A Phase 3, Randomized, Double-Masked, Placebo-Controlled, Parallel-Group, Multicenter Study Evaluating Teprotumumab (HZN-001) Treatment in Subjects With Active Thyroid Eye Disease
Phase: PHASE3
Conditions: Thyroid Eye Disease, Graves' Orbitopathy
Sponsor: Amgen

Horizon Pharma USA, Inc. 
 
Teprotumumab (HZN-001) IND: 112952 
Date: 31 January 2019 
 
Protocol: HZNP-TEP-301 
 
 
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CLINICAL STUDY PROTOCOL  
FOR TEPROTUMUMAB (HZN-001) 
IND: 112952 
Protocol Number: HZNP-TEP-301 
EudraCT No.: 2017-002763-18 
 
A Phase 3, Randomized, Double-Masked, Placebo-Controlled, Parallel-Group, 
Multicenter Study Evaluating Teprotumumab (HZN-001) Treatment in 
Subjects with Active Thyroid Eye Disease 
 Short Title:  
 
Treatment of Graves’ Orbitopathy to Reduce Proptosis with Teprotumumab Infusions in a 
Randomized, Placebo-Controlled, Clinical Study 
Date: 31 January 2019 
Version 4.0, incorporating Amendment 3 
Sponsor: 
Horizon Pharma USA, Inc. 
150 S. Saunders Road 
Lake Forest, IL  60045 
 
 
 
This protocol is the confidential information of Horizon Pharma USA, 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 Pharma USA, Inc. 
CONFIDENTIAL 
 

Horizon Pharma USA, Inc. 
 
Teprotumumab (HZN-001) IND: 112952 
Date: 31 January 2019 
 
Protocol: HZNP-TEP-301 
 
 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
HZNP-TEP-301 
Version: 
4.0, incorporating Amendment 3 
Protocol Title: 
A Phase 3, Randomized, Double-Masked, Placebo-Controlled, 
Parallel-Group, Multicenter Study Evaluating Teprotumumab (HZN-001) 
Treatment in Subjects with Active Thyroid Eye Disease (OPTIC) 
Version Date: 
31 January 2019 
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 Pharma USA, Inc. 
 
Teprotumumab (HZN-001) IND: 112952 
Date: 31 January 2019 
 
Protocol: HZNP-TEP-301 
 
 
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SUMMARY OF CHANGES 
Protocol HZNP-TEP-301 
Version 4.0, incorporating Amendment 3 
Version 3.0 of the protocol, which was approved 16 April 2018, has been amended to 
incorporate the changes of Amendment 3. 
• Add diplopia responder rate (defined as the percentage of subjects with baseline diplopia 
> 0 in study eye who have a reduction of ≥ 1 grade with no corresponding deterioration 
[≥ 1 grade worsening] in the fellow eye at Week 24) as a secondary endpoint. 
• Add 2 additional follow-up contacts (telephone or email) at 6 and 12 months after the 
Week 72 Visit to assess any additional thyroid eye disease (TED) treatment received 
since last study contact. 
• Clarify that female subjects of childbearing potential who are sexually active with a 
non-vasectomized male partner must agree to use 2 reliable forms of contraception, one 
of which is recommended to be hormonal, during the trial and for 180 days after the last 
dose of study drug. 
• Clarify that male subjects who are sexually active with a female partner of childbearing 
potential must agree to use a barrier contraceptive method from Screening through 
180 days after the last dose of study drug. 
• Change the number of teprotumumab doses that will be administered in the open-label 
extension study (HZNP-TEP-302) from “up to 8” to ‘8’. 
• Clarify that Clinical Activity Score (CAS) criteria for determining relapse refers only to 
the study eye. 
• Amend the CAS relapse criterion to include an increase in CAS of ≥ 2 points since 
Week 24 with an absolute CAS ≥ 4 following the Week 24 Visit.  
• Specify the minimum duration of study drug infusions.  
• Clarify that the weight obtained at Week 12 can be used for the calculation of study drug 
dose beginning at Week 12 or Week 15. 
• Remove the specified temperature collection methods (oral or tympanic). 
• Correct that the urine sample collected at Week 15 is for pregnancy testing only. 
• Change the definition of the end of the trial to date of the last subject contact at 
Week 120. 
• Update statistical analysis methods. 
• Update Sponsor Representative title. 
• Correct minor typographical errors (changes are not detailed below).  
The following sections of the protocol are affected: 2, 2.1, 7.1.3.4.5.5.1, 8.2, 9.1, Figure 9.1, 
9.3.1, 9.3.4, 9.4.1, 9.4.6.2, 9.4.6.3.1, 9.4.6.3.2, 9.5.1, 9.5.5.4, 9.5.5.5, 9.5.7.1, 9.5.7.2, 9.5.7.6, 
9.5.7.8, 9.5.7.9, 9.5.7.10, 9.5.7.12, 9.5.7.13, 9.5.7.14, 9.5.7.15, 9.5.7.16, 9.5.7.17, 9.5.7.18, 

Horizon Pharma USA, Inc. 
 
Teprotumumab (HZN-001) IND: 112952 
Date: 31 January 2019 
 
Protocol: HZNP-TEP-301 
 
 
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9.5.7.19, 9.6.1.2, 9.6.3, 9.6.4.2, and 17.1. Additional text is marked in red, underlined, and 
bolded; deleted text is marked as strikethrough text. 
2   SYNOPSIS 
Objectives: 
Secondary Objectives (analyzed hierarchically) 
4. 
Evaluate the effect of teprotumumab versus placebo on the diplopia responder rate 
(i.e., the percentage of subjects with baseline diplopia > 0 in study eye who have a 
reduction of ≥ 1 grade with no corresponding deterioration [≥ 1 grade worsening] in 
the fellow eye) at Week 24. 
5.4. 
Evaluate the effect of teprotumumab versus placebo on the mean change from Baseline to 
Week 24 in the Graves’ Ophthalmopathy Quality of Life (GO-QoL) questionnaire overall 
score. 
Study Design: 
At the end of the double-masked Treatment Period (Week 24), subjects who are proptosis 
non-responders (study eye has < 2 mm decrease in proptosis) will be eligible to enter an open-
label extension study (HZNP-TEP-302) in which subjects may receive up to 8 infusions of 
teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for the remaining 7 infusions) in an 
open-label fashion.  
Subjects who complete the Week 72 Visit will be contacted 6 and 12 months later via phone 
or email by research staff to enquire if any treatment for TED has been received since last 
study contact. If yes, subject will be questioned regarding type of treatment and 
outcome/response. 

Horizon Pharma USA, Inc. 
 
Teprotumumab (HZN-001) IND: 112952 
Date: 31 January 2019 
 
Protocol: HZNP-TEP-301 
 
 
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Screen 
Baseline 
Double-Masked Treatment Period 
Teprotumumab or Placebo 1, 2 
24 Weeks 
Follow-Up Period 
48 Weeks 3,4 
Follow-Up 
Contact5  
48 Weeks 
 
< –––––––––––––––––––––––––– Clinic Visits ––––––––––––––––––––––––––––––––– > < –––––––– Clinic Visits –––––– >  
 
* 
 
* 
 
* 
* 
* 
* 
* 
* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 to 6 
weeks 
predose 
Day 1 6 
W1 
W3 6 
W4 
M1 
W6 
W9 
W12 
M3 
W15 
W18 
W21 
W24 7 
M6  
W28 
M7  
W36 
M9 
W48 
M12 
W60 
M15 
W72 
M18 
W96 
M24 
W120 
M30 
 
 
Randomization 
n=38/group 1 
< –––––––––––––––––––––––––––––––––––– Study Week/Month –––––––––––––––––––––––––––––––––––––––––– > 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Infusion of study drug. 
1. 
Subjects will be randomized in a 1:1 ratio (stratified by tobacco use status) to receive: 
a. Teprotumumab 20 mg/kg (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 ± 1 day for Weeks 1 and 4, ± 3 days for Weeks 3, 6, 9, 12, 15, 18, and 21, and ± 7 days for Week 24. 
3. 
Subjects who are proptosis responders or non-responders who do not elect to participate in the open-label extension study will enter a 48-week 
Follow-Up Period. Subjects who are responders at Week 24 but relapse during the Follow-Up Period may enter the open-label study and receive 
up to 8 infusions if they meet specified criteria. 
4. 
Visit windows of ± 7 days. 
5. 
Subjects who complete the Week 72 Visit will be contacted via phone or email by research staff to enquire if any treatment for TED has 
been received since last study contact. 
65. Subjects will be contacted by phone/email the day following the first and second infusions for safety and tolerability assessments; phone/email 
contacts will also occur the day after any clinic visit where a subject experiences an infusion-related adverse event. 
76. Subjects who are proptosis non-responders at Week 24 of the double-masked Treatment Period will be offered the option to enter an open-label 
extension study and receive up to 8 additional infusions of teprotumumab 20 mg/kg (10 mg/kg on Day 1 followed by 20 mg/kg for the remaining 
7 infusions all subsequent doses). 
Inclusion Criteria: 
10. 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]) 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 through Week 48 of 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 
one 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 less than 1% per year), when 
used consistently and correctly, includes implants, injectables, combined oral 
contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomized 
partner.  
11.  Male subjects must be surgically sterile or, if sexually active with a female partner of 
childbearing potential, must agree to use a barrier contraceptive method from Screening 
through 180 days after the last dose of study drug.  
Dose Regimen/Route of Administration: 
The infusion rate may be reduced and the dose may be interrupted or held based on tolerability 
(see Section 9.4.6.3.2 for details). The first and second infusions will be administered over 
approximately 90 minutes (but not less than 80 minutes). Subsequent infusions will be 

Horizon Pharma USA, Inc. 
 
Teprotumumab (HZN-001) IND: 112952 
Date: 31 January 2019 
 
Protocol: HZNP-TEP-301 
 
 
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administered over a approximately 60 minutes (but not less than 50 minutes), period 
providing there are no significant infusion-associated events. 
Duration of Treatment and Follow-up: 
Subjects who complete the Week 72 Visit will be contacted 6 and 12 months later via phone 
or email by research staff to enquire if any treatment for TED has been received since last 
study contact.   
Criteria for Evaluation: 
Efficacy will be assessed by proptosis (measured as exophthalmos evaluation of the Clinical 
Measures of Severity using a Hertel instrument provided by the Sponsor for consistency in 
measurement), CAS (7-item scale), diplopia (measured as part of the Clinical Measures of 
Severity), and Clinical Measures of Severity (including motility restriction assessments).  
Statistical Analyses 
Secondary Efficacy Endpoints (analyzed hierarchically): 
4. 
The effect of teprotumumab versus placebo on the diplopia responder rate 
(percentage of subjects with baseline diplopia > 0 in study eye who have a reduction of 
≥ 1 grade with no corresponding deterioration [≥ 1 grade worsening] in the fellow eye) 
at Week 24. 
5.4. The effect of teprotumumab versus placebo on the mean change from Baseline to Week 24 
in the GO-QoL questionnaire overall score. 
Statistical Analysis of Efficacy Parameters: 
The primary analyses will be conducted in the Intent-to-Treat (ITT) population. The analysis of 
the primary proptosis responder endpoint will assess risk difference (difference in response 
rates) in a stratified analysis. The analysis will use Cochran-Mantel-Haenszel (CMH) 
weighting to estimate the common risk difference within strata and to estimate the 
standard error of the common risk difference. be a logistic regression with treatment group as 
the model effect. Subjects missing the Week 24 evaluation will be considered to be treatment 
failures (non-responders) for the primary analysis. Further, subjects who prematurely 
discontinue study drug dosing prior to Week 21 during the double-masked Treatment 
Period will be considered to be treatment failures (non-responders), unless an assessment 
at Week 24 is available. Stratification for the analysis will use the same factor as was used 
to stratify randomization, tobacco use (non-user, user). Since tobacco use status (non user vs. 
user) is used to stratify the randomization, it will be included as a categorical covariate. The 
difference in response rates, comparing teprotumumab to placebo, will be estimated Odds 
ratio comparing teprotumumab to placebo will be estimated along with the corresponding 95% 
confidence interval (CI) and p-value.  
An analysis of risk difference with stratification by tobacco use (non-user vs. user) Logistic 
regression will also be used to analyze the 32 secondary categorical endpoints (overall responder 
rate, CAS [value of 0 or 1] and diplopia responder rate). For the analysis of proptosis as a 
continuous secondary endpoint and GO-QoL, a Mixed-Model Repeated-Measures (MMRM) 
analysis of covariance (ANCOVA) model will be fit to the individual change from baseline 

Horizon Pharma USA, Inc. 
 
Teprotumumab (HZN-001) IND: 112952 
Date: 31 January 2019 
 
Protocol: HZNP-TEP-301 
 
 
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scores for the study eye, with terms in the model being the baseline score, tobacco use status, 
treatment group, visit, and the visit-by-treatment and visit-by-baseline-score interactions. The 
main focus of the analysis will be to test the treatment differences at Week 24, with the main 
results consisting of the Week 24 estimated Least Square (LS) means and their differences with 
95% CIs and p-values. 
To control the overall Type 1 error rate of the study, taking into consideration the one primary 
and 54 secondary outcome measures, the outcome measures will be tested in a hierarchical 
stepwise fashion. For each outcome measure, teprotumumab will be tested against placebo at the 
0.05 level only if teprotumumab was statistically significant for the outcome measure preceding 
it in the hierarchical order.

Horizon Pharma USA, Inc. 
 
 Teprotumumab (HZN-001) IND: 112952 
Date: 31 January 2019 
 
                         Protocol: HZNP-TEP-301 
 
 
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9.8.  
 TED must be moderate to severe in intensity (non-sight threatening but appreciable impact on daily life) with an onset of symptoms (as determined by subject records) 
within 9 months prior to the Baseline Visit for study enrollment. 
10.9.   Dosing will be adjusted if there is a change in weight during the Treatment Period. The weight obtained at Week 12 can be used in dose calculations beginning at 
Week 12 or Week 15. 
11.10.   Subjects will be randomized in a 1:1 ratio (stratified by tobacco use status) to receive either: a) teprotumumab (10 mg/kg on Day 1 followed by 20 mg/kg q3W for the 
remaining 7 infusions) or b) placebo (q3W for all 8 infusions). 
12.11.   Phone (or email) contact by research staff focusing on safety and tolerability aspects will be made the day after 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. 
13.12.   CAS must be ≥ 4 for enrollment and randomization.  
14.13.   Subjects whose CAS score decreases 2 or more points in the study eye from Screening are not eligible for randomization. 
15.14.   Subjects who have a ≥ 2 mm decrease in proptosis in the study eye from Screening are not eligible for randomization. 
16.15.   Serum pregnancy test at Screening and urine pregnancy tests prior to dose 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]). 
17.16.   Pregnancy test only performed for female subjects of childbearing potential who enter the Follow-Up Period but discontinue study participation prior to Week 48. 
18.17.   Physical exam will include assessment of presence or absence of pretibial myxedema on Day 1 and Week 24 (or PW) of the Treatment Period and Week 72 (or PW) of the 
Follow-Up Period. If present, measurements of instep and calf will be taken. 
19.18.   Height will be measured at Screening only. 
20.19.   Ophthalmic exam: best corrected visual acuity, pupil exam, color vision assessment, Ishihara color plates (or equivalent) or related red desaturation, intraocular pressure, 
and slit lamp exam. If significant abnormalities are noted compared to previous visits, including a loss of 2 lines or more of vision, development of pupil abnormalities 
including APD, rise in intraocular pressure, development of corneal infiltrates or other abnormalities not here specified but of concern to the ophthalmologist, further 
investigations of visual function will be conducted according to the ophthalmologist decision. 
21.20.   Subjects who have decreased best-corrected visual acuity due to optic neuropathy (defined by a decrease in vision of 2 lines on the Snellen chart, new visual field defect, or 
color defect secondary to optic nerve involvement within the last 6 months) are not eligible for randomization. 
22.21.   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-dose on all other infusion days. Additional vital signs will be monitored if infusion-associated AEs occur (see Section 9.5.5.4 for details). 
23.22.   Non-diabetic subjects should be fasting at Weeks 1 and 4 only. Diabetic subjects should be fasting at each visit blood glucose is evaluated. 
24.23.   ALT/AST must be ≤3 x the upper limit of normal (ULN) and serum creatinine must be <1.5 x the ULN according to age to be eligible for randomization. 
25.24.   Subjects must be euthyroid with the baseline disease under control or have mild hypo- or hyperthyroidism (defined as free thyroxine [FT4] and free triiodothyronine 
[FT3] levels < 50% above or below the normal limits). Every effort should be made to correct the mild hypo- or hyperthyroidism promptly and to maintain the euthyroid 
state for the full duration of the clinical trial.  
26.25.   HbA1c must be < 9.0% for randomization. If the HbA1c is elevated and considered clinically significant at any time point after Screening, it will be repeated approximately 
every 45 days until it returns to normal or baseline value. 
27.26   If a sample is positive in the ADA test, after confirmatory and reactive titer testing, the sample will then be tested for NAb. If the subject tests positive for NAb, he/she will 
be followed until levels either revert to Baseline or the subject’s value decreases or remains stable. Any subject with a positive NAb test at Week 72 (or PW) during the 
Follow-Up Period will continue to be followed until the subject’s value decreases or remains stable. 
28. 
Not collected for subjects who prematurely discontinue from the Treatment Period. 

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Date: 31 January 2019 
 
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29.27.   Adverse events (AEs) that occur within 2 weeks prior to Day 1 and prior to dosing on Day 1 will be considered baseline signs/symptoms. Adverse events occurring or 
worsening after the dose on Day 1 through the end of the Treatment Period will be considered treatment-emergent AEs (TEAEs). Adverse events occurring or worsening 
during the Follow-Up Period will be considered postdose AEs. All SAEs that occur from the signing of informed consent through 30 days after study discontinuation will 
be recorded. 
30.28.   Serum (two 5.0 mL samples) will be obtained on Day 1 and Weeks 12 and 24 of the Treatment Period for possible analysis of interleukin (IL)-4, IL-6, IL-10, IL-12, IL-13, 
IL-17, IL-23, IL-1β, sIL-1RA, INFγ, TGFβ, TNFα, micRNA and TSH-R-Ab. Based on the results of the above assays, other similar serum biomarkers may be assayed to 
further explore drug and disease mechanisms. 
31.29.   PK samples will be collected prior to, and at the end of, the infusion on Day 1 and Weeks 3 and 9 of the Treatment Period; additional single samples will be collected at 
Weeks 1, 4, and 24. 
32. 
 If TED treatment has been received since last contact, the subject will be questioned regarding type of treatment and outcome/response. 
30. 
Not collected for subjects who prematurely discontinue from the Treatment Period. 
 
 
 
 

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Teprotumumab (HZN-001) IND: 112952 
Date: 31 January 2019 
 
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7.1.3.4.5.5.1 Overview and Precautions for AESIs 
In general, the decision to keep a subject on study treatment with teprotumumab should take into 
consideration potential risks and benefits to the subject. Prior to all future infusions of 
teprotumumab, these subjects should be pre-medicated with IV diphenhydramine 1 to 
1.25 mg/kg (maximum: 50 mg), IV ranitidine 50 mg, IV dexamethasone 0.4 mg/kg (maximum: 
20 mg), and/or acetaminophen 500 mg. In addition, all future infusions should be administered 
over approximately 90 minutes (but not less than 80 minutes). Vital signs should be taken 
every 15 minutes during the infusion. 
8.2 
Secondary Objectives 
4. 
Evaluate the effect of teprotumumab versus placebo on the diplopia responder rate 
(i.e., the percentage of subjects with baseline diplopia > 0 in study eye who have a 
reduction of ≥ 1 grade with no corresponding deterioration [≥ 1 grade worsening] in 
the fellow eye) at Week 24. 
5.4. 
Evaluate the effect of teprotumumab versus placebo on the mean change from Baseline to 
Week 24 in the Graves’ Ophthalmopathy Quality of Life (GO-QoL) questionnaire overall 
score. 
9.1 
Overall Study Design and Plan 
Study Design: 
At the end of the double-masked Treatment Period (Week 24), subjects who are proptosis 
non-responders (study eye has < 2 mm decrease in proptosis) will be eligible to enter an open-
label extension study (HZNP-TEP-302) in which subjects may receive up to 8 infusions of 
teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for the remaining 7 infusions) in an 
open-label fashion. Discussion of this option with the subject and informed consent presentation 
for HZNP-TEP-302 should be discussed at the Week 24 Visit given enrollment in HZNP-TEP-
302 must occur within 2 weeks of the Week 24 Visit. 
Subjects who complete the Week 72 Visit will be contacted 6 and 12 months later via phone 
or email by research staff to enquire if any treatment for TED has been received since last 
study contact. If yes, subject will be questioned regarding type of treatment and 
outcome/response. 
 

Horizon Pharma USA, Inc. 
 
