Clinical trial NCT04583735
Conditions: Thyroid Eye Disease Chronic (Inactive) Thyroid Eye Disease
Keywords: Proptosis
Sponsor: Amgen
Start date: 2021-09-02; Completion date: 2023-10-12
Enrollment: 62 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The overall objective is to investigate the efficacy, safety and tolerability of TEPEZZA® in participants with chronic (inactive) TED (thyroid eye disease). Approximately 57 participants will be enrolled. There will be a treatment period (through Week 24) and a follow up period (where TEPEZZA will not be infused).

Detailed description:
This is a randomized, double-masked, placebo-controlled, parallel-group, multicenter trial. Participants will be screened for the trial within 4 weeks prior to Baseline (Day 1). Approximately 57 participants who meet the trial eligibility criteria will be randomized on Day 1 in a 2:1 ratio to receive 8 infusions of TEPEZZA or placebo once every 3 weeks.

All participants will enter a 24-week double-masked Treatment Period, during which trial 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 of the 24-week Treatment Period). At the end of the double-masked Treatment Period (Week 24), all patients will be assessed for treatment response. Non-responders may choose to receive 8 infusions of TEPEZZA in an open-label fashion q3W at Weeks 24, 27, 30, 33, 36, 39, 42 and 45.

Study acquired from Horizon in 2024.

Arms: arm 1: Participants received intravenous infusion of 10 milligrams per kilogram (mg/kg) teprotumumab at first infusion and then 20 mg/kg once every 3 weeks (Q3W) for next 7 infusions during the double masked treatment period. Proptosis non-responders who completed the double-masked treatment period had opted to receive 10 mg/kg teprotumumab at first infusion and then 20 mg/kg Q3W for next 7 infusions during open label treatment period. arm 2: Participants received teprotumumab matching placebo by intravenous infusion, Q3W for 8 infusions during the double masked treatment period. Proptosis non-responders who completed the double-masked treatment period had opted to receive 10 mg/kg teprotumumab at first infusion and then 20 mg/kg Q3W for next 7 infusions during open label treatment period.
Interventions: intervention 1: TEPEZZA intervention 2: Placebo
Intervention descriptions: intervention 1: Intravenous infusion intervention 2: Intravenous infusion

Protocol documents:
Prot_000.pdf: 
llorizon Therapeutics U.S.A., Inc. 
Date: 19 May 2023 
T l:l'L:ZZA ~ (tcprutumumab-trbw; I IZN-00 I) 
l'rolo c.:u l: HZ 1\JP-TEl'-'10 3 
Vcr., ion 5.0, Amcndmcnt 4 
. : 
HORIZON 
CLINICAL TRIAL PROTOCOL 
J1OR TEPEZZA (teprotumumab-trbw) 
Protocol Number: HZNP-TEP-403 
A Phase 4, Randomized, Double-masked, Placebo-controlled, Multiccntcr 
Trial to Evaluate the Efficacy and Safety of TEPEZZA ® in Treating Patients 
with Chronic (Inactive) Thyroid Eye Disease 
Vcr·sion 5.0, Amrndmcnt 4.0 
19 May 2023 
Sponsor: 
Horizon Therapeutics U.S.A., Inc. 
1 Horizon Way 
Deerfield, TL 60015 
Tbis protocol i~ the confidential information ofllorizon 'Therapeutics 11.S.A .. Inc. and is intended solely for the guidance of the clinical 
iovestigarion. Th.is protocol may uot be disclosed to parties oot associated with the clinical investigatioo or used for any purpose without the 
prior written consent of Horizon n,crapcutics U.S.A .. Inc. 
CONFIDENTIAL 
PRJV A TE AND CONFIDENTIAL INFORM A TIOJ\ OF HORIZON THERAPEUTICS U.S.A., [NC. 
Page I of99 


Hcri:zon Th:rapeucics C.S.A .. In..:. 
D;;1e: 19 l\fay 202_; 
TEPEZZA ® ( 1eprotumumab-trbw; HZN-00 I) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
PROTOCOL 
1 
TITLE PAGE 
Trial Title: A Phase-+, Randomized, Double-masked, Placebo-controlled, 
l\Iulticemer Trial co Evaluate the Efficacy and Safety of 
TEPEZZ.-\ ~ in Treating Patients with Chronic (Inactive) Thyroid 
Eye Disease 
Protocol ~umber: HZXP-TEP-403 
Version: 
5.0, Amendment 4.0 
Investigation al Product: TEPEZZA (teprorumumab-trbw; HZN-001) 
Indication: 
Chronic (Inactive) Thyroid Eye Disease (TED) 
Sponsor: Horizon Therapeutics U.S.A., Inc. 
I Horizon Way 
Deeriield. Tl 60015 
Development Phase: 4 ~~~-------------. 
Sponsor's R esponsible pp D 
'\1e-clical Officer: 
onzon 
1erapeut1cs 
. . A., nc. 
I Horizon Way 
Deerfield, IL 60015 
Approval Date: 
19 May 2023 
co:...-TACT D'\1 THE EVINT OF A..'\1 EMERGENCY 
Any death. life-threatening event. or other serious adverse event experienced by a patient during 
the course of the trial. whether or not judged drug-related, must be reported within 24 hours of 
knowledge of the event by entering the information into the electronic case report form (eCRF). 
If Jnable to access the eCRF, the event must be reported by submitting the completed Serious 
Adverse Event Form via email or fax to the contacts provided below. 
Fax: 
PD 
------
Email: 
clinicalsafety@horizontherapeutics.com 
?Rr:xr::: A.\"D CO:\"FJDE~ITI."L f},"fOR.MA TTON OF HO:UZO'-i TIERAPEUTICS l'.S A' NC. 
Page 2 of 99 


Horizon Therapeutics U.S.A., Inc. 
Date: 19 May 2023 
TEPEZZA ® (teprotumumab-trbw; HZN-00 I) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
Protocol Number: 
Version: 
SPONSOR SIGNATURE PAGE 
HZNP-TEP-403 
5.0, Amendment 4.0 
Protocol Title: 
A Phase 4, Randomized, Double-masked, Placebo-controlled, Multicenter 
Trial to Evaluate the Efficacy and Safety of TEPEZZA ® in Treating 
Patients with Chronic (Inactive) Thyroid Eye Disease 
V crsion Date: 
19 May 2023 
Approved by: 
PPD 
~PPD 
I 
Date 
Horizon Therapeutics U.S.A., Inc. 
~pp
_ 
p p D 
Date 
Horizon Therapeutics U.S.A., Inc. 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS U.S.A., INC. 
Page 3 of99 


Horizon Therapeutics U.S.A., Inc. 
Darn: 19 \fay 2023 
TEPEZZA ® (teprotumumab-trbw; HZN-00 I) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
PRINCIPAL Th1VESTIGATOR SIGNATURE PAGE 
Protocol ~umber: 
Version: 
Protocol Title: 
Version Date: 
HZl\'P-TEP-403 
5.0, Amendment 4.0 
A Phase 4, Randomized, Double-masked, Placebo-controlled, Multicenter 
Trial to Evaluate the Efficacy and Safety of TEPEZZA ~ in Treating 
Patients with Chronic (Inactive) Thyroid Eye Disease 
19 May 2023 
I agree to conduct the trial according to the protocol named above. I fully understand that any 
changes instituted by the Principal Investigator without previous discussion with the Sponsor 
constitute a violation of the protocol, unless necessary to eliminate an immediate hazard to the 
safety or well-being of a patient. 
I :11.·knowlcdgc that T hm ,' read and understand t.hc protul'L)I named abon; anJ agrt'e ll) can-y uul 
,111 uf its il.:rm:- in an:ord.111cc with applicabk regulations anJ laws. 
I n:-su!'I.' chat lilt: crial drug supplied by the Spo11s1)!' will be used only as described in lht' prnlocol 
namt'd abon:. 
Siguaturt': 
Na.me 
Ttial Center 
Address 
City State CoW1try 
Pil.l\'ATE A~D CONF!DE:--IT!AL fNFOR.v!ATIO~ OF HORIZON THERAPEUTICS C.S.A, INC. 
Date 
Page 4 of 99 


I lorizon Therapeutics U.S.A., Inc. 
1Ja1c: 19 May :2023 
TEl'l::ZZA ~ (tcproturnumab-trhw; I IZN-00 I) 
l'rotornl : HZNl'-Tr.P-401 
Version 5.0, Amc1u.ln1cnt 4 
SUMMARY OF CHANGF.S 
Protocol HZNP-TEP-403 
Version 5.0, Amendment 4.0 
Key revisions and clarifications to Version 5.0, Amendment 4.0 of the protocol include: 
• 
Per a recent Investigator's Brochure update (Ed. 14), revisions were made to safety and 
AESI language arow1d hyperglycemia/diabetic complications, muscle spasms, infusion-
related reactions, inllammatory bowel disease and bearing loss. 
• 
In-text references were added to Section 7. l. l Thyroid Eye Disease and Section 7 .1.2 
TEPEZZA. 
• 
Addition of new reference (Marcovecchio, L. (2017)) lo Section 16. References. 
PRJV A TE AND CONFIDENTIAL rNFORMA TION OF HORIZON THERAPEUTICS U.S.A., INC. 
Page 5 ,::if 99 


Horizon Therapeutics U.S A., Inc. 
Date: 19 May 2023 
TEPEZZA ® (teprorumumab-trbw; HZN-00 l) 
Proiocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
SU~:\1ARY TABLE OF CHANGES 
Text 
Amended Text 
AdministratiH Change 1 to Version 4.0, 
Version 5.0, Amendment 4.0 
Reason for Change 
Amendmen t 3.0 
19 :\1ay 2023 
15 December 2022 
Section 7. I . I Th1roid Eve Disease 
Section 7. I. I Thyroid Eye Disease 
Updated to include missing 
The annual incidence rate of TED in the 
Tli,: am1ual incider.ce rate of TED in the 
in-text references 
L'S has been estimated to be 16 cases per 
US ha$ b~en estimated to be 16 cases per 
I fl0,000 people for women and 2.9 cases 
100.000 people for women and 2.9 cases 
per ! 00,000 people for men. The incidence 
per I 00,(100 peopk for men [ Ba11lcy, 
appears to be comparable in Europe. 
~
l The incidence appears tu be 
Patients aged between 30 and 50 years are 
..:ump.11Jl>le in Enrnpi.: (J\b1ah:1m-
most frequently affected, with severe cases 
Nordling el al. 2011 ; 
more frequent rn those over 50 years. The 
Moslbeck et al, 1998; >lath ct al. 2001; 
occun-ence and severity of TED are 
T:rndn ct al. 2013 ). Patients aged between 
a,soc1ated with smoking. 
30 and 5() yearn arc most frequently 
affected. with severe cases more frequent 
A m0unting body of evidence in the 
in those older than 50 years (Dirkin;;on 
sciencifk li:cranm.· indicJte, that the 
2017). The occUITence and severity of 
pJthoph,·si0logy of acti,.:: TED in\'olves 
TEO are associated with smoking 
a·Jtoimmune actintion and proliferation of 
[Prummel ct al. 1993]. 
orbital librohlasts. The acti\'ati0n of 
. .l. noun ting body of evidence in the 
fibroblas1s crig_gers release of inflammatory 
scientific literature indicates that the 
c:,1okines. infiltracion of immune cells inco 
pathophysiology of active TED involves 
orbital soft cissue (muscle, interstitial and 
adipose). exce,si,·e s~·ntbesis of 
autoimmune activation and proliferation 
extraceliular matrix and tissue expansion 
of c'rbi1al fibroblasts [Bahn, 20 IO; Bose hi 
and fibnxic rec10deling libid). During the 
et al, ::'.005; S1:1ith, 20 10]. The activation 
inactive phase, in!lamma1ion is absent and 
of :ibroblasts triggers release of 
infbrrJTiatory C)1okincs, infiltration of 
the disease plateaus, but significant 
immune cells into orbital soft tissues 
remodeling of orbital tissue remains and 
(muscle, interstitial and adipose), 
ra.rely does ihc patient rcrurn cc, Baseline.' 
exc-es5ive synthesis of extracellular 
matrix. aod tissue expansion and fibrotic 
Clinical features of TED 111clude orbital 
remodeling (ibid) During the inactive 
pain, swelling, dry eye, redness and 
phase, inflammation is absent and the 
discomfort or the lids and ocular surface, 
disease plateaus, but significant 
thickening and retraction of the eyelids and 
remodeling of orbital tissue remains and 
prupiosis (exophthalmos'i due to the 
rarely does the patient return to Baseline. 
expansion of ti;su:! behind the eye. 
Although TED is heterogenous and 
Clinical ieatun:s of TED include orbital 
variable and in presentation. proptosis is 
pain, swelling, dry eye, redness and 
Ont> of tbe most prevalent and widely 
discomfort of the lids and ocular surface, 
kno\\u ~ymptoms of TED. TED has high 
thickcning anti retraction of Ilic cyclids, 
morbidiry. i\1orbidity t:ikes the form of 
and proptosis (exophthalmos) due to the 
orbital pain. together with a number of 
expansioa of tissue behind the eye (Bahn. 
serious. , ision or sight threatening 
20 IO; Burch ct al. 1993; Dickinson 2017; 
condi1ion, including diplopia (due to 
MaJlika et al, 2009]. Although TED is 
inability to correctly align the eye). corneal 
heteroizenous and variable in oresentation. 
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Horizon Therapeutics U.S.A., Inc. 
Date: 19 May 2023 
ulceration (due to inability to close lids) 
and dysthyroid optic ncuropathy (due to 
proptosis, tissue crowding, and SlTess on 
the optic nenie). These combine to 
produce marked reductions in quality of 
life (e.g., physical functioning, role 
functioning, social functioning, mental 
health, health perceptions and pain). TED 
can also produce profound psychosocial 
problems, in particular anxiety and 
depression, due to the alarming and 
disfiguring changes in appearance. Taken 
together, these data show that T ED is a 
physically and emotionally debilitating 
condition (Figure 7.1). 
Section 7.1.2 TEPEZZ A 
Previous tcprotumumab clinical trials for 
the TED indication include 2 independent, 
randomized, double-masked, placebo-
controlled, parallel-group, multicenter 
trials (Phase 2 Trial and Phase 3 Trial 
l lZNP-TEP-30 I [Douglas ct al, 20201) 
Section 9. 5.3 .1.1.5 Adverse Events of 
Special Interest 
Based on previous clinical experience in 
TED, the following will be AESls for this 
trial: 
• 
lnfusion reactions (r.g., transient 
increase in blood pressure, feeling hot. 
tachycardia, dyspnea. headache and 
muscular pain) 
• 
Hyperglycemia 
• 
Hearing impainncnt 
TEPEZZA'9 (tepronunumab-trbw; HZN-00 I) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
prupLUsis is one of the most prevalent and 
widely known symptoms of TED. 
Thyroid eye disease has high rnorbiJity 
[Bartalena et al, 2008; Rartlcy, 1994; 
Dickinson, 2011; Gerding ct al. 1997). 
Morbidity takes the form of orbital pain, 
together with a number of serious, 
vision- or sight-threatening conditions, 
including diplopia ( due to inability to 
correctly align the eyes), corneal 
ulceraiion (due to inability to close lid,) 
and dy$lhyroid optic neuropathy (due to 
proptosis, tissue crowding, and stress on 
the optic nerve). These combine to 
produce marked reductions in quality of 
life (cg, physical functioning, role 
functioning, social functioning, mental 
health, health perceptions and pain) 
(Gerding et al 1997; Terwee et al, 2001). 
Thyroid eye disease can also produce 
profound psychosocial problems, in 
particular anxiety and depression, due to 
the alarming and disfiguring changes in 
appearance [Bartley ct al, 1996; Coulter 
et al. 2007; Kahaly et al 2005). Taken 
together, these data show that TED is a 
physically and emotionally debilitating 
condition (Figure 7.1 ). 
Section 7 .1.2 TEPEZZA 
Previous tcprotumumab clinical trials for 
the TED indication include 
2 independent, randomized, double-
masked, placebo-controlled, parallel-
group, multicenter trials (Phase 2 Trial 
TEDO I RV [Smith cl al, 20 I Z] and Phase 
3 Trial IIZNP-TEP-301 
(Dou!!l!IS el al, 2020]). 
Section 9.5.3.1. 1.5 Adverse Events of 
Special interest 
Based on previous clinical experience in 
TED, the following will be AESls for this 
trial• 
• 
Infusion reactions (e.g .. treAsieAt 
ieeFease ia 0laeel 11ress1We, feeliag 
bet. laceycaFdia, dyspeea, eeaelaehe 
and muscular pain) 
• 
Hyperglycemia 
• 
Muscle spasms 
Updated to include missing 
in-text references 
Per a recent Investigator's 
Brochure (edition 14) 
update, revisions were made 
to the safety language and 
AF.ST sections around 
diabetic complications. 
infusion related reactions. 
IBO and hearing loss. 
PRNATE AND CONFTDENTIAL INFORMATIOt- OF HORIZON THERAPEUTICS U.S.A., fNC. 
Page 7 of99 


Horizon Therapeutics U.S.A., Inc. 
Date: 19 May 2023 
• 
Kew onset inflammatory bowel 
disc.isc and exacerbacion of 
inflammatory bowel disease 
Management of infusion reaclions and 
hyperglycemia is described in 
Section 9 4.6.3.2. 
l'.HIL'I\($ t
0 Xpt-r1c11,111g hr.iring 1mp,111T11cnt 
, twuld ,,,nuc, the ill\ cs!lg:tti,)11:ll sur for 
n ·,1hi.1ti,1u ,111d .1,,,·s,111r111s f\ alu.1tio11 
m:iy include :1n :rndiogram. 
TEPEZZA® (teprotumurnab-rrbw; HZN-001) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
• 
Hearing impai1mcnt 
• 
New onset inflammatory bowel 
disease and exacerbation of 
inflammatory bowel disease 
Risk of Hypersensitivity (lnfusion-
related events) 
Admi nislTation of m/\bs may cause 
infusion-related symptoms, such as fever, 
chills, hypotension, shortness of breath, 
skin rash and headache. Such reactions 
typically occur during or shortly after the 
infusion of mAbs and are usually 
associated with the first infusion. Their 
incidence and severity typ ically decrease 
witJ1 subsequent infusions. Scv:;rc 
infusion-rdatcd reactions might be 
clinically indisiing11ishahlc from 
an:iphylnctic reactions. 
Infusion-related event;. observe<l with 
teprorumumab to date have not been 
anaphylacliL" in nature. However, because 
of the protein nature of tcprotumumab 
and the potemiul for infusion-relalt"d 
re.1dions and hypersensitivity reactions, 
tcproruummnb should be :i<lministL'rcd in 
a setting with emergency equipment and 
staff who are trained to monitor mediral 
siruations and respond to emergencies. 
For the first 3 infusions, patients should 
be monitored for any events during 
iufus10n and for 60 minutes after 
completion of infosiou. Fur ~ubscqucul 
infusions (the fourth dose and beyond). 
patients who have not previously 
experienced an infusion reaction should 
be monitored during the infusion and for 
at least 30 minutes after the infusion. 
Patients who exhibit immediate 
hypersensitivity reactions or infusion-
related reactions during an infusion of 
teprorurnumab should have the infusion 
interrupted or the infusion rate slowed. 
Symptomatic treatment, e.g., antipyretics, 
anti.histamines and/or corticosteroids, 
oxygen, beta agonists and JV fluids, 
should be administered to the patient. 
Following an immediate hvnersensitivitv 
PRIVATE A>.'D CO~Ei\7T\L INFORMATIO~ OF HORIZON HIERAPEUTICS U.S.A., INC. 
Page 8 of99 


Horizon Therapeutics U.S.A., Inc. 
Date 19 May 2023 
TEPEZZA ® (teprotumumab-trbw; HZN-00 I) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
reaction or infusion-associated reaction, 
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 detenninations. The infusion 
may be restarted upon complete 
resolution of symptoms except in the case 
of patients who experience an 
anaphylactic reaction o f life-threatening 
intensity; these patients should be 
removed from the trial. 
In general, the decision co keep a patient 
on trial treatment with teprotumumab 
should take into consid.eration potential 
risks and benefits to the patient. Prior to 
future infusions ofteprotumumab, these 
patients may be premedicated with IV 
diphenhydramine I to I .25 mg/kg 
(m,1ximum 50 mg), IV ran111d111c 50 mg, 
IV famotidinc 0.5 mg/kg, IV 
<.kxan,clhasonc 0.4 ntKlkg (maximum 20 
mg) and/or accta111in0phcn 500 mg. In 
addition, all fol'ure infusions should he 
:idministered over 90 minutes. V ital signs 
should be taken every I 5 minutes during 
the infusion through GO minutes after 
infusion completion. 
Patients who cxpcrienee dclayccl-lypc 
hypcrsc11si1 ivi1y rcaclions (e.g., ski11 rash) 
may remain in the trial at the discretion of 
the lnvestigalc>r and, prior to all future 
infusions ofteproi-umumah, may he 
premedicated with the above medications 
(diphenhydramine, ranitidioc, famotidinc, 
<.kxamethasone and acctaminopheo). 
However, if a rash worsens following 
repeated dosing or other signs of scrum 
sickness (e.g., delayed fever, myalgias, 
arthralgias) arc present, trial drug dosing 
will he pennanently discontinued. 
Risk of New Onset or .Exacerbation of 
lBD 
In Phase 2 TEDO l RV, 2 teprotumumab-
treated patients with a history of lBD 
reported serious TEAEs (Diarrhoea in I 
patient and lnflammato,y bowel disease 
in I patient) that Jed to discontinuation of 
PRIVATE ANO CONFIDENTIAL INFORMATION 01' HORIZON TIIERAPEIJTICS U.S.A., INC. 
Page 9 of99 


