A Multicenter, Open-label Extension Trial to Evaluate the Efficacy, Safety and Tolerability 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:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
Version 3.0, Amendment 2 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 1 of 119 
 
  
 
 
CLINICAL TRIAL PROTOCOL  
FOR FIPAXALPARANT (HZN-825) 
Protocol Number:  HZNP-HZN-825-302 
IND:  112818 
EU CT Number:  2023-509783-23-00 
 
A Multicenter, Open-label Extension Trial to Evaluate the Efficacy, Safety 
and Tolerability of HZN-825 in Patients with  
Diffuse Cutaneous Systemic Sclerosis 
 
Date:  14 October 2024 
Version 3.0 
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:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
Version 3.0, Amendment 2 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 2 of 119 
 
PROTOCOL 
1 
TITLE PAGE 
Trial Title: A Multicenter, Open-label Extension Trial to 
Evaluate the Efficacy, Safety and Tolerability of 
HZN-825 in Patients with Diffuse Cutaneous 
Systemic Sclerosis 
Protocol Number: HZNP-HZN-825-302 
Version: 3.0 
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: 14 October 2024 
 
 
 CONTACT IN THE EVENT OF AN EMERGENCY 
Any death, life-threatening event or other serious adverse event experienced by a subject during 
the course of the trial, whether or not judged drug-related, must be reported immediately and not 
later than 24 hours of knowledge of the event by entering the information into the electronic 
case report form (eCRF).  If unable to access the eCRF, the event must be reported by submitting 
the completed Serious Adverse Event Form via email or fax to the contacts provided below. 
Email (worldwide): svc-ags-in-us@amgen.com 
US Fax: 1-888-814-8653 (toll free, within USA) 
Ex-US Fax: +44 (0)207-136-1046 
 
 
 
 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
Version 3.0, Amendment 2 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
Page 3 of 119 
 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
HZNP-HZN-825-302 
Version: 
3.0 
Protocol Title: 
A Multicenter, Open-label Extension Trial to Evaluate the Efficacy, Safety 
and Tolerability of HZN-825 in Patients with Diffuse Cutaneous Systemic 
Sclerosis 
Version Date: 
14 October 2024 
I agree to conduct the trial according to the protocol named above.  I fully understand that any 
changes instituted by the Principal Investigator without previous discussion with the Sponsor 
constitute a violation of the protocol, unless necessary to eliminate an immediate hazard to the 
safety or well-being of a subject. 
I acknowledge that I have read and understand the protocol named above and agree to carry out 
all of its terms in accordance with applicable regulations and laws. 
I assure that the trial drug supplied by the Sponsor will be used only as described in the protocol 
named above. 
Signature: 
 
 
 
 
 
 
 
Name  
Trial Center 
Address 
City State Country 
 
Date 
 
 
 
 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
Version 3.0, Amendment 2 
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SUMMARY TABLE OF CHANGES 
Protocol Version 2.0, Amendment 1 (19 October 2022) to 
Protocol Version 3.0, Amendment 2 (14 October 2024) 
Text 
Version 2.0 
19 October 2022 
Amended Text 
Version 3.0, Amendment 2 
14 October 2024 
Reason for 
Change 
Global 
HZN-825 
Global 
fipaxalparant (HZN-825) 
To incorporate 
non-proprietary 
name 
throughout 
document 
Global 
Physician Global Assessment (MDGA) 
Global 
Clinician Global Assessment (CGA) 
To align with 
industry 
standard 
language 
Cover Page 
EudraCT Number:  2021-006271-42 
Cover Page 
EU CT Number:  2023-509783-23-00 
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: 
, MD, MS 
Vice President, Clinical Development 
Horizon Therapeutics U.S.A., Inc. 
1 Horizon Way 
Deerfield, IL  60015 
Title Page 
Sponsor’s Responsible Medical Officer: 
, MD 
Medical Director, Clinical Development 
Horizon Therapeutics U.S.A., Inc. 
1 Horizon Way 
Deerfield, IL  60015 
To change the 
Sponsor’s 
approver with 
shift to Amgen 
processes and 
update medical 
officer 
information 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
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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 
Email:  clinicalsafety@horizontherapeutics.com 
US Fax:  800-860-7836 
Ex-US Fax:  +1-224-855-5055 
Title Page 
Email (worldwide):  svc-ags-in-us@amgen.com 
US Fax:  1-888-814-8653 (toll free, within USA) 
Ex-US Fax:   +44 (0)207-136-1046 
To update with 
new company 
structure 
Sponsor Signature Page 
Removed 
To change the 
Sponsor’s 
approver with 
shift to Amgen 
processes 
Synopsis – Objectives and Section 8 Trial Objectives and 
Section 9.6.1 Endpoints 
 
HZN-825 Baseline, defined as the latest measurement prior to 
the first dose of HZN-825 in either Trial HZNP-HZN-825-301 
or this extension trial.  For subjects who received placebo in 
Trial HZNP-HZN-825-301, Trial Baseline will be the same as 
HZN-825 Baseline. 
Synopsis – Objectives and Section 8 Trial Objectives and 
Section 9.6.1 Endpoints 
 
Fipaxalparant (HZN-825) Baseline, defined as the latest 
measurement prior to the first dose of the trial drug in Trial 
HZNP-HZN-825-301. 
To improve 
clarity on 
baseline 
definitions 
Synopsis – Exploratory Objectives and Section 8.2 Exploratory 
Objectives 
 
Change from both Baselines in Health Assessment 
Questionnaire - Disability Index (HAQ-DI); Physician Global 
Assessment (MDGA); Patient Global Assessment (PTGA); the 
Physical Effects and Physical Limitations subscales of the 
scleroderma skin patient-reported outcome (SSPRO-18); the 
modified Rodnan skin score (mRSS); American College of 
Rheumatology-Composite Response Index in Systemic 
Sclerosis (ACR-CRISS), defined as improvement from each 
Synopsis – Exploratory Objectives and Section 8.2 Exploratory 
Objectives 
 
Change from both Baselines in the modified Rodnan skin 
score (mRSS), the Revised Composite Response Index in 
Systemic Sclerosis (Revised CRISS [CRISS 25]), Health 
Assessment Questionnaire - Disability Index (HAQ-DI); 
Clinician Global Assessment (CGA); Patient Global 
Assessment (PTGA); the Physical Effects and Physical 
Limitations subscales of the scleroderma skin patient-reported 
outcome (SSPRO-18); proportion of subjects with clinically 
To align with 
updates in the 
HZN-825-301 
study objectives 
with a goal of 
enhancing the 
ability to 
demonstrate 
overall 
improvement in 
the disease -

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
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Baseline in mRSS, HAQ-DI, PTGA, MDGA and FVC % 
predicted; ACR-CRISS-20, defined as improvement from both 
Baselines in ≥3 core set measures of ≥20% in mRSS, ≥20% in 
HAQ-DI, ≥20% in PTGA, ≥20% in MDGA and ≥5% in FVC 
% predicted; the SSPRO-18; the University of California Los 
Angeles Scleroderma Clinical Trial Consortium 
Gastrointestinal Tract (UCLA SCTC GIT 2.0); Raynaud’s 
phenomenon using the Raynaud’s Assessment; the 
Scleroderma HAQ (SHAQ); Systemic Sclerosis Quality of 
Life Questionnaire (SScQoL); SF-12® Health Survey (SF-12); 
pain and pain component scale scores; fatigue based on the 
Functional Assessment of Chronic Illness Therapy – Fatigue 
Scale (FACIT-F); lung fibrosis in subjects with suitable 
Baseline high-resolution computed tomography (HRCT); 
diffusing capacity of the lungs for carbon monoxide (DLCO); 
serum and plasma biomarkers associated with LPAR1 
pathway, inflammation and/or fibrosis; and 
 
 
 
 
The pharmacokinetics (PK) of HZN-825 and metabolite(s). 
important change in the mRSS; American College of 
Rheumatology-Composite Response Index in Systemic 
Sclerosis (ACR-CRISS), defined as improvement from each 
Baseline in mRSS, HAQ-DI, PTGA, CGA and FVC % 
predicted; the SSPRO-18; the University of California Los 
Angeles Scleroderma Clinical Trial Consortium 
Gastrointestinal Tract (UCLA SCTC GIT 2.0); Raynaud’s 
phenomenon using the Raynaud’s Assessment; the 
Scleroderma HAQ (SHAQ); Systemic Sclerosis Quality of 
Life Questionnaire (SScQoL); SF-12® Health Survey (SF-12); 
pain and pain component scale scores; fatigue based on the 
Functional Assessment of Chronic Illness Therapy – Fatigue 
Scale (FACIT-F); lung fibrosis in subjects with suitable 
baseline high-resolution computed tomography (HRCT); 
diffusing capacity of the lungs for carbon monoxide (DLCO); 
serum and plasma biomarkers associated with LPAR1 
pathway, inflammation and/or fibrosis; and 
 
 
 
 
The pharmacokinetics (PK) of fipaxalparant (HZN-825). 
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. 
Synopsis – Trial Design and Section 9.1 Overall Trial Design 
and Plan 
Subjects entering this extension trial will complete the Week 52 
Visit activities in HZNP-HZN-825-301 and will not complete the 
Safety Follow-up Visit 4 weeks after the last dose of trial drug in 
HZNP-HZN-825-301.   
Synopsis – Trial Design and Section 9.1 Overall Trial Design 
and Plan 
Subjects entering this extension trial will complete the Week 52 
Visit activities in HZNP-HZN-825-301 and will not complete the 
Safety Follow-up Visit 4 weeks after the last dose of trial drug in 
HZNP-HZN-825-301.  All HZNP-HZN-825-301 Week 52 
assessments should be performed before the first dose of the 
extension trial drug is administered. 
To ensure 
subjects 
complete the 
previous study 
in its entirety 
before starting 
the next 
treatment 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
Version 3.0, Amendment 2 
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Synopsis – Trial Design Schematic and Figure 9.1 Schematic of 
Trial Design– Trial Baseline Column and Footnote 
Day 1 (Week 52 Visit of  
HZNP-HZN-825-301) 
BID=twice daily 
Synopsis – Trial Design Schematic and Figure 9.1 Schematic of 
Trial Design– Trial Baseline Column and Footnote 
Day 1 (Week 52 Visit of  
HZNP-HZN-825-301)1 
BID=twice daily 
1. All HZNP-HZN-825-301 Week 52 assessments should be 
performed before the first dose of the extension trial drug is 
administered. 
To ensure 
subjects 
complete the 
previous study 
in its entirety 
before starting 
the next 
treatment 
Synopsis – Criteria for Evaluation 
Blood samples for HZN-825 and metabolite(s) PK assessment, 
autoantibodies and biomarkers associated with the LPAR1 pathway, 
inflammation and/or fibrosis will be collected. 
Synopsis – Criteria for Evaluation 
Blood samples for fipaxalparant (HZN-825) PK assessment, 
autoantibodies and biomarkers associated with the LPAR1 pathway, 
inflammation and/or fibrosis will be collected. 
To align with 
the HZN-825-
301 study 
Synopsis – Statistical Analyses – Exploratory Efficacy 
Endpoints and Section 9.6.1.2 Exploratory Efficacy Endpoints 
1. Change from both Baselines in HAQ-DI at Week 52. 
2. Change from both Baselines in MDGA at Week 52. 
3. Change from both Baselines in PTGA at Week 52. 
4. Change from both Baselines in the Physical Effects subscale of 
the SSPRO-18 at Week 52.  
5. Change from both Baselines 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 both Baselines 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 both Baselines:  ≥20% in mRSS, ≥20% in HAQ DI, 
≥20% in PTGA, ≥20% in MDGA and ≥5% in FVC % predicted at 
Week 52 (ACR CRISS 20). 
9. Change from both Baselines in the SSPRO-18 at Week 52. 
10. Change from both Baselines in each scale of the UCLA SCTC 
GIT 2.0 and the total GIT score at Week 52. 
Synopsis – Statistical Analyses – Exploratory Efficacy 
Endpoints and Section 9.6.1.2 Exploratory Efficacy Endpoints 
1. Change from both Baselines in the mRSS at Week 52. 
2. Proportion of subjects responding to treatment based on CRISS 25 
at Week 52. 
3. Change from both Baselines in HAQ-DI at Week 52. 
4. Change from both Baselines in CGA at Week 52. 
5. Change from both Baselines in PTGA at Week 52. 
6. Change from both Baselines in the Physical Effects subscale of 
the SSPRO-18 at Week 52.  
7. Change from both Baselines 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 both Baselines at Week 52. 
9. Responder rate (defined as ACR-CRISS [predicted probability] of 
at least 0.6) at Week 52. 
10. Change from both Baselines in the SSPRO-18 at Week 52. 
11. Change from both Baselines in each scale of the UCLA SCTC 
GIT 2.0 and the total GIT score at Week 52. 
To align with 
updates in the 
HZN-825-301 
study endpoints 
with a goal of 
enhancing 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 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
Version 3.0, Amendment 2 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
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11. Change from both Baselines in Raynaud’s phenomenon using 
the Raynaud’s Assessment at Week 52. 
12. Change from both Baselines in the SHAQ at Week 52. 
13. Change from both Baselines in SScQoL scores at Week 52. 
14. Change from both Baselines in SF-12 scores at Week 52. 
15. Change from both Baselines in pain and pain component scale 
scores at Week 52. 
16. Change from both Baselines in the FACIT-F score at Week 52. 
17. Change from both Baselines in the mRSS at Week 52. 
18. Change from both Baselines in lung fibrosis based on HRCT at 
Week 52. 
19. Change from both Baselines in DLCO at Week 52. 
20. Change from both Baselines in serum and plasma biomarkers 
associated with LPAR1 pathway, inflammation and/or fibrosis at 
 
21. Change from both Baselines in
 
12. Change from both Baselines in Raynaud’s phenomenon using 
the Raynaud’s Assessment at Week 52. 
13. Change from both Baselines in the SHAQ at Week 52. 
14. Change from both Baselines in SScQoL scores at Week 52. 
15. Change from both Baselines in SF-12 scores at Week 52. 
16. Change from both Baselines in pain and pain component scale 
scores at Week 52. 
17. Change from both Baselines in the FACIT-F score at Week 52. 
18. Change from both Baselines in lung fibrosis based on HRCT at 
Week 52. 
19. Change from both Baselines in DLCO at Week 52. 
20. Change from both Baselines in serum and plasma biomarkers 
associated with LPAR1 pathway, inflammation and/or fibrosis at 
 