Teprotumumab (HZN-001) IND: 112952 
Date: 31 January 2019 
 
                        Protocol: HZNP-TEP-301 
 
 
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Figure 9.1 
Schematic of Study Design 
Screen 
Baseline 
Double-Masked Treatment Period 
Teprotumumab or Placebo 1, 2 
24 Weeks 
Follow-Up Period 
48 Weeks 3,4 
Follow-Up 
Contact5  
48 Weeks 
 
< –––––––––––––––––––––––––– Clinic Visits ––––––––––––––––––––––––––––––––– > < –––––––– Clinic Visits –––––– >  
 
* 
 
* 
 
* 
* 
* 
* 
* 
* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 to 6 
weeks 
predose 
Day 1 6 
W1 
W3 6 
W4 
M1 
W6 
W9 
W12 
M3 
W15 
W18 
W21 
W24 7 
M6  
W28 
M7  
W36 
M9 
W48 
M12 
W60 
M15 
W72 
M18 
W96 
M24 
W120 
M30 
 
 
Randomization 
n=38/group 1 
< –––––––––––––––––––––––––––––––––––– Study Week/Month –––––––––––––––––––––––––––––––––––––––––– > 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Infusion of study drug. 
1. 
Subjects will be randomized in a 1:1 ratio (stratified by tobacco use status) to receive: 
a. Teprotumumab 20 mg/kg (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 ± 1 day for Weeks 1 and 4, ± 3 days for Weeks 3, 6, 9, 12, 15, 18, and 21, and ± 7 days for Week 24. 
3. 
Subjects who are proptosis responders or non-responders who do not elect to participate in the open-label extension study will enter a 48-week 
Follow-Up Period. Subjects who are responders at Week 24 but relapse during the Follow-Up Period may enter the open-label study and receive 
up to 8 infusions if they meet the criteria defined in Section 9.3.4. 
4. 
Visit windows of ± 7 days. 
5. 
Subjects who complete the Week 72 Visit will be contacted via phone or email by research staff to enquire if any treatment for TED has 
been received since last study contact. 
65. Subjects will be contacted by phone/email the day following the first and second infusions for safety and tolerability assessments; phone/email 
contacts will also occur the day after any clinic visit where a subject experiences an infusion-related AE. 
76. Subjects who are proptosis non-responders at Week 24 of the double-masked Treatment Period will be offered the option to enter an open-label 
extension study and receive up to 8 additional infusions of teprotumumab 20 mg/kg (10 mg/kg on Day 1 followed by 20 mg/kg for the remaining 
7 infusions all subsequent doses). 
 
9.3.1 
Inclusion Criteria 
10. 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]) 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 through Week 48 of 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 
one 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 less than 1% per year), when 
used consistently and correctly, includes implants, injectables, combined oral 
contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomized 
partner.  
11.  Male subjects must be surgically sterile or, if sexually active with a female partner of 
childbearing potential, must agree to use a barrier contraceptive method from Screening 
through 180 days after the last dose of study drug.  

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9.3.4 
Criteria for Responders Who Relapse 
If subjects meet the response criteria at Week 24 but subsequently experience a disease relapse 
during the 48-week Follow-Up Period, they will have the option to enter the open-label study 
with teprotumumab (HZNP-TEP-302) and receive up to 8 infusions of teprotumumab. The 
criteria to determine relapse is the following: 
• Increase in proptosis of ≥ 2 mm in the study eye since Week 24, or 
• An increase in CAS of ≥ 2 points since Week 24 with an absolute CAS of ≥ 4 in the 
study eye following the Week 24 Visit. 
• In addition to one of the bullet points above, the Investigator should also consider the 
subject’s symptomology to ensure a relapse has occurred (e.g., new onset of double 
vision). 
9.4.1 
Treatments Administered 
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), period providing there are no significant 
infusion-associated events. 
9.4.6.2 Determination of Dose Volume 
The volume of study drug to be administered will be determined by the interactive web response 
system (IWRS) and will be based on the subject’s weight. The first dose will be 10 mg/kg, and 
subsequent doses will be 20 mg/kg. Weight will be measured at Screening and Weeks 12 and 24 
during the Treatment Period. The dose on Day 1 of the double-masked Treatment Period will be 
based on the Screening weight. The weight obtained at Week 12 can be used to adjust the 
dose beginning at Week 12 or Week 15, as appropriate.and the dose may be adjusted at Week 
12, as appropriate.  
9.4.6.3.1 Preparation and Administration of Teprotumumab 
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. 

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9.4.6.3.2 Dose Modifications, Interruptions, and Delays 
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) period with vital signs monitored 
every 15 minutes from the start of the infusion through 60 minutes after infusion completion. 
9.5.1 
Efficacy Variables 
Efficacy will be assessed by proptosis (measured as exophthalmos evaluation of the Clinical 
Measures of Severity using a Hertel instrument provided by the Sponsor for consistency in 
measurement), CAS (7-item scale), diplopia (measured as part of the Clinical Measures of 
Severity) and Clinical Measures of Severity (including motility restriction assessments).  
9.5.5.4 Vital Signs 
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 predose on all other infusion 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. 
Blood pressure and pulse measurements will be obtained with the subject’s arm 
unconstrained by clothing or other material and while the subject is sitting up. When 
possible, the same arm will be used for measurements in all study visits. Temperature will be 
obtained orally or via the ear. 
9.5.5.5 Physical and Ophthalmic Examinations, Height, and Weight 
Weight will be measured at Screening and every 12 weeks throughout the study (Weeks 12 and 
24 [or PW] during the Treatment Period and Weeks 36, 48, 60, and 72 [or PW] of the Follow-Up 
Period). The dose on Day 1 of the double-masked Treatment Period will be based on the 
Screening weight. The weight obtained at Week 12 can be used in dose calculations 
beginning at Week 12 or Week 15., and the dose may be adjusted at Week 12 as appropriate. 
9.5.7.1 Screening 
• Complete the efficacy assessments (CAS, Clinical Measures of Severity including 
proptosis, diplopia and motility restriction). 

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9.5.7.2 Day 1/Baseline 
• Perform predose Baseline efficacy assessments (CAS, Clinical Measures of Severity 
including proptosis, diplopia and motility restriction proptosis, CAS, Clinical 
Measures of Severity including motility restriction). Proptosis and CAS may not decrease 
> 2 mm/points in the study eye from Screening to be eligible for enrollment. 
9.5.7.6 Week 6 
• Perform predose efficacy assessments (CAS, Clinical Measures of Severity including 
proptosis, diplopia and motility restriction). 
9.5.7.8 Week 12 
• Perform predose efficacy assessments (CAS, Clinical Measures of Severity including 
proptosis, diplopia and motility restriction). 
9.5.7.9 Week 15 
• Collect predose urine sample for urinalysis and also a pregnancy test for females of 
childbearing potential; the pregnancy test must be negative for the subject to receive 
study drug. 
9.5.7.10 Week 18 
• Perform predose efficacy assessments (CAS, Clinical Measures of Severity including 
proptosis, diplopia and motility restriction). 
9.5.7.12 Week 24 
• Perform predose efficacy assessments (CAS, Clinical Measures of Severity including 
proptosis, diplopia and motility restriction). 
Subjects who are proptosis non-responders will be offered the opportunity to receive up to 8 
additional infusions of teprotumumab in an open-label extension study, HZNP-TEP-302. 
9.5.7.13 Week 28 
• Perform efficacy assessments (CAS, Clinical Measures of Severity including proptosis, 
diplopia and motility restriction). 
9.5.7.14 Week 36 
• Perform efficacy assessments (CAS, Clinical Measures of Severity including proptosis, 
diplopia and motility restriction). 

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9.5.7.15 Week 48 
• Perform efficacy assessments (CAS, Clinical Measures of Severity including proptosis, 
diplopia and motility restriction). 
9.5.7.16 Week 60 
• Perform efficacy assessments (CAS, Clinical Measures of Severity including proptosis, 
diplopia and motility restriction). 
9.5.7.17 Week 72 
• Perform efficacy assessments (CAS, Clinical Measures of Severity including proptosis, 
diplopia and motility restriction). 
Subjects will be discharged from the study center after all of the procedures have been 
completed. 
The end of the trial is defined as the date of the last visit of the last subject undergoing the trial.  
9.5.7.18 Week 96 – Follow-Up Contact 
Subjects who complete the Week 72 Visit will be contacted 6 months later via phone or 
email by research staff to enquire if any treatment for TED has been received since last 
study contact. If yes, subject will be questioned regarding type of treatment and 
outcome/response. 
9.5.7.19 Week 120 – Follow-Up Contact 
Subjects who complete the Week 72 Visit will be contacted 12 months later via phone or 
email by research staff to enquire if any treatment for TED has been received since last 
study contact. If yes, subject will be questioned regarding type of treatment and 
outcome/response. 
The end of the trial is defined as the date of the last subject contact at Week 120.  
9.6.1.2 Secondary Endpoints 
Secondary Endpoints (analyzed hierarchically): 
4. 
Diplopia responder rate (percentage of subjects with baseline diplopia > 0 in study 
eye who have a reduction of ≥ 1 grade with no corresponding deterioration [≥ 1 
grade worsening] in the fellow eye) at Week 24. 
5.4. 
Mean change from Baseline to Week 24 in the GO-QoL questionnaire overall score. 
 

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9.6.3 
Primary and Secondary Endpoint Analysis 
The primary analyses will be conducted in the ITT population. The analysis of the primary 
proptosis responder endpoint will assess risk difference (difference in response rates) in a 
stratified analysis. The analysis will use Cochran-Mantel-Haenszel (CMH) weighting to 
estimate the common risk difference within strata and to estimate the standard error of the 
common risk difference. be a logistic regression with treatment group as the model effect. 
Subjects missing the Week 24 evaluation will be considered to be treatment failures 
(non-responders) for the primary analysis. Further, subjects who prematurely discontinue 
study drug dosing prior to Week 21 during the double-masked Treatment Period will be 
considered to be treatment failures (non-responders), unless an assessment at Week 24 is 
available. Stratification for the analysis will use the same factor as was used to stratify 
randomization, tobacco use (non-user, user). Since tobacco use status (non user vs. user) is 
used to stratify the randomization, it will be included as a categorical covariate. The difference 
in response rates, comparing teprotumumab to placebo, will be estimated Odds ratio 
comparing teprotumumab to placebo will be estimated along with the corresponding 95% 
confidence interval (CI) and p-value.  
An analysis of risk difference with stratification by tobacco use (non-user vs. user) Logistic 
regressionwill also be used to analyze the 32 secondary categorical endpoints. For the analysis of 
proptosis and GO-QoL (see Section 9.6.4.4 for details) as continuous secondary endpoints, a 
Mixed-Model Repeated-Measures (MMRM) analysis of covariance (ANCOVA) model will be 
fit to the individual change from baseline scores for the study eye, with terms in the model 
being the baseline score, tobacco use status, treatment group, visit, and the visit-by-treatment and 
visit-by-baseline-score interactions. The main focus of the analysis will be to test the treatment 
differences at Week 24, with the main results consisting of the Week 24 estimated Least Square 
(LS) means and their differences with 95% CIs and p-values. 
To control the overall Type 1 error rate of the study, taking into consideration the one primary 
and 54 secondary outcome measures, the outcome measures will be tested in a hierarchical 
stepwise fashion. For each outcome measure, teprotumumab will be tested against placebo at the 
0.05 level only if teprotumumab was statistically significant for the outcome measure preceding 
it in the hierarchical order. 
9.6.4.2 Clinical Measures of Severity 
The Clinical Measures of Severity results (see Table 9.3) for each item will be summarized at 
each designated visit for each eye with the number and percentage of subjects being classified as 
responders on each individual criterion. The proportions of responders will be analyzed using the 
same risk difference method described for the primary endpoint a Chi square testin 
Section 9.6.3. 

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2 
SYNOPSIS 
Protocol Title: A Phase 3, Randomized, Double-Masked, Placebo-Controlled, Parallel-Group, Multicenter 
Study Evaluating Teprotumumab (HZN-001) Treatment in Subjects with Active Thyroid Eye Disease (OPTIC) 
Protocol Number: HZNP-TEP-301 
Phase: 3 
Protocol Version: 4.0 
 
Test Drug: Teprotumumab (HZN-001) 
Indication: Active Thyroid Eye Disease (TED) 
Number and Country of Study Sites: Up to 16 study centers in the United States and Europe. 
Objectives:  
The overall objective is to investigate the efficacy, tolerability, and safety of teprotumumab (HZN-001, a fully 
human monoclonal antibody [mAb] inhibitor of the insulin-like growth factor-1 receptor [IGF-1R]) 
administered once every 3 weeks (q3W) for 24 weeks, in comparison to placebo, in the treatment of subjects 
with moderate-to-severe active TED. 
Primary Objective 
The primary objective is to evaluate the effect of teprotumumab versus placebo on the proptosis responder rate 
(i.e., the percentage of subjects with a ≥ 2 mm reduction from Baseline in the study eye without deterioration 
[≥ 2 mm increase] of proptosis in the fellow eye) at Week 24. 
Secondary Objectives (analyzed hierarchically) 
1. Evaluate the effect of teprotumumab versus placebo on the overall responder rate (percentage of subjects 
with ≥ 2-point reduction in Clinical Activity Score [CAS] AND ≥ 2 mm reduction in proptosis from 
Baseline, provided there is no corresponding deterioration [≥ 2-point/mm increase] in CAS or proptosis in 
the fellow eye) at Week 24. 
2. Evaluate the effect of teprotumumab versus placebo on the percentage of subjects with a CAS value of 
0 or 1 at Week 24 in the study eye. 
3. Evaluate the effect of teprotumumab versus placebo on the mean change from Baseline to Week 24 in 
proptosis measurement in the study eye. 
4. Evaluate the effect of teprotumumab versus placebo on the diplopia responder rate (i.e., the percentage of 
subjects with baseline diplopia > 0 in study eye who have a reduction of ≥ 1 grade with no corresponding 
deterioration [≥ 1 grade worsening] in the fellow eye) at Week 24. 
5. Evaluate the effect of teprotumumab versus placebo on the mean change from Baseline to Week 24 in the 
Graves’ Ophthalmopathy Quality of Life (GO-QoL) questionnaire overall score. 
Exploratory Objectives 
1. Evaluate the effect of teprotumumab versus placebo on the Clinical Measures of Severity individual 
response status frequencies and percentage of responders for each component of clinical severity from 
Baseline to Week 24. 
2. Evaluate the effect of teprotumumab versus placebo on the mean change from Baseline to Week 24 in the 
CAS. 
3. Evaluate the effect of teprotumumab versus placebo on the overall responder rate at Week 24 stratified by 
the level of response (high responders, responders, low responders, and non-responders; see 
Section 9.6.4.3.1 for definitions). 
4. Evaluate pharmacokinetic (PK) parameters of teprotumumab to estimate exposure and understand 
PK-pharmacodynamic (PD) relationships. 
5. Evaluate the effect of teprotumumab versus placebo on the mean change from Baseline to Week 24 in the 
GO-QoL questionnaire visual functioning (VF) and appearance (A) subscale scores. 
6. Evaluate the effect of teprotumumab on the mean change from Baseline to Week 24 in blood and serum 
biomarkers. 
7. Evaluate the effect of teprotumumab versus placebo on the mean change from Baseline to Week 24 on the 
motility component of the Clinical Measures of Severity. 

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Study Design: 
This is a randomized, double-masked, placebo-controlled, parallel-group, multicenter study. Subjects will be 
screened for the study within 2 to 6 weeks prior to the Baseline (Day 1) Visit. Approximately 76 subjects 
(38/group) who meet the study eligibility criteria will be randomized on Day 1 in a 1:1 ratio (stratified by 
tobacco use status) to receive 8 infusions of teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for the 
remaining 7 infusions) or placebo q3W. All subjects will enter a 24-week double-masked Treatment Period, 
during which study drug will be infused on Day 1 (Baseline), and Weeks 3, 6, 9, 12, 15, 18, and 21 (with a final 
visit at Week 24). All study drug dosing will be performed at the clinic under the supervision of clinic staff, and 
at any scheduled infusion, the infusion rate may be reduced or the dose may be interrupted or held based on 
decreased 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 dosing. After each of the first 2 infusions, subjects will be contacted 
by phone/email the following day and will return to the clinic 1 week after the infusion (Weeks 1 and 4) for 
safety and tolerability assessments; additional phone/email contacts and clinic visits may also be conducted for 
any subject experiencing an infusion-associated event. 
At the end of the double-masked Treatment Period (Week 24), subjects who are proptosis non-responders (study 
eye has < 2 mm decrease in proptosis) will be eligible to enter an open-label extension study (HZNP-TEP-302) 
in which subjects may receive 8 infusions of teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for 
the remaining 7 infusions) in an open-label fashion.  
At Week 24, proptosis responders, as well as non-responders who choose not to enroll in the open-label 
extension study (HZNP-TEP-302), will enter a 48-week Follow-Up Period, during which study drug will not be 
administered and clinic visits are scheduled for Weeks 28, 36, 48, 60, and 72 (Months 7, 9, 12, 15, and 18). 
Subjects who are considered responders at Week 24 but who meet criteria for re-treatment due to relapse during 
the Follow-Up Period may enroll in the open-label extension study, HZNP-TEP-302 (see Section 9.3.4). 
Subjects who prematurely discontinue study drug dosing prior to Week 21 of the Treatment Period will return to 
the clinic and undergo the scheduled Week 24 assessments and will be encouraged to participate in the Follow-
Up Period unless they initiated another intervention due to lack of efficacy. Subjects who enter the Follow-Up 
Period but prematurely discontinue study participation prior to 48 weeks following the double-masked 
Treatment Period will return for a final visit and undergo the scheduled Week 72 assessments prior to study 
discharge.  
Subjects who complete the Week 72 Visit will be contacted 6 and 12 months later via phone or email by 
research staff to enquire if any treatment for TED has been received since last study contact. If yes, subject will 
be questioned regarding type of treatment and outcome/response. 
An overview of the study design is presented in the schematic below, and details of study activities are provided 
in Section 2.1, Schedule of Assessments. 

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Screen 
Baseline 
Double-Masked Treatment Period 
Teprotumumab or Placebo 1, 2 
24 Weeks 
Follow-Up Period 
48 Weeks 3,4 
Follow-Up 
Contact5  
48 Weeks 
 
< –––––––––––––––––––––––––– Clinic Visits ––––––––––––––––––––––––––––––––– > < –––––––– Clinic Visits –––––– >  
 
* 
 
* 
 
* 
* 
* 
* 
* 
* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 to 6 
weeks 
predose 
Day 1 6 
W1 
W3 6 
W4 
M1 
W6 
W9 
W12 
M3 
W15 
W18 
W21 
W24 7 
M6  
W28 
M7  
W36 
M9 
W48 
M12 
W60 
M15 
W72 
M18 
W96 
M24 
W120 
M30 
 
 
Randomization 
n=38/group 1 
< –––––––––––––––––––––––––––––––––––– Study Week/Month –––––––––––––––––––––––––––––––––––––––––– > 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Infusion of study drug. 
1. 
Subjects will be randomized in a 1:1 ratio (stratified by tobacco use status) to receive: 
a. Teprotumumab 20 mg/kg (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 ± 1 day for Weeks 1 and 4, ± 3 days for Weeks 3, 6, 9, 12, 15, 18, and 21, and ± 7 days for Week 24. 
3. 
Subjects who are proptosis responders or non-responders who do not elect to participate in the open-label extension study will enter a 48-week 
Follow-Up Period. Subjects who are responders at Week 24 but relapse during the Follow-Up Period may enter the open-label study and receive 
8 infusions if they meet specified criteria. 
4. 
Visit windows of ± 7 days. 
5. 
Subjects who complete the Week 72 Visit will be contacted via phone or email by research staff to enquire if any treatment for TED has been 
received since last study contact. 
6. 
Subjects will be contacted by phone/email the day following the first and second infusions for safety and tolerability assessments; phone/email 
contacts will also occur the day after any clinic visit where a subject experiences an infusion-related adverse event. 
7. Subjects who are proptosis non-responders at Week 24 of the double-masked Treatment Period will be offered the option to enter an open-label 
extension study and receive 8 infusions of teprotumumab 20 mg/kg (10 mg/kg on Day 1 followed by 20 mg/kg for the remaining 7 infusions). 
Subject Population: 
Approximately 76 (38/group) male and non-pregnant female subjects between the ages of 18 and 80 years, 
inclusive, with a clinical diagnosis of Graves’ disease associated with moderate-to-severe, active TED and a 
CAS ≥ 4 (using 7-item scale) for the most severely affected eye will be enrolled.  
Inclusion Criteria: 
Eligible subjects must meet/provide all of the following criteria: 
1. Written informed consent. 
2. Male or female subject between the ages of 18 and 80 years, inclusive, at Screening. 
3. Clinical diagnosis of Graves’ disease associated with active TED with a CAS ≥ 4 (on the 7-item scale) 
for the most severely affected eye at Screening and Baseline. 
4. Moderate-to-severe active TED (not sight-threatening but has an appreciable impact on daily life), 
usually associated with one or more of the following: lid retraction >2 mm, moderate or severe soft 
tissue involvement, exophthalmos > 3 mm above normal for race and gender, and/or inconstant or 
constant diplopia. 
5. Onset of active TED symptoms (as determined by subject records) within 9 months prior to Baseline. 
6. Subjects must be euthyroid with the baseline disease under control, or have mild hypo- or 
hyperthyroidism (defined as free thyroxine [FT4] and free triiodothyronine [FT3] levels < 50% above 
or below the normal limits) at Screening. Every effort should be made to correct the mild hypo- or 
hyperthyroidism promptly and to maintain the euthyroid state for the full duration of the clinical trial.  
7. Does not require immediate surgical ophthalmological intervention and is not planning corrective 
surgery/irradiation during the course of the study. 
8. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3 times the upper limit of 
normal (ULN) or serum creatinine <1.5 times the ULN according to age at Screening. 