Horizon Therapeutics U .S A., Inc. 
Date: l 9 May 2023 
TEPEZZA'~ (teprotumumab-rrbw; HZN-00 1) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
trial drug. Dased on these serious events 
and ihe fact that a placebo patient with 
Crohn's disease did not experience these 
types of events. patients with a history of 
IBD are either excluded from current 
trials or must be in clinical remission. 
Patients who experience progressive and 
persistent diarrhea or other 18D 
symptoms, such as bloody stools or 
abdominal pain, should undergo prompt 
C\'aluation 10 exclude new onset or 
exacerbation of preexisting IBD or other 
serious conditions. If possible, 
medications knovm to cause diarrhea. 
such as laxatives and magnesium shall be 
avoided. If new onset or exacerbation of 
IBO is suspected, teprotumumab shall be 
discontinued. 
Risk of Hyperglycemia 
In nonclinical studies, there was no in 
vi1ro cross-reactivity ofteprorumumab 
with the insulin receptor. Cl inical trials in 
Active TED have shown a higher 
incidence of hyperglycemia in patients 
treated with teprorumumab compared to 
placebo. Patients with pre-existi.ng 
diabetes rnellitus (who were under 
appropriate glycemic control upon trial 
entry) or impaired glucose tolerance were 
more likely to experience an event of 
hyperglycemia after exposure to 
leprorumumab. 
Mana~ement of Patients with Diabetes 
:\fellitus 
Patients with known conrrolled diabetes 
mcllims are allowed to participate in trials 
with teprotumumab. HbAlc levels should 
be monitored every 6 weeks in these 
patients. 
Investigator:; art· strnogly encouraged to 
adjust their patient:-· diabetes 
nia.nagement to m,1intain HbA l c levels 
:58°/c,. In the event a patient's I lb Al r level 
rises to >8% while in the trial, the 
Investigator must assess the risk versus 
benefit for the oatient to remain in the 
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l-loiizon Therapeutics U.S A .. Inc. 
Date. 19 May 2023 
TEPl •:ZZA '1J> (teprorumumah-trbw; HZN-00 I) 
i'rulucul: IIZNP-TEP-403 
Vcr~ion 5.0, Amendment I\ 
1:rilll, <focuss with spons0r's medical 
monitor or designcc. and document the 
decision. 
Management of Hvperglvcemia 
Fasting glucose: levels should he tested al 
Basel ine. Random non-fasting glucose 
levels should be monitore<l at a minimum 
as per visit schedule. 
Patients with recurrent hyperglycemia, 
defined as a fasting glucose > 126 mg/dL, 
will require evaluation for diabetes 
mellit11s (e.g., fasting glucose, glucose 
tolerance and HbA I c tests) and 
appropriate. medical management, at the 
discretion of the Jnvestigator. 
Management of Severe Diabetic 
Complications 
Hyperglycemia can cause serious acutt; 
complications, pr..:scnting as cndo..:rinc 
cmergcm:ic.s, sucfr as Dbl.u;tic 
kctoncidosis (OKA) and hyperglycemic 
hyperosmolar state (HHS). Boch these 
conditions are caused by relative or 
absolute insulin deficiency associated 
with excessive counter-regulatory 
h0r111ones (glucagon, growth hormone, 
cortisol, catecholamines) (Marcovecchio 
2017). Both OKA and HHS arc usually 
triggered by an underlying illness or 
event such as acute infection, infarction. 
non-compliance with diet and skipped 
insulin doses or insulin pump failure. 
DK.A and HHS are life-threatening 
emergencies. Prompt clinical suspicion 
and confinnation of these diagnoses is 
very important. The goal of treatment for 
DKA a nd HIIS is to correct volume 
deficits, hyperglycemia, and electrolyte 
abnormalities which will include, bu1 is 
not limited to, IV fluid resuscitation, IV 
insulin, and IV potassium. Every effort 
should be made to identify the cause, so 
that future preventive rneasun::s can be 
taken. Participants experiencing DK.A or 
HHS should be discontinued from study 
treatment. Manae:emenl of infusion 
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H,1n-1-H1 Thn"pculil·s l l.~.:\., Inc. 
Dulc: I 9 i\ !.iy ~0~: 
l"r.l'E.::Z .. \ 1b ltcpro111mumilh-trbw; .1 IZN-00 I) 
Pro10c0I : HZN l'-TEl'-403 
\"nsion 5.0. AmroJrm:nt •I 
rea.:tions and hyperglycemia is also 
described in Section 9.4.6.3.2. 
Risk of Muscle Spasms 
Among teprotumumab-trea1ed patiems, 
Afust'lc spasms was lh<.: mo,a commonly 
n:poncd TEA[ in dinirnl triub of Active 
TED (Douhle-Masked Treatment Period: 
26.2% ttpr0tumurnat, compared to 7.0% 
placebo: Open-Label Extension Trial: 
41.3° o). All eYenls were non-serious and 
the majority were mild in intensity. 
If possible, avoid mi::J i.::itions known to 
cause muscle: spasms or muscle toxici ty, 
such as diuretics or scatins. If mus.: le 
~pasm occurs, rvaluatc for other causes of 
muscle spasm. such as electrolyte 
abnormalities and dehydration 
Risk oflle.aring Impairment 
AJven;c rcJctions or miJdk- ll> !ugh-
rang,' s1.·ns(1rinrnr'1l l:c:ari11g hJss luvc 
been reported in hath hc.1lthy vl1lu11rcc1s 
and patient~ with rnalign:incics wh0 
received as little as I dose (lf v:iriNJS 
llif-lR mAbs. 
Eighteen 1::1·ents associated with hearing 
1111pa1rmcr11 ha\'e bet:n observed in 
1-l te1m•num1ruab o·c:itcd patients in the 
TED t.J ials, with no rcpo1 ts clbsl·rwd in 
placebo treated patients. Ea,h of these 
events wen" n0nserious, mild or m0derate 
in intensity and none led to premature 
discontinuation of trial drug: these events 
usuaUy improYcd or resolved. lf possible, 
patients should avoid ototoxic dmgs 
while re-cciving reprorumumab. 
A re, iew of the post-marketing data in a 
larger patient population shows tb:11 while 
the reporting rate of hearing impainnent 
related to AEs in a post-marketing sening 
and the incidence in clinical trials appears 
similar. there are some post-marketing 
cases suggestive of gr.:ater increased 
severity (eg, severe or. rarely. pennanent 
heariu!! imoairment) than what was seen 
PT/.IVA TE A.'iD co:--.-FJDENTIAL })ff ORM A 110\' OF HORIZON THERAPEUTICS U.S.A., INC. 
Page 12 of99 


Hori zon Therapeutics U.S.A., Inc. 
Date: 19 May 2023 
Section 16. References 
TEPEZZA ® (teprotumumab-trbw; HZN-00 I) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
in clinical trials. No risk factors were 
identified based on current available data. 
In addition, patients experiencing hearing 
impairment should contact the 
investigational site for evaluation and 
assessments. Evaluation may include an 
audiogram. The audiogram report w ill 
include the following: 
• Pure tone 
The following tests may also be included: 
• Speech Recognition 
• Distortion product otoacoustic emission 
inner ear hair cell function test 
• Evaluation of Eustachian cube func.tion 
Patients experiencing complete or 
profound hearing loss should be 
discontinued fron1 study trcatm.;nl. 
~c:clion 16. References 
Updated lo indude missing 
Marcovccchio. L.(2017). Complications 
rckn.;nc..: (Marcovccchio 
of acute and chronic hyperglycemia. US 
{2017), S..:ction <J.5.J. 1. 1.5) 
Endocrinology, IJ (I), 17-2 1. 
PR NA TE AND CONFIDENTIAL !NFORMA TION OF HORIZON TIIERAPEUTICS U.S.A., INC. 
Page 13 of99 


Horizon Therapeurics U.S.A., Inc. 
Date: 19 May 2023 
TEPEZZA ® (teprotumumab-trbw; HZN-00 I) 
Protocol HZNP-TEP-403 
Version 5.0, Amendment 4 
2 
SYNOPSIS 
Protocol Title: A Phase 4, Randomized, Double-masked, Placebo-controlled, Multicenter Trial to Evaluate the 
Efficacy and Safety of TEPEZZA t in Treating Patients with Chronic (Inactive) ThyToid Eye Disease 
Protocol Number: HZNP-TEP-403 
Phase: 4 
Protocol Version: 5.0, Amendment 4.0 
Test Drug: TEPEZZA (teprotumumab-trbw) 
Indication: Chronic (fnactive) ThyTOid Eye Disease 
lTED) 
Number and Country of Sites: Approximately IO trial centers in the United States. 
Objectives: 
The overall objective is to investigate the efficacy. safety and tolerability of TEPEZZA J!l (teprotumumab-trbw, 
hereafter refened to as TEPEZZA) in comparison to placebo in treating patients with chronic (inactive) TED. 
Primary Obiective 
The primary objectin: is to evaluate the effect ofTEPEZZA versus placebo on the change of proptosis 
li1easurements in the srudy eye from Baseline at Week 24 in patients with chronic (inactive) TED. 
Other Objectives 
I. 
To evaluate the effect c1fTEPEZZA versus placebo on the propwsis responder rate (i.e., the percentage o 
patient$ with a 2:2-mm reduction from Baseline in the study eye without deterioration [2:2-mm increa$e] 
of proptosis in the fellow cye1 at Week 24. 
2. To eYaluate the effect ofTEPEZZA versus placebo on the change from Baseline at Week 24 in the 
Graves' Opbtha!moparhy Quality of Life (GO-QoLJ questionnaire appearance and visual functioning 
subscales. 
3. 
To enluate the effect ofTEPEZZA versus placebo on the 
4. 
To eYaluate the efface ofTEPEZZA versus 
5. 
Pham1acokinetic and Anti-dmg Antibody Objectives 
1. 
To evaluate the phannacokinetics (PK) ofTE?EZZA. 
2. 
To evaluate the 1:nmunogcnicity of TEPEZZA. 
Safety and Tolerability Obicctivcs 
To assess safety and tolerabi lity of TEPEZZA versus placebo based on 
I. 
Adverse events 1.AEs) 
2 
A.Es oi special interest (AES!s) (infusi0n reactions, hyperglycemia, hearing impairmmt, new onset 
inflammatory bowel disease and exacerbation of inflammatory bowel disease) 
3 
Vital signs 
4. 
Visual acuity 
5. 
Cli:ucil safety laboratory evaluations (hematology, fasting chemisn-y, thyroid fun..:tion tests and glycated 
hemoglobin [HbAlc)) 
PRl\'A TE A'Hl COXFIDE~Tfl . .\L fNTORMA T:Ol\ OF l!ORIZON TI!ERAPEUTJCS U.S.A., NC. 
Page 14 of99 


llorizon Thcraprnlics U.S./\ .. Inc. 
IJalC: 19 M,1y 1013 
F.x 
Ob' eclive 
I. 
To evaluate the 
Trial Design: 
Tcl'EZZA'"' (tcprotumumah-trhw; 11 ZN-00 I) 
1'1 otucol: HZNP-Tl:P-40.1 
Version 5.0, /\111c11cJ111cnt 4 
This is a randomized, double-masked, placebo-controlled, parallel-group, multicenter trial. Patients will be 
screened for the trial within 4 weeks prior to the Baseline (Day I) Visit. Approximately 57 patients who meet the 
trial eligibility criteria will be randomized on Day I in a 2: I ratio to receive 8 infusions of TEPEZZA ( 10 mg/kg 
for the first infusion and 20 mg/kg for the remaining 7 infusions) or placebo once every 3 weeks (q3W). All 
patients will enter a 24-week double-masked Treatment Period, during which trial drug will be infused on Day I 
(Baseline) and Weeks 3, 6, 9, 12, 15, 18 and 21 (with a final visit at Week 24 of the 24-week Treatment Period). 
All trial drng dosing will be performed at the clinic or infusion center under adequate healthcare professional 
supervision. Al any scheduled infusion, the infusion rate may be reduced. or the dose may be interrupted or held 
based on tolerability (see Section 9.4.6.3.'.2 for details). On each dosing day, scheduled assessments (except for 
AE and concomitant medication use monitoring. which will be monitored throughout the clinic visit) will be 
completed prior to dosing. After each o f the fi rst 2 infusions. patients will be cont.acted by phone/email the 
following day for safety and tolerability assessments. An additional phone/email contact and clinic visit may be 
conducted for any patient experiencing an infusion-associated event. 
At the end of the double-masked Treatment Period (Week 24), all patients will be assessed for treatment 
response: proptosis responders (study eye has ?:2-mm reduction in proptosis from Baseline without deterioration 
[?:2-mm increase in proptosis) in fellow eye) or proptosis non-responders (study eye has <2-mm reduction in 
proptosis). Proptosis non-responders who have completed the double-masked Treatment Period may choose to 
teceive 8 infusions of TEPEZZA (IO mg/kg for the first infusion and 20 mg/kg for the remaining 7 infusions) in 
an open-label fashion q3W at Weeks 24, 27, 30, 33, 36, 39, 42 and 45. These patients will rcrum to the clinic at 
Week 48 for End-of-Treatment assessments, and patients will be contacted by phone/email 30 days after the 
Week 48 Visit for safety assessment. ?roptosis responders, as well as non-responders who choose not to receive 
TEPEZZA in an open-label fashfon, will enter a 30-day Follow-up Period, during which trial drug will not be 
administered. These patients will be contacted by phone/email 30 days after the Week 24 Visit for safety 
assessment. 
Patients who prematurely discontinue trial drug dosing prior to Weck 2 1 ofl11e doublt:-1nasked Treatment Period 
br prior to Week 45 of the open-label Treatment Period will return to the clinic, undergo the scheduled End-of-
Treatment assessments (with the exception of the collection of blood samples for biomarker evaluations) and 
enter the Follow-up Period. provided such continued panicipation will not detrimentally affect the health, safety 
and welfare of the patient per Investigator detennination. An overview of the trial design is presented in the 
schematic below, and details of trial activities are provided in Section 2.1, Schedule of Assessments. 
PRJV A TE ANO CONFIDENTIAL INFORMATION OF HOR JZON Tl fERAPEUTICS U.S.A., TNC. 
Page 15 of99 


I ltin:c,,n rl1rr.ipcu11.:s U .S.:\ .. l1K. 
D.!!c. l 9 l\ [.iv .W2_; 
TEl'EZ.ZA '1'-' llcprnturnumub-1r bw; HZN-00 I) 
l'rnlncol: HZ l'-TEl'-1IOJ 
Version 5.0, Amendment 4 
4 wrck., 
rrr.cin.-:e 
Al 
wv 
Vio 
Douhlc-mM;k,·<l Tn:dtn1cnt Pcr,oJ 
TF l-'F77 A 01 Plarch<'l.2 
24 Weeks 
\)l>l.'.'n-ld,cl fn:i,tnu:nc Pc, iolt= 
(Prorto!-is. Non-rc~pondcN1 wh1, ChC'0sc 1i, R,·rciq,• 
Oµcn-labd l cPEZZA) 
IV'/ 
\VI ~ 
\V I .I 
\VI~ 
W21 
V/l-1 1··'·' W171 
W10 
W)) 
WJ6 
WJ'J 
W42 
W4~ 
IV48' 
1Chlay 
Follow-
up 
Period' 
R,111d,H11i 111ti11n' <-- --------- ------Trfal \Vcrk------------------>-
• lnt\Jsior of trial drug (TEPEZZJ\ or plncebo in doublc-mnslled Tre,im,nc Peri,,d nnd npcn-lahc· TF.PF.Z? A in open-label T,cacmcnc Pcriorl\ 
BL~Bnsc]inc; qJWzonceevery 3 weeks; \\/;Week. 
l. 
P:.Hicn l.:;. will b<.~ rJndomi7cd m a :.!: t ratio tu rc..:i.:1vc· 
a. TIPF77 A \ 10 mg/kg: fin £)3~· I f;illowf'<l r"y ?0 ms kg q3\ ' fort he l"C'm::tinint 7 infus1('1ns): or 
b Plo,cb,, 1plcccb" q3W for oil S infusions). 
2. 
\ '1sic \\ md-.lws .uc --:-J dJys fuf \\·ce~ J. ~. 9. 1.!. 15. I~ and.! I \'.If ,fo111.Jk:-m.1sk,:·d Tr\:a(mcnl Peiivd anJ \\'n;ks 2.7, JO, 33, 30, J9. 42 J.ml -~5 of 
C'f't"n-'at-eJ Tre-..6rm:>:nt 'Pe~od. and +'7 day'lt fo( \Ve.:ak J .. i of douhlc-ma!-kOO l (e:1.tme-n1 Pcrit,J. \\leek 4~ flf opcn•lr1hcl Trn,tll"lc1H rcriod ;md .10-day 
follow-up Perod . 
.3. 
A,, pUH"nL, will he i:vn1llctN b) phN1c/em.lil lhc ,1Jy J!ler mCU.Sion for chc lir!it and sei:ond infusions during the doubh:.masked Treatmcnc Period 
a-d d'.)ring the f1r,e:n-l:t~rl 7'"'t'~l,.,ent Peri r'lrl. lnd :hcre:ttl~: .\s ck·emed apprflrriare: :i.rtditicm:tl phone/email ccmtncts will ocr.ur rhc: day Jftcr .ony 
c ,:11, ,·•si: where a paticn1 c'tpcr.cnc:s an infus101,-rcl31ed adverse: ever.I. 
4. 
Pa1icnts w'x, are proptosis 110:1-r<-,prndcrs at Wee, 24 of the d0ubk-m,sked Treatment Period v.sll be ,,ffcrcd the option 10 receive 8 infus ions of 
TEPEZZ.-\ ( 10 mg/kg on Day I foll,,w,•d by 20 mg/kg for che c,rr,o·ning 7 infu.,ions) in an open-label fashion. 
5. .-\II ra<icnls will he c0n1ttctc<l vii phc>nc c'< en-ad JO days (= 7 d!ys) following the Week 2~ (responders and non-responders who choose not to 
recc"ivc oocn-label TE.PEZ.ZA\ or Week 48 (non-~ondcr.s who receive oocn-lobcl TEPEZZAl Vi.sic. 
P,1lk11I Popuh1tio11: 
Appf\)X1111atdy 5- m.1k ,11 n,1n-pn:g.11J1\I fcmak palicnls JI leJSI l 8 ye.us o ld wi1h chronic (in:iclivc) T ED will be 
cnrolkd. 
Inclusion Criteri;1; 
l:l1g1blc patiems must mecl provide all the f,il lowing criteria: 
' 
..,_ 
6. 
8 
9. 
Writtc'n tnformed cnn;;enc 
M:ile ,,r icm:1lc :it lc:ist IS ye:m old nt Screen int!. 
lnici:il di,,gnosi, ,,f TF.D :::: years but < IO ye.us pri,,r to Sn·crning. Clinical diagnosis of stabk. chroni..: 
(inactive) TFD. as determined h· pnticnc medical records indicnting n C'linicnl Aclivity Score (CAS) < I 
in boch eye;; for at lease I year pri0r to ~c-reenini: or all 0fthe folknvinir 
a. 
no pr0~ession in proptosis fo r a1 lc:ist I year prior to Screening 
\-,. 
if rnticnl has hi,t0ry of d iploria due 10 TED, uo prog1cssi,,n in diplopia for a l leas! I year prior to 
Screening 
c. 
no new inflamm:itNy TF.D symptoms fo r :it !cost I year µrior to S..:reening. 
C :\S < I at the S.:rcc:ni.ng .rnd Baseline Visits. 
Prupt0sis ~3-nun increast' fu.Jm 1hc pa1icn1's baselin<: (prior to diagnosis of TED). as cstimalcd by 
tr,J1ing phy:;ici:in .1ud·or proprn,is :::3 mm above normal flir race and gender. 
Pat.iems must b,· cnth)Toid with the pa1icnt's baseline <ltscasc under control or have mild hypo- or 
hypcnhyroidism (ddincd as free thyroxim: and free Jriio<lotliyronine lcvcb , 50% above or below 1.hc 
nonml limits) at Screening. Every cffot1 should be made to com·ct the mild hypo- or hypenhyroidism 
promptly and 10 mctintain the euthyroid state for the full duration of the trial. 
Does not require immediate surgical ophthalmological in1ervention and is not planning corrective 
surge:-y/irradiation during the course of the trial. 
Diabetic patients must have HbA lc :::8.0% at Screening. 
Pa1ie1:tS with a history of inflammatory bowel disease. ulcerative colitis or Crohn's disease must be in 
clinical re1mssion ror at least 3 mon1hs, wi1h no history of bowel surgery within 6 months prior to 
sc;eening and no planned surge!)' during the lrial. Concomitant stable therapies for inflammatory bowel 
diseas-: without modifications in the 3 months prior to Screening are allowed. 
PRr\·A TE Ai'fD CO\IFIDEJ',:TIAL NFOR\iATIO)',: OF HORIZON THERAPEUTICS US.A., INC. 
Page 16 of 99 


