
17.13 Serious Adverse Events Anticipated in the Trial Population ....................................... 153 
17.15 Detailed Requirements for the Evaluation of Patients Detected with Abnormal Liver 
Function Test .......................................................................................................................... 157 
 
 

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LIST OF TABLES 
Table 6.1 Table of Non-Sponsor Trial Responsibilities ............................................................ 54 
Table 9.1 Restricted Medications .............................................................................................. 76 
Table 9.2 Rescue Medications Allowed After Week 28 Due to Clinically Significant 
Deterioration .............................................................................................................. 78 
 
LIST OF FIGURES 
Figure 9.1 Schematic of Trial Design ......................................................................................... 65 
Figure 9.2 Schematic of Hochberg Testing Procedure ............................................................. 120 
 

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4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACR-CRISS 
American College of Rheumatology-Composite Response Index in Systemic Sclerosis 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT  
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
AUC 
area under the concentration-time curve 
AUC0-12h 
area under the concentration-time curve from 0 to 12 hours  
BID 
twice daily 
CFR 
Code of Federal Regulations 
CGA 
Clinician Global Assessment 
Cmax 
maximum observed concentration 
COVID-19 
coronavirus disease 2019 
CRISS 25 
Composite Response Index in Systemic Sclerosis 25 
Ctrough 
minimum total trough concentration  
CYP 
cytochrome P450 
DOCA 
deoxycorticosterone acetate 
DSUR 
Development Safety Update Report 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ESR 
erythrocyte sedimentation rate 
EU 
European Union 
FDA 
Food and Drug Administration 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
HAQ-DI 
Health Assessment Questionnaire – Disability Index 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 

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Abbreviation 
Definition 
hsCRP 
high-sensitivity C-reactive protein  
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use 
IDMC 
independent data monitoring committee 
IEC 
Independent Ethics Committee 
ILD 
interstitial lung disease 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IPF 
idiopathic pulmonary fibrosis 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
LPA 
lysophosphatidic acid 
LPAR1 
lysophosphatidic acid receptor 1 
MDGA 
Physician Global Assessment 
mRSS 
modified Rodnan skin score 
NRI-MI 
non-responder imputation in conjunction with multiple imputation 
PAH 
pulmonary arterial hypertension 
PK 
pharmacokinetic 
PTGA 
Patient Global Assessment 
QD 
once daily 
Revised CRISS  
Revised Composite Response Index in Systemic Sclerosis 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SSc 
systemic sclerosis  
SSPRO-18 
scleroderma skin patient-reported outcome 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
Tsk-1 
tight-skin 1 

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Abbreviation 
Definition 
ULN 
upper limit of normal 
US 
United States 
U.S.A. 
United States of America 
VAS 
visual analog scale 
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 Institutional Review Board (IRB) or Independent Ethics Committee (IEC) for review 
and approval/favorable opinion.  A letter confirming the IRB/IEC approval/favorable opinion of 
the protocol, the subject ICF and applicable trial documentation, a list of the IRB/IEC members 
involved in the vote, as well as a statement that the IRB/IEC 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 IRB/IEC 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. 
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 

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information and/or the written ICF.  The Investigator will inform the subject of changes in a 
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 IRB/IEC`s 
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, IRB/IEC 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 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 up to 135 trial sites globally; the Coordinating Investigator will be 
, MD, MSc (Table 6.1).  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 
Person/Organization 
Coordinating Investigator  
, MD, MSc 
Contract research organization 
(project management, monitoring and statistical analysis) 
PPD Biotech 
929 North Front Street 
Wilmington, NC  28401 
Central safety laboratory 
PPD Laboratories – North, South and Latin 
America 
2 Tesseneer Drive  
Highland Heights, KY  41076 
PPD Laboratories – Europe, 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 Diffuse Cutaneous Systemic Sclerosis 
The term scleroderma is used to describe the presence of thickened, hardened skin.  Scleroderma 
is the cardinal feature of systemic sclerosis (SSc).  Patients with SSc are commonly classified 
into 2 distinct subsets on the basis of the pattern of skin involvement.  Diffuse cutaneous SSc is 
dominated by rapidly progressive fibrosis of the skin, lungs and other internal organs.  By 
contrast, limited cutaneous SSc is dominated by vascular manifestations and skin and organ 
fibrosis is generally limited and slow to progress [Varga and Abraham, 2007].  SSc has a 
worldwide distribution and is more frequent in women than men [Mayes et al., 2003].  Based on 
incidence and survival rates, an estimated 75,000 to 100,000 individuals in the US have SSc 
[Varga and Abraham, 2007]. 
The involvement of multiple organs is the distinguishing hallmark of diffuse cutaneous SSc and 
accounts for much of the morbidity and mortality associated with the disease [Varga and 
Abraham, 2007; Asano, 2017; Volkmann and Varga, 2019].  Immune perturbations and vascular 
injury precede and contribute to the development of fibrosis, which, in turn, further exacerbates 
vascular and immune damage [Varga and Abraham, 2007; Bhattacharyya et al., 2011; Asano and 
Sato, 2015; Volkmann and Varga, 2019].  The disease is considered incurable and diffuse 
cutaneous SSc carries the highest risk of fatality of the connective tissue diseases, with 55% 
survival at 10 years [Mayes et al., 2003; Varga and Abraham, 2007]. 
There is no clear understanding of the initial disease triggers but it is generally accepted that 
genetic, epigenetic modifications and/or environmental factors cause an injury to the vasculature 
leading to a complex pathogenesis involving immune activation, inflammation, small vessel 
damage and an increase in the synthesis and deposition of extracellular matrix components 
resulting in multiorgan fibrosis [Asano and Sato, 2015; Asano, 2017; Volkmann and Varga, 
2019].  This complex pathogenesis includes but is not limited to activation of dermal fibroblasts, 
skewing of T helper populations to a Th2/Th17 phenotype, differentiation of macrophages to an 
M2 phenotype, increased infiltration of plasmacytoid dendritic cells, endothelial-to-
mesenchymal transition, epithelial cell activation and differentiation of various cell types into 
myofibroblasts [Asano, 2017].  
SSc is highly heterogeneous in its multisystem clinical manifestations, including Raynaud’s 
phenomenon, cutaneous telangiectasia, nail fold capillary alterations, pulmonary arterial 
hypertension (PAH), gastric antral vascular ectasia and scleroderma renal crisis with malignant 
hypertension [Varga and Abraham, 2007].  The disease severity varies among patients and 
follows a variable and unpredictable course and response to treatment [Varga and Abraham, 
2007; Bhattacharyya et al., 2011; Volkmann and Varga, 2019].  The complexity and 
heterogeneity of the disease pose unique challenges for the development of effective therapies. 

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7.1.2 Lysophosphatidic Acid Receptor 1 (LPAR1) 
Lysophosphatidic acid (LPA) signaling has been associated with skin, pulmonary, cardiac, 
peritoneal and tubulointerstitial fibrosis, and may be a new therapeutic target for treating fibrotic 
diseases, including SSc.  LPA is a bioactive phospholipid that regulates diverse cellular 
processes, including cell motility, proliferation, chemotaxis, survival and differentiation through 
binding to and activating a family of 6 specific G protein-coupled receptors (LPAR1 to LPAR6) 
[Chun et al., 2002].  LPA levels are increased in biological fluids of patients with inflammatory 
or fibrotic diseases, including SSc [Tager et al., 2008; Tokumura et al., 2009]. 
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 idiopathic pulmonary fibrosis (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 cell apoptosis 
following bleomycin administration [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 

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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. 
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 versus 
time curve 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 
nonclinical pharmacokinetics (PK) studies is provided in the current version of the Investigator’s 
Brochure. 

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7.1.3.4 Clinical Experience 
Fipaxalparant (HZN-825) has been administered to 244 healthy subjects in 9 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 form 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 
 
, overall disease severity and pruritus [Allanore et al., 2018].  
No SAEs or severe adverse events (AEs) occurred in Phase 1 trials.  Two subjects experienced 
AEs leading to permanent trial drug discontinuation (Nausea and Abdominal pain in one subject 
after receiving fipaxalparant (HZN-825) 300 mg BID and midazolam and asymptomatic 
COVID-19 in 1 subject after receiving a single dose of fipaxalparant (HZN-825) 300 mg).  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. 
 
that will continue to be monitored as an AE of special interest (AESI) 
(Section 9.5.4.1.1.4).  Additionally, increases in 
 have been seen in blinded 
clinical studies with fipaxalparant.  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 
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 
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 
, 
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 
 
, postural dizziness, flatulence and abdominal pain were slightly more frequent in 
fipaxalparant (HZN-825)-treated than in placebo-treated subjects.  
 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 

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(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).   
AESIs are considered monitorable. Taking into account mitigation measures to minimize risk to 
subjects in this trial, the potential risk 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 
subjects.  More detailed information on the benefits and risks of fipaxalparant (HZN-825) is 
provided in the Investigator’s Brochure Section 6.2 and Section 12. 
7.2 
Rationale for this Trial 
Diffuse cutaneous SSc is a rare and devastating autoimmune disease characterized by skin 
fibrosis, beginning on the fingers and face, that rapidly becomes generalized with internal organ 
manifestations of fibrosis.  The disease carries a high morbidity and mortality rate; patients with 
diffuse cutaneous SSc have a 10-year survival rate of 55% [Mayes et al., 2003; Varga and 
Abraham, 2007].  Death is most often caused by lung, heart and kidney involvement [Tyndall et 
al., 2010; Hao et al., 2017; Pokeerbux et al., 2019]. 
Currently, there is no effective treatment or cure for generalized SSc.  Treatment depends on the 
symptoms that are present and the organs that are affected and may include medication and 
surgery [Kowal-Bielecka et al., 2009].  To date, all available therapeutic options 
(e.g., corticosteroids, methotrexate, cyclophosphamide, azathioprine and mycophenolate mofetil) 
have demonstrated only limited efficacy and/or have safety issues that impact their use and are 
not indicated for use in patients with SSc.  One treatment, nintedanib, was approved, although it 
only slows the decline of pulmonary function in adults with interstitial lung disease (ILD) 
associated with SSc.  Additionally, subcutaneous tocilizumab was also approved in the US for 
slowing the rate of decline in pulmonary function in patients with SSc-associated ILD.  The 
anti-CD20 monoclonal antibody rituximab (Rituxan®) was approved in Japan in 2021 by the 
Ministry of Health, Labour and Welfare for an additional indication of SSc, but it is not approved 
for the treatment of SSc in the US and Europe.  Thus, there is a substantial unmet clinical need 
for an effective and well-tolerated treatment for SSc. 
Fipaxalparant (HZN-825) is under investigation as a novel therapy for SSc because it selectively 
antagonizes LPAR1, which has been shown to be associated with skin, pulmonary, cardiac, 
peritoneal and tubulointerstitial fibrosis, and may be a new therapeutic target for treating fibrotic 
diseases, including SSc.  Details are provided in the current version of the Investigator’s 
Brochure. 
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 
 SRL and Siegfried 
Barbera S.L. 

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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.  
The observed mean steady-state trough concentration (Ctrough) was 7300 ng/mL in the Phase 2a 
trial. 
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 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 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, 
fipaxalparant (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 PK results from Trial HZNP-HZN-825-101, 300 mg BID dosing with a meal using 
fipaxalparant (HZN-825) 
 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 increase in systemic exposures of 
fipaxalparant (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 
 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 SSc to enable 
selection of an appropriate regimen for replication of results in a second trial and registration. 