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9. Diabetic subjects must have well-controlled stable disease (defined as HbA1c < 9.0% with no new 
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, non-therapy-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 through 
Week 48 of 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 one 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 less than 1% per year), when used consistently and 
correctly, includes implants, injectables, combined oral contraceptives, some intrauterine devices 
(IUDs), sexual abstinence or vasectomized partner.  
11. Male subjects must be surgically sterile or, if sexually active with a female partner of childbearing 
potential, must agree to use a barrier contraceptive method from Screening through 180 days after the 
last dose of study drug.  
12. Subject is willing and able to comply with the prescribed treatment protocol and evaluations for the 
duration of the study. 
Exclusion Criteria: 
Subjects will be ineligible for study participation if they meet any of the following criteria: 
1. Decreased best corrected visual acuity due to optic neuropathy as defined by a decrease in vision of 2 
lines on the Snellen chart, new visual field defect, or color defect secondary to optic nerve involvement 
within the last 6 months. 
2. Corneal decompensation unresponsive to medical management.  
3. Decrease in CAS of ≥ 2 points in the study eye between Screening and Baseline. 
4. Decrease in proptosis of ≥ 2 mm in the study eye between Screening and Baseline. 
5. Previous orbital irradiation or surgery for TED. 
6. Any steroid use (intravenous [IV] or oral) with a cumulative dose equivalent to ≥ 1 g of 
methylprednisolone for the treatment of TED. Previous steroid use (IV or oral) with a cumulative dose 
of <1 g methylprednisolone or equivalent for the treatment of TED and previous use of steroid eye 
drops is allowed if discontinued at least 4 weeks prior to Screening. 
7. Corticosteroid use for conditions other than TED within 4 weeks prior to Screening (topical steroids for 
dermatological conditions and inhaled steroids are allowed). 
8. Selenium and biotin must be discontinued 3 weeks prior to Screening and must not be restarted during 
the clinical trial; however, taking a multivitamin that includes selenium and/or biotin is allowed. 
9. Any previous treatment with rituximab (Rituxan® or MabThera®) or tocilizumab (Actemra® or 
Roactemra®). Use of any other non-steroid immunosuppressive agent within 3 months prior to 
Screening. 
10. Use of an investigational agent for any condition within 60 days prior to Screening or anticipated use 
during the course of the trial. 
11. Identified pre-existing ophthalmic disease that, in the judgment of the Investigator, would preclude 
study participation or complicate interpretation of study results. 
12. Bleeding diathesis that in the judgment of the Investigator would preclude inclusion in the clinical trial. 
13. Malignant condition in the past 12 months (except successfully treated basal/squamous cell carcinoma 
of the skin). 
14. Pregnant or lactating women. 

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15. Current drug or alcohol abuse, or history of either within the previous 2 years, in the opinion of the 
Investigator or as reported by the subject. 
16. Biopsy-proven or clinically suspected inflammatory bowel disease (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). 
17. Known hypersensitivity to any of the components of teprotumumab or prior hypersensitivity reactions 
to mAbs. 
18. Any other condition that, in the opinion of the Investigator, would preclude inclusion in the study. 
19. Previous enrollment in this study or participation in a prior teprotumumab clinical trial. 
20. HIV, hepatitis C or hepatitis B infections. 
Dose Regimen/Route of Administration: 
All study drug dosing will be performed at the clinic under the supervision of clinic staff. On Day 1 of the 
double-masked Treatment Period, subjects will be randomized in a 1:1 ratio (stratified by tobacco use status) to 
receive infusions of either: 
1. Teprotumumab 20 mg/kg (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 (see 
Section 9.4.6.3.2 for details). 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. 
Dosage Form and Strength Formulation: 
Teprotumumab 500 mg will be provided in single-dose 20 mL glass vials as a freeze-dried powder. Each vial of 
teprotumumab will be reconstituted with 10 mL of water for injection. The resulting solution will have an 
approximate concentration of 50 mg/mL teprotumumab. Reconstituted teprotumumab solution will be further 
diluted in 0.9% (w/v) sodium chloride (NaCl) solution prior to administration. 
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 teprotumumab to be placed into the infusion bag will be first 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 teprotumumab reconstituted drug 
product solution will be diluted with normal saline (0.9% NaCl) in the infusion bag. 
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.  
Duration of Treatment and Follow-Up: 
The planned duration of the double-masked Treatment Period is 24 weeks (6 months). Subjects who are 
considered proptosis non-responders at Week 24 or subjects who were responders at Week 24 but who meet 
criteria for re-treatment due to relapse during the Follow-Up Period may enroll in the open-label extension 
study, HZNP-TEP-302 (see Section 9.3.4). 
At Week 24, proptosis responders, as well as non-responders who choose not to enroll in the open-label 
extension study, will enter a 48-week Follow-Up Period.  
Subjects who complete the Week 72 Visit will be contacted 6 and 12 months later via phone or email by 
research staff to enquire if any treatment for TED has been received since last study contact. 
Criteria for Evaluation: 
The most severely affected eye will be defined as the "study eye" at the Baseline (Day 1) Visit. If there is a 
discrepancy between CAS and proptosis in determining the study eye, this will be adjudicated always to the eye 

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with the most significant proptosis. If both eyes are affected equally, the Investigator will choose the “study 
eye”. Both eyes will be assessed for efficacy but the study eye will be used to assess the primary outcome 
measure. 
Efficacy will be assessed by proptosis (measured as exophthalmos evaluation of the Clinical Measures of 
Severity using a Hertel instrument provided by the Sponsor for consistency in measurement), CAS (7-item 
scale), diplopia (measured as part of the Clinical Measures of Severity), and Clinical Measures of Severity 
(including motility restriction assessments).  
Quality of life will be assessed using the GO-QoL questionnaire. 
Blood samples for teprotumumab PK assessment will be collected prior to, and at the end of, the infusion on 
Day 1 and Weeks 3 and 9 during the Treatment Period; in addition, single samples will be collected at Weeks 1, 
4, and 24. PK/PD relationships will be explored. 
Serum samples may be analyzed for biomarkers (IL-4, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, IL-1β,  sIL-1RA, 
INFγ, TGFβ, TNFα,  and micRNA) and possibly functional thyroid stimulating hormone receptor stimulating, 
blocking, and binding antibody (TSH-R-Ab) during the Treatment Period. Based on the results of the above 
assays, other similar serum biomarkers may be assayed to further explore drug and disease mechanisms. 
Safety will be assessed via AE and concomitant medication use monitoring, immunogenicity testing, physical 
and ophthalmic examinations, vital signs, clinical safety laboratory evaluations (complete blood count, 
chemistry (including thyroid panel and HbA1c), and urinalysis), pregnancy testing (if applicable), and 
electrocardiograms (ECG). The study will also be monitored by a Data Safety Monitoring Board (DSMB). 
Statistical Analyses: 
Primary Efficacy Endpoint 
The primary outcome measure is the effect of teprotumumab versus placebo on the proptosis responder rate 
(percentage of subjects with a ≥ 2 mm reduction from Baseline in proptosis in the study eye, without 
deterioration [≥ 2 mm increase] of proptosis in the fellow eye) at Week 24. 
Secondary Efficacy Endpoints (analyzed hierarchically) 
1. The effect of teprotumumab versus placebo on the overall responder rate (percentage of subjects with 
≥ 2-point reduction in CAS AND ≥ 2 mm reduction in proptosis from Baseline, provided there is no 
corresponding deterioration [≥ 2-point/mm increase] in CAS or proptosis in the fellow eye) at 
Week 24. 
2. The effect of teprotumumab versus placebo on the percentage of subjects with a CAS value of 0 or 1 at 
Week 24 in the study eye. 
3. The effect of teprotumumab versus placebo on the mean change from Baseline to Week 24 in proptosis 
measurement in the study eye. 
4. The effect of teprotumumab versus placebo on the diplopia responder rate (percentage of subjects with 
baseline diplopia > 0 in study eye who have a reduction of ≥ 1 grade with no corresponding 
deterioration [≥ 1 grade worsening] in the fellow eye) at Week 24. 
5. The effect of teprotumumab versus placebo on the mean change from Baseline to Week 24 in the 
GO-QoL questionnaire overall score. 
Exploratory Efficacy Endpoints 
1. The effect of teprotumumab versus placebo on the Clinical Measures of Severity individual response 
status frequencies and percentage of responders for each component of clinical severity from Baseline 
to Week 24. 
2. The effect of teprotumumab versus placebo on the mean change from Baseline to Week 24 in the CAS. 
3. The effect of teprotumumab versus placebo on the overall responder rate at Week 24 stratified by the 
level of response (high responders, responders, low responders, and non-responders). 
4. To evaluate the PK parameters of teprotumumab to estimate exposure and understand the PK-PD 
relationships. 

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5. Evaluate the effect of teprotumumab versus placebo on the mean change from Baseline to Week 24 in 
the GO-QoL questionnaire VF and A subscale scores. 
6. To evaluate the effect of teprotumumab on the mean change from Baseline to Week 24 in blood and 
serum markers. 
7. To evaluate the effect of teprotumumab versus placebo on the mean change from Baseline to Week 24 
on the motility component of the Clinical Measures of Severity. 
Statistical Analysis on Efficacy Parameters 
The primary analyses will be conducted in the Intent-to-Treat (ITT) population. The analysis of the primary 
proptosis responder endpoint will assess risk difference (difference in response rates) in a stratified analysis. The 
analysis will use Cochran-Mantel-Haenszel (CMH) weighting to estimate the common risk difference within 
strata and to estimate the standard error of the common risk difference. Subjects missing the Week 24 evaluation 
will be considered to be treatment failures (non-responders) for the primary analysis. Further, subjects who 
prematurely discontinue study drug dosing prior to Week 21 during the double-masked Treatment Period will be 
considered to be treatment failures (non-responders), unless an assessment at Week 24 is available. Stratification 
for the analysis will use the same factor as was used to stratify randomization, tobacco use (non-user, user). The 
difference in response rates, comparing teprotumumab to placebo, will be estimated along with the 
corresponding 95% confidence interval (CI) and p-value.  
An analysis of risk difference with stratification by tobacco use (non-user vs. user) will also be used to analyze 
the 3 secondary categorical endpoints (overall responder rate, CAS [value of 0 or 1] and diplopia responder 
rate). For the analysis of proptosis as a continuous secondary endpoint and GO-QoL, a Mixed-Model Repeated-
Measures (MMRM) analysis of covariance (ANCOVA) model will be fit to the individual change from baseline 
scores for the study eye, with terms in the model being the baseline score, tobacco use status, treatment group, 
visit, and the visit-by-treatment and visit-by-baseline-score interactions. The main focus of the analysis will be 
to test the treatment differences at Week 24, with the main results consisting of the Week 24 estimated Least 
Square (LS) means and their differences with 95% CIs and p-values. 
To control the overall Type 1 error rate of the study, taking into consideration the one primary and 5 secondary 
outcome measures, the outcome measures will be tested in a hierarchical stepwise fashion. For each outcome 
measure, teprotumumab will be tested against placebo at the 0.05 level only if teprotumumab was statistically 
significant for the outcome measure preceding it in the hierarchical order. 
Sample Size Estimate: 
In the prior TED01RV study, a 51% difference (71% vs 20%) in proptosis reduction of 2 mm or more between 
teprotumumab (10 mg/kg for the first infusion followed by 20 mg/kg for the remaining 7 infusions) and placebo 
was observed at Week 24 in favor of teprotumumab. A sample size of 38 subjects per group provides 90% 
power at the 2-sided alpha 0.05 level to detect a difference of 39% between teprotumumab and placebo; the 
sample size has been adjusted to allow for a 16% discontinuation rate. 

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11. Subjects will be randomized in a 1:1 ratio (stratified by tobacco use status) to receive either: a) teprotumumab (10 mg/kg on Day 1 followed by 20 mg/kg q3W for the 
remaining 7 infusions) or b) placebo (q3W for all 8 infusions). 
12. Phone (or email) contact by research staff focusing on safety and tolerability aspects will be made the day after 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. 
13. CAS must be ≥ 4 for enrollment and randomization.  
14. Subjects whose CAS score decreases 2 or more points in the study eye from Screening are not eligible for randomization. 
15. Subjects who have a ≥ 2 mm decrease in proptosis in the study eye from Screening are not eligible for randomization. 
16. Serum pregnancy test at Screening and urine pregnancy tests prior to dose 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]). 
17. Pregnancy test only performed for female subjects of childbearing potential who enter the Follow-Up Period but discontinue study participation prior to Week 48. 
18. Physical exam will include assessment of presence or absence of pretibial myxedema on Day 1 and Week 24 (or PW) of the Treatment Period and Week 72 (or PW) of the 
Follow-Up Period. If present, measurements of instep and calf will be taken. 
19. Height will be measured at Screening only. 
20. Ophthalmic exam: best corrected visual acuity, pupil exam, color vision assessment, Ishihara color plates (or equivalent) or related red desaturation, intraocular pressure, and 
slit lamp exam. If significant abnormalities are noted compared to previous visits, including a loss of 2 lines or more of vision, development of pupil abnormalities including 
APD, rise in intraocular pressure, development of corneal infiltrates or other abnormalities not here specified but of concern to the ophthalmologist, further investigations of 
visual function will be conducted according to the ophthalmologist decision. 
21. Subjects who have decreased best-corrected visual acuity due to optic neuropathy (defined by a decrease in vision of 2 lines on the Snellen chart, new visual field defect, or 
color defect secondary to optic nerve involvement within the last 6 months) are not eligible for randomization. 
22. 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-dose on all other infusion days. Additional vital signs will be monitored if infusion-associated AEs occur (see Section 9.5.5.4 for details). 
23. Non-diabetic subjects should be fasting at Weeks 1 and 4 only. Diabetic subjects should be fasting at each visit blood glucose is evaluated. 
24. ALT/AST must be ≤3 x the upper limit of normal (ULN) and serum creatinine must be <1.5 x the ULN according to age to be eligible for randomization. 
25. Subjects must be euthyroid with the baseline disease under control or have mild hypo- or hyperthyroidism (defined as free thyroxine [FT4] and free triiodothyronine [FT3] 
levels < 50% above or below the normal limits). Every effort should be made to correct the mild hypo- or hyperthyroidism promptly and to maintain the euthyroid state for the 
full duration of the clinical trial.  
26. HbA1c must be < 9.0% for randomization. If the HbA1c is elevated and considered clinically significant at any time point after Screening, it will be repeated approximately 
every 45 days until it returns to normal or baseline value. 
27. If a sample is positive in the ADA test, after confirmatory and reactive titer testing, the sample will then be tested for NAb. If the subject tests positive for NAb, he/she will be 
followed until levels either revert to Baseline or the subject’s value decreases or remains stable. Any subject with a positive NAb test at Week 72 (or PW) during the 
Follow-Up Period will continue to be followed until the subject’s value decreases or remains stable. 
28. Not collected for subjects who prematurely discontinue from the Treatment Period. 
29. Adverse events (AEs) that occur within 2 weeks prior to Day 1 and prior to dosing on Day 1 will be considered baseline signs/symptoms. Adverse events occurring or 
worsening after the dose on Day 1 through the end of the Treatment Period will be considered treatment-emergent AEs (TEAEs). Adverse events occurring or worsening 
during the Follow-Up Period will be considered postdose AEs. All SAEs that occur from the signing of informed consent through 30 days after study discontinuation will be 
recorded. 

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30. Serum (two 5.0 mL samples) will be obtained on Day 1 and Weeks 12 and 24 of the Treatment Period for possible analysis of interleukin (IL)-4, IL-6, IL-10, IL-12, IL-13, 
IL-17, IL-23, IL-1β, sIL-1RA, INFγ, TGFβ, TNFα, micRNA and TSH-R-Ab. Based on the results of the above assays, other similar serum biomarkers may be assayed to 
further explore drug and disease mechanisms. 
31. PK samples will be collected prior to, and at the end of, the infusion on Day 1 and Weeks 3 and 9 of the Treatment Period; additional single samples will be collected at 
Weeks 1, 4, and 24. 
32. If TED treatment has been received since last contact, the subject will be questioned regarding type of treatment and outcome/response. 

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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .......................................................................................................................... 2 
2 
SYNOPSIS ............................................................................................................................ 22 
2.1 
Schedule of Assessments ............................................................................................... 29 
3 
TABLE OF CONTENTS ...................................................................................................... 33 
4 
LIST OF ABBREVIATIONS ............................................................................................... 39 
5 
ETHICS ................................................................................................................................. 42 
5.1 
Institutional Review Board/Independent Ethics Committee .......................................... 42 
5.2 
Ethical Conduct of the Study ......................................................................................... 42 
5.3 
Subject Information and Consent ................................................................................... 42 
5.4 
Compensation for Health Damage of Subjects/Insurance .............................................. 43 
5.5 
Confidentiality ................................................................................................................ 43 
6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................... 43 
7 
INTRODUCTION ................................................................................................................ 45 
7.1 
Background .................................................................................................................... 45 
7.1.1 
Thyroid Eye Disease ............................................................................................... 45 
7.1.2 
Insulin-like Growth Factor-1 Receptor (IGF-1R) ................................................... 48 
7.1.3 
Teprotumumab ........................................................................................................ 49 
7.1.3.1 Physiochemical Properties .................................................................................. 49 
7.1.3.2 Safety Pharmacology........................................................................................... 50 
7.1.3.3 Non-Clinical Pharmacokinetics ........................................................................... 51 
7.1.3.4 Clinical Experience ............................................................................................. 52 
7.1.3.4.1 
Introduction ............................................................................................... 52 
7.1.3.4.2 
Efficacy ...................................................................................................... 53 
7.1.3.4.3 
Pharmacokinetics ....................................................................................... 53 
7.1.3.4.4 
Pharmacodynamic Markers ....................................................................... 55 
7.1.3.4.5 
Safety ......................................................................................................... 55 
7.2 
Rationale for this Study .................................................................................................. 61 
7.3 
Rationale for Dose Selection .......................................................................................... 62 
8 
STUDY OBJECTIVES ......................................................................................................... 62 
8.1 
Primary Objective .......................................................................................................... 62 

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8.2 
Secondary Objectives ..................................................................................................... 63 
8.3 
Exploratory Objectives ................................................................................................... 63 
9 
INVESTIGATIONAL PLAN ............................................................................................... 64 
9.1 
Overall Study Design and Plan ...................................................................................... 64 
9.2 
Discussion of Study Design ........................................................................................... 65 
9.3 
Selection of Study Population ........................................................................................ 66 
9.3.1 
Inclusion Criteria .................................................................................................... 66 
9.3.2 
Exclusion Criteria ................................................................................................... 67 
9.3.3 
Removal of Subjects from Therapy or Assessment ................................................ 68 
9.3.4 
Criteria for Responders Who Relapse ..................................................................... 70 
9.3.5 
Replacement Policy ................................................................................................ 70 
9.3.5.1 Subjects ............................................................................................................... 70 
9.3.5.2 Centers ................................................................................................................. 70 
9.3.5.3 Screen Failures .................................................................................................... 70 
9.4 
Treatments ...................................................................................................................... 70 
9.4.1 
Treatments Administered ........................................................................................ 70 
9.4.2 
Identity of Investigational Products ........................................................................ 71 
9.4.2.1 Teprotumumab .................................................................................................... 71 
9.4.2.2 Placebo ................................................................................................................ 71 
9.4.3 
Labeling .................................................................................................................. 71 
9.4.4 
Storage .................................................................................................................... 71 
9.4.5 
Drug Accountability................................................................................................ 72 
9.4.6 
Study Drug Administration and Timing of Dose for each Subject ......................... 72 
9.4.6.1 Description of Clinical Supplies ......................................................................... 72 
9.4.6.2 Determination of Dose Volume .......................................................................... 72 
9.4.6.3 Details Concerning Timing and Dose Administration ........................................ 73 
9.4.6.3.1 
Preparation and Administration of Teprotumumab ................................... 73 
9.4.6.3.2 
Dose Modifications, Interruptions, and Delays ......................................... 74 
9.4.7 
Method of Assigning Subjects to Treatment Groups .............................................. 75 
9.4.8 
Masking and Unmasking ........................................................................................ 75 
9.4.9 
Concomitant Therapy and Restricted Medications ................................................. 76 

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9.4.9.1 Restricted Therapy and Medications ................................................................... 76 
9.4.10 
Treatment Compliance ............................................................................................ 78 
9.5 
Efficacy, Quality-of-Life, Pharmacokinetic, and Safety Variables ............................... 78 
9.5.1 
Efficacy Variables ................................................................................................... 78 
9.5.1.1 Proptosis (Exophthalmos) ................................................................................... 78 
9.5.1.2 Clinical Activity Score (CAS)............................................................................. 79 
9.5.1.3 Clinical Measures of Severity ............................................................................. 79 
9.5.1.3.1 
Motility Restriction – Details for Measurement ........................................ 80 
9.5.2 
Quality-of-Life Assessment .................................................................................... 81 
9.5.3 
Pharmacokinetic Measurements ............................................................................. 81 
9.5.4 
Biomarker Assessments .......................................................................................... 81 
9.5.5 
Safety Variables ...................................................................................................... 82 
9.5.5.1 Adverse Events .................................................................................................... 82 
9.5.5.1.1 
Definitions ................................................................................................. 82 
9.5.5.1.2 
Documentation of Adverse Events ............................................................ 84 
9.5.5.1.3 
Intensity of Adverse Events ....................................................................... 84 
9.5.5.1.4 
Relationship to Study Drug ....................................................................... 84 
9.5.5.1.5 
Reporting and Documenting SAEs ............................................................ 85 
9.5.5.1.6 
Follow-Up of Adverse Events ................................................................... 86 
9.5.5.1.7 
Medication Error and Overdose ................................................................ 86 
9.5.5.1.8 
Review of Adverse Events and Emerging New Safety Information ......... 86 
9.5.5.1.9 
Reporting of IND Safety Reports .............................................................. 87 
9.5.5.1.10 Reporting of Suspected Unexpected Serious Adverse Reactions in 
the EU ........................................................................................................ 87 
9.5.5.1.11 Development Safety Update Reports ........................................................ 87 
9.5.5.2 Pregnancy Reporting ........................................................................................... 87 
9.5.5.3 Medical History ................................................................................................... 88 
9.5.5.4 Vital Signs ........................................................................................................... 88 
9.5.5.5 Physical and Ophthalmic Examinations, Height, and Weight ............................ 88 
9.5.5.6 ECGs ................................................................................................................... 89 
9.5.5.7 Clinical Laboratory Safety Tests ......................................................................... 89 
9.5.5.8 Immunogenicity Testing ..................................................................................... 90 