Horizon Therapeutics U.S.A., Inc. 
Date: I 9 May 2023 
TEPEZZA ® (teprotumumab-rrbw; HZN-001) 
Protocol: HZNl'-TEP-403 
Version 5.0, Amendment 4 
I 0. Women of childbearing potential (including those with an onset of menopause <2 years prior to 
Screening, non-therapy-induced amenorrhea for < 12 monchs prior to Screening, or not surgically sterile 
[absence of ovaries and/or uterus)) must have a negative scrum pregnancy test at Screening and negative 
urine pregnancy tests at all protocol-specified time points (i.e., prior to each dose and throughout 
patient's participation); patients who are sexually active with a non-vasectomized male partner must 
agree to use 2 reliable forms of contraception during the trial, I of which is recommended to be 
hormonal, such as an oral contraceptive. Hormonal contraception must be started at least I full cycle 
prior to Baseline and continue for I 80 days after the last dose of trial drug. Highly effective 
contraceptive methods (failure rate < I% per year), when used consistently and correctly, include 
implants, injectables, combination oral contraceptives, some intrauterine devices, sexual abstinence and 
vasectomized partner. 
I I. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of 
the trial. 
'Exclusion Criteria: 
Patients will be ineligible for trial participation if they meet any of the fol lowing criteria: 
1. 
Decreased best-corrected visual acuity due tci optic neuropathy, defined by a decrease in vision of 
J. 
4. 
5. 
6. 
7. 
8. 
9. 
2 lines on the Snellen chart, new visual field defect or color defect secondary to optic nerve involvement 
within the last 6 months. 
C-tllll(';tl ,lcc,1mpcns:11iun lllllCSl)OIISivc: IO ll lt:dical 111;.111agc111c111 ill iht: s1u(ly eye. 
Ur<.:1t:asr i11 p1 uphis1s uL.::2 111111 in lhc sl.udy eye bc1wcc11 Succning a11J Bascli11c. 
Pnor ,11·b1tal 1rradia11on or 01bi1al dt:comprt:ssion 111 the study eye. 
Prior strabismus surgery 
Alanine ammotransferasc or aspartatc aminotransferase >3 x tht: upper limit of nom1al or estimated 
glomcrular filtration r:itc :::'.30 mL/min/1. 73 m! al Screening. 
Use or any steroid (intravenous, oral, steroid ..:ye drops) for the treatment of TED or other conditions 
within 3 weeks prior to Screening. Steroids cannot be initiated dw-ing the trial. Exceptions include 
topical and inhaled steroids and steroids used to treat infusion reactions. 
Any treatment with ri1uxi.mab (Rituxan® or MabTherafi)) within 12 months prior to the first infi.tsion of 
trial drug or to,:ilizumab tActemra'"' or Roactcnu·a:Ji)) within 6 months prior to the first infusion of trial 
drug. Use of any other non-s1croid inu11unosuppressivc agent within 3 months prior to the ftrst infusion 
of t1 ial dt ug. 
Any prel'ious llcalment with TEPEZZA, including previous cnrollmcnl in this trial or participation in a 
prior tcprot11111u111ab trial. 
Treatment with any monoclonal antibody wi1hin 3 months prior 10 Screening. 
11. ldcntitied pre-existing ophthalmic disease that, in the judgment of the Investigator, would preclude trial 
participation or complicate interpretation of 1rial results. 
12. Use of an investigational agent for any conditiou within 60 days or 5 half-lives, whichever is longer, 
prior co Screening or anticipated use dUJing the course of the trial. 
13. Malignant condition in the past 12 months (except successfully treated basal/squamous cell carcinoma 
of the skin or cervical cancer in sini). 
l4. 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 patient. 
16. Known hypersensitivity to any oftht:: components ofTEPEZZA or prior hypersensitivity reactions to 
monoclonal antibodies. 
PRJV A TE AND CO~TDENTIAL INFORMATION OF HORIZON TITERAPEUTICS U.S.A , rKC. 
Page 17 of99 


l !,,n1,11 rhlT.1pn1111.:s U.S.A .. lnc. 
0 d(t'. It) \fav 21) ::'.• 
TEPL.::LZA ,I\! t tcprotumurn.1b-1rbw; 1 !ZN-Oll I) 
l'rntm.:ol: I l/.NP-TEP-40J 
Version 5.0. A111cmln1c11t 4 
l 7 P,, 1,rlY c0ntr0llt'd h11111an imm1mo<leli,iency vims infection 0r unrre:ited 0r positive viral lo:1d for 
hepa:itis C or hepati tis 8 infections. 
18 Any N her ,,,nditi1,n that. in the <•pini0n of the Tnve,tig:itor, w0uld preclude inclu, ion in the hi:d. 
D-0~e Rt•gim,•n/Rouce of .\dministn1tion: 
:\II n-ial drug Josin~ will be µ~·rtimncd .lt the ch:1ic or 1nti1sio11 center under adequate hca l!hcure professional 
, up:rv1;;11,11. 1.)11 Day I ,,fthe Jt)J bk-111.1skcd T1,-:i1111cnt f>eric,1, ;:iat1..:nts wi ll be randomized in a 2: 1 ratio to 
~,Yn w !\' inti.1,1<>n,: 11fci1hc1 : 
I. 
TE PE LZ.-\ \ 10 mg k~ or. Day l followcd by 20 111.:!ik,: q3W for the remaining : infi1s1ons). or 
PIJcehn (qJ\V t~,r .111 ~ infu,i0ns). 
FM .ion-n>.,1,,,n,·.a, th:H receive ,,prn-1:,t,l'I tn-:itmcnt fol l1,wing n•mplrtion of chc doublc-nuskcd T 1c:it111r11t 
Pcn,,d. :ill rJrient, wil. n:-,-ei,·e :< infosi0n, of TFPF// A t I O mg kg for rh.- first in fu~i0n fr,ll0wc:d t,y 20 mg/kg 
q3W for the remaining~ infos ions). 
Thr fir,t :: in:'usions 0f 1hr dN1hlc-m:-iskcd nnd cipcn-lJbcl Trc:itrncnt Pcriod.s w ill be administered ovc1 
appr0x imateh· 90 minutes (bm not ·.rs, than l<() minutes). All subsequent infusions will be administered oYer 
approximatelv 6 L) minutes t hut n,)t iess than 50 minute~). For tht' fi rst 3 infusions. patients will be monitored for 
2ny A Es cu ring the 111fusion and for 60 minuces after co mpletion of the in t'usion. For suhsrquent infosions (if no 
prt'viou.s i:1 fo;ion reJctions). ;iat1ems will be rno:1itored dw-ing and for 30 minutes at'ter completion of the 
mfi:sion. At any scheduled infusion, the ir.fus1on rate may be reduced. or the dose interrupted or held based on 
tokr:ibilif: tscc Sernon 9 . ..:.6.3.: for dc:1ails). 
Dos:igc Form :ind Stn·nglh Fonnul:llion: 
TEPE ZZA 50Ll mg will bi: p10, idrd m s111glt'-lfl,sc 20-mL gl..1,s vials a:- a (1cc:rc-dncd powd('r. Each vi;il of 
TEPF 77A wili lK rL-c,,n,titucnl with l O ml L>f ,tcri lc water for injt'ction. T he rc~ulting sol utiun w ill have a 
wnccntr:1ti0n 0f 4., .6 m& 'ml tcprnnimum:il, :-intibody. Rcconstinitcd TF.PEZZA soluti,H1 will be fu1 thcr Ji luh:d 
in ().u% , w \·) ~odium chloride solutic,n prior to administr3tic,n. 
D0srs k.,, rhn:\ 1 ~00 mg will he ndmini,tcrcd in a totnl infusion volume of 100 mL. n11d <loses 11'0() mg and 
abon- v.i ll 'tie administered in a tot:111nfosion v1,lume of2:,0 ml. T0 maintain a constant YOlume in the infusi011 
bags. a \·olume equal io the volume of TEPEZZA to be placed into the infusion bag will he first removed from 
tbc infusion bag using a sterile syruige and ueedle. The appropriate volume of reconstiruted T EPEZZA solution 
b,1sed on the pJticnt's dose and body weight will be withdrawn from the reconstituted TEPEZZA vial(s) and 
tr\111s fcrrcd mm an 1mJaYe1wus bag containing uormal saline (0.9% sodium chloride) to prepare a diluted solution 
with c, u ! wlumc 01 I lJO ml tk>r doses , 18t)0 mg) or 250 mL (for doses :::: I 800 mg). 
PLm:bo will consist ofa nonnal saline (0.9~o NaCl) s11lucion and wi ll be administered in JOO mL or 250 mL 
infusion bags, as appropriate. per we1ght-bas..:d dosing volumes. 
Duration of Treatment and f ollow-up: 
The planned duration of the double-masked Treatmenc Period is 24 wech . The planned dmation 0fthc open-
label Treatment Period is 24 weeks. 
Patients wi:l enter a 30-day Follow-up Period at lhe enct of either the d0uhle-maskect or open-label Treatment 
Period. 
PRIVATE A'-ID CO'-ll'fDE'ITIAL NFORMATIOK OF IIORJZONTHERAPEUTICS U.S.A, INC. 
Page 18 of99 


Horizon Therapeutics U.S.A., Inc. 
Da1e: 19 May 2023 
TEPEZZA <t<) (teprotumumab-trbw; HZN-00 I) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
Criteria for Evaluation: 
At the Baseline (Day I) Visit, the "srudy eye" (i.e., the eye with most significant proptosis) will be identified. If 
both eyes are affected equally, the Investigator will choose the "srudy eye." Both eyes wi ll be assessed for 
efficacy, but the study eye will be used to assess the primary efficacy endpoint. 
E 
will be assesse 
I roptosis (m 
cd as proptosis 
tion of the er 
Safety will be assessed via AE (including /\ES!s) and concomitant medication use monitoring, immunogenicity 
testing, best-corrected visual acuity, vital signs, clinical safety laboratory evaluations (complete blood count and 
fasting chemistry [including thyroid panel and HbA lc)) and pregnancy testing (ifapplieable). 
Patients experiencing hearing impairment should contact the investigational site for evaluation and assessments. 
Evaluation may include an audiogram. 
Statistical Analyses: 
Prima 
Efficac End oint 
The primary efficacy endpoint is the change from Baseline at Week 24 in proptosis in the study eye. 
Other Efficacy Endpoints 
I. 
The proptosis responder rnle (percentage or patients with a ?.2-rrnn reduction from Baseline in proplosis 
in the study eye, without dc.:11:rioration [2:2-mm increascj or proprosis in the.; tcllow eye) at Wc..:k 24. 
2. 
The change from Baseline at Weck 24 in the UO-Qo L questionnaire appearance and visual functioning 
3. 
4. 
5. 
subseales. 
Pharmacokinetic and Anti-dru Antibod End oinrs 
I. 
.. 
The peak ;md trough rnncentrations ofTF.PF.ZZA. 
The aoti-dmg antibody (ADA) incidence and titers . 
Safet and Tolcrabili 
End oints 
I. 
The iucidencc of treatment-emergent adverse events (TEAEs), serious AEs (SA.Es), TEAEs resulting in 
premature diseontinuatiou of trcatmcnl and AESJs (infusion reactions, hyperglyeeroia, hearing 
impairment, new onset inflanunatory bowel disease and exacerbation of inflammatory bowel disease). 
2. 
The incidence of ?:Grade 3 TEAEs. 
3. 
The change from Baseline to each scheduled visit in vital signs (blood pre~sure, heart rate, respiratory 
rate and temperature). 
4. 
The results of best-corrected visual acuity. 
5. 
The incidence of?:Grade 3 fasting glucose values. 
6. 
The change from Baseline to each .scheduled visit in laboratory evaluations (hematology and fasting 
chemistry [including thyroid panel and HbAlc]). 
PRN A TE AND CONFIDENTIAL fNFORMA TION OF HORIZON THERAPEUTICS U.S.A., rNC. 
Page 19 of99 


Ho1izon Therapeutics U.S.A., Inc. 
Date: 19 May 2023 
Ex 
I. 
3. 
Statistical Analyses: 
Statistical Anal sis 
TEPEZZA ® (tcprotumumab-trbw; HZN-00 I) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
Efficacy analyses wi II be perfonncd on the intent-to-treat (ITT) set, consisting of palients who are randomized to 
trial drug (either TEPEZZA or placebo). Safety analyses will be perfonned on the safety set, consisting of 
patients who receive at least 1 dose of trial drug. The PK analysis sc:t \,ill include all patients who receive at least 
I dose of trial drug and have at least I post-dose PK sample. 
Prima 
sis: 
The primary efficacy analysis will be conducted on the ITT set. A Mixed-Model for Repeated-Measures 
(MMRM) analysis of covariance model fitting to the individual change from Baseline scores for the study eye 
will be used for the analysis of change from Baseline in proptosis. The model includes Baseline score, treatment 
group, visit, visit-by-treatment and visit-by-Baseline score as covariates. The unstructured covariance will be 
used. The treatment difference (TEPEZZA minus placebo) based on the estimated least squares (LS) means at 
Week 24 will be presented with associated standard error (SE), 95% confidence interval CJ) and -value. 
Safotv and Tolerahilitv 
proptosis responder ra 
assess risk differenc 
rv 
· 
· 
The number and percentage of patients experiencing at least I occurrence of a TEAE, SAE, TEAE resulting in 
premature discontinuation of treatment and AES! for each unique System Organ Class and Preferred Term will 
be summarized by treatment group. TEAEs and SAEs will be summarized by severity and relationship to trial 
drug, as assessed by the Investigator. Grade 3 and higher TEAEs, as graded by the National Cancer Institute 
Common Terminology Criteria for Adverse Events C~ CI-CTCAE), will also be summarized for each unique 
Sys,cm Organ Class and Preferred Tenn. 
lite number aud percentage of patients in each ln:atment group using concomitant medications will be 
summarized by A1utomical T herapeutic Chemical Level 4 tem1 and Prefe1Ted Tenn. 
ror bt:st-,orre..:ted visual a..:uity. shift tables will be presented providing the c0uot of patients in each treatment 
group with each type of finding (no1mal, abnonnal - not climcally significant, or abnormal - clinically 
significant) at Baseline compared to each postbaseline visit. 
PRl\'A TE .-\'ID CONFJDENTJAL INFOR1'1A TIO'< OF l iORIZON TifERAPEUTICS U.S.A, i'-lC. 
Page 20 of99 


Horizon Therapeutics U.S.A., Jnc. 
Date: 19 May 2023 
TEPEZZA ® (teprotumumab-trbw; HZN-00 I) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
Descriptive summaries of observed and change from Baseline values will be presented for each vital sign 
parameter by treatment group and visit. A shift table for vital signs by NCI-CTCAE grade and visit will be 
generated by treatment group. 
Safety laboratory (hematology and fasting chcmisiry [including thyroid panel and HbAI cl) values and change 
from Baseline will be summarized by visit and treatment group using descriptive statistics. The laboratory 
assessment will be categorized as low, normal or high based on normal ranges and graded using the NCI-CTCAE 
grading scale, when available. Shift tables using categories of low, normal and high from Baseline to each visit 
will be generated by treatment group. Additionally, a shift table for glucose by NCI-CTCAE grade and visit will 
be generated by treatment group. Summaries will be provided separately for hyperglycemia. 
The rate and titer of positive ADA samples will be summarized by visit and treatment group using descriptive 
statistics. Tcprotumumab peak and trough (i.e., prior to dose) concentrations will also be summarized by visit 
using descriptive statistics. 
Sample Size Estimate: 
A total of 57 patients (38 in the TEPEZZA group and 19 in the placebo group) will be enrolled in the trial to 
detect at least a 2-mm mean di fference between the 2 treatment groups in the change from Baseline ofproptosis 
values at Week 24 in order to have 81 % power al the 2-sided 0.05 level of significance. The sample size was 
determined assuming that the mean difference in proptosis change between the 2 groups is at least 2.0 mm 
( clinically relevant) and the standard deviation of proptosis change values is 2.5 for both groups (larger than 
observed in Phase 2 and Phase 3 active TED trials). 
PR IVA TE ANO CONFIDENTIAL INFOR,'vlA TION OF I IOR IZON Tl tERAl'EUTICS U.S.A., INC. 
Page21 of99 


Horizon Therapeutics U.S./\., Inc. 
Date: 19 May 2023 
2. 1 
Schedule of Assessments 
Trial Visit Scrt:~ning1 
Week(W) 
-211 d:iys 
Visit Window (±days) 
Informed consent 
X 
Review inclusion/exclusion criteria 
X 
Demol!raphics 
X 
Medical history and prior 
xs 
medications4 
Wcight6 
X 
Randomization 7 
Efficacy assessments 
Clinical Measures of Severity -
includes proptosis aad 
X 
=-
X 
X 
GO-QoL Questionnaire 
Treatment response assessment'' 
Safety assessments 
Pregnancy test12 
X 
Visual acuity 
X" 
Vital signs1" 
X 
Clinical laboratorY tests 
Fasting chemistry 
X 
Thyroid function 
X 
(FTJ, fT4, TSH)15 
Hematology 
X 
l 
Day I/ 
BL 
X 
X 
X 
x• 
X 
X 
X 
X 
X 
x•• 
X 
X 
X 
Double-masked Tre:itment Period 
2 
3 
4 
s 
6 
7 
8 
W3 
W6 W9 W12 WIS W Iii W2 1 
:::3 
±3 
±3 
±3 
±3 
±3 
±3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X" 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PRIVATE AN]) CONFll)El':TIAL INl'ORMATION OF HOR 17.0N TllERAl'FlJTICS US A .. INC 
9/EOTl/ 
PWI-' 
W24 
+7 
X 
x• 
X 
X 
X 
X 
X 
X 
X 
x14 
X 
X 
X 
TEPEZZA" (tcp rotumumab-trbw; 1 IZN-00 I) 
Prolocol: 1 IZNP-Tl!P-403 
Versio11 5.0, Amendment 4 
Open-label Treatment Period 
JO days 1 
(Proptosls Non-responders who Choose to 
after 
Receivt Open-label TEPEZZA) 
17/EOT2/ W24 or 
10 
II 
12 
13 
14 
15 
16 
PW23 
W48/ 
EOS/ 
W27 WJO W33 W36 W39 W42 W45 
W48 
PW 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 22 nf99 


Horizon Therapeutics U.S.A .. Inc. 
Date: 19 May 2023 
Trial Visit 
Week (" ) 
Visit Window (:!:days) 
HbA Jc 
ADNNAb samples17 
AE. SAE assess1m:nl 
Prior/concomitant medications 
Pham,acokinetic samples 1~ 
-
Pholographs21 
Trial drug infusion 
Contact (phone/email) for safely 
24 hours post dose23 
Screening1 
1 
-28 da~ s 
Day II 
BL 
X ; 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x:; 
Doublc--mask<'d Treatment P<'riod 
2 
3 
4 
s 
b 
7 
8 
\ VJ 
\\ 6 W9 Wl2 WIS ~\ 1S W21 
±3 
:1:.., :3 
=.3 
±3 
=3 
:!:3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x:i 
9/EOTI/ 
PWl1 
W24 
=1 
X 
X 
X 
X 
X 
x •o 
X 
x1~ 
x:!3 
TEPf.7.ZA-. (teprotumumab-rrbw; H7.N-00I) 
Protocol: HZ 'P-TEP....103 
Version 5.0, Amcndmcnl 4 
Optn-label Treatment Period 
30 days1 
(Proptosls JI.on-responders who Choose to 
aflt'r 
Receive Open-label TEPEZZA) 
17/EOT?/ W24 or 
10 
11 
12 
13 
14 
15 
16 
PW21 
W48I 
EO / 
W27 W30 W33 W36 W39 W42 W45 
W48 
PW 
:!:3 
:!:3 
:!:3 
:!:3 
±3 
:1:3 
:!:3 
±7 
±7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xn 
ADA=anti-drug antibody; AE=.rdvcrse event; Bl .- Baseline; EOS -Emi-ol-Study/T1 ,al; EO r- End-nf-Tn.:atmcnl; FTi free lrriodothyruninc: FT,- ftee thyroxine; GO-QoL- Gravc~• 
Ophthalmopathy Quality of Lile; I lb A I c· glyeated hemoglobm; NAb- ncutralw ng antibody; PW-prcmallllC withdrawal: q3 W once every 3 wcch; SAE-serious adverse event; 
TSH=thyroid-stimulating hormone; W week. 
Footnotes· 
I. All patients will be contackd via phone or email 30 days(± 7 days) following the Weck 24 (rc;ponder~ and non-rc~ponclcrs who choose not lo receive opcn-lahd TEPEZLA) or 
Week 48 (non-responders who receive open-label TEPE77.A) Vi"t 
2. Screening procedures can occur over more lhan I day/clmic visit provided ..:onscnl 1s ob11111..:d 111~1 and all assessments arc cornplch:d w1lh111 the designated window. 
3. !fa patient prematurely discontinues trial drug dunng the double-masked Treatment Period 0 1 the open label Treatment Pcnod, he/she will return for a clinic visit and undergo 
the W24/PW l or W48/PW2 assessments, rcspccttvcly, with !he exception of lhe eollect1on of blood samples lor b10111arkcr cvaluallons. 
4. !v1edical history will include tobacco. alcohol and other substance use history and thyroid disc~sc history and treatment. 
5. Thyroid eye disease must be stable, chronic (inac11ve) (not progressing. 11on-sigh1-threa1cn111g but with an apprcci.iblc impact on daily lifr), with thyroid eye disease diabrnosed 
2:2 years but <IO years prior to Screening. 
6. The weight obtained at Screening will be usccl to calculate close for Day I and Weeks 3, 6 and 9. The weight obtained at Week 9 will be used 111 dose calculotions at Weeks 12. 
IS, 18 and 21. The dose on Weeks 24. 27, 30 and 31 of the open-label Treatment Period will be based on the Weck 24 wc1i,:hl, weight measured at Weck 33 will be used 111 
dose calculations at Week~ 36. J9, 42 anc1 4 ~ 
7. On Day I, patients will be rnndom1zed m u 2: I rJtlo to receive either; a) I EPFZZA (IO mg/kg on Oay I lollowcd by 20 111g/kK q3W for the 1emaining 7 infusions) or 
b) placebo (q3W for all 8 mlt1s1ons). baseline assessments will be performed prior tu dosing. 
PRIVATE ANO CONFIDENTIA i INFORMATION OF HORIZON TIIERAl'HrrlC'S U.S /\., 1)./(' 
Page 23 of99 


llorizon Therapeutics U.S./\., Inc. 
Date: 19 May 2023 
8. Patients who have a >2-mni decrease from Screening in proptosis in the study eye arc not ehg1ble for iandumimtion. 
9. 
TEPEZZA~' (tcprotumumab-trhw; 1 IZN-00 I) 
Protocol: HZNf>-Tl:iP-403 
Version 5.0, Amendment 4 
I 0. Patients at I clinical investigative site will undergo 
uring Screening 3nd at the Weck 24 Visit and Week 48 Visit (proptosis non-responders who 
elect to receive open-label TEPEZZA). The Weck 24 
will not need lo be performed on the same day as other Week 24 ass~ssmcnts as long as II is 
performed within the visit window ond prior lo the Weck l4 mtus1on (proptos1s non-responders who elect to receive open-label TEPEZZA). The Weck 48 
ill not need to be performed on the same day as other Weck 48 assessments as long as it is performed within the visit window 
11. Clinical Activity Score must he <I 111 holh eyes at the Screening and Baseline Visits. 
12. For women of childbearing potential (including those with an onset of menopause <2 years prior to Screening, non-therapy-induced amenorrhea for <12 month~ prior tu 
St:ret!ning, or riot surgically sterile [abscncc uf uvarics and/or uterus]), a scrum pn:gnant:y lesl will be Jl'-'rlttnm:d al Sernening and urine pregnam;y tests will be performed prior 
to dosing at all other visits, as applicable, and at the End-of-Treatment Visit. 
13. Patients who have decreased best-corrected visual ac111ty due to optic neu1opathy (defined by a decrease in vision uf2 lines on the Snellen chart, new visual field defect, or 
color defect secondary to optic nerve involvement within the Ja5t 6 months) »re not eligible for randomization. 
14. Vital signs (hlood pressure, heart rate, respiratory rate, temperature) will be measured at all clinic visits. Vital signs will be measured pre- and post-infusion un Day I and 
Week 3 (all patients). pre- and post-infusion at Week 24 and Weck 27 (proptosis r1on-responders who elect to receive open-label TEPEZZA) and pre-infusion on all other 
infusion days. Additional vital signs will b.., monitored if infusion-associated AEs occur (sec Section 9.5.3.4 for details). 
15. Patients must be euthyroid, with the Baseline disease under control or have mild hypo- or hyperthyroidism (defined as FT• and FT1 levels <50% above or below the normal 
limits). Fvery effort should be mad.: tu correct the mild hypo- or hyperthyroidism promptly and to maintain the en thyroid state for the full duration of the trial. 
16. HbAk must b" <8.0% to be eligihle for the trial. If the I lbA I c is elevated and considc.:rcd clinically significant at any time point after Screening, it will be repeated 
approximatdy every 90 days until ii returns lo normal or Baseline valu.:. 
17. ADA sample will be collected prior to the inli.1sion. If the ADA test is positive aflcr confirmatory and reactive tiler testmg, the sample will thea be tested for :-.!Ab. lfthe patient 
tests positive for NAb. the patient may be followed until levels either return lo Baseline or the patient's level decreases or remains stable. ADA samples will be collected 
during any visit triggered by suspected 1mmunolog1cally related AEs. 
18. Pbarmacokiaellc samples will be colk ctcd prior to, and at the end of, the infusion on Day I. Week 3 and Week 12 of the double-masked Treatment Period (all patients) and 
Weck 24, Weck 27 and Week 36 of the open-label Treatment Period (proptosis non-responders who elect to receive open-label TEPEZZA); a single sample will be collected al 
Weck 24 (proptosis responders and proptosis non-responders who elect not to receive open-label TEPEZZA) and Week 4R (proptosis non-responders who elect to receive 
open-label TEPEZZA). 
l9. 
20. 
21. For those patients who have consented, photographs of the patient's eyes will be taken prior to the first infusion and at Weck 24 (all patients) aod Week 48 (non-responders 
who elect to receive open-label TEPEZZA). 
22. For non-responders who choose to receive opcn-bbcl treatment, ·1 EPEZZA infusion will be performed at Weck 24 (first of 8 infosions). All Weck 24 assessments except AE 
and concomitant medication monitoring. post-infosion PK sample collection and 24-hour post-dose phone/email contact must be completed prior to TEPEZZA infusion. 
23. Phone (or email) contact by research staff focusing on satcty and tolerability aspects will be made the day after infusion tor the first and second infusions during the 
double-masked Treatment Period and during the open-label Treatment Period, and thercallcr as deemed appropnatc. In addition, patients who experience an 
PRIVATE AN!) CONFffiENTIAL INFORMATION OF IIORIZON THERAPF.1/TfCS US A . 1\/C. 
Page 2'1 of 99 