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8 
TRIAL OBJECTIVES 
The overall objective 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 diffuse cutaneous SSc. 
8.1 
Primary Objective 
The primary objective is to demonstrate the efficacy of 1 or 2 dose regimens of fipaxalparant 
(HZN-825) versus placebo in subjects with diffuse cutaneous SSc, as determined by a 
comparison of change in FVC % predicted after 52 weeks of treatment. 
8.2 
Secondary Objectives 
1.  Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on the 
modified Rodnan skin score (mRSS), after 52 weeks of treatment. 
2. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on the 
Revised Composite Response Index in Systemic Sclerosis (Revised CRISS [CRISS 25]) 
after 52 weeks of treatment. 
3. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on 
Health Assessment Questionnaire-Disability Index [HAQ-DI] after 52 weeks of 
treatment. 
4. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on 
Clinician Global Assessment (CGA) after 52 weeks of treatment. 
5. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on 
Patient Global Assessment (PTGA) after 52 weeks of treatment. 
6. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on the 
Physical Effects subscale of the scleroderma skin patient-reported outcome (SSPRO-18) 
after 52 weeks of treatment. 
7. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on the 
Physical Limitations subscale of the SSPRO-18 after 52 weeks of treatment. 
8. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on 
proportion of subjects with clinically important change in the mRSS, after 52 weeks of 
treatment. 
9. Evaluate the effect of 2 dose regimens of fipaxalparant (HZN-825) versus placebo on 
American College of Rheumatology-Composite Response Index in Systemic Sclerosis 
(ACR-CRISS), defined as improvement from Baseline in mRSS, HAQ-DI, PTGA, CGA 
and FVC % predicted after 52 weeks of treatment. 
10. Assess safety and tolerability of fipaxalparant (HZN-825) based on AEs, the AESI 
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electrocardiogram (ECG) and clinical safety laboratory evaluations (hematology, 
chemistry, inflammatory parameters, coagulation panel and urinalysis). 
11. Evaluate the PK of fipaxalparant (HZN-825). 

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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Trial Design and Plan 
This trial will be conducted at up to 135 sites globally. 
This is a randomized, double-blind, placebo-controlled, repeat-dose, multicenter trial.  Subjects 
will be screened within 6 weeks prior to the Baseline (Day 1) Visit.  Approximately 300 subjects 
who meet the trial eligibility criteria will be randomized on Day 1 in a 1:1:1 ratio to receive 
fipaxalparant (HZN-825) 300 mg QD, fipaxalparant (HZN-825) 300 mg BID or placebo for 52 
weeks.  Randomization will be stratified according to Screening use of mycophenolate mofetil 
(yes/no) and presence of ILD (yes/no) based on a Screening 
 scan. 
The trial will include up to a 42-day Screening Period and a 52-week Double-blind Treatment 
Period.  Subjects will take their first dose of trial drug at the clinic and will participate in trial 
visits at Week 4 and every 6 weeks thereafter until Week 52.  All subjects who complete the 
Double-blind Treatment Period (Week 52) will be eligible to enter a 52-week extension trial 
(HZNP-HZN-825-302).  All Week 52 assessments should be performed before the first dose of 
the extension trial drug is administered.  Subjects not entering the extension trial will participate 
in a Safety Follow-up Visit 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.  Subjects will participate in a Safety Follow-up Visit 
4 weeks after the last dose of trial drug. 
A futility analysis will be conducted after approximately 50% of the subjects reach Week 52 or 
discontinue the trial before Week 52 and these unblinded efficacy and safety data will be 
provided to an independent data monitoring committee (IDMC).  The IDMC will also review 
accumulating safety data to ensure subject safety. 
An overview of the trial design is presented in Figure 9.1 and details of trial activities are 
provided in Section 2.1, Schedule of Assessments. 

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Figure 9.1 
Schematic of Trial Design 
Screening 
Baseline 
Double-blind Treatment Period 
Fipaxalparant (HZN-825) or Placebo 1,2 
52 Weeks 
Safety Follow-up 
Visit 
< –––––––––––––––––––––––––––––––––––––––––––– Trial Visits 3 ––––––––––––––––––––––—————————–– > 
 
 
 
 
 
 
 
42 days 
prior to first 
dose of trial 
drug 
Day 1 
Week 4 and every 6 weeks thereafter 
Week 524 
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 trial (HZNP-HZN-825-302) will participate in a Safety 
Follow-up Visit 4 weeks after the last dose of trial drug. 
3. 
Visit windows are ±3 days for Week 4, ±5 days for Week 10 to Week 52, inclusive, and ±14 days for the Safety Follow-up Visit.  
4. 
Subjects who complete the Double-blind Treatment Period (Week 52) will be eligible to enter a 52-week extension trial  
(HZNP-HZN-825-302).  All Week 52 assessments should be performed before the first dose of the extension trial drug is administered. 
 
9.1.1 Independent Data Monitoring Committee (IDMC) 
An external IDMC will be convened to review data for safety and efficacy, with the possibility 
of IDMC recommendation on trial design modification per a pre-defined IDMC charter. 
The IDMC will include at least 1 statistician and at least 2 clinicians experienced in clinical trials 
and the therapeutic area.  The IDMC charter will include decision rules for stopping the trial 
based on the comparative, unblinded summary of safety and efficacy. There will be no 
possibility of stopping the study early for positive efficacy. 
9.1.2 Adjudication Committee 
A clinical adjudication committee will be established for this trial to adjudicate ACR-CRISS 
Step 1 events defined in Section 9.5.1.4 that include scleroderma renal crisis, PAH, ILD, left 
ventricular failure and others. Cause of death will also be adjudicated; a determination will be 
made if the cause of death is related to SSc or an alternative etiology.  The committee will 
comprise physicians with experience in nephrology, rheumatology and cardiovascular diseases.  
Periodically, the adjudication committee will review all these events.  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 the 
diffuse cutaneous SSc population that was designed according to standard principles.  The 
measurements used in this trial to assess safety and efficacy are established and well-defined. 

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A treatment duration of 12 months is typically the common length of exposure to trial drug in 
randomized, double-blind, placebo-controlled clinical trials of SSc [Del Galdo et al., 2020; 
Pope, 2020] and reflects the length of time needed to see convincing clinical benefits.  Receipt of 
placebo longer than 12 months would not be ethical in subjects with diffuse cutaneous SSc in 
particular, since this patient population is enriched for a worse prognosis across multiple body 
systems.  Since clinically important detectable improvements may require an even longer 
duration of treatment [Pope, 2020], an extension (HZNP-HZN-825-302) of this clinical trial 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.  Subjects will be allowed to continue 
standard-of-care treatments, within guidelines outlined in the protocol, as well as 
protocol-permissible rescue therapy. 
A treatment duration of 12 months is appropriate to observe separation from placebo with respect 
to change in FVC % predicted [Khanna and Denton et al., 2016; Khanna et al., 2018; Distler et 
al., 2019]. 
In addition, the ACR-CRISS was developed to show a difference of an active treatment versus 
placebo at 12 months [Khanna and Berrocal et al., 2016; Khanna et al., 2019]. 
9.3 
Selection of Trial Population 
9.3.1 Inclusion Criteria 
Eligible subjects must meet/provide all of the following criteria: 
1. Written informed consent. 
2. Male or female between the ages of 18 and 75 years, inclusive, at Screening. 
3. Meets the 2013 American College of Rheumatology/European League Against 
Rheumatism classification criteria for SSc with a total score of ≥9 [Van den Hoogen et 
al., 2013].   
4. Classified as having skin involvement proximal to elbow and/or knee (diffuse cutaneous 
SSc subset by LeRoy and Medsger, 2001). 
5. At the time of enrollment, less than or equal to 72 months (6 years) since the onset of the 
first SSc manifestation, other than Raynaud’s phenomenon. 
6. Skin in the forearm suitable for repeat biopsy (only applicable to the first 110 subjects for 
whom biopsy will be performed). 
7. mRSS units ≥15 at Screening.  
8. FVC ≥45% predicted at Screening, as determined by spirometry.  
9. Willing and able to comply with the prescribed treatment protocol and evaluations for the 
duration of the trial. 
9.3.2 Exclusion Criteria 
Subjects will be ineligible for trial participation if they meet any of the following criteria: 

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1. Positive for anti-centromere antibodies with the exception that subjects who are positive 
for both anti-centromere and anti-topoisomerase 1 antibodies may be enrolled. 
2. Diagnosed with sine scleroderma or limited cutaneous SSc. 
3. Diagnosed with other autoimmune connective tissue diseases except for fibromyalgia, 
scleroderma-associated myopathy and secondary Sjogren’s syndrome.  
4. Scleroderma renal crisis diagnosed within 6 months of the Screening Visit (see 
Section 9.5.1.4). 
5. Any of the following cardiovascular diseases:   
a. uncontrolled, severe hypertension (≥160/100 mmHg) or persistent low blood 
pressure (systolic blood pressure <90 mmHg) within 6 months of Screening, 
b. myocardial infarction within 6 months of Screening,  
c. unstable cardiac angina within 6 months of Screening. 
6. DLCO <40% predicted (corrected for hemoglobin).  If severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) exposure is of clinical concern for any subject, consider 
using a DLCO up to 6 months before the Screening Visit.  
7. PAH by right heart catheterization requiring treatment with more than 1 oral 
PAH-approved therapy or any parenteral therapy.  Treatment is allowed for erectile 
dysfunction and/or Raynaud’s phenomenon/digital ulcers. 
8. Corticosteroid use for conditions other than SSc within 4 weeks prior to Screening 
(topical steroids for dermatological conditions and inhaled/intranasal/intra-articular 
steroids are allowed). 
9. Use of any other non-steroid immunosuppressive agent, small biologic molecule, 
cytotoxic or anti-fibrotic drug within 4 weeks prior to Screening, including 
cyclophosphamide, azathioprine (Imuran®) or other immunosuppressive or cytotoxic 
medication.  Avoiding the use of listed prohibited treatments must not be considered 
detrimental and must be indicated by the treating physician.  Exceptions include 
mycophenolate mofetil (CellCept®), mycophenolic acid (Myfortic®), methotrexate and 
low-dose prednisone, as follows:  use of CellCept ≤3 g/day, Myfortic ≤2.14 g/day, 
methotrexate ≤20 mg/week and prednisone ≤10 mg/day (or equivalent dosing of 
glucocorticoids) is allowed.  See Table 9.1 for full details.  Subjects taking CellCept, 
Myfortic or methotrexate must have been doing so for ≥6 months and the dose must have 
been stable for ≥4 weeks prior to the Day 1 Visit.  Prednisone must have been at a stable 
dose for ≥8 weeks prior to the Day 1 Visit.  It is acceptable to be on background low-dose 
prednisone and anti-malarial drug along with CellCept, Myfortic or methotrexate.  
Rituximab must not have been used within 6 months of the Day 1 Visit.  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. 

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10. Known active bacterial, viral, fungal, mycobacterial or other infection, including 
tuberculosis or atypical mycobacterial disease (fungal infections of nail beds are allowed) 
at the time of randomization . 
11. Use of a US Food and Drug Administration-approved agent for SSc or an investigational 
agent for any condition within 90 days or 5 half-lives, whichever is longer, prior to 
Screening or anticipated use during the course of the trial. 
12. Malignant condition in the past 5 years (except successfully treated basal/squamous cell 
carcinoma of the skin or cervical cancer in situ). 
13. 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.  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.  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. 
14. Pregnant or lactating women. 
15. 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. 
16. Previous enrollment in this trial or participation in a prior fipaxalparant (HZN-825) or 
SAR100842 clinical trial. 
17. 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. 
18. 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. 

