A Randomized, Double-Blind, Placebo-Controlled, Repeat-Dose, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics, and Explore Efficacy of TEPEZZA in Patients With Diffuse Cutaneous Systemic Sclerosis
Phase: PHASE1
Conditions: Diffuse Cutaneous Systemic Sclerosis
Sponsor: Amgen

Horizon Therapeutics U.S.A., Inc.
TEPEZZA (teprotumumab-trbw; HZN-001)
Date:  02 February 2022
Protocol:  HZNP-TEP-001
IND 147532
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PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS U.S.A., INC.
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CLINICAL STUDY PROTOCOL 
FOR TEPEZZA (teprotumumab-trbw; HZN-001)
Protocol Number:  HZNP-TEP-001
A Randomized, Double-Blind, Placebo-Controlled, Repeat-Dose, Multicenter 
Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics, and Explore Efficacy of TEPEZZA in Patients with 
Diffuse Cutaneous Systemic Sclerosis
Date:  02 February 2022
Version 5.0, Amendment 4
IND 147532
Sponsor:
Horizon Therapeutics U.S.A., Inc.
1 Horizon Way
Deerfield, IL  60015
This protocol is the confidential information of Horizon Therapeutics U.S.A., Inc. and is intended solely for the guidance of the clinical 
investigation. This protocol may not be disclosed to parties not associated with the clinical investigation or used for any purpose without the 
prior written consent of Horizon Therapeutics U.S.A., Inc.
CONFIDENTIAL

Horizon Therapeutics U.S.A., Inc. 
 
TEPEZZA (teprotumumab-trbw; HZN-001) 
Date:  02 February 2022
Protocol:  HZNP-TEP-001
IND 147532 
 
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PROTOCOL 
1 
TITLE PAGE 
Study Title: A Randomized, Double-Blind, 
Placebo-Controlled Repeat-Dose, Multicenter 
Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics, and 
Explore Efficacy of TEPEZZA in Patients with 
Diffuse Cutaneous Systemic Sclerosis 
Protocol Number: HZNP-TEP-001 
Version: 5.0, Amendment 4 
IND 147532 
Investigational Product: TEPEZZA (teprotumumab-trbw; HZN-001) 
Indication: Diffuse Cutaneous Systemic Sclerosis 
Sponsor: Horizon Therapeutics U.S.A., Inc. 
1 Horizon Way 
Deerfield, IL  60015 
Development Phase: 1 
 
 
 
Horizon Therapeutics U.S.A., Inc. 
1 Horizon Way 
Deerfield, IL  60015 
Sponsor Signatory: 
 
 
Horizon Therapeutics U.S.A., Inc. 
Approval Date: 02 February 2022 
 
 
 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 study, whether or not judged drug-related, must be reported within 24 hours of 
knowledge of the event by entering the information into the electronic case report form (eCRF).  
If unable to access the eCRF, the event must be reported by submitting the completed Serious 
Adverse Event Form via email or fax to the contacts provided below. 
Fax:
 
Email:
clinicalsafety@horizontherapeutics.com 
 
 
PPD
PPD
PPD

Horizon Therapeutics U.S.A., Inc.
TEPEZZA (teprotumumab-trbw; HZN-001)
Date:  02 February 2022
Protocol:  HZNP-TEP-001
IND 147532
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SPONSOR SIGNATURE PAGE
Protocol Number:
HZNP-TEP-001
Version:
5.0, Amendment 4
Protocol Title:
A Randomized, Double-Blind, Placebo-Controlled, Repeat-Dose, 
Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics
and Pharmacodynamics, and Explore Efficacy of TEPEZZA in Patients 
with Diffuse Cutaneous Systemic Sclerosis
Version Date:
02 February 2022
Approved by:
Horizon Therapeutics U.S.A., Inc.
Horizon Therapeutics U.S.A., Inc.
PPD
PPD
PPD
PPD
PPD
PPD

Horizon Therapeutics U.S.A., Inc. 
 
TEPEZZA (teprotumumab-trbw; HZN-001) 
Date:  02 February 2022
Protocol:  HZNP-TEP-001
IND 147532 
 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
HZNP-TEP-001 
Version: 
5.0, Amendment 4 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Repeat-Dose, 
Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics, and Explore Efficacy of TEPEZZA in Patients 
with Diffuse Cutaneous Systemic Sclerosis  
Version Date: 
02 February 2022 
I agree to conduct the study 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 study drug supplied by the Sponsor will be used only as described in the 
protocol named above. 
Signature: 
 
 
 
 
 
 
 
Name  
Study Center 
Address 
City State Country 
 
Date 
 
 
 
 

Horizon Therapeutics U.S.A., Inc. 
 
TEPEZZA (teprotumumab-trbw; HZN-001) 
Date:  02 February 2022
Protocol:  HZNP-TEP-001
IND 147532 
 
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SUMMARY OF CHANGES 
Protocol HZNP-TEP-001 
Version 5.0 Amendment 4, incorporating Protocol Version 4.0 
Additions, revisions and clarifications to Version 4.0 of the protocol include: 
 Changing the responsible study statistician. 
 Removing inclusion criterion 5.  The primary objective of this study is to evaluate the 
safety of TEPEZZA in patients with dcSSc.  Inclusion criterion 5 restricts study 
enrollment to subjects who lack improvement or have worsening disease on current 
therapy, which is a small subset of patients eligible for this study.  Removal of this 
inclusion criterion will allow for a more representative study population. 
 Adding Plaquenil® as an example of an anti-malarial in exclusion criterion 7 and revising 
exclusion criterion 7 to improve clarity.   
 Modifying exclusion criteria 19 and 20 to be less restrictive (i.e., platelets <100×103/μL 
instead of <120×103/μL and hemoglobin <8 g/dL instead of <10 g/dL).  TEPEZZA is not 
expected to increase bleeding during 
; thus, lower platelet and hemoglobin 
levels are appropriate. 
 Removing the ±3-day visit window from the Day 1 Visit, as a visit window is not 
applicable for the Day 1 Visit. 
 Emphasizing that subjects are encouraged to remain in the study even if study drug has 
been discontinued. 
 Clarifying which personnel may be unblinded for the Week 24 primary analyses. 
 Correcting minor typographical errors (changes are not detailed below). 
CCI
CCI

Horizon Therapeutics U.S.A., Inc.
TEPEZZA (teprotumumab-trbw; HZN-001)
Date:  02 February 2022 
 
Protocol:  HZNP-TEP-001 
IND 147532 
 
Version 5.0, Amendment 4 
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Text 
Version 4.0, Amendment 3 
12 July 2021 
Amended Text 
Version 5.0, Amendment 4 
02 February 2022 
Reason for 
Change 
Synopsis  Exclusion Criteria and Section 9.3.2 Exclusion 
Criteria 
7. Use of any other non-steroid immunosuppressive agent, 
cytotoxic or anti-fibrotic drug within 4 weeks of Screening 
other than an anti-malarial.  This includes cyclophosphamide, 
azathioprine (Imuran®), methotrexate or other 
immunosuppressive or cytotoxic medication except 
mycophenolate mofetil (CellCept) or mycophenolic acid 
(Myfortic), which are permitted with use according to 
inclusion criterion. 
Synopsis  Exclusion Criteria and Section 9.3.2 Exclusion 
Criteria 
7. 
Use of a non-steroidal immunosuppressive agent, cytotoxic or 
anti-fibrotic drug within 4 weeks of Screening, including 
cyclophosphamide, azathioprine (Imuran®), methotrexate or 
other immunosuppressive or cytotoxic 
medication.  Exceptions are mycophenolate mofetil 
(CellCept) and mycophenolic acid (Myfortic), which are 
permitted according to inclusion criterion 8, and anti-malarials 
(e.g., hydroxychloroquine [Plaquenil®]). 
To provide an 
example of an 
anti-malarial drug 
and improve 
clarity of text 
Synopsis  Exclusion Criteria and Section 9.3.2 Exclusion 
Criteria 
19. Platelets <120×103/μL. 
20. Hemoglobin <10 g/dL. 
Synopsis  Exclusion Criteria and Section 9.3.2 Exclusion 
Criteria 
19. Platelets <100×103/μL. 
20. Hemoglobin <8 g/dL. 
TEPEZZA is not 
expected to 
increase bleeding 
during skin 
biopsy; thus, 
lower platelet and 
hemoglobin levels 
are appropriate. 
Synopsis  Statistical Analyses 
Efficacy 
 
 
 
 
 
Quality of Life  
QOL data will be analyzed using the intent-to-treat analysis set.   
Synopsis  Statistical Analyses 
Efficacy 
 
 
 
 
Quality of Life  
QOL data will be analyzed using the full analysis set.   
CCI
CCI
CCI

Horizon Therapeutics U.S.A., Inc.
TEPEZZA (teprotumumab-trbw; HZN-001)
Date:  02 February 2022 
 
Protocol:  HZNP-TEP-001 
IND 147532 
 
Version 5.0, Amendment 4 
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Text 
Version 4.0, Amendment 3 
12 July 2021 
Amended Text 
Version 5.0, Amendment 4 
02 February 2022 
Reason for 
Change 
Section 9.6.5 Interim Analyses 
No interim analyses are planned. 
The primary analysis time point for this study is Week 24.  
Therefore, the database will be locked after all subjects complete 
Week 24 assessments or withdraw from study prematurely prior to 
Week 24 for primary analyses.  However, the study team and study 
site personnel will remain blinded until the completion of the study 
in order to complete the analysis of remaining time points, 
including Week 48. 
Section 9.6.5 Interim Analyses 
No interim analyses are planned. 
The primary analysis time point for this study is Week 24.  
Therefore, the database will be locked after all subjects complete 
Week 24 assessments or withdraw from study prematurely prior to 
Week 24 for primary analyses.  Select Sponsor 
personnel/designees may be unblinded after the database lock for 
the Week 24 analyses. 
To clarify which 
personnel may be 
unblinded for the 
Week 24 primary 
analyses 

Horizon Therapeutics U.S.A., Inc.
TEPEZZA (HZN-001)
Date:  02 February 2022 
 
Protocol:  HZNP-TEP-001 
IND 147532 
 
 
 
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10. Subjects will be randomized in a 3:2 ratio to receive either TEPEZZA (10 mg/kg on Day 1 followed by 20 mg/kg q3W for the remaining 7 infusions) or placebo (q3W for all 
8 infusions). 
11. Phone (or email) contact by research staff focusing on safety and tolerability aspects will be made the day after (within 24 hours) the infusion for the first and second infusions, 
and thereafter as deemed appropriate.  In addition, subjects who experience an infusion-associated event after any subsequent infusion will also be contacted by phone (or 
email) by research staff the day after the infusion, and thereafter as deemed appropriate. 
12
 
 
13. If the subject has had the test <3 months prior to Screening, then the Screening spirometry need not be performed. 
14. Serum pregnancy test at Screening and Week 48 (or as needed).  Urine pregnancy tests prior to dosing at all other visits, as applicable.  Perform for female subjects of 
childbearing potential (including those with an onset of menopause <2 years prior to Screening, non-therapy-induced amenorrhea for <12 months prior to Screening or not 
surgically sterile [absence of ovaries and/or uterus]). 
15. Vital signs (blood pressure, heart rate, respiratory rate, temperature) will be measured at all clinic visits.  Vital signs will be measured pre- and post-infusion on Day 1 and 
Week 3 and pre-infusion on all other dosing days.  Additional vital signs will be monitored if infusion-associated AEs occur (see Section 9.5.7.4 for details). 
16. Additional ECGs will be assessed, as needed. 
17. 
 
18. HbA1c must be 8.0% for randomization.  If the HbA1c is elevated and considered clinically significant at any time point after Screening, it will be repeated approximately 
every 90 days until it returns to normal or Baseline value. 
19. Blood samples for immunogenicity testing will be collected pre-infusion on Day 1 and Weeks 3, 12 and 18; a single sample will be collected at Weeks 24, 36 and 48.  If a 
sample is ADA positive after confirmatory and reactive titer testing, the sample will then be tested for NAb.  
20. AEs that occur after signing the informed consent form and prior to dosing on Day 1 will be considered Baseline signs/symptoms.  AEs occurring or worsening after initiation 
of the infusion on Day 1 through 3 weeks (21 days) after last dose of study drug will be considered treatment-emergent AEs.  AEs occurring after 3 weeks (21 days) after last 
dose of study drug through Week 48 will be considered follow-up AEs.  All AEs and SAEs that occur from the signing of informed consent through Week 48 will be recorded. 
21. 
 
 
   
22. PK samples will be collected pre- and post-infusion on Day 1 and Weeks 3, 12 and 18; a single sample will be collected at Weeks 24 and 36. 
23. 
   
CCI
CCI
CCI
CCI

Horizon Therapeutics U.S.A., Inc. 
 
TEPEZZA (HZN-001) 
Date:  02 February 2022
Protocol:  HZNP-TEP-001
IND 147532 
 
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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .......................................................................................................................... 2 
2 
SYNOPSIS ............................................................................................................................ 11 
2.1 
Schedule of Assessments ............................................................................................... 20 
3 
TABLE OF CONTENTS ...................................................................................................... 23 
4 
LIST OF ABBREVIATIONS ............................................................................................... 29 
5 
ETHICS ................................................................................................................................. 31 
5.1 
Institutional Review Board/Independent Ethics Committee .......................................... 31 
5.2 
Ethical Conduct of the Study ......................................................................................... 31 
5.3 
Subject Information and Consent ................................................................................... 31 
5.4 
Compensation for Health Damage of Subjects/Insurance .............................................. 32 
5.5 
Confidentiality ................................................................................................................ 32 
6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE............................ 33 
7 
INTRODUCTION ................................................................................................................ 34 
7.1 
Background .................................................................................................................... 34 
7.1.1 
Diffuse Cutaneous Systemic Sclerosis.................................................................... 34 
7.1.2 
Insulin-like Growth Factor-1 Receptor (IGF-1R) ................................................... 35 
7.1.3 
TEPEZZA ............................................................................................................... 36 
7.1.3.1 Physiochemical Properties .................................................................................. 36 
7.1.3.2 Safety Pharmacology........................................................................................... 37 
7.1.3.3 Nonclinical Pharmacokinetics ............................................................................. 37 
7.1.3.4 Clinical Experience ............................................................................................. 37 
7.1.3.4.1 
Efficacy ...................................................................................................... 37 
7.1.3.4.2 
Pharmacokinetics ....................................................................................... 38 
7.1.3.4.3 
Pharmacodynamics .................................................................................... 39 
7.1.3.4.4 
Safety ......................................................................................................... 39 
7.2 
Rationale for this Study .................................................................................................. 42 
7.3 
Rationale for Dose Selection .......................................................................................... 42 
8 
STUDY OBJECTIVES ......................................................................................................... 42 
8.1 
Primary Objective .......................................................................................................... 43 
8.2 
Other Objectives ............................................................................................................. 43 

Horizon Therapeutics U.S.A., Inc. 
 