Horizon Therapeutics U.S.A., Inc. 
Date: 19 May 2023 
TEPEZZA ~ (teprotumumab-trbw; H ZN-001 ) 
Protocol: HZNP-T~P-403 
Version 5.0, Amendment 4 
infusion-associated event after any subsequent infusion will also be cuntaclt:d by phone (or email) by research staff the duy oiler the infusion, und thcreallcr us deemed 
appropriate. 
PRIVATE AND CONFIDENTIAL fNf70l<MATION OF IIORIZON TIJERAl'EUTICS U.S.A., INC. 
Page 25 of99 


l·h,riz,1n Thn :1prut1cs l 1.:-. A .. In,. 
Date 1 •J ~ !:l\· 2tl 2_; 
T l:PEZL..\'"' (tepmtumum:ib-trbw; HZN-()l) I) 
l'rottlcnl: IIZNP-TEl'-40J 
\"crsion 5.0. A111rnc.lmcnt 4 
T ABLF. OF C'O~TF.NTS 
TTTLF PAG·E .................... ..................................................................................................... 2 
1 
SY~OPSlS ............................................................................................................................ 14 
2. I 
Schedule of Assessments ............................................................................................... 22 
3 
TABLE OF COt TEI\TS ....................................................................................................... 26 
4 
LIST OF ABBREVTA TIONS ............................................................................................... 3 1 
5 
ETHICS ...................................................................................................................... '" .......... 33 
5. 1 
Tnstiturional Review Board/Independent Ethics Committee .......................................... 33 
5.2 
Ethical Conduct of the Trial ......................................................................................... 33 
5.3 
Patient Information and Consent ..................... ............................................................... 33 
5 .4 
Compensation for Health Damage of Patients/Insurance .............................................. 34 
5.5 
Confidentiality .......... ..................................................................................................... 34 
b 
lNVESTIGATORS AND TRI.-\L ADMINISTRA TlVE STRUCTURE ............................. 35 
., 
N TR()DUCTION ....... 
. .................................................................................................. 36 
7.1 
8:ickgnJund ................................................................................................................... 36 
7 . I 
Thyroid Eye Disease ............................................................................................... 36 
7. 1.2 
TEPEZZA.s' ............................................................................................................. 37 
7.~ 
R;1tiom1lc for this Trial ................................................................................................... 38 
7.3 
Rationale for Dose Selection ... ..................................................................................... 39 
8 
TRIA.L OBJECTlv'ES ............................................................................. , ............................ 40 
8.1 
Primary Objective ......................................................................................................... 40 
S.2 
Ocher Objectives ........................... ................................................................................. 40 
8.3 
Phannacokinetic and Anti-drug Antibody Objectives ................................................... 40 
S.4 
S;1fery and Tolerability Objectiws ................... .............................................................. 41 
8.5 
Exploratmy Objecti\'e .................................................................................................... 41 
9 
TN\'ESTIG . .\TIONAL PLAN ............................................................................................... 42 
9.1 
Overall Trial Design and Plan ........................................................................................ 42 
9 .2 
Discussion of Trial Design ..................... ............... ......................................................... 43 
9.3 
Selection of Trial Population ........ , .................... , ........................................................... 44 
9.3.1 
Inclusion Criteria .............................................. ...................................................... 44 
PR l\'A TE AJ\D CO:S.'FJDE1'TIAL INFOR.'vlA TIO'l OF EORIZON THERAPEuTICS U.S.A, ll\C. 
Page 26 of 99 


Horizon Therapeutics U.S.A., In-:. 
Date: 19 May 20.lJ 
TEPEZZA'P' (leprotumumab-lrbw; I IZN-00 I) 
Protocol: IIZNl'-TEP-403 
V<.:r~io11 5.0, /\mcndmcnl 4 
9.1.2 
Exclusion Criteria ............................................... , ................................................... 45 
9.3.3 
Removal of Patients from Treatment or the Trial.. ................................................. 46 
9.3.3.1 Discontinuation of Patients from Treatment . ..................................................... 46 
9.3.3.2 Removal of Patients from the Trial.. ................................................................... 47 
9.3.4 
Replacement Policy ................................................................................................ 48 
9.3.4.l Patients ................................................................................................. , .............. 48 
9.3.4.2 Centers .................................................................................................................. 48 
9.3.4.3 Screen failures ..................................................................................... , .............. 48 
9.4 
Treatments ............................. .......................................................................................... 48 
9 .4.1 
Treatments Administered ........................................................................................ 48 
9.4. 1.1 Double-masked Treatment Period ....................................................................... 48 
9.4.1.2 Open-label Treatment Period ............................................................... , .............. 49 
9.4.2 
hknlity uf l11vestigational Product... ....................................................................... 49 
9.4.2. 1 TEPEZZA ............................................................................................................ 49 
9.4.2.2 Placebo ................................................................................................................ 49 
9.4.3 
Labeling .................................................................................................................. 49 
9.4.4 
Storage .................................................................................................................... 49 
9.4.5 
Drug Accountability ................................................................................................ 50 
9.4.6 
Trial Drng Administration and Timing of Dose for Each Patient .......................... 50 
9 .4.6.1 Description of Clinical Supplies ......................................................................... 50 
9.4.6.2 Detennination of Dose Volume .................. ....................................................... 50 
9 .4.6.3 Details Concerning Timing and Dose Administration ..... ................................... 51 
9.4.6.3.1 
Preparation and Administration ofTEPEZZA .......................................... 51 
9.4.6.3.2 
Dose Modifications, Interruptions and Delays .......................................... 52 
9 .4. 7 
Method of Assigning Patients to Treatment Groups ............................................... 53 
9.4.8 
Masking ................................................................................................................... 53 
9.4.9 
Concomitant Therapy and Restricted Medications ................................................. 54 
9 .4. 9 .1 Concomitant Therapy ............................................ ............... ............................. 54 
9.4.9.2 Restricted Therapy and Medications ................................................................... 54 
9.4.10 Treatment Compliance ............................................................................................ 55 
PRIVATE A~ CO"lFIDENTIAL TNFORMA TION OF HORIZON TllERAPEUTICS U.S.A , INC. 
Page 27 of99 


Horizon Therapeutics U.S.A., Inc. 
Date: 19 May 2023 
TEPEZZA ® (teprotumumab-trbw; HZN-00 1) 
Protocol: HZl\TP-TEP-403 
Version 5.0, Amendment 4 
9.5 
Efficacy, Pharmacokinetic, Safety and-
' ariables ........................................ 56 
9.5.1 
Efficacy Variables ................................................................................................... 56 
9.5.1.1 Proptosis .............................................................................................................. 56 
9.5.1.2 
., .......................................................................................... 56 
9.5. l.3 
9.5.1.4 
........................................... 57 
9.5. J .5 Clinical Activity Score ........................................................................................ 57 
9.5.1 .6 Quality-of-Life Assessment ..................... ........................................................... 58 
9.5.2 
Phannacokinetic Measurements ............... ............................................................. 58 
9.5.3 
Safety \ -'atiables ......... .. , .......................................................................................... 59 
9.5.3.1 Adverse Events .................................................................................................... 59 
9.5.3.1. l 
Definitions ................................................................................................. 59 
9.5.3.1.2 
D0cument:1tion of Adverse fa·cnts ............................................................ 64 
9.5.3. l .3 
Intensity of Adverse Events ....................................................................... 65 
9.5.3.1.4 
Relationship to Trial Drng .... ..................................................................... 65 
9.5.3. 1.5 
Reporting and Documenting Serious Adverse Events .............................. 66 
9.5.J. I .6 
Follow-up 0f Adverse Events ........... ...... ................................................. 66 
() 5.3. 1. 7 
\tledication En-or and Overdose ................................................................ 67 
9.5.3 . l.8 
Review oL\dvcrse fa ents and Emerging New Safety Information ......... 67 
9.5.3 .1. 9 
Reporting oflnvestigational New Drug Safety Reports ............................ 67 
9.5.3.1. 10 Devdopment Safety Update Repo11s ........................................................ 67 
9.5 . .1.2 Pregnancy Repoiting ........ .............. .. ................................... ......... ....................... 67 
9.5.3 .3 Medical History ............... ................................................................................... 68 
9.5.3.4 Vital Signs ,md Weight ........... ............ .................................................... ......... 68 
9.5.3.:-
Ph()rng-raphs ............. ......................................... .......................................... ....... 69 
9.5.3.6 \'isual Al~Uity ....................................................................................................... 69 
9.5.3.7 Clinical Laboratory Safety Tests .. .............. ........................................................ 69 
9.5.3.8 .lmmunogenicity Testing ..... , .................................. ............................................. 69 
9.5.4 
......................................................................................... 70 
9.5.5 
Appropriateness of Measurements .......................................................................... 70 
PRIVATE A'lD CONFIDEt\TlAL fNFOR.\.!ATIO'l OF IIORJZON THERAPEUTICS U.S.A., INC. 
Page 28 of99 


Horizon Therapeutics U.S.A .. Inc. 
Dale: 19 May 2023 
Tl iPEZZA ® (tcprotumumab-trbw; I IZN-00 I) 
l'rnlm:ol: I 17.N'P-TEP-403 
V..:rsio11 5.0. Amendment 4 
9.5.6 
Trial Procedures ...................................................................................................... 70 
9.5.6.1 Screening ............................................................................... .............................. 70 
9.5.6.2 Douhle-masked Treatment Period ...................................................................... 72 
9.5.6.2.l 
Dayl .......................................................................................................... 72 
9.5.6.2.2 
Week 3 ....................................................................................................... 73 
9.5.6.2.3 
Weeks 6, 12 and 18 .................................................................................... 74 
9.5.6.2.4 
Weeks 9, 15 and 21 .................................................................................... 75 
9.5.6.2.5 
Week 24/End-of-Treatment !/First Infusion of Open-label 
Treatment Period ....................................................................................... 75 
9.5.6.3 Open-label Treatment Period Visits After Week 24 - Proptosis Non-responders 
Who Choose to Receive Open-label TEPEZZA ................................................ 77 
9.5.6.3.1 
Week 27 ..................................................................................................... 77 
9.5.6.3.2 
Weeks 30, 36 and 42 .................................................... ............................. 77 
9.5.6.3.3 
Weeks 33, 39 and 45 .................................................................................. 78 
9.5.6.3.4 
Weck 48/Ell(l-uf-Trealment 2 ................................................................... . 79 
9.5.6.4 Follow-up Period (End-of-Study/Trial) .............................................................. 79 
9.6 
Statistical Methods and Determination of Sample Size ............................................. ... 80 
9.6.1 
Endpoints ................................................................................................................ 80 
9 .6.1. l P1i1nary Endpoint ................................................................................................ 80 
9.6.1.2 Other Efficacy Endpoints .................................................................................... 80 
9 .6.1.3 Pbarmacokinelic and Anti-drug Antibody Endpoints ......................................... 80 
9.6.1.4 Safety and Tolerability Endpoints ....................................................................... 80 
9 .6.1.5 Exploratory Endpoint .......................................................................................... 81 
9 .6.2 
Analysis Sets ........................................................................................................... 81 
9 .6.3 
Primary Efficacy Endpoint Analysis ...................................................................... 81 
9 .6.4 
Other Efficacy Endpoints Analyses ........................................................................ 81 
9.6.5 
Safety and Tolerability Analyses ............................................................................ 82 
9.6.6 
Interim Analyses ..................................................................................................... 83 
9.6.7 
Sample Size and Power Considerations .................................................................. 83 
9.7 
Changes in the Conduct ofthc Trial... ............................................................................ 83 
10 
SOURCE DOCUMENTATION AND INVESTIGATOR FILES ....................................... 84 
PRIVATE AND CONFrDENTIAL f:\IFORMATION OF HORIZOJ\ THERAPEUTICS U.S.A., INC. 
Page 29 of99 


lk,ri1m1 Tht:rnpn1tic:s U.S.A .. Inc·. 
Dulc: 19 \lay 20~3 
TEl'EZZA® ttcprutumumnb-trhw; HZN-00 I) 
Prococul: HZNl'-TEl'-40.I 
Vc;r~ion 5.0, A111c11Jmcn1 4 
11 
C ASF RFP()RT FORMS ..................................................................................................... 85 
12 
TlZLI\L tvlON.ITORlNG ........................................................................................................ 86 
13 
OATA MANAGEMFNT ...................................................................................................... 88 
14 
RETENTION OF R.ECO.RDS ............................................................................................... 89 
15 
Plffil 1CA TTON ...................... .............................................................................................. 90 
16 REFERENCES ...... ............................................................................................................... 91 
17 
APPENDICES ....................................................................................................................... 93 
1 7.1 Administrative Append.ix ............................................................................................... 94 
17.2 
............................................................................ 95 
17.3 Sampson Criteria for Anaphylactic Reaction ................................................................. 96 
17.4 Proptosis (Exophthalmometry) Method ......................................................................... 97 
17.5 Graves· Ophthalmopathy Quality of Life Questionnaire ............................................... 99 
LTST OF TABLES 
Table 6.1 
Table 9.1 
Table 9.2 
Table 9.3 
Table of Non-Sponsor Trial Responsibilities .. .......................................................... 35 
Restricted Medications and Therapies ....................................................................... 55 
Clinical Measures of Severity ................................................................................... 57 
Clinical Activity Score Assessment.. .......... ............................................................... 58 
LIST OF FIGURES 
Figure 7. 1 Thyroid Eye Disease Photographs ............................................................................. 37 
Figure 9.1 Schematic of Trial Design ......................................................................................... 43 
PR I\' A TE A\'D c o :--;FIDE'<TI -\L [NFORJl!A TJOJ\ OF IIOR IZON T!JERAPEUTICS U.S.A ' INC. 
Page 30 of99 


Horizon Therapeutics U.S.A., Toe. 
Date: 19 May 2023 
TEPEZZA ® (teprotumumab-trbw; HZN-001) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
anti-drug antibody 
AE 
adverse event 
AESJ 
adverse event of special interest 
CAS 
Clinical Activity Score 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CRO 
Contract Rt:search Organization 
EDC 
electronic data capture 
eCRF 
electronic case report form 
FDA 
Food and Drng Administration 
GCP 
Good Clinical Practice 
GO-QoL 
Graves' Ophthalmopathy Quality of Life 
HbAlc 
glycated hemoglobin 
JCF 
informed consent form 
ICH 
International Counci l for Hannonization of Technical Requirements for 
Pharmaceuticals for Human Use 
TGF 
insulin-like growth factor 
IGF-IR 
insulin-like groMh factor- I receptor 
IRB 
lnstitutiooal Review Board 
ITT 
intent-to-treat 
IV 
intravenous(ly) 
mAb 
monoclonal antibody 
MMRM 
Mixed-Model for Repeated-Measures 
NaCl 
sodium chloride 
NCI-CTCAE 
National Cancer Instin1te Common Terminology Criteria for Adverse Events 
PK 
pharmacokinctic 
PW 
premature withdrawal 
PWl 
premature withdrawal during the double-masked Treatment Period 
PW2 
premature withdiawal dLUing the:: opcn-labd Treatment Pc1 iod 
q3W 
once every 3 weeks 
SAE 
serious adverse event 
TEAE 
treatment-emergent adverse event 
PR[VAfE AND CONFIDENTIAL INFORMATION OF I IORJZON HIERAPEUTICS U.S.A., INC. 
Page 31 of99 


llori:ll,n Thcr.1pcutii.:s U.S.A .. Im:. 
Onti:: 19 l\llly 2L1~.1 
TEl'EZLA® (tcprotumumab-trhw; H/.N-00 I) 
l'rocueol: HZNP-TEl'-40J 
Vcrsiu11 5.0, Amendment 4 
Abbreviation 
Definition 
TED 
TEPEZZA 
tcprotumumab-crbw; HZN-00 I 
US (or l ' S.A) 
United States (United States of Amcricn) 
USP 
United States Ph:mnacopr.ia 
_....:._ ____________________ -l 
Ahhreviat.icin;: that appear only in tigur_.s and rahks are defined •,vith the relevant figures and tahlcs. 
PRIVATE AND CO'-lffDEKTIAL NFOR"'1A TIO~ OF HORIZO'.'i THERAPECTICS U.S.A., INC. 
Page 32 of99 


Ho1izon Therapeutics U.S.A., Inc. 
Date: 19 May 2023 
5 
ETHICS 
TEPEZZA ® (teprotumumab-trbw; HZN-00 I) 
Protocol: H;lNP-TEP-403 
Version 5.0, Amendment 4 
5.1 
Institutional Review Board/Independent Ethics Committee 
The Investigator, Sponsor and/or Contract Research Organization (CRO) authorized by the 
Sponsor will submit this protocol, any protocol modifications, the informed consent form (ICF) 
and all applicable trial documentation to be used in this trial to the appropriate Institutional 
Review Board (IRB) for review and approval/favorable opinion. A letter confirming the lRB 
approval/favorable opinion of the protocol, the patient ICF and applicable trial documentation, a 
list of the IRB members involved in the vote, as well as a statement that the TRB 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 patients into the trial. 
A copy of the approved ICF will also be forwarded to the Sponsor or its designee. Appropriate 
reports on the progress of the trial will be made to the TRB 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 T,·ial 
The Invc:stigalors will ensure that this trial is conducted in a manner that fu lly conforms with the 
principles of the Declaration of Helsinki or with the laws and regulations of the Uni ted States 
( US), whichever affords the greater protection lo the individual. The trial must fully adhere to the 
principles outlined in ·'Guideline for Good Clinical Practice" Jnternational Council for 
Hannonization of Technical Requirements for Phannaceuticals for Human Use (ICII) Tripartite 
Guideline or with local law if it affords greater protection to the patient. for trials conducted in 
the United States of America (US.A.) or under US lnvestigational New Drug program, the 
Investigator will additionally ensure adherence to the basic principles of GCP, as outlined in the 
cutTent version of 21 Code of Federal Regulations (CFR), suhchapter D, part 3 12, 
"Rcsponsihilities of Sponsors and Investigators," part 50, "Protection of Human Suhjects" and 
part 56, "Institutional Review Boards." 
5.3 
Patient Information and Consent 
It is the responsibility of the Investigator, or a person designated by the Investigator (if 
acceptable by local regulations), to obtain a signed TCF from each patient prior to participating in 
this l1ial after adequate explanation of the aims, methods, anticipated benefits and potential 
hazards of the trial. 
TI1c Investigator or dcsigncc must also explain that patients are completely free to refuse to enter 
tile trial or lo withdraw from it at auy time, for any n.:aso11. 
Optional photographic analysis will only be performed if the patient has voluntarily signed and 
dated the photographic informed consent, approved by an lRB, after the nature of the 
phowgraphs has been explained and the patient has had an opportunity to ask questions. The 
PR[VATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS U.S.A., INC. 
Page 33 of99 


l-h1ri·1,,11 Thri-.1pcul.1,s l 1.S.A .. lnr . 
D:ur: l ') l\ lay 2l)~_; 
TEPEZLA -1\l l tcprotumumab-trbw; 11 /.N-OO I) 
l'rn1,1c,,I: II ZN 1'-Tl:Y-11O.1 
\ \:rsiu11 5.0. Amrndmc111 4 
patient mn:;t provide consent t,, he phot0gr:1phed bdore the procedure is perfonned. ff the patic-nt 
does not c1.~nsent to being r h01ographed, it will not impart the patient's participation in the trial. 
The ICFs and any other written infonnat:ion proYided to patients will be revised if important new 
infonnation becomes avaibhle that may be releVJnr to the patient's consent. or an amendment to 
the protocol necessitates a change to the content of the patirnt infonnaLion and'or the wrillcn 
lCFs. The lnYcstigator will infonn the patient of changci'i in a timdy rnanncr and w ill ask the 
patient to continn his.'hrr participation in the trial by signing the revised lCFs. Any revised 
written TCF and written information must receive the IRB ·s approval/favorable opinion in 
ad\'ance of use. 
:\11 signed lCFs ;1re to remain in the Investigator's site file or, if locally required, in the patients' 
nmes, 'files of the medical institution. 
TI1c dectronic case 1Tport forms (eCRFs) for this trial contain a section for documenting all 
patiem infonned consents, and this must be completed appropriately. 
5.4 
Comp(•nsation for Hc:1lth Damage of P:llicnts/lnsuranct 
The: Spl'llSL)r 111ai1Hai11s clinical trial insun111cc coverage for this trial in accordance with the laws 
.111d regulations lif thc US. 
5.5 
Confidl'llfiality 
.-\ II records id,·11tifying the patient will be kept confidential and, to the extent pamitted by the 
applicable laws ,md 1or 11.:gulations, will not be made publicly available. 
Patient names will not be supplied to the Sponsor. Only the patient number will be recorded in 
the cCRF, :1.nd if the patient's name appears on any other document, it must be obliterated before 
a copy of the document is supplied to tl1e Sponsor. Trial findings stored on a computer will be 
stored in accordance with local data protection laws. As part of the informed consent process, the 
patients will be iJJfonncd in writing that representatives of the Sponsor, IRB, or regulatory 
authorities may inspect their medical records to verify the infonnation collected. and that all 
personal infonnarion made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
If the results of the rrial are published, the patient's identity will remain confidential. 
The Investigator will maintain a list to enable patients to be identified. 
PR[\' A TE A-'ffi CO:'-,l'lDEl\TlAL NF ORM A T!Ol\ OF HORIZON THERAPEUTICS C.S.A., INC. 
Page 34 of99 