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19. Current alcoholic liver disease, primary biliary cirrhosis or primary sclerosing cholangitis 
or moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment by Child-Pugh 
scoring system. 
20. Previous organ transplant (including allogeneic and autologous marrow transplant). 
21. 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 (only 
applicable to the first 110 subjects for whom biopsy will be performed). 
22. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × ULN. 
23. Estimated glomerular filtration rate <30 mL/min/1.73 m2 at Screening.   
24. Total bilirubin >2 × ULN.  Subjects with documented diagnosis of Gilbert’s syndrome 
may be enrolled if their total bilirubin is ≤3.0 mg/dL. 
25. Any other condition that, in the opinion of the Investigator, would preclude inclusion in 
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. 
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 will participate in a Safety Follow-up Visit 
4 weeks after the last dose of trial drug. 
9.3.3.1 Removal of Subjects from Treatment 
The primary reason for discontinuation from trial drug should be recorded on the eCRF using 
one of the following categories: 
 Adverse event 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. 
 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) 

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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 (refer to Appendix 17.15).  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 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. 
 Restricted medications. Initiation of any therapy prohibited in the trial per Table 9.1 or 
use of any rescue medications listed in Table 9.2 prior to Week 28 may lead to subject 
discontinuation.  The investigator may consult with the trial Medical Monitor before 
initiation of the restricted medications. 
 Withdrawal by subject/guardian.  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, IRB/IEC or regulatory agency terminates the 
trial. 
 Pregnancy.   
 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 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 

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the event is obtained, in addition to being encouraged to continue participation in all planned 
assessments. 
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 trial, including the Safety Follow-up Visit (if the 
subject does not enroll into the extension trial). 
 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.   

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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, but results must meet eligibility prior to randomization.  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 
On Day 1 of the Double-blind Treatment Period, subjects will be randomized in a 1:1:1 ratio to 
receive: 
1. 
Fipaxalparant (HZN-825) 300 mg QD, or  
2. 
Fipaxalparant (HZN-825) 300 mg BID, or 
3. 
Placebo. 
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:  mannitol, microcrystalline 
cellulose, crospovidone, magnesium stearate, povidone, sodium laurylsulfate, sodium docusate, 
polyvinyl alcohol, macrogol, titanium dioxide and talc.   
9.4.2.2 Placebo 
Placebo tablets match the appearance of active tablets and include the following excipients: 
mannitol, microcrystalline cellulose, magnesium stearate, polyvinyl alcohol, macrogol, titanium 
dioxide and talc. 
9.4.3 Labeling 
Fipaxalparant (HZN-825) 150 mg and placebo tablets will be packaged in blinded blister packs 
according to the dose regimens identified in Section 9.4.1.  Trial drug packaging will be in 

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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 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 trial drug (fipaxalparant [HZN-825] 150 mg and/or placebo) orally 
in the morning and evening with a meal. 
Fipaxalparant (HZN-825) 300 mg QD regimen: One set of 2 fipaxalparant (HZN-825) 150 mg 
tablets in the morning and one set of 2 placebo tablets in the evening.  
Fipaxalparant (HZN-825) 300 mg BID regimen: One set of 2 fipaxalparant (HZN-825) 150 mg 
tablets in the morning and one set of 2 fipaxalparant (HZN-825) 150 mg tablets in the evening. 
Placebo regimen: One set of 2 placebo tablets in the morning and these same tablets again in the 
evening. 
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 

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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. 
9.4.6.1.2 Drug-induced Liver Injury 
Elevated 
 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 
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. 
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. 
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 IRT manual for unblinding a subject. 
CCI

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The Sponsor or designee will unblind the identity of the trial drug for a drug-related SAE for 
submission to health authorities and IRB/IEC 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. 
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.  A futility 
analysis will be performed when approximately 50% of the subjects reach Week 52 or 
discontinue the trial before Week 52 and will include comparative unblinded efficacy and safety 
data. 
9.4.9 Concomitant Therapy and Restricted Medications 
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 3 
Steroids for conditions other than diffuse 
cutaneous SSc 
 
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. 
Oral or parenteral therapy approved for PAH 
Receipt of no more than 1 approved therapy during the trial.  
Parenteral therapy is not allowed (therapy is allowed for 
erectile dysfunction and/or Raynaud’s phenomenon/digital 
ulcers).   
Use of any non-steroid immunosuppressive agent, 
small biologic molecule, cytotoxic or anti-fibrotic 
drug, including cyclophosphamide, cyclosporine1, 
azathioprine (Imuran®) or other 
immunosuppressive or cytotoxic medication other 
than mycophenolate mofetil, mycophenolic acid, 
low-dose prednisone or an anti-malarial 
At least 4 weeks prior to Screening through trial completion. 
For more details refer to Table 9.2. 
Rituximab 
6 months prior to the Day 1 Visit through trial completion. 
United States Food and Drug Administration-
approved agent for SSc or an investigational 
agent 
90 days 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. 
Rifampin2 
2 weeks prior to dosing through trial completion 
OATP inhibitors:  clarithromycin, and 
gemfibrozil. 
BCRP inhibitor:  eltrombopag 
3 days prior to dosing through trial completion 
BCRP=breast cancer resistance protein; CYP=cytochrome P450; OATP=organic anion transporter polypeptide; 
PAH=pulmonary arterial hypertension; SSc=systemic sclerosis 
1.  Cyclosporine is also an OATP and BCRP inhibitor. 
2.  Rifampicin is a CYP enzyme inducer and an OATP inhibitor. 
3.  Rescue medications are allowed after Week 28 due to clinically significant deterioration, refer to Table 9.2. 
 
Concomitant treatment with CellCept (mycophenolate mofetil) ≤3 g/day or Myfortic 
(mycophenolic acid) ≤2.14 g/day, methotrexate ≤20 mg/week and low-dose prednisone 
(≤10 mg/day) or equivalent dosing of glucocorticoids is allowed during the trial.  Subjects taking 
CellCept, Myfortic or methotrexate must have been doing so for ≥6 months and the dose must 
have been stable for ≥4 weeks prior to the Day 1 Visit.  Subjects taking prednisone must have 
been at a stable dose for ≥8 weeks prior to the Day 1 Visit. 
For subjects taking warfarin, physicians should monitor their INR, as needed.  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 

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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 coadministering 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 coadministering fipaxalparant (HZN-825) with strong 
inhibitors of CYP2C9 or CYP2D6. 
In case of a clinically significant deterioration in SSc, 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. 
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 
 
≥15% since Baseline, or  
 Relative change since Baseline in mRSS of >25% and an absolute change since Baseline 
of >5 points, or  
 Clinically significant deterioration in other organ systems or that does not meet above 
criteria, per Investigator assessment, may be appropriate (consultation with the Medical 
Monitor should occur prior). 
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. 

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Table 9.2 
Rescue Medications Allowed After Week 28 Due to Clinically Significant 
Deterioration 
Medication 
Screening Period  
Treatment and Post-treatment 
Follow-up Periods 
Non-steroidal medication 
Stable therapy with mycophenolate 
mofetil/CellCept ≤3 g/day, Myfortic 
≤2.14 g/day 
Permitted if subject has been receiving for 
≥6 months and dose has been stable for ≥4 
weeks prior to the Day 1 Visit 
Pre-trial dose to be continued except 
for deterioration 1 
Methotrexate 2 ≤20 mg/week 
Permitted if subject has been receiving for 
≥6 months and dose has been stable for ≥4 
weeks prior to the Day 1 Visit 
Pre-trial dose to be continued except 
for deterioration 1 (≤20 mg/week in 
any event) 
Azathioprine  
Not permitted for 4 weeks prior to 
Screening and throughout Screening 
Not permitted except for 
deterioration 1 
Cyclophosphamide  
Not permitted for 4 weeks prior to 
Screening and throughout Screening 
Not permitted except for 
deterioration 1 
Hydroxychloroquine  
Permitted if subject has been receiving for 
≥6 months and dose has been stable for ≥4 
weeks prior to the Day 1 Visit 
Pre-trial dose to be continued except 
for deterioration 1 
Colchicine, D-penicillamine, 
sulfasalazine 
Not permitted 
Not permitted except for 
deterioration 1 
Rituximab 
Not permitted within 6 months prior to the 
Day 1 Visit 
Not permitted except for 
deterioration 1 
Tocilizumab, abatacept, 
leflunomide, tacrolimus, newer 
antiarthritic treatments such as 
tofacitinib, potassium 
para-aminobenzoate  
Not permitted 6 months prior to Screening 
Not permitted except for 
deterioration 1 
Pirfenidone  
Not permitted 
Not permitted except for 
deterioration 1 
Nintedanib  
 
Not permitted 
Not permitted except for 
deterioration 1 
Steroids 
Prednisone >10 mg/day  
Not permitted 8 weeks prior to the Day 1 
Visit 
Not permitted except for 
deterioration 1 
; FVC=forced vital capacity; mRSS=modified Rodnan skin score; 
OATP=organic anion transporter polypeptide 
1. 
Initiation/change in dose permitted after the Week 28 Visit in case of clinically significant deterioration, defined as:  
 
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 
 ≥15% since Baseline, or  
 
Relative change since Baseline in mRSS of >25% and an absolute change since Baseline of >5 points, or  
 
Clinically significant deterioration in other organ systems or that does not meet above criteria, per Investigator 
assessment, may be appropriate (consultation with the Medical Monitor should occur prior). 
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. 
2. 
Fipaxalparant (HZN-825) is an in vitro inhibitor of organic anion transporters 1 and 3 (OAT1 and OAT3) and may 
increase the systemic exposures of methotrexate. 

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All concomitant treatment (for diffuse cutaneous SSc and other conditions) must be documented 
in the eCRF, including herbs and supplements. 
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, Pharmacokinetic and Safety Variables 
Refer to the Schedule of Assessments (Section 2.1) 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.  
Spirometry measurements must be performed according to American Thoracic Society 
(ATS)/European Respiratory Society (ERS) 2019 guidelines [Graham et al., 2019].  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.   
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.  

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In addition, the subject will be asked the following anchor (additional) questions at the time 
points indicated in Section 2.1. 
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 Clinician Global Assessment 
The CGA is also known as Physician Global Assessment (MDGA).  The CGA is an 11-point 
Likert scale ranging from 0 to 10 (0=excellent to 10=extremely poor) on which the physician 
rates the subject’s overall health over the past week.  There is also a 5-point scale (from 1 to 5; 
1=much better to 5=much worse) on which the physician rates the subject’s overall scleroderma 
condition compared to the last clinic visit.  
A copy of the CGA is provided in Section 17.2. 
9.5.1.3 Modified Rodnan Skin Score 
The mRSS is a validated method for estimating skin thickening.  Seventeen different body areas 
are scored as normal (0), mild thickening (1), moderate thickening (2) and severe thickening (3), 
with a maximum score of 51.  The assessment should be performed by the Investigator (or 
designee) who is trained in skin scoring.  Except when strictly unavoidable, the same person 
should perform the assessment at each evaluation during the trial. 
A copy of the form for assessing the mRSS is provided in Section 17.3. 
9.5.1.4 American College of Rheumatology-Composite Response Index in Systemic 
Sclerosis 
Subjects will be evaluated using the ACR-CRISS, an outcome measure for diffuse cutaneous 
SSc.  The ACR-CRISS includes core items that assess change in 2 prominent manifestations of 