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9.5.5.9 Data Safety Monitoring Board ............................................................................ 91 
9.5.6 
Appropriateness of Measurements .......................................................................... 91 
9.5.7 
Study Procedures .................................................................................................... 91 
9.5.7.1 Screening ............................................................................................................. 91 
9.5.7.2 Day 1/Baseline .................................................................................................... 93 
9.5.7.3 Week 1 ................................................................................................................. 94 
9.5.7.4 Week 3 ................................................................................................................. 94 
9.5.7.5 Week 4 ................................................................................................................. 95 
9.5.7.6 Week 6 ................................................................................................................. 95 
9.5.7.7 Week 9 ................................................................................................................. 96 
9.5.7.8 Week 12 ............................................................................................................... 96 
9.5.7.9 Week 15 ............................................................................................................... 97 
9.5.7.10 Week 18 ............................................................................................................... 98 
9.5.7.11 Week 21 ............................................................................................................... 98 
9.5.7.12 Week 24 ............................................................................................................... 99 
9.5.7.13 Week 28 ............................................................................................................. 100 
9.5.7.14 Week 36 ............................................................................................................. 100 
9.5.7.15 Week 48 ............................................................................................................. 100 
9.5.7.16 Week 60 ............................................................................................................. 101 
9.5.7.17 Week 72 (Termination Visit or Premature Withdrawal Visit) .......................... 101 
9.5.7.18 Week 96 – Follow-Up Contact .......................................................................... 102 
9.5.7.19 Week 120 – Follow-Up Contact ........................................................................ 102 
9.6 
Statistical Methods and Determination of Sample Size ............................................... 102 
9.6.1 
Endpoints .............................................................................................................. 102 
9.6.1.1 Primary Endpoint .............................................................................................. 102 
9.6.1.2 Secondary Endpoints (analyzed hierarchically) ................................................ 102 
9.6.1.3 Exploratory Endpoints ....................................................................................... 102 
9.6.2 
Populations for Analysis ....................................................................................... 103 
9.6.3 
Primary and Secondary Endpoint Analysis .......................................................... 103 
9.6.4 
Exploratory Analyses ............................................................................................ 104 
9.6.4.1 Pharmacokinetics/Pharmacodynamics .............................................................. 104 

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9.6.4.2 Clinical Measures of Severity ........................................................................... 104 
9.6.4.2.1 
Motility Component of the Clinical Measures of Severity ...................... 104 
9.6.4.3 Clinical Activity Score (CAS)........................................................................... 104 
9.6.4.3.1 
Stratification of Proptosis and CAS Response into Four Responses 
Categories ................................................................................................ 104 
9.6.4.4 Quality of Life Analysis .................................................................................... 105 
9.6.4.5 Blood and Serum Biomarkers ........................................................................... 105 
9.6.4.6 Safety Analyses ................................................................................................. 105 
9.6.4.7 Interim Analyses ............................................................................................... 105 
9.6.5 
Sample Size and Power Considerations ................................................................ 105 
9.7 
Changes in the Conduct of the Study ........................................................................... 106 
10 SOURCE DOCUMENTATION AND INVESTIGATOR FILES ..................................... 106 
11 CASE REPORT FORMS ................................................................................................... 107 
12 STUDY MONITORING..................................................................................................... 107 
13 DATA MANAGEMENT .................................................................................................... 108 
14 RETENTION OF RECORDS ............................................................................................. 109 
15 PUBLICATION .................................................................................................................. 109 
16 REFERENCES ................................................................................................................... 109 
17 APPENDICES .................................................................................................................... 115 
17.1 Administrative Appendix ............................................................................................. 115 
17.2 Proptosis (Exophthalmometry) Method ....................................................................... 116 
17.3 Graves’ Ophthalmopathy Quality of Life Questionnaire ............................................. 117 
 
 
 

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LIST OF TABLES 
Table 6.1 
Table of Non-Sponsor Study Responsibilities ........................................................... 44 
Table 7.1 
Single-Dose Pharmacokinetic Parameters (CHO Material) ...................................... 54 
Table 7.2 
Summary of TEAEs Reported in at Least 5% of Subjects in Teprotumumab 
Treatment Group and % is Greater Than Placebo ..................................................... 56 
Table 7.3 
Summary of SAEs Reported in Either Treatment Group by Preferred Term ............ 57 
Table 9.1 
Restricted Medications and Therapies ....................................................................... 77 
Table 9.2 
Clinical Activity Score (CAS) Assessment ............................................................... 79 
Table 9.3 
Clinical Measures of Severity .................................................................................... 80 
Table 9.4 
Schedule of Clinical Laboratory Safety Tests, Including Thyroid Panel and 
Hyperglycemia Monitoring ....................................................................................... 90 
 
LIST OF FIGURES 
Figure 7.1 Thyroid Eye Disease Photographs ............................................................................. 47 
Figure 9.1 Schematic of Study Design ........................................................................................ 65 
 

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4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
A subscale 
Appearance subscale of GO-QoL 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
APD 
Afferent pupillary defect 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
CAS 
Clinical activity score 
CFR 
Code of Federal Regulations 
CHO 
Chinese hamster ovary 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum observed concentration 
CMH 
Cochran-Mantel-Haenszel 
CPI 
Coordinating principal investigator 
CRO 
Contract research organization 
CS 
Clinically significant 
Ctrough 
Trough concentration 
CV 
Coefficient of variance 
DSMB 
Data safety monitoring board 
EAA 
European Economic Area 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EU 
European Union 
EUGOGO 
European Group on Graves’ Ophthalmopathy 
FDA 
Food and Drug Administration 
FT3 
Free triiodothyronine 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice 
GD-IgG 
Graves’ disease immunoglobulin G 

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Abbreviation 
Definition 
GO 
Graves’ ophthalmopathy or orbitopathy 
GO-QoL 
Graves’ Ophthalmopathy Quality of Life 
HbA1c 
Glycated hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HZN-001 
Teprotumumab (previously RV 001) 
IB 
Investigator’s brochure 
IBD 
Inflammatory bowel disease 
ICD 
Intercanthal distance 
ICF 
Informed consent form 
ICH 
International Conference of Harmonization 
IEC 
Independent ethics committee 
IGF-1R 
Insulin-like growth factor-1 receptor 
IL 
Interleukin 
IND 
Investigational new drug 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
IV 
Intravenous  
IWRS 
Interactive Web Response System 
LR 
Light reflex 
LS 
Least squares 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified intent-to-treat 
MMRM 
Mixed-Model Repeated-Measures 
NAb 
Neutralizing antibody 
NCI 
National Cancer Institute 
NCI-CTCAE  
National Cancer Institute Common Terminology Criteria for Adverse Events 
NCS 
Not clinically significant 
PBMC 
Peripheral blood mononuclear cells 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PopPK 
Population pharmacokinetics 

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Abbreviation 
Definition 
PP 
Per-protocol 
PVC 
Polyvinyl chloride 
PW 
Premature withdrawal 
q3W 
Once every 3 weeks 
QoL 
Quality of life 
qW 
Once per week 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SST 
Serum separator tube 
SUSAR 
Suspected unexpected serious adverse reaction 
T1/2 
Terminal phase elimination half-life 
Tmax 
Time to observed maximum concentration 
TAO 
Thyroid-associated ophthalmopathy 
TEAE 
Treatment-emergent adverse event 
TED 
Thyroid eye disease 
TSH 
Thyroid stimulating hormone 
TSHR 
Thyroid-stimulating-hormone receptor 
TSH-R-Ab 
TSH-Receptor stimulating, blocking and binding antibody 
ULN 
Upper limit of normal 
VF subscale 
Visual functioning subscale of GO-QoL 
Vss 
Volume of distribution at steady-state 
WHODrug 
World Health Organization Drug Dictionary 

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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 
the principles of the “Declaration of Helsinki” or with the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the individual. The 
study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” 
International Conference of Harmonization (ICH) Tripartite Guideline or with local law if it 
affords greater protection to the subject. For studies conducted in the European Union/European 
Economic Area (EU/EEA) countries, the Investigator will ensure compliance with the EU 
Clinical Trial Directive [2001/20/EC]. For studies conducted in the USA or under US 
Investigational New Drug (IND), the Investigator will additionally ensure adherence to the basic 
principles of “Good Clinical Practice” as outlined in the current version of 21 Code of Federal 
Regulations (CFR), subchapter D, part 312, “Responsibilities of Sponsors and Investigators”, 
part 50, “Protection of Human Subjects”, and part 56, “Institutional Review Boards”. 
In other countries where a “Guideline for Good Clinical Practice” exists, the Sponsor and the 
Investigators will strictly ensure adherence to the stated provisions. 
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.  

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The ICF and any other written information provided to subjects will be revised whenever 
important new information becomes available that may be relevant to the subject’s consent, or 
there is an amendment to the protocol that necessitates a change to the content of the subject 
information and/or the written ICF. The Investigator will inform the subject of changes in a 
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’s site file or, if locally required, in the subjects’ 
notes/files of the medical institution. 
The electronic case report forms (eCRFs) for this study contain a section for documenting all 
subject informed consents, and this must be completed appropriately. If new safety information 
results in significant changes in the risk/benefit assessment, the consent form 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 the study are published, the subject’s identity will remain confidential. 
The Investigator will maintain a list to enable subjects to be identified. 
6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
The Sponsor of this study is Horizon Pharma USA, Inc. (Horizon). Horizon personnel will serve 
as the Medical Monitor and the Sponsor’s regulatory representative (see Section 17.1 for details). 
The Sponsor’s regulatory representative will be responsible for timely reporting of serious 

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considered as 2 distinct conditions: “active TED,” which is an autoimmune inflammatory 
response targeting orbital soft tissues; and “inactive TED,” which is the name given to the 
expanded and fibrotic tissues that are the sequelae of the active disease. Active TED typically 
lasts 1 to 3 years, and then the inflammation spontaneously subsides to leave the permanent 
pathology of inactive TED [Burch et al, 1993]. 
The annual incidence rate of TED in the US has been estimated to be 16 cases per 100,000 
people for women and 2.9 cases per 100,000 people for men [Bartley, 1994]. The incidence 
appears to be comparable in Europe [Abraham-Nordling et al, 2011; Mostbeck et al, 1998; Noth 
et al, 2001; Tanda et al, 2013]. Patients aged between 30 and 50 years are most frequently 
affected, with severe cases more frequent in those older than 50 years [Dickinson, 2010]. The 
occurrence and severity of TED is associated with smoking [Prummel et al, 1993]. 
A mounting body of evidence in the scientific literature indicates that the pathophysiology of 
active TED involves the autoimmune activation and proliferation of orbital fibroblasts [Bahn, 
2010; Boschi et al, 2005; Smith, 2010]. The activation of fibroblasts triggers release of 
inflammatory cytokines, infiltration of immune cells into orbital soft tissues (muscle, interstitial 
and adipose), excessive synthesis of extracellular matrix, and tissue expansion and remodeling 
(ibid). Clinical features of moderate-to-severe TED include orbital pain, swelling, dry eye, 
redness and discomfort of the lids and ocular surface, thickening and retraction of the eyelids, 
and proptosis (exophthalmos) due to the expansion of tissue behind the eye [Bahn, 2010; Burch 
et al, 1993; Dickinson, 2010; Mallika et al, 2009]. 
In its moderate-to-severe form, TED has high morbidity [Bartalena et al, 2008; Bartley, 1994; 
Dickinson, 2010; Gerding et al, 1997]. Morbidity takes the form of orbital pain, together with a 
number of serious, sight-threatening conditions, including diplopia (due to inability to correctly 
align the eyes), corneal ulceration (due to inability to close lids), and dysthyroid optic neuropathy 
(due to proptosis, tissue crowding, and stress on the optic nerve). These combine to produce 
marked reductions in quality of life (QoL) (e.g., physical functioning, role functioning, social 
functioning, mental health, health perceptions, and pain) [Gerding et al, 1997; C. Terwee et al, 
2002]. TED can also produce profound psychosocial problems, in particular anxiety and 
depression, due to the alarming and disfiguring changes in appearance [Bartley et al, 1996; 
Coulter et al, 2007; G. J. Kahaly et al, 2005]. Taken together, these data show that moderate-to-
severe active TED is a physically and emotionally debilitating condition (Figure 7.1). 

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Teprotumumab has the potential to meet these requirements by specifically blocking the 
autoimmune pathophysiology thought to underlie active TED. 
7.1.2 Insulin-like Growth Factor-1 Receptor (IGF-1R) 
The key underlying mechanism in Graves’ hyperthyroidism is the generation of auto-antibodies 
(Grave’ Disease immunoglobulin G; GD-IgGs) that act on the thyroid to produce 
hyperthyroidism [Akamizu, 2001]. The primary molecular mechanism through which GD-IgGs 
produce hyperthyroidism is believed to be activation of thyroid stimulating hormone receptors 
(TSHR) in thyroid follicular cells [Akamizu, 2001]. TED also has an autoimmune basis, but in 
this case, the primary cellular target appears to be orbital fibroblasts. GD-IgGs stimulate orbital 
fibroblasts to proliferate, release cytokines, initiate an inflammatory response, differentiate into 
adipocytes and myofibroblasts, and to secrete excessive amounts of extracellular matrix (e.g., 
hyaluronan), which in turn results in fibrosis and edema [Smith, 2010]. It was initially assumed 
that, as with Graves’ hyperthyroidism, GD-IgGs produced TED through activation of TSHR. 
However, the data for this has never been definitive and a number of lines of evidence argue 
against there being a single, common molecular target for the 2 conditions. For example, it is not 
uncommon for there to be longitudinal misalignments in the time courses of Graves’ 
hyperthyroidism and TED; approximately 10% of TED patients never become hyperthyroid and 
some TED patients experience unilateral eye symptoms. Moreover, there is disagreement in the 
literature about whether the levels of TSHR expressed in orbital tissues are alone sufficient to 
trigger and drive TED (e.g., [Bahn, 2010; Boschi et al, 2005; Smith et al, 2004]). 
There are no well-established animal models for TED, and this has hampered both the study of 
mechanism and the discovery of novel therapeutics. Nevertheless, evidence is now accumulating 
that TSHR may not be the only autoantigen that is involved in regulating TED pathology. 
Specifically, a substantial body of data has been generated arguing that the insulin-like growth 
factor-1 receptor (IGF-1R) plays an important role in regulating the pathophysiological 
responses produced in orbital an immune cells by GD-IgGs. Key nonclinical data supporting the 
involvement of IGF-1R in the mechanism of active TED are: 
1. IGF-1R is localized on orbital fibroblasts and binding of IGF to fibroblasts can be 
displaced by GD-IgGs [Weightman et al, 1993]. 
2. IGF-1R is up-regulated in cultured orbital fibroblasts from patients with TED, while 
TSHR is only expressed at low levels [Tsui et al, 2008]. 
3. Stimulation of IGF-1R by GD-IgGs in orbital fibroblasts from patients with TED causes 
increased release of the T-cell attracting cytokines IL-16 and RANTES [Pritchard et al, 
2003]. Importantly, this effect of GD-IgGs is fully reversed by a monoclonal antibody 
(mAb) antagonist specific for IGF-1R. 
4. IGF-1 and GD-IgGs increase hyaluronan synthesis in orbital fibroblasts from patients 
with TED, but not in orbital fibroblasts from control subjects or dermal fibroblasts [Smith 
et al, 2004]. Again, this effect of GD-IgGs is blocked by a selective IGF-1R antagonist 
antibody. Interestingly, in these studies thyroid stimulating hormone (TSH) failed to 
stimulate hyaluronan synthesis in orbital fibroblasts from patients with TED. 

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7.1.3.4 Clinical Experience 
7.1.3.4.1 Introduction 
Teprotumumab was originally developed by F. Hoffman-La Roche Ltd. for the treatment of 
subjects 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 more than 700 subjects treated in the oncology program.  
Teprotumumab is currently being developed by Horizon for subjects with moderate-to-severe 
active TED (also known as Graves’ Ophthalmopathy or Orbitopathy [GO] and 
Thyroid-Associated Ophthalmopathy [TAO]). 
The pharmacokinetics (PK) of teprotumumab were characterized by Roche. A biomarker to 
assess target interaction – increases in serum IGF-1 – was also identified. PK/PD modeling 
indicated that concentrations of 20 μg/mL resulted in > 90% IGF-1R receptor occupancy, and 
that doses that produced teprotumumab trough blood concentrations of 20 μg/mL were well 
tolerated. 
The clinical safety database of teprotumumab in oncology was likely confounded by the 
comorbidity of late stage cancer and concomitant administration of other treatments. The 
oncology studies, however, did identify a number of potential AEs of special interest (AESIs: 
infusion-associated events, thrombocytopenia, hyperglycemia, and anemia) and these events 
were monitored carefully in the initial study in TED subjects, TED01RV. 
TED01RV was the first study in which non-oncology subjects received teprotumumab. This 
study enrolled 87 subjects (43 teprotumumab; 44 placebo) between the ages of 18 and 75 years 
with recent onset (≤ 9 months from diagnosis) moderate-to-severe active TED. The primary 
efficacy endpoint was the overall responder rate (decreases from Baseline of ≥ 2 points in overall 
Clinical Activity Score [CAS] and ≥ 2 mm in proptosis, provided that there was no deterioration 
[i.e., increases of ≥ 2 points in CAS or ≥ 2 mm in proptosis] in the non-study eye) at the end of 
the 24-week treatment phase. In this study, the responder rate was significantly greater with 
teprotumumab treatment compared to placebo (69% versus 20%; p < 0.001) at Week 24. 
Therapeutic effects were rapid, with increased responder rates in the teprotumumab group 
relative to placebo detected at Weeks 6, 12, and 18 (all p < 0.001). The secondary endpoints 
(QoL, proptosis, and CAS as continuous variables) all supported the primary analysis conclusion 
that teprotumumab was superior to placebo in the treatment of TED. Population PK modeling in 
TED01RV confirmed that trough concentrations were consistently above the 20 μg/mL 
threshold, which had been previously determined by Roche PK/PD modeling as resulting in 
> 90% IGF-1R occupancy in the tissues. Results of the TED01RV study were published in the 
New England Journal of Medicine [Smith et al, 2017]. 
Of the AESIs identified in the oncology studies (i.e., infusion-associated events, 
thrombocytopenia, hyperglycemia, and anemia), the only one that emerged in the initial trial in 
subjects with TED was hyperglycemia. Among subjects treated with teprotumumab, 
hyperglycemia was uniformly mild in non-diabetic subjects and adequately controlled by 

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Table 7.2 
Summary of TEAEs Reported in at Least 5% of Subjects in Teprotumumab 
Treatment Group and % is Greater Than Placebo 
TEAEs 
Placebo 
N=44 
n (%) 
Teprotumumab 
N=43 
n (%) 
Summary Details for TEAEs  
in Teprotumumab Group 
Any TEAE 
32 (72.7) 
32 (74.4) 
 
Nausea 
4 (9.1) 
8 (18.6) 
Generally mild and reported after first/second infusions  
Muscle spasms 
2 (4.5) 
8 (18.6) 
Intermittent, 2/8 cases experienced for >1 week and treated with 
muscle relaxants 
Diarrhea 
2 (4.5) 
6 (14.0) 
Treatment required in 2/6 cases, 1 designated an SAE (see 
below) 
Hyperglycemia 
2 (4.5) 
5 (11.6) 
Mechanism-based AE  
Alopecia 
2 (4.5) 
3 (7.0) 
All mild and no treatment required 
Dry skin 
0 
3 (7.0) 
All mild, one case used topical dry skin cream 
Dysgeusia 
0 
3 (7.0) 
For 2/3 cases a transient “metallic” taste on Days 1-2 
Headache 
2 (4.5) 
3 (7.0) 
Generally mild, one subject took paracetamol 
Paresthesia 
0 
3 (7.0) 
“Tingling” reported in nose, feet or chest; variable onset and in 
2/3 cases occurred on 1 day 
Hearing impaired 
0 
3 (7.0) 
Disparate symptoms, onset and duration (i.e., one unilateral with 
onset 16 weeks after end of therapy, one mild bilateral that 
resolved, one intermittent in a subject with positive history of 
tinnitus) 
Weight loss 
0 
3 (7.0) 
Variable timing; decreases range from 5-9 lb. 
 
No deaths occurred in TED01RV, and early terminations were comparable in each treatment 
group (6/group). SAEs occurred in 5/43 (11.6%) of the subjects in the teprotumumab group and 
1/45 (2.2%) of the subjects in the placebo group (Table 7.3). Two SAEs in the teprotumumab 
group were categorized by the Investigators as “possibly related” (diarrhea and mental 
confusion, which had a provisional diagnosis of Hashimoto’s encephalopathy); the remaining 
were categorized as “unrelated”. In the teprotumumab group, 4 discontinuations for SAEs 
occurred after the following number of infusions: diarrhea after 6 infusions; inflammatory bowel 
disease (IBD) after 7 infusions; Escherichia coli sepsis after 3 infusions; and Hashimoto’s 
encephalopathy after 6 infusions. 
Clinically relevant levels of ADAs were not detected in any subject. 
In the Phase 2 study, three non-serious adverse events (AEs) involving hearing impairment 
occurred in the teprotumumab group. A 59-year-old subject experienced acute bilateral hearing 
abnormality approximately 12 weeks following the 1st infusion of teprotumumab with resolution 
several months following the last infusion. A second 43-year-old subject with eustachian tube 
dysfunction experienced hearing loss nearly 4 months following discontinuation of 
teprotumumab. A third 60-year-old subject with a history of tinnitus experienced hearing loss 
following loud noise exposure. While a causal relationship between teprotumumab and the event 

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of hearing impairment is considered doubtful, it may be reasonable to avoid ototoxic drugs while 
receiving teprotumumab, if possible. 
Table 7.3 
Summary of SAEs Reported in Either Treatment Group by Preferred Term  
SAE 
Placebo 
N=44 
n (%) 
Teprotumumab 
N=43 
n (%) 
Summary Details for SAEs in  
Teprotumumab Group 
Any SAE 
1 (2.3) 
5 (11.6) 
 
Optic neuropathy 
1 (2.3) 
0 
 
Diarrhea 
0 
1 (2.3) 
Severe diarrhea in one subject with 6-month 
history of ulcerative colitis – hospitalized 
IBD 
0 
1 (2.3) 
Subject with recent diagnosis of ileitis and colitis, 
diagnosed and treated for IBD while on therapy – 
hospitalized  
Escherichia sepsis 
0 
1 (2.3) 
E. coli infection of unknown origin, treated with 
IV antibiotics – hospitalized 
Suspected Hashimoto's 
encephalopathy 
0 
1 (2.3) 
Provisional diagnosis for episodic mental 
confusion with no other neurological symptoms – 
hospitalized 
Urinary retention  
0 
1 (2.3) 
Occurred following an inguinal herniorrhaphy – 
hospitalized 
 
AEs Previously Identified as Special Interest 
AESIs identified in the oncology studies (infusion-associated events, hyperglycemia, 
thrombocytopenia, and anemia; see Section 7.1.3.4.5.5) were examined in TED01RV. 
Infusion-associated AEs were reported for 1 teprotumumab-treated subject (facial flushing and 
warmth with concomitant elevated heart rate and blood pressure at the end of the 90-minute 
observation period after the second infusion). At the third infusion visit, the subject was pre-
medicated with diphenhydramine, dexamethasone, famotidine and Tylenol and had a similar 
reaction prior to the study drug infusion. 
Among non-diabetic subjects, hyperglycemia occurred at comparable rates in both treatment 
groups and was uniformly Grade 1 and intermittent. Among diabetic subjects, Grade 2 or 3 
hyperglycemia occurred in some teprotumumab-treated subjects; this was well-controlled after 
diabetes medication adjustment. Glycemic control, as assessed by HbA1c, was at baseline levels 
following the treatment phase for all subjects in the teprotumumab group.  
No subjects experienced thrombocytopenia as an AE. There were small differences in the 
population means of platelet values in the teprotumumab group compared to placebo that were 
not considered clinically significant and, importantly, diminished with continued dosing. 
No subjects experienced anemia as an AE. 