Horizon Therapeutics U.S.A., Inc. 
Date: 1 9 May 2023 
TEPEZZA ® (teprotumumab-trbw; HZN-00 I) 
Protocol: HZNP-T EP-403 
Version 5.0, Amendment 4 
6 
Il'fVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE 
The Sponsor of this trial is Horizon Therapeutics U.S.A., Inc. (Horizon). Horizon personnel will 
serve as the Medical Monitor and the Sponsor's regulatory representative (see Section 17. 1 for 
details). The Sponsor will be responsible for timely reporting of serious adverse events (SAEs) to 
regulatory authorities as required. The Sponsor will be responsible for timely reporting of SAEs 
and any other new pertinent safety infomrntion to all Investigators as required. 
The trial will be conducted at approximately l O sites in the US. Prior to initiation of the trial, 
each Investigator will provide the Sponsor or its designee a fully executed and signed Food and 
Drng Administration (FDA) Form 1572 (or equivalent) and a Financial Disclosure Form. 
Financial Disclosure Fonns will also be completed by all sub-investigators. It is the 
responsibility of the Investigators or sub-investigators to advise the Sponsor of any change in the 
relevant financial interests that occur during the trial and the I-year period following its 
completion. 
Table 6.1 lists other organizations critical to the conduct of the trial: 
Table 6.1 
Table of Non-Sponsor Trial l{esponsibilitics 
Trial Rl::sponsibility 
Organization 
Contr;lct research organi?.:1tio11 
Clinical Jrug supply ,l11d dist1 ibution 
Central safely laboratory 
PRN ATE ANO CONFIDENTIAL £NFOIUvlA TION OF HORJZOK TIIERAPEUTJCS U.S.A., INC. 
Page 35 of99 


Horizon Therapeutics U.S.A., Inc. 
Date: 19 May 2023 
7 
I~TRODUCTION 
7.1 
Background 
7.1.1 Thyroid Eye Disease 
TEPEZZA ® (teprotumumab-trbw; HZN-001) 
Protocol HZNP-TEP-403 
Version 5.0, Amendment 4 
Thyroid eye disease (TED), also termed Graves' ophthalmopathy/orbitopathy and 
thyroid-associated ophthalmopathy, is a serious, debilitating and painful autoimmune disease that 
can, in severe cases, lead to blindness. TED is commonly associated with Graves' 
hyperthyroidism/disease, but also occurs in a proportion of patients w ith other autoimmune 
thyroid diseases, including Hashimoto 's thyroiditis. The natural history involves an "active 
TED,'' which is an autoimmune inflammatory response targeting orbital soft tissues, and 
"inactive TED," in which there is tissue expansion remodeling. Active TED typically lasts I to 
3 years, and then the inflammation spontaneously subsides to leave the 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 
I 00,000 people for women and 2.9 cases per I 00,000 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, 200 I ; Tanda ct 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, 2017]. The occurrence and severity of TED are associated with smoking 
[Prummel etal. 1993] . 
. -\ mounting body of t'vi1.knce in the s.::icntific literature indicates that the pathophysiology of 
Jctivl:' TED involves autoimmune activation and proliferation uf orbital fibroblasts I.Bahn, 20 I 0: 
Boschi et al, 2005; Smith, 20 I OJ The acti varion of fibroblasts triggers release of inflammatory 
cytokines. infiltration of immune cells into orbital soft tissues (muscle. interstitial and adipose). 
excessiYe s.yn1hesis () f extracellular mallix. and tissue expansion and fibrotic remodeling (ibid). 
During the inactive phase. inflammation is absent and the disease plateaus. hut significant 
remodeling of ortiiwl tissue remains nnd rarely docs the patient rcmm to Baseline. 
C'linic:-.1 feature~ of TED include orbit~II pain, swelling. dry eye, rcdm;ss anJ discomfort of the 
lids and ocular surface. thirkrning ,111d rctra.::tion of the cydiJs. an<l proptosis (exuphtbalmos) 
Jue to the'. exp.msion ot'tissuc": behind che eye- [Balm. 2010; Burch et a]. 1993; Dickinson, 2017; 
Mallika et al, 2009]. Although TED is hecerogenous and variable in presentation, proptosis is one 
of the most prevalem and widdy known symptoms of TED. Thyroid eye disease has high 
morbiJiry lBartalena et al. 2008; Bartley. 1994; Dickinson, 2017: Gerding et al, 1997]. 
1\forbidicy takes the fonn or orbical pain, together with a number of serious. vision- or sight-
threatcmng conditions. including diplopia (due to inability to co1Tectly align the eyes). corneal 
ulceration (due to inability w c\o:-e lids) and dysthyroid optic neuropathy (due to prc,ptosis. tissue 
cwwding. and stress 011 the optic nerve). These combine to produce marked reductions in quality 
l~flife (eg. physical functioning, role functioning. socinl functioning. mental health, health 
perceptit~ns :-.nd pain) [Gerding et al. 1997: Terwee et al, 2002]. Thyroid eye disease l·an also 
produce pn)found psyd wsocial problems. in parlil:ular aJLXic1y and dcprc~sion, Jue to the 
PR[YA TE A:S.11) CO~l'JDEKTfAL ['ffOR.!l!ATIOJ\ OF HORIZON Tl rERA.PEUTICS U.S.A , NC. 
Page 36 of99 


I lori:i:011 Therapeutics U.S.A .. Inc. 
Date: 19 May 202.1 
TEPEZZA® (tcprotumumab-trbw; 111.N-0O I) 
Protocol: HZNl'-T El'-403 
V..:rsion 5.0, Amendment 4 
alarming and disfiguring changes in appearance !Bartley et al. 1996; Coulter et al. 2007; 
Kahaly et al, 2005]. Taken together, these data show that TED is a physically and emotionally 
debilitating condition (Figure 7.1 ). 
Figure 7.1 
ThJroid Eye Disease ·rhotographs 
Lcll - uppt:r & lower: Prnptosis Jue lo 11,c expansion of tissue volwne behind the eye, forc iug the eyeball 0111 ()flhc orbit. 
Center - urper & h>wcr: lnn11mmatio11 ofnrhital tissues - a hullmark sy111p1nr11 <>fthy,oid eye disease. 
Right - upper & lower: Comt'al inflammation and 11lc~ration - a problem when patients are unable to fully close their eyelids. 
7.1.2 
TEPEZZA® 
TEPEZZA'lll (teprotumumab-trbw, hereafter referred to as TEPEZZA) is a fully human 
imrnw1oglobulin G l monoclonal antibody (mAb) directed against human insulin-like growth 
factor (JGF)-1 receptor (IGF-lR). The IGF-lR is a tyrosine kinase cell surface receptor that 
shares ~50% overall homology with the insulin receptor (Ullrich et al, 1986]. TEPEZZA binds 
with high affinity and selectivity to the extracellular domain of IGF-lR and prevents its 
activation by the endogenous ligands, IGF-1 and IGF-2. 
TEPEZZA has no partial agonist activity at IGF-l R, as assessed by activation of the canonical 
signaling pathway (phosphoinositide 3 kinase/Akt) and has no affinity for the insulin receptor. In 
addition, TEPEZZA causes direct inactivation of TGF-1 R through antibody-induced cellular 
internalization and degradation. Binding of TEPEZZA has been shown to inhibit canonical 
signal transduction and cellular proliferation and survival functions mediated by lGF-1 R in 
cancer cells. TEPEZZA does not indµce antibody-dependent cellular cytotoxicity. 
TEPEZZAiE (teprotumumab-trbw) was approved by the US FDA on 21 January 2020 for the 
treatment of TED. 
Previous teprotumumab clinical trials for the TED indication include 2 independent, randomized, 
double-masked, placebo-controlled, parallel-group, multicenter trials (Phase 2 Trial TED0 l RV 
PRIVATE AND CONFIDENTIAL INFORMATION OF l lORIZON THERAPEUTICS U.S.A., INC. 
Page 37 of99 


IIL11iz,111 Thcrnpcut.1.:s ll .S.;\ .. Inc 
D.Hc: !9 l\l;;y 20 ~_; 
TEl'ELZA ® l tcpn.>tumum:1b-trbw; 1 IZN-00 I) 
l'rotocul: HZ1 1'-TEl'-40.1 
\'cr~iun 5.0. Amendment 4 
[Smith et al. 2017] and Phase 3 Trial HZNP-TEP-301 [Douglas et al, 2020]). In these 2 trials, 
teprocumumab resulted in staristically significam and clinically relevant improvements in 
measures chac assessed multiple facets of TED (proptosi.s, inflammation as measured by Clinical 
Activity Score [CAS]. diplopia and quality of life). Tn addition, the persistence of effect was 
demonstrated after approximately l year off treatment. Consistent results \.Vere shown across all 
efficacy endpoints and all subpopulations. 
In the Phase :2 trial. the majority ofrcporred adverse cYents (AEs) wen: mild, required no 
trealment and resolved while patients remained on drug. Hyperglycemia, which was monitored 
by as:;essing blood glucose and glycated hemoglobin (HbAlc), was the only mechanism-based 
anticipated AE clearly identified as related to trial drug. 
ln the Phase 3 trial, teprotumumab was well tolerated and demonstrated an acceptable safety 
profile, replicating the results of the Phase 2 trial. 
7.2 
Rationale for this Trial 
IGF- l R pl.lys a 1-..ey mlc in TFD and inhibition of this target blucks the underlying 
immttnopathogcnesis that drin~s the orbital in11ammalion. excessive synthesis of extracellular 
matrix and tissue proliteration that are the hal lmarks or TED. In vitro studies demonstrating the 
significanc~ t'f IGF- 1 Rand phamiarnlogic effects of anti-!Gf-1 R were performed with human 
vrbital tibrvblasts obtained mainly from patients with inactive TED post-decompression 
surgeries. Thus, TEPEZZA may have the potenlial to reverse the symptomatology and pathology 
in patients with inactive TED. 
A.dm111istering TEPEZZA for the treatment of chronic (inactive) TED may have a beneficial 
effect in reducing the need for conective surgeries. Previous clinical expe1i ence indicates that, at 
doses that are phannacologically relcYant for blocking IGF- IR. TEPEZZA produced statistically 
significant and clinically relernnt imprm·ements in measures that assessed multiple facets of 
acrive TED (proptosis. inflammation as measured by C AS, diplopia and quality of life). Tn 
addition. TEPEZZA has an acceptable safety profile following intravenous (IV) infusion and is, 
therefo re>. a suitable drng candidate to be investigated in a chronic (inactive) TED patient 
population. 
Data on natural history ofproptosis change were taken from the TEPEZZA Phase 2 and Phase 3 
tri:-ils In the Phase 2 and Phase 3 trials. patients entered the trials with TED diagnosis a mean of 
5 months prior to enrollment. These patients were followed for 72 weeks. Io addition, the 
majority of the placebo patients (67'87) had a CAS score of less than or equal to 3 out of7 
(defines chronic [inaccive] T ED for these trials) in the fellow-eye during the treatment period. 
The findings with regards to proptosis in this patient population are the following: mean change 
from baseline in proptosis at Week 72 (n'=35) for the study eye was -1.2 mm with 95% 
confidence inter1al (Cl) (-1.84, -0.67). while the non-study eye change from baseline for n=35 
was 0.43 with 95% CI (-1.07, 0.21). The mean change in proptosis for the inactive TED 
population identified above (n=3 l ) was -0.48 with 95% CI (-1.1 4, 0.17). lt is therefore concluded 
PRIVATE A;-..,1) CO'IFIDH, 1 !AL INFORMATION OF HORIZON Tl fERAPEUTICS U.S.A , t\C. 
Page 38 of99 


Horizon Therapeutics U.S.A., Inc. 
Date: 19 May 2023 
TEPEZZA ® (teprotumumab-trbw; HZN-00 I) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
that patients with TED, who have CAS less than or equal to 3 and were diagnosed with TED at 
least 2 years prior, will have a decrease from baseline in proptosis of less than l mm, on average, 
without treatment. 
7 .3 
Rationale for Dose Selection 
The US FDA-approved dosing duration for TEPEZZA is 10 mg/kg for the first dose followed by 
20 mg/kg administered IV once every 3 weeks (q3W) for 7 additional infusions. 
Since there is no expected difference in TEPEZZA pharmacokinetic (PK) between active and 
chronic (inactive) TED patients, the same dose regimen will be used in this trial. 
PR!V A TE A'-ID CONFlDENTIAL INFORMA TJON OF HORIZON THERAPEUTICS U.S.A , INC. 
Page 39 of99 


Horizon Therapeutics U.S.A., Inc. 
Date: l 9 May 2023 
8 
TRIAL OBJECTIVES 
TEPEZZA® (tcprotumumab-trbw; HZN-001) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
The overall objective is to investigate the efficacy, safety and tolerability ofTEPEZZA ® in 
comparison to placebo in treating patients with chronic (inactive) TED. 
8.1 
Primary Objectin 
The primary objective is to evaluate the effect ofTEPEZZA versus placebo on the change of 
proptosis measurements in the study eye from Baseline at Week 24 in patients with cluonic 
(inactive) TED. 
8.2 
Other Objectins 
I. To evaluate the effect of TEPEZZA versus placebo on the proptosis responder rate 
(i.e., the percentage of patients with a 2:2-mm reduction from Baseline in the study eye 
without deterioration [2:2-mm increase) of proptosis in the fellow eye) at Week 24. 
2. To evaluate the effect of TEPEZZA versus placebo on the change from Baseline at 
Week 24 in the Graves' Ophthalmopathy Quality of Li fe (GO-QoL) questionnaire 
appearance and visual functioning subscales. 
3. To evaluate the effect ofTEPEZZA versus placebo on the 
5. 
8.3 
Pharmacokinetic and Anti-drug Antibody Objectives 
1. To evaluate the PK ofTEPEZZA. 
2. To evaluate the immunogenicity of TEPEZZA. 
PRl\"ATE AND CO:WfDE1'TIAL l:>ffOR..\1A TIOJ\" OF HORIZON TIIERAPEUTICS U.S.A., INC. 
Page 40 of99 


Horizon Therapeutics U.S.A., Inc. 
Date: 19 May 2023 
8.4 
Safety and Tolerability Objectives 
TEPEZZA ® (teprotumumab-trbw; HZN-00 I) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
To assess safety and tolerability of TEPEZZA versus placebo based on: 
I. AEs 
2. AEs of special interest (AESis) (infusion reactions, hyperglycemia, hearing impairment, 
new onset inflammatory bowel disease and exacerbation of inflammatory bowel disease) 
3. Vital signs 
4. Visual acuity 
5. Clinical safety laboratory evaluations (hematology, fasting chemistry, thyroid function 
tests and HbAlc) 
8.5 
Exploratory Objective 
I. 
2. 
PRIVATE AND CONFIDENTIAL INFORMA TTON OF HORIZON Tl 11:.RAPEUTICS U.S.A., INC. 
Page 4 1 of99 


lll,ri·,<'ll Thcr-1prn1i,s l 1.::,;. ,\ .. In,. 
Dul<:. I();-. fay 20:~ 
Q 
lNVFSTlGATIONAL Pl.AN 
9.1 
Overall Trial Design and Plan 
l'r.Pl•:I.ZA -'' llcprulun,umab-tTbw; I lZN-00 1) 
f'roloClil; I IL 1'-TFP-403 
Version 5.0. A111cll(]1111.:11l •I 
This is a randomized. double-masked, placebo-conrrolled, parallel-group, multicenter trial. 
Patients will be screened for the trial within 4 weeks prior to the Baseline (Day 1) Visit. 
Approximately 57 patients who meet the trial eligibility criteria will be randomized on Day l in a 
2: l ratio to receive 8 infusions of TEPEZZA (IO mg/kg for the first infusion and 20 mg/kg for 
the remaining 7 infusions) or placebo q3W. All patients will enter a 24-week double-masked 
Treatment Period, during which trial 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 of the 24-week Treatment Period). 
All trial drug dosing will be perfonned at the clinic or infusion center under adequate healthcare 
professional supervision At any scheduled infusion, the infusion rate may be reduced, or the 
dose may be intem1pted or held based on 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 dosing. After each 
of the first 2 infusions, patients will be contacted by phone/email the following day for safety 
and tolerability assessments. An additional phone/email contact and clinic visit may be 
conducted for any patient experiencing an infusion-associated event. 
At the end of the double-masked Treatment Period (Week 24), all patients will be assessed for 
treatment response: proptosis responders (study eye has ~2-rnrn reduction in proptosis from 
Baseline without deterioration [:::2-mm increase in proptosis] in fellow eye) or proptosis 
non-responders (study eye has <2-mm reduction in proptosis). Proptosis non-responders who 
have l'Ompkted the double-masked Treatment Period may choose to receive 8 infusions of 
TEPEZZA (10 mg kg for the first infusion and 20 mg/kg for the remaining 7 infusions) in an 
open-label fashion q3W at Weeks 24, 27, 30, 33, 36, 39, 42 and 45. These patients will return to 
the clinic at Week 48 for End-of-Treatment assessments, and patients will be contacted by 
phone/email 30 davs after the Week 48 Visit for !\afety assessment. Proptosis responders, as well 
as non-responders who choose not to receive TEPEZZA in an open-label fashion, will enter a 30-
day Follow-up Period. during which trial dmg wi ll not be administered. These patients will be 
contacted by phone/email 30 days after the Week 24 \'isit for safety assessment. 
Patients who prematurely discontinue trial drug dosing prior to Weck 21 of the double-masked 
Treatment Period or prior to \Vcck 45 of thl' opcn-labd Treatment Paiod will rdurn to the 
dinic. undergo the schcduk<l End-of-Treatment assc:ssments (with the exception of the -
and enter the Follow-up Period, provided such 
contmued participation will not detrimentally affrct the health, safety and welfare of the patient 
per Investigator dete1n1ination. 
A.n o,·erview uf the trial design is pn:-scntcJ in Figure 9. 1, and details of trial activities are 
presented in Section 2. I, Schedule of Assessmenrs 
PRIVATE A>fD CO'>'FJDE:'ITL-'.L l>IFORJ\lATION OF IIORIZON THERAPEUTICS U.S.A., INC. 
Page 42 of99 


llori:wn Therapeutics U.S.A., Inc. 
Date: 19 May 202J 
TEl'EZZA <!J> (tcprotumumab-trbw; 1 IZN-00 I) 
l'rutucol: I IZN P-T l:P-403 
Version 5.0. A1rn.:11drncn1 4 
Figure 9.1 
Screen 
BL 
4 weeks 
Day I' 
?rcdose 
Schematic of Trial Design 
Double-masked Treatment Period 
TEPEZZA or l'lacebo'·' 
24 Weeks 
Open-label Treatment Period1 
(Propto;is Non-responders who Choose to Receive 
Open-I abcl TFPEZ7 A J 
• 
W3' 
W6 
W9 
Wl2 
WIS 
WI& 
W2 I W24-'·'·' W2'1' 
W30 
W33 
\V36 
W39 
W42 W45 IV48' 
3U-day 
Follow-
up 
Period' 
R:mdomization1 <--------------- Trial Weck-----------------> 
• lnlusi,,n ol' I rial drug (TEPEZ7.A or placel>o ,n double-masked Trcstmenl Period am! open-label TEPEZZ,\ in up,·n-labcl Trealmenl Period). 
nr .=-Ba.,;cli11c. q'\\V -fincc every 3 weeks: \V- \Vcck 
I. 
Patients wi II be randomized in a 2: I ratio 10 receive: 
a. TEPEZZA I 10 mg/kg on Day l followed by ).0 mglkr: q3 W for th~ rcmarnrng 7 infusions); or 
h. f'Ja<.:dm (placcl,o -.1J\\' for :tll R infiisin11s). 
2. 
Visit windows arc ±3 days for Weeks 3, 6, ?, 12, 15, I 8 and 21 of double-masked Treatment Pcnod and Weeks 27, 30, 33, 36, 39, 42 and 45 or 
open-label rreatmcnt Period, and+ 7 days for Weck 24 of double-rmskcd 'i'rcllmcn1 Pcnod. Week 48 of oµen-labd i'reatment Period <1nrl 10-,lay 
Follu w•up Period. 
All ra1ienl< will he contacted by phone/email the day after inti.Lsion for the first and second infusions durin~ the double-masked Tn:a1mcnt Period and 
during the open-label Trea1mcnt Pcnod. and lhereatler as deemed appropriate; additional phondcmail contacls will occur the day after any clime visit 
where o paticnl experiences an infusion-related itd\1Cl'SC event 
~. Pt,rie:11.: who rue rror11).,;;is nm1•rr;:;po,111~r~ iH Weck 24 of the dnuhlc--maskcd Treatment Period wi 11 be offered the oplion t<> receive X infusions of 
TEP£2ZA (IO mg/kg on Day I followed by 7.0 mgi~g for the remaining 7 infu.sions) ,n an open-label fashion. 
5. :\II patients w,11 be (Ontadcd vi~ phone or ernatl J() days(·• 7 days) following the \Verk 7,1 (r'tSporukrs .md non-responders whv ,.:ho~c not to •c<.:rivc 
operi-bt,e-1 TFPf7.7.A) or \Vtck 4~ (n<·n-r~ poorler, ""'•h<, r<·•n·iv(· {'lpt u-lihel TFPF7.ZA) Vi~il. 
9.2 
Discussion of Trial Design 
The ttial population is well-defined and consistent with the US FDA-approved indication (for the 
treatment of TED) in the TEPEZZA prescribing information. 
This trial is a randomized, double-masked, placebo-controlled, parallel-group, multicenter trial 
designed according to standard principles for adequate and well-controlled trials. The 
measurements used in this trial for the efficacy endpoints (proptosis, 
•
• md GO-QoL qut:slionnaire) are established endpoints in TED clinical trials that have been 
shown to correlate significantly with TED. 
The sampk size for this trial was dete1mined assuming that the mean difference in proptosis 
change between the 2 groups is at least 2.0 mm (clinically relevant) and the standard deviation of 
proptosis change values is 2.5 for both groups (larger than observed in Phase 2 and Phase 3 
active TED trials). A total of 57 patients (38 in the TEPEZZA group and 19 in the placebo 
group) will be enrolled in the trial to detect at least a 2-mm mean difference between the 
2 treatment groups in the change from Baseline of proptosis values at Week 24 in order to have 
81 % power at the 2-sided 0.05 level of significance. 
Given the teratogenic effects of TEPEZZA noted in animal reproduction studies and its 
mechanism of action (see the current edition of the TEPEZZA Investigator's Brochure), women 
of childbearing potential who arc sexually active with a non-vasectomized male partner are 
required to use adequate contraception and report any pregnancies for at least 6 months after the 
last dose of trial drug. Six months after the last dose, the estimated plasma concentration (0.2 
PR NATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS U.S.A .. TNC. 
Page 43 of99 