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early diffuse cutaneous SSc (skin and ILD), functional disability (HAQ-DI) and patient and 
clinician global assessments.  In addition, the score captures a clinically meaningful worsening 
of internal organ involvement requiring treatment. 
The ACR-CRISS is a 2-step process that assigns a probability of improvement for a subject that 
ranges from 0.0 (no improvement) to 1.0 (marked improvement).  Step 1 will be evaluated as 
part of the AE assessment, at which time the Investigator will assess if a subject has developed 
new or worsening cardiopulmonary and/or renal involvement due to SSc, as outlined below.  
Step 1 events will be adjudicated (see Section 9.1.2). 
 New scleroderma renal crisis, defined as follows (adapted from Steen et al., 2003): 
Hypertensive scleroderma renal crisis: 
1. 
New onset hypertension, defined as any of the following: 
a. systolic blood pressure ≥140 mmHg 
b. diastolic blood pressure ≥90 mmHg 
c. rise in systolic blood pressure ≥30 mmHg 
d. rise in diastolic blood pressure ≥20 mmHg 
AND 
2. 
One of the following 5 features: 
a. increase in serum creatinine by ≥50% over Baseline OR serum creatinine 
≥120% of ULN for local laboratory 
b. proteinuria ≥2+ by dipstick 
c. hematuria ≥2+ by dipstick or ≥10 red blood cells/high-powered field 
d. thrombocytopenia: <100,000 platelets/mm3 
e. hemolysis, defined as anemia not due to other causes and either of the 
following: 
1) schistocytes or other red blood cell fragments seen on blood smear 
2) increased reticulocyte count 
Normotensive scleroderma renal crisis: 
1. 
Increase in serum creatinine >50% over Baseline OR serum creatinine ≥120% of 
ULN for local laboratory: 
AND 
2. 
One of the following 5 features: 
a. proteinuria ≥2+ by dipstick 
b. hematuria ≥2+ by dipstick or ≥10 red blood cells/high-powered field 
c. thrombocytopenia: <100,000 platelets/mm3 

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d. hemolysis, defined as anemia not due to other causes and either of the 
following: 
1) schistocytes or other red blood cell fragments seen on blood smear 
2) increased reticulocyte count 
e. Renal biopsy findings consistent with scleroderma renal crisis 
(microangiopathy) 
 Decline in FVC % predicted ≥15% (relative), confirmed by another FVC % within a 
month, 
 to confirm ILD (if previous scan did not show ILD) and FVC % predicted 
<80%  
 New onset of left ventricular failure (defined as ejection fraction ≤45%) requiring 
treatment 
 New onset of PAH on right heart catheterization requiring treatment. 
 Gastrointestinal dysmotility requiring enteral (tube feeding) or parenteral nutrition 
 Digital ischemia with gangrene, amputation, or hospitalization requiring treatment  
If a subject meets any of these criteria, the subject is assigned a probability of 0.  Otherwise, in 
Step 2, the probability of improvement is calculated based on the 5 core measures incorporated 
into the ACR-CRISS, including changes in mRSS, FVC % predicted, HAQ-DI, PTGA and CGA 
[Khanna and Berrocal et al., 2016].   
In addition, the subject will be asked the following ACR-CRISS anchor (additional) questions at 
the time points indicated in Section 2.1. 
Rate the severity of your systemic sclerosis in the last week: 
 0:  none 
 1:  mild 
 2:  moderate 
 3:  severe 
 4:  very severe 
Rate the change in your overall health since you started 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 
Rate the change in your systemic sclerosis since you started the trial.  

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 +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 
9.5.1.5 Revised Composite Response Index in Systemic Sclerosis (CRISS 25) 
The Revised CRISS (CRISS 25) is defined as improvement in at least 2 components: ≥5% 
increase for FVCpp and/or ≥25% decrease for mRSS, HAQ-DI, PTGA, CGA and worsening in 
no more than one component: ≥5% decrease percent predicted FVC and/or ≥25% increase for 
mRSS, HAQ-DI, PTGA, CGA, at 52 weeks.  Revised CRISS (CRISS 25) is also a 2-step 
process.  If the subject meets Step 1 (as defined in Section 9.5.1.4), they are considered not 
improved, given a percentage change of 0% for each core set item.  In Step 2, the five core set 
measures are individually collected and scored. 

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9.5.1.10 Patient-reported Outcome Assessments 
9.5.1.10.1 Health Assessment Questionnaire – Disability Index 
The HAQ-DI, which is part of the 
 assesses the subject’s level of 
functional ability and includes questions of fine movements of the upper extremity, locomotor 
activities of the lower extremity and activities that involve both upper and lower extremities.  
There are 20 questions in 8 categories of functioning including dressing, rising, eating, walking, 
hygiene, reach, grip and usual activities [Cole et al., 2006].  The subject’s ability to accomplish 
each activity in the past week is indicated as:  without any difficulty, with some difficulty, with 
much difficulty and unable to do.  Any devices that are usually used to complete activities and 
any categories for which help from another person is needed is also assessed.  
A copy of the 
 is provided in Section 
 
In addition, the subject will be asked the following anchor (additional) questions at the time 
points specified in Section 2.1. 
How did your systemic sclerosis limit your daily activities in the last week? 
 0:  did not limit activity 
 1:  mildly limited my activity 
 2:  moderately limited my activity 
 3:  severely limited my activity 
 4:  very severely limited my activity 
How has limitation of your daily activities changed since the start of the trial?   
 +3:   very much less limited 
 +2:   much less limited 
 +1:   a little less limited 
▪   0:  no change  
 -1:   a little more limited 
 -2:   much more limited 
 -3:   very much more limited 
9.5.1.10.2 Patient Global Assessment 
The PTGA is an 11-point Likert scale ranging from 0 to 10 (0=excellent to 10=extremely poor) 
on which the subject rates his/her overall health and illness-related pain level over the past week 
and how much the skin involvement due to scleroderma has interfered with daily activity and 
how rapidly the skin disease has been progressing over the past month.  There is also a 5-point 
Likert scale (from 1 to 5; 1=much better to 5=much worse) on which the subject rates overall 
scleroderma skin involvement compared to the last clinic visit. 

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A copy of the PTGA is provided in Section 17.5. 
9.5.1.10.3 Scleroderma Skin Patient-reported Outcome Instrument 
The SSPRO-18, developed through concept elicitation in patients with diffuse cutaneous and 
limited cutaneous SSC based on 3 focus groups, is an 18-item, patient-reported outcome 
instrument that specifically assesses skin-related quality of life in patients with SSc and was 
developed with extensive patient input and according to the FDA patient-reported outcomes 
guidance [Man et al., 2017].  The SSPRO-18 comprises 4 major conceptual constructs—physical 
effects, emotional effects, physical limitations and social effects—and has reproducibility and 
high internal consistency.  This instrument reflects how subjects feel and function from several 
different health perspectives.  Good test-retest reliability and construct validity has been shown 
[Man et al., 2017]. Responsiveness has been shown for lenabasum vs placebo [Spiera et al., 
2020].  
A copy of the SSPRO-18 is provided in Section 17.6. 
In addition, the subject will be asked the following anchor (additional) questions at the time 
points indicated in Section 2.1. 
How severely was your skin affected by systemic sclerosis in the last week? 
 0:  My skin was not affected by systemic sclerosis. 
 1:  My skin was mildly affected by systemic sclerosis. 
 2:  My skin was moderately affected by systemic sclerosis. 
 3:  My skin was severely affected by systemic sclerosis. 
 4:  My skin was very severely affected by systemic sclerosis. 
How much did your skin’s tightness limit your daily activities in the last week?  
 0:  skin tightness did not limit activity 
 1:  skin tightness mildly limited my activity 
 2:  skin tightness moderately limited my activity 
 3:  skin tightness severely limited my activity 
 4:  skin tightness very severely limited my activity 
How has your skin 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 

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 -3:   very much worse 

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9.5.1.10.7 Exit Interviews 
To understand what patients 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) in a subset of subjects.  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 and some of the 
core set measures of the Revised CRISS (CRISS 25). 
These interviews are covered and conducted under a separate protocol, and are not part of the 
schedule of assessments for HZNP-HZN-825-301. 
9.5.1.11 Health Status and Systemic Sclerosis-Specific Quality of Life Measures  

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9.5.2 Pharmacokinetic Measurements 
Blood samples will be collected from all subjects to evaluate the PK of fipaxalparant (HZN-825) 
at the following visits:  Day 1 (at 2 to 4 hours after the first dose of trial drug), Week 4 (pre-
dose), Week 10 (anytime at the visit), Weeks 16 and 28 (pre-dose and 2 to 4 hours post-dose) 
and Weeks 40 and 52 (pre-dose).  For the Day 1, Week 16 and Week 28 Visits with post-dose 
PK samples, the first (Day 1) or morning (Weeks 16 and 28) 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 trial, a sample will be 
collected anytime during the Week 52 Visit.  PK sample collection time 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 
(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 with a meal 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. with 
a meal 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 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.   

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9.5.4 Safety Variables 
Safety will be assessed via AEs, concomitant medication use, physical examinations, vital signs, 
, laboratory evaluations and 12-lead ECG. 
9.5.4.1 Adverse Events 
9.5.4.1.1 Definitions 
9.5.4.1.1.1 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.  
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., SSc).  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. 
9.5.4.1.1.2 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 
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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. 
9.5.4.1.1.3 Non-serious Adverse Event Definition 
A non-serious AE includes any AE that is not described in the previous SAE category. 
9.5.4.1.1.4 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 
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: 
 
 procedure will be performed as outlined in Section 2.1 on 
Day 1 and at Weeks 4, 28 and 52/premature discontinuation, as detailed in the 
 
 in Section 
. 

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If any symptoms occur during the assessment in combination with the blood pressure reductions 
noted above, they are considered as part of the 
 event and will not be 
recorded separately as individual AEs. 
If above symptoms are reported by the subject throughout the assessment, without the blood 
pressure reductions noted above, then the symptoms will only be recorded separately as AEs if 
they meet any of the criteria below, and 
 will not be recorded.  
 The symptoms are severe and/or require medical interventions. 
 The symptoms triggered by the 
 maneuver and persist 
for a significantly longer duration beyond the 
 period. 
 The symptoms are assessed not due to the maneuver of 
 
. 
Signs and symptoms associated with 
 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. 
9.5.4.1.2 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 per Section 9.5.4.1.5. 
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 9.5.4.1.5.  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. 

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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. 
9.5.4.1.3 Intensity or Severity of Adverse Events 
All AEs, both serious and non-serious, will be assessed for severity using the Rheumatology 
Common Toxicity Criteria (RCTC) 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 
 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 
9.5.4.1.4 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. 

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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. 
9.5.4.1.5 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 form immediately and not later than 24 hours after 
becoming aware that a subject has experienced an SAE. 
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. 

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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 
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. 
9.5.4.1.5.1 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 17.13 (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. 
9.5.4.1.6 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 

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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 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. 
9.5.4.1.7 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 9.5.4.1.2 and 9.5.4.1.5, 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.   
9.5.4.1.8 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. 

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9.5.4.1.9 Reporting of Investigational New Drug Safety Reports 
The Sponsor will report SAEs associated with fipaxalparant (HZN-825) blinded therapy to the 
appropriate regulatory authorities and all Investigators in accordance with the local and regional 
regulatory authorities laws and regulations. 
9.5.4.1.10  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. 
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. 
9.5.4.1.11 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 (eg, 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 (eg, 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.  

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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. 
9.5.4.1.12 Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in the Sponsor’s safety surveillance and 
signal management processes. 
9.5.4.2 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. Serum pregnancy 
test will be analyzed 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). A urine 
pregnancy test will also be done at the Safety Follow-up Visit (whether at the clinic or at a 
remote 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: 
 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 (IUD) 
 Intrauterine hormone-releasing system (IUS)  

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 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 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.  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. 
9.5.4.3 Medical History 
Medical history, including diffuse cutaneous SSc history and treatment and substance use 
history, will be recorded.   
9.5.4.4 Vital Signs, Weight and Height 
Blood pressure 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.   