TEPEZZA (HZN-001) 
Date:  02 February 2022
Protocol:  HZNP-TEP-001
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8.3 
Pharmacokinetic and Anti-drug Antibody Objectives ................................................... 44 
8.4 
Safety and Tolerability Objectives ................................................................................. 44 
9 
INVESTIGATIONAL PLAN ............................................................................................... 45 
9.1 
Overall Study Design and Plan ...................................................................................... 45 
9.2 
Discussion of Study Design ........................................................................................... 46 
9.3 
Selection of Study Population ........................................................................................ 47 
9.3.1 
Inclusion Criteria .................................................................................................... 47 
9.3.2 
Exclusion Criteria ................................................................................................... 48 
9.3.3 
Removal of Subjects from Treatment or the Study ................................................ 49 
9.3.3.1 Removal of Subjects from Treatment ................................................................. 49 
9.3.3.2 Removal of Subjects from the Study................................................................... 50 
9.3.4 
Replacement Policy ................................................................................................ 50 
9.3.4.1 Subjects ............................................................................................................... 50 
9.3.4.2 Centers ................................................................................................................. 51 
9.3.4.3 Screen Failures .................................................................................................... 51 
9.4 
Treatments ...................................................................................................................... 51 
9.4.1 
Treatments Administered ........................................................................................ 51 
9.4.2 
Identity of Investigational Products ........................................................................ 51 
9.4.2.1 TEPEZZA............................................................................................................ 51 
9.4.2.2 Placebo ................................................................................................................ 52 
9.4.3 
Labeling .................................................................................................................. 52 
9.4.4 
Storage .................................................................................................................... 52 
9.4.5 
Drug Accountability................................................................................................ 52 
9.4.6 
Study Drug Administration and Timing of Dose for Each Subject ........................ 53 
9.4.6.1 Description of Clinical Supplies ......................................................................... 53 
9.4.6.2 Determination of Dose Volume .......................................................................... 53 
9.4.6.3 Details Concerning Timing and Dose Administration ........................................ 53 
9.4.6.3.1 
Preparation and Administration of TEPEZZA .......................................... 53 
9.4.6.3.2 
Dose Modifications, Interruptions and Delays .......................................... 54 
9.4.7 
Method of Assigning Subjects to Treatment Groups .............................................. 55 
9.4.8 
Blinding and Unblinding......................................................................................... 56 

Horizon Therapeutics U.S.A., Inc. 
 
TEPEZZA (HZN-001) 
Date:  02 February 2022
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9.5.7.1.10 Development Safety Update Reports ........................................................ 67 
9.5.7.2 Pregnancy Reporting ........................................................................................... 67 
9.5.7.3 Medical History ................................................................................................... 68 
9.5.7.4 Vital Signs, Weight and Height........................................................................... 68 
9.5.7.5 Physical Examination .......................................................................................... 69 
9.5.7.6 Electrocardiograms.............................................................................................. 69 
9.5.7.7 Clinical Laboratory Safety Tests ......................................................................... 69 
9.5.8 
Appropriateness of Measurements .......................................................................... 70 
9.5.9 
Study Procedures .................................................................................................... 71 
9.5.9.1 Screening ............................................................................................................. 71 
9.5.9.2 Treatment Period ................................................................................................. 72 
9.5.9.2.1 
Day 1/Baseline ........................................................................................... 72 
9.5.9.2.2 
Week 3 ....................................................................................................... 73 
9.5.9.2.3 
Week 6 ....................................................................................................... 74 
9.5.9.2.4 
Week 9 ....................................................................................................... 75 
9.5.9.2.5 
Week 12 ..................................................................................................... 75 
9.5.9.2.6 
Week 15 ..................................................................................................... 76 
9.5.9.2.7 
Week 18 ..................................................................................................... 77 
9.5.9.2.8 
Week 21 ..................................................................................................... 77 
9.5.9.2.9 
Week 24 (End of Treatment) ..................................................................... 78 
9.5.9.3 Follow-up Period ................................................................................................. 79 
9.5.9.3.1 
Week 28 ..................................................................................................... 79 
9.5.9.3.2 
Week 32 ..................................................................................................... 79 
9.5.9.3.3 
Week 36 ..................................................................................................... 79 
9.5.9.3.4 
Week 42 ..................................................................................................... 80 
9.5.9.3.5 
Week 48 (End of Study) ............................................................................ 80 
9.6 
Statistical Methods and Determination of Sample Size ................................................. 81 
9.6.1 
Endpoints ................................................................................................................ 81 
9.6.1.1 Primary Endpoint ................................................................................................ 81 
9.6.1.2 Efficacy Endpoints .............................................................................................. 81 
9.6.1.3 Quality-of-Life Endpoints ................................................................................... 81 

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TEPEZZA (HZN-001) 
Date:  02 February 2022
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LIST OF TABLES 
Table 6.1 
Table of Non-Sponsor Study Responsibilities ........................................................... 33 
Table 9.1 
Restricted Medications .............................................................................................. 57 
Table 9.2 
Schedule of Clinical Laboratory Safety Tests ........................................................... 70 
 
LIST OF FIGURES 
Figure 9.1 Schematic of Study Design ........................................................................................ 46 
 

Horizon Therapeutics U.S.A., Inc. 
 
TEPEZZA (HZN-001) 
Date:  02 February 2022
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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 
(CRO) authorized by the Sponsor will submit this protocol, any protocol modifications and the 
informed consent form (ICF) and all applicable study documentation to be used in this study 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 study 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 
study.  A copy of the approved ICF will also be forwarded to the Sponsor or its designee.  
Appropriate reports on the progress of the study 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 Study 
The Investigators will ensure that this study is conducted in a manner that fully conforms with 
which the research is conducted, whichever affords the greater protection to the individual.  The 
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 studies conducted in the United States (US) or under a US Investigational New 
Drug program, the Investigator will additionally ensure adherence to the basic principles of 
Code of Federal Regulations 
(CFR)
Investigator
 and 
.  
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 study after adequate explanation of the aims, methods, anticipated benefits 
and potential hazards of the study. 
The Investigator or designee must also explain that the subjects are completely free to refuse to 
enter the study 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 
 
there is an amendment to the protocol that necessitates a change to the content of the subject 

Horizon Therapeutics U.S.A., Inc. 
 
TEPEZZA (HZN-001) 
Date:  02 February 2022
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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 study 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  site file or, if locally required, in the subject  
notes/files of the medical institution. 
The electronic case report forms (eCRFs) for this study 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 
study. 
5.4 
Compensation for Health Damage of Subjects/Insurance 
The Sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study 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.  Study 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 th
 
The Investigator will maintain a list to enable subjects to be identified. 

Horizon Therapeutics U.S.A., Inc. 
 
TEPEZZA (HZN-001) 
Date:  02 February 2022
Protocol:  HZNP-TEP-001
IND 147532 
 
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6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
The Sponsor of this study is Horizon Therapeutics U.S.A., Inc. (Horizon).  Horizon 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 study will be conducted at up to 12 study centers in the U.S. and the Coordinating 
Investigator will be 
 (Table 6.1).  Prior to initiation of the study, each 
Principal Investigator 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 study and the 1-year period following its 
completion. 
Table 6.1 lists other organizations that are critical to the conduct of the study, with a brief 
description of their roles: 
Table 6.1 
Table of Non-Sponsor Study Responsibilities 
Study Responsibility 
Person/Organization 
Coordinating Investigator  
 
Contract research organization 
(feasibility, project management and monitoring) 
 
 
 
Central safety laboratory 
 
 
 
 
Clinical drug supply and distribution 
 
 
 
 
PPD
PPD
PPD
PPD
PPD

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Protocol:  HZNP-TEP-001
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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 
(dcSSc) 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, 2007].  
The involvement of multiple organs is the distinguishing hallmark of dcSSc and accounts for 
much of the morbidity and mortality associated with the disease [Asano, 2017; Varga, 2007; 
Volkmann, 2019].  Immune perturbations and vascular injury precede and contribute to the 
development of fibrosis, which, in turn, further exacerbates vascular and immune damage 
[Asano, 2015; Bhattacharyya, 2011; Varga, 2007; Volkmann, 2019].  The disease is considered 
incurable and dcSSc carries the highest risk of fatality of the connective tissue diseases, with 
55% survival at 10 years [Mayes, 2003; Varga, 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, 2015; Asano, 2017; Volkmann, 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  
phenomenon, cutaneous telangiectasia, nail fold capillary alterations, pulmonary arterial 
hypertension (PAH), gastric antral vascular ectasia and scleroderma renal crisis with malignant 
hypertension [Varga, 2007].  The disease severity varies among patients and follows a variable 
and unpredictable course and response to treatment [Varga, 2007; Bhattacharyya, 2011; 
Volkmann, 2019].  
SSc has a worldwide distribution and is more frequent in women than men [Mayes, 2003].  
Based on incidence and survival rates, an estimated 75,000 100,000 individuals in the US have 
SSc [Varga, 2007].  
The goal of skin fibrosis treatment is the restoration of abnormally activated dermal fibroblasts 
producing the excessive amount of extracellular matrix [Asano, 2017].  However, the complexity 

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and heterogeneity of the disease pose unique challenges for the development of effective 
therapies. 
7.1.2 Insulin-like Growth Factor-1 Receptor (IGF-1R) 
The insulin-like growth factor-1 receptor (IGF-1R) is a tyrosine kinase cell surface receptor that 
shares approximately 60% overall homology with the insulin receptor [Schumacher, 1991].  
When activated by its ligands, insulin-like growth factor (IGF)-1 and IGF-2, IGF-1R regulates 
important cellular activities involving cell proliferation, differentiation and inflammation 
[Khandwala, 2000; Li, 2018; Ullrich, 1986]. 
Increasing evidence provides support to the role of the IGF-1/IGF-1R pathway in the 
pathogenesis of dcSSc including the presence of elevated levels of IGF-1 and associated binding 
proteins in serum and skin of diseased individuals, ability of IGF-1R stimulation to cause 
fibroblast migration, proliferation and differentiation into myofibroblasts and the requirement for 
IGF-1R signaling for M2 macrophage polarization.  Additionally, preclinical evidence in mice 
supports a role for the IGF-1R receptor in lung fibrosis following injury. 
Key data supporting the involvement of IGF-1R in the dcSSc pathogenesis: 
1. 
IGF-1 protein levels as well as protein levels of one of its binding partners, 
insulin-like growth factor binding protein (IGFBP)-3, are elevated in the serum of 
patients with dcSSc as compared with healthy controls and patients with systemic 
lupus erythematosus or limited cutaneous SSc [Hamaguchi, 2008].  
2. 
Ribonucleic acid levels of IGF-1 and another binding partner, IGFBP-5, have also 
been shown to be elevated in skin fibroblasts derived from SSc patients [Feghali, 
1999; Hamaguchi, 2008].   
3. 
IGF-1 ribonucleic acid and protein levels were found to be elevated in the skin and 
serum of patients with Morphea, a chronic disorder with sclerotic plaques and 
increased fibrosis [Fawzi, 2008].  
4. 
Case reports have noted where treatment with an IGF-1 antagonist, octreotide, 
a patient with carcinoid syndrome [Pavlovic, 1995; Shinohara, 2000]. 
5. 
In vitro studies have demonstrated that IGF-1 stimulated differentiation of fibroblasts 
into myofibroblasts [Hung, 2013].  
6. 
In animal models of acute lung injury, IGF-1R blockade following injury increases 
survival and decreases time for fibrosis resolution, hydroxyproline content and the 
number of myofibroblasts and alpha smooth muscle actin expressing cells, in the 
lungs [Choi, 2009; Hung, 2013].   
7. 
In a model of bleomycin-induced lung injury, mice with conditional IGF-1R deletion 
in lungs showed reduced mortality, reduced alveolar damage and reduced 
erythrocytes, neutrophils, macrophages and lymphocytes in bronchoalveolar lavage 
fluid as well as prevented vascular permeability changes [Pineiro-Hermida, 2017].  
8. 
IGF-1R has also been shown to be important in M2 macrophage polarization.  IGF-1 
is highly expressed in M2 macrophages as compared to M0/M1 macrophages 
[Spadaro, 2017].  IGF-1R has also been shown to influence the macrophage activation 
process as mice with the IGF-1R gene knocked out in cells of the myeloid lineage 

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showed decreased ability to induce the M2 polarization process, reduced transcripts 
associated with an M2 phenotype as well as an increase in responsiveness to interferon 
gamma, a phenotype normally observed in M1 macrophages [Barrett, 2015; 
Spadaro, 2017].  
7.1.3 TEPEZZA  
TEPEZZA (teprotumumab-trbw), a fully human monoclonal antibody (mAb), is an IGF-1R 
inhibitor that received approval from the FDA for the treatment of thyroid eye disease (TED) in 
January 2020.  
In vitro, IGF-1R antagonists have shown the ability to block signaling through multiple signal 
transduction pathways (e.g., extracellular-signal-regulated kinase pathway, mitogen activated 
protein kinase), decrease the expression of cytokines and reduce secretion of disease related 
glycosaminoglycan [Chen, 2014; Pritchard, 2003; Smith, 2004; Tsui, 2008].  TED and dcSSc 
have common disease features including activation of fibroblasts, elevated levels of 
inflammatory cytokines, infiltration of immune cells into disease tissue and excessive synthesis 
of extracellular matrix components [Bahn, 2010; Boschi, 2005; Smith, 2010].  By blocking 
signaling and down-regulating IGF-1R in fibroblasts, myofibroblasts, fibrocytes and cells of the 
immune system, TEPEZZA has the potential to specifically target the key underlying 
pathophysiology of dcSSc, thereby reducing the severity and progression of the disease. 
7.1.3.1 Physiochemical Properties 
The human variable regions of TEPEZZA were derived from a hybridoma obtained from a 
transgenic HCo7 mouse immunized with recombinant human IGF-1R protein.  The antibody is 
made up of 2 heterodimers, each composed of a heavy and light polypeptide chain.  The 
4 peptide chains are linked by disulfide bonds.  The antibody bears a single carbohydrate chain 
in the constant region of both heavy chains.  The manufacture of teprotumumab-trbw drug 
substance consists of fermentation cell culture and purification.  A stable antibody-producing cell 
line was established in the Chinese hamster ovary cell line CHO-DG44.  Current product 
specifications for planned studies are as follows: 
Generic Name/USAN: 
Teprotumumab-trbw 
Company Drug Code: 
HZN-001 
Chemical Abstracts Service 
Number: 
89957-37-9 
Drug Product: 
Each vial delivers 500 mg TEPEZZA formulated with 20 mmol/L Histidine-
Histidine Chloride, 250 mmol/L trehalose and 0.01% polysorbate 20 (w/v) as a 
lyophilized powder packaged in a 20 mL clear, glass vial. 
Chemical Name: 
Immunoglobulin G1 anti-(human insulin-like growth factor 1 receptor) (human 
monoclonal heavy chain), disulfide with human monoclonal light chain, dimer 
Chemical Structure: 
H2L2 polypeptide structure consisting of 2 light chains and 2 heavy chains 
held together by disulfide bonds 
Molecular Weight: 
148 kDA 
Appearance: 
White to off-white powder for reconstitution 
USAN=United States Adopted Name. 
 