21. Change from both Baselines in 
 
 
help in global 
evaluation of 
likelihood of 
improvement. 
Synopsis – Statistical Analyses – Safety and Tolerability 
Endpoints and Section 9.6.1.3 Safety and Tolerability Endpoints 
3. Change from both Baselines in vital signs. 
4. Change from both Baselines in 12-lead ECG measurements. 
5. Change from both Baselines in clinical safety laboratory test 
results. 
Synopsis – Statistical Analyses – Safety and Tolerability 
Endpoints and Section 9.6.1.3 Safety and Tolerability Endpoints 
3. Vital signs. 
4. 12-lead ECGs. 
5. Clinical safety laboratory evaluations. 
To align with 
the HZN-825-
301 study 
Synopsis – Statistical Analyses – Pharmacokinetic Endpoint and 
Section 9.6.1.4 Pharmacokinetic Endpoint 
1. Pre- and post-dose concentrations of HZN-825 and metabolite(s). 
Synopsis – Statistical Analyses – Pharmacokinetic Endpoint and 
Section 9.6.1.4 Pharmacokinetic Endpoint 
1. Pre- and post-dose concentrations of fipaxalparant (HZN-825). 
To align with 
the HZN-825-
301 study 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
Version 3.0, Amendment 2 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS IRELAND DAC 
 Page 10 of 119 
 
Section 2.1 Schedule of Assessments – Safety Follow-up Column 
Safety Follow-up Visit 1 
Section 2.1 Schedule of Assessments – Safety Follow-up Column 
Safety Follow-up Visit 
To provide 
clarity that 
Safety Follow-
up cannot be 
performed by 
home health 
visit 
List of Abbreviations 
List of Abbreviations 
CGA Clinician Global Assessment 
CRISS 25 Composite Response Index in Systemic Sclerosis 25 
DSUR Development Safety Update Report 
EDC  electronic data capture 
EU European Union 
Revised CRISS Revised Composite Response Index in Systemic 
Sclerosis 
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 102 healthy subjects in 6 
completed Phase 1 clinical trials and 31 subjects with diffuse 
cutaneous SSc in a Phase 2a clinical trial.  In clinical trials 
completed as of 28 February 2022, HZN-825 was well-tolerated and 
showed similar safety and PK profiles across healthy subjects 
(including elderly healthy subjects) and subjects with diffuse 
cutaneous SSc.   
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 PK profiles across healthy subjects (including 
elderly healthy subjects) and subjects with diffuse cutaneous SSc.   
To update 
numbers based 
on most recently 
completed 
studies 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
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Section 7.1.3.4 Clinical Experience 
 
 that will continue to be 
monitored as an AE of special interest (AESI) (Section 9.5.3.1.1.4). 
Section 7.1.3.4 Clinical Experience 
 
that will continue to be 
monitored as an AE of special interest (AESI) (Section 9.5.3.1.1.4).  
Additionally, increases in 
 have been seen in 
blinded clinical studies with fipaxalparant (HZN-825).  These 
events are mostly non-serious and reversible.  Liver enzyme 
elevation will be monitored per FDA guidelines (Section 9.3.3.1). 
To update in 
alignment with 
additional risks 
observed with 
use of 
investigational 
product 
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 
The dose regimen to be evaluated in this trial is 300 mg BID taken 
with a meal using HZN 825 tablets manufactured by 
 
.   
Section 7.3 Rationale for Dose Selection 
The dose regimen to be evaluated in this trial is 300 mg BID taken 
with a meal using fipaxalparant (HZN-825) tablets manufactured by 
 and 
   
To account for 
additional 
manufacturing 
site 
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 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. 
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 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. 
To remove 
option for 
continued 
dosage and 
promote subject 
safety 
CCI
CCI

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
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Section 9.4.6.1.2 Drug-induced Liver Injury 
Refer to Section 9.3.3.1 for criteria regarding discontinuation of 
HZN-825 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 reversible.  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 9.4.9 Concomitant Therapy and Restricted Medications 
Caution should be observed when coadministering fipaxalparant 
(HZN-825) with strong inhibitors of 
.   
Section 9.4.9 Concomitant Therapy and Restricted Medications 
Caution should be observed when coadministering fipaxalparant 
(HZN-825) with strong inhibitors of 
.  
Fipaxalparant (HZN-825) is an in vitro inhibitor of OAT1 and 
OAT3 and may increase the systemic exposures of methotrexate. 
To advise 
caution on 
potential safety 
risks 
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 
Section 9.5.1.5 Revised Composite Response Index in Systemic 
Sclerosis (CRISS 25) 
New section, subsequent sections re-numbered with this 
insertion 
Section 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 FVC % predicted 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 9.5.1.6 Plasma and Serum Biomarkers 
Blood samples will be collected prior to dosing on 
, 
 as well as at the 
 Visit for analysis 
Section 9.5.1.6 Plasma and Serum Biomarkers 
Blood samples will be collected prior to dosing on 
, 
 as well as at the 
 Visit for analysis 
To correct the 
samples 
collected Week 

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of plasma and serum biomarkers associated with the LPAR1 
pathway, inflammation or fibrosis.   
of plasma and serum biomarkers associated with the LPAR1 
pathway, inflammation or fibrosis.   
42 to the correct 
Week 40 
Section 9.5.2 Pharmacokinetic Measurements 
Blood samples will be collected from all subjects to evaluate the PK 
of HZN-825 and metabolite(s) at each of the following visits:  
Day 1 (pre-dose), Week 4 (pre-dose and 2 to 4 hours post-dose) and 
Weeks 16, 28 and 40 (pre-dose only at these 3 visits).   
Section 9.5.2  Pharmacokinetic Measurements 
Blood samples will be collected from all subjects to evaluate the PK 
of fipaxalparant (HZN-825) at each of the following visits:  Day 1 
(pre-dose), Week 4 (pre-dose and 2 to 4 hours post-dose) and 
Weeks 16, 28 and 40 (pre-dose only at these 3 visits).   
To align with 
the HZN-825-
301 study 
Section 9.5.3.1.2 Documentation of Adverse Events 
If the Investigator observes an SAE after trial completion that 
he/she believes was possibly caused by HZN 825, the Investigator 
will report this SAE using the procedures described in 
Section 9.5.3.1.5. 
Section 9.5.3.1.2 Documentation of Adverse Events 
If the Investigator observes an SAE after trial completion that 
he/she believes was possibly caused by fipaxalparant (HZN-825), 
the Investigator will report this SAE using the procedures described 
in Section 9.5.3.1.5.  The Investigator is responsible for collecting 
and documenting the outcome of AEs/SAEs. 
If specifically requested, the Investigator may need to provide 
additional follow-up information, such as discharge summaries, 
medical records, or extracts from the medical records.  In this case, 
all subject identifiers, except for the subject number, will be blinded 
on the copies of the medical records before submission to the 
Sponsor. 
To align with 
expected 
reporting and 
subject 
confidentiality 
Section 9.5.3.1.4  Relationship or Causality to Fipaxalparant 
(HZN-825) 
The relationship of HZN-825 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. 
Section 9.5.3.1.4  Relationship or Causality to Fipaxalparant 
(HZN-825) 
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. 
To align with 
new sponsor 
standard safety 
reporting 
language 

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The Investigator will also consult the Investigator’s Brochure and/or 
product information, for marketed products, in their assessment. 
For each AE/SAE, the Investigator must document in the medical 
notes that they have reviewed the AE/SAE and has provided an 
assessment of causality. 
There may be situations in which a SAE has occurred and the 
Investigator has minimal information to include in the initial report.  
However, it is very important that the Investigator always assess 
causality for every event before the initial transmission of the SAE 
data. 
The Investigator may change their opinion of causality in light of 
follow-up information and send a SAE follow-up report with the 
updated causality assessment. 
The relationship of fipaxalparant (HZN-825) 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. 
Section 9.5.3.1.5 Reporting and Documenting Serious Adverse 
Events 
1. Report the SAE to the Sponsor by entering the information into 
the eCRF immediately, without undue delay but not later than 
24 hours after becoming aware that a subject has experienced an 
SAE.  If unable to access the eCRF, the event must be reported by 
submitting the completed SAE form immediately, without undue 
delay but not later than 24 hours after becoming aware that a 
subject has experienced an SAE (see Section 17.1 for contact 
information). 
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.   
Section 9.5.3.1.5 Reporting and Documenting Serious Adverse 
Events 
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. 
To align with 
new sponsor 
standard safety 
reporting 
language 

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4. Review each SAE report and evaluate the relationship of the SAE 
to HZN-825. 
2. Perform appropriate diagnostic tests and therapeutic measures and 
submit all follow-up substantiating data, such as diagnostic test 
reports, hospital discharge summaries and autopsy report to the 
Sponsor’s representative. 
3. Conduct appropriate consultation and follow-up evaluation until 
the SAE outcome is known or the SAE is resolved.  Outcomes for 
reported AEs/SAEs/AESIs are to be defined as follows:  
 
Recovering/Resolving  
 
Recovered/Resolved 
 
Not Recovered/Not Resolved 
 
Recovered/Resolved with sequelae 
 
Fatal 
 
Unknown 
4. All new information for previously reported SAEs must be sent to 
the Sponsor immediately and no later than 24 hours after 
Investigator’s awareness of the new information.  If specifically 
requested, the Investigator may need to provide additional follow-
up information, such as discharge summaries, medical records, or 
extracts 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 9.5.3.1.6 Follow-up of Adverse Events 
The Investigator is obligated to follow-up any reported AE, SAE or 
AESI until all relevant clinical data are known to allow for an 
outcome or the event is resolved, in addition to confirming the 
causality assessment.  Any ongoing trial drug-related AE present at 
the time of trial termination, including a clinically significant 
laboratory test abnormality, will be followed until the event is 
resolved or until the outcome is known. 
Section 9.5.3.1.6 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 
reporting 
language 
Section 9.5.3.1.10  Development Safety Update Reports 
The Sponsor will prepare and submit annual safety reports to the 
US FDA.  Developmental safety update reports will also be 
submitted to countries and territories as required. 
Section 9.5.3.1.10  Development Safety Update Reports 
The Sponsor will prepare and submit Development Safety Update 
Reports (DSUR) to all relevant regulatory authorities in countries 
and regions where the trial is conducted. 
The Sponsor will prepare a single 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 
To add the 
development 
safety update 
report to align 
with 
recommendatio
ns from 
regulatory 
agencies and 

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include appropriate information on any other investigational 
products used in the clinical study, if applicable. 
9.5.3.1.11 Regulatory Reporting Requirements for Safety 
Information 
If subject is permanently withdrawn from investigational product(s), 
and/or noninvestigational product(s)/auxiliary medicinal product(s) 
because of a SAE, this information must be submitted to the 
Sponsor. 
Prompt notification by the Investigator to the Sponsor of SAEs is 
essential so that legal obligations and ethical responsibilities 
towards the safety of subjects and the safety of a study treatment 
under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about the safety 
of a study treatment under clinical investigation.  The Sponsor will 
comply with country-specific regulatory requirements relating to 
safety reporting to the external review body and Investigators. 
Individual safety reports for suspected unexpected serious adverse 
reactions will be reported by the Sponsor according to local 
regulatory requirements (e.g., electronic submission to the 
Eudravigilance database in the EU as per EU Clinical Trial 
Regulation 536/2014) as well as Sponsor policy and forwarded to 
Investigators as necessary. 
An Investigator who receives an individual safety report describing 
a SAE or other specific safety information (e.g., summary or listing 
of SAEs) from the Sponsor will file it along with the Investigator’s 
Brochure and will notify the external review body, if appropriate 
according to local requirements. 
9.5.3.1.12 Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in the 
Sponsor’s safety surveillance and signal management processes. 
additional 
sections To 
align with new 
sponsor 
standard safety 
reporting 
language 

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Section 9.5.3.2 Pregnancy and Lactation Reporting 
9.5.3.2  Pregnancy Reporting 
Pregnancy testing will be performed for WOCBP.  Serum 
pregnancy tests will be analyzed at a central trial laboratory and the 
urine pregnancy tests will be performed locally.  In addition, at 
home pregnancy tests will be completed by WOCBP at 
 
, and results will be reported to the site.  
A urine pregnancy test will also be done at the Safety Follow-up 
Visit (whether at the clinic or at a remote site). 
Section 9.5.3.2 Pregnancy and Lactation Reporting 
9.5.3.2 Pregnancy and Lactation Reporting 
Pregnancy testing will be performed for WOCBP.  Serum 
pregnancy tests will be analyzed at a central trial laboratory and the 
urine pregnancy tests will be performed locally.  In addition, urine 
pregnancy tests should also be done every 4 weeks after Day 1, 
which includes both in-clinic testing at scheduled visits prior to 
dosing 
 and at home (±7 day window) 
by the subject and reported to the site 
 
  A urine pregnancy test will also be done at the Safety 
Follow-up Visit (whether at the clinic or at a remote site). 
To align with 
new sponsor 
standard safety 
reporting 
language 
Section 9.5.3.2 Pregnancy and Lactation Reporting 
Abstinence should only be used as a contraceptive method if it is in 
line with the subject’s usual and preferred lifestyle.  Periodic 
abstinence (calendar, symptothermal, postovulation methods) is not 
an acceptable method of contraception. 
The Investigator should report pregnancies to the Sponsor within 
24 hours by submitting the completed pregnancy report form within 
24 hours after becoming aware that the subject/subject’s female 
partner has become pregnant (see Section 17.1 for contact 
information).  The Investigator should counsel the subject and 
discuss the possible risks of continuing the pregnancy.  If pregnancy 
continues and the subject signs the pregnancy consent form, 
monitoring should also continue to the conclusion of the pregnancy 
and the outcome of the pregnancy should be reported to the 
Sponsor. 
Section 9.5.3.2 Pregnancy and Lactation Reporting 
Abstinence should only be used as a contraceptive method if it is in 
line with the subject’s usual and preferred lifestyle.  Periodic 
abstinence (calendar, symptothermal, postovulation methods) is not 
an acceptable method of contraception. 
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 
Section 17.1 for contact information).  The Investigator should 
counsel the subject and discuss the possible risks of continuing the 
pregnancy.  If pregnancy continues and the subject signs the 
pregnancy consent form, monitoring should also continue to the 
conclusion of the pregnancy and the outcome of the pregnancy 
should be reported to the Sponsor. 
Lactation information will be recorded on the Lactation Notification 
Form and submitted to Sponsor Global Patient Safety immediately 
To align with 
new sponsor 
standard safety 
reporting 
language 

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and no later than 24 hours of the Investigator’s awareness of the 
event. 
Section 9.5.3.8  Laboratory Tests for Evaluation 
Hematology parameters to be evaluated include hemoglobin, 
hematocrit, red blood cell count (with morphology if blood cell 
count is abnormal), mean corpuscular volume (MCV), mean 
corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), red blood cell distribution width (RDW), 
reticulocyte count, white blood cell count with differential 
(neutrophils, eosinophils, basophils, monocytes, lymphocytes) and 
platelet count.   
Section 9.5.3.8  Laboratory Tests for Evaluation 
Hematology parameters to be evaluated include hemoglobin, 
hematocrit, red blood cell count (with morphology if blood cell 
count is abnormal), mean corpuscular volume (MCV), mean 
corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), red blood cell distribution width (RDW), 
reticulocyte count, white blood cell count with differential 
(neutrophils, eosinophils, basophils, monocytes, lymphocytes) and 
platelet count.  
 