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9.5.4.6 Physical Examination 
A complete physical examination, including but not limited to cardiac, pulmonary, neurologic 
and skin assessments, as well as directed rheumatology assessments 
 
 will be performed per the Schedule 
of Assessments (Section 2.1).  
9.5.4.7 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. 
9.5.4.8 Echocardiogram 
A standard transthoracic echocardiogram will be conducted at Screening.  However, an 
echocardiogram that has been performed within the 3 months prior to Screening can serve as the 
Baseline echocardiogram if the subject has been clinically stable. 
Additional echocardiograms will be conducted, if clinically indicated.   
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. 
9.5.4.9 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 or at-home, as 
applicable, in order to maintain monthly pregnancy testing.   
Chemistry parameters to be evaluated include total protein, albumin, sodium, glucose, phosphate, 
potassium, calcium, chloride, bicarbonate, blood urea nitrogen, creatinine, creatine kinase, uric 
acid, lactate dehydrogenase and liver function tests (alanine aminotransferase, aspartate 
aminotransferase, gamma glutamyltransferase, alkaline phosphatase, total bile acid, total 
bilirubin, conjugated and unconjugated bilirubin, if applicable). 

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Lipid profile (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein 
cholesterol, triglycerides) will also be evaluated.   
Subjects should be fasting for the Day 1, Week 28 and Week 52/Premature Discontinuation 
Visits.  
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.   
Samples for clinical inflammatory laboratory evaluations (hsCRP and ESR) will also be 
collected.  
Urinalysis parameters, including reflex testing if abnormal on dipstick, to be evaluated include 
urine glucose, protein, bilirubin, urobilinogen, pH, blood, ketone, nitrite, leukocyte esterase, 
appearance, specific gravity and color. 
To determine risk of bleeding for 
, a coagulation profile, including prothrombin time, 
partial thromboplastin time, INR and fibrinogen, will be performed at Screening prior to any 
biopsy and at Week 10. Only the first 110 consenting subjects will have these assessments 
completed. For subjects taking warfarin or for evaluation of suspected drug induced liver injury, 
physicians should monitor the international normalized ratio or other coagulation parameters, as 
needed. 
Instructions for the collection, handling and analysis of clinical laboratory samples will be 
provided to the site prior to trial site initiation. 
9.5.5 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 HAQ-DI [Cole et al., 2006],
 SSPRO-18 [Man et al., 2017],
 
 
have been 
validated for use in subjects with SSc. 
9.5.6 Trial Procedures 
Subjects who provide informed consent and who meet all the entry criteria for participation in 
this trial will be randomized. 

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Select visits may be completed at an alternative remote location, e.g., a subject’s home, by a 
visiting home healthcare professional.  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. 
 
9.5.6.1 Screening 
Due to the large number of Screening assessments, the Screening Visit may be completed in 
more than 1 day.  During the Screening Visit, potential trial subjects will be informed fully 
regarding the nature of the trial and possible AEs and will receive a copy of the ICF for review.  
Potential trial subjects must read the ICF and sign the document after the Investigator has 
answered all questions to the trial candidate’s satisfaction.  Further procedures can begin only 
after the ICF has been signed.  The original signed ICF will be retained by the Investigator and a 
copy will be given to the trial subject. 
Trial candidates will be evaluated for trial entry according to the stated inclusion and exclusion 
criteria (Section 9.3).  The Investigator will evaluate the results of all examinations, including 
clinical laboratory tests and will determine each candidate’s suitability for the trial.  The 
Investigator must review the results of all Screening tests before determining that a candidate is 
eligible for trial drug treatment.  The serum pregnancy test performed at Screening on all 
WOCBP must be negative for those subjects to be eligible for initiation of treatment.  All 
Screening procedures must be completed within 42 days prior to Day 1 (i.e., the first day of 
administration of trial drug).  The following procedures will be performed during Screening to 
establish each candidate’s general health and eligibility for enrollment into the trial: 
 Obtain signed, written informed consent and permission to use Protected Health 
Information (in accordance with the Health Insurance Portability and Accountability 
Act).  Refusal to provide this permission excludes an individual from eligibility for trial 
participation.  Record date and time informed consent was given and who conducted the 
process on the appropriate source documentation. 
 Determine trial eligibility through review of the inclusion/exclusion criteria (see 
Section 9.3).  
 Obtain demographics. 
 Obtain medical history, including diffuse cutaneous SSc history and treatment, as well as 
substance use history. 
 Inquire about prior medications (see Table 9.1 for restrictions regarding medications). 
 Query subjects regarding signs and symptoms. 
 Measure weight and height. 

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 Perform physical examination, including the directed rheumatology assessments 
 
. 
 Measure vital signs (blood pressure, heart rate, respiratory rate and temperature) 
according to standardized instructions.   
 Perform 12-lead ECG. 
 Perform echocardiogram. 
 Perform 
  If SARS-CoV-2 exposure is of clinical concern for any subject, 
consider using a 
 up to 6 months before the Screening Visit and measure 
hemoglobin at Screening to make a correction. 
 Collect a blood sample for autoantibodies. 
 Collect blood samples for hematology, coagulation, chemistry (including ESR and 
hsCRP) and hepatitis serology for all subjects, and pregnancy testing for WOCBP (only 
the first 110 consenting subjects will have their coagulation profile assessed).   
 Collect a blood sample for lipid profile. 
 Collect urine sample for urinalysis. 
 Record mRSS. 
 Measure FVC % predicted and ask the FVC % predicted anchor question. 
 If no 
 is available within the last 3 months, perform Baseline lung 
 only after 
meeting all other eligibility and in time to receive reading prior to randomization. 
 Enter visit data in the EDC system. 
9.5.6.2 Double-blind Treatment Period 
Once randomized into the Double-blind Treatment Period, 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 return for a clinic visit and undergo the Week 52/premature 
discontinuation assessments.  Subjects not entering the 52-week extension trial 
(HZNP-HZN-825-302) will participate in a Safety Follow-up Visit 4 weeks after the last dose of 
trial drug. 

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9.5.6.2.1 Day 1/Baseline 
On Day 1, subjects will return to the clinic for Baseline assessments, randomization and the first 
dose of trial drug.  Subjects should be fasting for this visit. 
 Perform review of inclusion/exclusion criteria. 
 Review medical history. 
 Query subjects regarding signs and symptoms and medications since Screening. 
 Measure weight.  
 Perform physical examination, including the directed rheumatology assessments 
 
. 
 Measure pre-dose vital signs (blood pressure, heart rate, respiratory rate and temperature) 
according to standardized instructions.   
 Perform pre-dose 
. 
 Perform pre-dose 12-lead ECG. 
 Collect pre-dose blood samples for hematology and chemistry (including ESR and 
hsCRP) analysis.  
 Collect a pre-dose blood sample for lipid profile. 
 Collect pre-dose urine sample for urinalysis and also for pregnancy testing for WOCBP; 
the pregnancy test must be negative for the subject to receive trial drug. 
 
 
 
 
 
 
 
 Measure Baseline (pre-dose) FVC % predicted. 
 Complete the Baseline (pre-dose) mRSS, 
 PTGA and CGA assessments. 
 Complete the 
 and SSPRO-18 pre-dose. 
CCI

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 Ask the FVC % predicted, HAQ-DI, ACR-CRISS (overall health in last week) and 
SSPRO-18 anchor questions. 
 Complete the 
 and 
 pre-dose. 
 Dispense handheld electronic diary device, provide subject instruction and ask the subject 
to complete the 
 using the device.  
 Obtain randomization assignment and trial drug dosing information from the IRT system. 
 Dispense trial drug.  
 Administer dose of trial drug and record dosing time. 
 Collect a blood sample for PK analysis 2 to 4 hours post-dose; record date/time of 
sample.  
 Enter visit data in the EDC system. 
Subjects will be discharged from the trial center after all of the Day 1 procedures have been 
completed and instructed to return for a clinic visit at Week 4. 
9.5.6.2.2 Week 4 
 Query subjects regarding AEs and concomitant medications. 
 Assess trial drug compliance.  
 Measure vital signs (blood pressure, heart rate, respiratory rate and temperature) 
according to standardized instructions.   
 Perform 
 
 Perform 12-lead ECG. 
 Collect blood samples for hematology and chemistry (including ESR and hsCRP) 
analysis.  
 Collect urine sample for urinalysis and also for pregnancy testing for WOCBP; the 
pregnancy test must be negative for the subject to receive trial drug. 
 Collect a pre-dose blood sample for PK analysis; record date/time of sample.  Record 
date and time of last dose prior to visit. 
 
 

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 Dispense urine pregnancy test kit for at-home use at Week 8 for WOCBP; contact the 
subject at Week 8 to obtain pregnancy test results. 
 Dispense trial drug. 
 Enter visit data in the EDC system. 
Subjects will be discharged from the trial center after all of the Week 4 procedures have been 
completed and instructed to attend a trial visit at Week 10. 
9.5.6.2.3 Week 10 
 Query subjects regarding AEs and concomitant medications. 
 Assess trial drug compliance.  
 Measure vital signs (blood pressure, heart rate, respiratory rate and temperature) 
according to standardized instructions.   
 Collect blood samples for hematology, coagulation and chemistry (including ESR and 
hsCRP) analysis (only the first 110 consenting subjects will have their coagulation profile 
assessed).  
 Collect urine sample for urinalysis. 
 Collect a blood sample for PK analysis anytime during the visit; record date/time of 
sample.  Record date and time of last dose prior to visit. 
 Dispense urine pregnancy test kit for at-home use at Week 12 for WOCBP; contact the 
subject at Week 12 to obtain pregnancy test results. 
 Dispense trial drug. 
 Enter visit data in the EDC system. 
Subjects will be discharged from the trial center after all of the Week 10 procedures have been 
completed and instructed to return for a clinic visit at Week 16. 
9.5.6.2.4 Week 16 
 Query subjects regarding AEs and concomitant medications. 
 Assess trial drug compliance.  
 Measure vital signs (blood pressure, heart rate, respiratory rate and temperature) 
according to standardized instructions.   

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 Perform 12-lead ECG. 
 Collect blood samples for hematology and chemistry (including ESR and hsCRP) 
analysis.  
 Collect urine sample for urinalysis and also for pregnancy testing for WOCBP; the 
pregnancy test must be negative for the subject to receive trial drug. 
 
 
 Measure FVC % predicted. 
 Complete the mRSS, 
 PTGA and CGA assessments. 
 Complete the 
 and SSPRO-18. 
 Ask the FVC % predicted, ACR-CRISS (overall health in last week), HAQ-DI and 
SSPRO-18 anchor questions. 
 Complete the 
 and 
. 
 Collect a pre-dose blood sample for PK analysis; record date/time of sample.  Record 
date and time of last dose prior to visit. 
 Administer dose of trial drug and record dosing time. 
 Dispense urine pregnancy test kit for at-home use at Week 20 for WOCBP; contact the 
subject at Week 20 to obtain pregnancy test results. 
 Dispense trial drug. 
 Collect a blood sample for PK analysis 2 to 4 hours post-dose; record date/time of 
sample. 
 Enter visit data in the EDC system. 
Subjects will be discharged from the trial center after all of the Week 16 procedures have been 
completed and instructed to attend a trial visit at Week 22. 
9.5.6.2.5 Week 22 
 Query subjects regarding AEs and concomitant medications. 
 Assess trial drug compliance.  