 

Horizon Therapeutics U.S.A., Inc. 
 
TEPEZZA (HZN-001) 
Date:  02 February 2022
Protocol:  HZNP-TEP-001
IND 147532 
 
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7.1.3.2 Safety Pharmacology 
In the repeat-dose toxicity studies at dose levels up to 75 mg/kg twice weekly for 7 weeks or 
75 mg/kg once weekly for up to 39 weeks, there were no findings from clinical observations, 
physical examinations (including measurements of vital signs such as heart rate, respiration rate 
and body temperature) or electrocardiogram (ECG) examinations at various intervals that 
suggested potential effects of TEPEZZA in central nervous, respiratory or cardiovascular 
systems.  An overview of the nonclinical safety pharmacology studies is provided in the current 
version of the Investigator s Brochure. 
7.1.3.3 Nonclinical Pharmacokinetics 
Teprotumumab showed low systemic clearances and long terminal half-lives following 
intravenous (IV) administration in both rats and monkeys, consistent with pharmacokinetic (PK) 
characteristics of mAbs.  No gender differences were apparent for any dose level tested in either 
species.  Metabolism of antibodies is generally known, i.e., degradation to smaller peptides and 
amino acids (Ryman, 2017); as a result, TEPEZZA is not expected to be involved in classical 
drug-drug interactions.  An overview of the nonclinical PK studies is provided in the current 
version of the Investigator s Brochure. 
7.1.3.4 Clinical Experience 
7.1.3.4.1 Efficacy 
To date, TEPEZZA has been studied in 2 independent, randomized, double-blind, 
placebo-controlled, parallel-group, multicenter studies that evaluated the efficacy and safety of 
TEPEZZA (Phase 2 Study TED01RV and Phase 3 Study HZNP-TEP-301) for the treatment of 
TED and an open-label extension of Study HZNP-TEP-301 (Study HZNP-TEP-302).  TEPEZZA 
received approval from the FDA for the treatment of TED in January 2020. 
The effectiveness of TEPEZZA in the treatment of TED has been demonstrated in randomized, 
double-blind, placebo-controlled Studies TED01RV and HZNP-TEP-301.  Subjects who met 
eligibility criteria were randomized in a 1:1 ratio (stratified by tobacco use status) to receive 
8 infusions of TEPEZZA (10 mg/kg for the first infusion and 20 mg/kg for the remaining 
7 infusions) or placebo administered once every 3 weeks (q3W).  TEPEZZA resulted in 
statistically significant and clinically relevant improvements in measures that assessed multiple 
facets of TED (proptosis, inflammation as measured by Clinical Activity Score, diplopia and 
quality of life [QOL]).  Consistent results were shown across all efficacy endpoints and all 
subpopulations. 
Data from the off-treatment Follow-up Period in Study HZNP-TEP-301 showed that the 
response to treatment achieved for the primary and secondary responder endpoints at the end of 
the Double-Masked Treatment Period was also observed for the majority of the teprotumumab 
subjects at the end of the 48-week off-treatment Follow-up Period. 
Results of Study HZNP-TEP-302 demonstrated efficacy of teprotumumab in subjects who had 
TED for a longer period of time than in the original Phase 2 and Phase 3 trials.  The majority of 

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eligible subjects for this open-label extension trial were randomized to placebo in 
Study HZNP-TEP-301 and were also non-responders in Study HZNP-TEP-301.  The duration of 
TED before the first dose of teprotumumab in these subjects in Study HZNP-TEP-302 was an 
average of 6 months longer than in Study HZNP-TEP-301 (12 vs. 6 months); however, similar 
efficacy was observed in those who transitioned from placebo in Study HZNP-TEP-301 to 
teprotumumab in Study HZNP-TEP-302, indicating that teprotumumab is as efficacious in 
subjects with longer TED duration.  In addition, results indicate that, although sample sizes were 
small, additional treatment with teprotumumab has potential to benefit patients who were 
previous proptosis non responders after 6 months of initial treatment or who relapsed in off-
treatment follow up.  There were no new safety signals identified in subjects in this trial, 
including those subjects who received additional treatment with teprotumumab. 
TEPEZZA has not been studied in the dcSSc population. 
7.1.3.4.2 Pharmacokinetics 
Characteristics 
The PK of teprotumumab (IV infusion) was derived from a Phase 1 study in oncology subjects 
(Study BO19373) and Phase 2 and 3 studies in subjects with TED (TED01RV and 
HZNP-TEP-301), using both non-compartmental and population PK analyses. 
The PK of teprotumumab was characterized in 96 oncology subjects and 83 TED subjects at 
doses of 1 to 20 mg/kg.  Overall, the PK characteristics of teprotumumab were consistent with 
other immunoglobulin G1 mAbs, with low systemic clearance (0.334 L/day), low volume of 
distribution (3.94 L for central compartment and 4.21 L for peripheral compartment) and long 
elimination half-life (geometric mean of 19.9 days in TED subjects) [Dirks, 2010; Ryman, 
2017].  Target-mediated drug disposition was saturated at higher doses of TEPEZZA 
 mg/kg) 
and teprotumumab PK were linear at the clinical dose range (10 to 20 mg/kg) in TED subjects. 
Population PK analysis indicated that weight, age, sex and race had no effect on teprotumumab 
exposures.  Female subjects had a 14.5% higher maximum serum concentration (Cmax), but 
similar area under the concentration-time curve (AUC) compared to male subjects, which is not 
considered clinically relevant.  Covariates including smoking status, mild or moderate renal 
impairment and hepatic function (total bilirubin, aspartate aminotransferase and alanine 
aminotransferase) did not have any impact on teprotumumab PK.  
Drug-drug interactions between TEPEZZA and thyroid medications (e.g., levothyroxine, 
propylthiouracil) commonly used by TED subjects are not expected, as TEPEZZA and small 
molecule drugs do not share common or overlapping clearance pathways [Zhou, 2011]. 
Immunogenicity of TEPEZZA was assessed in serum samples in Studies TED01RV and 
HZNP-TEP-301.  There was no clinically relevant immunogenic response observed after 
administration of TEPEZZA.  No subjects treated with teprotumumab in Study HZNP-TEP-302 
were positive for anti-drug antibodies. 

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7.1.3.4.3 Pharmacodynamics 
Total serum IGF-1 levels were increased after TEPEZZA treatment at all dose regimens tested in 
oncology subjects (1 to 16 mg/kg q3W and 1 to 9 mg/kg once weekly), suggesting that 
TEPEZZA blocked the binding of IGF-1 to its receptor IGF-1R at the clinical doses evaluated. 
7.1.3.4.4 Safety 
7.1.3.4.4.1 Thyroid Eye Disease Studies 
TEPEZZA was generally well tolerated at the dose investigated (10 mg/kg for the first dose 
followed by an IV infusion of 20 mg/kg q3W for a total of 8 doses) in the TED population, with 
more than 90% of subjects completing the 24-Week Double-blind Treatment Period.  Among the 
121 subjects exposed to TEPEZZA across Studies TED01RV, HZNP-TEP-301 and HZNP-TEP-
302, no deaths occurred and few subjects experienced treatment-emergent adverse events 
(TEAEs) that were serious (8/121 subjects, 6.6%), severe or higher in intensity (4/121 subjects, 
3.3%) or led to discontinuation of study drug (6/121 subjects, 5.0%).   
The most commonly reported TEAEs among subjects treated with TEPEZZA in the 
Double-blind 
Muscle spasms 
(26.2%), Nausea (16.7%), Alopecia (15.5%), Diarrhoea (13.1%), Dry skin (9.5%), Fatigue 
(9.5%), Dysgeusia (8.3%), Headache (8.3%), Hyperglycaemia (7.1%) and Weight decreased 
(6.0%).  Each of these commonly reported TEAEs in the Double-blind Treatment Period were 
nonserious, mild or moderate in intensity and did not result in discontinuation from study drug, 
with the exception of 1 event of Diarrhoea (likely exacerbation of pre-existing inflammatory 
bowel disease (IBD), which was serious, severe and led to discontinuation of study drug) and 1 
event of Headache (severe).  Among the events of Diarrhoea reported, no events of new-onset 
IBD have been observed.  TEAEs associated with hyperglycemia (Hyperglycaemia or Blood 
glucose increased) were more likely to occur in subjects with pre-existing diabetes mellitus or 
impaired glucose tolerance; the events were managed with medications for glycemic control as 
needed.   
TEAEs associated with hearing impairment (reported as Deafness, Hypoacusis, Eustachian tube 
dysfunction, Hyperacusis, Autophony or Eustachian tube patulous) were observed in 
teprotumumab-treated subjects (9.5%) in the Double-Masked Population compared to no reports 
among placebo-treated subjects.  All of these events were nonserious, mild or moderate in 
intensity, and none led to premature discontinuation of study drug; these events usually improved 
or resolved.  
Infusion reactions were observed in 3 TEPEZZA-treated subjects in the TED clinical program; 
these events were managed with symptomatic treatment and all events resolved without 
complication.   
No clinically significant changes in laboratory values, vital signs or ECGs were observed in 
subjects treated with TEPEZZA in the Double-blind Treatment Period.  Over the 24-Week 
Double-blind Treatment Period, a greater proportion of TEPEZZA subjects (18.4%) had a 

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 decrease in weight compared with placebo subjects (2.5%).  In addition, no significant 
anti-teprotumumab-trbw antibodies were detected up to 48 weeks after the final administration of 
TEPEZZA. 
Data from the off-treatment Follow-up Period in Study HZNP-TEP-301 showed no significant 
change in the safety profile of teprotumumab through approximately 1 year off treatment, which 
was also demonstrated in the same off-treatment Follow-up period in Study TED01RV.   
The safety profile observed in Study HZNP-TEP-302 was consistent with the results of previous 
Phase 2 and 3 studies of teprotumumab in TED.  Teprotumumab was well tolerated and 
demonstrated an acceptable safety profile in the TED population in Study HZNP-TEP-302, 
including subjects who were retreated with teprotumumab after receiving teprotumumab in 
Study HZNP-TEP-301. 
7.1.3.4.4.2 Oncology Studies 
TEPEZZA was originally developed by F. Hoffman-La Roche Ltd. for the treatment of patients 
with advanced solid tumors, including sarcoma.  Development for this indication was 
discontinued based on insufficient clinical efficacy and was not based on any observed safety 
issues.  
In the oncology program, over 700 subjects were treated with TEPEZZA at dose levels ranging 
from 1 to 27 mg/kg q3W to 1 to 9 mg/kg once weekly.  Taking into consideration progression of 
disease and prior/concomitant treatment with cytotoxic agents, TEPEZZA was generally 
well-tolerated with a safety profile similar to that seen in the TED population.  Safety data from 
the oncology program are presented in the current version of the Investigator s Brochure. 
7.1.3.4.4.3 Diabetic Macular Edema Studies 
In a study conducted in 5 subjects with diabetic macular edema who were treated with 
TEPEZZA (Study DME01RV), the most frequent TEAEs included events associated with 
hyperglycemia (4 subjects; Blood sugar increased, Blood glucose increased and 
Hyperglycaemia) and Dizziness (2 subjects).  No subjects experienced serious TEAEs.  Two 
subjects withdrew early from the study prior to the last infusion due to hyperglycemia.  No 
additional studies of TEPEZZA have been conducted or planned in subjects with diabetic 
macular edema. 
7.1.3.4.4.4 Adverse Events of Special Interest 
Following a comprehensive review of the safety data from the TEPEZZA studies conducted in 
TED, the following adverse events of special interest (AESI) have been identified for the current 
study: 
 Hyperglycemia  
 Hearing impairment 
 Infusion-associated events, including anaphylactic reaction 
 New onset or exacerbation of IBD 