To provide 
additional 
guidance to 
promote subject 
safety 
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 
(e.g., Clinical Monitor) or the Clinical Out-of-Hours Support 
Program:  https://wwwext.amgen.com/science/clinical-
trials/clinical-out-of-hours-support-program immediately and no 
later than 1 calendar day from the time of awareness. 
A Serious Breach is a breach of any of the following: 
 
Good Clinical Practice (GCP) 
 
the clinical trial protocol 
 
an applicable regulation 
To update 
requirements 
for Principal 
Investigator 
responsibilities 
to report serious 
breaches per 
regulatory 
recommendatio
ns 

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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 
Medical Monitor : 
, MD 
Associate Medical Director 
 Horizon Therapeutics U.S.A., Inc. 
 1 Horizon Way 
 Deerfield, IL  60015 
 Business telephone number:  
 
 Email:  
  
 
Sponsor Representative : 
 
 Sr. Manager, Clinical Operations 
 Horizon Therapeutics U.S.A., Inc. 
 1 Horizon Way 
 Deerfield, IL  60015 
 Business telephone number:  
 
 Email:  
  
 
Sponsor Contact for  Serious Adverse Event Reporting: 
Horizon Therapeutics U.S.A., Inc. 
 US Fax:   800-860-7836 
 Ex US Fax:  +1-224-855-5055 
 Email:  clinicalsafety@horizontherapeutics.com 
Section 17.1 Administrative Appendix 
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:
  
 
Sponsor Contact for Serious Adverse Event Reporting: 
 Horizon Therapeutics U.S.A., Inc. 
 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 key 
contact 
information 

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Section 17.14 
 
Version dated 28 Feb 2022. 
Section 17.14 
 
Updated to version dated 14 June 2023. 
To align with 
latest guidance 
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 
TBL >2 × ULN should be followed by repeat testing (ALT, AST, 
alkaline phosphatase, 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 
To align with 
guidance from 
regulatory 
agencies and 
sponsor. 
CCI
CCI

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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. 
 

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2 
SYNOPSIS 
Protocol Title:  A Multicenter, Open-label Extension Trial to Evaluate the Efficacy, Safety and Tolerability of 
HZN-825 in Patients with Diffuse Cutaneous Systemic Sclerosis 
Protocol Number:  HZNP-HZN-825-302 
Phase:  2b 
Protocol Version:  3.0 
 
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 fipaxalparant (HZN-825), a selective 
antagonist of lysophosphatidic acid receptor-1 (LPAR1), administered twice daily (BID) to subjects with diffuse 
cutaneous systemic sclerosis (diffuse cutaneous SSc) in a 52-week open-label extension following completion of 
the randomized, double-blind, 52-week clinical trial (HZNP-HZN-825-301). 
Two types of Baseline are defined: 
 
Trial Baseline, defined as the latest measurement prior to the first dose of fipaxalparant (HZN-825) in 
this extension trial 
 
Fipaxalparant (HZN-825) Baseline, defined as the latest measurement prior to the first dose of the trial 
drug in Trial HZNP-HZN-825-301. 
Primary Objectives 
 
The primary efficacy objective is to assess the efficacy of 52 weeks of open-label treatment with 
fipaxalparant (HZN-825) in subjects with diffuse cutaneous SSc, as measured by change from both 
Baselines in forced vital capacity (FVC) % predicted. 
 
The primary safety objective is to examine the safety and tolerability of 52 weeks of open-label treatment 
with fipaxalparant (HZN-825), inclusive of, but not limited to, adverse events (AEs), serious AEs and the 
adverse event of special interest (AESI), from Day 1 to 4 weeks after last dose. 
Exploratory Objectives 
The exploratory objectives are to evaluate the following after 52 weeks of open-label treatment with 
fipaxalparant (HZN-825):  
 
Change from both Baselines in the modified Rodnan skin score (mRSS), the Revised Composite Response 
Index in Systemic Sclerosis (Revised CRISS [CRISS 25]), Health Assessment Questionnaire - Disability 
Index (HAQ-DI); Clinician Global Assessment (CGA); Patient Global Assessment (PTGA); the Physical 
Effects and Physical Limitations subscales of the scleroderma skin patient-reported outcome (SSPRO-18); 
proportion of subjects with clinically important change in the mRSS; American College of Rheumatology-
Composite Response Index in Systemic Sclerosis (ACR-CRISS), defined as improvement from each 
Baseline in mRSS, HAQ-DI, PTGA, CGA and FVC % predicted; the SSPRO-18; the University of 
California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA SCTC GIT 
2.0); Raynaud’s phenomenon using the Raynaud’s Assessment; the Scleroderma HAQ (SHAQ); Systemic 
Sclerosis Quality of Life Questionnaire (SScQoL); SF-12® Health Survey (SF-12); pain and pain component 
scale scores; fatigue based on the Functional Assessment of Chronic Illness Therapy – Fatigue Scale 
(FACIT-F); lung fibrosis in subjects with suitable baseline high-resolution computed tomography (HRCT); 
diffusing capacity of the lungs for carbon monoxide (DLCO); serum and plasma biomarkers associated with 
LPAR1 pathway, inflammation and/or fibrosis; and 
 
. 
 
The pharmacokinetics (PK) of fipaxalparant (HZN-825). 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
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Trial Design: 
This is an open-label, repeat-dose, multicenter extension trial of HZNP-HZN-825-301.  Subjects who complete 
the double-blind Treatment Period (Week 52) in Trial HZNP-HZN-825-301 will be eligible to enter this 52-week 
extension trial.  Subjects entering this extension trial will complete the Week 52 Visit activities in 
HZNP-HZN-825-301 and will not complete the Safety Follow-up Visit 4 weeks after the last dose of trial drug in 
HZNP-HZN-825-301.  All HZNP-HZN-825-301 Week 52 assessments should be performed before the first dose 
of the extension trial drug is administered. 
On Day 1 (Week 52 Visit of HZNP-HZN-825-301), subjects will receive their first dose of 
fipaxalparant (HZN-825) in this extension trial at the clinic and will participate in trial visits at Week 4 and every 
6 weeks thereafter until Week 52.  The Week 52 Visit activities in HZNP-HZN-825-301 will serve as Trial 
Baseline for this extension trial.   
If a subject prematurely discontinues trial drug, he/she will be asked to remain in the trial, participating in the 
scheduled trial visits through Week 52.  If a subject prematurely discontinues trial drug and does not wish to 
continue in the trial, he/she will 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 fipaxalparant (HZN-825). 
An overview of the trial design is presented in the schematic below. 
Trial Baseline 
Open-label Treatment Period 
Fipaxalparant (HZN-825) 300 mg BID 
52 Weeks 
Safety  
Follow-up 
Visit 
< –––––––––––––––––––––––––––––––––––––––––––––– Trial Visits––––––––––––––––––––—————————— > 
 
 
 
 
 
 
 
 
Day 1 (Week 52 Visit of  
HZNP-HZN-825-301)1 
Week 4 and every 6 weeks thereafter 
Week 52 4 weeks after 
last dose of 
fipaxalparant 
(HZN-825) 
BID=twice daily 
1. 
All HZNP-HZN-825-301 Week 52 assessments should be performed before the first dose of the extension trial drug is administered. 
Subject Population: 
Inclusion Criteria: 
1. Written informed consent. 
2. Completed the double-blind Treatment Period (Week 52) in Trial HZNP-HZN-825-301; subjects prematurely 
discontinued from trial drug in Trial HZNP-HZN-825-301 for reasons other than safety or toxicity can be 
included at the discretion of the Investigator after completing Trial HZNP-HZN-825-301 scheduled visits, 
including Week 52 assessments. 
3. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the 
trial. 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
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Exclusion Criteria: 
1. Anticipated use of another investigational agent for any condition during the course of the trial.  
2. New diagnosis of malignant condition after enrolling in Trial HZNP-HZN-825-301 (except successfully 
treated basal/squamous cell carcinoma of the skin or cervical cancer in situ).  
3. 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. 
4. Pregnant or lactating women.  
5. Any new development with the subject’s disease or condition or any significant laboratory test abnormality 
during the course of Trial HZNP-HZN-825-301 that, in the opinion of the Investigator, would potentially put 
the subject at unacceptable risk. 
6. Subjects will be ineligible if, in the opinion of the Investigator, they are unlikely to comply with the trial 
protocol or have a concomitant disease or condition that could interfere with the conduct of the trial. 
Dose Regimen/Route of Administration: 
The dose regimen for all subjects will be fipaxalparant (HZN-825) 300 mg BID.  Subjects will take 2 
fipaxalparant (HZN-825) 150 mg tablets orally in the morning and evening with a meal.   
Dosage Form, Strength, Formulation and Storage: 
Fipaxalparant (HZN-825) 150 mg tablets will be used in this trial and will be packaged in blister packs.  The 
film-coated tablets are stored at controlled room temperature (20ºC to 25Cº, 68ºF to 77Fº). 
Duration of Treatment and Follow-up: 
The duration of the Treatment Period is 52 weeks.  Subjects will participate in a Safety Follow-up Visit 4 weeks 
after the last dose of fipaxalparant (HZN-825). 
Criteria for Evaluation: 
Details of time points for trial activities and assessments are provided in Section 2.1.  
Efficacy will be assessed by change in FVC % predicted, CGA, mRSS, ACR-CRISS, patient-reported outcomes 
(HAQ-DI, SHAQ global questions, PTGA, SSPRO-18, UCLA SCTC GIT 2.0 and Raynaud’s Assessment), 
quality-of-life, health status and fatigue evaluations (SScQoL, SF-12, pain scores, fatigue scores [FACIT-F]), 
HRCT and DLCO.   
Blood samples for fipaxalparant (HZN-825) PK assessment, autoantibodies and biomarkers associated with the 
LPAR1 pathway, inflammation and/or fibrosis will be collected. 
Safety will be assessed via AEs, concomitant medication use, physical examinations, vital signs, 
 
, laboratory evaluations and 12-lead electrocardiogram (ECG).   

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
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Statistical Analyses: 
Primary Efficacy Endpoint 
Change from both Baselines in FVC % predicted at Week 52. 
Exploratory Efficacy Endpoints 
1. Change from both Baselines in the mRSS at Week 52. 
2. Proportion of subjects responding to treatment based on CRISS 25 at Week 52. 
3. Change from both Baselines in HAQ-DI at Week 52. 
4. Change from both Baselines in CGA at Week 52. 
5. Change from both Baselines in PTGA at Week 52. 
6. Change from both Baselines in the Physical Effects subscale of the SSPRO-18 at Week 52.  
7. Change from both Baselines 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 both Baselines at Week 52. 
9. Responder rate (defined as ACR-CRISS [predicted probability] of at least 0.6) at Week 52. 
10. Change from both Baselines in the SSPRO-18 at Week 52. 
11. Change from both Baselines in each scale of the UCLA SCTC GIT 2.0 and the total GIT score at Week 52. 
12. Change from both Baselines in Raynaud’s phenomenon using the Raynaud’s Assessment at Week 52. 
13. Change from both Baselines in the SHAQ at Week 52. 
14. Change from both Baselines in SScQoL scores at Week 52. 
15. Change from both Baselines in SF-12 scores at Week 52. 
16. Change from both Baselines in pain and pain component scale scores at Week 52. 
17. Change from both Baselines in the FACIT-F score at Week 52. 
18. Change from both Baselines in lung fibrosis based on HRCT at Week 52. 
19. Change from both Baselines in DLCO at Week 52. 
20. Change from both Baselines in serum and plasma biomarkers associated with LPAR1 pathway, inflammation 
and/or fibrosis at 
 
21. Change from both Baselines in 
 
.  
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. 
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 full analysis set (FAS), consisting of all subjects who were enrolled 
(i.e., signed the informed consent form) and who received at least 1 dose or partial dose of 
fipaxalparant (HZN-825) in this extension trial.  Subjects will be analyzed according to the treatment group to 
which they were randomized in the previous trial, and combined into an ‘overall’ group. 
Safety analyses will be performed on the safety analysis set, consisting of all subjects who receive at least 1 dose 
or partial dose of fipaxalparant (HZN-825) in this extension trial.  This analysis set will be analyzed according to 
the group determined by the treatment that the subject received in the previous trial and overall.  
The Per-Protocol (PP) analysis set will consist of all subjects in the FAS with no major protocol violations.  The 
PP analysis set will be used, as needed, for supportive analysis of the primary endpoint and potentially other key 
endpoints.  Subjects in this analysis set will be analyzed according to the treatment group to which they were 
randomized in the previous, and combined into an ‘overall’ group. 
All efficacy and safety endpoints will be summarized using descriptive statistics. 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
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Sample Size Estimate: 
The sample size is based on the number of subjects who completed Trial HZNP-HZN-825-301.   
 