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In general, the decision to keep a subject on study treatment with teprotumumab should take into 
consideration potential risks and benefits to the subject. Prior to all future infusions of 
teprotumumab, these subjects should be pre-medicated with IV diphenhydramine 1 to 
1.25 mg/kg (maximum: 50 mg), IV ranitidine 50 mg, IV dexamethasone 0.4 mg/kg (maximum: 
20 mg), and/or acetaminophen 500 mg. In addition, all future infusions should be administered 
over approximately 90 minutes (but not less than 80 minutes). Vital signs should be taken every 
15 minutes during the infusion.  
Subjects who experience delayed-type hypersensitivity reactions (e.g., skin rash) may remain in 
the study at the discretion of the Investigator, and prior to all future infusions of teprotumumab, 
should be pre-medicated with the above medications (diphenhydramine, ranitidine, 
dexamethasone, and/or acetaminophen). Subjects who experience a worsening delayed-type 
hypersensitivity reaction following repeated infusions of teprotumumab or who have other signs 
of serum-sickness (e.g., delayed fever, myalgias, arthralgias) may be removed from the study 
after discussion with the Investigator and Sponsor.  
Hyperglycemia  
In preclinical studies, there was no in vitro cross-reactivity of teprotumumab with the insulin 
receptor. During TED01RV, among non-diabetic subjects, hyperglycemia occurred at 
comparable rates in both treatment groups and was uniformly Grade 1 and intermittent. Among 
diabetic subjects, Grade 2 or 3 hyperglycemia occurred in some teprotumumab-treated subjects; 
this was well-controlled after diabetes medication adjustment. Glycemic control, as assessed by 
HbA1c, was at baseline levels following the treatment phase for all subjects in the teprotumumab 
group.  
Subjects with known controlled diabetes mellitus are allowed to participate in studies with 
teprotumumab. HbA1c levels should be monitored regularly in these subjects. Investigators are 
strongly encouraged to adjust their subjects’ diabetes management to maintain subjects’ HbA1c 
levels at ≤ 7%. In the event a subject’s HbA1c level rises to > 7% while in the study, the 
Investigator must determine the risk versus benefit for each subject to remain in the study.  
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 level of moderate intensity (glucose >160 – 250 mg/dL), will require evaluation 
for diabetes mellitus (e.g., fasting glucose, glucose tolerance, and HbA1c tests) and appropriate 
medical management at the discretion of the Investigator. 
Muscle Spasms 
During the TED01RV study, muscle spasms were identified in 19% of the subjects receiving 
teprotumumab versus 5% of those receiving placebo. In the teprotumumab group, 8 subjects had 
muscle spasms (6 had Grade 1 and 2 had Grade 2); only 2 subjects experienced the event for 
longer than one week and were treated with muscle relaxants. If possible, avoid medications 
known to cause muscle spasms or muscle toxicity such as diuretics or statins and evaluate for 
other causes of muscle spasm such as electrolyte abnormalities and dehydration. 

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Diarrhea 
In the TED01RV study, diarrhea occurred in 14% of subjects receiving teprotumumab versus 5% 
of those receiving placebo. In the teprotumumab group, 8 subjects had diarrhea (5 had Grade 1, 
2 had Grade 2, and 1 had a Grade 3 [severe]), with 2 subjects requiring treatment. The severe 
diarrhea (Grade 3) occurred in a subject with a history of colitis and was considered possibly 
related to study drug. This subject was subsequently diagnosed with ulcerative colitis and 
required colectomy leading to discontinuation from the study. Additionally, another subject was 
diagnosed with IBD during the course of the study.  
Both subjects likely had IBD as a pre-existing condition, prior to study start. However, given the 
temporal sequence, exacerbation of underlying IBD by teprotumumab cannot be excluded at this 
time. Therefore, diarrhea that is progressive and persistent, or has features of IBD such as bloody 
stools or abdominal pain, should undergo prompt evaluation to exclude IBD or other serious 
conditions. If possible, avoid medications known to cause diarrhea such as laxatives and 
magnesium. 
7.2 
Rationale for this Study 
Multiple lines of evidence indicate that IGF-1R plays a critical role in regulating the autoimmune 
response that underlies TED. Teprotumumab is a mAb with low nanomolar affinity for human 
IGF-1R. Binding of teprotumumab to IGF-1R blocks receptor activation by agonists, IGF1 and 
IGF2, and also causes direct inactivation of the receptor through antibody-induced 
internalization. Teprotumumab has no agonist activity for canonical IGF-1R signaling pathways 
and is highly selective; in particular, it does not recognize the insulin receptor. Teprotumumab is 
well-tolerated in humans at doses that produce > 90% IGF-1R occupancy. Systemic 
administration of teprotumumab to subjects with moderate-to-severe active TED should, 
therefore, attenuate all disease symptoms that are dependent on IGF-1R activation. This 
argument holds whether IGF-1R is being activated by GD-IgG or endogenous ligands IGF-1 and 
IGF2, or whether the receptor is expressed on fibroblasts, progenitor fibrocytes, adipocytes, or 
lymphocytes. Moreover, inhibition of IGF-1R receptor function with an antibody may also 
attenuate signaling through the TSHR, an autoantigen that has been implicated in TED, because 
IGF-1R and TSHR are physically and functionally coupled. Teprotumumab, therefore, has the 
potential to treat TED at multiple different molecular and cellular levels.  
Administering teprotumumab early in active TED is designed to reduce the intensity and 
duration of the active disease, minimize the sequelae that are carried over to constitute inactive 
TED, and thereby have a beneficial effect on long-term outcome, reducing the need for 
corrective surgeries. Previous preclinical and clinical experience indicates that, at doses that are 
pharmacologically relevant for blocking IGF-1R, teprotumumab has an acceptable safety profile 
following IV infusion and is, therefore, a suitable drug candidate to be investigated in the TED 
indication.  

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8.2 
Secondary Objectives 
The secondary objectives (analyzed hierarchically) are: 
1. Evaluate the effect of teprotumumab versus placebo on the overall responder rate 
(percentage of subjects with ≥ 2-point reduction in CAS AND ≥ 2 mm reduction in 
proptosis from Baseline, provided there is no corresponding deterioration [≥ 2 point/mm 
increase] in CAS or proptosis in the fellow eye) at Week 24. 
2. Evaluate the effect of teprotumumab versus placebo on the percentage of subjects with a 
CAS value of 0 or 1 at Week 24 in the study eye. 
3. Evaluate the effect of teprotumumab versus placebo on the mean change from Baseline to 
Week 24 in proptosis measurement in the study eye. 
4. Evaluate the effect of teprotumumab versus placebo on the diplopia responder rate (i.e., 
the percentage of subjects with baseline diplopia > 0 in study eye who have a reduction of 
≥ 1 grade with no corresponding deterioration [≥ 1 grade worsening] in the fellow eye) at 
Week 24. 
5. Evaluate the effect of teprotumumab versus placebo on the mean change from Baseline to 
Week 24 in the Graves' Ophthalmopathy Quality of Life (GO-QoL) questionnaire overall 
score. 
8.3 
Exploratory Objectives 
The exploratory objectives are: 
1. Evaluate the effect of teprotumumab versus placebo on the Clinical Measures of Severity 
individual response status frequencies and percentage of responders for each component 
of clinical severity from Baseline to Week 24.  
2. Evaluate the effect of teprotumumab versus placebo on the mean change from Baseline to 
Week 24 in the CAS. 
3. Evaluate the effect of teprotumumab versus placebo on the overall responder rate at 
Week 24 stratified by the level of response (high responders, responders, low responders, 
and non-responders; see Section 9.6.4.3.1 for definitions). 
4. Evaluate pharmacokinetic (PK) parameters of teprotumumab to estimate exposure and 
understand PK-PD relationships. 
5. Evaluate the effect of teprotumumab versus placebo on the mean change from Baseline to 
Week 24 in the GO-QoL questionnaire visual functioning (VF) and appearance (A) 
subscale scores. 
6. Evaluate the effect of teprotumumab on the mean change from Baseline to Week 24 in 
blood and serum biomarkers. 
7. Evaluate the effect of teprotumumab versus placebo on the mean change from Baseline to 
Week 24 on the motility component of the Clinical Measures of Severity. 

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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This study will be conducted at up to 16 sites in the United States and Europe. 
This is a randomized, double-masked, placebo-controlled, parallel-group, multicenter study. 
Subjects will be screened for the study within 2 to 6 weeks prior to the Baseline (Day 1) Visit. 
Approximately 76 subjects (38/group) who meet the study eligibility criteria will be randomized 
on Day 1 in a 1:1 ratio (stratified by tobacco use status) to receive 8 infusions of teprotumumab 
(10 mg/kg for the first infusion and 20 mg/kg for the remaining 7 infusions) or placebo every 
3 weeks (q3W). All subjects will enter a 24-week double-masked Treatment Period, during 
which study drug will be infused on Day 1 (Baseline), and Weeks 3, 6, 9, 12, 15, 18, and 21 
(with a final visit at Week 24). All study drug dosing will be performed at the clinic under the 
supervision of clinic staff, and at any scheduled infusion, the infusion rate may be reduced or the 
dose may be interrupted or held based on decreased tolerability (see Section 9.4.6.3.2 for 
details). On each dosing day, scheduled assessments (except for AE and concomitant medication 
use monitoring, which will be monitored throughout the clinic visit) will be completed prior to 
study drug dosing. After each of the first 2 infusions, subjects will be contacted by phone/email 
the following day and will return to the clinic 1 week after the infusion (Weeks 1 and 4) for 
safety and tolerability assessments; additional phone/email contacts and clinic visits may also be 
conducted for any subject experiencing an infusion-associated event. 
At the end of the double-masked Treatment Period (Week 24), subjects who are proptosis 
non-responders (study eye has < 2 mm decrease in proptosis) will be eligible to enter an 
open-label extension study (HZNP-TEP-302) in which subjects may receive 8 infusions of 
teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for the remaining 7 infusions) in an 
open-label fashion. Discussion of this option with the subject and informed consent presentation 
for HZNP-TEP-302 should be discussed at the Week 24 Visit given enrollment in HZNP-TEP-
302 must occur within 2 weeks of the Week 24 Visit. 
At Week 24, proptosis responders, as well as non-responders who choose not to enroll in the 
open-label extension study (HZNP-TEP-302), will enter a 48-week Follow-Up Period, during 
which study drug will not be administered and clinic visits are scheduled for Weeks 28, 36, 48, 
60, and 72 (Months 7, 9, 12, 15, and 18). Subjects who are responders at Week 24 but who meet 
the criteria for re-treatment due to a relapse during the Follow-Up Period may enroll in the 
open-label extension study, HZNP-TEP-302 (see Section 9.3.4 for details). 
Subjects who prematurely discontinue study drug dosing prior to Week 21 of the Treatment 
Period will return to the clinic and undergo the scheduled Week 24 assessments and will be 
encouraged to participate in the Follow-Up Period unless they initiated another intervention due 
to lack of efficacy. Subjects who enter the Follow-Up Period but prematurely discontinue study 
participation prior to 48 weeks following the double-masked Treatment Period will return for a 
final visit and undergo the scheduled Week 72 assessments prior to study discharge. 

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Subjects who complete the Week 72 Visit will be contacted 6 and 12 months later via phone or 
email by research staff to enquire if any treatment for TED has been received since last study 
contact. If yes, subject will be questioned regarding type of treatment and outcome/response. 
An overview of the study design is presented in Figure 9.1, and details of study activities were 
previously presented in Section 2.1, Schedule of Assessments.  
Figure 9.1 
Schematic of Study Design 
Screen 
Baseline 
Double-Masked Treatment Period 
Teprotumumab or Placebo 1, 2 
24 Weeks 
Follow-Up Period 
48 Weeks 3,4 
Follow-Up 
Contact5  
48 Weeks 
 
< –––––––––––––––––––––––––– Clinic Visits ––––––––––––––––––––––––––––––––– > < –––––––– Clinic Visits –––––– >  
 
* 
 
* 
 
* 
* 
* 
* 
* 
* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 to 6 
weeks 
predose 
Day 1 6 
W1 
W3 6 
W4 
M1 
W6 
W9 
W12 
M3 
W15 
W18 
W21 
W24 7 
M6  
W28 
M7  
W36 
M9 
W48 
M12 
W60 
M15 
W72 
M18 
W96 
M24 
W120 
M30 
 
 
Randomization 
n=38/group 1 
< –––––––––––––––––––––––––––––––––––– Study Week/Month –––––––––––––––––––––––––––––––––––––––––– > 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Infusion of study drug. 
1. 
Subjects will be randomized in a 1:1 ratio (stratified by tobacco use status) to receive: 
a. Teprotumumab 20 mg/kg (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 ± 1 day for Weeks 1 and 4, ± 3 days for Weeks 3, 6, 9, 12, 15, 18, and 21, and ± 7 days for Week 24. 
3. 
Subjects who are proptosis responders or non-responders who do not elect to participate in the open-label extension study will enter a 48-week 
Follow-Up Period. Subjects who are responders at Week 24 but relapse during the Follow-Up Period may enter the open-label study and receive 
8 infusions if they meet the criteria defined in Section 9.3.4. 
4. 
Visit windows of ± 7 days. 
5. 
Subjects who complete the Week 72 Visit will be contacted via phone or email by research staff to enquire if any treatment for TED has been 
received since last study contact. 
6. 
Subjects will be contacted by phone/email the day following the first and second infusions for safety and tolerability assessments; phone/email 
contacts will also occur the day after any clinic visit where a subject experiences an infusion-related AE. 
7. Subjects who are proptosis non-responders at Week 24 of the double-masked Treatment Period will be offered the option to enter an open-label 
extension study and receive 8 infusions of teprotumumab 20 mg/kg (10 mg/kg on Day 1 followed by 20 mg/kg for the remaining 7 infusions). 
 
9.2 
Discussion of Study Design 
This study is a randomized, double-masked, placebo-controlled, parallel-group, multi-center 
study designed according to standard principles for adequate and well-controlled studies. The 
study population is well-defined and is consistent with the expected target population for whom 
teprotumumab will be indicated (adult subjects with Graves’ disease and moderate-to-severe 
active TED). 
The measurements used in this study for the primary and secondary endpoints (proptosis, CAS, 
and GO-QoL questionnaire) are established and well-validated endpoints that have been shown 
to correlate significantly with TED. 
The sample size for this study was based on the data from the TED01RV study. A sample size of 
38 subjects per group provides 90% power at the 2-sided alpha 0.05 level to detect a difference 
of 39% between teprotumumab and placebo in the proptosis responder rate; this sample size has 
been adjusted for a 16% dropout rate. 

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Given the teratogenic effects of teprotumumab noted in a monkey embryo-fetal development 
toxicity study (see Section 7.1.3.2 for details) and pharmacokinetic profile of teprotumumab (see 
Section 7.1.3.4.3), all subjects (men and women) 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 µg/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. 
9.3 
Selection of Study Population 
9.3.1 Inclusion Criteria 
Eligible subjects must meet all of the following criteria: 
1. Written informed consent. 
2. Male or female subject between the ages of 18 and 80 years, inclusive, at Screening. 
3. Clinical diagnosis of Graves’ disease associated with active TED with a CAS ≥ 4 (on the 
7-item scale) for the most severely affected eye at Screening and Baseline. 
4. Moderate-to-severe active TED (not sight-threatening but has an appreciable impact on 
daily life), usually associated with one or more of the following: lid retraction > 2 mm, 
moderate or severe soft tissue involvement, exophthalmos > 3 mm above normal for race 
and gender, and/or inconstant or constant diplopia. 
5. Onset of active TED symptoms (as determined by subject records) within 9 months prior 
to Baseline. 
6. Subjects must be euthyroid with the baseline disease under control or have mild hypo- or 
hyperthyroidism (defined as free thyroxine [FT4] and free triiodothyronine [FT3] levels 
< 50% above or below the normal limits) at Screening. Every effort should be made to 
correct the mild hypo- or hyperthyroidism promptly and to maintain the euthyroid state 
for the full duration of the clinical trial.  
7. Does not require immediate surgical ophthalmological intervention and is not planning 
corrective surgery/irradiation during the course of the study. 
8.  Alanine aminotransferase (ALT) or AST ≤3 times the upper limit of normal (ULN) or 
serum creatinine <1.5 times the ULN according to age at Screening. 
9. Diabetic subjects must have well-controlled stable disease (defined as HbA1c < 9.0% 
with no new 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, non-therapy-induced amenorrhea for <12 months prior to Screening, 

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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 through Week 48 of 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 
one 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 less than 1% per year), 
when used consistently and correctly, includes implants, injectables, combined oral 
contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomized 
partner.  
11. Male subjects must be surgically sterile or, if sexually active with a female partner of 
childbearing potential, must agree to use a barrier contraceptive method from Screening 
through 180 days after the last dose of study drug.  
12. Subject is 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. Decreased best corrected visual acuity due to optic neuropathy as defined by a decrease 
in vision of 2 lines on the Snellen chart, new visual field defect, or color defect secondary 
to optic nerve involvement within the last 6 months. 
2. Corneal decompensation unresponsive to medical management.  
3. Decrease in CAS of ≥ 2 points in the study eye between Screening and Baseline. 
4. Decrease in proptosis of ≥ 2 mm in the study eye between Screening and Baseline. 
5. Previous orbital irradiation or surgery for TED. 
6. Any steroid use (intravenous [IV] or oral) with a cumulative dose equivalent to ≥ 1 g of 
methylprednisolone for the treatment of TED. Previous steroid use (IV or oral) with a 
cumulative dose of <1 g methylprednisolone or equivalent for the treatment of TED and 
previous use of steroid eye drops is allowed if discontinued at least 4 weeks prior to 
Screening. 
7. Corticosteroid use for conditions other than TED within 4 weeks prior to Screening 
(topical steroids for dermatological conditions and inhaled steroids are allowed).  
8. Selenium and biotin must be discontinued 3 weeks prior to Screening and must not be 
restarted during the clinical trial; however, taking a multivitamin that includes selenium 
and/or biotin is allowed. 