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An overview of the AESIs, including general precautions, is presented in the following 
paragraphs. 
Hyperglycemia 
In nonclinical studies, there was no in vitro cross-reactivity of TEPEZZA with the insulin 
receptor.  TEPEZZA clinical studies in TED have shown a higher incidence of hyperglycemia in 
subjects treated with TEPEZZA compared to placebo.  Subjects with pre-existing diabetes 
mellitus (who were under appropriate glycemic control upon study entry) or impaired glucose 
tolerance were more likely to experience an event of hyperglycemia after exposure to TEPEZZA. 
Subjects with known controlled diabetes mellitus are allowed to participate in studies with 
TEPEZZA.  Glycated hemoglobin (HbA1c) levels should be monitored regularly in these 
subjects.  Investigator
the individual, balancing complications due to diabetes and hyperglycemia.  A reasonable goal is 
American Diabetes Association, 2019a].  However, it is also acceptable to 
set a higher goal of 8% in older individuals [Huang, 2008].   
Hearing Impairment 
Adverse reactions of middle to high range sensorineural hearing loss have been reported in both 
healthy volunteers and subjects with malignancies who received as little as 1 dose of various 
IGF-1R mAbs.   
In the TEPEZZA TED clinical program as of the data cutoff of 19 June 2020, 14 (11.6%) of the 
121 subjects exposed to TEPEZZA have experienced events associated with hearing impairment, 
with no reports of hearing impairment in subjects who received placebo.  Each of these events 
were nonserious, mild or moderate in intensity and none led to premature discontinuation of 
study drug; these events usually improved or resolved.  If possible, subjects should avoid 
ototoxic drugs while receiving teprotumumab. 
Infusion-related and Anaphylactic Reactions 
A total of 3 subjects were identified by the Sponsor adjudication process as having experienced 
infusion-related reactions during treatment with TEPEZZA for TED.  The associated symptoms 
included transient increases in blood pressure, feeling hot, tachycardia, headache, dyspnea and 
muscular pain.  The reactions occurred during or within 1.5 hours after the first or second 
infusion in 2 of the subjects and during the fifth infusion in the remaining subject.  The reactions 
were considered mild or moderate in intensity and were treated with a glucocorticoid and/or 
antihistamine.  Each of the reactions resolved without sequelae.  Among the 3 subjects, 2 were 
discontinued from treatment and 1 was pre-medicated prior to study drug infusions with 
diphenhydramine, dexamethasone, famotidine and acetaminophen and completed all subsequent 
infusions at a slower infusion rate without reoccurrence of infusion reaction. 
Treatment with mAbs may cause infusion-associated symptoms such as fever, chills, 
hypotension, shortness of breath, skin rash and headache.  Such reactions typically occur during 

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or shortly after the infusion of mAbs and are usually associated with the first infusion.  Their 
incidence and severity typically decrease with subsequent infusion.  Severe infusion-associated 
reactions might be clinically indistinguishable from anaphylactic reactions.  
New Onset or Exacerbation of Inflammatory Bowel Disease 
Exacerbation and suspected exacerbation of underlying IBD occurred in 2 subjects in the TED 
Phase 2 study.  Subjects with IBD were excluded from Study HZNP-TEP-301 (Phase 3) and will 
be excluded from this study.  No events suggestive of new onset IBD were observed in the TED 
Phase 3 studies. 
7.2 
Rationale for this Study 
dcSSc is a rare and devastating autoimmune disease characterized by skin fibrosis, beginning on 
the fingers and face, that rapidly becomes generalized with internal organ manifestations of 
fibrosis.  The disease carries a high morbidity and mortality rate; patients with dcSSc have a 
10-year survival rate of 55% [Mayes, 2003; Varga, 2007].  Death is most often caused by lung, 
heart and kidney involvement [Hao, 2017; Pokeerbux, 2019; Tyndall, 2010].  
Currently, there is no effective treatment or cure for dcSSc.  Treatment depends on the symptoms 
that are present and the organs that are affected and may include medication and surgery.  To 
date, all available therapeutic options (e.g., steroids, methotrexate, cyclophosphamide, 
azathioprine and mycophenolate mofetil) have demonstrated only limited efficacy and/or have 
safety issues that impact their use.  Thus, there is a substantial unmet clinical need for a safe and 
effective treatment for dcSSc. 
By blocking signaling and downregulating IGF-1R in fibroblasts, myofibroblasts, fibrocytes and 
cells of the immune system, TEPEZZA has the potential to specifically target the key underlying 
pathophysiology of dcSSc, thereby reducing the severity and progression of the disease.  The 
current study was designed to evaluate the safety, tolerability and effect of TEPEZZA on IGF-1, 
inflammatory and fibrotic biomarkers in subjects with dcSSc.  
7.3 
Rationale for Dose Selection 
The selected dose regimen for dcSSc subjects is the same as that studied in TED subjects (i.e., an 
initial single dose of 10 mg/kg followed by 20 mg/kg q3W).  In the Phase 2 and Phase 3 TED 
studies, this selected regimen was highly effective, generally well tolerated and provided 
TEPEZZA concentrations maintaining >90% saturation of IGF-1R throughout the dosing 
interval in all subjects.  Given the apparent similarity of mechanical- and immune-mediated 
drivers of disease in dcSSc to those in TED, maintaining >90% saturation of IGF-1R throughout 
the dosing interval would be an appropriate strategy in dcSSc as well. 
8 
STUDY OBJECTIVES 
The overall objective of this study is to evaluate the safety, tolerability and effect on IGF-1, 
inflammatory and fibrotic biomarkers of TEPEZZA (teprotumumab-trbw; HZN-001), a fully 

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8.3 
Pharmacokinetic and Anti-drug Antibody Objectives 
1. Evaluate the PK of teprotumumab. 
2. Evaluate the immunogenicity of TEPEZZA. 
8.4 
Safety and Tolerability Objectives 
To assess safety and tolerability of TEPEZZA based on treatment-emergent adverse events 
(TEAEs), AESIs (hyperglycemia, hearing impairment, infusion reaction, new onset or 
exacerbation of IBD), concomitant medication use, vital signs, clinical safety laboratory 
evaluations and inflammatory laboratory evaluations. 

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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This study will be conducted at up to 12 sites in the United States. 
This is a randomized, double-blind, placebo-controlled, repeat-dose, multicenter study.  Subjects 
will be screened for the study within 4 weeks prior to the Baseline (Day 1) Visit.  Approximately 
25 subjects who meet the study eligibility criteria will be randomized on Day 1 in a 3:2 ratio to 
receive 8 infusions of TEPEZZA (10 mg/kg for the first infusion and 20 mg/kg for the remaining 
7 infusions) or placebo q3W.  During the 24-week double-blind Treatment Period, study drug 
will be infused on Day 1 (Baseline) and Weeks 3, 6, 9, 12, 15, 18 and 21 with a comprehensive 
visit at Week 24 (end of treatment).  All study drug dosing will be performed at the clinic or 
infusion center under the supervision of clinic staff or nurses.  At any scheduled infusion, the 
infusion rate may be reduced or the dose may be interrupted or held based on tolerability (see 
Section 9.4.6.3.2 for details).  On each dosing day, scheduled assessments (except for adverse 
event [AE] and concomitant medication use monitoring, which will be monitored throughout the 
clinic visit) will be completed prior to study drug infusions.  After each of the first 2 infusions, 
subjects will be contacted by phone/email the following day.  Additional phone/email contacts 
and clinic visits may also be conducted for any subject experiencing an infusion-associated 
event. 
At the end of the Treatment Period (Week 24), subjects will enter a 24-week Follow-up Period, 
during which study drug will not be administered and a clinic visit will be scheduled for 
Weeks 28, 36 and 48.  A phone call or email at Weeks 32 and 42 will occur to inquire how the 
subject is doing and women of childbearing potential will be asked if they have missed a 
menstrual cycle and will have a serum pregnancy test, if required. 
If a subject prematurely discontinues prior to completing the Treatment Period, he/she will return 
to the clinic and undergo the Week 24 assessments; such subjects will also be encouraged to 
continue in the 24-week Follow-up Period.  If a subject prematurely discontinues prior to 
completing the 24-week Follow-up Period, he/she will return to the clinic and undergo the 
Week 48 assessments. 
An overview of the study design is presented in Figure 9.1 and details of study activities are 
provided in Section 2.1, Schedule of Assessments. 

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Figure 9.1 
Schematic of Study Design 
Screening 
Baseline 
Double-blind Treatment Period 
TEPEZZA or Placebo 1 
24 Weeks 2 
Follow-up Period 
24 Weeks 3 
< 
 Clinic Visits 
 > 
< 
 Clinic or Phone/Email Visits 
 > 
 
* 
* 
* 
* 
* 
* 
* 
* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
4 weeks 
predose 
Day 1 4 
W3 4 
W6 
W9 
W12 
M3 
W15 
W18 
 
W21 
W24 5
M6 
W28 
M7 
W32 6
M8 
W36 
M9 
W42 6 
 
W48 7 
M12 
 
Randomization 1 
< 
 Study Week/Month 
 > 
 
 
 
* Infusion of study drug 
AE=adverse event; M=Month; q3W=every 3 weeks; W=Week 
1. 
Subjects will be randomized in a 3:2 ratio (15 TEPEZZA and 10 placebo) to receive: 
a. TEPEZZA (10 mg/kg on Day 1 followed by 20 mg/kg q3W for the remaining 7 infusions); or 
b. Placebo (placebo q3W for all 8 infusions). 
2. 
Visit windows are ±3 days for Weeks 3 to 21, inclusive. 
3. 
Visit windows are ±7 days for Weeks 24 to 48, inclusive. 
4. 
All subjects will be contacted by phone/email the day following the first (Day 1) and second (Week 3) infusions for safety and tolerability 
assessments; additional phone/email contacts will occur the day after any clinic visit where a subject experiences an infusion-related AE. 
5. 
If a subject prematurely discontinues prior to completing the 24-week Treatment Period, he/she will return to the clinic and undergo the Week 24 
assessments.  Subjects will be encouraged to continue in the 24-week Follow-up Period. 
6. 
All subjects will be contacted via phone or email at Weeks 32 and 42 to inquire how subjects are doing and to ask women of childbearing potential 
about their menstrual cycle. 
7. 
If a subject prematurely discontinues prior to completing the 24-week Follow-up Period, he/she will return to the clinic and undergo the Week 48 
assessments. 
 
9.2 
Discussion of Study Design 
This study is a randomized, double-blind, placebo-controlled, repeat-dose, multicenter study in 
the dcSSc population designed according to standard principles.  The measurements used in this 
study to assess safety and efficacy are established and well-defined. 
Because patients with dcSSc have a potential risk of weight loss and malnutrition as 
manifestations of their disease [Hughes, 2020; Richard, 2019; Baron, 2009; Wojteczek, 2020; 
Gyger, 2015], weight will be measured frequently in this study.  Dosing will be based on the 
weight at Week 9 for dosing at Weeks 12, 15, 18 and 21. 
Given the teratogenic effects of TEPEZZA noted in a monkey embryo-fetal development toxicity 
study and the PK profile of teprotumumab (see Section 7.1.3.4.2), female subjects are required to 
use adequate contraception and report any pregnancies for at least 6 months after the last dose of 
study drug.  Six months after the last dose, the estimated plasma concentration (0.2 g/mL) is 
considered reasonably safe with a low risk of teratogenicity.  Furthermore, a 6-month waiting 
period is in line with recommendations given for other teratogens, such as cytostatic 
chemotherapy. 

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9.3 
Selection of Study Population 
9.3.1 Inclusion Criteria 
Eligible subjects must meet/provide all of the following criteria: 
1. Written informed consent. 
2. Male or female between the ages of 18 and 80 years, inclusive, at Screening. 
3. Meets the 2013 American College of Rheumatology/European League Against 
 [Van den Hoogen, 
2013].   
4. Classified as having skin involvement proximal to elbow, knee, face and neck, dcSSc 
subset [LeRoy and Medsger, 2001]. 
5. At the time of enrollment, no more than 60 months must have elapsed since the onset of 
the first dcSSc manifestations, other 
. 
6. Skin thickening from dcSSc in the forearm suitable for repeat biopsy. 
7. mRSS units 10 and 45 at Screening.  
8. Subjects will be allowed to take CellCept® (mycophenolate mofetil) up to 3 g/day or 
Myfortic® (mycophenolic acid) up to 2.14 g/day and low-
or equivalent dosing of glucocorticoids).  Subjects taking CellCept or Myfortic have been 
 
Day 1 V
Visit. 
9. 
diabetic medication (oral or 
insulin) or more than a 10% change in the dose of a currently prescribed diabetic 
medication within 60 days prior to Screening.  
10. Women of childbearing potential (including those with an onset of menopause <2 years 
prior to Screening, nontherapy-induced amenorrhea for <12 months prior to Screening or 
not surgically sterile [absence of ovaries and/or uterus]) must have a negative serum 
pregnancy test at Screening and negative urine pregnancy tests at all protocol-specified 
timepoints (i.e., prior to each dose and throughout the 
 the 
Follow-up Period); subjects who are sexually active with a non-vasectomized male 
partner must agree to use 2 reliable forms of contraception during the trial, one of which 
is recommended to be hormonal, such as an oral contraceptive.  Hormonal contraception 
must be started at least 1 full cycle prior to Baseline and continue for 180 days after the 
last dose of study drug.  Highly effective contraceptive methods (with a failure rate 
<1% per year), when used consistently and correctly, include implants, injectables, 
combined oral contraceptives, some intrauterine devices, sexual abstinence or 
vasectomized partner.  