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Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
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2.1 
Schedule of Assessments 
 
Open-label Treatment Period (Fipaxalparant [HZN-825] 300 mg BID) 
Safety 
Follow-up 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
4 weeks 
after last 
dose of 
fipaxalpar
ant 
(HZN-825) 
Trial Visit
Trial Week (W) Day 1 2 W4 W10 1 
W16 
W22 1 
W28 
W34 1 
W40 
W46 1 W52/
PD 
 
Visit Window (±days)
 
(±5) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±14) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Review eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 3 
 
 
 
 
X 
 
 
 
X 
 
Fipaxalparant (HZN-825) 
dispensing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
mRSS 4 
X 3 
 
 
X 
 
X 
 
X 
 
X 
 
FVC % predicted/spirometry 4 
X 3 
 
 
X 
 
X 
 
X 
 
X 
 
CGA 
X 3 
 
 
X 
 
X 
 
X 
 
X 
 
Lung HRCT  
X 3 
 
 
 
 
 
 
 
 
X 5 
 
DLCO 
X 3 
 
 
 
 
X 6 
 
 
 
X 6 
 
Patient-reported outcome 
assessments 
 
 
 
 
 
 
 
 
 
 
 
SHAQ 
X 3 
 
 
X 
 
X 
 
X 
 
X 
 
PTGA  
X 3 
 
 
X 
 
X 
 
X 
 
X 
 
UCLA SCTC GIT 2.0 
X 3 
 
 
 
 
X 
 
 
 
X 
 
SSPRO-18 
X 3 
 
 
 
 
X 
 
 
 
X 
 
SScQoL 
X 3 
 
 
 
 
X 
 
 
 
X 
 
SF-12 
X 3 
 
 
 
 
X 
 
 
 
X 
 
Pain questionnaire 
X 3 
 
 
 
 
X 
 
 
 
X 
 
Fatigue (FACIT-F) 
X 3 
 
 
 
 
X 
 
 
 
X 
 
Raynaud’s assessment 7 
X 3 
 
 
 
X 
 
 
 
X 
 
 

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Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
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Open-label Treatment Period (Fipaxalparant [HZN-825] 300 mg BID) 
Safety 
Follow-up 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
4 weeks 
after last 
dose of 
fipaxalpar
ant 
(HZN-825) 
Trial Visit
Trial Week (W) Day 1 2 W4 W10 1 
W16 
W22 1 
W28 
W34 1 
W40 
W46 1 W52/
PD 
 
Visit Window (±days)
 
(±5) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±14) 
Anchor questions 
 
 
 
 
 
 
 
 
 
 
 
ACR-CRISS (last week) 
X 3 
 
 
X 
 
X 
 
X 
 
X 
 
ACR-CRISS (overall health 
and change since start of 
trial) 
 
 
 
 
 
X 
 
 
 
X 
 
FVC (last week) 
X 3 
 
 
X 
 
X 
 
X 
 
X 
 
FVC (change since start of 
trial) 
X 3 
 
 
 
 
X 
 
 
 
X 
 
HAQ-DI (last week) 
X 3 
 
 
X 
 
X 
 
X 
 
X 
 
HAQ-DI (change since start 
of trial) 
 
 
 
 
 
X 
 
 
 
X 
 
SSPRO-18 (last week) 
X 3 
 
 
 
 
X 
 
 
 
X 
 
SSPRO-18 (change since 
start of trial) 
 
 
 
 
 
X 
 
 
 
X 
 
Pregnancy test 8 
Physical examination 9 
X 3 
 
 
 
 
X 
 
 
 
X 
X 
Vital signs 10 
X 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogram 11 
X 3 
X 
 
X 
 
X 
 
 
 
X 
 
Echocardiogram 11 
X 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory safety tests 12 
 
 
 
 
 
 
 
 
 
 
 
Chemistry 
X 3 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Lipids 
X 3 
 
 
 
 
X 
 
 
 
X 
 
Hematology 
X 3 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Urinalysis 
X 3 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
ESR 13 and hsCRP 
X 3 
 
 
 
 
 
 
 
 
X 
X 
Autoantibodies 14 
X 3 
 
 
 
 
 
 
 
 
X 
 
PK samples 15 
X 3 
X 
 
X 
 
X 
 
X 
 
 
 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
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Open-label Treatment Period (Fipaxalparant [HZN-825] 300 mg BID) 
Safety 
Follow-up 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
4 weeks 
after last 
dose of 
fipaxalpar
ant 
(HZN-825) 
Trial Visit
Trial Week (W) Day 1 2 W4 W10 1 
W16 
W22 1 
W28 
W34 1 
W40 
W46 1 W52/
PD 
 
Visit Window (±days)
 
(±5) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±7) 
(±14) 
Serum biomarkers 16 
 
Plasma biomarkers 16 
 
Adverse event assessment 17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/ 
concomitant medications 18 
X 3 
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; DLCO=diffusing capacity of the lungs for carbon monoxide; ESR=erythrocyte 
sedimentation rate; FACIT-F=Functional Assessment of Chronic Illness Therapy – Fatigue Scale; FVC=forced vital capacity; 
HAQ-DI=Health Assessment Questionnaire – Disability Index; HRCT=high-resolution computed tomography; hsCRP=high-
sensitivity C-reactive protein; mRSS=modified Rodnan skin score; PD=premature discontinuation; PK=pharmacokinetic; 
PTGA=Patient Global Assessment; SF-12=SF-12® Health Survey; SHAQ=Scleroderma Health Assessment Questionnaire; 
SScQoL=Systemic Sclerosis Quality of Life Questionnaire; SSPRO-18=scleroderma skin patient-reported outcome; UCLA 
SCTC GIT 2.0=University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract; W=Week; 
WOCBP=women of childbearing potential 
1. Visits may be conducted as home health visits, as available within local regions. 
2. On Day 1 (Baseline), subjects will receive the first dose of fipaxalparant (HZN-825) in this extension trial in the clinic.  All 
Day 1 assessments should be performed before the first dose of trial drug is administered in the clinic. 
3. Performed as part of the Week 52 Visit of HZNP-HZN-825-301; if applicable, the result will be considered a Trial Baseline 
value for this extension trial. 
4. Except when strictly unavoidable, the same person should perform the assessment at each evaluation during the trial.  The 
mRSS assessment should be performed by a qualified Investigator (or designee).   
5. The lung HRCT scan should be performed within ±2 weeks of the Week 52/PD Visit. 
6. DLCO can be assessed within ±2-weeks of the Week 28 and Week 52/PD Visits. 
7. Daily electronic diaries will be completed for 4 weeks starting on Day 1, 4 weeks starting at the Week 22 Visit and 4 weeks 
starting at the Week 46 Visit. 
8. Perform for WOCBP.  Serum pregnancy test at 
 (or as needed).  Urine pregnancy tests should also be done every 
4 weeks after Day 1, which includes both in-clinic testing at scheduled visits prior to dosing 
 and 
at home (also a ±7-day window) by the subject and reported to the site 
  A urine 
pregnancy test will also be done at the Safety Follow-up Visit. 
9. A complete physical examination, including but not limited to cardiac, pulmonary, neurologic and skin assessments, as well 
as directed rheumatology assessments 
 
10. Vital signs (blood pressure, heart rate, respiratory rate, temperature) will be measured at each visit.   
11. Additional electrocardiograms or echocardiograms will be conducted, if clinically indicated.  A standard transthoracic 
echocardiogram will be conducted on Day 1.  However, an echocardiogram that has been performed during 
HZNP-HZN-825-301 and within the 3 months prior to HZNP-HZN-825-302 Day 1 can serve as the Trial Baseline 
echocardiogram if the subject has been clinically stable. 
12. See Section 9.5.3.8 for details. 
13. ESR must be processed within 1 hour of the blood draw. 
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Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
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14. Autoantibodies include anti-centromere antibody, anti-RNA polymerase antibody, anti-topoisomerase 1 and anti-U1 small 
nuclear ribonucleoprotein. 
15. PK samples will be collected at each of the following visits:  Day 1 (pre-dose), Week 4 (pre-dose and 2 to 4 hours post-dose) 
and Weeks 16, 28 and 40 (pre-dose).  Note: all pre-dose samples will be collected prior to any fipaxalparant (HZN-825) 
administration for the day. 
16. Blood samples will be collected for serum and plasma biomarkers prior to dosing on Day 
 
as well as at the 
 Visit. 
17. Adverse events occurring or worsening after the first dose of fipaxalparant (HZN-825) on Day 1 through the Safety 
Follow-up Visit will be considered treatment-emergent adverse events for this trial.  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 of left ventricular failure, new onset of pulmonary arterial 
hypertension or right heart catheterization requiring treatment, gastrointestinal dysmotility requiring enteral (tube feeding) or 
parenteral nutrition or digital ischemia with gangrene, amputation or hospitalization requiring treatment. 
18. Includes recording of herb/supplement use.  See Table 9.1 for restrictions regarding medications. 
CCI

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Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .......................................................................................................................... 2 
2 
SYNOPSIS ............................................................................................................................ 23 
2.1 
Schedule of Assessments ............................................................................................... 28 
3 
TABLE OF CONTENTS ...................................................................................................... 32 
4 
LIST OF ABBREVIATIONS ............................................................................................... 38 
5 
ETHICS ................................................................................................................................. 40 
5.1 
Institutional Review Board/Independent Ethics Committee .......................................... 40 
5.2 
Ethical Conduct of the Trial ........................................................................................... 40 
5.3 
Subject Information and Consent ................................................................................... 40 
5.4 
Compensation for Health Damage of Subjects/Insurance .............................................. 41 
5.5 
Confidentiality ................................................................................................................ 41 
6 
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE ............................. 42 
7 
INTRODUCTION ................................................................................................................ 43 
7.1 
Background .................................................................................................................... 43 
7.1.1 
Diffuse Cutaneous Systemic Sclerosis.................................................................... 43 
7.1.2 
Lysophosphatidic Acid Receptor 1 (LPAR1) .......................................................... 44 
7.1.3 
Fipaxalparant (HZN-825) ....................................................................................... 44 
7.1.3.1 Pharmacology Related to Potential Therapeutic Activity ................................... 44 
7.1.3.2 Nonclinical Safety ............................................................................................... 45 
7.1.3.3 Nonclinical Pharmacokinetics ............................................................................. 45 
7.1.3.4 Clinical Experience ............................................................................................. 46 
7.1.3.5 Benefit/Risk Assessment ..................................................................................... 46 
7.2 
Rationale for this Trial ................................................................................................... 47 
7.3 
Rationale for Dose Selection .......................................................................................... 47 
8 
TRIAL OBJECTIVES .......................................................................................................... 49 
8.1 
Primary Objectives ......................................................................................................... 49 
8.2 
Exploratory Objectives ................................................................................................... 49 
9 
INVESTIGATIONAL PLAN ............................................................................................... 51 
9.1 
Overall Trial Design and Plan ........................................................................................ 51 
9.2 
Discussion of Trial Design ............................................................................................. 51 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
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9.3 
Selection of Trial Population ......................................................................................... 52 
9.3.1 
Inclusion Criteria .................................................................................................... 52 
9.3.2 
Exclusion Criteria ................................................................................................... 52 
9.3.3 
Removal of Subjects from Treatment or the Trial .................................................. 53 
9.3.3.1 Removal of Subjects from Treatment ................................................................. 53 
9.3.3.2 Removal of Subjects from the Trial .................................................................... 55 
9.3.4 
Discontinuation of the Trial .................................................................................... 55 
9.3.5 
Replacement Policy ................................................................................................ 56 
9.3.5.1 Subjects ............................................................................................................... 56 
9.3.5.2 Centers ................................................................................................................. 56 
9.4 
Treatments ...................................................................................................................... 56 
9.4.1 
Treatments Administered ........................................................................................ 56 
9.4.2 
Identity of Investigational Product.......................................................................... 56 
9.4.3 
Labeling .................................................................................................................. 56 
9.4.4 
Storage .................................................................................................................... 56 
9.4.5 
Drug Accountability................................................................................................ 56 
9.4.6 
Trial Drug Administration and Timing of Dose for Each Subject .......................... 57 
9.4.6.1 Dose Modifications, Interruptions and Delays .................................................... 57 
9.4.6.1.2 
Drug-induced Liver Injury ......................................................................... 57 
9.4.7 
Method of Assigning Subjects to Treatment Groups .............................................. 57 
9.4.8 
Blinding and Unblinding......................................................................................... 58 
9.4.9 
Concomitant Therapy and Restricted Medications ................................................. 58 
9.4.10 Treatment Compliance ............................................................................................ 59 
9.5 
Efficacy, Pharmacokinetic and Safety Variables ........................................................... 60 
9.5.1 
Efficacy Variables ................................................................................................... 60 
9.5.1.1 Spirometry ........................................................................................................... 60 
9.5.1.2 Clinician Global Assessment .............................................................................. 61 
9.5.1.3 Modified Rodnan Skin Score .............................................................................. 61 
9.5.1.4 American College of Rheumatology-Composite Response Index in Systemic 
Sclerosis ............................................................................................................................ 61 
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Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
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9.5.1.5 Revised Composite Response Index in Systemic Sclerosis (CRISS 25) ............ 63 
9.5.1.6 Plasma and Serum Biomarkers ........................................................................... 64 
9.5.1.7 Lung High-resolution Computed Tomography ................................................... 64 
9.5.1.8 Diffusing Capacity of the Lungs for Carbon Monoxide ..................................... 64 
9.5.1.9 Patient-reported Outcome Assessments .............................................................. 64 
9.5.1.9.1 
Health Assessment Questionnaire – Disability Index ............................... 65 
9.5.1.9.2 
Patient Global Assessment ........................................................................ 65 
9.5.1.9.3 
Scleroderma Skin Patient-reported Outcome Instrument .......................... 65 
9.5.1.9.4 
Scleroderma Health Assessment Questionnaire ........................................ 66 
9.5.1.9.5 
UCLA Scleroderma Clinical Trial Consortium Gastrointestinal 
Tract Instrument ........................................................................................ 67 
9.5.1.9.6 
Raynaud’s Assessment .............................................................................. 67 
9.5.1.10 Health Status and Systemic Sclerosis-specific Quality of Life Measures .......... 67 
9.5.1.10.1 Systemic Sclerosis Quality of Life Questionnaire ..................................... 67 
9.5.1.10.2 SF-12 Health Survey ................................................................................. 68 
9.5.1.10.3 Pain Questionnaire ..................................................................................... 68 
9.5.1.10.4 Functional Assessment of Chronic Illness Therapy – Fatigue Scale ......... 68 
9.5.2 
Pharmacokinetic Measurements ............................................................................. 68 
9.5.3 
Safety Variables ...................................................................................................... 69 
9.5.3.1 Adverse Events .................................................................................................... 69 
9.5.3.1.1 
Definitions ................................................................................................. 69 
9.5.3.1.2 
Documentation of Adverse Events ............................................................ 71 
9.5.3.1.3 
Intensity or Severity of Adverse Events .................................................... 72 
9.5.3.1.4 
Relationship or Causality to Fipaxalparant (HZN-825) ............................ 72 
9.5.3.1.5 
Reporting and Documenting Serious Adverse Events .............................. 73 
9.5.3.1.6 
Follow-up of Adverse Events .................................................................... 75 
9.5.3.1.7 
Medication Errors ...................................................................................... 75 
9.5.3.1.8 
Review of Adverse Events and Emerging New Safety Information ......... 75 
9.5.3.1.9 
Reporting of Investigational New Drug Safety Reports ............................ 76 
9.5.3.1.10 Development Safety Update Reports ........................................................ 76 
9.5.3.1.11 Regulatory Reporting Requirements for Safety Information .................... 76 