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 Measure vital signs (blood pressure, heart rate, respiratory rate and temperature) 
according to standardized instructions.   
 Collect blood samples for hematology and chemistry (including ESR and hsCRP) 
analysis.  
 Collect urine sample for urinalysis. 
 Dispense urine pregnancy test kit for at-home use at Week 24 for WOCBP; contact the 
subject at Week 24 to obtain pregnancy test results. 
 Dispense trial drug.  
 Enter visit data in the EDC system. 
Subjects will be discharged from the trial center after all of the Week 22 procedures have been 
completed and will be instructed to return to the clinic at Week 28. 
9.5.6.2.6 Week 28 
Subjects should be fasting for this visit. 
 Query subjects regarding AEs and concomitant medications. 
 Measure weight. 
 Assess trial drug compliance.  
 Perform physical examination, including the directed rheumatology assessments 
 
. 
 Measure vital signs (blood pressure, heart rate, respiratory rate and temperature) 
according to standardized instructions.   
 Perform 
 
 Perform 12-lead ECG. 
 Perform 
 (within ±2 weeks of visit date).   
 Collect blood samples for hematology and chemistry (including ESR and hsCRP) 
analysis.  
 Collect a blood sample for lipid profile. 

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 Collect urine sample for urinalysis and also for pregnancy testing for WOCBP; the 
pregnancy test must be negative for the subject to receive trial drug. 
 Measure FVC % predicted. 
 Complete the mRSS, 
 PTGA and CGA assessments. 
 Complete the 
 and SSPRO-18. 
 Ask the FVC % predicted, HAQ-DI, ACR-CRISS (overall health in last week, and since 
start of trial) and SSPRO-18 anchor questions. 
 Complete the 
 and 
. 
 Collect a pre-dose blood sample for PK analysis; record date/time of sample.  Record 
date and time of last dose prior to visit. 
 
 
 Administer trial drug and record the dosing time. 
 Dispense urine pregnancy test kit for at-home use at Week 32 for WOCBP; contact the 
subject at Week 32 to obtain pregnancy test results. 
 Dispense trial drug.  
 Collect a blood sample for PK analysis 2 to 4 hours post-dose; record date/time of 
sample. 
 Enter visit data in the EDC system. 
Subjects will be discharged from the trial center after all of the Week 28 procedures have been 
completed and will be instructed to attend a trial visit at Week 34. 
9.5.6.2.7 Week 34 
 Query subjects regarding AEs and concomitant medications. 
 Assess trial drug compliance.  
 Measure vital signs (blood pressure, heart rate, respiratory rate and temperature) 
according to standardized instructions.   
 Collect blood samples for hematology and chemistry (including ESR and hsCRP) 
analysis.  

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 Collect urine sample for urinalysis. 
 Dispense urine pregnancy test kit for at-home use at Week 36 for WOCBP; contact the 
subject at Week 36 to obtain pregnancy test results. 
 Dispense trial drug.  
 Enter visit data in the EDC system. 
Subjects will be discharged from the trial center after all of the Week 34 procedures have been 
completed and instructed to return for a clinic visit at Week 40. 
9.5.6.2.8 Week 40 
 Query subjects regarding AEs and concomitant medications. 
 Assess trial drug compliance.  
 Measure vital signs (blood pressure, heart rate, respiratory rate and temperature) 
according to standardized instructions.   
 Collect blood samples for hematology and chemistry (including ESR and hsCRP) 
analysis.  
 Collect urine sample for urinalysis and also for pregnancy testing for WOCBP; the 
pregnancy test must be negative for the subject to receive trial drug. 
 Measure FVC % predicted. 
 Complete the mRSS, 
 PTGA and CGA assessments. 
 Complete the 
 and SSPRO-18. 
 Ask FVC % predicted, HAQ-DI, ACR-CRISS (overall health in last week) and 
SSPRO-18 anchor questions.  
 Complete the 
 and 
. 
 Collect a pre-dose blood sample for PK analysis; record date/time of sample.  Record 
date and time of last dose prior to visit. 
 Dispense urine pregnancy test kit for at-home use at Week 44 for WOCBP; contact the 
subject at Week 44 to obtain pregnancy test results. 
 Dispense trial drug.  

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 Enter visit data in the EDC system. 
Subjects will be discharged from the trial center after all of the Week 40 procedures have been 
completed and instructed to attend a trial visit at Week 46.  
9.5.6.2.9 Week 46 
 Query subjects regarding AEs and concomitant medications. 
 Assess trial drug compliance.  
 Measure vital signs (blood pressure, heart rate, respiratory rate and temperature) 
according to standardized instructions.   
 Collect blood samples for hematology and chemistry (including ESR and hsCRP) 
analysis.  
 Collect urine sample for urinalysis. 
 Dispense urine pregnancy test kit for at-home use at Week 48 for WOCBP; contact the 
subject at Week 48 to obtain pregnancy test results. 
 Dispense trial drug.  
 Enter visit data in the EDC system. 
Subjects will be discharged from the trial center after all of the Week 46 procedures have been 
completed and instructed to return for a clinic visit at Week 52. 
9.5.6.2.10 Week 52 (End of Treatment) 
Week 52 is the final visit of the Double-blind Treatment Period.  Subjects should be fasting for 
this visit. 
 Query subjects regarding AEs and concomitant medications. 
 Assess trial drug compliance.  
 Measure weight. 
 Perform physical examination, including the directed rheumatology assessments 
 
. 
 Measure vital signs (blood pressure, heart rate, respiratory rate and temperature) 
according to standardized instructions.   

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 Perform 
   
 Perform 12-lead ECG. 
 Perform 
 (within ±2 weeks of visit date).   
 Collect a blood sample for autoantibodies. 
 Collect blood samples for hematology and chemistry (including ESR and hsCRP) 
analysis for all subjects and pregnancy testing for WOCBP; the pregnancy test must be 
negative for the subject to receive trial drug in the extension trial.  
 Collect a blood sample for lipid profile. 
 Collect urine sample for urinalysis. 
 Measure FVC % predicted. 
 Complete the mRSS, 
 PTGA and CGA assessments. 
 Complete the 
 and SSPRO-18. 
 Ask FVC % predicted, HAQ-DI, ACR-CRISS (overall health in last week and since start 
of trial) and SSPRO-18 anchor questions. 
 Complete the 
 and 
. 
 Perform lung 
 
 Perform patient interview to conduct cognitive debriefing and concept elicitation, if 
applicable. 
 Collect blood sample for PK analysis; record date/time of sample.  Record date and time 
of last dose prior to visit.  For subjects entering the extension trial, this sample is 
collected before the subject takes any trial drug under that protocol. 
 
. 
 Dispense trial drug to subjects who elect to enroll in the extension trial. 
 Enter visit data in the EDC system. 
Subjects who complete the Double-blind Treatment Period (Week 52) will be eligible enter an 
extension trial, HZNP-HZN-825-302.  All Week 52 assessments should be performed before the 
first dose of the extension trial drug is administered. 

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9.5.6.3 Safety Follow-up Visit 
Subjects not entering the extension trial will participate in a Safety Follow-up Visit 4 weeks after 
the last dose of trial drug.  This visit is not applicable to subjects who have completed all other 
trial visits and enter the extension trial.  
 Query subjects regarding AEs and concomitant medications. 
 Perform physical examination, including the directed rheumatology assessments 
 
. 
 Measure vital signs (blood pressure, heart rate, respiratory rate and temperature) 
according to standardized instructions.   
 Collect blood samples for hematology and chemistry (including ESR and hsCRP) 
analysis.  
 Collect urine sample for urinalysis and also for pregnancy testing for WOCBP. 
 Enter visit data in the EDC system. 
Subjects will be discharged from the trial after all of the Safety Follow-up Visit procedures have 
been completed.   
The end of the trial is defined as the date of the last visit of the last subject undergoing the trial. 
9.5.6.4 Effect of a Pandemic on Trial Procedures 
In situations due to coronavirus disease 2019 (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.  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 phone 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 Endpoints 
9.6.1.1 Primary Efficacy Endpoint 
The primary endpoint is the change in FVC % predicted from Baseline to Week 52. 
9.6.1.2 Secondary Efficacy Endpoints  
1. Change from Baseline in the mRSS at Week 52. 
2. Proportion of subjects responding to treatment based on CRISS 25 at Week 52. 
3. Change from Baseline in HAQ-DI at Week 52. 
4. Change from Baseline in CGA at Week 52. 
5. Change from Baseline in PTGA at Week 52. 
6. Change from Baseline in the Physical Effects subscale of the SSPRO-18 at Week 52. 
7. Change from Baseline in the Physical Limitations subscale of the SSPRO-18 at 
Week 52. 
8. Proportion of subjects with an mRSS decrease of ≥5 points and 25% from Baseline at 
Week 52. 
9. Responder rate (defined as ACR-CRISS [predicted probability] of at least 0.6) at 
Week 52. 

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9.6.1.4 Safety and Tolerability Endpoints 
1. Incidence of TEAEs and the AESI 
 
2. Concomitant medication use. 
3. Vital signs.  
4. 12-lead ECGs. 
5. Clinical safety laboratory evaluations.  
9.6.1.5 Pharmacokinetic Endpoint 
1. Pre- and post-dose concentrations of fipaxalparant (HZN-825). 
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 fipaxalparant (HZN-825) and have at least 1 PK sample post 
fipaxalparant (HZN-825) treatment.  
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 fipaxalparant (HZN-825) and placebo, using the 
treatment policy strategy approach to intercurrent events.  Details will be provided in the 
statistical analysis plan.  All subjects who are randomized will be included in the primary 
efficacy analyses (ITT analysis set).  The primary efficacy endpoint will be change from 
Baseline in FVC % predicted to Week 52.  A mixed model for repeated measures (MMRM) will 
be fit to the data using observed change in FVC % predicted values from all planned post-
Baseline assessments (Weeks 16, 28, 40 and 52) and including factors used for stratifying 
randomization as covariates (use of mycophenolate mofetil [yes/no] and presence of ILD 
[yes/no]).  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 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.   
In the tipping point analysis, data from fipaxalparant (HZN-825) and placebo groups will be 
imputed under an Missing Not at Random (MNAR) assumption. The missing values in each 
treatment group will be imputed separately based on observed values in each group, respectively. 

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Then adjustments for each treatment group (placebo and fipaxalparant [HZN-825]) will be added 
to the imputed data and vary to find conditions with non-significant treatment effect. Sensitivity 
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 
sensitivity 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 event of initiation of rescue medication.  
A detailed plan for analyses, including how to handle the data impacted by COVID-19, will be 
provided in the statistical analysis plan. 
9.6.4 Secondary Efficacy Endpoint Analyses 
The key secondary endpoint for the trial will be change in mRSS from Baseline to Week 52.  
Analysis will follow that of the primary efficacy endpoint.  Statistical significance on change in 
mRSS will only be concluded if statistical significance was achieved for the primary endpoint. 
The proportion of subjects responding to treatment based on CRISS 25 will be evaluated using 
logistic model.  The Revised CRISS (CRISS 25) is defined as improvement in at least 2 
components: ≥5% increase for FVCpp and/or ≥25% decrease for mRSS, HAQ-DI, PTGA, CGA 
and worsening in no more than one component: ≥5% decrease percent predicted FVC and/or 
≥25% increase for mRSS, HAQ-DI, PTGA, CGA, at 52 weeks.  Revised CRISS (CRISS 25) is 
also a 2-step process.  If the subject meets Step 1 (as defined in Section 9.5.1.4), they are 
considered not improved, given a percentage change of 0% for each core set item.  In Step 2, the 
five core set measures are individually collected and scored. 
The CGA, PTGA and Physical Effects and Physical Limitations subscales of the SSPRO-18 will 
be analyzed analogously to the primary efficacy endpoint. 
The proportion of subjects with an mRSS decrease of ≥5 points and 25% from Baseline at 
Week 52 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 (CMH) 
weighting.   
Components of the ACR-CRISS composite endpoint will be used to calculate the probability that 
a subject improved.  If a subject does not have an event in Step 1 of the calculation and the 
equation in Step 2 shows a probability of at least 0.6 for an individual subject at Week 52, that 
subject will be classified as a responder; otherwise, the subject will be classified as a 
non-responder.  
The predicted probability of improvement for each subject will be computed using the following 
equation in Step 2 (equation to derive predicted probabilities from a logistic regression model): 

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where ∆MRSS indicates the change in mRSS from Baseline, ∆FVC% denotes the change in FVC% 
predicted from Baseline, ∆Pt-glob indicates the change in PTGA, ∆MD-glob denotes the change in 
CGA, and ∆HAQ-DI is the change in HAQ-DI.  All changes are absolute change (Time2 –
Timebaseline). 
Analyses of ACR-CRISS and Revised CRISS (CRISS 25) response rates will be done using 
summary statistics and logistic models. 
We will use NRI-MI (Non-Responder Imputation in conjunction with Multiple Imputation) for 
missing values observed in calculations of mRSS and ACR-CRISS responders at Week 52; and 
patients who died before Week 52 will be categorized as non-responders.  This same rule will be 
applied to Revised CRISS (CRISS 25) analysis. 
9.6.6 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 highest dose 
received. Supplemental analyses based on randomized dose groups for key safety analysis 
parameters if there are more than 5% patients with dose error in the trial. 
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 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 System Organ 
Class 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. 
Safety laboratory assessments (hematology and chemistry) and change from 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 Baseline to each visit will be summarized.   