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11. Willing and able to comply with the prescribed treatment protocol and evaluations for the 
duration of the study. 
9.3.2 Exclusion Criteria 
Subjects will be ineligible for study participation if they meet any of the following criteria: 
1. Diagnosed with limited cutaneous SSc or sine scleroderma. 
2. Diagnosed with other autoimmune connective tissue diseases except for fibromyalgia, 
scleroderma-associated myopathy and 
 
3. Scleroderma renal crisis diagnosed within 6 months of the Screening Visit, characterized 
by abrupt onset of hypertension and acute kidney injury (see Section 9.5.1.1). 
4. FVC <50% predicted, diffusing capacity of the lungs for carbon monoxide (DLCO) 
<40% predicted or PAH by right heart catheterization requiring treatment with more than 
one oral PAH-approved therapy or parenteral therapy (intermittent use of 
phosphodiesterase-5 inhibitors are allowed for erectile dysfunction and/
phenomenon/digital ulcers).  
5. Corticosteroid use for conditions other than dcSSc within 4 weeks prior to Screening 
(topical steroids for dermatological conditions and inhaled steroids are allowed). 
6. Previous treatment with rituximab (Rituxan® or MabThera®) within 12 months prior to 
the first infusion. 
7. Use of a non-steroidal immunosuppressive agent, cytotoxic or anti-fibrotic drug within 
4 weeks of Screening, including cyclophosphamide, azathioprine (Imuran®), 
methotrexate or other immunosuppressive or cytotoxic medication.  Exceptions are 
mycophenolate mofetil (CellCept) and mycophenolic acid (Myfortic), which are 
permitted according to inclusion criterion 8, and anti-malarials (e.g., hydroxychloroquine 
[Plaquenil®]). 
8. Use of biologics or small molecules approved for rheumatoid arthritis, psoriatic arthritis 
and other rheumatic diseases within 4 weeks prior to Screening. 
9. Use of an investigational agent for any condition within 90 days or 5 half-lives, 
whichever is longer, prior to Screening or anticipated use during the course of the trial. 
10. Malignant condition in the past 5 years (except successfully treated basal/squamous cell 
carcinoma of the skin or cervical cancer in situ). 
11. Pregnant or lactating women. 
12. Current drug or alcohol abuse or history of either within the previous 2 years, in the 
opinion of the Investigator or as reported by the subject. 
13. Biopsy-proven or clinically suspected IBD (e.g., diarrhea with or without blood or rectal 
bleeding associated with abdominal pain or cramping/colic, urgency, tenesmus or 
incontinence for more than 4 weeks without a confirmed alternative diagnosis OR 

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endoscopic or radiologic evidence of enteritis/colitis without a confirmed alternative 
diagnosis). 
14. Known hypersensitivity to any of the components of TEPEZZA or prior hypersensitivity 
reactions to mAbs. 
15. Previous enrollment in this study or participation in a prior teprotumumab-trbw clinical 
trial. 
16. Human immunodeficiency virus, untreated or positive viral load for hepatitis C or 
hepatitis B infections. 
17. Previous organ transplant (including allogeneic and autologous marrow transplant). 
18. Alanine aminotransferase or aspartate aminotransferase >2.5 times the upper limit of 
normal or estimated glomerular filtration rate of <30 mL/min/1.73m2 at Screening. 
19. Platelets <100×103/µL. 
20. Hemoglobin <8 g/dL.  
21. Any other condition that, in the opinion of the Investigator, would preclude inclusion in 
the study. 
9.3.3 Removal of Subjects from Treatment or the Study 
All subjects are free to withdraw from study participation at any time, for any reason and without 
prejudice to their further medical care.  Subjects who prematurely discontinue study drug during 
the Treatment Period will be encouraged to continue study participation, particularly returning 
for the Week 24 (end of treatment) assessments, and continue in the 24-week Follow-up Period.  
 Subjects who discontinue study drug due to an AE should be followed until resolution or 
stabilization of the AE, or an adequate explanation for the event is obtained. 
If further participation in the study is not in the best interest of the subject, the Investigator may 
terminate a subject from treatment or from the study. 
9.3.3.1 Removal of Subjects from Treatment 
The primary reason for discontinuation from study drug should be recorded on the eCRF using 
one of the following categories: 
 Adverse event.  The subject experiences an AE that imposes an unacceptable risk to the 
 or the subject is unwilling to continue receiving treatment because of an 
AE.  Subjects who discontinue study drug due to an AE will remain in the study unless 
they withdraw from the study for another reason.  AEs requiring permanent study drug 
discontinuation per the protocol include: 
o A drug-related anaphylactic reaction. 
o Severe drug-related hyperglycemia (e.g., blood glucose >250 mg/dL) that does 
not abate to mild or moderate intensity with anti-diabetic treatment (dose may be 
skipped up to 2 times prior to permanently discontinuing study drug; see 
Section 9.4.6.3.2 for details). 

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o Diagnosed or suspected IBD (e.g., diarrhea with or without blood or rectal 
bleeding associated with abdominal pain or cramping/colic, urgency, tenesmus or 
incontinence for more than 4 weeks without a confirmed alternative diagnosis OR 
endoscopic or radiologic evidence of enteritis/colitis without a confirmed 
alternative diagnosis). 
 Lack of efficacy.  Discontinuation of study drug due to lack of efficacy is at the 
discretion of the Investigator or subject and may occur if the Investigator determines that 
study drug administration is not benefitting the subject.  Subjects who discontinue study 
drug due to lack of efficacy will remain in the study unless they withdraw from the study 
for another reason. 
 Withdrawal by subject/guardian.  The subject wishes to withdraw from study treatment.  
The clinical site should attempt to determine the underlying reason for the voluntary 
withdrawal and document it on the eCRF. 
 Study terminated by Sponsor.  The Sponsor, IRB/IEC or regulatory agency terminates the 
study. 
 Pregnancy. 
 Death. 
 Completed.  The subject completed treatment. 
9.3.3.2 Removal of Subjects from the Study 
The primary reason for discontinuation from the study should be recorded on the eCRF using 
one of the following categories: 
 Lost to follow-up.  The subject does not return to the clinic for scheduled assessments 
and does n
 
 Withdrawal by subject/guardian.  The subject wishes to withdraw from the study.  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 study. 
If a subject prematurely discontinues from the study during the Follow-up Period, he/she will 
return for a clinic visit and undergo the Week 48 (end of study) assessments.   
9.3.4 Replacement Policy 
9.3.4.1 Subjects 
In general, no subject prematurely discontinued from the study for any reason will be replaced.  
An exception may be made for subjects who are unevaluable due to the impact of an event, for 
example, a pandemic or a natural disaster, and associated restrictions on movement and work. 

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Subjects unable to receive treatment or be evaluated due to restrictions during the event may be 
replaced, at the discretion of the Sponsor.  This may result in more subjects being enrolled into 
the study to allow for the planned number to be evaluable for the efficacy and safety analyses. 
9.3.4.2 Centers 
A center may be closed and/or replaced for the following administrative reasons:   
 Excessively slow recruitment. 
 Poor protocol adherence. 
9.3.4.3 Screen Failures 
Subjects who do not meet all of the inclusion criteria or meet any of the exclusion criteria will be 
considered screen failures.  Screen failures may be allowed to rescreen for the study if both the 
Investigator and Sponsor are in agreement regarding rescreening and if the Investigator 
determines that the subject can satisfy all of the eligibility criteria.   
9.4 
Treatments 
9.4.1 Treatments Administered 
All study drug dosing will be performed at the clinic or infusion center under the supervision of 
clinic staff or nurses.  On Day 1 of the double-blind Treatment Period, subjects will be 
randomized in a 3:2 ratio to receive infusions of either: 
1. 
TEPEZZA (10 mg/kg on Day 1 followed by 20 mg/kg q3W for the remaining 
7 infusions), or  
2. 
Placebo (q3W for all 8 infusions). 
The infusion rate may be reduced and the dose may be interrupted or held based on tolerability.  
The first and second infusions will be administered over approximately 90 minutes (but not less 
than 80 minutes).  Subsequent infusions will be administered over approximately 60 minutes (but 
not less than 50 minutes), providing there are no significant infusion-associated events. 
9.4.2 Identity of Investigational Products 
9.4.2.1 TEPEZZA  
TEPEZZA (teprotumumab-trbw; HZN-001) is a fully human anti-IGF-1R mAb.  The 
physiochemical properties were previously presented in Section 7.1.3.1.  TEPEZZA will be 
provided in single-dose, 20-mL glass vials as a freeze-dried powder containing, in addition to the 
drug substance, 20 mmol/L histidine-histidine chloride, 250 mmol/L trehalose and 
0.01% polysorbate 20 (w/v).  
Prior to administration, each vial containing 500 mg TEPEZZA freeze-dried powder will be 
reconstituted with 10 mL of sterile water for injection.  The resulting solution will have a 
concentration of 47.6 mg/mL TEPEZZA.  Reconstituted TEPEZZA solution will be further 

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diluted in 0.9% (w/v) sodium chloride (NaCl) solution prior to administration (see 
Section 9.4.6.3 for details). 
9.4.2.2 Placebo 
Placebo will consist of a normal saline (0.9% NaCl) solution and will be administered in 100 mL 
or 250 mL infusion bags, as appropriate, per weight-based dosing volumes. 
9.4.3 Labeling 
Study drug packaging will be in compliance with Sponsor/CRO standard procedures and will 
meet all local requirements.   
Upon arrival of investigational products at the site, the investigational unblinded pharmacist (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 
Recommended storage conditions for the freeze-dried TEPEZZA drug product are between 2°C 
and 8°C (36°F to 46°F), protected from light.  
The storage instructions for reconstituted TEPEZZA solution in the vial and the diluted solution 
in the infusion bag containing 0.9% Sodium Chloride Injection, United States Pharmacopeia 
(USP) 
.  An Investigational 
Pharmacy Manual will be provided to all sites to further describe these processes in detail. 
At the clinic, all TEPEZZA must be stored in a secure area with limited access, and a daily 
temperature log of the drug storage area will be maintained every working day; deviations from 
the specified temperature range will be reported as protocol deviations. 
9.4.5 Drug Accountability 
The Principal Investigator at each site is responsible for the control of all study drug and 
delegating infusion bag preparation and drug accountability responsibilities to an unblinded 
pharmacist (or designee in accordance with institutional policies and local regulations), who 
must maintain adequate records of the receipt and disposition of all study medication shipped to 
the study center.  Records will include receipt dates, condition at time of receipt, quantities 
received, quantities dispensed, quantities returned or destroyed and the identification numbers of 
the subjects who received study medication. 
As permitted by site policy, all empty, partially empty and full vials of study drug must be 
retained by the study center under locked storage until drug accountability has been completed.  
Periodically throughout the study and at the conclusion of the study, inventory checks and 
accountability of study materials will be conducted by an unblinded representative of the 
Sponsor.  
return of study medication (used, partially used and unused vials that were retained by the study 

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center as permitted by site policy) to the 3rd party vendor (see Table 6.1).  The completed Drug 
Accountability and Drug Return/Destruction Record(s) will be returned to the unblinded CRO 
manager.  The Investigator
Record(s) must document accurately the return and/or onsite destruction of all study drug 
supplies and be maintained by the unblinded pharmacist or designee until the study is complete 
and the database is locked.  Records will also include disposition dates and quantities destroyed 
onsite or returned to the designated facility. 
9.4.6 Study Drug Administration and Timing of Dose for Each Subject 
9.4.6.1 Description of Clinical Supplies 
The clinical supply vendor will supply study drug to clinical sites.  Ancillary supplies for dosing 
will be provided by the study site (i.e., infusion bags containing normal saline, infusion 
administration sets, syringes, needles, alcohol swabs, gauze pads, bandages and biohazard 
containers for safe storage of used needles and syringes). 
9.4.6.2 Determination of Dose Volume  
The volume of study drug to be administered will be determined by the electronic data capture 
(EDC) system and 
weight.  The first dose will be 10 mg/kg, 
followed by 20 mg/kg q3W for the remaining 7 infusions.  Weight will be measured at Screening 
and on each clinic visit during the double-blind Treatment Period.  Dosing on Day 1 and at 
Weeks 3, 6 and 9 during the double-blind Treatment Period will be based on the weight 
measured on Day 1.  Dosing at Weeks 12, 15, 18 and 21 during the double-blind Treatment 
Period will be based on the weight measured at Week 9. 
9.4.6.3 Details Concerning Timing and Dose Administration 
9.4.6.3.1 Preparation and Administration of TEPEZZA 
TEPEZZA will be prepared by the site pharmacist (or designee in accordance with institutional 
policies and local regulations), who is not blinded to the identity of the study medication.  Each 
vial of TEPEZZA will be reconstituted with 10 mL of sterile water for injection.  The resulting 
solution will have a concentration of 47.6 mg/mL teprotumumab-trbw antibody.  Reconstituted 
TEPEZZA solution will be further diluted in 0.9% (w/v) NaCl solution prior to administration by 
the site pharmacist or designee. 
Doses up to 1800 mg will be administered in a total infusion volume of 100 mL and those above 
1800 mg will be administered in a total infusion volume of 250 mL.  To maintain a constant 
volume in the infusion bags, a volume equal to the volume of TEPEZZA to be placed into the 
infusion bag will first be removed from the infusion bag using a sterile syringe and needle.  The 
appropriate volume of reconstituted drug product solution based on the subject`s dose and body 
weight will be withdrawn and the TEPEZZA drug product solution will be diluted with normal 
saline (0.9% NaCl) in the infusion bag.  Dosing on Day 1 and at Weeks 3, 6 and 9 during the 
double-blind Treatment Period will be based on the weight measured on Day 1.  Dosing at 

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Weeks 12, 15, 18 and 21 during the double-blind Treatment Period will be based on the weight 
measured at Week 9. 
The infusion is to be administered at room temperature (20°C to 25°C [68°F to 77°F]).   
The storage time of reconstituted TEPEZZA solution in the vial and the diluted solution in the 
infusion bag are outlined in the most recent version of the 
 and in the 
Investigational Pharmacy Manual provided to the site.  If refrigerated prior to administration, 
allow the diluted solution to reach room temperature prior to infusion. 
No incompatibilities between TEPEZZA and polyethylene, polyvinyl chloride, polyurethane or 
polyolefin bags and IV administration sets have been observed.  Exposure of the solution to 
direct sunlight should be avoided. 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration, whenever solution and container permit.  Upon reconstitution, TEPEZZA 
is a colorless or slightly brown, clear to opalescent solution which is free of foreign particulate 
matter.  Discard the solution if any particulate matter or discoloration are observed. 
Do not freeze the reconstituted or diluted solution. 
Partially used vials should not be re-used. 
The first and second IV infusions on Day 1 and Week 3 will be administered over approximately 
90 minutes (but not less than 80 minutes) for all subjects; subsequent infusions may be 
administered over a shorter time period (approximately 60 minutes, but not less than 50 minutes) 
in the absence of any infusion-associated events.  All subjects will be monitored for AEs from 
the start of infusion through 60 minutes after infusion completion for the first 3 doses; the 
monitoring period for subsequent doses may be reduced to 30 minutes after infusion completion 
for subjects who do not experience infusion-associated events. 
9.4.6.3.2 Dose Modifications, Interruptions and Delays 
All dosing instructions are applicable for TEPEZZA and placebo administration.  
Subjects will be monitored for immediate infusion-associated events (e.g., facial flushing, 
warmth, dyspnea, dizziness, hypertension, hypotension, pruritus) and delayed  
infusion-associated events (e.g., rash).  If immediate infusion-associated events are noted, the 
infusion rate will be slowed or interrupted, symptomatic treatment (e.g., antipyretics, 
antihistamines, beta-agonists, oxygen, IV fluid) may be administered and vital signs 
(temperature, blood pressure, pulse and respiratory rate) will be monitored every 5 minutes until 
stable and then every 15 minutes for 2 additional determinations.  The infusion may be restarted 
upon complete resolution of symptoms; however, study drug dosing will be permanently 
discontinued if the event is an anaphylactic reaction.  