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9.5.3.1.12 Safety Monitoring Plan .............................................................................. 76 
9.5.3.2 Pregnancy and Lactation Reporting .................................................................... 77 
9.5.3.3 Vital Signs and Weight ....................................................................................... 78 
9.5.3.5 Physical Examination .......................................................................................... 78 
9.5.3.6 Electrocardiogram ............................................................................................... 79 
9.5.3.7 Echocardiogram .................................................................................................. 79 
9.5.3.8 Laboratory Tests for Evaluation .......................................................................... 79 
9.5.4 
Appropriateness of Measurements .......................................................................... 80 
9.5.5 
Trial Procedures ...................................................................................................... 80 
9.5.5.1 Effect of a Pandemic on Trial Procedures ........................................................... 80 
9.6 
Statistical Methods and Determination of Sample Size ................................................. 81 
9.6.1 
Endpoints ................................................................................................................ 81 
9.6.1.1 Primary Efficacy Endpoint .................................................................................. 81 
9.6.1.2 Exploratory Efficacy Endpoints .......................................................................... 81 
9.6.1.3 Safety and Tolerability Endpoints ....................................................................... 82 
9.6.1.4 Pharmacokinetic Endpoint .................................................................................. 82 
9.6.2 
Analysis Sets ........................................................................................................... 82 
9.6.3 
Efficacy Endpoint Analysis .................................................................................... 83 
9.6.4 
Safety and Tolerability Analyses ............................................................................ 83 
9.6.5 
Pharmacokinetic Analyses ...................................................................................... 84 
9.6.6 
Autoantibody Analyses ........................................................................................... 84 
9.6.7 
Interim Analyses ..................................................................................................... 84 
9.6.8 
Sample Size and Power Considerations .................................................................. 84 
9.7 
Changes in the Conduct of the Trial............................................................................... 84 
10 SOURCE DOCUMENTATION AND INVESTIGATOR FILES ....................................... 85 
11 CASE REPORT FORMS ..................................................................................................... 86 
12 TRIAL MONITORING ........................................................................................................ 87 
13 DATA MANAGEMENT ...................................................................................................... 89 
14 RETENTION OF RECORDS ............................................................................................... 90 
15 PUBLICATION .................................................................................................................... 91 
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16 REFERENCES ..................................................................................................................... 92 
17 APPENDICES ...................................................................................................................... 96 
17.1 Administrative Appendix ............................................................................................... 96 
17.2 Clinician Global Assessment (CGA) ............................................................................. 97 
17.3 Modified Rodnan Skin Score (mRSS) ........................................................................... 98 
17.4 Scleroderma Health Assessment Questionnaire (SHAQ) .............................................. 99 
17.5 Patient Global Assessment (PTGA) ............................................................................. 102 
17.6 Scleroderma Skin Patient-reported Outcome (SSPRO-18) .......................................... 103 
17.7 University of California Los Angeles Scleroderma Clinical Trial Consortium 
Gastrointestinal Tract (UCLA SCTC GIT 2.0) Instrument .................................................... 105 
17.8 Raynaud’s Assessment ................................................................................................. 109 
17.9 Systemic Sclerosis Quality of Life Questionnaire (SScQoL) ...................................... 110 
17.10 SF-12® Health Survey (SF-12) ..................................................................................... 112 
17.11 Pain Questionnaire ....................................................................................................... 113 
17.12 Functional Assessment of Chronic Illness Therapy – Fatigue Scale (FACIT-F) ........ 114 
17.13 Serious Adverse Events Anticipated in the Trial Population ....................................... 115 
17.15 Detailed Requirements for the Evaluation of Patients Detected with Abnormal Liver 
Function Test .......................................................................................................................... 119 
 
 
 
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LIST OF TABLES 
Table 6.1 Table of Non-Sponsor Trial Responsibilities ............................................................ 42 
Table 9.1 Restricted Medications .............................................................................................. 58 
 
LIST OF FIGURES 
Figure 9.1 Schematic of Trial Design ......................................................................................... 51 
 

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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 
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 
CRISS 25 
Composite Response Index in Systemic Sclerosis 25 
Ctrough 
trough concentration  
DOCA 
deoxycorticosterone acetate 
DLCO 
diffusing capacity of the lungs for carbon monoxide  
DSUR 
Development Safety Update Report 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EU 
European Union 
FACIT-F 
Functional Assessment of Chronic Illness Therapy – Fatigue Scale 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
HAQ-DI 
Health Assessment Questionnaire – Disability Index 
HRCT 
high-resolution computed tomography 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 

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Abbreviation 
Definition 
IEC 
Independent Ethics Committee 
ILD 
interstitial lung disease 
IND 
Investigational New Drug 
IPF 
idiopathic pulmonary fibrosis 
IRB 
Institutional Review Board 
LPA 
lysophosphatidic acid 
LPAR1 
lysophosphatidic acid receptor 1 
mRSS 
modified Rodnan skin score 
OAT 
organic anion transporter 
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 
SF-12 
SF-12® Health Survey 
SHAQ 
Scleroderma Health Assessment Questionnaire 
SSc 
systemic sclerosis  
SScQoL 
Systemic Sclerosis Quality of Life Questionnaire 
SSPRO-18 
scleroderma skin patient-reported outcome 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
UCLA SCTC GIT 2.0 
University of California Los Angeles Scleroderma Clinical Trial Consortium 
Gastrointestinal Tract 
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 tables or in a single paragraph are defined with the relevant 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 17.1 for details).  The Sponsor will be responsible for timely reporting of serious 
adverse events (SAEs) to regulatory authorities as required.  The Sponsor will be responsible for 
timely reporting of SAEs and any other new pertinent safety information to all Investigators as 
required. 
The trial will be conducted at 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 cells 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 
7.1.3.3 Nonclinical Pharmacokinetics 
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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 PK profiles across healthy subjects 
(including elderly healthy subjects) and subjects with diffuse cutaneous SSc.  In the Phase 2a 
trial, treatment with fipaxalparant (HZN-825) 300 mg twice daily (BID) resulted in numerical 
improvement from baseline compared with placebo at the end of the 8-week double-blind period 
and at the end of the 16-week open-label period based on clinical outcomes, including the 
modified Rodnan skin score (mRSS), Health Assessment Questionnaire – Disability Index 
(HAQ-DI) and other components of the Scleroderma Health Assessment Questionnaire (SHAQ), 
overall disease severity and pruritus [Allanore et al., 2018].   
No SAEs or severe adverse events (AEs) occurred in Phase 1 trials.  One subject experienced 
AEs leading to permanent trial drug discontinuation (Nausea and Abdominal pain) on 
fipaxalparant (HZN-825) 300 mg BID and midazolam.  In the Phase 2a trial, 
fipaxalparant (HZN-825) 300 mg BID given up to 24 weeks was well-tolerated.  During the 
8-week double blind period, the most frequent treatment emergent adverse events (TEAEs) in the 
fipaxalparant (HZN-825) group were headache, diarrhea, nausea and fall. 
 
 
  Additionally, increases in 
 have been seen in blinded 
clinical studies with fipaxalparant (HZN-825).  These events are mostly non-serious and 
reversible.  Liver enzyme elevation will be monitored per FDA guidelines (Section 9.3.3.1). 
7.1.3.5 Benefit/Risk Assessment 
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 
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. 
This trial is designed as an open-label extension of HZNP-HZN-825-301, in which subjects 
received fipaxalparant (HZN-825) 300 mg QD, fipaxalparant (HZN-825) 300 mg BID or placebo 
during the 52-week double-blind Treatment Period.  Subjects in this extension trial will receive 
open-label fipaxalparant (HZN-825) 300 mg BID.  This extension 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.  This trial will allow examination of long-term safety and 
tolerability of fipaxalparant (HZN-825), assessment of the durability of response and/or 
improved response in subjects who received fipaxalparant (HZN-825) in HZNP-HZN-825-301 
and evaluation of efficacy in subjects who received placebo in HZNP-HZN-825-301. 
7.3 
Rationale for Dose Selection 
The dose regimen to be evaluated in this trial is 300 mg BID taken with a meal using 
fipaxalparant (HZN-825) tablets manufactured by 
 and 
 
.  This regimen was 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.  

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Based on preliminary 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 above the values based on in vitro potency 
evaluations.  Additionally, after adjusting for plasma protein binding of fipaxalparant (HZN-825) 
between humans and rats (99.97% and 99.92%, respectively), 300 mg BID is expected to achieve 
AUC0-12h above the AUC0-12h that showed efficacy in the rat DOCA model.   
In summary, the plasma exposure associated with fipaxalparant (HZN-825) 300 mg BID is 
anticipated to be well tolerated and have clinical efficacy. 

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8 
TRIAL OBJECTIVES 
The overall objective is to investigate the efficacy, safety and tolerability of 
fipaxalparant (HZN-825), a selective antagonist of LPAR1, administered BID to subjects with 
diffuse cutaneous SSc in a 52-week open-label extension following completion of the 
randomized, double-blind, 52-week clinical trial (HZNP-HZN-825-301). 
Two types of Baseline are defined: 
 Trial Baseline, defined as the latest measurement prior to the first dose of 
fipaxalparant (HZN-825) in this extension trial 
 Fipaxalparant (HZN-825) Baseline, defined as the latest measurement prior to the first 
dose of the trial drug in Trial HZNP-HZN-825-301. 
8.1 
Primary Objectives 
 The primary efficacy objective is to assess the efficacy of 52 weeks of open-label 
treatment with fipaxalparant (HZN-825) in subjects with diffuse cutaneous SSc, as 
measured by change from both Baselines in FVC % predicted. 
 The primary safety objective is to examine the safety and tolerability of 52 weeks of 
open-label treatment with fipaxalparant (HZN-825), inclusive of, but not limited to, AEs, 
SAEs and the AESI, from Day 1 to 4 weeks after last dose. 
8.2 
Exploratory Objectives 
The exploratory objectives are to evaluate the following after 52 weeks of open-label treatment 
with fipaxalparant (HZN-825): 
 Change from both Baselines in the mRSS, the Revised CRISS (CRISS 25), HAQ-DI; 
Clinician Global Assessment (CGA); Patient Global Assessment (PTGA); the Physical 
Effects and Physical Limitations subscales of the scleroderma skin patient-reported 
outcome (SSPRO-18); proportion of subjects with clinically important change in the 
mRSS; American College of Rheumatology-Composite Response Index in Systemic 
Sclerosis (ACR-CRISS), defined as improvement from each Baseline in mRSS, HAQ-DI, 
PTGA, CGA and FVC % predicted; the SSPRO-18; the University of California Los 
Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA SCTC 
GIT 2.0); Raynaud’s phenomenon using the Raynaud’s Assessment; the SHAQ; 
Systemic Sclerosis Quality of Life Questionnaire (SScQoL); SF-12® Health Survey 
(SF-12); pain and pain component scale scores; fatigue based on the Functional 
Assessment of Chronic Illness Therapy – Fatigue Scale (FACIT-F); lung fibrosis in 
subjects with suitable baseline high-resolution computed tomography (HRCT); diffusing 

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capacity of the lungs for carbon monoxide (DLCO); serum and plasma biomarkers 
associated with LPAR1 pathway, inflammation and/or fibrosis; and 
 
 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 an open-label, repeat-dose, multicenter extension trial of HZNP-HZN-825-301.  Subjects 
who complete the double-blind Treatment Period (Week 52) in Trial HZNP-HZN-825-301 will 
be eligible to enter this 52-week extension trial.  Subjects entering this extension trial will 
complete the Week 52 Visit activities in HZNP-HZN-825-301 and will not complete the Safety 
Follow-up Visit 4 weeks after the last dose of trial drug in HZNP-HZN-825-301.  All 
HZNP-HZN-825-301 Week 52 assessments should be performed before the first dose of the 
extension trial drug is administered. 
On Day 1 (Week 52 Visit of HZNP-HZN-825-301), subjects will receive their first dose of 
fipaxalparant (HZN-825) in this extension trial at the clinic and will participate in trial visits at 
Week 4 and every 6 weeks thereafter until Week 52.  The Week 52 Visit activities in 
HZNP-HZN-825-301 will serve as Trial Baseline for this extension trial.   
If a subject prematurely discontinues trial drug, he/she will be asked to remain in the trial, 
participating in the scheduled trial visits through Week 52.  If a subject prematurely discontinues 
trial drug and does not wish to continue in the trial, he/she will 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 fipaxalparant (HZN-825).   
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. 
Figure 9.1 
Schematic of Trial Design 
Trial Baseline 
Open-label Treatment Period 
Fipaxalparant (HZN-825) 300 mg BID 
52 Weeks 
Safety  
Follow-up 
Visit 
< –––––––––––––––––––––––––––––––––––––––––––––– Trial Visits––––––––––––––––––––—————————— > 
 