llori:wn lhcrc1pcul1.:s U.S.A .. lnr. 
Dille I 9 ~ Id\ 2\l2J 
1 "El' EZZA ® l tcprutumumalHrbw; 11 ZN-00 I) 
l'nll,lCLll: I IZNP- r El'-'10.1 
Vc1siu11 5.0. l\mcnd111t;nt 4 
~tgimL) ofreprotumumah is considered reasonably safe with a low risk oftcratogcnicity and is 
consistent with t.hc TFPFZZA US Prescribing Information. 
9.3 
Selection of Trial Population 
9.3.1 
Inclusion Criteria 
Eligible patienb must meet provide:: all the following criteria: 
1. Written in.fom1ed consent. 
2. Male or female at least l 8 years old at Screening . 
. 1. Initial diagnosis of TED 2:2 years but <10 yc:a.rs prior to Scrc:ening. Clinical diagnosis of 
stable. chronic (inal:tivc) TED, as detcm1incd by patient mcdkal records indicating a CAS 
=:::1 in both eyes for at least 1 year prior to Screening or all of the following: 
a. no progression in proptosis for at least I year prior to Screening 
b. if patient has history of diplopia due to TED, no progression in diplopia for at least 
I year prior to Screening 
c. 
no new infl:11nrnatl1t")' TED .sympll>ms for al lea.st 1 year prior tu Screening. 
4. C..\S ~I al Ilic Screening and Baseline Visits. 
5. Proptosis c::3-rnm increase from the palient"s baseline (prior to ctiagnosis ofTFD), ::is 
estimated by treating physician and/or proptosis ~3 mm above normal for race and gender. 
6. Parients must be euthyroid with the patient's baseline di~ease under control or have mild 
hypo- or hyperthyroidism (defined as free thyroxine and free lriioclothyroninc lcvcb <50% 
above or below the 1w1 mal limits) at Screening. Every effort should be made to con-eel the 
mild hypo- or hyvathyroidism promptly and to maintain the euthyroid state for the full 
duration of the !rial. 
7. Does not require immediate surgical ophthalmological intervention and is not planning 
corrective surgery, irradiation during the course of the trial. 
R. Diabetic patient~ must have HbA le ::::g_0% at Screening. 
9. Patients witJ1 a history of inflammatory bowel disease, ulcerative colitis or Crohn's disease 
must be in clinical remission for at least 3 months, with no history of bowel surgery within 
6 months prior to screening and no planned surgery dUiing the trial. Concomitant stable 
therapies for inflammatory bowel disease without modifications in the 3 months prior to 
Screening arc allowed. 
PR!\ A rE A'lD CONFIDENT:AL fNFORMA TlO:S: OF l!ORILON THERAPEUTICS U.S.A., l'iC. 
Page 44 of99 


Horizon Therapeutics U.S.A., Inc. 
Date: 19 May 2023 
TEPEZZA ® (teprotumumab-trbw; HZN-00 I) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
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 
time points (i.e., prior to each dose and throughout patient's participation); patients who are 
sexually active with a non-vasectomized male partner must agree to use 2 reliable forms of 
contraception during the trial, I of which is recommended to be hormonal, such as an oral 
contraceptive. Hormonal contraception must be started at least 1 full cycle prior to 
Baseline and continue for 180 days after the last dose of trial drug. Highly effective 
contraceptive methods (failure rate <l % per year), when used consistently and correctly, 
include implants, injectables, combination oral contraceptives, some intrauterine devices, 
sexual abstinence and vasectomized partner. 
11. Willing and able to comply with the prescribed treatment protocol and evaluations for the 
duration of the trial. 
9.3.2 
Exclusion Criteria 
Patients will be ineligible for trial participation if they meet any of the following criteria: 
I. 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. 
2. Corneal decompensation unresponsive to medical management in the study eye. 
3. Decrease in proptosis of :::2 mm in the study eye between Screening and Baseline. 
4. Prior orbital irradiation or orbital decompression in the study eye. 
5. Prior strabismus surgery. 
6. Alanine aminotransferase or aspartate aminotransferase > 3 x the upper limit of normal or 
estimated glomerular filtration rate :S30 mUmin/ 1.73 m2 at Screening. 
7. Use of any steroid (IV, oral, steroid eye drops) for the treatment of TED or other 
conditions within 3 weeks prior to Screening. Steroids cannot be initiated during the trial. 
Exceptions include topical and inhaled steroids and steroids used to treat infusion 
reactions. 
8. Any treatment with rituximab (Rituxan® or MabThera~) within 12 months prior to the 
first infusion of trial drng or tocilizumab (Actemra® or Roactemra®) within 6 months 
prior to the first infusion of tri al drug. Use of any other non-steroid immunosuppressive 
agent within 3 months prior to the first infusion of trial drug. 
9. Any previous treatment with TEPEZZA, including previous enrollment in this trial or 
participation in a prior teprotumumab trial. 
I 0. Treatment with any mAb within 3 months ptior to Screening. 
11. Identified pre-existing ophthalmic disease that, in the judgment of the Investigator, would 
preclude trial participation or complicate interpretation of trial results. 
PRlV A TE A~ CONFIDENTIAL INFORMATION OF IIORJZON TIIERAPEUTICS U.S.A , INC. 
Page 45 of 99 


Horiz0n Therapeutics U.S.A., Inc. 
Da1e: 19 Mey 2023 
TEPEZZA ® (teprotumumab-trbw; HZN-00 I) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
I 2. Use of an investigational agent for any condition within 60 days or 5 half-lives, 
whichever is longer, prior to Screening or anticipated use during the course of the trial. 
13. Malignant condition in the past 12 months (except successfully treated basal/squamous 
cell carcinoma of the skin or cervical cancer in situ). 
14. Pregnam or lactating women. 
15. Current drng or alcohol abuse or history of either within the previous 2 years, in the 
opinion of the Investigator or as reported by the patient. 
16. Known hypersensitivity to any of the components ofTEPEZZA or prior hypersensitivity 
reactions to rn.A.bs. 
17. Poorly controlled human immunodeficiency virus infection or untreated or positive viral 
load for hepatitis C or hepatitis B infections. 
18. Any other condition that, in the opinion of the Investigator, would preclude inclusion in 
the trial. 
9.3.3 
Removal of Patients from Treatment or the Trial 
.·\l l p.1ticn1s ace free- tl) withd1~1w from trial participation at any time for any reason and without 
prc'judicc' 10 tht.:1r lurther medkal care. In addition, 1he Investigator may tc1111inate a patient from 
ln.:'atment or from 1he !rial at any time. if further participation in the trial is not in the best interest 
of the p;Hicnt. 
9.3.3.l 
Discontinuation of Patients from Treatment 
The prim:-iry re:-ison for disrnntinuation from trial drug should be recorded 011 the ..:CRf using 
l of the folio\\ ing ..:at-.·gL,rii:s: 
• 
.-\E. The patient experiences an AE that imposes an unacceptable risk to the patient's 
health. or the patient 1s unwilling to continue because of an AE. Patients who disconrinue 
trial drug due to an AE will remain in the nial unless they withdraw from rhe trial for 
another reason. AFs requi1ing permanent Ilia! drng disconcinuation per the protocol 
include: 
c 
.-\ drug-related anaphylactic re-action as defined by Sampson criteria (see 
.-\ppendix I 7 .3 for clinical ~riteria ). 
o 
Diagnosed or suspe~ted i11fla1111natvr) buwd 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 c0minned altematiYe diagnosis OR endoscopic or radiologic evidence of 
ente1itis,colitis without a confinned alternative diagnosis). 
• 
Lack uf Efficacy. Discontinuatiun of trial drug due to lack of efficacy is at the discretion 
ufthe Investigator or patient and may occur if the lnYestigator determines that hial drug 
administration is nut benefiting the patient. Patients who discontinue trial dmg due to 
?RIV A TE A~ CO'ITIDENTIAL r.--iTORJ\IATTON OF I !OR!ZON TilERAPEUT!CS U.S.A., INC. 
Page 46 of99 


Horizon Therapeutics U.S.A., lnc. 
Date: 19 May 2023 
TEPEZZA ® (teprotumumab-trbw; HZN-001) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
lack of efficacy will remain in the trial unless they withdraw from the trial for another 
reason. 
• 
Lost to Follow-up. The patient does not return to the clinic for scheduled assessments and 
does not respond to the site's attempts to contact the patient. 
• 
Withdrawal by Patient/Guardian. The patient wishes to withdraw from trial drug. The 
clinical site should attempt to determine the underlying reason for the voluntary 
withdrawal and document it on the eCRF 
• 
Trial Terminated by Sponsor. The Sponsor, IRB or regulatory agency terminates the trial. 
• 
Pregnancy. 
• 
Death. 
• 
Completed. The patient completed treatment. 
Patients who prematurely discontinue trial drng prior to Week 2 1 of the double-masked 
Treatment Period or who enter the open-label Treatment Period and discontinue trial drug prior 
to Weck 45 of the open-label Treatment Period wi ll return to the clinic, undergo the scheduled 
End-of-Treatment assessments (with the exception of the 
---- and enter the Follow-up Period. Patients who discontinue due to an AE 
~ i i  
resolution or stabilization of the AE, or an adequate explanation for the 
event is obtained. 
Patients who expe1;ence an infusion-associated event after any infusion will be contacted via 
phone/email the day after the infusion. 
9.3.3.2 Rcmo, 1al of Patients from the Trial 
The prima1y reason for discontinuation from the trial should be recorded on the eCRF using 1 of 
the following categories: 
• 
Lost to Follow-up. The patient does not return to the clinic for scheduled assessments and 
does not respond to the site's attempts to contact the patient. 
• 
Withdrawal by Patient/Guardian. The patient wishes to withdraw from the t1;a1. The 
clinical site should attempt to determine the underlying reason for the voluntary 
withdrawal and document it on the eCRF. 
• 
Trial Te,minated by Sponsor. The Sponsor, lRB or regulatory agency terminates the trial. 
• 
Death. 
• 
Completed. The patient completed the trial. 
PRIVATE At'{O CO'-IFIDENTIAL INFORivlATION OF HORIZON Tll(;RAPEUTICS U.S.A., INC. 
Page 47 of99 


Horizon Therapeutics U.S.A., Inc. 
Date: 19 May 2023 
9.3.4 
Replacement Policy 
9.3.4.1 Patients 
TEPEZZA ® (teprotumumab-trbw; HZN-00 I) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
In general, patients premahi.rely discontinued from the trial for any reason may be replaced at the 
discretion of the Sponsor. Reasons for patient replacement include, but are not limited to, 
unevaluability due to the impact of an event, for example, a pandemic or a natural disaster, and 
associated restrictions on moYement and work. 
This may result in more patients being enrolled into the trial to allow for the planned number to 
be euluable for the primary efficacy and safety analyses. 
9.3.4.2 Centers 
A center may be closed and/or replaced for the following administrative reasons: 
• 
Excessively slow recruitment. 
• 
Poor protocol adherence. 
9.3.4.3 Screen f;;1iluns 
P:nicnts whl) do th'I nH.'l't all the inclusion nitcri:1 or lllCCI any of1hc cxdusion nitt:ria will be 
~·nnsidcrcd sncrn failures. Scrcl'n fai lure:_; 111ay be allowed to rc·scrc(·n for 1he trial if both the 
ln,·c:_;tig:1tor am] Spllnsor are in agn:em~11t rcg,1rding rescrcrni11g. 
9.4 
Treatments 
9 .4.1 
Treatments Administered 
The first 2 infusions of the double-masked :ind open-bbcl Treatment Periods ,,·ill be 
administered over approximately 90 minutes (but nor less than 80 minutes). A ll subsequent 
infusions will be administered O\·er approximately 60 minules (bul not less than 50 minut~s). For 
the first J infusions, patienrs will be monitored for any AEs during the infusion and for 
60 minutes after completion of the infusion. For subsequent infusions (_if no previous infusion 
reactions), patients will be monitored during and for 30 minutes after completion of the infusion. 
At any scheduled infusion, the infusion rate may be reduced or the dose intem1pted or held based 
on tolerability (see Section 9.-4.6.3.2 for details). 
9.4.1.1 Double-masked Treatment Period 
All tii al drug dosing will be performed at the clinic or infusion center under adequate healthcare 
professional superYision. On Day I of the double-masked Treatment Period, patients wi II be 
randomized in a 2:1 ratio to receive infusions of either: 
1. TEPEZZA ( 10 mg/kg on Day 1 followed by 20 mg/kg q3W for the remaining 7 
infusions), or 
2. Placebo ( q3 W for all 8 infusions). 
?RIYA TT. AND CO\'F!DEKTIAL fNFORMAT10N OF HORIZON THERAPEUTICS U.S.A., !NC. 
Page 48 of99 


Horizon Therapeutics U.S.A., Inc. 
Date: 19 May 2023 
9.4.1.2 Open-label Treatment Period 
TEPEZZA ® (teprotumumab-trbw; HZN-00 I) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
At the end of the double-masked Treatment Period (Week 24), proptosis non-responders who 
have completed tbe double-masked Treatment Period may choose to receive 8 infusions of 
TEPEZZA (10 mg/kg for the first infusion followed by 20 mg/kg q3W for the remaining 
7 infusions) in an open-label fashion. 
9.4.2 
Identity of lnvestigational Product 
9.4.2. I TF:PF:ZZA 
TEPEZZA (teprotumumab-trbw; HZN-001) is a fully human anti-JGF-lR mAb. TEPEZZA will 
be provided in single-dose 20-mL glass vials as a freeze-dried powder containing, in addition to 
the drng substance . .,,mol/T , histidine-histidine chloride,.nmol/L trehalose and -
polysorbate 20 (w/v). 
Prior to administration., each vial containing 500 mg TEPEZZA freeze-dried powder will be 
reconstituted w ith IO mL of sterile water for injection. The resulting solution will have a 
concentration of 47.6 mg/mL teprotumumab antibody. Reconstituted TEPEZZA solution will 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 Placcho 
Placebo will consist of a nonnal saline (0.9'% NaCl) solution and will be administered in I 00 mL 
or 250 mL infusion bags, as appropriate, per weight-based dosing volumes. 
9.4.3 
Labeling 
T,ial drug packaging ,,viii be in compliance with Sponsor standard procedures and will meet all 
local requirements. 
Upon arrival of i1wcs!igational products at the site, the invcstigational unmasked pharmacist (or 
designee in accordance with institutional policies and local regulations) should inspect them for 
damage and verify proper identity, quantity, integrity of seals and temperature conditions and 
report any deviations or product complaints to the unmasked monitor/Sponsor upon discovery. 
9.4.4 Storage 
Recommended storage conditions for the freeze-dried TEPEZZA drug product are between 2°C 
and 8°C (36°F to 46°F), protected from light. 
The combined storage time of reconstituted TEPEZZA solution in the vial and the diluted 
solution in the infusion bag containing 0.9% Sodium Chloride Injection, United States 
Pharmacopeia (USP) is a total of 4 hours at room temperature 20°C to 25°C (68°F to 77°F) or up 
to 48 hours under refrigerated conditions 2°C to 8°C (36°F to 46°F) protected from light. If 
refrigerated prior to administration, allow the diluted solution to reach room temperature prior to 
PRJV A TE AND CONFIDENTIAL fNFORMA TIO!\ OF HORIZON TIJERAPEUTICS U.S.A., rNC. 
Page 49 of99 


llt,riz~•n rhrr.1prn111.:s ll.~.A. Inc 
0 .!lc: 1--> :--fay 2ll~_; 
l'l;PEZZ.-\-1l> lltprotumum:1b-lrbw: HZN-00 I) 
l'roloc,)I: II/.NP-TFl'-403 
\ -,r,i,m 5.0. A111,;11u111<.:11t 4 
infusion. An lm·estigatioml Product Manual will be provided to all sites co funher describe these 
prucesses in detail. 
At the clinic, all TEPEZZA must be scored in a secure area wi1J1 limited access, and a daily 
temperamre log of the drug s1orage rcfrigerator(s) will be maintained every working day: 
de\'iacions from the specified ccmperalme range w ill lie rep0rted as protocol deviations. 
9.4.S 
Drug Accountahility 
The Principal !J1Ycstigator at c-ach site is rcsponsibk for the Gontrol of all trial drugs and 
dekgatiug infusion bag preparation and drug accow1tability resp0nsibilities to an unmasked 
phanuacist (or designee in accordance with instimcional policies and local regulations). who 
must maimain adequate records of the receipt and disposition of all trial drugs shipped to the site. 
Records will inclu,k receipt dates, condition at time of receipt. quantities received, quantities 
dis-pensed, quantitit'S returned or destroyed and the identification numbers of the patients who 
rec-eiYed trial dmg . 
.-\;; pem1itted by site policy. all emi,1y. p:1rtinlly empty 3nd Full vi:ils of trial drug must be 
retained by the sit, under locked storage until drug accou11t1bility has been cornpktcd. 
Pcriodic 1lly tltr(1ugl10ut !hi.' (rial anJ at thl.' ,·tll11.:lusio11 o f !he trial. invl.'ntory ch'-·cks a11d 
:ILYounubility of 1ri,1l 111,1tcria ls will be c011du,·tcJ by an u11111askl.'J representative of Ilic Sponsur. 
Once a,,·ounu bility is compkted, the Sp0nsor's rcpre.sentative will either aullll)rize oniiitc 
destruction or the return of trial drug tall used, partially used and unused vials) to PC l C linical 
Services. The completed Drug Accountability and Drug Return/Destruction Record(s) will be 
returned to tbe unmasked Sponsor's representative. The l11vestigator's copy of the Drug 
Accoumability and Drug ReturnD estruction Record(s) must document accurately the return 
and/or destrnction of all trial drug and be maintained by the unmasked pham1acist or designee. 
9.4.6 
Trial Drug Administration and Timing of Dose for Each Patient 
9.4.6.1 
Description of Clinical Supplies 
viii surply trial drng to clinical sites. Ancillary supplies for dosing 
(i.e .. infusion bags containing nom1al saline, infusion administration sets, S)Tinges, needks, 
akohol swabs, gauze pads, bandages and biohaza.rd containers for safe storage of used needles, 
syringes. infusion bags and infusion administration secs) will be provided by the site. 
9.4.6 . .! Determination of Dose Volume 
The rnlnme of trial drng to be administered will be determined by the electronic data capture 
(EOC') system and will be based on the patient's dose and body weight. The first dose of 
double-masked rreanuem and open-label tJTatmcnt will be· IO mg/kg, and subsequem dOSl'.S will 
be 20 mg/kg. Weight will bl~ measured as described in Section 2.1 . The dose on Day I and 
Wceks :;_ 6 and 9 of the doubk-masked Treatment Pe1i od will be based on the Screening weight; 
weight measured at ¥:eek 9 will be used in dose calculations ar Weeks 12, 15, 18 and 21 . The 
dose on Weeks 24, 27, 30 and 33 of the open-label Treatment Period will be based on the 
?RIVA TE A'.\7) CO'IFmE1' .. Tl-\L NFOR.\IA TlON OF HORJZON TllERAPEUTICS U.S.A., INC. 
Page 50 of 99 