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Following the appearance of either immediate or delayed infusion-associated events, subsequent 
doses may be pre-treated with diphenhydramine (1 to 1.25 mg/kg IV; maximum of 50 mg), 
ranitidine (50 mg IV), famotidine (0.5 mg/kg IV), dexamethasone (0.4 mg/kg IV; maximum of 
20 mg) and/or acetaminophen (500 mg).  All subsequent infusions will be administered over 
approximately 90 minutes (but not less than 80 minutes) with vital signs monitored every 
15 minutes from the start of the infusion through 60 minutes after infusion completion. 
If delayed infusion-associated events are noted, subjects may continue dosing at the 
if a rash worsens following repeated dosing or other signs of 
serum sickness (e.g., delayed fever, myalgias, arthralgias) are present, study drug dosing will be 
permanently discontinued. 
In general, the decision to continue dosing should take into consideration the potential benefit 
and risk to a subject.  
8% while in the study, the Investigator must 
determine the risk versus benefit for each subject to remain in the study.  
Increase in blood glucose is a known AE observed in previous clinical trials with TEPEZZA and 
other IGF-1R antagonists and is known to respond to treatment.  Fasting glucose levels (after at 
least an 8-hour fast) should be tested at Baseline.  Hyperglycemia should be promptly 
investigated and managed.  Subjects with recurrent hyperglycemia, defined as a fasting glucose 
(e.g., fasting glucose, glucose tolerance and HbA1c tests) and appropriate medical management 
at the discretion of the Investigator [American Diabetes Association, 2019b]. 
Since a referral for treatment of hyperglycemia may take some time, if the Investigator considers 
it appropriate to continue the subject in the study, the next scheduled infusion visit may be 
skipped to allow modified anti-diabetic treatment to show its activity and hyperglycemia to 
return to mild/moderate level before dosing.  The subject would then be dosed at the next 
scheduled visit (i.e., 6 weeks after the previous infusion).  Fasting blood glucose levels must 
return to mild/moderate severity before the next scheduled infusion.  The above process of 
withholding a scheduled infusion will be permitted only twice during the study. 
Any changes to the scheduled dosing interval (q3W) or adjustments in the infusion rate should 
be reported to the Sponsor/CRO. 
9.4.7 Method of Assigning Subjects to Treatment Groups 
A randomization schedule will be generated by an unblinded statistician not otherwise associated 
with the study prior to shipment of any study drug to the clinical sites.  On Day 1 of the double-
blind Treatment Period, once all Baseline procedures other than administration of drug have been 
completed, the authorized site personnel will use the EDC system to randomize the subject.  The 
unblinded pharmacist or designee will then use the EDC system to obtain dosing information and 
dispense the appropriate study drug.  Only the pharmacist at the site will have access to dosing 
information. 

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9.4.8 Blinding and Unblinding 
The pharmacists or designees responsible for preparing the TEPEZZA or placebo solutions for 
IV administration will not be blinded to the identity of the study drug.  Pharmacists/designees 
will provide study drug in infusion bags (fully diluted for administration) to study site personnel 
with appropriate blinded labels.  The subject, Investigator and all other study site personnel will 
be blinded to the treatment being administered. 
The study blind should be broken only if the safety of a subject is at risk and the treatment plan 
depends on which medication he or she received.  Unless the subject is at immediate risk, the 
Investigator 
esignee before 
unblinding 
 
unblinded without prior knowledge of the 
Sponsor, the Investigator must notify the Sponsor as soon as possible and no later than the next 
business day.  All circumstances surrounding the event must be clearly documented.  Please refer 
to the instructions in the eCRF guidelines for unblinding a subject by the pharmacist.  
The Sponsor or designee will unblind the identity of the study medication for an unexpected, 
drug-related SAE for submission to health authorities and IRB/IEC according to applicable 
regulatory requirements.  However, the results will not be shared with other Sponsor 
representatives or staff at study sites.  Details of subjects who are unblinded during the study will 
be included in the clinical study report. 
Unblinding for independent pharmacological analysis of biological samples or SAE reporting 
will be performed according to procedures in place to ensure integrity of the data.  
All investigative site staff and Sponsor personnel directly involved in this study will remain 
blinded from Screening through analysis of the follow-up data and all site close-out visits 
(i.e., through Week 48).  Select Sponsor personnel/designees may be unblinded after the 
database lock following completion of all subjects in the double-blind Treatment Period. 
9.4.9 Concomitant Therapy and Restricted Medications 
Concomitant treatment with CellCept (mycophenolate mofetil) up to 3 g/day or Myfortic 
(mycophenolic acid) up to 2.14 g/day and low-
dosing of glucocorticoids is allowed during the study.  Subjects taking CellCept or Myfortic have 
t have been stable for 
 
prior to the Day 1 Visit. 
Symptomatic treatment (e.g., antipyretics, antihistamines and/or corticosteroids, beta-agonists, 
oxygen, IV fluid) may be administered to subjects who experience immediate 
infusion-associated AEs.  Following the appearance of either immediate or delayed 
infusion-associated events, subsequent dosing of study drug may be pre-treated with 
diphenhydramine (1 to 1.25 mg/kg IV; maximum of 50 mg), ranitidine (50 mg IV), famotidine 
(0.5 mg/kg IV), dexamethasone (0.4 mg/kg IV; maximum of 20 mg) and/or acetaminophen 
(500 mg).   

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Medication use that is restricted during the study is presented in Table 9.1. 
Table 9.1 
Restricted Medications 
Medication 
Restricted Time Period 
Steroids for conditions other than dcSSc 
 
4 weeks prior to Screening through study completion.  
Topical steroids for dermatological conditions and inhaled 
steroids are allowed during the study.   
Steroid therapy (parenteral/oral) for infusion-associated AEs 
is allowed (see Section 9.4.9 for details). 
Oral or parenteral therapy approved for PAH 
Receipt of >1 approved therapy during the study (use of 
PDE-5 inhibitors are allowed for erectile dysfunction and/or 
 
Rituximab (Rituxan® or MabThera®)  
12 months prior to first infusion through study completion.  
Use of any non-steroid immunosuppressive agent, 
cytotoxic or anti-fibrotic drug, other than 
mycophenolate mofetil, mycophenolic acid or an 
anti-malarial (e.g., hydroxychloroquine 
[Plaquenil®]) 
4 weeks prior to Screening through study completion. 
Biologics or small molecules approved for 
rheumatoid arthritis, psoriatic arthritis and other 
rheumatic diseases 
4 weeks prior to Screening through study completion. 
Investigational agent 
90 days or 5 half-lives, whichever is longer, prior to 
Screening through study completion. 
Illicit drug/alcohol use 
History of abuse within the past 2 years or abuse during 
study. 
AE=adverse event; dcSSc=diffuse cutaneous systemic sclerosis; IV=intravenous; PAH=pulmonary arterial 
hypertension; PDE-5=phosphodiesterase-5 
 
Subjects should avoid ototoxic medications and medications that may cause muscle 
spasm/cramps (such as diuretics or statins) during the study.  If a muscle spasm occurs, evaluate 
for other causes of muscle spasm such as electrolyte abnormalities and dehydration. 
All concomitant treatment (for dcSSc and other conditions) in the Treatment Period and the 
Follow-up Period 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. 
All infusions of study medication will be administered at the clinic or infusion center under the 
supervision of clinic staff or nurses.  Infusion volumes and start and stop times of the infusions 
will be recorded in the eCRF. 

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An inventory of the study medication supplies will be performed by the site or authorized study 
records or equivalent.  
9.5 
Efficacy, Quality-of-Life, Pharmacokinetic and Safety Variables 
The Schedule of Assessments is provided in Section 2.1. 
9.5.1 Efficacy Variables 
9.5.1.1 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
9.5.1.1.1 
 
 
 
 
 
 
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9.5.1.1.2 
 
 
 
 
 
 
 
9.5.1.1.3 
  
 
9.5.1.1.4 
 
 
 
 
 
 
 
 
 
9.5.1.1.5 
 
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9.5.2.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
9.5.3 Pharmacokinetic Measurements 
Blood samples will be collected from all subjects to evaluate PK at the following time points:  
pre- and post-infusion on Day 1 and Weeks 3, 12 and 18; a single sample will be collected at 
Weeks 24 and 36.   
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.   
9.5.4 Immunogenicity Testing 
Blood samples will be collected from all subjects for immunogenicity testing (anti-drug 
antibodies [ADA] and possibly neutralizing antibodies [NAb]) at the following time points:  
pre-infusion on Day 1 and Weeks 3, 12 and 18; a single sample will be collected at Weeks 24, 36 
and 48.   
If a sample is ADA positive after confirmatory and reactive titer testing, the sample will then be 
tested for NAb.   
Instructions for collection, processing, handling, storing and shipping of immunogenicity 
samples will be detailed in a laboratory manual that will be provided to each site prior to site 
initiation. 
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9.5.5 Serum Biomarker Assessments 
Blood samples will be collected from all subjects to analyze for biomarkers of the IGF-1 
pathway at the following time points:  pre-infusion on Day 1 and Weeks 3, 12 and 18; an 
additional single sample will be collected at Week 24. 
Based on the results of the 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 be stored for no more than 5 years after the study is completed.  All samples will be 
destroyed after all potential biomarkers have been tested or 5 years after the study is complete, 
whichever comes first.  
Instructions for collection, processing, handling, storing and shipping of samples will be detailed 
in a laboratory manual that will be provided to each site prior to site initiation. 
9.5.6 
  
 
 
   
 
 
9.5.7 Safety Variables 
Safety will be assessed by AE and concomitant medication use monitoring, physical 
examination, vital signs, clinical safety laboratory evaluations (complete blood count and 
chemistry [including HbA1c]), clinical inflammatory laboratory evaluations (
), 
pregnancy testing (if applicable) and a screening ECG. 
9.5.7.1 Adverse Events 
9.5.7.1.1 Definitions 
9.5.7.1.1.1 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.  
Pre-existing conditions that worsen during a study are to be reported as AEs.   
Unchanged, chronic conditions are NOT considered AEs and should not be recorded on the AE 
pages of the eCRF unless there is a clear exacerbation of a chronic condition.  
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ble to the 
disease for which the study drug is being studied (i.e., dcSSc).  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 treatment with the study drug. 
9.5.7.1.1.2 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 outcomes: 
 Death.  This includes any death that occurs during the conduct of a clinical study, 
including deaths that appear to be completely unrelated to the study 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. 
9.5.7.1.1.3 Non-serious Adverse Event Definition 
A non-serious AE includes any AE that is not described in the previous SAE category. 
9.5.7.1.1.4 Unexpected Adverse Event Definition 
An AE or suspected adverse reaction is considered unexpected if it is not listed in the Reference 
Safety Information section of the Investigator s Brochure or is not listed with the specificity or 

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severity that has been observed.  Unexpected, as used in this definition, also refers to AEs or 
suspected adverse reactions that are mentioned in the Reference Safety Information as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the drug, but are 
not specifically mentioned as occurring with the particular drug under investigation. 
9.5.7.1.1.5 Adverse Events of Special Interest 
Based on previous clinical experience with TEPEZZA, the following AESIs are identified for 
this study (See Section 7.1.3.4.4.4 for further information): 
 Hyperglycemia 
 Hearing impairment 
 Infusion reaction 
 New onset or exacerbation of IBD 
9.5.7.1.2 Documentation of Adverse Events 
Any AEs that occur after signing the ICF and prior to dosing on Day 1 will be considered 
Baseline signs/symptoms.  The TEAE reporting period begins with administration of the first 
dose of study medication on Day 1 and continues until 3 weeks (21 days) after last dose of study 
drug.  The follow-up AE reporting period begins 21 days after the last dose of study drug 
through completion of the Follow-up Period (Week 48 or premature withdrawal).  All Baseline 
signs/symptoms, TEAEs and AEs during the Follow-up Period must be recorded in the source 
doc
.  All AEs and SAEs that occur from the signing of 
informed consent through Week 48 will be recorded. 
If the Investigator observes an SAE after study completion that he/she believes was possibly 
caused by the study medication, the Investigator will report this SAE using the procedures 
described in Section 9.5.7.1.5. 
Detailed information regarding all SAEs must also be recorded on the Serious Adverse Event 
Reporting Form.  Whenever possible, the Investigator should group together into a single term 
the signs and symptoms that constitute a single diagnosis.  For example, cough, rhinitis and 
Investigator is 
confident of the diagnosis. 
9.5.7.1.3 Intensity of Adverse Events 
All clinical AEs encountered during the study will be reported on the AE form of the eCRF.  
Intensity of AEs will be graded on a 5-point scale (mild, moderate, severe, life-threatening, 
death) and reported in detail on the eCRF.  

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Intensity 
Definition 
Corresponding  
NCI-CTCAE Grade 
Mild 
discomfort noticed but no disruption of normal daily activity 
1 
Moderate 
discomfort sufficient to reduce or affect daily activity 
2 
Severe 
inability to work or perform normal daily activity 
3 
Life-threatening 
represents an immediate threat to life  
4 
Fatal 
results in death 
5 
NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events 
 
9.5.7.1.4 Relationship to Study Drug 
The relationship of the study drug to each AE will be determined by the Investigator and the 
Sponsor based on the following definitions: 
 No reasonable causal relationship (not related):  There is no plausible temporal 
relationship or there is another explanation that unequivocally provides a more plausible 
explanation for the event. 
 Yes, reasonable causal relationship (possibly 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. 
Within the reporting requirement under 21 CFR 312.32I(1)(i), the FDA provides the following 
examples of types of evidence that would suggest a causal relationship between the drug and the 
AE. 
 A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome). 
 One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon 
rupture). 