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9. Any previous treatment with rituximab (Rituxan® or MabThera®) or tocilizumab 
(Actemra® or Roactemra®). Use of any other non-steroid immunosuppressive agent 
within 3 months prior to Screening. 
10. Use of an investigational agent for any condition within 60 days prior to Screening or 
anticipated use during the course of the trial. 
11. Identified pre-existing ophthalmic disease that, in the judgment of the Investigator, would 
preclude study participation or complicate interpretation of study results. 
12. Bleeding diathesis that in the judgment of the Investigator would preclude inclusion in 
the clinical trial. 
13. Malignant condition in the past 12 months (except successfully treated basal/squamous 
cell carcinoma of the skin). 
14. Pregnant or lactating women. 
15. Current drug or alcohol abuse, or history of either within the previous 2 years, in the 
opinion of the Investigator or as reported by the subject. 
16. 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 
endoscopic or radiologic evidence of enteritis/colitis without a confirmed alternative 
diagnosis). 
17. Known hypersensitivity to any of the components of teprotumumab or prior 
hypersensitivity reactions to mAbs. 
18. Any other condition that, in the opinion of the Investigator, would preclude inclusion in 
the study. 
19. Previous enrollment in this study or participation in a prior teprotumumab clinical trial. 
20. HIV, hepatitis C or hepatitis B infections. 
9.3.3 Removal of Subjects from Therapy or Assessment 
All subjects are free to withdraw from study participation at any time, for any reason, and 
without prejudice to their further medical care. In addition, the Investigator may terminate a 
subject from the study at any time. The primary reason for discontinuation from the study and/or 
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 
subject’s health, or the subject is unwilling to continue because of an AE. AEs requiring 
permanent study drug discontinuation per the protocol include: 

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o A drug-related anaphylactic reaction. 
o A persistently severe drug-related AE that does not abate to mild or moderate 
intensity at least 2 weeks prior to the next scheduled dose. 
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). 
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. Removal of a subject from the study is at the discretion of the 
Investigator and may occur if the Investigator determines that study drug administration 
is not benefitting the subject and eye symptoms linked to progressing disease worsen 
posing an unacceptable risk to the subject. The specific care of the subject is best 
determined by the Investigator and managing physician(s) involved in the subject’s care 
and may require removal from the study. All subjects are free to withdraw from study 
participation at any time, for any reason, allowing them to receive any specific treatment 
for TED that is considered necessary per their treating physician and local standard of 
care.  
• Non-Compliance with Study Drug/Other/Protocol Deviations. The subject has a 
significant protocol deviation, does not comply with study drug administration schedule, 
or fails to adhere to other study requirements as stated in the protocol. 
• Lost to Follow-Up. The subject does not return to the clinic for scheduled assessments, 
and does not respond to the site’s attempts to contact the subject. 
• 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; if the underlying reason is documented as an 
AE or lack of efficacy, the category of withdrawal should be marked in the corresponding 
category and not as voluntary withdrawal. 
• Study Terminated by Sponsor. The Sponsor, IRB/IEC, or regulatory agency terminates 
the study. 
• Pregnancy. 
Subjects who prematurely discontinue study drug dosing prior to Week 21 of the Treatment 
Period will return to the clinic and undergo the scheduled Week 24 assessments and will be 
encouraged to participate in the Follow-Up Period unless they initiated another intervention due 
to lack of efficacy. Subjects who enter the Follow-Up Period but prematurely discontinue study 
participation prior to 48 weeks following the Treatment Period will return for a final visit and 
undergo the scheduled Week 72 assessments prior to study discharge. Subjects who discontinue 

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due to an AE should be followed until resolution or stabilization of the AE, or an adequate 
explanation for the event is obtained. 
9.3.4 Criteria for Responders Who Relapse 
If subjects meet the response criteria at Week 24 but subsequently experience a disease relapse 
during the 48-week Follow-Up Period, they will have the option to enter the open-label study 
with teprotumumab (HZNP-TEP-302) and receive 8 infusions of teprotumumab. The criteria to 
determine relapse is the following: 
• Increase in proptosis of ≥ 2 mm in the study eye since Week 24, or 
• An increase in CAS ≥ 2 points since Week 24 with an absolute CAS of ≥ 4 in the study 
eye following the Week 24 Visit. 
• In addition to one of the bullet points above, the Investigator should also consider the 
subject’s symptomology to ensure a relapse has occurred (e.g., new onset of double 
vision). 
9.3.5 Replacement Policy 
9.3.5.1 Subjects 
No subject prematurely discontinued from the study for any reason will be replaced. 
9.3.5.2 Centers 
A center may be closed and/or replaced for the following administrative reasons:  
• Excessively slow recruitment. 
• Poor protocol adherence. 
9.3.5.3 Screen Failures 
Subjects who do not meet all of the inclusion criteria or meet any of the exclusion criteria will be 
considered screen failures. 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 they can satisfy all of the eligibility criteria. Based on the TED01RV study, the 
expected screen failure rate is 20 – 25% [Smith et al, 2017]. 
9.4 
Treatments 
9.4.1 Treatments Administered 
All study drug dosing will be performed at the clinic under the supervision of clinic staff. On 
Day 1 of the double-masked Treatment Period, subjects will be randomized in a 1:1 ratio 
(stratified by tobacco use status) to receive infusions of either: 
1. 
Teprotumumab 20 mg/kg (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). 

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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 Teprotumumab  
Teprotumumab (HZN-001) is a fully human anti-IGF-1R mAb. The physiochemical properties 
were previously presented in Section 7.1.3.1. Teprotumumab 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/w).  
Prior to administration, each vial containing 500 mg teprotumumab freeze-dried powder will be 
reconstituted with 10 mL of water for injection. The resulting solution has an approximate 
concentration of 50 mg/ mL teprotumumab. The reconstituted teprotumumab solution must be 
further 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 pharmacist or site 
personnel not assigned to the study should check 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 teprotumumab drug product are between 
2°C to 8°C (36°F to 46°F), protected from light. Storage at ambient temperature of the 
reconstituted teprotumumab solution should be limited to 4 hours. For batch-specific information 
on shelf-life, see the packaging. 
The IV infusion should be administered at room temperature (20°C to 24°C [68°F to 75°F]). The 
diluted product should be used within 4 hours of preparation. However, if not used within 
4 hours, and if dilution has taken place under controlled and validated aseptic conditions, the 
infusion solution can be stored for up to 24 hours at 2°C to 8°C (36°F to 46°F). An 
Investigational Pharmacy Manual will be provided to all sites and further describe these 
processes in detail. 

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At the clinic, all study medications 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 medication and 
delegating infusion bag preparation and drug accountability responsibilities to an unmasked 
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 unmasked representative of the 
Sponsor. Once accountability is completed, the Sponsor’s representative will authorize the return 
of study medication (all used, partially used, and unused vials) to the 3rd party vendor (see 
Table 6.1). The completed Drug Accountability and Drug Return/Destruction Record(s) will be 
returned to the unmasked CRO manager. The Investigator’s copy of the Drug Accountability and 
Drug Return/Destruction Record(s) must document accurately the return of all study drug 
supplies and be maintained by the unmasked pharmacist or designee until the study is complete 
and the database is locked. Records will also include disposition dates and quantities 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 
 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 interactive web response 
system (IWRS) and will be based on the subject’s weight. The first dose will be 10 mg/kg, and 
subsequent doses will be 20 mg/kg. Weight will be measured at Screening and Weeks 12 and 24 
during the Treatment Period. The dose on Day 1 of the double-masked Treatment Period will be 
based on the Screening weight. The weight obtained at Week 12 can be used to adjust the dose 
beginning at Week 12 or Week 15, as appropriate. 

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9.4.6.3 Details Concerning Timing and Dose Administration 
9.4.6.3.1 Preparation and Administration of Teprotumumab 
Teprotumumab will be prepared by the site pharmacist (or designee in accordance with 
institutional policies and local regulations), who is not masked to the identity of the study 
medication. Each vial of teprotumumab will be reconstituted with 10 mL of water for injection. 
The resulting solution will have an approximate concentration of 50 mg/mL teprotumumab 
antibody. Reconstituted teprotumumab solution will be further diluted in 0.9% (w/v) sodium 
chloride (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 teprotumumab to be placed into the 
infusion bag will be first 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 teprotumumab drug product solution will be diluted with 
normal saline (0.9% NaCl) in the infusion bag.  
The IV infusion is to be administered at room temperature (20°C to 24°C [68°F to 75°F]). The 
diluted product should be used within 4 hours. However, if not used within 4 hours, and if 
dilution has taken place under controlled and aseptic conditions, the infusion solution can be 
stored for up to 24 hours at 2°C to 8°C (36°F to 46°F).  
No incompatibilities have been observed with: 
• 
administration sets with product contact surface of polyethylene, polyvinyl chloride 
(PVC), or polyurethane 
• 
inline filters with product contact surface of polyether sulphone 
• 
IV bags (0.9% sodium chloride) with product contact surface of polyolefin or PVC. 
In-line filters are not required, but if a hospital is routinely using them, in-line filters with a 
0.2 μm pore size should be utilized. 
Exposure of the solution to direct sunlight should be avoided. 
All parenteral products should be visually inspected for particulates before administration. 
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 

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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 teprotumumab and placebo administration.  
Subjects will be monitored for immediate infusion-associated events (e.g., nausea, vomiting, 
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) will 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.  
If delayed infusion-associated events are noted, subjects may continue dosing at the 
Investigator's discretion; however, 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. 
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. 
In general, the decision to continue dosing should take into consideration the potential benefit 
and risk to a subject.  
Any severe drug-related AE must revert to mild or moderate in intensity at least 2 weeks prior to 
the next scheduled dose in order for the dose to be administered; if the AE remains severe in 
intensity within 2 weeks of the next scheduled dose, the subject will be withdrawn from 
treatment. 
Increase in blood glucose is a known AE observed in previous clinical trials with teprotumumab 
and other IGF-1R antagonists and is known to respond to treatment. 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. 

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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 the CRO prior to shipment of any study drug to 
the clinical sites. On Day 1 of the double-masked Treatment Period, once all Baseline procedures 
other than administration of drug have been completed, the masked site personnel will use the 
IWRS to randomize the subject. The unmasked pharmacist or designee will then use the IWRS to 
obtain dosing information, and dispense the appropriate study drug. 
9.4.8 Masking and Unmasking 
The pharmacists or designees responsible for preparing the teprotumumab or placebo solutions 
for IV administration will not be masked 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 masked labels. The subject, Investigator, and all other study site personnel will 
be masked to the treatment being administered. 
During the phase 2 TED01RV trial, hyperglycemia was the only laboratory finding and adverse 
event clearly identified by the Investigators as being related to teprotumumab. Furthermore, 
hyperglycemia was observed in both treatment groups, placebo and teprotumumab. Given the 
occurrence of this event in both treatment groups, it is not possible to determine the identity of 
the masked study product based on the occurrence of this particular event.  
The study mask 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 must make diligent attempts to contact the Sponsor or Sponsor’s designee before 
unmasking the subject’s data. If a subject’s data are unmasked 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.  
The Sponsor’s Pharmacovigilance department or designee will unmask 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 
unmasked during the study will be included in the Clinical Study Report. 
Unmasking for independent pharmacological analysis of biological samples or SAE reporting 
will be performed according to procedures in place to ensure integrity of the data.  
All investigative site staff directly involved in this study will remain masked from Screening 
through analysis of the Follow-Up data and all site close-out visits. The Sponsor and its 
designees will be unmasked after the database lock following completion of all subjects in the 
double-masked treatment phase. 

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9.4.9 Concomitant Therapy and Restricted Medications 
Local supportive measures for TED, simple analgesics (e.g., acetaminophen, non-steroidal 
anti-inflammatory therapies), and medications/supplements for conditions other than TED are 
permitted during the study. Topical corticosteroids for conditions other than TED are allowed; 
however, oral corticosteroid use during the study is restricted to subjects who experience 
infusion-associated AEs. 
Symptomatic treatment (e.g., antipyretics, antihistamines, 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).  
9.4.9.1 Restricted Therapy and Medications 
Subjects with a previous orbital irradiation or surgery for TED or who have a planned orbital 
irradiation or surgery for TED over the course of this study are not eligible for study enrollment. 
In addition, oral corticosteroids, selenium, biotin, immunosuppressive agents, investigational 
agents, and illicit drug/alcohol use are restricted as shown in Table 9.1. 

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Table 9.1 
Restricted Medications and Therapies 
Medication/Therapy 
Restricted Dose or Time Period 
Orbital irradiation for TED 
Any history or planned procedure during entire study 
duration (Screening through Week 72 of Follow-Up Period). 
Eye surgery for TED  
Any history or planned procedure during entire study 
duration (Screening through Week 72 of Follow-Up Period). 
Steroids for treatment of TED 
Any history of steroid use (IV or oral) with a cumulative 
dose equivalent to ≥ 1 g of methylprednisolone for the 
treatment of TED is excluded.  
Previous steroid use (IV or oral) with a cumulative dose <1 g 
methylprednisolone or equivalent for the treatment of TED is 
allowed if the corticosteroid was discontinued at least 
4 weeks prior to Screening. 
Steroid eye drops must be discontinued at least 4 weeks prior 
to screening. 
Steroids (IV or oral) for treatment of TED and steroid eye 
drops are not allowed during the entire study duration. 
 
Steroids for conditions other than TED 
Previous steroid use for conditions other than TED is 
allowed but must be discontinued at least 4 weeks prior to 
Screening.  
Topical steroids for dermatological conditions and inhaled 
steroids are allowed during the study.   
IV dexamethasone for infusion-associated AEs is allowed 
(see Section 9.4.9 for details). 
Non-steroid eye drops 
Vasoconstrictor eye drops are not allowed during the study. 
Other non-steroid drops such as saline or methylcellulose are 
allowed but should not be used on the day of a clinic visit.  
Selenium or biotin for TED  
3 weeks prior to Screening through study completion. A 
multivitamin containing selenium and/or biotin is allowed. 
Rituximab (Rituxan® or MabThera®) or 
tocilizumab (Actemra® or Roactemra®) 
Any previous use or anticipated use during the study. 
Non-steroid immunosuppressive agent (other than 
rituximab or tocilizumab) 
3 months prior to Screening through study completion. 
Investigational agent 
60 days prior to Screening through study completion. 
Illicit drug/alcohol use 
History of abuse within the past 2 years or abuse during 
study. 
 
Hearing loss and/or ototoxicity is not considered to be an adverse event causally associated with 
the use of teprotumumab. However, it may be reasonable to avoid ototoxic medications such as 
systemic administration of aminoglycoside and platinum-based chemotherapy during the study. 

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The following medications may cause muscle spasm/cramps and should be avoided during the 
study: donepezil, neostigmine, and vincristine. 
All concomitant treatment (for TED 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 under the supervision of 
clinic staff. Infusion volumes, and start and stop times of the infusions will be recorded in the 
eCRF. 
An inventory of the study medication supplies will be performed by the site or authorized study 
designee and recorded onto the Drug Accountability Log in the subject’s source document 
records or equivalent.  
9.5 
Efficacy, Quality-of-Life, Pharmacokinetic, and Safety Variables 
The Schedule of Assessments was previously provided in Section 2.1. 
9.5.1 Efficacy Variables 
Efficacy assessments will be performed for both eyes at each assessment time point. The most 
severely affected eye will be defined as the "study eye" at the Baseline (Day 1) Visit. If there is a 
discrepancy between CAS and proptosis in determining the study eye, this will be adjudicated 
always to the eye with the most significant proptosis. If both eyes are affected equally, the 
Investigator will choose the “study eye”. Both eyes will be assessed for efficacy but the study 
eye will be used to assess the primary outcome measure. 
Efficacy will be assessed by proptosis (measured as exophthalmos evaluation of the Clinical 
Measures of Severity using a Hertel instrument provided by the Sponsor for consistency in 
measurement), CAS (7-item scale), diplopia (measured as part of the Clinical Measures of 
Severity) and Clinical Measures of Severity (including motility restriction assessments).  
9.5.1.1 Proptosis (Exophthalmos) 
The most severely affected eye will be defined as the "study eye" at the Baseline (Day 1) Visit. 
Proptosis assessments will be performed using a Hertel exophthalmometer provided by the 
Sponsor for consistency in measurement, and (except when strictly unavoidable) the same Hertel 
instrument and same observer should be used at each evaluation for the full duration of the study. 
Additionally, the same intercanthal distance (ICD) must be used on each occasion. Instructions 
for the measurement of proptosis are included in Section 17.2. 
Proptosis will be measured for each eye at Screening, Day 1 and Weeks 6, 12, 18, and 24 (or 
premature withdrawal [PW]) during the Treatment Period, and at Weeks 28, 36, 48, 60, and 72 

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(or PW) during the Follow-Up Period. Subjects who have a ≥ 2 mm decrease in proptosis from 
Screening to Baseline in the study eye are not eligible for randomization. Measurements will be 
recorded on the Clinical Measures of Severity eCRF under exophthalmos. The Baseline value 
will also be recorded. 
9.5.1.2 Clinical Activity Score (CAS) 
The CAS will be completed at Screening, Day 1 and Weeks 6, 12, 18, and 24 (or PW) during the 
Treatment Period, and at Weeks 28, 36, 48, 60, and 72 (or PW) during the Follow-Up Period 
using the 7-item European Group on Graves’ Ophthalmopathy (EUGOGO) amended CAS 
[Mourits et al, 1989] (Table 9.2).  
The CAS must be ≥ 4 for enrollment and randomization. Subjects whose CAS score decreases 
2 or more points from Screening to Baseline are not eligible for randomization. 
Table 9.2 
Clinical Activity Score (CAS) Assessment 
Item 1 
Description 
1. 
Spontaneous orbital pain. 
2. 
Gaze evoked orbital pain. 
3. 
Eyelid swelling that is considered to be due to active (inflammatory phase) TED/GO. 
4. 
Eyelid erythema. 
5. 
Conjunctival redness that is considered to be due to active (inflammatory phase) TED/GO (ignore 
“equivocal” redness). 
6. 
Chemosis. 
7. 
Inflammation of caruncle or plica. 
1 Each item is scored (1=present; 0=absent) and scores for each item are summed for total score. 
 
To promote consistency in data collection across clinical trial sites, all Investigators will be 
provided with training and copies of the Clinical Manifestations chapter in Graves’ Orbitopathy: 
A Multidisciplinary Approach – Questions and Answers [Dickinson, 2010]. Except when strictly 
unavoidable, the same observer should conduct each CAS evaluation for the full duration of the 
study. 
9.5.1.3 Clinical Measures of Severity 
Based on the EUGOGO Consensus Statement [Bartalena et al, 2008; Wiersinga et al, 2006], the 
following items will be assessed at Screening, Day 1 and Weeks 6, 12, 18, and 24 (or PW) 
during the Treatment Period, and Weeks 28, 36, 48, 60, and 72 (or PW) during the Follow-Up 
Period (Table 9.3). Except when strictly unavoidable, the same observer should conduct each 
evaluation of severity measure for the full duration of the study. 

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Table 9.3 
Clinical Measures of Severity  
Item and Assessment Scale 
Minimum change required for classifying 
overall response 
Exophthalmos (measured in mm using the same Hertel 
exophthalmometer provided by the Sponsor for consistency in 
measurement and same intercanthal distance for each individual 
patient) 
Decrease ≥ 2 mm 
Lid aperture (distance between the lid margins in mm with the 
patient looking in the primary position, sitting relaxed and with 
distant fixation) 
Decrease ≥ 2 mm 
Swelling of the eyelids (absent, mild, moderate, severe) 
Decrease ≥ One grade  
Redness of the eyelids (absent, present) 
Decrease ≥ One grade  
Redness of the conjunctiva (absent, present) 
Decrease ≥ One grade 
Conjunctival edema (absent, present) 
Decrease ≥ One grade  
Inflammation of the caruncle or plica (absent, present) 
Decrease ≥ One grade 
Subjective diplopia score 
0=no diplopia;  
1=intermittent (diplopia in primary position of gaze, when tired or 
when first awakening);  
2=inconstant (diplopia at extremes of gaze);  
3=constant (continuous diplopia in primary or reading position) 
Decrease ≥ One grade 
Eye muscle involvement (ductions in degrees) 
Increase ≥ 8° in at least one direction of gaze 
Corneal involvement (absent/punctate keratopathy/ulcer) 
Decrease ≥ One grade 
Optic nerve involvement  
Best corrected visual acuity 
Color vision 
Optic disc 
Relative afferent pupillary defect (APD) (absent/present) 
Visual fields if optic nerve compression is suspected. 
Change of best corrected visual acuity by 
≥ 2 lines on Snellen chart, or substantial color 
vision change, or significant change of visual 
fields, or significant change in optic disc 
appearance, or (Dis-) appearance of relative 
afferent pupillary defect 
 
9.5.1.3.1 Motility Restriction – Details for Measurement 
Motility is examiner assessed by estimating the degrees of restriction in eye movements. It will 
be assessed at the same time points as the Clinical Measures of Severity. 
Monocular excursions in horizontal and vertical directions of gaze are recorded using the light 
reflex (LR) test [Dolman et al, 2012]. 
The clinician will shine a pen light in line with the eye being examined in ambient room light 
and observe the subject's eye along the light's axis. The subject will be asked to look in the 
4 cardinal directions and the position of the light reflex is viewed on the surface of the cornea. If 
the light touches the limbus, the eye is assessed to be turned 45 degrees, if half way between the 
limbus and pupil edge, the eye is assessed at 30 degrees, and if it is at the pupil edge, it was 

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Instructions for processing, handling, storing and shipping of samples will be detailed in a 
laboratory manual that will be provided to each site prior to site initiation. 
9.5.5 Safety Variables 
Safety will be assessed via AE and concomitant medication use monitoring, immunogenicity 
testing, physical and ophthalmic examinations, vital signs, clinical safety laboratory evaluations 
(complete blood count, chemistry [including thyroid panel and HbA1c], and urinalysis), 
pregnancy testing (if applicable), and ECGs. The study will also be monitored by a DSMB. 
9.5.5.1 Adverse Events 
9.5.5.1.1 Definitions 
9.5.5.1.1.1 Adverse Event Definition 
According to ICH, an AE is any untoward medical occurrence in a subject 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. New findings 
reported from the on-study ophthalmic examinations will not be reported as AEs if according to 
the Investigator the abnormalities are related to TED and not considered related to the 
investigational product. 
Unchanged, chronic conditions are NOT considered AEs and should not be recorded on the AE 
pages of the eCRF unless there is a clear exacerbation of a chronic condition.  
Disease progression can be considered as a worsening of a subject’s condition attributable to the 
disease for which the study drug is being studied (i.e., TED). It may be an increase in the severity 
of the disease under study and/or increases in the symptoms of the disease. The development of 
worsening proptosis may be considered as disease progression and not an AE. Events, which 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. 
9.5.5.1.1.2 Serious Adverse Event Definition 
A TEAE, baseline event, or suspected adverse reaction is considered serious if, in the view of 
either the Investigator or Sponsor, it results in any of the following 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). 

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• 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 which, 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 less than 24 hours in duration are not 
considered hospitalizations. 
9.5.5.1.1.3 Non-Serious Adverse Event Definition 
A non-serious AE includes any AE that is not described in the previous SAE category. 
9.5.5.1.1.4 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 IB or is not listed with the specificity or 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. 
9.5.5.1.1.5 Adverse Events of Special Interest 
Based on previous clinical experience in TED, the following AESIs are identified for this study 
(See Section 7.1.3.4.5.5 for further information): 
• Infusion reactions (e.g., nausea, vomiting, facial flushing, warmth, dyspnea, dizziness, 
hypertension, hypotension, pruritus) 
• Hyperglycemia 
• Muscle spasms 
• Diarrhea 

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9.5.5.1.2 Documentation of Adverse Events 
Adverse events that occur within 2 weeks prior to Day 1 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 after the last dose of 
study drug, and the Follow-Up AE reporting period begins 3 weeks after the last dose of study 
drug through completion of the Follow-Up Period (Week 72 or PW). All baseline 
signs/symptoms, TEAEs, and AEs during the Follow-Up Period must be recorded in the source 
documents and on the subject’s eCRF. 
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 9.5.5.1.5. 
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 
sneezing might be grouped together as “upper respiratory infection” if the Investigator is 
confident of the diagnosis. 
9.5.5.1.3 Intensity of Adverse Events 
All clinical AEs encountered during the clinical study will be reported on the AE form of the 
CRF. Intensity of AEs will be graded on a 5-point scale (mild, moderate, severe, life-threatening, 
death) and reported in detail on the eCRF.  
Intensity 
Definition 
Corresponding NCI 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 
 
9.5.5.1.4 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 (probably not related): There is no plausible temporal 
relationship or there is another explanation that unequivocally provides a more plausible 
explanation for the event. 