 
 
 
 
 
 
 
Day 1 (Week 52 Visit of  
HZNP-HZN-825-301)1 
Week 4 and every 6 weeks thereafter 
Week 52 4 weeks after 
last dose of 
fipaxalparant 
(HZN-825) 
BID=twice daily 
1. 
All HZNP-HZN-825-301 Week 52 assessments should be performed before the first dose of the extension trial drug is administered. 
9.2 
Discussion of Trial Design 
This trial is an open-label, repeat-dose, multicenter extension 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 may 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], this extension 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. 
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. Completed the double-blind Treatment Period (Week 52) in Trial HZNP-HZN-825-301; 
subjects prematurely discontinued from trial drug in Trial HZNP-HZN-825-301 for 
reasons other than safety or toxicity can be included at the discretion of the Investigator 
after completing Trial HZNP-HZN-825-301 scheduled visits, including Week 52 
assessments. 
3. 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: 
1. Anticipated use of another investigational agent for any condition during the course of 
the trial. 
2. New diagnosis of malignant condition after enrolling in Trial HZNP-HZN-825-301 
(except successfully treated basal/squamous cell carcinoma of the skin or cervical cancer 
in situ). 
3. 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 

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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. 
4. Pregnant or lactating women. 
5. Any new development with the subject’s disease or condition or any significant 
laboratory test abnormality during the course of Trial HZNP-HZN-825-301 that, in the 
opinion of the Investigator, would potentially put the subject at unacceptable risk. 
6. Subjects will be ineligible if, in the opinion of the Investigator, they are unlikely to 
comply with the trial protocol or have a concomitant disease or condition that could 
interfere with the conduct of the trial. 
9.3.3 Removal of Subjects from Treatment or the Trial 
All subjects are free to withdraw from trial participation at any time, for any reason and without 
prejudice to their further medical care.  In addition, the Investigator may terminate a subject from 
treatment at any time if further treatment in the trial is not in the best interest of the subject. 
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 fipaxalparant (HZN-825). 
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: 
 AE or clinically significant laboratory/electrocardiogram (ECG) abnormality.  The 
subject experiences an AE or clinically significant laboratory/ECG abnormality that 
imposes an unacceptable risk to the subject’s health, or the subject is unwilling to 
continue receiving treatment because of an AE or clinically significant laboratory/ECG 
abnormality.  Subjects who discontinue trial drug due to an AE or clinically significant 
laboratory/ECG abnormality will remain in the trial unless they withdraw from the trial 
for another reason.  In such cases, if the 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 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × upper 
limit of normal (ULN) 
o ALT or AST >5 × ULN for more than 2 weeks  

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o ALT or AST >3 × ULN and (total bilirubin [TBL] >2 × ULN or international 
normalized ratio >1.5) 
o ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%) 
Subjects who have ALT or AST levels >3 × ULN confirmed in a repeat test need 
to undergo close observation as prescribed by the FDA guidance on drug-induced 
liver injury (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 may 
lead to subject discontinuation from treatment.  The Investigator may consult with the 
trial Medical Monitor before initiation of the restricted or rescue 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 Open-label 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 

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AE should be followed until resolution or stabilization of the AE, or an adequate explanation for 
the event is obtained, in addition to being encouraged to continue participation in all planned 
assessments. 
9.3.3.2 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. 
 Trial terminated by Sponsor. 
9.3.4 Discontinuation of 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 
 Withdrawal of the license to manufacture (and/or of the permission to import) 

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9.3.5 Replacement Policy 
9.3.5.1 Subjects 
No subject prematurely discontinued from the trial for any reason will be replaced.   
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 reason:   
 Unacceptable protocol adherence. 
9.4 
Treatments 
9.4.1 Treatments Administered 
Subjects will receive fipaxalparant (HZN-825) 300 mg BID for 52 weeks.  
9.4.2 Identity of Investigational Product 
9.4.3 Labeling 
Fipaxalparant (HZN-825) 150 mg tablets will be packaged in blister packs in compliance with 
Sponsor/contract research organization standard procedures and all local requirements.  Each 
blister pack label will be labeled with a unique number.   
Upon arrival of fipaxalparant (HZN-825) tablet 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 
fipaxalparant (HZN-825) tablets and must maintain adequate records of the receipt and 
disposition of all fipaxalparant (HZN-825) tablets shipped to the trial center.  Records will 
CCI

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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 
fipaxalparant (HZN-825). 
Investigational clinical supplies will be received by a designated person(s) at the trial site, 
handled and stored safely and properly and kept in a secured location to which only the 
Investigator and designated assistants have access. 
At the end of the trial or if the subject prematurely discontinues the trial, the subjects should 
return any unused or partially used fipaxalparant (HZN-825) tablets to the site. 
9.4.6 Trial Drug Administration and Timing of Dose for Each Subject 
Subjects will take 2 tablets of fipaxalparant (HZN-825) orally in the morning and evening with a 
meal.  In the event a subject misses a dose, the dose should be taken along with the next planned 
dose (evening or morning) with a meal such that 4 tablets (600 mg) in total will be taken.  Due to 
a less than dose-proportional increase in fipaxalparant (HZN-825) systemic exposure, the 
600 mg dose taken in the event of a prior missed dose will be considered part of the planned 
dosing for this trial. 
9.4.6.1 Dose Modifications, Interruptions and Delays 
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 reversible.  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 
All subjects will receive fipaxalparant (HZN-825) 300 mg BID in this open-label extension trial. 
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9.4.8 Blinding and Unblinding 
This is an open-label extension trial. 
9.4.9 Concomitant Therapy and Restricted Medications 
Medication use restricted during the trial is presented in Table 9.1. 
Table 9.1 
Restricted Medications 
Medication 
Restricted Time Period 
Steroids for conditions other than diffuse cutaneous 
SSc 
 
Throughout the trial.  
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
or other immunosuppressive or 
cytotoxic medication other than mycophenolate 
mofetil, mycophenolic acid, low-dose prednisone or an 
anti-malarial 
Throughout the trial. 
United States Food and Drug Administration-approved 
agent for SSc or an investigational agent 
Throughout the trial. 
Drug/alcohol abuse 
Throughout the trial. 
PAH=pulmonary 
arterial hypertension; SSc=systemic sclerosis 
In case of a clinically significant deterioration in SSc, initiation of additional therapy or change 
in dose of background therapy is allowed following consultation with the trial Medical Monitor.  
If the additional therapy had been already initiated for clinically significant deterioration during 
the course of Trial HZNP-HZN-825-301, it can be continued.  The addition or change of 
background therapy for diffuse cutaneous SSc due to clinical deterioration will be referred to as 
“rescue therapy.”  Detailed (S)AE information following such events should be recorded in the 
eCRF. 

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or organic anion transporter (OAT)1/OAT3 that have narrow therapeutic windows. 
 
 Fipaxalparant (HZN-825) is an in vitro inhibitor of OAT1 
and OAT3 and may increase the systemic exposures of methotrexate. 
Clinically significant deterioration includes: 
 An absolute decline since Trial Baseline in FVC % predicted ≥10% or an absolute 
decline since Trial Baseline in FVC % predicted ≥5 to 9% with associated decline in 
DLCO ≥15% since Trial Baseline, or  
 Relative change since Trial Baseline in mRSS of >25% and an absolute change since 
Trial 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. 
All concomitant treatment (for diffuse cutaneous SSc and other conditions), including herbs and 
supplements, must be documented in the eCRF. 
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 fipaxalparant (HZN-825) 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.  

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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 as during 
Trial HZNP-HZN-825-301.  On days of clinic visits, subjects must refrain from strenuous 
activity at least 12 hours prior to pulmonary function testing.  Smoking should be discouraged 
throughout the visit days and will not be permitted in the 30-minute period prior to spirometry.  
Subjects should also avoid cold temperatures, environmental smoke, dust or areas with strong 
odors (e.g., perfumes).  If treated with bronchodilators, washout of 24 hours for long-acting and 
8 hours for short-acting bronchodilators should be observed before spirometry. 
Spirometry results will be electronically transmitted.  To ensure the quality of primary endpoint 
measurement, a central spirometry review will occur.  Results will be over-read by a central 
reader, confirmed by the clinical site and data will be transferred into the clinical database.  
In addition, the subject will be asked the following anchor (additional) questions at the time 
points indicated in Section 2.1. 
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 

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 +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 a qualified Investigator 
(or designee).  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 
early diffuse cutaneous SSc (skin and interstitial lung disease [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.   
 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 

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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 
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, HRCT 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  

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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.  
 +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 FVC % predicted 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 

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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. 
9.5.1.6 Plasma and Serum Biomarkers 
Blood samples will be collected prior to dosing on 
 as 
well as at the 
 Visit for analysis of plasma and serum biomarkers associated with the 
LPAR1 pathway, inflammation or fibrosis.  Only subjects who were able to provide a Baseline 
blood sample in Trial HZNP-HZN-825-301 for serum and plasma biomarkers will have this 
assessment completed.   
Examples of biomarkers that may be measured include, but are not limited to, proteins associated 
with the complement pathway and components of extracellular matrix pathways. 
Instructions for processing, handling, storing and shipping of samples will be detailed in the 
laboratory manual that will be provided to each site.  Samples will be collected, processed and 
stored at ≤-70ºC at the site until shipment to the central laboratory (PPD Central Laboratory).  
The central laboratory will store the samples at ≤-70ºC until shipment to the appropriate 
laboratory for testing.  Based on the results of the above assays, other similar serum biomarkers 
may be assayed to further explore drug and disease mechanisms.  Blood samples collected for 
analysis of biomarkers may be used for future testing should there be new information about the 
disease; however, the samples will not be stored for more than 5 years after the trial is 
completed.  All samples will be destroyed after all potential biomarkers have been evaluated or 5 
years after the trial is complete, whichever comes first. 
9.5.1.7 Lung High-resolution Computed Tomography 
Lung HRCT will be reviewed by a central reader.   
9.5.1.8 Diffusing Capacity of the Lungs for Carbon Monoxide 
The site will use its own DLCO equipment and conduct all measurements with the same DLCO 
equipment in case that several devices are available at the site.  Single-breath DLCO 
measurement will be carried out according to the ATS guideline on DLCO measurements when 
possible [Graham et al., 2017].   
DLCO values will be adjusted for the most recent hemoglobin value.  The DLCO assessment 
should always be performed after the FVC measurement and should always be started 
approximately the same time each day.  
9.5.1.9 Patient-reported Outcome Assessments 
A copy of each assessment is provided in the Appendix (Section 17). 

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9.5.1.9.1 Health Assessment Questionnaire – Disability Index 
The HAQ-DI, which is part of the SHAQ (Section 9.5.1.9.4), 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.  
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 
9.5.1.9.2 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. 
9.5.1.9.3 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 

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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].  
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 
 -3:   very much worse 
9.5.1.9.4 Scleroderma Health Assessment Questionnaire 
The SHAQ consists of the HAQ-DI (8 domains) and also includes a VAS for pain and the 
following scleroderma-specific VASs:  patient global assessment, vascular, digital ulcers, lung 
involvement and gastrointestinal involvement [Steen and Medsger, 1997].  Developers added the 
global questions to the HAQ-DI based on evaluation of SSc patients at the University of 

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Pittsburgh Scleroderma Clinic, their HAQ scores, patient report of symptoms and lab tests.  The 
5 scleroderma-specific VASs ask subjects how much symptoms interfere with daily activities 
and are scored similarly to a pain VAS.  Each VAS score is reported individually.  Studies have 
supported excellent test-retest reliability and construct validity (correlation with other measures 
in the direction and to the magnitude expected) and responsiveness of abatacept vs placebo for 
the global questions from the SHAQ [Johnson et al., 2005; Smyth et al., 2003; Khanna et al., 
2020].  
9.5.1.9.5 UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument 
The UCLA SCTC GIT 2.0 captures SSc-related gastrointestinal activity and severity.  This 
instrument is an improvement over the scleroderma gastrointestinal tract (SSC-GIT 1.0) 
instrument because it is shorter (34 items versus 52 items) but still reliable and valid instrument 
that differentiates reflux symptoms from symptoms of distension/bloating, adds a scale to 
evaluate rectal incontinence because of its high prevalence in SSc and develops a composite 
score that captures overall gastrointestinal tract burden associated with SSc [Khanna et 
al., 2009]. 
The UCLA SCTC GIT 2.0 has 7 scales—reflux, distension/bloating, diarrhea, fecal soilage, 
constipation, emotional well-being and social functioning; a total GIT score is also calculated to 
capture overall burden of SSc-associated gastrointestinal involvement.  Items are scored on a 0 to 
3 scale and do not require conversion to a 0 to 100 scale. 
9.5.1.9.6 Raynaud’s Assessment 
The Raynaud’s Condition Score Diary captures frequency, duration and severity of Raynaud’s 
phenomenon activity and has face, content, criterion, discriminant and construct validity in 
subjects with SSc [Merkel et al., 2003].  Subjects will be provided an electronic device to capture 
symptoms. 
9.5.1.10 Health Status and Systemic Sclerosis-specific Quality of Life Measures  
A copy of each assessment is provided in the Appendix (Section 17). 
9.5.1.10.1 Systemic Sclerosis Quality of Life Questionnaire 
The SScQoL, developed through concept elicitation interviews in patients with diffuse cutaneous 
and limited cutaneous SSc, is a validated tool that has 29 questions divided into 5 subscales 
relating to physical functioning, emotional functioning, social functioning, sleep and pain, which 
are important disease-specific factors associated with quality of life in SSc [Sierakowska et al., 
2019].  Good test-retest reliability and construct validity has been shown [Reay 2008].  No 
studies have yet determined responsiveness to date. 