1101 izo11 Therapeutics U.S. A., Inc. 
Date: I') May 202J 
Tl J'l:JZA "' (tcproturnumab-trbw; f IZN-00 I) 
Prulocol: I IZNP-TEP-403 
Vi;rsion 5.0. Amendment 4 
Week '.2'1 weight; weight measured at Week 33 will be used in dose calculations at Weeks 36, 39, 
42 and 45. 
9.4.6.3 Details Concerning Timing and Dose Administration 
9.4.6.3.1 Preparation and Administ.-ation ofTEPEZZA 
TEPEZZA will be prepared by lhc silc pharmacist (or designee in accordance with institutional 
policy and local regulations) who is not masked to the identity of the trial drug. Each vial of 
TEPEZZA will be reconstituted with IO mL of sterile water for injection. The resulting solution 
will have a concentration of 47.6 mg/mL teprotumumab antibody. Prior to administration, the 
reconstituted TEPEZZA solution must be further diluted in 0.9% (w/v) NaCl solution by the site 
phannacist or designee. 
Doses less than 1800 mg will be administered in a total infusion volume of 100 mL, and doses 
1800 mg and above will be administered in a total infusion volume of 250 mL. To maintain a 
constant volume in the infusion bags, a volume equal to the volume of TEPEZZA to be p laced 
into the infusion hag will he first removed from the infusion hag using a sterile syringe and 
needle. The appropriate volume of reconstituted TFPFZ7.A solution hased on the patient's dose 
:ind body weight will be withdrawn from the reconstituted TEPEZZA vial(s) and transferred into 
nn fV bag containing normal s::iline (0 9% N::i('I). 
The infosion is to be administered at room temperature (20°C to 25°C [68°F to 77°F]). 
The combined storage time of reconstituted TEPEZZA solution in the vial and the diluted 
solution in the infusion bag containing 0.9% Sodium Chloride lnJection, USP is a total of 4 hours 
at room tcmpcrahnc 20°C to 25°C (68°F to 77°F) or up to 48 hours under refrigerated conditions 
2°C Lo 8°C (36°F to 46°F) protected from light. lf refrigerated p1ior to administration, allow the 
diluted solution to reach room temperature prior to infusion. 
No incompatibilities between TEPEZZA and polyethylene, polyvinyl chloride, polyurethane or 
pulyolcfin bags and IV administration sets have been observed. Exposure of lhe solution lo direct 
sunlight should be avoided. 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior co administration, whenever solution and container pem1it. Upon reconstitution, TEPEZZA 
is a colorless or slightly brown, clear to opalescent solution that is free of foreign particulate 
matter. Discard the solution if any pa1tieulate matter or discoloration is observed. 
Do not freeze the reconstituted or diluted solution. 
Partially used vials should not be re-used. 
The first 2 infusions of the double-masked and open-label Treahnent Periods will be 
administered over approximately 90 minutes (but not less than 80 minutes). All subsequent 
PRNATE AND CONFIDENTIAL INFOMIATION OF HORIZON THERAPEUTICS C.S.A., INC. 
Page 51 of99 


lhitiz,,n rhffaf•,·ut1,·s U.~.i\ .. lm·. 
Ouk 
l 9 t-. la\ 21)23 
rL:l' l.:JJ.:\ ,~, l tcprotum11m:1b-trbw; I l ZN-Oll I) 
l'ro1ocol: HZNl'-TEl'-40.1 
Ycrsion 5.0. Amrndmcnl 4 
infusions will be administered O\'er approximately 60 minutes (but not less than 50 minutes) in 
the al,sence 0f any infosion-asscici:lted e\'ents. For the first 3 infusions. patients \.Vil\ be 
monitored for nny .\Es du.ring the infos ion :1nd for 60 minutes :1ftcr completion of the: infusion. 
For suhscqucnt infusions (ifno prc\'i0us infmion reactions). patic·nls will be monitored during 
nnd for 30 minutes after complcrion of the infusi~rn. 
9.4.6.3.2 Dose Modifications, Incerruptions and Ddays 
All dosing instrnctions are applicable for TEPEZZA and placebo ad.mi11is1rarion. 
Parients will be evaluated for safety throughout the trial. For the first 3 infusions, pati.:nts will be 
monitored for any :\Es during the infus ion and for 60 m inutes afler completion of the infusion 
for i111111cdiatc infusion-associated events (e.g., transient increase in blood pressure, feel ing hot, 
tachycardia. dyspnea. headache and muscular pain) and delayed infusion-associated events 
(e.g., rash). for subsequcnc infusions (ifno prc-vious infusion reactions), patients w ill be 
monicorcd during and for at lease 30 minutes after cornplerion of the infusion. 
If immeJiarc infusi~rn-nsso~·iaccd c,·c·nts me noted. tltc i11ti.1sion rate may be slowed or interrupted 
and syrnpll)matic tn.:atmcm (e.g .. antipyrctics, :1mihistami11es, bda-agonists, glucocorticoids. 
oxygen. 1\. tluid) may be administcn.:d, as necessary. Vital signs (temperature, blood pressure, 
pulse and respiratory rak) will be monitored every 5 minutes unti l siable and then every 
l 5 m1nmes for 2 additional detenninations. The in fusion may be rescarted upon complete 
resoltnion of symptoms: however, TEPEZZA dosing will be pennanently discontinued if the 
event is an anaphylactic reaction. 
If delayed infusion-associared e\'ents are noted. paliems may continue dosing al the Investigator's 
discrccion: however. if a rash worsens following repeated dosing or other signs of serum sickness 
(e.g .. delayed fever. myalgias. anhralgias) are present, TEPEZZA dosing will be pennanently 
discominued . If an infusion-associated event is experienced after patients are discharged from 
the site. the Investigator is to be contacted as soon as possible. 
Fallowing the appearance of either immediate or delayed infusion-associated events. patients 
who receive subsequent doses may be pre-treated with diphenhydramine ( 1 to l .25 mg/kg TV: 
maximum of 50 mg), ranitidine (50 mg IV). farnotidine (0.5 mg/kg fV). dex:1methasonc 
(0.4 mg.kg IV: maximum of20 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 strut of the infu:;ion tlu·ough 60 minutes after 
completion of the infusion. 
In general, the decision co continue dosing should take into consideration the potential benefit 
and tisk t0 a patient. 
Increase in blood glucose is a knov.11 AE observed in previous clinical trials with TEPEZZA and 
other IGF-1 R 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 
PR[VA TE A'.'-1'1) CO'IFfDE'.',.~P.L l'.Tf'OR.MATTON OF HORTZ0:--1 THERAPEUTICS U.S.A., INC. 
Page 52 of99 


l lori-zo11 Therapeutics U.S.A., Inc. 
Dale: 19 May 202.1 
TEPt--:Z/,A ~ (lcprotumumab-trbw; 1 IZN-00 I) 
l'rutucol IIZNl'-TU'-'10J 
Vcr~iorr 5.0, /\111c11Jmcnl 4 
patient in the trial, the next scheduled infusion visit may be skipped to allow modified 
anti-diabetic t.rcatment to take effect and hyperglycemia to return ro mild/moderate level before 
dosing. The patient would then be dosed at the next scheduled visit (i.e., 6 weeks after the 
previous infusion). fa:;Ling blood glucose levels must return to mild/moderate severity before the 
next scheduled infusion. The above process of with.holding a scheduled infusion is recommended 
10 0ccur at most twice during the trial for a single patient, after which dosing should continue 
only if the benefit of receiving continued ln;atment clearly outweighs the risk. 
Any changes to the scheduled dosing interval (q3W) or adjustments in the infusion rate should 
be reported to the Sponsor/CR 0 . 
9.4.7 
Method of Assigning Patients to Treatment Groups 
A randomization schedule will be generated by the CRO prior to shipment of any trial drug to 
the clinical sites. On Day I of the double-masked Treatment Period, once all Baseline procedures 
other than administration of trial dmg have been completed, the authorized site personnel will 
use the EDC system to randomize the patient. The unmasked pharmacist or designee will then 
use the EDC system to obtain dosing information ::md dispense the appropriate trial drug. 
9.4.8 
Masking 
The pharmacists or designces responsible for preparing the TEPEZZA or placebo solutions for 
IV administration will not be masked to the identity of the trial dnig. Pharmacists/designees will 
provide trial drug in infusion bags (fully diluted for administration) lo site personnel with 
appropriate masked labels. The patient, Investigator. and all other site personnel will be masked 
to the treatment being administered. 
The trial mask should be broken only if the safety of a patient is at risk and the treatment plan 
depends on which trial drug he or she received. Unless the patient is at immediate risk, the 
Investigator mu!-t make diligent attempts to contact the Sponsor or Sponsor's designee before 
unmasking the patient's data. The Investigator must use the Randomization and Trial Supply 
Management (RTSM) application to unmask the patient's data. Tf a patient'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 or designee will unmask the identity of the trial drug for an unexpected, 
Jrug -related SAE for submission to health authorities and IBB/Independent Ethics Committee 
according to applicable regulatory requirements. However, the results will not be shared with 
other Sponsor representatives or staff at investigative sites. Details of patients who are unmasked 
during the trial will be included in the clinical study report. 
Unmasking for independent pharmacological analysis of biological samples or SAE reporting 
will be perfonned according to procedures in place to ensure integrity of the data. 
PRJV A TE AND CONFIDENTIAL INFOR.MA TJON OF HORIZON THERAPEUTICS U.S.A , !NC. 
Page 53 of99 


!l(,ru,,n rt1,·r:1pcu11,s U.S .A .. Inc:. 
D.itc 19 l\la\ 20~:; 
l'El'EZZA -ll; l 1cprotumum11b-1rbw; HZN-00 I) 
f'rot,,col: I I ZN P-Tl:.P-40J 
Vcrsio11 5.0, Amc11Jrrn:nt 4 
All inwstigatiw sire staff directly inv0lved in this trial. except for unmasked pharmacy 
pers(1nnel. will remain masked from Screening through analysis of the open-label treatment data 
and all :-ire cl0se-out ,,isits. The Sponsor ::md its dcsignees may be umnaskcd after the 
double-masked Treatment Period database lock. 
9.4.9 
Concomitant Therapy and Rcstd ctcd Medications 
Local supportive measures for TED, simple analgesics (e.g., acetaminophen, non-steroidal 
anti-inflammatory therapies) and medications,supplemems for conditions other than TED are 
pem1irted during the rrial. 
9.4.9.1 Concomitant Therap)' 
Topical :md inhaled con icosreroids for cunditions other than TED are allowed; however, oral 
corticosccrnid usc: during the t1ial is restricted to patients who experience infusion-associated 
:\Es. 
Symprornatic treatment le,g., antipyTetics, antihistamines, beta-agonists, glucocorticoids, oxygen, 
l\/ fluid) may be administered to patients who experience immediate infosion-associated AEs. 
Following the appearance of either immediate or delayed infosion-associated events. during 
subsequent dosing of trial drug patients may be pre-treated with diphenhydramine 
(] to 1.25 mg kg 1\': maximum of 50 mg). ranitidine (50 mg TV), famotidine (0.5 mg/kg lV). 
dexamethasone (0.4 mg/kg IV: maximum of20 mg) and/or acetaminophen (500 mg). 
9.4.9.2 Restricted Therapy and Medications 
Pacients with a previous orbital irradiation, orbital decompression or strabismus surgery or who 
have a planned orbital irradiation or surgery for TED during this trial are not eligible for the trial. 
In addition, oral corticosteroids, immunosuppressive agents, investigational agents and illicit 
drug/alcohol use are restricted, as shown in Table 9.1 . 
PRIVATE A'.'D C0),,,'FfDEN7'1AL NFORMA TIOJ\ OF HORIZON THERAPEUTICS U.S.A., INC. 
Page 54 of 99 


llmizon Therapeutics U.S.A., Inc. 
[htc: 19 May 202.l 
TEPEZZA ® ( teprotumumab-trbw; I I ZN-00 I) 
l'rotocol: HZNT'-TEP-40.1 
Version 5.0, Arm.:11dmcnt 4 
Table 9.1 
Restricted Medications and Therapies 
Mcdicationffhcrnpy 
Orbital irradiation, orbital decompression or 
strabismus surgery 
Steroids 
Non-steroid eye drops 
Rituximab (Rituxant or MabThera<I'') 
Tocilizumab (Actemra® or Roaetemra®) 
TEPEZZA 
Monoclc,nal antibody 
Non-steroid immunosuppressive agent (other than 
ritu,ximab or tocilizurnab) 
lnvestigational agent 
l'ieomital Fe receptor (FcRn) agents 
Illicit drng/alcohol usc 
Restricted Dose or Time Period 
Any history or planned irradiation or surgery during the trial. 
Steroids (intravenous or oral) and steroid eye drops within 
3 weeks prior to Screening. Systemic steroid use 
(intravenous or oral) and steroid eye drops arc nut lo be 
initiated dw-ing the trial; however, topical and inhaled 
steroids an: allowed. Steroids for the tTcalmcnt of infusion 
reaction arc allowed. 
Non-steroid drops, such as saline or mcthylcellulose, 
antihistamines and vasoconstrietors are allowed but must not 
be used on the day of a clinic visit. 
Within 12 months prior to the first infusion oft1ial drug and 
during the trial. 
Within 6 months prior to the first infusion of trial drug and 
during the trial. 
Any prt'vious treatment with TEPEZZA or teprotumumab, 
including, but not limi ted to enrollment in this trial or 
participation in a prior TEPEZZA trial or program. 
Within 3 months prior to Screening. 
Within 3 months prior to the first infusion of trial drug and 
during the trial. 
Within 60 days or 5 half-lives, whichever is longer prior to 
Screening or anticipated use during the trial. 
Du.ring the trial. 
History of abuse within the past 2 years or abuse during the 
trial. 
It is recommended to avoid ototoxic medications and medications that may cause muscle 
spasm/cramps during the trial. 
All concomitant treatment (for TED and other conditions) must be documented in the eCRF. 
9 .4.10 Treatment Compliance 
The Principal 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. 
PRrYATE AND CONFIDENTIAL INFORMA T!ON OF HORIZON THERAPEUTICS U.S.A., INC. 
Page 55 of99 


11,)nwn rhcrnpcuti..:s U .S.A .. In.:. 
Oak. 19 :'\lav 2023 
TEPEZZA ;11, llcprotumumab-trbw; HZN-00 l) 
l'rOlocol• llZNl'-llY-40J 
\icr~ion 5.0. Amcn<lmcnl 4 
All infusions of trial drug will be administered at the clinic or infusion center under adequate 
healthcare professional supervision Calculated trial drng d0se and start and stop times of the 
infusions will be recorded in the cCRF. 
An inventory of the trial dnig supplies will be performed by the authori7.ed site designcc and 
recorded onto the Drug Accountability Log in the patienl's sou1cc documcuL n:cords or 
equivalent. 
9.5 
Effirncy, Phllrmacokinctic, Safet) and -
Variables 
l'hc Sd1cdule of Assessmcnt.s is pro\·ided iu SccL1on 2.1. 
9.5.1 
Etlicacy \' ariables 
At the Baseline (Day I) Visit, the "study eye" (i.e., the eye with most significant proptosis) will 
be identified. 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 efficacy 
endpoint. 
Efficacy wi 11 be assessed by proptosis (measured as proptosis evaluation of the Clinical 
Measures of 
· 
· 
· 
· 
· 
9.5.1.1 Proptosis 
Proptosis assessments will be performed using a Hertel exophthalmometer provided by the 
Sponsor for consistency in measurement and (e.xcept when strictly unavoidable), the same Hertel 
instrument and same observer should be used at each evaluation for the duration of the trial. 
Additionally, the same intercanthal distance must be used on each occasion. Instructions for the 
measurement of proptosis are included in Appendix 17.4. 
Proptosis will be measured for each eye at Screening, Day I and Weeks 3, 6, 12, 18 and 24 (or 
premature withdrawal I [PWI]) (all patients) and Weeks 27. 30. 36. 42 and 48 (or premature 
withdrawal 2 [PW2]) (proprosis non-responders who elect to receive open-label TEPEZZA) (see 
Section 2.1 ). Patients who ha\·e a 2:2-mm decrease in proptosis from Screening to Baseline in the 
srudy eye are nol eligible for randomization. l\leasurements will be recorded on the Clinical 
l'vkasures of Se\"erity eCRF under exophthalmos. 
9.5.1.2 
PRr,AT':: A}TI) CO"IFfDE\'Tl-',L fKFORMATlON OF IIORIZ0'-1 THERAPEUTICS U.S.A, INC. 
Page 56 of99 


I lorizon Thcrnpcutics U.S.A., Inc. 
L>atc: 19 May 202J 
Tahir 9.2 
Clinical Measures of Severity 
TEl'EZ/Xi<> (tcprntumumab-trbw; HZN-00 I) 
l'rutucol: f-l ZNP-T EP-'103 
Version 5.0, A111cndrncnt 4 
on Day I and Weeks 3, 6, 12, 18 and 24 (or PWI) (all 
paLients) and at Weeks 27, 30, 36, 42 and 8 (or PW2) (proptosis non-responders who elect to 
receive open-label TEPEZZA) (see Section 2.1 ). Patients will be asked to 
9.5.1.5 Clinical Activity Score 
The CAS assessment (Table 9.3) will be completed at Screening, Day I and Weeks 12 and 24 (or 
PWl) (all patients) and Weeks 36 and 48 (or PW2) (proptosis non-responders who elect to 
receive open-label TEPEZZA) using the 7-item European Group on Graves' Ophthalmopathy 
amended CAS (see Section 2.1 ). 
PRN Al£ ANl) CONFIDEJ-.'TTAL fNFORMA TION OF I IORIZO}I TIIERAPEUTICS U.S.A., rNC. 
Page 57 of99 


H0ri:wn n 1rr Jp.:u1.1.:s U.S. A.. In,. 
Dale: l 9 !'. fay 2L1.:_; 
Table 9.3 
Item 1 
Tf: PELZ..\ .g, l leprotumunnb-trbw; HZN-00 I) 
l'nllocol: 11/.Nl'-TEl'--!OJ 
Ycrsion 5.0. Amrn<lmrnl 4 
To promol~ consistency in data collection across sites, all Investigators will be provided with 
training :ind copies 1..1fthc Clinical l\fanifcstali1..1n~ chapter in (iranis · Orbitoparhy: A 
Jfulrldi:s,·iplinan Apprv,1<.:h - ~uestions Jnd Answers. except when strictly unavoidable, the 
same observer should rnnduct each C.-\S eYalualion for the duration of the trial. 
vers10n or the quest1onna1re 1s included in Appendix 17 .5. 
9.5.2 
Pharmacokinetic Measurements 
I3lood samples will be collected in 5-mL scrum separator collection tubes to evaluate PK at the 
following visits: pre- and post-infusion on Day I, Weeks 3 and l 2 of the double-masked 
Treatment Period (all patients) and at Weeks 24, 27 and 36 (non-responders who elect to receive 
open-label TEPEZZA); a single sample will also be collected at Week 24 (or PWI) of the 
double-masked Treatment Period (proptosis responders and proptosis non-responders who elect 
not to receive open-label TEPEZZA) and Week 48 (or PW2) of the open-label Treatment Period 
(non-responders who elect to receive open-label TEPEZZA) (see Section 2.1 ). 
PK samples will be collected, processed and stored at ~-70°C at the site until shipment to the 
ccntrnl laboratory ~ - The central laboratory will store the samples at 
~-70°C until shipm~
oratory for testing. 
Instructions for processing, handling, storing and shipping of PK samples will he detailed in a 
laboratory manual that will be provided to each site prior to site initiation. 
PRIVATE AND c o:--..'FTDENTl."'L {>;FORMATIOJ\ OF l!ORIZON TIIERAPEUTICS U.S./\. INC. 
Page 58 of99 


Horizon T hcrap.:uti,;s U.S.A, Inc 
Date: I<) May 2023 
9.5.3 
Snfcty Variables 
TEl'EZZA'P> (tcprotumumab-trbw; 1 IZN-00 I J 
l'rolocol: IIZNP-TEl'-'103 
Version S.O, Amc11dmc11I '1 
Safely will be assessed via AE (including AES ls) and concomilant medication use monitoring, 
immtmogenicily testing, best-corrected visual acuity, vital signs, clinical safety laboratory 
evaluations ( complete blood count and fasting chemistry [including thyroid panel and I lbA I c ]) 
and pregnancy testing (if applicable). 
9.5.3.1 
Adverse Events 
9.5.3.1.1 Definitions 
9.5.3.1.1.l Adverse Event Definition 
According to !CH, an AE is any untoward medical occurrence in a patient or clinical 
investigation subject administered a phannaceutical product and that does not necessarily have a 
causal relationship with this treaLment. 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 the trial are to be reported as AEs. New findings 
reported from the on-trial visual acuity assessments will not be repmted as AEs if, according to 
the Investigator, the abnormalities are related to TED and not considered related to the trial drug. 
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 patient's condition at1ributablc to the 
cfo:ease for which the t1ial drng is being studied (i.e., TED) and may be an increase in the 
severity of the disease under study and/or increase in the symptoms of the disease. The 
development of worsening proptosis may be considered as disease progression and not an AE. 
Events that are unequivocally due to disease progression should only be reported as AF.s if they 
fulfill any of the SAE criteria or are the reason for discontinuation of trial drng. 
9.5.3.1.1.2 Serious Adverse Event Definition 
A treatment-emergent adverse event (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 trial, including 
deaths that appear to be compktcly unrelated to the trial drug (e.g., due to car accident). 
• 
Life-threatening adverse experience. An AE or suspected advi.::rse reaction is considered 
life-threatening it: in the view of either the Investigator or the Sponsor, its occurrence 
places the patient at immediate risk of death. It does not include an AE or suspected 
adverse reaction that, had it occurred in a more severe fo1m, might have caused death. 
PRCVATE AND CONFIDENTIAL INFORMATION OF IIOR IZON THERAPEUTICS U.S.A., INC. 
Page 59 of99 


ll(>n1.,1n Thn:ipr:11t1c, l l.S.A .. In.:. 
D:itc: 19 i\!a,· 202_, 
• 
Persi~tenr or significant dis:-ihility or incapacity. 
r t--:Pl!/J.A ,s, ltcprutumunub-tTbw; H ZN-00 I) 
l'ro(ocol: I IZNl'-TEP~tOJ 
Ycrsio11 5.0. Arrn:mJmcn( 4 
• 
lnratient h,~sritalization c,r pr0long:1ti0n of :rn existing hospitalization. 
• 
Congenital an1.rn1aJ~, or bi1ih dcfec.t. 
• 
A.nother medically impo11am event that. according to appropriate medical judgment, may 
require medical or sw-gical interYention to prevent 1 of the outcomes listed above. 
Surgical procedures or 0ther therapeuric inten·entions themselves are not AEs, but the condition 
for which the surgery imervcntion is required is an AE and should be documented accordingly. 
Elective surgeries char require hospitalization and treatment received at an emergency room or 
similar faci lity will not be considered as SAEs unless I of the definitions of an SAE listed above 
1s met. 
In addition, a hospitalization for planned procedures is not considered an AE unless the 
hospitalization becomes prolonged. An emergency room visit less than 24 hours in dura1ion is 
nm considered a lwspitalization. 
9 .5.3.1. 1.3 I\" on-Sci-ious Adn rse Event Definition 
.-\ non-seriou~ i\E includes any AE th:1t is not included in the SAE definition. 
95.3. 1.1.4 l'nexpected Adverse Event Dd inition 
An AE or suspec!~i adwrse reaction is considered unexpected if it is not listed in the Rcfrrcm:c 
S.iti::ty lnfon11:1tion section of the Investigator· s Brochure or is not listed with the specificity or 
SC\ eriry tb,lt has been observed. Unexpected, as used in this definition, also refers to AEs or 
suspected ad\'crsc readions that ;.ire mentioned in the Reference Safety Jnfonnation as occuning 
with a class of drugs or as anticipati.'d from the phannacological properties of the drug but are 
nor specifically mentioned as occuning with the particular drug under investigation. 
9.5.3.1.1.S Adverse Events of Special Interest 
Based on previous clinical expetience in TED. the following will be AESTs for this trial: 
• 
Infusion reactions 
• 
H yperglyccmi:i 
• 
Muscle spasms 
• 
Hearing impainnent 
• 
New onset inflammatory bowel disease and exacerbation of inflammatory bowel disease 
Risk of Hypersensitivity {Infusion-related events) 
• 
Adminisrracion of mAbs may cause infusion-related symptoms, such as fever, chills, 
hypotension, shortness of breath, skin rash and headache. Such reactions typically occur 
PRIYATE A:--.U CO:',:FJDENTIAL NFORMATJOK OF HORIZON THERAPEUTICS U.S.A., INC. 
Page 60 of99 