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• 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 312.32(c)(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). 
• 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. 
9.5.5.1.5 Reporting and Documenting SAEs 
All SAEs beginning with the time of signing of the ICF and continuing until 30 days after study 
discharge 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 
, fax, or telephone within 24 hours 
after becoming aware that a subject has experienced an SAE (see Appendix 17.1 for 
contact information). 

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2. Perform appropriate diagnostic tests and therapeutic measures, and submit all 
follow-up substantiating data, such as diagnostic test reports, hospital discharge 
summaries, and autopsy report to the Sponsor’s representative. 
3. 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. 
9.5.5.1.6 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. 
9.5.5.1.7 Medication Error and Overdose 
An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to, or by a study subject, at a dose > 5% above that which is assigned to that individual 
subject according to the study protocol. 
All cases of medication errors and overdose (with or without associated AEs) will be 
documented on the eCRF in order to capture this important safety information consistently in the 
database. AEs associated with an overdose and SAEs of overdose are to be reported according to 
the procedures outlined in Sections 9.5.5.1.2 and 9.5.5.1.5, respectively. 
In the event of drug overdose, the subject is to be treated with symptomatic and supportive care 
as required. 
9.5.5.1.8 Review of Adverse Events and Emerging New Safety Information 
The Sponsor will perform an ongoing review of all AEs and all other emerging new information 
relevant to the safety of the drug, including periodic review and analyses of their entire safety 
database. 

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9.5.5.1.9 Reporting of IND Safety Reports 
The Sponsor will notify the US FDA and all Investigators on any new serious risks associated 
with the drug. 
9.5.5.1.10 Reporting of Suspected Unexpected Serious Adverse Reactions in the EU 
The Sponsor or designee will report all Suspected Unexpected Serious Adverse Reactions 
(SUSARs), to the competent authorities and the concerned ethics committee according to 
applicable law. Investigators will also be informed according to local requirements. 
9.5.5.1.11 Development Safety Update Reports 
The Sponsor will prepare and submit annual safety reports to competent authorities and 
concerned ethics committees. 
9.5.5.2 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, Baseline, prior to dosing during the Treatment Period (Weeks, 3, 6, 9, 12, 15, and 21), 
the end of the Treatment Period (Week 24 or PW), and at Weeks 28, 36, and 48 during the 
Follow-Up Period; 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 PW assessment. A serum 
pregnancy test will be performed at Screening and urine pregnancy tests will be performed prior 
to dose at all other visits, as applicable; the serum sample will be analyzed at a central study 
laboratory and the urinary pregnancy tests will be performed locally. 
If a female subject becomes pregnant during the Treatment Period, she should immediately 
notify the Investigator, and teprotumumab dosing should be permanently discontinued.  
Pregnancy occurring in the partner of a male subject participating in the study should be reported 
to the Investigator and the Sponsor. Monitoring of the partner should continue until conclusion 
of the pregnancy.  
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 
 fax, or 
telephone within 24 hours after becoming aware that the subject/subject’s female partner has 
become pregnant (see Appendix 17.1 for contact information). The Investigator should counsel 
the subject and discuss the possible risks of continuing the pregnancy. If pregnancy continues, 
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. 

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9.5.5.3 Medical History 
Medical history, including tobacco use history and Graves’ disease and treatment history, will be 
conducted at Screening. TED must be moderate to severe in intensity (non-sight threatening but 
appreciable impact on daily life) with an onset of ophthalmic symptoms (as determined by 
subject records) within 9 months prior to the Baseline Visit for study enrollment. 
9.5.5.4 Vital Signs 
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 predose on 
all other infusion 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. 
Blood pressure and pulse measurements will be obtained with the subject’s arm unconstrained by 
clothing or other material and while the subject is sitting up. When possible, the same arm will 
be used for measurements in all study visits.  
9.5.5.5 Physical and Ophthalmic Examinations, Height, and Weight 
A physical examination, including complete undilated ophthalmic examination, will be 
performed at Screening, Baseline (Day 1) and thereafter at Weeks 1, 6, 12, 18, and 24 (or PW) 
during the Treatment Period and at Weeks 48 and 72 (or PW) of the Follow-Up Period.  
The ophthalmic exam should include best-corrected visual acuity, pupil exam, color vision 
assessment, Ishihara color plates (or equivalent) or related red desaturation, intraocular pressure 
and slit lamp exam. If significant abnormalities are noted compared with previous visits, 
including a loss of 2 lines or more of vision, development of pupil abnormalities including 
afferent pupillary defect (APD), rise in intraocular pressure, development of corneal infiltrates or 
other abnormalities not here specified but of concern to the ophthalmologist, further 
investigations of visual function will be conducted according to the ophthalmologist decision.  
Subjects who have decreased best-corrected visual acuity due to optic neuropathy (defined by a 
decrease in vision of 2 lines on the Snellen chart, new visual field defect, or color defect 
secondary to optic nerve involvement within the last 6 months) at Screening are not eligible for 
enrollment. 
New findings reported from on-study ophthalmic examinations will not be reported as AEs if, 
according to the Investigator, the abnormalities are related to TED and not related to the study 
drug. 
Physical exam will include assessment of presence or absence of pretibial myxedema on Day 1, 
Week 24 (or PW) of the Treatment Period, and Week 72 (or PW) of the Follow-Up Period. If 

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present, measurements of instep and calf will be taken. Height will be measured at Screening 
only. 
Weight will be measured at Screening and every 12 weeks throughout the study (Weeks 12 and 
24 [or PW] during the Treatment Period and Weeks 36, 48, 60, and 72 [or PW] of the Follow-Up 
Period). The dose on Day 1 of the double-masked Treatment Period will be based on the 
Screening weight. The weight obtained at Week 12 can be used in dose calculations beginning at 
Week 12 or Week 15. 
9.5.5.6 ECGs  
12-lead ECGs will be performed at Screening, Baseline, Weeks 3, 6, 12, and 24 (or PW) of the 
Treatment Period, and Week 72 (or PW) of the Follow-Up Period. At infusion visits, the ECG 
will be performed prior to the infusion. The results will be recorded as normal or abnormal on 
the eCRF and all abnormal results will be evaluated as clinically (CS) or not clinically significant 
(NCS) by the Investigator. A copy of the ECG tracing will remain with the source documents. 
9.5.5.7 Clinical Laboratory Safety Tests 
With the exception of urine pregnancy tests, a central study laboratory will be used for all 
protocol-specified clinical laboratory parameters. Urine pregnancy tests will be performed 
locally (see Section 9.5.5.2 for details). Details concerning the collection of these samples are 
presented in Table 9.4. 

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Table 9.4 
Schedule of Clinical Laboratory Safety Tests, Including Thyroid Panel and 
Hyperglycemia Monitoring 
Analysis Panel 
 
Treatment Period 
Follow-Up Period 
SCR 
BL 
 
W1 
 
W3 
 
W4 
M1 
W6 
 
W9 
 
W12 
M3 
W15 
 
W18 
 
W21 
 
W24 
M6 
W28 
M7 
W36 
M9 
W48 
M12 
W60 
M15 
W72 
M18 
Chemistry (excl. 
glucose) 
X 1 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
Thyroid (FT3, FT4, 
TSH) 2 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
Glucose 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
HbA1c 4 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
Urinalysis  
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
Serum pregnancy 5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 5 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 6 
BL=Baseline; FT3=free triiodothyronine; FT4=free thyroxine; HbA1c=glycated hemoglobin; M=Month; SCR=Screening; 
TSH=thyroid stimulating hormone; W=Week. 
1. 
ALT/AST must be ≤ 3 x the ULN and serum creatinine must be < 1.5 x the ULN according to age for randomization. 
2. 
Subjects must be euthyroid with the baseline disease under control or have mild hypo- or hyperthyroidism (defined as FT4 
and FT3 levels < 50% above or below the normal limits). Every effort should be made to correct the mild hypo- or 
hyperthyroidism promptly and to maintain the euthyroid state for the full duration of the clinical trial.  
3. 
Non-diabetic subjects will fast at Weeks 1 and 4 only. Diabetic subjects will fast for each blood glucose evaluation. NOTE: 
Subjects with severe hyperglycemia 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) will be 
permanently discontinued from study drug. 
4. 
HbA1c must be < 9.0% for randomization. If the HbA1c is elevated and considered clinically significant at any time point 
after Screening, it will be repeated approximately every 45 days until it returns to normal or baseline value. 
5. 
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]). 
6. 
Perform for female subjects of childbearing potential who enter the Follow-Up Period but discontinue study participation 
prior to Week 48. 
Instructions for the collection, handling and analysis of clinical laboratory samples will be 
provided to the site prior to study site initiation. 
9.5.5.8 Immunogenicity Testing 
Blood samples will be collected in a 5 mL SST collection tube for immunogenicity testing (ADA 
and possibly Neutralizing Antibodies [NAb]) from all subjects prior to dosing on Day 1, prior to 
dosing on Weeks 3 and 9, and at Week 24 (or PW) of the Treatment Period, and Weeks 36 and 
72 (or PW) of the Follow-Up Period. Samples will be collected, processed, and stored at ≥ -70°C 
at the site until shipment to the central laboratory 
. 
 
will store the samples at ≥ –70°C until shipment to 
 for immunogenicity testing (see 
Table 6.1). If a subject tests positive for ADA after confirmatory and reactive titer testing, the 
sample will then be tested for NAb. If the subject tests positive for NAb, he/she will be followed 
until levels either revert to Baseline or the subject’s value decreases or remains stable. Any 

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subject with a positive NAb test at Week 72 (or PW) of the Follow-Up Period will continue to be 
followed until the subject’s value decreases or remains stable. 
Instructions for 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. 
9.5.5.9 Data Safety Monitoring Board 
 The study will be monitored by a DSMB, which will advise the Sponsor regarding the 
continuing safety of study subjects and potential subjects as well as continuing validity and 
scientific merit of the trial. The details regarding frequency of meetings, members, and the safety 
review criteria will be outlined in a separate DSMB Charter. ACI Clinical will manage the 
logistics of the DSMB (Table 6.1). 
9.5.6 Appropriateness of Measurements 
This study, which is a randomized, double-masked, placebo-controlled, parallel-group, multi-
center study, is designed according to standard principles for adequate and well-controlled 
studies. The study population is well-defined and is consistent with the expected target 
population for whom teprotumumab will be indicated (adult subjects previously diagnosed with 
Graves’ hyperthyroidism and with moderate-to-severe active TED). 
9.5.7 Study Procedures 
Subjects who provide informed consent and who meet all the entry criteria for participation in 
this study will be randomized to treatment. 
9.5.7.1 Screening 
Due to the large number of screening assessments, the Screening Visit may be completed in 
more than one 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 
answered all questions to the study candidate’s satisfaction. Further procedures can begin only 
after the ICF has been signed. The original signed ICF will be retained by the Investigator and a 
copy will be given to the 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 will determine each candidate’s suitability for the study. 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 42 to 14 days prior to 
Study Day 1 (i.e., the first day of administration of study drug). The following procedures will be 
performed during Screening to establish each candidate’s general health and eligibility for 
enrollment into the study: 

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• Obtain signed, written informed consent and permission to use Protected Health 
Information (in accordance with the Health Insurance Portability and Accountability Act 
[HIPAA]). Refusal to provide this permission excludes an individual from eligibility for 
study participation. Record date informed consent was given and who conducted the 
process on the appropriate source documentation. 
• Collect medical history, including tobacco use history and Graves’ disease and treatment 
history. Ensure active TED is moderate to severe in intensity (non-sight threatening but 
appreciable impact on daily life) with an onset of ophthalmic symptoms (as determined 
by subject records) within 9 months prior to the projected Baseline Visit. 
• Determine study eligibility through review of the inclusion/exclusion criteria (see 
Section 9.3) 
• Obtain demographics. 
• Enquire about prior medications (see Table 9.1 for restrictions regarding medications). 
• Obtain a serum sample from all females of childbearing potential for performance of a 
pregnancy test. 
• Perform a physical examination, including measurements of height and weight. 
• Perform ophthalmic examination. Subjects who have decreased best-corrected visual 
acuity due to optic neuropathy (defined by a decrease in vision of 2 lines on the Snellen 
chart, new visual field defect, or color defect secondary to optic nerve involvement 
within the last 6 months) are not eligible for enrollment. 
• Perform 12-lead ECG. 
• Record vital signs (blood pressure, pulse, respiration rate, and temperature). These 
measurements will be performed according to standardized instructions. Record on the 
appropriate source documentation. 
• Obtain blood samples for hematology and chemistry (including thyroid, glucose, and 
HbA1c) analysis (see Section 9.5.5.7 for details concerning test results and study 
participation). 
• Obtain a urine sample for urinalysis. 
• Complete the efficacy assessments (CAS, Clinical Measures of Severity including 
proptosis, diplopia and motility restriction). 
• Query subjects regarding signs and symptoms. 
• Contact IWRS to register the Screening Visit. 

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For all subjects enrolled in the study, the source documentation record will be transcribed onto 
the eCRF. 
9.5.7.2 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. 
• Obtain predose blood samples for hematology and chemistry (including thyroid, glucose, 
but not HbA1c) analysis (see Section 9.5.5.7 for details concerning test results and study 
participation). 
• Collect predose blood samples for immunogenicity testing. 
• Collect predose blood samples for biomarker analyses.  
• Collect predose urine sample for urinalysis and also for a pregnancy test for females of 
childbearing potential; the pregnancy test must be negative for the subject to receive 
study drug. 
• Enquire about signs and symptoms within previous 2 weeks and concomitant 
medications. 
• Perform predose physical and ophthalmic examinations. 
• Perform predose 12-lead ECG. 
• Perform predose Baseline efficacy assessments (CAS, Clinical Measures of Severity 
including proptosis, diplopia and motility restriction). Proptosis and CAS may not 
decrease > 2 mm/points in the study eye from Screening to be eligible for enrollment. 
• Administer the predose GO-QoL questionnaire. 
• Contact IWRS to obtain randomization number in order for the unmasked pharmacy to 
receive study drug dosing information. 
• Monitor vital signs prior to and at the end of the infusion. Additional vital sign 
monitoring may be performed in the event of infusion-associated AEs (see 
Section 9.5.5.4 for details). 
• Collect blood samples for PK analyses prior to and at the end of the infusion.  

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• Administer the first dose of study drug and record date, volume and rate of infusion, and 
start/stop times of dosing. 
Subjects will be discharged from the study center after all of the Study Day 1 procedures have 
been completed and will be contacted the following day to enquire about AEs and concomitant 
medication use. 
9.5.7.3 Week 1 
• Collect blood samples for hematology and glucose testing (see Section 9.5.5.7 for details 
concerning test results and study participation). 
• Collect blood sample for PK analyses. Record date/time of sample collection. 
• Perform physical and ophthalmic examinations, including vital signs. 
• Enquire about AEs and concomitant medication use. 
Subjects will be released from the study center after all of the visit procedures have been 
completed and instructed to return to the clinic at Week 3. 
9.5.7.4 Week 3 
• Obtain predose blood samples for hematology and chemistry (including thyroid, glucose, 
but not HbA1c) analysis (see Section 9.5.5.7 for details concerning test results and study 
participation). 
• Collect predose urine sample for urinalysis and also for a pregnancy test for females of 
childbearing potential; the pregnancy test must be negative for the subject to receive 
study drug. 
• Collect predose blood sample for immunogenicity testing. 
• Enquire about signs and symptoms and concomitant medications throughout the visit. 
• Perform predose 12-lead ECG. 
• Monitor vital signs prior to and at the end of the infusion. Additional vital sign 
monitoring may be performed in the event of infusion-associated AEs (see Section 
9.5.5.4 for details). 
• Collect blood samples for PK analyses prior to and at the end of the infusion.  
• Contact IWRS to obtain study medication vial assignment and to determine the volume 
of study drug to be administered. 

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• Administer study drug and record date, volume and rate of infusion, and start/stop times 
of dosing. 
Subjects will be discharged from the study center after all of the procedures have been completed 
and will be contacted the following day to enquire about AEs and concomitant medication use. 
9.5.7.5 Week 4 
• Collect blood samples for hematology and glucose testing (see Section 9.5.5.7 for details 
concerning test results and study participation). 
• Collect blood sample for PK analyses. Record date/time of sample collection. 
• Collect vital signs. 
• Enquire about AEs and concomitant medication use. 
Subjects will be released from the study center after all of the visit procedures have been 
completed and instructed to return to the clinic at Week 6. 
9.5.7.6 Week 6 
• Obtain predose blood samples for hematology and chemistry (including thyroid, glucose, 
but not HbA1c) analysis (see Section 9.5.5.7 for details concerning test results and study 
participation). 
• Collect predose urine sample for urinalysis and also for a pregnancy test for females of 
childbearing potential; the pregnancy test must be negative for the subject to receive 
study drug. 
• Enquire about signs and symptoms and concomitant medications throughout the visit. 
• Perform predose 12-lead ECG. 
• Perform predose physical and ophthalmic examinations, including vital signs. Additional 
vital sign monitoring may be performed in the event of infusion-associated AEs (see 
Section 9.5.5.4 for details). 
• Perform predose efficacy assessments (CAS, Clinical Measures of Severity including 
proptosis, diplopia and motility restriction). 
• Administer predose GO-QoL questionnaire.  
• Contact IWRS to obtain study medication vial assignment and to determine the volume 
of study drug to be administered. 

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• Administer study drug and record date, volume and rate of infusion, and start/stop times 
of dosing. 
Subjects will be discharged from the study center after all of the procedures have been completed 
and instructed to return for a clinic visit at Week 9. 
9.5.7.7 Week 9 
• Obtain predose blood samples for hematology and chemistry (including thyroid, glucose, 
but not HbA1c) analysis (see Section 9.5.5.7 for details concerning test results and study 
participation). 
• Collect predose urine sample for urinalysis and also for a pregnancy test for females of 
childbearing potential; the pregnancy test must be negative for the subject to receive 
study drug. 
• Collect predose blood samples for immunogenicity testing. 
• Enquire about signs and symptoms and concomitant medications throughout the visit. 
• Collect predose vital signs. Additional vital sign monitoring may be performed in the 
event of infusion-associated AEs (see Section 9.5.5.4 for details). 
• Collect blood samples for PK analyses prior to and at the end of the infusion.  
• Contact IWRS to obtain study medication vial assignment and to determine the volume 
of study drug to be administered. 
• Administer study drug and record date, volume and rate of infusion, and start/stop times 
of dosing. 
Subjects will be discharged from the study center after all of the procedures have been completed 
and instructed to return for a clinic visit at Week 12. 
9.5.7.8 Week 12 
• Obtain predose blood samples for hematology and chemistry (including thyroid, glucose, 
and HbA1c) analysis (see Section 9.5.5.7 for details concerning test results and study 
participation). 
• Collect predose urine sample for urinalysis and also for a pregnancy test for females of 
childbearing potential; the pregnancy test must be negative for the subject to receive 
study drug. 
• Collect predose blood samples for biomarker analyses.  
• Enquire about signs and symptoms and concomitant medications throughout the visit. 

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• Perform predose 12-lead ECG. 
• Perform predose physical and ophthalmic examinations, including vital signs. Additional 
vital sign monitoring may be performed in the event of infusion-associated AEs (see 
Section 9.5.5.4 for details). 
• Measure weight. 
• Perform predose efficacy assessments (CAS, Clinical Measures of Severity including 
proptosis, diplopia and motility restriction). 
• Administer predose GO-QoL questionnaire.  
• Contact IWRS to obtain study medication vial assignment and to determine the volume 
of study drug to be administered. 
• Administer study drug and record date, volume and rate of infusion, and start/stop times 
of dosing. 
Subjects will be discharged from the study center after all of the procedures have been completed 
and will be instructed to return to the clinic at Week 15. 
9.5.7.9 Week 15 
• Obtain predose blood samples for hematology and glucose analysis (see Section 9.5.5.7 
for details concerning test results and study participation). 
• Collect predose urine sample for a pregnancy test for females of childbearing potential; 
the pregnancy test must be negative for the subject to receive study drug. 
• Enquire about signs and symptoms and concomitant medications throughout the visit. 
• Collect predose vital signs. Additional vital sign monitoring may be performed in the 
event of infusion-associated AEs (see Section 9.5.5.4 for details).  
• Contact IWRS to obtain study medication vial assignment and to determine the volume 
of study drug to be administered. 
• Administer study drug and record date, volume and rate of infusion, and start/stop times 
of dosing. 
Subjects will be discharged from the study center after all of the procedures have been completed 
and will be instructed to return to the clinic at Week 18. 