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9.5.1.10.2 SF-12 Health Survey 
The SF-12 [Ware et al., 1996] is a 12-item survey used to assess general health-related quality of 
life.  The SF-12 items are scored to generate a physical component score (PCS) and mental 
component score (MCS) from the subject’s perspective.  The SF-12 examines 8 domains of 
health outcomes, including physical functioning, role-physical, bodily pain, general health, 
vitality, social functioning, role-emotional and mental health. 
9.5.1.10.3 Pain Questionnaire 
Subjects will complete a pain questionnaire that has 3 questions regarding the severity of pain 
experienced during the past week due to Raynaud’s, arthritis and finger ulceration and/or 
calcinosis.  Subjects will rate their pain from 0 (no pain) to 10 (very severe pain). 
9.5.1.10.4 Functional Assessment of Chronic Illness Therapy – Fatigue Scale 
The FACIT-F is a 13-item measure that assesses self-reported fatigue and its impact upon daily 
activities and function.  It was developed in the mid-1990s to meet a growing demand for more 
precise evaluation of fatigue associated with anemia in cancer patients.  Subsequent to its 
development, it has been employed in over 150 published studies, including over 
40,000 patients.  Studied groups have included patients with cancer, rheumatoid arthritis, 
osteoarthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, psoriasis and SSc.  
The FACIT-F is reliable and valid in subjects with SSc [Harel et al., 2012; Strickland et al., 
2012].   
9.5.2 Pharmacokinetic Measurements 
Blood samples will be collected from all subjects to evaluate the PK of fipaxalparant (HZN-825) 
at each of the following visits:  Day 1 (pre-dose), Week 4 (pre-dose and 2 to 4 hours post-dose) 
and Weeks 16, 28 and 40 (pre-dose only at these 3 visits).  For the Week 4 Visit (the only visit 
with post-dose PK samples), the morning dose regimen will be taken in the clinic.  All pre-dose 
samples will be collected prior to any fipaxalparant (HZN-825) administration for the day.  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., Day 1 and Weeks 4, 16, 28 and 40), subjects will be instructed to withhold taking 
fipaxalparant (HZN-825) before the visit, and fipaxalparant (HZN-825) and a meal will be 
administered in the clinic after the pre-dose PK samples are taken.  Time of 
fipaxalparant (HZN-825) 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 Week 4 Visit. 
If the clinic visit is in the afternoon, on days when a pre-dose PK sample will be collected 
(i.e., Day 1 and Weeks 4, 16, 28 and 40), subjects will be instructed to take 
fipaxalparant (HZN-825) before 8 a.m. with a meal and record dosing time; 1 PK sample will be 

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collected anytime during the clinic.  For the Week 4 Visit, 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 and 
an additional PK sample will be collected 2 to 4 hours post-dose during this visit.  At Weeks 16, 
28 and 40, subjects will be instructed to take the evening dose at regular dosing time. 
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.   
9.5.3 Safety Variables 
Safety will be assessed via AEs, concomitant medication use, physical examination, vital signs, 
 assessment, laboratory evaluations and 12-lead ECG. 
9.5.3.1 Adverse Events 
9.5.3.1.1 Definitions 
9.5.3.1.1.1 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. 
9.5.3.1.1.2 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: 

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 Death.  This includes any death that occurs during the conduct of a clinical trial, 
including deaths that appear to be completely unrelated to the trial drug (e.g., car 
accidents). 
 Life-threatening adverse experience.  An AE or suspected adverse reaction is considered 
life-threatening if, in the view of either the Investigator or the Sponsor, its occurrence 
places the subject at immediate risk of death.  It does not include an AE or suspected 
adverse reaction that, had it occurred in a more severe form, might have caused death. 
 Persistent or significant disability or incapacity. 
 Inpatient hospitalization or prolongation of an existing hospitalization. 
 Congenital anomaly or birth defect. 
 Other medically important event that, according to appropriate medical judgment, may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Surgical procedures or other therapeutic interventions themselves are not AEs, but the condition 
for which the surgery/intervention is required is an AE and should be documented accordingly.  
Elective surgeries that require hospitalization and treatment received at an emergency room or 
similar facility will not be considered as SAEs unless one of the definitions of an SAE listed 
above is met. 
In addition, hospitalizations for planned procedures are not considered an AE, unless they are 
prolonged hospitalizations and emergency room visits <24 hours in duration are not considered 
hospitalizations. 
9.5.3.1.1.3 Non-serious Adverse Event Definition 
A non-serious AE includes any AE that is not described in the previous SAE category. 
9.5.3.1.1.4 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: 
CCI

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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 symptoms are reported by the subject throughout the assessment, without the blood pressure 
reductions noted above, then the symptoms will be recorded separately as AEs and 
 
 will not be recorded. 
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. 
9.5.3.1.2 Documentation of Adverse Events 
AEs that are ongoing at the completion of HZNP-HZN-825-301 and/or occur prior to dosing on 
Day 1 will be considered pre-dose AEs.  The TEAE reporting period begins with administration 
of the first dose of fipaxalparant (HZN-825) in this extension trial on Day 1 and continues until 4 
weeks after the last dose of fipaxalparant (HZN-825) or premature discontinuation.  All pre-dose 
AEs, TEAEs and AEs during the Follow-up Period must be recorded in the source documents 
and on the subject’s eCRF.  If a subject discontinues due to an SAE, that subject will be followed 
per Section 9.5.3.1.5. 
If the Investigator observes an SAE after trial completion that he/she believes was possibly 
caused by fipaxalparant (HZN-825), the Investigator will report this SAE using the procedures 
described in Section 9.5.3.1.5.  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. 
9.5.3.1.3 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), fipaxalparant (HZN-825) continued 
 Grade 3 (severe) – prolonged symptoms, reversible, major functional impairment, 
prescription medications/partial relief, hospitalized <24 hours, temporary 
fipaxalparant (HZN-825) discontinuation or/and dose reduced 
 Grade 4 (includes life-threatening) – at risk of death, substantial disability, especially if 
permanent, hospitalized >24 hours, permanent fipaxalparant (HZN-825) discontinuation 
9.5.3.1.4 Relationship or Causality to Fipaxalparant (HZN-825) 
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 fipaxalparant (HZN-825) 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. 
9.5.3.1.5 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 fipaxalparant (HZN-825) 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 
fipaxalparant (HZN-825):   
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. 

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2. Perform appropriate diagnostic tests and therapeutic measures and submit all 
follow-up substantiating data, such as diagnostic test reports, hospital discharge 
summaries and autopsy report to the Sponsor’s representative. 
3. Conduct appropriate consultation and follow-up evaluation until the SAE outcome is 
known or the SAE is resolved.  Outcomes for reported AEs/SAEs/AESIs are to be 
defined as follows:  
 Recovering/Resolving  
 Recovered/Resolved 
 Not Recovered/Not Resolved 
 Recovered/Resolved with sequelae 
 Fatal 
 Unknown 
4. All new information for previously reported SAEs must be sent to the Sponsor 
immediately and no later than 24 hours after Investigator’s awareness of the new 
information.  If specifically requested, the Investigator may need to provide 
additional follow-up information, such as discharge summaries, medical records, or 
extracts 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. 
9.5.3.1.5.1 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 
fipaxalparant (HZN-825).  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. 

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9.5.3.1.6 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. 
9.5.3.1.7 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 9.5.3.1.2 and 9.5.3.1.5, 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.   
9.5.3.1.8 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 fipaxalparant (HZN-825), including periodic review and analyses of 
cumulative safety data for the trial. 

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9.5.3.1.9 Reporting of Investigational New Drug Safety Reports 
The Sponsor will report SAEs associated with fipaxalparant (HZN-825) to the appropriate 
regulatory authorities and all Investigators in accordance with the local and regional regulatory 
authorities laws and regulations. 
9.5.3.1.10 Development Safety Update Reports 
The Sponsor will prepare and submit Development Safety Update Reports (DSUR) to all 
relevant regulatory authorities in countries and regions where the trial is conducted. 
The Sponsor will prepare a single 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. 
9.5.3.1.11 Regulatory Reporting Requirements for Safety Information 
If subject is permanently withdrawn from investigational product(s), and/or noninvestigational 
product(s)/auxiliary medicinal product(s) because of a SAE, this information must be submitted 
to the Sponsor. 
Prompt notification by the Investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a study 
treatment under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation.  The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the external review body and Investigators. 
Individual safety reports for suspected unexpected serious adverse reactions will be reported by 
the Sponsor according to local regulatory requirements (e.g., electronic submission to the 
Eudravigilance database in the EU as per EU Clinical Trial Regulation 536/2014) as well as 
Sponsor policy and forwarded to Investigators as necessary. 
An Investigator who receives an individual safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will file it along with the 
Investigator’s Brochure and will notify the external review body, if appropriate according to 
local requirements. 
9.5.3.1.12 Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in the Sponsor’s safety surveillance and 
signal management processes. 

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9.5.3.2 Pregnancy and Lactation Reporting 
Pregnancy testing will be performed for WOCBP.  Serum pregnancy tests will be analyzed at a 
central trial laboratory and the urine pregnancy tests will be performed locally.  In addition, urine 
pregnancy tests should also be done every 4 weeks after Day 1, which includes both in-clinic 
testing at scheduled visits prior to dosing 
 and at home 
(±7 day-window) by the subject and reported to the site 
  
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 Treatment Period, she should immediately 
notify the Investigator and fipaxalparant (HZN-825) 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 
fipaxalparant (HZN-825).  Pregnancies occurring up to 4 weeks after the last dose of 
fipaxalparant (HZN-825) 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)  
 Bilateral tubal ligation 
 Vasectomized partner 
 Sexual abstinence from heterosexual intercourse 
There are no expected drug interactions between fipaxalparant (HZN-825) and hormonal 
contraceptives. 

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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 Section 17.1 for contact information).  The Investigator should counsel the 
subject and discuss the possible risks of continuing the pregnancy.  If pregnancy continues and 
the subject signs the pregnancy consent form, monitoring should also continue to the conclusion 
of the pregnancy and the outcome of the pregnancy should be reported to the Sponsor. 
Lactation information will be recorded on the Lactation Notification Form and submitted to 
Sponsor Global Patient Safety immediately and no later than 24 hours of the Investigator’s 
awareness of the event. 
9.5.3.3 Vital Signs and Weight  
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 will be measured.  To limit the potential for variability in weight collection, the subject 
should wear lightweight clothing and no shoes during weighing.   
9.5.3.5 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.  

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9.5.3.6 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. 
9.5.3.7 Echocardiogram 
A standard transthoracic echocardiogram will be conducted on Day 1.  However, an 
echocardiogram that has been performed during HZNP-HZN-825-301 and within the 3 months 
prior to HZNP-HZN-825-302 Day 1 can serve as the Trial 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. 
9.5.3.8 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 (ALT, AST, gamma glutamyltransferase, 
alkaline phosphatase, total bile acid, TBL, conjugated and unconjugated bilirubin, if applicable). 
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.  
 

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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. 
Samples for high-sensitivity C-reactive protein (hsCRP), erythrocyte sedimentation rate (ESR) 
and autoantibodies (anti-centromere antibody, anti-RNA polymerase antibody, 
anti-topoisomerase 1 and anti-U1 small nuclear ribonucleoprotein) will also be collected. 
Instructions for the collection, handling and analysis of clinical laboratory samples will be 
provided to the site prior to trial site initiation. 
9.5.4 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], SHAQ [Johnson et al., 2005; Steen and Medsger, 1997], UCLA 
SCTC GIT 2.0 [Khanna et al., 2009], SSPRO-18 [Man et al., 2017], Raynaud’s Condition Score 
Diary [Merkel et al., 2003], SScQoL [Sierakowska et al., 2019], SF-12 [Andrade et al., 2007; 
Khanna et al., 2010] and FACIT-F [Harel et al., 2012; Strickland et al., 2012] have been 
validated for use in subjects with SSc. 
9.5.5 Trial Procedures 
Trial procedures and timing are detailed in the Schedule of Assessments (Section 2.1). 
Select visits may be completed at an alternative remote location, e.g., a subject’s home, by a 
visiting home healthcare professional and will be based on local availability and as allowable 
based on local laws and regulations.  Remote locations will be discussed during the consent 
process per subject’s preference and as approved by the Investigator.  Site Investigators will have 
direct awareness and oversight of remote subject visits.   
The end of the trial is defined as the date of the last visit of the last subject undergoing the trial. 
9.5.5.1 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 to monitor safety and results will be communicated to the 
Medical Monitor.  A telephone visit, virtual visit or home visit may be used to collect 

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information on AEs and drug compliance.  Investigators may also consider shipping 
fipaxalparant (HZN-825) to a subject’s home via appropriate courier, if necessary.   
 If data are captured in an irregular manner (e.g., patient-reported outcomes via telephone 
or FVC in-home) this should be captured via source documentation.  If possible, these 
protocol modifications should be discussed with the Sponsor and contract research 
organization prior to implementation, but deviations to immediately address subject 
safety are possible per the Investigator’s discretion. 
9.6 
Statistical Methods and Determination of Sample Size  
9.6.1 Endpoints 
Two types of Baseline are defined: 
 Trial Baseline, defined as the latest measurement prior to the first dose of 
fipaxalparant (HZN-825) in this extension trial 
 Fipaxalparant (HZN-825) Baseline, defined as the latest measurement prior to the first 
dose of the trial drug in Trial HZNP-HZN-825-301. 
9.6.1.1 Primary Efficacy Endpoint 
The primary endpoint is the change from both Baselines in FVC % predicted at Week 52. 
9.6.1.2 Exploratory Efficacy Endpoints  
1. Change from both Baselines in the mRSS at Week 52. 
2. Proportion of subjects responding to treatment based on CRISS 25 at Week 52. 
3. Change from both Baselines in HAQ-DI at Week 52. 
4. Change from both Baselines in CGA at Week 52. 
5. Change from both Baselines in PTGA at Week 52. 
6. Change from both Baselines in the Physical Effects subscale of the SSPRO-18 at 
Week 52. 
7. Change from both Baselines 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 both Baselines 
at Week 52. 
9. Responder rate (defined as ACR-CRISS [predicted probability] of at least 0.6) at 
Week 52. 
10. Change from both Baselines in the SSPRO-18 at Week 52. 
11. Change from both Baselines in each scale of the UCLA SCTC GIT 2.0 and the total GIT 
score at Week 52. 
12. Change from both Baselines in Raynaud’s phenomenon using the Raynaud’s Assessment 
at Week 52. 
13. Change from both Baselines in the SHAQ at Week 52. 