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 An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events 
that commonly occur in the study population independent of drug therapy) that indicates 
those events occur more frequently in the drug treatment group than in a concurrent or 
historical control group. 
9.5.7.1.5 Reporting and Documenting Serious Adverse Events 
All SAEs beginning with the time of signing of the ICF and continuing through Week 48 
(end-of-study visit) 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 the study medication:   
1. Report the SAE to the Sponsor by entering the information into the eCRF within 
24 hours after becoming aware that a subject has experienced an SAE.  If unable to 
access the eCRF, the event must be reported by submitting the completed SAE form 
by email to clinicalsafety@horizontherapeutics.com, fax or telephone within 
24 hours after becoming aware that a subject has experienced an SAE (see 
Appendix 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 
representative. 
3. Respond in a timely manner to any queries from Sponsor regarding the SAE. 
4. Conduct appropriate consultation and follow-up evaluation until the SAE is resolved, 
stabilized or otherwise explained by the Investigator. 
5. Review each SAE report and evaluate the relationship of the SAE to study treatment.  
The Sponsor will determine whether the SAE is unexpected in nature. 
6. The Investigator must report all AEs or SAEs that meet the criteria for Unanticipated 
Problems Involving Risks to Human Subjects or Others to the IRB/IEC. 
9.5.7.1.6 Follow-up of Adverse Events 
Any ongoing study drug-related AE present at the time of study 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.  
In the event of unexplained, treatment-emergent, clinically significant abnormal laboratory test 
results or clinically significant changes in laboratory test results, the tests should be repeated 
immediately and followed until the values have returned to within the reference range or to 
Baseline for that subject. 

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9.5.7.1.7 Medication Errors 
A medication error is any unintended failure in the drug treatment process, such as mistakes in 
the prescribing, dispensing, storing, preparation or administration of a medicine that leads to, or 
has the potential to lead to, harm to the patient.   
All cases of medication errors, which include overdose, will be documented on the eCRF in 
order to capture this important safety information consistently in the database.  AEs associated 
with a medication error, such as an overdose, or an SAE of overdose are to be reported according 
to the procedures outlined in Sections 9.5.7.1.2 and 9.5.7.1.5, respectively. 
An overdose is defined as a known deliberate or accidental administration of investigational drug 
to a subject.  For this study, any dose of TEPEZZA that is greater than 27 mg/kg q3W over the 
dose that has been assigned will be considered an overdose.   
In the event of drug overdose, the subject is to be treated with symptomatic and supportive care, 
as required.   
9.5.7.1.8 Review of Adverse Events and Emerging New Safety Information 
The Sponsor will perform an ongoing review of all AEs and all other emerging new information 
relevant to the safety of the drug, including periodic review and analyses of their entire safety 
database. 
9.5.7.1.9 Reporting of Investigational New Drug Safety Reports 
The Sponsor will notify the US FDA and all Investigators of any new serious risks associated 
with the drug. 
9.5.7.1.10  Development Safety Update Reports 
The Sponsor will prepare and submit annual safety reports to the US FDA. 
9.5.7.2 Pregnancy Reporting 
Pregnancy testing will be performed for women of childbearing potential (including those with 
an onset of menopause <2 years prior to Screening, non-therapy-induced amenorrhea for 
<12 months prior to Screening or not surgically sterile [absence of ovaries and/or uterus]) at 
Screening, prior to dosing on Day 1 and Weeks 3, 6, 9, 12, 15, 18 and 21 and at Weeks 24, 28, 
36 and 48.  If a subject discontinues study participation during the Follow-up Period prior to the 
Week 48 Visit, a pregnancy test will be performed at the premature withdrawal visit.  A serum 
pregnancy test will be performed at Screening and at Week 48; urine pregnancy tests will be 
performed at all other visits, as applicable.  Serum pregnancy tests will be analyzed at a central 
study laboratory and the urine pregnancy tests will be performed locally. 

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Women of childbearing potential will be contacted via phone or email at Week 32 and Week 42 
(or 6 months after last infusion if withdrawn early from treatment) to inquire if they have missed 
a menstrual cycle and will have a serum pregnancy test performed, if required.  The serum 
pregnancy test may be performed by a local laboratory with the result provided to the 
Investigator or a subject may return to the clinic for testing by the central laboratory.  
If a female subject becomes pregnant during the Treatment Period, she should immediately 
notify the Investigator and TEPEZZA dosing should be permanently discontinued.   
Pregnancies occurring up to 180 days after the last dose must also be reported to the Investigator. 
The Investigator should report pregnancies to the Sponsor within 24 hours by submitting the 
completed pregnancy report form by email to clinicalsafety@horizontherapeutics.com, fax or 
telephone within 24 hours after becoming aware that the subject has become pregnant (see 
Appendix 17.1 for contact information).  The Investigator should counsel the subject and discuss 
the possible risks of continuing the pregnancy.  If pregnancy continues and the subject signs the 
pregnancy consent form, monitoring should also continue to the conclusion of the pregnancy.  
Subjects should be instructed to continue contraception for 180 days after their last dose of study 
drug. 
9.5.7.3 Medical History 
Medical history, including dcSSc history and treatment and substance use history, will be 
conducted at Screening and on Day 1.  The subject must have a diagnosis of dcSSc (with onset 
 
, at 
Screening
Screening. 
9.5.7.4 Vital Signs, Weight and Height 
Vital signs (heart rate, blood pressure, respiratory rate, temperature) will be measured at all clinic 
visits.  Vital signs will be measured pre- and post-infusion on Day 1 and Week 3 and 
pre-infusion on all other dosing days.  In addition, if immediate infusion-associated events are 
noted during the infusion, vital signs will be monitored every 5 minutes until stable and then 
every 15 minutes for 2 additional determinations.  Also, vital signs will be monitored every 
15 minutes from the start of the infusion through 60 minutes after infusion completion for any 
subsequent infusions after the previous occurrence of immediate or delayed infusion-associated 
events. 
clothing or other material and while the subject is sitting up.  When possible, the same arm will 
be used for measurements in all study visits.  
Weight will be measured at Screening and on Day 1, Weeks 3, 6, 9, 12, 15, 18, 21, 24, 36 and 
48.  To limit the potential for variability in weight collection, the subject should wear lightweight 

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clothing and no shoes during weighing.  Dosing on Day 1 and at Weeks 3, 6 and 9 during the 
double-blind Treatment Period will be based on the weight measured on Day 1.  Dosing at 
Weeks 12, 15, 18 and 21 during the double-blind Treatment Period will be based on the weight 
measured at Week 9. 
Height will be measured at Screening only. 
9.5.7.5 Physical Examination 
A physical examination will be performed at Screening, Day 1 and Weeks 3, 12, 24 and 48.  
9.5.7.6 Electrocardiograms 
A 12-lead ECG will be performed at Screening.  Additional ECGs will be performed, as needed.  
The results will be recorded as normal or abnormal on the eCRF and all abnormal results will be 
evaluated by the Investigator as clinically significant or not clinically significant.  A copy of the 
ECG tracing will remain with the source documents. 
9.5.7.7 Clinical Laboratory Safety Tests 
A central study laboratory will be used for all protocol-specified clinical laboratory parameters, 
with the exception of urine pregnancy tests that will be performed locally (see Section 9.5.7.2 for 
details).  Details concerning the collection of these samples are presented in Table 9.2. 

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9.5.9 Study Procedures 
Subjects who provide informed consent and who meet all the entry criteria for participation in 
this study will be randomized to treatment. 
9.5.9.1 Screening 
Due to the large number of Screening assessments, the Screening Visit may be completed in 
more than 1 day.  During the Screening Visit, potential study subjects will be informed fully 
regarding the nature of the study and possible AEs and will receive a copy of the ICF for review.  
Potential study subjects must read the ICF and sign the document after the Investigator has 
  Further procedures can begin only 
after the ICF has been signed.  The original signed ICF will be retained by the Investigator and a 
copy will be given to the study subject. 
Study candidates will be evaluated for study entry according to the stated inclusion and exclusion 
criteria (Section 9.3).  The Investigator will evaluate the results of all examinations, including 
clinical laboratory tests and 
  The 
Investigator must review the results of all Screening tests before determining that a candidate is 
eligible for study drug treatment.  The serum pregnancy test performed at Screening on all 
female candidates of childbearing potential must be negative for those subjects to be eligible for 
initiation of treatment.  All Screening procedures must be completed within 28 days prior to 
Day 1 (i.e., the first day of administration of study drug).  The following procedures will be 
performed during Screening 
th and eligibility for 
enrollment into the study: 
 Obtain signed, written informed consent and permission to use Protected Health 
Information (in accordance with the Health Insurance Portability and Accountability 
Act).  Refusal to provide this permission excludes an individual from eligibility for study 
participation.  Record date and time informed consent was given and who conducted the 
process on the appropriate source documentation. 
 Determine study eligibility through review of the inclusion/exclusion criteria (see 
Section 9.3) 
 Obtain demographics. 
 Obtain medical history, including dcSSc history and treatment, as well as substance use 
history. 
 Inquire about prior medications (see Table 9.1 for restrictions regarding medications). 
 Query subjects regarding signs and symptoms. 
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 Measure weight and height. 
 Perform physical examination. 
 Measure vital signs (blood pressure, heart rate, respiratory rate and temperature).  These 
measurements will be performed according to standardized instructions.   
 Perform 12-lead ECG. 
 Collect blood samples for hematology, coagulation and chemistry (including glucose and 
HbA1c) analysis for all subjects (see Section 9.5.7.7 for details concerning test results 
and study participation) and pregnancy testing for females of childbearing potential.  
 Collect urine sample for urinalysis. 
 
 
 
 Enter Screening Visit data in the EDC system. 
9.5.9.2 Treatment Period 
9.5.9.2.1 Day 1/Baseline 
On Day 1, subjects will return to the clinic for Baseline assessments, randomization and the first 
dose of study drug.  
 Perform review of inclusion/exclusion criteria. 
 Review medical history. 
 Query subjects regarding signs and symptoms and concomitant medications within 
previous 2 weeks. 
 Measure pre-infusion weight.  
 Perform pre-infusion physical examination. 
 Collect pre-infusion blood samples for hematology and chemistry (including 
 
 and glucose, but not HbA1c) analysis (see Section 9.5.7.7 for details concerning 
test results and study participation). 
 Collect pre-infusion blood samples for ADA/NAb immunogenicity testing. 
 
 
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 Collect pre-infusion urine sample for urinalysis and also for pregnancy testing for 
females of childbearing potential; the pregnancy test must be negative for the subject to 
receive study drug. 
 
 
 
 
 
 
 Enter visit data in the EDC system in order for unblinded personnel to obtain 
randomization assignment and study drug dosing information. 
 Measure vital signs pre- and post-infusion.  Additional vital sign monitoring may be 
performed in the event of infusion-associated AEs (see Section 9.5.7.4 for details). 
 Collect pre- and post-infusion blood samples for PK analyses.  
 Administer the first dose of study drug and monitor subject for 60 minutes after the end 
of the infusion. 
Subjects will be discharged from the study center after all of the Day 1 procedures have been 
completed and will be contacted the following day to inquire about AEs and concomitant 
medication use. 
9.5.9.2.2 Week 3 
 Perform pre-infusion physical examination, including measuring of weight. 
 Query subjects regarding AEs and concomitant medications. 
 Collect pre-infusion blood samples for hematology and chemistry (including glucose, but 
not HbA1c) analysis (see Section 9.5.7.7 for details concerning test results and study 
participation). 
 Collect pre-infusion blood samples for ADA/NAb immunogenicity testing. 
 
 
 
 
 Collect pre-infusion urine sample for urinalysis and also for pregnancy testing for 
females of childbearing potential; the pregnancy test must be negative for the subject to 
receive study drug. 
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 Measure vital signs pre- and post-infusion.  Additional vital sign monitoring may be 
performed in the event of infusion-associated AEs (see Section 9.5.7.4 for details). 
 Collect pre- and post-infusion blood samples for PK analyses.  
 Complete Step 1 events. 
 Enter visit data in the EDC system in order for unblinded personnel to obtain study drug 
dosing information. 
 Administer study drug and monitor subject for 60 minutes after the end of the infusion. 
Subjects will be discharged from the study center after all of the Week 3 procedures have been 
completed and will be contacted the following day to inquire about AEs and concomitant 
medication use. 
9.5.9.2.3 Week 6 
 Measure weight. 
 Query subjects regarding AEs and concomitant medications. 
 Collect pre-infusion blood samples for hematology and chemistry analysis (see 
Section 9.5.7.7 for details concerning test results and study participation). 
 Collect pre-infusion urine sample for urinalysis and also for pregnancy testing for 
females of childbearing potential; the pregnancy test must be negative for the subject to 
receive study drug. 
 Measure pre-infusion vital signs.  Additional vital sign monitoring may be performed in 
the event of infusion-associated AEs (see Section 9.5.7.4 for details). 
 
 
 Enter visit data in the EDC system in order for unblinded personnel to obtain study drug 
dosing information. 
 Administer study drug and monitor subject for 60 minutes after the end of the infusion. 
Subjects will be discharged from the study center after all of the Week 6 procedures have been 
completed and instructed to return for a clinic visit at Week 9. 
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9.5.9.2.4 Week 9 
 Measure weight. 
 Query subjects regarding AEs and concomitant medications. 
 Collect pre-infusion blood samples for hematology and chemistry analysis (see 
Section 9.5.7.7 for details concerning test results and study participation). 
 Collect pre-infusion urine sample for urinalysis and also for pregnancy testing for 
females of childbearing potential; the pregnancy test must be negative for the subject to 
receive study drug. 
 Measure pre-infusion vital signs.  Additional vital sign monitoring may be performed in 
the event of infusion-associated AEs (see Section 9.5.7.4 for details). 
 Complete Step 1 events. 
 Enter visit data in the EDC system in order for unblinded personnel to obtain study drug 
dosing information. 
 Administer study drug and monitor subject for at least 30 minutes after the end of the 
infusion. 
Subjects will be discharged from the study center after all of the Week 9 procedures have been 
completed and instructed to return for a clinic visit at Week 12. 
9.5.9.2.5 Week 12 
 Measure weight. 
 Perform pre-infusion physical examination. 
 Query subjects regarding AEs and concomitant medications. 
 Collect pre-infusion blood samples for hematology and chemistry (including glucose and 
HbA1c) analysis (see Section 9.5.7.7 for details concerning test results and study 
participation). 
 Collect pre-infusion blood samples for ADA/NAb immunogenicity testing. 
 
 
 Collect pre-infusion urine sample for urinalysis and also for pregnancy testing for 
females of childbearing potential; the pregnancy test must be negative for the subject to 
receive study drug. 
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Date:  02 February 2022
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 Measure pre-infusion vital signs.  Additional vital sign monitoring may be performed in 
the event of infusion-associated AEs (see Section 9.5.7.4 for details). 
 Collect pre- and post-infusion blood samples for PK analyses.  
 