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Descriptive summaries of observed and change from Baseline values will be presented for each 
vital sign parameter by visit.  A shift table for vital signs by toxicity grade and visit will be 
summarized. 
No inferential statistics are planned for any safety endpoint. But if needed, the exact methods 
may be used to evaluate AE/SAE risks for individual groups (i.e., QD, BID, and placebo) and 
difference between 2 groups (QD vs placebo, BID vs placebo). 
9.6.7 Pharmacokinetic Analyses 
PK data will be analyzed using the PK analysis set.  Plasma concentrations of fipaxalparant 
(HZN-825) (if applicable) 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.   
9.6.9 Interim Analyses 
After approximately 50% of the subjects reach Week 52 or discontinue the trial before Week 52, 
a futility analysis will be conducted using unblinded, comparative data.  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 data will be reviewed by the IDMC.  But 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. 
Additionally, safety will be assessed, and a 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. 
9.6.10 Multiple Comparisons 
The overall statistical level is α=0.05 (2-sided). 

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Since 2 dose regimens of fipaxalparant (HZN-825) will be compared to placebo in the final 
analysis, adjustment for multiplicity will be used to preserve the family-wise error rate for 
multiple comparisons in the primary analysis. For the primary endpoint change from Baseline in 
FVC % predicted at Week 52, a Hochberg testing procedure will be used for the comparisons of 
fipaxalparant (HZN-825) BID vs. placebo and fipaxalparant (HZN-825) QD vs placebo. The 
resulting p-values will be ranked, and the larger p-value will be evaluated at the α = 0.05 
(2-sided) threshold. If statistically significant, then both comparisons will be considered 
significant. If the larger of the two P-values is not statistically significant at α = 0.05 (2-sided), 
then the smaller P-value will be compared to an α = 0.025 (2-sided).  
If 1 or both dose regimens of the primary endpoint are not rejected after completing testing, no 
further testing will occur due to exhaustion of all alpha.  If both fipaxalparant (HZN-825) doses 
are statistically significantly better than the placebo for the primary efficacy endpoint at α=0.05 
(2-sided), the same Hochberg testing procedure will subsequently be used to evaluate the key 
secondary endpoint.  If both dose regimens of fipaxalparant (HZN-825) for the key secondary 
endpoint are considered significant, subsequent secondary endpoints will be tested sequentially 
within each dose in the order shown in Section 9.6.1.2, using α=0.025 (2-sided) in a sequential 
testing procedure.  If all preceding sequentially tested hypotheses are rejected at α=0.025 
(2-sided), the next hypothesis will be tested. Once a hypothesis is not rejected, all subsequent 
endpoints within the same dose will not be tested due to alpha exhaustion.  A graphic 
representation of the proposed multiplicity testing approach is presented in Figure 9.2. 

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Figure 9.2 
Schematic of Hochberg Testing Procedure 
Accept H1(Dose with p < 0.025) and 
Accept H0(Dose with p ≥ 0.05)
STOP
Is pfirst < 0.025?
Accept H0(Dose 1) and H0(Dose 2)
STOP
Is plast < 0.05?
Accept H1(Dose 1) and 
H1(Dose 2)
START 
Test Primary Endpoint for 2 doses: 300 mg QD and 300 mg BID 
Sort p-values in ascending order, start with last p-value
Is plast < 0.05?
Is pfirst < 0.025?
Accept H0(Dose 1) and H0(Dose 2)
STOP
Test Key Secondary Endpoint for 2 doses: 300 mg QD and 300 mg BID 
Sort p-values in ascending order, start with last p-value
Kth Ordered Secondary Endpoint, starting with K = 2
DOSE 1: 300 mg QD DOSE 2: 300 mg BID
Is p < 0.025?
Is p < 0.025?
Accept H0for the tested 
endpoint at the dose.
STOP
Accept H1(Dose 1) and 
H1(Dose 2)
Accept H1(Dose with p < 0.025) and 
Accept H0(Dose with p ≥ 0.05)
STOP
Accept H1 for the 
tested endpoint at 
the dose; test next 
endpoint
NO
NO
NO
NO
NO
NO
YES
YES
YES
YES
YES
YES
 

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9.6.11 Sample Size and Power Considerations 
Based on prior trials of tocilizumab [Khanna and Denton et al., 2016; Khanna and Lin et al., 
2020] and abatacept [Khanna and Spino et al., 2020] in a similar subject population, change in 
FVC % predicted is expected to have a standard deviation of 8 to 8.5 percentage points after 
52 weeks of treatment.  Assuming a clinically important difference between fipaxalparant 
(HZN-825) and placebo of 4 percentage points and a standard deviation of 8.5, a sample size of 
100 subjects per treatment group will provide 85% power to demonstrate an improvement 
between a dose regimen of fipaxalparant (HZN-825) and placebo using α=0.025, 2-sided. 
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 IRB/IEC. 
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 IRB/IEC 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, 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. 

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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. 

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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 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 US 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 

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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 (eg 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: 
 Good Clinical Practice (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 

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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. 

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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, 
IRB/IEC 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. 

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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. 

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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. 
Asano Y. Recent advances in the treatment of skin involvement in systemic sclerosis. Inflamm 
Regen. 2017;37:12. 
Asano Y, Sato S. Vasculopathy in scleroderma. Semin Immunopathol. 2015;37(5):489-500. 
Bhattacharyya S, Wei J, Varga J. Understanding fibrosis in systemic sclerosis:  shifting 
paradigms, emerging opportunities. Nat Rev Rheumatol. 2011;8(1):42-54. 
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. 
Cole JC, Khanna D, Clements PJ, et al. Single-factor scoring validation for the Health 
Assessment Questionnaire-Disability Index (HAQ-DI) in patients with systemic sclerosis and 
comparison with early rheumatoid arthritis patients. Qual Life Res. 2006;15(8):1383-94. 
Del Galdo F, Hartley C, Allanore Y. Randomised controlled trials in systemic sclerosis:  patient 
selection and endpoints for next generation trials. Lancet Rheumatol. 2020:e173-84. 
Distler O, Highland KB, Gahlemann, et al. Nintedanib for systemic sclerosis-associated 
interstitial lung disease. N Engl J Med. 2019;380:2518-28. 
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. 
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. 
Hao Y, Hudson M, Baron M, et al. Early mortality in a multinational systemic sclerosis inception 
cohort. Arthritis Rheumatol. 2017;69(5):1067-77. 

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Human Albumin. Transfus Med Hemother. 2009;36:399-407. 
Khanna D, Berrocal VJ, Giannini EH, et al. The American College of Rheumatology Provisional 
Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis. 
Arthritis Rheumatol. 2016;68(2):299-311. 
Khanna D, Clements PH, Volkmann ER, et al. Minimal clinically important differences for the 
modified Rodnan Skin score:  results from the Scleroderma Lung Studies (SLS-I and SLS-II). 
Arthritis Res Ther. 2019;21:23. 
Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of subcutaneous tocilizumab in 
adults with systemic sclerosis (faSScinate):  a phase 2, randomised, controlled trial. Lancet. 
2016;387:2630-40. 
Khanna D, Furst DE, Clements PJ, et al. Standardization of the modified Rodnan skin score for 
use in clinical trials of systemic sclerosis. J Scleroderma Relat Disord. 2017;2(1):11-8. 
Khanna D, Lin CJF, Furst DE, et al. Tocilizumab in systemic sclerosis: a randomised, 
double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2020;8:963-74. 
Khanna D, Lin CJF, Kuwana M, et al. Efficacy and safety of tocilizumab for the treatment of 
systemic sclerosis:  results from a phase 3 randomized controlled trial. Available at:  
https://acrabstracts.org/sessions/3s089-acr-abstract-systemic-sclerosis-amp-rel-doclinical-i-
clinical-trials-i-898903-2018. 
Khanna D, Spino C, Johnson S, et al. Abatacept in early diffuse cutaneous systemic sclerosis:  
results of a phase 2 investigator-initiated, multicenter, double-blind, randomized, placebo-
controlled trial. Arthritis Rheumatol. 2020;72:125-36. 

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Kowal-Bielecka O, Landewe R, Avouac J, et al. EULAR recommendations for the treatment of 
systemic sclerosis:  a report from the EULAR scleroderma trials and research group (EUSTAR). 
Ann Rheum Dis. 2009;68:620-8. 
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;doi:  
10.1111/bph.15190. 
LeRoy EC, Medsger TA Jr. Criteria for the classification of early systemic sclerosis. 
J Rheumatol. 2001;28:1573–6. 
Man A, Correa JK, Ziemek J, Simms RW, Felson DT, Lafyatis R. Development and validation 
of a patient-reported outcome instrument for skin involvement in patients with systemic 
sclerosis. Ann Rheum Dis. 2017;76:1374-80. 
Mayes M, Lacey J Jr, Beebe-Dimmer J, et al. Prevalence, incidence, survival and disease 
characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 
2003;48(8):2246–55. 
Ninou I, Magkrioti C, Aidinis V. Autotaxin in pathophysiology and pulmonary fibrosis. Front 
Med (Lausanne). 2018;5:180. 
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. 
Pokeerbux MR, Giovannelli J, Dauchet L, et al. Survival and prognosis factors in systemic 
sclerosis:  data of a French multicenter cohort, systematic review, and meta-analysis of the 
literature. Arthritis Res Ther. 2019;21(1):86. 
Pope JE. The future of treatment in systemic sclerosis:  can we design better trials? Lancet 
Rheumatol. 2020:e185-94.  
Pradère JP, Klein J, Grès S, et al. LPA1 receptor activation promotes renal interstitial fibrosis. 
J Am Soc Nephrol. 2007;18(12):3110-8. 
Reay N. The quality of life in patients with diffuse and limited systemic sclerosis. Published 
online 2008. https://etheses.whiterose.ac.uk/26111/1/503274.pdf. 