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14. Change from both Baselines in SScQoL scores at Week 52. 
15. Change from both Baselines in SF-12 scores at Week 52. 
16. Change from both Baselines in pain and pain component scale scores at Week 52. 
17. Change from both Baselines in the FACIT-F score at Week 52. 
18. Change from both Baselines in lung fibrosis based on HRCT at Week 52. 
19. Change from both Baselines in DLCO at Week 52. 
20. Change from both Baselines in serum and plasma biomarkers associated with LPAR1 
pathway, inflammation and/or fibrosis at 
 
21. Change from both Baselines in
 
 
9.6.1.3 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. 
9.6.1.4 Pharmacokinetic Endpoint 
1. Pre- and post-dose concentrations of fipaxalparant (HZN-825). 
9.6.2 Analysis Sets 
Four analysis sets will be defined for this trial.   
 The full analysis set (FAS) will include all subjects who were enrolled (i.e., signed the 
ICF) and who received at least 1 dose or partial dose of fipaxalparant (HZN-825) in this 
extension trial.  This will be the analysis set used for efficacy data analyses and subjects 
will be analyzed according to the treatment group to which they were randomized in the 
previous trial, and combined into an ‘overall’ group.   
 The safety analysis set will include all subjects who received at least 1 dose or partial 
dose of fipaxalparant (HZN-825) in this extension trial.  Subjects in this analysis set will 
be analyzed according to the group determined by the treatment that the subject received 
in the previous trial and overall, and combined into an ‘overall’ group. 
 The PK analysis set will include all subjects who received at least 1 dose or partial dose 
of fipaxalparant (HZN-825) and had at least 1 PK sample post fipaxalparant (HZN-825) 
treatment in this extension trial.  
 The Per-Protocol (PP) analysis set will consist of all subjects in the FAS with no major 
protocol violations.  The PP analysis set will be used, as needed, for supportive analysis 
of the primary endpoint and potentially other key endpoints.  Subjects in this analysis set 

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will be analyzed according to the treatment group to which they were randomized in the 
previous trial, and combined into an ‘overall’ group. 
9.6.3 Efficacy Endpoint Analysis 
All efficacy endpoints will be summarized for the FAS using descriptive statistics, presented by 
the treatment group subjects were randomly assigned to in HZNP-HZN-825-301 and overall. 
A mixed model for repeated measures (MMRM) will be fit to the data for descriptive purposes 
using observed change in FVC % predicted values from all planned post-Trial Baseline 
assessments (Weeks 16, 28, 40 and 52).  The model will include the fixed covariates of:  factors 
used for stratifying randomization (use of mycophenolate mofetil [yes/no] and presence of ILD 
[yes/no]), treatment the subject received in the previous trial, treatment by Visit Week and Visit 
Week.  The Trial Baseline value will be used as a continuous covariate.  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 Trial Baseline to Week 52 from MMRM will be estimated from this model.  For subjects 
with missing data at 1 or more time points, the available data will be included in the analysis. 
Exploratory endpoints will be summarized at each time point.  Change from Baseline will be 
evaluated separately for each of the defined Baselines.   
9.6.4 Safety and Tolerability Analyses 
All safety endpoints will be summarized using descriptive statistics. 
The number and percentage of subjects reporting at least 1 TEAE, SAE, AESI and TEAE 
resulting in premature discontinuation of fipaxalparant (HZN-825) 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 
fipaxalparant (HZN-825), as assessed by the Investigator.  Grade 3 and above TEAEs will also 
be summarized for each unique System Organ Class and Preferred Term.  AESIs will be 
summarized. 
The number and percentage of subjects using concomitant medications will be summarized by 
Anatomical Therapeutic Chemical Level 4 term and Preferred Term. 
Laboratory values and change from Trial Baseline and fipaxalparant (HZN-825) Baseline will be 
summarized by visit using descriptive statistics.  The laboratory assessment will be categorized 
as low, normal or high based on normal ranges.  Shift tables using categories of low, normal and 
high from each Baseline to each visit in the open-label extension will be summarized.  If toxicity 
grading is available, then those grades will also be used for shift table summaries.   

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Descriptive summaries of observed and change from Trial Baseline and 
fipaxalparant (HZN-825) Baseline will be presented for each vital sign parameter by visit.  A 
shift table for vital signs by toxicity grade and visit will be summarized. 
9.6.5 Pharmacokinetic Analyses 
PK data will be analyzed using the PK analysis set.  Plasma concentrations of 
fipaxalparant (HZN-825) and metabolite(s) (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 in HZNP-HZN-825-301 and by 
time point.  Population PK analysis may be performed.   
9.6.6 Autoantibody Analyses 
The presence of anti-centromere antibody, anti-RNA polymerase antibody, anti-topoisomerase 1 
and anti-U1 small nuclear ribonucleoprotein will be evaluated. 
9.6.7 Interim Analyses 
No interim analyses are planned. 
9.6.8 Sample Size and Power Considerations 
The sample size is based on the number of subjects who completed Trial HZNP-HZN-825-301. 
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, echocardiogram, electroencephalogram, 
radiology, pathology and special assessment reports; dispensing records; signed ICFs; consultant 
letters; and subject 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 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 (e.g., Clinical Monitor) or the 
Clinical Out-of-Hours Support Program:  https://wwwext.amgen.com/science/clinical-
trials/clinical-out-of-hours-support-program immediately and no later than 1 calendar day from 
the time of awareness. 
A Serious Breach is a breach of any of the following: 
 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. 
Andrade TL, Camelier AA, Rosa FW, et al. Applicability of the 12-Item Short-Form Health 
Survey in patients with progressive systemic sclerosis. J Bras Pneumol. 2007;33:414-22. 
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. 
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. 
Harel D, Thombs BD, Hudson M, Baron M, Steele R, Canadian Scleroderma Research Group. 
Measuring fatigue in SSc: a comparison of the Short Form-36 Vitality subscale and Functional 
Assessment of Chronic Illness Therapy-Fatigue scale. Rheumatology (Oxford). 
2012:51:2177-85. 
Human Albumin. Transfus Med Hemother. 2009;36:399-407. 

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Johnson SR, Hawker GA, Davis AM. The Health Assessment Questionnaire Disability Index 
and Scleroderma Health Assessment Questionnaire in scleroderma trials: an evaluation of their 
measurement properties. Arthritis Rheum. 2005;53:256-62. 
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, Frech T, Khanna PP, et al. Valuation of scleroderma and psoriatic arthritis health 
states by the general public. Health Qual Life Outcomes. 2010;8:112. 
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, Hays RD, Maranian P, et al. Reliability and validity of UCLA Scleroderma Clinical 
Trial Consortium Gastrointestinal Tract (UCLA SCTC GIT 2.0) instrument. Arthritis Rheumatol. 
2009;61(9):1257-63. 
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. 
Ledein L, Léger B, Dees C, et al. Translational engagement of lysophosphatidic acid receptor 1 
in skin fibrosis: from dermal fibroblasts of patients with scleroderma to tight skin 1 mouse. 
Br J Pharmacol. 2020;177(18):4296-309. 
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. 
Merkel PA, Clements PJ, Reveille JD, et al. Current status of outcome measure development for 
clinical trials in systemic sclerosis. Report from OMERACT 6. J Rheumatol. 2003;30:1630-47. 
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. 
Pope JE. The future of treatment in systemic sclerosis:  can we design better trials? Lancet 
Rheumatol. 2020:e185-94.  

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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. 
Sierakowska M, Doroszkiewicz H, Sierakowska J, et al. Factors associated with quality of life in 
systemic sclerosis:  a cross-sectional study. Qual Life Res. 2019;28:3347-54. 
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. 
Steen VD, Medsger TA Jr. The value of the Health Assessment Questionnaire and special 
patient-generated scales to demonstrate change in systemic sclerosis patients over time. Arthritis 
Rheum. 1997;40:1984-91. 
Strickland G, Pauling J, Cavill C, McHugh N. Predictors of health-related quality of life and 
fatigue in systemic sclerosis: evaluation of the EuroQol-5D and FACIT-F assessment tools. Clin 
Rheumatol. 2012;31:1215-22. 
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. 
US Department of Health and Human Services, Food and Drug Administration. Drug-induced 
liver injury:  premarketing clinical evaluation. July 2009. 
Varga J, Abraham D. Systemic sclerosis:  a prototypic multisystem fibrotic disorder. J Clin 
Invest. 2007;117(3):557-67. 

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Volkmann E, Varga J. Emerging targets of disease-modifying therapy for systemic sclerosis. Nat 
Rev Rheumatol. 2019;15(4):208-24. 
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:  
  
 
Sponsor Contact for 
Horizon Therapeutics U.S.A., Inc. 
Serious Adverse Event Reporting 
 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 

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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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17.4 
Scleroderma Health Assessment Questionnaire (SHAQ) 
 

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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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17.7 
University of California Los Angeles Scleroderma Clinical Trial Consortium 
Gastrointestinal Tract (UCLA SCTC GIT 2.0) Instrument 
 

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17.8 
Raynaud’s Assessment 
 
 
 
 

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17.9 
Systemic Sclerosis Quality of Life Questionnaire (SScQoL) 
 

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Date:  14 October 2024 
 
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17.10 SF-12® Health Survey (SF-12) 
 

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17.11 Pain Questionnaire 
 

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17.12 Functional Assessment of Chronic Illness Therapy – Fatigue Scale (FACIT-F) 
 

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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 9.5.3.1.1.2 (Serious Adverse Event Definition).  The Investigator is 
required to follow the requirements detailed in Section 9.5.3.1.5 (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 to events without fipaxalparant (HZN-825), 
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 

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
IND 112818 
 
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Date:  14 October 2024 
 
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IND 112818 
 
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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 TBL >2 × ULN should be 
followed by repeat testing (ALT, AST, alkaline phosphatase, 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 20230131 2
Document Description:
Fipaxalparant 20230131 PA2
Document Number:
CLIN-000354472
Approval Date:
18 Oct 2024
Type of Study Protocol:
Amendment
Protocol Amendment No.: 2
Document Approvals
Reason for Signing: Management
Name: 
Date of Signature: 18-Oct-2024 13:59:29 GMT+0000

Horizon Therapeutics Ireland DAC 
 
Fipaxalparant (HZN-825) 
Date:  14 October 2024 
 
Protocol:  HZNP-HZN-825-302 
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SUMMARY OF CHANGES 
Protocol HZNP-HZN-825-302 
Protocol Version 2.0, Amendment 1 (19 October 2022) to 
Protocol Version 3.0, Amendment 2 (14 October 2024) 
Key additions, revisions and clarifications to Version 3.0 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 exploratory objectives to align with updates in the 
HZN-825-301 study objectives with a goal of enhancing 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 that trial drug must not begin until the subject is completely done with the 
HZN-825-301 study. 
 Updating Physician Global Assessment to Clinician Global Assessment throughout the 
document to align with industry standards. 
 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. 
 Updating manufacturer list to include 
 
 Introducing the revised CRISS (CRISS 25) into the endpoints and associated definitions 
to align throughout the protocol. 
 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. 
 Updating Principal Investigator responsibilities to report serious breaches. 
 Including definition of serious adverse events (SAE) and 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). 
 Other editorial, administrative, or alignment updates were made for consistency with the 
HZN-825-301 study. 
 

Horizon Therapeutics Ireland DAC 
 
HZN-825 
Date:  19 October 2022 
 
Protocol:  HZNP-HZN-825-302 
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SUMMARY OF CHANGES 
Protocol HZNP-HZN-825-301 
Version 2.0 Amendment 1, incorporating Protocol Version 1.0 and Administrative 
Change 1 
Key additions, revisions and clarifications to Version 1.0 of the protocol are: 
• Updating the Sponsor’s address. 
• Adding an ex-United States (US) fax number for emergency contact/serious adverse 
event reporting. 
• Changing the signatory trial statistician. 
• Clarifying the primary safety objective. 
• Adding an exploratory objective and endpoint regarding evaluation of rheumatologic 
assessments and specifying what these assessments are
 
 
• Adding new requirements around condom use and aligning text with Section 9.5.3.2 in 
exclusion criterion 3. 
• Allowing subject visits to be performed at locations other than the trial site and adding 
clarity as to which visits are eligible to be performed at an alternate site location.  
• 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. 
• Specifying that a clinically significant laboratory or electrocardiogram (ECG) 
abnormality may lead to removal of subjects from treatment. 
• Including restricted medication use as a specific reason for discontinuation from trial 
treatment. 
• Specifying that attempts should be made to contact subjects who are initially lost to 
follow-up. 
• Adding rationale to support the safety of up to a 600 mg dose of HZN-825. 
• Specifying that any completely missed dose should be recorded on the electronic case 
report form (eCRF). 
• Updating restrictions regarding concomitant medications and removing P-glycoprotein 
(P-gp) inhibitors from the list of restricted medications because the strong P-gp 
transporter inhibitor itraconazole had no impact on HZN-825 exposure at clinically 
relevant doses in a Phase 1 trial. 
• Deleting the table that delineated specific rescue therapy, as such therapy will be 
determined in consultation with the trial Medical Monitor. 
• Including some additional cautions around use of specific concomitant medications. 
CCI

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Date:  19 October 2022 
 
Protocol:  HZNP-HZN-825-302 
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• Stressing the importance of compliance with trial drug. 
• Clarifying language for obtaining diffusing capacity of the lungs for carbon monoxide 
(DLCO) measurement. 
• Providing detail regarding taking trial drug with a meal. 
• Adding the definition of a suspected adverse reaction. 
• Clarifying when pre-existing conditions should be reported as AEs. 
• Clarifying documentation and reporting for medication errors. 
• Adding clarification around abstinence as a contraceptive method. 
• Alerting trial personnel that the actual assessment instruments used may differ from those 
in Section 17 of the protocol. 
• Updating the SF-12® Health Survey to the most current version. 
• Updating the 
 Manual and protocol language to align 
the process of assessing 
 with current guidelines, to clarify the 
manual to make the process more understandable and improve the method of data 
collection for 
 
• Specifying that a repeat resting ECG should be conducted if a clinically significant ECG 
result is obtained. 
• Specifying the urinalysis parameters. 
• Making changes for consistency with the schedule of assessments. 
Changes considered not key, minor wording changes and correction of minor typographical 
errors are not detailed below. 
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