 
 
 Enter visit data in the EDC system in order for unblinded personnel to obtain study drug 
dosing information. 
 Administer study drug and monitor subject for at least 30 minutes after the end of the 
infusion. 
Subjects will be discharged from the study center after all of the Week 12 procedures have been 
completed and will be instructed to return to the clinic at Week 15. 
9.5.9.2.6 Week 15 
 Measure weight. 
 Query subjects regarding AEs and concomitant medications. 
 Collect blood samples for hematology and chemistry (including glucose, 
 
) analysis (see Section 9.5.7.7 for details concerning test results and study 
participation). 
 Collect pre-infusion urine sample for urinalysis and also for pregnancy testing for 
females of childbearing potential; the pregnancy test must be negative for the subject to 
receive study drug. 
 Measure vital signs.   
 Complete Step 1 events. 
 Enter visit data in the EDC system in order for unblinded personnel to obtain study drug 
dosing information. 
 Administer study drug and monitor subject for at least 30 minutes after the end of the 
infusion. 
Subjects will be discharged from the study center after all of the Week 15 procedures have been 
completed and will be instructed to return to the clinic at Week 18. 
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9.5.9.2.7 Week 18 
 Measure weight. 
 Query subjects regarding AEs and concomitant medications. 
 Collect pre-infusion blood samples for hematology and chemistry analysis (see 
Section 9.5.7.7 for details concerning test results and study participation). 
 Collect pre-infusion urine sample for urinalysis and also for pregnancy testing for 
females of childbearing potential; the pregnancy test must be negative for the subject to 
receive study drug. 
 Measure pre-infusion vital signs.  Additional vital sign monitoring may be performed in 
the event of infusion-associated AEs (see Section 9.5.7.4 for details). 
 Collect pre-infusion blood samples for ADA/NAb immunogenicity testing. 
 
 
 Collect pre- and post-infusion blood samples for PK analyses.  
 Complete Step 1 events. 
 Enter visit data in the EDC system in order for unblinded personnel to obtain study drug 
dosing information. 
 Administer study drug and monitor subject for at least 30 minutes after the end of the 
infusion. 
Subjects will be discharged from the study center after all of the Week 18 procedures have been 
completed and instructed to return for a clinic visit at Week 21. 
9.5.9.2.8 Week 21 
 Measure weight. 
 Query subjects regarding AEs and concomitant medications. 
 Collect pre-infusion blood samples for hematology and chemistry analysis (see 
Section 9.5.7.7 for details concerning test results and study participation). 
 Collect pre-infusion urine sample for urinalysis and also for pregnancy testing for 
females of childbearing potential; the pregnancy test must be negative for the subject to 
receive study drug. 
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Date:  02 February 2022
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 Measure pre-infusion vital signs.  Additional vital sign monitoring may be performed in 
the event of infusion-associated AEs (see Section 9.5.7.4 for details). 
 Complete Step 1 events. 
 Enter visit data in the EDC system in order for unblinded personnel to obtain study drug 
dosing information. 
 Administer study drug and monitor subject for at least 30 minutes after the end of the 
infusion. 
Subjects will be discharged from the study center after all of the Week 21 procedures have been 
completed and instructed to return for a clinic visit at Week 24. 
9.5.9.2.9 Week 24 (End of Treatment) 
Week 24 is the final visit of the Treatment Period.  Study drug is not administered. 
 Perform physical examination, including measuring of weight. 
 Query subjects regarding AEs and concomitant medications. 
 Collect blood samples for hematology and chemistry (including glucose, 
 
and HbA1c) analysis. 
 Collect blood samples for ADA/NAb immunogenicity testing. 
 
 
 Collect blood samples for PK analyses.  
 
 
 Collect urine sample for urinalysis and also for pregnancy testing for females of 
childbearing potential. 
 Measure vital signs.   
 
 
 
 
 
 Enter visit data in the EDC system. 
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Subjects will be discharged from the study center after all of the Week 24 procedures have been 
completed and will enter the Follow-up Period.  Subjects will be instructed to return for a clinic 
visit at Week 28.   
If a subject prematurely discontinues from the study during the Treatment Period, he/she will be 
instructed to return for a clinic visit and undergo the Week 24 assessments. 
9.5.9.3 Follow-up Period 
9.5.9.3.1 Week 28 
 Query subjects regarding AEs and concomitant medications. 
 Collect blood samples for hematology and chemistry (including glucose but not HbA1c) 
analysis. 
 Collect urine sample for urinalysis and also for pregnancy testing for females of 
childbearing potential. 
 Measure vital signs.   
 Enter visit data in the EDC system. 
Subjects will be discharged from the study center after all of the Week 28 procedures have been 
completed.  Subjects will be contacted via phone or email at Week 32. 
9.5.9.3.2 Week 32 
All subjects will be contacted via phone or email at Week 32 to inquire about signs and 
symptoms, concomitant medications and if women of childbearing potential have missed a 
menstrual cycle.  If a menstrual cycle has been missed, the subject will have a serum pregnancy 
test performed, if required.   
Subjects will be instructed to return to the clinic at Week 36. 
9.5.9.3.3 Week 36  
 Measure weight. 
 Query subjects regarding AEs and concomitant medications. 
 Collect blood samples for hematology and chemistry (including glucose but not HbA1c) 
analysis. 
 Collect blood samples for ADA/NAb immunogenicity testing. 

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 Collect urine sample for urinalysis and also for pregnancy testing for females of 
childbearing potential. 
 Measure vital signs.   
 
 
 
 
 Enter visit data in the EDC system. 
Subjects will be discharged from the study center after all of the Week 36 procedures have been 
completed.  Subjects will be contacted via phone or email at Week 42. 
9.5.9.3.4 Week 42  
All subjects will be contacted via phone or email at Week 42 to inquire about AEs, concomitant 
medications and if women of childbearing potential have missed a menstrual cycle.  If a 
menstrual cycle has been missed, the subject will have a serum pregnancy test performed, if 
required.   
Subjects will be instructed to return to the clinic at Week 48. 
9.5.9.3.5 Week 48 (End of Study) 
 Perform physical examination, including measuring of weight. 
 Query subjects regarding AEs and concomitant medications. 
 Collect blood samples for hematology and chemistry (including glucose, 
 
) analysis (see Section 9.5.7.7 for details concerning test results and study 
participation) and pregnancy testing for females of childbearing potential. 
 Collect blood samples for ADA/NAb immunogenicity testing. 
 Collect urine sample for urinalysis. 
 Measure vital signs.   
 
 
 
 
 
 Enter visit data in the EDC system. 
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Date:  02 February 2022
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9.6.1.5 Safety and Tolerability Endpoints 
1. Incidence of TEAEs and AESIs (hyperglycemia, hearing impairment, infusion reaction, 
new onset or exacerbation of IBD). 
2. Vital signs:  change from Baseline at each scheduled visit.  
3. Clinical safety laboratory tests:  change from Baseline at each scheduled visit.  
9.6.2 Analysis Sets 
The following analysis sets will be defined for this study:   
 
 
  
 
 
 
 
 
 
  
 
 
 
9.6.3 Safety, Efficacy and Quality-of-Life Endpoint Analyses 
9.6.3.1 Primary Endpoint Analysis 
The primary analysis will be conducted using the safety analysis set.  The number and 
percentage of subjects who experience a TEAE will be summarized by treatment group. 
9.6.3.2 Efficacy Endpoint Analyses 
The efficacy analysis will be conducted using the full analysis set, with select endpoints also 
summarized for the per protocol analysis set.   
 
 
 
 
 
 
 
 
   
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9.6.3.4 Safety and Tolerability Analyses 
Safety analyses will be performed using the safety analysis set. 
The number and percentage of subjects in each treatment group reporting at least one occurrence 
of a TEAE, a TEAE of grade 3 or higher, a serious TEAE, a TEAE related to study drug, an 
AESI and a TEAE resulting in discontinuation of treatment will be summarized by treatment 
group.  TEAEs and SAEs will additionally be summarized by system organ class and preferred 
term. 
Concomitant medications will be summarized by Anatomical Therapeutic Chemical Level 4 
term and preferred term using counts and percentage of subjects for each treatment group. 
Descriptive summaries of observed and change from Baseline values will be presented for each 
vital sign parameter by treatment group and visit.  A shift table for weight gain and weight loss 
as well as hypertension by NCI-CTCAE grade and visit will be presented by treatment group. 
Safety laboratory parameters (chemistry [including HbA1c], hematology, inflammatory 
evaluations [
] and urinalysis)) and change from Baseline (if applicable) will be 
summarized by visit and treatment group using descriptive statistics.  The laboratory values will 
be categorized as low, normal and high based on normal ranges.  Shift tables using categories of 
low, normal and high from Baseline to each visit will be summarized by treatment group.  
Additionally, a shift table for glucose by NCI-CTCAE grade and visit will be summarized by 
treatment group.  Summaries will be provided separately for hyperglycemia. 
9.6.4 Pharmacokinetic and Anti-drug Antibody Analyses  
PK data will be analyzed using the PK analysis set.  Serum concentrations of teprotumumab will 
be summarized descriptively, including arithmetic means, standard deviations, geometric means, 
coefficients of variation, medians and ranges, by time point.  The relationship between clinical 
endpoints and the serum concentrations of teprotumumab may be explored in a descriptive 
manner.   
Immunogenicity data will be analyzed using the safety analysis set.  Immunogenicity endpoints 
include the incidence of ADA and NAb (of positive ADA samples) by visit and treatment group.  
Overall positive ADA result for a subject will be defined as at least 1 positive ADA 
measurement at any assayed time point.  Cumulative negative result will be defined as negative 
ADA results at all time points for a subject.   
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9.6.5 Interim Analyses 
No interim analyses are planned. 
The primary analysis time point for this study is Week 24.  Therefore, the database will be 
locked after all subjects complete Week 24 assessments or withdraw from study prematurely 
prior to Week 24 for primary analyses.  Select Sponsor personnel/designees may be unblinded 
after the database lock for the Week 24 analyses. 
9.6.6 Multiple Comparisons 
While p-values will be calculated for many endpoints, decision-making will not be based on 
formal testing procedures.  Nominal p-values, whether or not they are less than 0.05, will be 
considered in conjunction with estimates of magnitude of treatment effect and consistency of 
direction in planning future studies.  As such, no adjustment for multiple comparisons will be 
made.  
9.6.7 Sample Size and Power Considerations 
For a TEAE that occurs in 20% of TEPEZZA-treated subjects in the dcSSc population, a sample 
size of 15 subjects provides approximately 95% probability that the TEAE will be observed at 
least once. 
This study is not powered to detect a statistically significant difference in the proportion of 
responders unless the difference is very large.  For example, if 10% of all placebo 
subjects were responders and 75% of all TEPEZZA subjects were responders, this study would 
have 87% power to detect that diff
-tailed). 
9.7 
Changes in the Conduct of the Study 
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. 
to protocol entry 
criteria on a case-by-case basis.  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 
ll determine whether the subject 
should continue to participate in the study. 
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 study and to ensure that study data can be subsequently verified.  These documents should be 
classified in 2 separate categories:  (1) Investigator study 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 
notes; appointment book; original laboratory, ECG, electroencephalogram, radiology, pathology 
and special assessment reports; dispensing records; signed ICFs; consultant letters; and subject 
Screening and enrollment logs. 
In order to comply with regulatory requirements, it is the policy of the Sponsor that, at a 
minimum, the following be documented in source documents at the study center: 
 Medical history/physical condition and diagnosis of the subject before involvement in the 
study sufficient to verify that the subject meets protocol entry criteria.  
 Study 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 study visit including each study assessment and the identity of the staff 
member performing the assessment. 
 Study drug dispensing and return. 
 Review by the Investigator or qualified personnel on the 1572 of laboratory test results. 
 AEs (start and stop date, description, action taken and resolution). 
 Investigator or Sub-Investigator
AE. 
 Concomitant medications (start and stop dates, reason for use). 
 Condition of subject upon completion of, or premature withdrawal from, the study. 

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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. 
12 STUDY MONITORING 
The Investigator will ensure that the study is conducted in accordance with all regulations 
governing the protection of human subjects.  The Investigator will adhere to the basic principles 
and Investigator
 
Investigator
:  Consolidated Guidance.   Additionally, 
this study 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 study protocol and Investigator's Brochure to all Sub-Investigators, pharmacists and 
other staff responsible for study conduct. 
All aspects of the study will be monitored by qualified individuals designated by the Sponsor.  
The Sponsor will ensure that the study is monitored adequately in accordance with GCP 
guidelines. 
Prior to initiation of the study, 
personnel information regarding the investigational drug, protocol requirements, monitoring 
requirements and reporting of SAEs. 
At intervals during the study, as well as after the completion of subject enrollment, the study 
center will be monitored by the Sponsor or designee for compliance.  During these visits, the 
blinded monitor will discuss study progress, verify adherence to the protocol and verify 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 study conduct (e.g., sample storage).  The Investigator agrees to allow unblinded 
monitors access to the clinical supplies, dispensing and storage areas and clinical records of the 
study subjects and, if requested, agrees to assist the monitors.  The Investigator must cooperate 

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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 study 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 study.  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 study and to 
have direct access to inspect, for purposes of verification, the hospital or clinical records of all 
subjects enrolled in this study.  A statement to this effect should be included in the ICF. 
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. 
14 RETENTION OF RECORDS 
No study documents at the study site should be destroyed without prior written agreement 
between the Sponsor and the Investigator.  All subjects
Investigator
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 study-related files must be retained for at least 
2 years following the date of discontinuation of the clinical development program for TEPEZZA 
and for a period in compliance with all federal, state and local regulations.  The Sponsor must be 
notified prior to the disposal of any study-related files.  If the Investigator leaves the practice or 

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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 study was conducted. 
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. 

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16 REFERENCES  
American Diabetes Association. 6. Glycemic targets:  standards of medical care in diabetes-
2019. Diabetes Care. 2019a;42(Suppl. 1):S61 S70. 
American Diabetes Association. 2. Classification and diagnosis of diabetes:  standards of 
medical care in diabetes-2019. Diabetes Care. 2019b;42(Suppl. 1):S13 S28. 
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Wojteczek A, 
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