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Smyth A, MacGregor A, Mukerjee D, Brough G, Black C, Denton C. A cross-sectional 
comparison of three self-reported functional indices in scleroderma. Rheumatology. 
2003;42(6):732-8. 
Spiera R, Hummers L, Chung L, et al. Safety and efficacy of lenabasum in a Phase II, 
randomized, placebo-controlled trial in adults with systemic sclerosis. Arthritis Rheumatol. 
2020;72(8):1350-60. 
Steen VD, Mayes MD, Merkel PA. Assessment of kidney involvement. Clin Exp Rheumatol. 
2003;21(3Suppl29):S29-31. 
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. 
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. 
Tokumura A, Carbone LD, Yoshioka Y, et al. Elevated serum levels of 
arachidonoyllysophosphatidic acid and sphingosine 1-phosphate in systemic sclerosis. Int J Med 
Sci. 2009;6:168-76. 
Tyndall AJ, Bannert B, Vonk M, et al. Causes and risk factors for death in systemic sclerosis:  a 
study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis. 
2010;69(10):1809-15. 
US Department of Health and Human Services, Food and Drug Administration. Drug-induced 
liver injury:  premarketing clinical evaluation. July 2009. 
Van den Hoogen F, Khanna D, Fransen J, et al. 2013 Classification criteria for systemic 
sclerosis. Arthritis Rheum. 2013; 65:2737-47. 
Varga J, Abraham D. Systemic sclerosis:  a prototypic multisystem fibrotic disorder. J Clin 
Invest. 2007;117(3):557-67. 
Volkmann E, Varga J. Emerging targets of disease-modifying therapy for systemic sclerosis. Nat 
Rev Rheumatol. 2019;15(4):208-24. 

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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. 

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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 
IRB/IEC must be notified of changes that are made to this section, but IRB/IEC 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 
 MD 
 
Medical Director 
 
Horizon Therapeutics U.S.A., Inc. 
 
1 Horizon Way 
 
Deerfield, IL  60015 
 
Business 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: 
 
 

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17.2 Clinician Global Assessment (CGA) 
 

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17.3 Modified Rodnan Skin Score (mRSS) 
 
Source:  Khanna et al., 2017 

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17.5 Patient Global Assessment (PTGA) 
 

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17.6 Scleroderma Skin Patient-reported Outcome (SSPRO-18) 
 

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17.13 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 9.5.4.1.1.2 (Serious Adverse Event Definition).  The Investigator is 
required to follow the requirements detailed in Section 9.5.4.1.5 (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 fipaxalparant (HZN-825) compared with placebo, an expedited IND safety report 
may be submitted to the FDA. 
Renal system:  scleroderma renal crisis (refer to Section 9.5.1.1 for the definition), accelerated 
hypertension 
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, forced vital 
capacity decreased, interstitial lung disease 
Gastrointestinal system:  nausea, vomiting, diarrhea, intestinal pseudo-obstruction, malnutrition, 
abnormal loss of weight 
Skin and subcutaneous system:  skin ulcer, gangrene, extremity necrosis 

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17.15 Detailed Requirements for the Evaluation of Patients Detected with Abnormal 
Liver Function Test 
Per protocol Section 9.3.3.1, 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. 
An increase of serum aminotransferases to >3 × ULN and/or total bilirubin (TBL) >2 × 
ULN should be followed by repeat testing (ALT, AST, ALP, and TBL at minimum) within 
48 to 72 hours to confirm the abnormality*. 
A confirmed ALT/AST >3 × ULN and/or TBL >2 × ULN should be considered to record as AE.  
Please reach out to the Medical Monitor via Electronic Protocol Inquiry Platform to inform such 
events. 
It is critical to exclude the other possible causes of increased liver enzymes.  If needed, please 
consider hepatologist/gastroenterologist consultation early in the evaluation.  Additional imaging 
and laboratory tests (e.g., abdominal ultrasound, Hepatitis panel testing, etc.), as deemed 
necessary, should be performed to ascertain the etiology. 
Below are the requirements which need to be followed to ensure the close observation of patients 
who have confirmed ALT or AST levels >3 × ULN and/or TBL >2 × ULN: 
 Repeating liver enzyme and serum bilirubin tests two or three times weekly.  Frequency 
of retesting can decrease to once a week or less if abnormalities stabilize or the trial drug 
has been discontinued and the subject is asymptomatic. 
 Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
 Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets. 
 Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy; and biliary tract 
disease. 
 Obtaining a history of exposure to environmental chemical agents. 
 Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin). 
 Considering gastroenterology or hepatology consultations. 
*If it is difficult for the subjects to return to the trial site promptly, the repeat test can be analyzed 
locally, but normal laboratory ranges should be recorded.  Results should be made available to 
trial investigators immediately and the data should be included in the case report forms. 
The subject should return to the site for the lab testing as soon as possible. 

Approval Signatures
Document Name:
Protocol Amendment fipaxalparant 20230130 4
Document Description:
HZNP-HZN-825-301 v5.0 Protocol Amendment 4
Document Number:
CLIN-000346537
Approval Date:
23 Aug 2024
Type of Study Protocol:
Amendment
Protocol Amendment No.: 4
Document Approvals
Reason for Signing: Management
Name: 
Date of Signature: 23-Aug-2024 17:40:00 GMT+0000

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SUMMARY OF CHANGES 
Protocol HZNP-HZN-825-301 
Version 3.0 Amendment 2, incorporating Protocol Version 2.0 and Protocol Version 2.1 
(protocol amendment for the United Kingdom) 
Key additions, revisions and clarifications to Version 2.0 of the protocol are: 
• Updating the Sponsor’s address. 
• 
• 
• Updating the primary analysis set definition (i.e., changing the primary analysis set from 
the intent-to-treat analysis set to the full analysis set). 
• Clarifying that the 
 can be taken from affected or unaffected skin in the 
forearm and that this requirement is applicable to the first 110 subjects. 
• Highlighting that 
 collection can occur anytime during Screening prior to the 
first dose of trial drug. 
• Clarifying that the coagulation profile should be assessed before 
 if the 
 is 
performed during Screening. 
• Including further guidance about acceptable use of restricted medications as part of the 
entry criteria evaluation in exclusion criterion 9. 
• Adding new requirements around condom use and aligning text with Section 9.5.4.2 in 
exclusion criterion 13. 
• Clarifying the definition of active hepatitis B and reformatting exclusion criterion 18 for 
clarity. 
• Updating the multiplicity handling approach to the Hochberg method. 
• Updating the protocol with information from the current Investigator’s Brochure 
(Version 8) with respect to clinical experience with HZN-825 and rationale for this trial. 
• Including information on the potential benefits of HZN-825 in the benefit/risk assessment 
section. 
• Including restricted medication use as a specific reason for discontinuation from trial 
treatment. 
• 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). 
• Including some additional cautions around use of specific concomitant medications. 
• 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  14 July 2022 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
Version 3.0, Amendment 2 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 6 of 143 
 
• Deleting mention of subject (i.e., exit) interviews from the schedule of assessments and 
clarifying that they will be covered by a separate protocol. 
• Adding the definition of a suspected adverse reaction. 
• Clarifying documentation and reporting for medication errors. 
• Adding clarification around abstinence as a contraceptive method. 
• Allowing subject visits to be performed at locations other than the trial site. 
• Alerting trial personnel that the actual assessment instruments used may differ from those 
in Section 17 of the protocol. 
• 
• 
Minor wording changes and correction of minor typographical errors are not detailed below. 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  04 October 2021 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
Version 2.0, Amendment 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 5 of 163 
 
SUMMARY OF CHANGES 
Protocol HZNP-HZN-825-301 
Version 2.0 Amendment 1, incorporating Protocol Version 1.0, Administrative Change 1, 
Amendment 1.1 (protocol amendment for France) and Version 1.0 Addenda for 
Germany/Austria, Italy, Portugal and Spain 
Key additions, revisions and clarifications to Version 1.0 of the protocol include: 
• Changing the Medical Monitor to 
, MD. 
• 
• In inclusion criterion 4, matching the accepted disease definition of diffuse cutaneous 
systemic sclerosis and aligning with the criterion described in the referenced publication.   
• Removed inclusion criterion 6 to focus solely on patients with early disease and 
significant skin involvement (mRSS 15 or higher). 
• Removed inclusion criterion 7 to remove the elevated acute phase reactants criteria since 
patients are allowed to enter the study with protocol-specified, stable, concomitant 
immunosuppression. 
• Updating the development phase of the trial from 2b/3 to 2b. 
• 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. 
• Excluding subjects with moderate to severe hepatic impairment. 
• Adding a physical examination at Week 28 and clarifying the assessments (cardiac, 
pulmonary, neurologic, skin and directed rheumatology assessments) to be included as 
part of the physical examination. 
• Specifying that subjects should be fasting for the Day 1, Week 28 and Week 52/End of 
Treatment/Premature Discontinuation Visits. 
• Changing the blood sample collection for lipid profile to occur at Screening and the 
Day 1, Week 28 (was Week 16 in version 1.0 of the protocol) and Week 52/End of 
Treatment/Premature Discontinuation Visits. 
• Specifying that erythrocyte sedimentation rate must be processed within 1 hour of the 
blood collection for hematology. 
• 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. 
• Updating nonclinical information pertaining to LPAR1 and HZN-825 nonclinical 
pharmacology as it pertains to lung fibrosis. 
• Updating clinical data to be current as of 10 January 2021. 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  04 October 2021 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
Version 2.0, Amendment 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 6 of 163 
 
• Adding a section on the assessment of benefits and risks of HZN-825 treatment. 
• Specifying that trial drug should be taken with a meal to achieve sufficient targeted drug 
exposure. 
• Updating various sections for consistency with the electronic case report form (eCRF), 
other HZN-825 protocols and/or the Investigator’s Brochure. 
• Clarifying that, prior to any site closure, discussion should occur among the site Principal 
Investigator, Medical Monitor, Trial Manager and possibly the Site Monitor. 
• Clarifying how missed doses of trial drug should be handled. 
• Adding cyclosporine, organic anion transporter polypeptide (OATP) inhibitors, 
P-glycoprotein (P-gp) inhibitors and a breast cancer resistance protein (BRCP) inhibitor 
as restricted medications. 
• Adding international normalized ratio (INR) monitoring when warfarin is used, since 
HZN-825 is a very weak cytochrome P450 (CYP)2C9 inhibitor. 
• Emphasizing that, even for deterioration, the methotrexate dosage must be ≤15 mg/week. 
• Clarifying that the first dose of trial drug on Day 1 and the morning dose of trial drug at 
the Week 16 and Week 28 Visits are to be taken in the clinic (i.e., visits with post-dose 
pharmacokinetic samples). 
• Adding definitions of women of childbearing potential (WOCBP), postmenopausal 
women and fertile men to exclusion criterion 13. 
• Changing pregnancy testing to every 4 weeks and adding examples of highly effective 
contraceptive methods. 
• Adding a statement that development safety update reports will be submitted to countries 
and territories as required. 
• Adding the definition of “end-of-trial.” 
• Clarifying that unblinded information will be restricted from Horizon trial team members 
who are involved in all aspects of trial conduct and management. 
• Providing guidance regarding restarting trial drug after a subject experiences clinically 
significant 
. 
• Providing regional addresses for the central safety laboratory. 
• Removing long-term survival follow-up. 
• Clarifying serious adverse event (SAE) reporting requirements. 
• Adding reasons that a treatment group or the trial may be discontinued. 
• Indicating Investigator discretion in repeat of spirometry prior to rescue medication. 
• Clarifying that azathioprine and cyclophosphamide are not permitted for 4 weeks prior to 
Screening and throughout Screening. 
• Adding a section on echocardiogram for consistency with other HZN-825 protocols. 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  04 October 2021 
 
Protocol:  HZNP-HZN-825-301 
IND 112818 
 
Version 2.0, Amendment 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 7 of 163 
 
• Specifying collection of a fasting blood sample for lipid profile in Section 9.5.6 (Trial 
Procedures) at Day 1, Week 28 and Week 52/End of Treatment/Premature 
Discontinuation for consistency with the Schedule of Assessments. 
Minor wording changes and correction of minor typographical errors are not detailed below.