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9.5.7.10 Week 18 
• Obtain predose blood samples for hematology and chemistry (including thyroid, glucose, 
but not HbA1c) analysis (see Section 9.5.5.7 for details concerning test results and study 
participation). 
• Collect predose urine sample for urinalysis and also for a pregnancy test for females of 
childbearing potential; the pregnancy test must be negative for the subject to receive 
study drug. 
• Enquire about signs and symptoms and concomitant medications throughout the visit. 
• Perform predose physical and ophthalmic examinations, including vital signs. Additional 
vital sign monitoring may be performed in the event of infusion-associated AEs (see 
Section 9.5.5.4 for details). 
• Perform predose efficacy assessments (CAS, Clinical Measures of Severity including 
proptosis, diplopia and motility restriction).  
• Contact IWRS to obtain study medication vial assignment and to determine the volume 
of study drug to be administered. 
• Administer study drug and record date, volume and rate of infusion, and start/stop times 
of dosing. 
Subjects will be discharged from the study center after all of the procedures have been completed 
and will be instructed to return to the clinic at Week 21. 
9.5.7.11 Week 21 
• Obtain predose blood samples for hematology and glucose analysis (see Section 9.5.5.7 
for details concerning test results and study participation). 
• Collect predose urine sample for a pregnancy test for females of childbearing potential. 
The pregnancy test must be negative for those subjects to receive study drug. 
• Enquire about signs and symptoms and concomitant medications throughout the visit. 
• Collect predose vital signs. Additional vital sign monitoring may be performed in the 
event of infusion-associated AEs (see Section 9.5.5.4 for details). 
• Contact IWRS to obtain study medication vial assignment and to determine the volume 
of study drug to be administered. 
• Administer study drug and record date, volume and rate of infusion, and start/stop times 
of dosing. 

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Subjects will be discharged from the study center after all of the procedures have been completed 
and will be instructed to return to the clinic at Week 24. 
9.5.7.12 Week 24 
Week 24 is the final visit of the Treatment Period. Study drug is not administered. 
• Obtain blood samples for hematology and chemistry (including thyroid, glucose, and 
HbA1c) analysis (see Section 9.5.5.7 for details concerning test results and study 
participation). 
• Collect urine sample for urinalysis and also for a pregnancy test for females of 
childbearing potential.  
• Collect blood sample for biomarker analyses.  
• Collect blood sample for immunogenicity testing (only subjects who complete the 
Treatment Period, not those who prematurely discontinue study drug administration).  
• Collect blood sample for PK analysis (only subjects who complete the Treatment Period, 
not those who prematurely discontinue study drug administration).  
• Enquire about signs and symptoms and concomitant medications throughout the visit. 
• Perform 12-lead ECG. 
• Perform physical and ophthalmic examinations, including vital signs. 
• Measure weight. 
• Perform efficacy assessments (CAS, Clinical Measures of Severity including proptosis, 
diplopia and motility restriction). 
• Administer GO-QoL questionnaire. 
• Contact IWRS to register the End-of-Treatment Visit. 
Subjects will be discharged from the study center after all of the procedures have been 
completed.  
Subjects who are proptosis non-responders will be offered the opportunity to receive 8 infusions 
of teprotumumab in an open-label extension study, HZNP-TEP-302. 
Subjects who are proptosis responders and those who are non-responders and do not elect to 
participate in the open-label extension study will enter the Follow-Up Period and will be 
instructed to return to the clinic in 4 weeks for the first follow-up visit.  

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9.5.7.13 Week 28 
• Collect urine sample for a pregnancy test for females of childbearing potential. 
• Enquire about signs and symptoms and concomitant medications throughout the visit. 
• Collect vital signs. 
• Perform efficacy assessments (CAS, Clinical Measures of Severity including proptosis, 
diplopia and motility restriction). 
• Administer GO-QoL questionnaire. 
Subjects will be discharged from the study center after all of the procedures have been completed 
and will be instructed to return to the clinic at Week 36. 
9.5.7.14 Week 36  
• Obtain blood samples for hematology and chemistry (including thyroid, glucose, and 
HbA1c) analysis. 
• Collect urine sample for urinalysis and also for a pregnancy test for females of 
childbearing potential. 
• Enquire about signs and symptoms and concomitant medications throughout the visit. 
• Collect blood sample for immunogenicity testing.  
• Collect vital signs. 
• Measure weight. 
• Perform efficacy assessments (CAS, Clinical Measures of Severity including proptosis, 
diplopia and motility restriction). 
Subjects will be discharged from the study center after all of the procedures have been completed 
and will be instructed to return to the clinic at Week 48. 
9.5.7.15 Week 48 
• Enquire about signs and symptoms and concomitant medications throughout the visit. 
• Perform physical and ophthalmic examinations, including vital signs. 
• Measure weight. 
• Administer GO-QoL questionnaire. 

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• Perform efficacy assessments (CAS, Clinical Measures of Severity including proptosis, 
diplopia and motility restriction). 
Subjects will be discharged from the study center after all of the procedures have been completed 
and will be instructed to return to the clinic at Week 60. 
9.5.7.16 Week 60 
• Enquire about signs and symptoms and concomitant medications throughout the visit. 
• Collect vital signs. 
• Measure weight. 
• Perform efficacy assessments (CAS, Clinical Measures of Severity including proptosis, 
diplopia and motility restriction). 
Subjects will be discharged from the study center after all of the procedures have been completed 
and will be instructed to return to the clinic at Week 72. 
9.5.7.17 Week 72 (Termination Visit or Premature Withdrawal Visit) 
• Obtain blood samples for hematology and chemistry (including thyroid, glucose, and 
HbA1c) analysis. 
• Collect urine sample for urinalysis.  
• Collect urine sample for a pregnancy test for females of childbearing potential if the 
subject discontinued from the study prior to Week 36. 
• Collect blood sample for immunogenicity testing. 
• Enquire about signs and symptoms and concomitant medications throughout the visit. 
• Perform 12-lead ECG. 
• Perform physical and ophthalmic examinations, including vital signs. 
• Measure weight. 
• Perform efficacy assessments (CAS, Clinical Measures of Severity including proptosis, 
diplopia, and motility restriction). 
• Administer GO-QoL questionnaire. 
Subjects will be discharged from the study center after all of the procedures have been 
completed. 

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9.5.7.18 Week 96 – Follow-Up Contact 
Subjects who complete the Week 72 Visit will be contacted 6 months later via phone or email by 
research staff to enquire if any treatment for TED has been received since last study contact. If 
yes, subject will be questioned regarding type of treatment and outcome/response. 
9.5.7.19 Week 120 – Follow-Up Contact 
Subjects who complete the Week 72 Visit will be contacted 12 months later via phone or email 
by research staff to enquire if any treatment for TED has been received since last study contact. 
If yes, subject will be questioned regarding type of treatment and outcome/response. 
The end of the trial is defined as the date of the last subject contact at Week 120. 
9.6 
Statistical Methods and Determination of Sample Size  
Detailed statistical analyses will be presented in a separate statistical analysis plan (SAP), and 
analyses presented in the SAP will supersede those presented in the protocol. Some key points 
identified for statistical analyses are outlined below. 
9.6.1 Endpoints 
9.6.1.1 Primary Endpoint 
The primary outcome measure is the proptosis responder rate (percentage of subjects with a 
≥ 2 mm reduction from Baseline in proptosis in the study eye, without deterioration [≥ 2 mm 
increase] of proptosis in the fellow eye) at Week 24. 
9.6.1.2 Secondary Endpoints (analyzed hierarchically) 
1. The overall responder rate (percentage of subjects with ≥ 2-point reduction in CAS AND 
≥ 2 mm reduction in proptosis from Baseline, provided there is no corresponding 
deterioration [≥ 2 point/mm increase] in CAS or proptosis in the fellow eye) at Week 24. 
2. Percentage of subjects with a CAS value of 0 or 1 in the study eye at Week 24. 
3. Mean change from Baseline to Week 24 in proptosis measurement in the study eye. 
4. Diplopia responder rate (percentage of subjects with baseline diplopia > 0 in study eye 
who have a reduction of ≥ 1 grade with no corresponding deterioration [≥ 1 grade 
worsening] in the fellow eye) at Week 24. 
5. Mean change from Baseline to Week 24 in the GO-QoL questionnaire overall score. 
9.6.1.3 Exploratory Endpoints  
1. Evaluate the effect of teprotumumab versus placebo on the Clinical Measures of Severity 
individual response status frequencies and percentage of responders for each component 
of clinical severity from Baseline to Week 24.  
2. Evaluate the effect of teprotumumab versus placebo on the mean change from Baseline to 
Week 24 in the CAS. 

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3. Evaluate the effect of teprotumumab versus placebo on the overall responder rate at 
Week 24 stratified by the level of response (high responders, responders, low responders, 
and non-responders; see Section 9.6.4.3.1 for definitions). 
4. Evaluate pharmacokinetic (PK) parameters of teprotumumab to estimate exposure and 
understand PK-PD relationships. 
5. Mean change from Baseline to Week 24 in the GO-QoL questionnaire VF and A subscale 
scores. 
6. Evaluate the effect of teprotumumab on the mean change from Baseline to Week 24 in 
blood and serum biomarkers. 
7. Evaluate the effect of teprotumumab versus placebo on the mean change from Baseline to 
Week 24 on the motility component of the Clinical Measures of Severity. 
9.6.2 Populations for Analysis 
The following analysis populations will be defined for this study:  
• Intent-to-Treat (ITT)  
• Modified Intent-to-Treat (MITT) population 
• Per Protocol (PP) population 
• Safety Population 
The ITT population will include all subjects who are randomized to treatment. Full details of the 
analysis populations will be described in the SAP. 
9.6.3 Primary and Secondary Endpoint Analysis 
The primary analyses will be conducted in the ITT population. The analysis of the primary 
proptosis responder endpoint will assess risk difference (difference in response rates) in a 
stratified analysis. The analysis will use Cochran-Mantel-Haenszel (CMH) weighting to estimate 
the common risk difference within strata and to estimate the standard error of the common risk 
difference. Subjects missing the Week 24 evaluation will be considered to be treatment failures 
(non-responders) for the primary analysis. Further, subjects who prematurely discontinue study 
drug dosing prior to Week 21 during the double-masked Treatment Period will be considered to 
be treatment failures (non-responders), unless an assessment at Week 24 is available. 
Stratification for the analysis will use the same factor as was used to stratify randomization, 
tobacco use (non-user, user). The difference in response rates, comparing teprotumumab to 
placebo, will be estimated along with the corresponding 95% confidence interval (CI) and 
p-value.  
An analysis of risk difference with stratification by tobacco use (non-user vs. user) will also be 
used to analyze the 3 secondary categorical endpoints. For the analysis of proptosis and GO-QoL 
(see Section 9.6.4.4 for details) as continuous secondary endpoints, a Mixed-Model Repeated-
Measures (MMRM) analysis of covariance (ANCOVA) model will be fit to the individual 
change from baseline scores for the study eye, with terms in the model being the baseline score, 

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tobacco use status, treatment group, visit, and the visit-by-treatment and visit-by-baseline-score 
interactions. The main focus of the analysis will be to test the treatment differences at Week 24, 
with the main results consisting of the Week 24 estimated Least Square (LS) means and their 
differences with 95% CIs and p-values. 
To control the overall Type 1 error rate of the study, taking into consideration the one primary 
and 5 secondary outcome measures, the outcome measures will be tested in a hierarchical 
stepwise fashion. For each outcome measure, teprotumumab will be tested against placebo at the 
0.05 level only if teprotumumab was statistically significant for the outcome measure preceding 
it in the hierarchical order. 
9.6.4 Exploratory Analyses 
9.6.4.1 Pharmacokinetics/Pharmacodynamics 
All PK data and parameters will be presented descriptively, including arithmetic means, standard 
deviations, geometric means, CVs, medians, and ranges. The key data are Ctrough plasma levels at 
Week 9 prior to infusion and at Week 24, important to confirm that plasma concentrations were 
maintained above the 20 µg/ml level through the course of the dosing period. 
The relationship between clinical endpoints and the plasma concentrations of teprotumumab will 
be explored in a descriptive manner. 
9.6.4.2 Clinical Measures of Severity  
The Clinical Measures of Severity results (see Table 9.3) for each item will be summarized at 
each designated visit for each eye with the number and percentage of subjects being classified as 
responders on each individual criterion. The proportions of responders will be analyzed using the 
same risk difference method described for the primary endpoint in Section 9.6.3. 
9.6.4.2.1 Motility Component of the Clinical Measures of Severity 
The monocular ductions of the study eye (degrees) will be compared between the 2 treatment 
groups at each evaluation period for adduction, abduction, supraduction and infraduction.  
For each motility measure, the analysis of the changes from baseline in the target eye will be 
conducted using the same MMRM ANCOVA analysis as the continuous secondary endpoint 
analysis in Section 9.6.3, substituting the appropriate baseline assessments. 
9.6.4.3 Clinical Activity Score (CAS) 
CAS will be measured as a continuous variable using the MMRM ANCOVA model described 
above to compare the treatment groups. 
9.6.4.3.1 Stratification of Proptosis and CAS Response into Four Responses Categories 
To further explore the response based on both proptosis and CAS reduction, each subject will be 
classified into one of 4 response categories at Week 24: 

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• High responders: Subjects who had a reduction in both proptosis and CAS of 3 or more 
(>3) from Baseline in the study eye, and no deterioration in the fellow eye (i.e., increase 
in CAS ≥ 2 points or increase in proptosis > 2 mm). 
• Responders: Subjects who had a reduction in both CAS and proptosis of 2 or more (but 
less than 3) from Baseline in the study eye, and no deterioration in the fellow eye. 
• Low Responders: Subjects who had a reduction in both CAS and proptosis of 1 or more 
(but less than 2) from Baseline in the study eye, and no deterioration in the fellow eye. 
• 
Non-Responders: Subjects who did not fit into any of the above categories, or were not 
present for the Week 24 evaluation. 
A logistic regression analysis will be used to compare the treatment groups on the basis of this 
ordered 4-category classification. 
9.6.4.4 Quality of Life Analysis 
QoL assessments will be used to derive pre-specified QoL scores according to the directions for 
the GO-QoL scale. These scores will be summarized by descriptive summary tables at Baseline 
and over time. The overall score, and the VF and A subscale scores, will be evaluated at 
Week 24 using the MMRM model described above. Final analysis plans will be provided in the 
SAP. 
9.6.4.5 Blood and Serum Biomarkers 
Biomarker data will be summarized using descriptive statistics. 
9.6.4.6 Safety Analyses 
The safety analysis population will include all subjects who receive at least one dose and had at 
least one post-dose safety assessment. All safety parameters will be summarized and presented in 
tables based on this safety population. Details of the safety data analysis will be presented in the 
SAP. 
9.6.4.7 Interim Analyses 
No interim analyses are planned. 
9.6.5 Sample Size and Power Considerations 
In the prior study, TED01RV, a 51% difference (71% vs 20%) between teprotumumab 
(10 mg/kg for the first infusion followed by 20 mg/kg for the remaining 7 infusions) and placebo 
was observed at Week 24 in favor of teprotumumab in proptosis reduction of 2 mm or more. A 
sample size of 38 subjects per group provides 90% power at the 2-sided alpha 0.05 level to detect 
a difference of 39% between teprotumumab and placebo; the sample size has been adjusted to 
allow for a 16% discontinuation rate. 

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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. 
The Sponsor’s Medical Monitor will consider any requests for exceptions 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 in 
. In the event of a protocol deviation, the Investigator 
and Sponsor’s Medical Monitor will determine whether the subject should continue to participate 
in the 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. 
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 records; physicians’ and nurses’ 
notes; appointment book; original laboratory, ECG, electroencephalogram, radiology, pathology, 
and special assessment reports; dispensing records; signed ICFs; consultant letters; and subject 
screening and enrollment logs. 
In order to comply with regulatory requirements, it is the policy of the Sponsor that, at a 
minimum, the following be documented in source documents at the 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. 

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• Review by the Investigator or qualified personnel on the 1572 of laboratory test results. 
• Adverse events (start and stop date, description, action taken, and resolution). 
• Investigator or sub-investigator’s signed assessment of each AE. 
• Concomitant medications (start and stop dates, reason for use). 
• Condition of subject upon completion of, or PW from, the study. 
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. Data captured on the eCRF, and requested anonymized copies of supporting 
documents, will be transferred to the Sponsor at study completion. 
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 CRO Data Management System. Final eCRFs will be provided to the 
Investigator and Sponsor by CRO 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 
of GCP as outlined in Title 21 of the CFR, Part 312, Subpart D, “Responsibilities of Sponsors 
and Investigators”; 21 CFR, Part 50, “Protection of Human Subjects”; 21 CFR, Part 56, 
“Institutional Review Boards”; 21 CFR, Part 54 “Financial Disclosure by Clinical Investigators”; 
and the ICH guideline entitled “Good Clinical Practice: Consolidated Guidance”. Additionally, 
this 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 IB 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. 

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Prior to initiation of the study, the Sponsor’s representatives will review with study center 
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 
masked monitor will discuss study progress, verify adherence to the protocol and the 
completeness, consistency, and accuracy of the data being entered on the eCRF (source data 
verification); oversee the resolution of outstanding data discrepancies, and check on various 
aspects of study conduct (e.g., drug accountability, sample storage). The Investigator agrees to 
allow unmasked 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 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 CRO’s 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 
the CRO vendor and reviewed and approved by the Sponsor. Concomitant medications will be 
coded using the World Health Organization Drug Dictionary (WHODrug) and AE/medical 
history/surgery/non-drug therapy terms will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). 

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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’ medical records, the Investigator’s copy 
of the eCRF, other supporting data, records of drug dispensing and accountability, signed ICFs, 
IRB/IEC correspondence, and correspondence with the Sponsor must be kept by the Investigator 
for at least 2 years and or 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 
teprotumumab 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 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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Method validation bioanalytical report for analysis of RO4858696 in monkey serum by ELISA 
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Roche Report No. 1016690. 21 April 2005.  
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RO4858696/F01 01 (HuMAb IGF 1R) (Covance Study No. 6131-491, HLR Study No. 09302). 
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cynomolgus monkey tissues (PAIStudy No. IM1202, HLR Study No. 09256). Roche Report No. 
1019358. 03 October 2005.  

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Cynomolgus monkey as IGF-1R cross reactive species for RO4858696. Roche Report No. 
1019598. 08 August 2005.  
13-day intravenous administration toxicity study in the cynomolgus monkey (Covance Study No. 
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A 13-week toxicity and toxicokinetic study of RO4858696 administered once weekly by 
intravenous injection to cynomolgus monkeys, with a 12-week recovery period (CRL Study No. 
AGD00022, HLR Study No. 09927). Roche Report No. 1023600. March 2008.  
In vitro evaluation of the Influence of RO4858696 on human and cynomolgus monkey whole 
blood hemolysis and plasma flocculation (PCS MTL Study No. 600237, Roche Study No. 
10218). Roche Report No. 1026030. 14 September 2007.  
RO4858696-F03/F05-01: A single dose intravenous comparative pharmacokinetic and 
pharmacodynamic study of RO4858696 administered to male cynomolgus monkeys (Study No. 
09722). Interim draft report. Roche Report No. 1026674. 2007.  
A 39-week toxicity study of RO4858696 administered once weekly by intravenous injection to 
cynomolgus monkeys, with a 24-week recovery period.  (Charles River Study No. AGD00061, 
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17.2 Proptosis (Exophthalmometry) Method 
1. 
Choose a Hertel exophthalmometer provided by the Study Sponsor for consistency in 
measurement with a snug mechanism and preferably a square angle where it sits 
against the orbital rim (a). 
2. 
Open it wider than required. 
3. 
Sit opposite the patient and at the same level. 
4. 
Keep the patient relaxed, avoiding breath holding and excessive eyelid retraction. 
 
5. 
Position left foot of Hertel against the patient’s right lateral orbital rim, at level of 
lateral canthus (b).  
It should sit firmly as medially as possible, but outside lateral canthus and without 
distorting position of globe. 
6. 
Slide right foot medially into identical position on left orbital rim (c). This will feel 
tight and slightly uncomfortable, but minimizes potential side slippage of Hertel. 
7. 
Ask patient to fix their right eye on your left eye while you occlude the patient’s left 
visual axis with your right thumb. In this position, align the instrument such that the 
vertical mark (or cone) is aligned with the manufacturer’s pre-marked position on the 
ruler. Once aligned, rotate the instrument slightly around the horizontal plane such as 
to view the apex of the cornea in the mirror. Record the position of the corneal apex 
on the ruler. This is Hertel value. 
8. 
To record the left eye, hold the instrument stationary and move your head. Then use 
your right eye to record the patients left eye. Again, the opposite visual axis is 
occluded by your left thumb, while the patient is asked to fix on your right eye. 
Ensure that the corneal apex is measured by rotating the instrument slightly around 
the horizontal plane if required.  
 

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17.3 Graves’ Ophthalmopathy Quality of Life Questionnaire 
Directions: 
• The following questions deal specifically with your thyroid eye disease. Please focus on 
the past week while answering these questions.  
• Please tick only one box that matches your answer. The boxes correspond with the 
answers above them. 
During the past week, to what extent were you limited in carrying out the following 
activities, because of your thyroid eye disease? 
 
Yes – 
seriously 
limited 
Yes – a little 
limited 
No – not at 
all limited 
1) 
Bicycling   (check here if never learned to ride a bike) 
 
 
 
 
2) 
Driving  (check here if no driver’s license) 
 
 
 
 
3) 
Moving around the house      
 
 
 
4) 
Walking outdoors 
 
 
 
5) 
Reading 
 
 
 
6) 
Watching TV 
 
 
 
7) 
Hobby or pastime, specify: _____________________________ 
 
 
 
 
Yes – severely 
hindered 
Yes – a little 
hindered 
No – not at 
all hindered 
8) 
During the past week, did you feel hindered from something that you 
wanted to do because of your thyroid eye disease? 
 
 
 
 
The following questions deal with your thyroid eye disease in general. 
 
Yes – very 
much so 
Yes – a little 
No – not at 
all 
9) 
Do you feel that your appearance has changed because of your thyroid eye 
disease? 
 
 
 
10) Do you feel that you are stared at in the streets because of your thyroid 
eye disease?     
 
 
 
11) Do you feel that people react unpleasantly because of your thyroid eye 
disease? 
 
 
 
12) Do you feel that your thyroid eye disease has an influence on your self-
confidence? 
 
 
 
13) Do you feel socially isolated because of your thyroid eye disease?      
 
 
 
14) Do you feel that your thyroid eye disease has an influence on making 
friends?     
 
 
 
15) Do you feel that you appear less often on photos than before you had 
thyroid eye disease? 
 
 
 
16) Do you try to mask changes in appearance caused by your thyroid eye 
disease?