I lorizon Therap-.utics U.S.A .. Inc. 
Date: 19 May 2023 
Tll'EZZA'~' llcprotumumab-trbw; 111/.N-OO I) 
l'rotocol: 1 IZN P-Tl:-,l'-403 
V,;rsion 5.0, Amendment 4 
during or shortly after the infusion of mAbs and are usually associated with the first 
infusion. Tl1eir incidence and s1.:verity typically decrease with subsequent infusions. 
Severe infusion-related reactions might be clinically indistinguishable from anaphylaclic 
reactions. 
• 
fnfusion-related events observed wirh teprotumumah to date have not been anaphylactic 
in nature. rlowcvcr. because of the protein nature ofteprotumumah and the potential for 
infusion-related readions and hypersensitivity reactions, teprotumumab should be 
administered in a setting with emergency equipment and staff who are trained to monitor 
medical situations and respond to emergencies. For the first 3 infusions. patients should 
be monitored for any events during infusion and for 60 minutes after completion of 
infusion. For subsequent infusions (the fourth dose and beyond), patients who have not 
previously experienced an infusion reaction should be monitored during the infusion and 
for at least 30 minutes after the infusion. 
• 
Patients who exhibit immediate hypersensitivity reactions or infusion-related reactions 
during an infusion oftcprotumumab should have the infusion interrupted or the infusion 
rate slowed. Symptomatic treatment, e.g., antipyrctics, antihistamines and/or 
corticosteroids, oxygen, beta agonisls and IV fluids, should be administered to the 
patient. Following an immediate hypersensitivity reaction or infusion-associated reaction, 
vital signs (temperatme, blood pressure, pulse and respiratory rate) will be monitored 
every 5 minutes until stable. and then every 15 minutes for 2 additional dctcnninations. 
The infusion may be restarted upon complete resolution of symptoms except in the case 
of patients wbo experience an anaphylactic reaction of life-threatening intensity; these 
patients should be removed from the trial. 
• 
1n general, the decision to keep a patient on trial treatment with tcprotumumab should 
lake into consideration potential risks and benefits to the patient. Prior to future infusions 
of teprotumumab, these patients may be premedicatcd with JV diphenhydramine 1 to 1.25 
mg/kg (maximum 50 mg), JV ranitidine 50 mg. IV famotidine 0.5 mg/kg, IV 
dexamethasone 0.4 mg/kg (maximum 20 mg) and/or acetaminophen 500 mg. Tn addition, 
all future infusions should be administered over 90 minutes. Vital signs should be taken 
every 15 minutes during the infusion through 60 minutes after infusion completion. 
• 
Patients who experience delayed-type hypersensitivity reactions (e.g., skin rash) may 
remain in the ttial at the discretion of the Investigator and, prior to all future infusions of 
teprotumumab, may be premedicated with the above medications (diphenhydramine, 
ranitidine, famotidine, dexamethasone and acetaminophen). However, if a rash worsens 
PRIVATE AND CONFIDEl\TIAL fNFOR.i\1ATION OF HORIZON TIIERAPEUTICS U.S.A., INC. 
Page6 l of99 


Horizon Therapeucics U.S.A., Inc. 
Daie 19 May 2023 
TEPEZZA ® ( teprotumumab-tTbw; H ZN-00 I) 
Protocol: HZl\TP-TEP-403 
Version 5.0, Amendment 4 
following repeated dosing or other signs of serum sickness ( e.g., delayed fever, myalgias, 
arthralgias) are present, trial drug dosing will be permanently discontinued. 
Risk of New Onset or Exacerbation ofIBD 
• 
In Phase 2 TEDO IRV, 2 teprotumumab-treaced patients with a history ofIBD reported 
serious TEAEs (Diarrhoea in l patient and Inflammatory bowel disease in l patient) that 
led co discontinuation of trial d.rng. Based on these serious events and the fact that a 
placebo pariem with Crohn's disease did not experience these types of events, patiems 
with a history of IBD are either excluded from current trials or must be in clinical 
rem1ss1on. 
• 
Patients who experience progressive and persistent diarrhea or other IBD symptoms, such 
as bloody stools or abdominal pain, should undergo prompt evaluation to exclude new 
onset or exacerbation of preexisting IBD or other serious conditions. If possible, 
medications known to cause diarrhea, such as laxatives and magnesium shall be avoided. 
If new on.set or CXJ('Crbation of IBO is suspected, teprotumumab shall be discontinued. 
Risk of Hyperglycemia 
• 
ln nonclinical .studies. there was no in rit.ro cross-rc::a.;tivity ofteprotumumab with the 
insulin receptor. Clinical t1ials in Active TED have shown a higher incidence of 
hyperglycemia in patient~ treated with teprotumumab compared to pbcebo. Patients with 
pre-existing diabetes mellirus (who ,,en; undl'.r approprial(' glyccmic control upon trial 
entry) or impaired glucose tolcra11cc:: were more likdy lLl experience an event of 
hyperglycemia after exposure to teprorumumab. 
Management of Patients with Diabetes MeUitus 
• 
Patic>nts with known contro lled diabc>tes melli11.1s are allowed to participate in tria ls with 
tcprommum;1b. llbAlc lc,·els should be monitored every 6 weeks in thc:-c patients. 
• 
ln vestiga1ors are strongly encouraged to adjust their patients' diabc::tes management to 
maintain HbAlc levels :S8%. In the event a patient's HbAlc level rises to >8%, w hile in 
the tria l, c.he Investigator must :-issess the risk versus benefit for the patient to remain in 
the rriJ I. Ji:;.:uss \,·ith sponslir's rncdieal monitor or <lc:signcc, and UlKUmcut. the decision. 
Management of Hyperglycemia 
• 
Fasting glucose levels should be tested at Baseline. Random non-fasting glucose levels 
should be monitored at a minimum as per visit schedule. 
PKJV ATE AND CONFIDENTIAL INFORMATION OF IIORIZON Tl IERAPEUTICS U.S.A., INC. 
Page 62 of99 


I lorizon Therapeutics LJ.::..A., Inc. 
l>atc: 19 Muy 202..\ 
TEl'EZZJ\ '1', (tc.:protumumab-Lrbw; I IZN-00 I) 
l'rolucul: HZNl'-TFl'-40.1 
Version .5.0, A111c.:11<ln11.:nt 4 
• 
Patients with recurrent hyperglycemia, defined as a fasti ng glucose > 126 mg/dL, wil l 
require evaluation for diabetes mellitus (e.g., fasting glucose, glucose tolerance and 
HbAlc tests) and appropriate medical management, al the discretion of the Investigator, 
Management of Severe Diabetic Complications 
Hyperglycemia can cause serious acute complications, presenting as endocrine emergencies, 
such as Diabetic ketoacidosis (OKA) and hyperglycemic hyperosmolar state (HHS). Both of 
these conditions are caused by relative or absolute insulin deficiency associated with excessive 
counter-regulatory hormones (glucagon, growth hormone. cortisol, catecholamines) 
(Marcovecchio 2017). Both DKA and HHS are usually triggered bv an underlying illness or 
event such as acute infection, infarction, non-compliance with diet and skipped insulin doses or 
insulin pump failure. DKA and HHS are life-threatening emergencies. Prompt clinical suspicion 
and confirmation of these diagnoses is very important The goal of treatment for DKA and HHS 
is tu correct volume deficits, hyperglycemia, and electrolyte abnormalities which will include, 
but is not limited to, IV fluid resuscitation, IV insulin, and IV potassium. Every effort should be 
made to identify the cause, so that future preventive measures can be taken. Patticipants 
experiencing OKA or HHS should be discontinued from study treatment. Management of 
infusion reactions and hyperglycemia is also described in Section 9,4.6,3.2. 
Risk ofMuscle Spasms 
Among reprotumumab-treated patients, Muscle spasms was the most commonly reported TRAE 
in clinical trials of Active TED (Double-Masked Treatment Period: 26.2% tcprotumumab 
compared to 7.0% placebo; Open-Label Extension Trial: 41 .3%). /\II events were non-serious 
and the majority were mild in intensity. 
lf possible, avoid medications known to cause muscle spasms or muscle toxicity, such as 
diurelics or statins. If muscle spasm occurs, evaluate for other causes of muscle spasm, such as 
electrolyte abno1malities and dehydration. 
Risk of Hearin!!, Impairment 
Adverse reactions of middle- to high-range sensorineural hearing loss have been reponed in both 
healthy volunteers and patients with malignancies who received as little as I dose of various 
IGF-IR mi\bs. 
Eighteen events associated with hearing impairment have been observed in 14 teprotumumab 
treated patients in the TED trials, with no reports observed in placebo treated patients. Each of 
these events were nonserious, mild or moderate in intensity and none led to premature 
discontinuation of trial drng; these events usually improved or resolved, If possible, patients 
should avoid ototoxic drugs while receiving teprotumumab, 
PR!V A TE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS U.S.A., INC. 
Page 63 of99 


HL,ri:t,>n rhrrnp'l.'.ut-i.;s U.S.A .. In,·. 
Oak' : ],);\l:!v .W2_i 
rEPl-:Zi',A ~ t tcprotumumab-1rbw; 1 IZN-00 I) 
Protocol: 11 L 1'-TFP-40J 
Version S.(l. Amcmln1cnt 4 
A re\'iew c•fthe po:-t-rnarkering d313 in 3 larger patient population shm,vs that while the reporting 
rate of hearing imr,Jirment rebted to .>\F.s in a post-marketing setting and the incidence in 
clinicnl rrinls nrpe3rS similnr, there Jrc some post-mJrketiug cusc:,; suggestive of gn.::ilcr 
in.:-rc;iscd seYcriry (cg. severe or. rarely, permanent hearing impairment) than what was seen in 
dinicnl tri:1\s. 1\o risk fad()rs were identified based on cmrcnt av~1ilable data. 
In Jddition. pnticms expcric:nring hearing impainnrnt should contact the investigational site for 
cvulu:11io11 and assessments. Evaluatiou may indu<le an audiogram. The audiogram report will 
induJc rhc following: 
• Pure tone 
The following tests may also be included: 
• Speech Recognition 
• Distortion product otoacoustic emission inner ear hair cell function test 
• E,aluation of Eustachian tube function 
Patiems experiencing c0mr lete or rrofound heJring loss should be discontinued from sn1dy 
tre~iment. 
9.5.3. 1.2 Oocumentation of AdYrrsr Events 
AEs that occur during Screening and prior to dosing on Day 1 will be considered pre-treatment 
A Es. The TEAE reporting period begins with administration of the first dose of trial drug on 
Day 1 and continues until 3 weeks after the last dose of trial drug. The Follow-up AE reporting 
period begins 3 weeks after the last dose of trial drug through completion of the Follow-up 
Period. All pre-treatment AEs. TEAEs and AE.s during the Follow-up Period must be recorded in 
the source documents and on the patient's eCRF. 
If the Investigator observes an SAE after trial completion that heishe believes was possibly 
caused by rrial drug, the Investigator will repmt this SAE using the procedures described in 
Section 9.5.3. 1.5. 
o~'tailed inforn1Jtion regarding all SAEs mus t also be recorded on the Serious Adverse Event 
Reporting Fonn. \,\'henever possible, the Investigator should group together into a single term 
the sign~ 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. For diagnoses of infusion-associated events or anaphylaxis, signs and 
symptoms will be captured separately in the eCRF. 
? RIVA TE AND CO>.'FJDEl'<T [AL NFOR\!A TlO1' OF HORIZON TIIERAPEUTICS U.S.A., INC. 
Page 64 of 99 


Horizon Therapeutics U.S./\., Inc. 
Date: 19 l\-1ay 2()2.l 
9.5.3.1.3 Cntrusity of Adverse F,vents 
TEPE/ZA .P) (lcprotumumob-lrbw; 111/,N-00 I) 
Protocol: HZNl'-TEP-4UJ 
Vcrsio 11 5.0, Amend ment 4 
All /\Es occurring during the trial will be rcpo11cd on the AE fonn of the eCRF. Intensity of AEs 
will be graded on a 5-point scale (mild, moderate, severe, life-threatening, death) and reported in 
derail on the cCRF. 
Intensity 
Mild 
Definition 
discomfort noticed but no disruption of normal daily 
activity 
Moderate 
discomfort sufficient to reduce or affect daily 
activity 
Severe 
inability to work or perform normal daily activity 
Life-Threatening 
represents an immediate threat co life 
Fatal 
results in death 
9.5.3.1.4 Relationship to Trial Drug 
Conesponding National <.:anccr lnstilutc-
Common Terminology Criteria for 
AdYcrsc EYents (NCI-CTCAE) Grade 
2 
3 
4 
5 
The relationship of trial drug to each AE will be detcnnined by the Investigator and the Sponsor 
based on the following definitions: 
• 
No reasonable causal relationship (not related): There is no plausible temporal 
relationship or there is another explanation that unequivocally provides a more plausible 
explanation for the event. 
• 
Reasonable causal relationship (related): There is evidence in favor of a causal 
relationship (i.e., there is a plausible time course) and at least I of the following criteria 
apply: 
• 
• 
• 
• 
• 
There is a reasonable phannacological 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 )( I )(i), the FDA provides the following 
examples of types of evidence that would suggest a causal relationship between the drug and the 
AE. 
PRIVATE AND CONFIDENTIAL INFORMATION OF JIORJZO>J TIIERAPEUTICS U.S.A., INC. 
Page 65 of99 


Hori·t,)(J Thcrnrrnt1c, U.S.A., Inc. 
Date : 19 1\1:i~· 2l12] 
TEPEZZAJ'J (11.:prutumumab-lTbw; HZN-001) 
f'rolornl: 1 IZ. l'-TFP-403 
V crsit)n 5.0. Amendment 4 
• 
A. single oc-cmwnce of an e\'ent that is uncommon and known to be strongly associated 
with drng e'i:posure ( e.g .. nngiocdema, hepatic injury, Stcvcns-Jolmson Syndronu.:). 
• 
One or more occurrence~ of an eYent that is nor conu11only associated with drug exposure 
bm is oti1crwisc l1tKon11non in the population ex.posed co che dmg ( e.g., tendon rupture). 
• 
.-\u Jgg,rc-gate analysis of specific eYents obscned in a clinical trial (such as known 
..:on sequences of the underlying disease or condition under investigation or other events 
thm commonly occm in the trial population independent of drug therapy) that indicates 
those events occur more frequently in the drug treatment group than in a concmrent or 
historical concrol group. 
9.5.3.1.5 Reporting and Documenting Serious Adverse Ennts 
All SAEs beginning with the time of signing of the ICF and continuing until 30 days after trial 
discharge must be reported The following steps will be taken to report promptly and document 
accurately any SAE. whether or nm it appears to be related to trial drug: 
I. Report ihe SAE to the Sponsor by entering the information in the eCRF within 
., 
24 hours after becoming aware that a patient has experienced an SAE. lf unable to 
access the eCRF. the event must be repo1ted by submitting the completed SAE form 
by email to clinicalsafetv@horjzontherapeutics.com , or via fax within 24 hours after 
becoming aware that a patient has experienced an SAE (see Appendix 17.1 for 
contact infon nation). 
Perfonn appropriate diagnostic tests and therapeutic measures. and submit all 
follow-up substantiating data. such as diagnnstic test reports. hospital discharge 
summaries and autopi-y reran to the Sponsnr's representative. 
3. Respond in a timely manner to any queries from Sponsor regarding the SAE. 
4. Conduct appropriace consultation and follow-up evaluation unril the SAE is resolved, 
stabilized. or othe,w ise explained by the Investigator. 
5. Review each SAE repon and evaluate the relationship of the SAE to trial treatment. 
The Sponsor will dete1mine whether the SAE is unexpected in nah.Jre. 
6. The Investigator must report to the lRB all AEs or SAEs that meet the criteria for 
Unanticipated Problems Involving Risks to Human Subjects or Others. 
9.5.3.1.6 Follow-up of Adverse Events 
Any ongoing trial drug-related AE, including a clinically significant laboratory test abnonnality, 
will be followed until resolved or until the event stabilizes and the overall clinical outcome has 
been ascertained. 
PRl\.'A TI A>.'D CO:s!FfDEt\TIAL !'.'FOR.MA TlOJ\' OF IIORIZON TIIERAPEUTICS U.S.A., NC. 
Page 66 of99 


l101izon Therapeutics U.S.A .. Inc. 
IJat<::: 19 May 2023 
TEPEZZA ® (tc::prolumumab-trbw; HZN-00 I) 
l'rolocol HZN P-TEl'-40J 
Version 5.0, Amendment 4 
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 
Base Ii ne for that patient 
9.5.3.1.7 Medication Errnr and Overdose 
An overdose is defined as a deliberate or accidental administration of investigational drug to or 
by a trial patient, at a dose equivalent to 27 mg/kg q3W or greater. 
A medication error is defined as any unintended failure in the drug treatment process, such as 
mistakes in the prescribing, dispensing, storing, preparing or administering of a medicine that 
leads to, or has the potential to lead to, harm to the patient. 
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. A Es associaled wilh an overdose and SAEs of overdose are to be reported according to 
the procedures outlined in Sections 9.5.3.1.2 and 9.5.3. 1.5, respectively. 
There is no antidote for TEPEZZA; therefore, in the event of drug overdose, the patient is to be 
treated with symptomatic and supportive care as required. 
9.5.3.1.8 Review of Adverse Events and Emerging New Safety Information 
The Sponsor will perform an ongoing review of all AEs and all other emerging information 
relevant to the safety of the drug, including periodic review and analyses of their entire safety 
database. 
9.5.3.1.9 Reporting of lnvestigational New Drug Safety Reports 
The Sponsor will notify the US FDA and all Investigators regarding any new serious risks 
associated with the drug. 
9.5.3.1.10 Development Safety Update Reports 
The Sponsor will prepare and submit annual safety reports to competent authorities and 
concerned ethics committees. 
9.5.3.2 Pregnancy Reporting 
Sernm 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 amenon-hea for 
<12 months prior to Screening or not surgically sterile [absence of ovaries and/or uterus]) at 
Screening; urine pregnancy testing will be perfonned prior to dosing at all subsequent clinic 
visits, as applicable, and at the End-of-Treatment Visit. 
PRN A TE AND CONFIDENTIAL INFORJvlA TION OF HORIZON THERAPEUTICS U.S.A., !NC. 
Page 67 of99 


l k11 i:wn Therapl'ulic:s U.S.A .. Inc. 
Dat..:: 19 t-.lay l()L, 
TEPEZZA 
<!<> (tcprotumumab-lTbw; l !ZN-00 I) 
Protocol: HZNP-TEl'-403 
\'.:rsi011 5.0. Amc:ndm..:111 4 
Patients should be instrnctcd to continue contraception for 180 days after their last dose of trial 
drug. 
If a female patient becomes pregnant during treacment, she should immediately notify the 
Investigator, and trial drug dosing should be pemrnncntly discontinued. Pregnancies occurring up 
to 180 days after the lase dose must be reported to the Investigator. 
TI1e Investigator should report pregnancies to the Sponsor by submitting the completed 
pregnancy report form by email to cli11icalsafety@hori2011d1erapeutics.com or via fax within 
24 hours after becoming aware that the patient/patient's female partner has become pregnant (see 
Appendix 17. l for contact information). The Investigator should counsel the patient and discuss 
the possible risks of continuing the pregnancy. 1f pregnancy continues and the patient signs the 
pregnancy consent fon11. monitoring should continue to the conclusion of the pregnancy. 
9.5.3.3 Medical History 
Medical history, including tobacco, alcohol and other substance use history and thyroid disease 
history and treatment, wi II be captured at Screening. The initial diagnosis of TED must be 
:::2 years but < IO years prior to Screening for trial enrollment. Stable, chronic (inactive) TED 
must be decennined by medical records indicating a CAS :SI in both eyes for at least I year prior 
to Screening or no progression in proptosis, no progression of diplopia (in those with a history of 
diplopia due to TED) and no new TED symptoms for at least 1 year prior to Screening. 
9.5.3.4 Vital Signs and Weight 
Demi led timing of vital sign and weight measurements is described in Section 2.1. 
Vital signs (blood pressure. heart rate, respiratory rate, temperature) will be measured at all clinic 
visits. Vital signs will be measured pre- and post-infusion on Day I and Week 3 (all patients). 
pre- and post-infusion at Week 24 and Week 27 (proptosis non-responders who elect to receive 
open-label TEPEZZA) and pre-infusion on all other infusion days. ln addition, if immediate 
infusion-associated evenrs 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 l:,e 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 patient's arm unconstrained by 
clothing or other material and while the patient is sitting up. When possible, the same ann will be 
used for measurements at all trial visits. 
Weigh! ,,·ill be measured al Screening and Weeks 9 and 24 (or P\Vl) (all patients) and Wec:ks 33 
and 4~ (l1r PW 2) (proptosis non n.:.sponder.s who elect to receive open-label TEPEZZA). The 
dose: on Day I and Weeks J, 6 and 9 of the double-masked Treatmenl Period will be based on the 
Screening weight: weight measured at Week 9 will be used in dose calculations at Weeks 12. 15, 
l ~ and 2 1 . The dose on Weeks 24, 2 7, 3 0 and ., 3 of the open-label Treatment Period ,,vi II be 
PR !\"ATE ANU CO"il'IDENTl,\L NFOR.MATION Of I IOR TZON TI-11:RAPEUTICS U.S.A., INC. 
Page 68 of99 


I lrnizon Therapeutics U.S.A., Inc. 
Dale: 19 May 2023 
Tl::l'EZZA "' (teprotumumab-trhw; 1 IZN-00 I) 
Protocol: I IZNl'-TEP-403 
Version 5.0, A1m:111lnu.:nt 4 
based on the Week 24 weight; weight measured at Week 33 w ill be used in dose calculations at 
Weeks 36, 39. 42 and 45. 
9.5.3.5 Photographs 
For patients who provide written consent and taking photographs is part of site routine or 
standard of care, photographs of patient's eyes will be taken prior to the first infusion and at 
Week 24 ( or PW l ) ( all patients) and at Week 48 ( or PW2) (non-responders who elect to receive 
open-label TEPEZZA). 
9.5.3.6 Visual Acuity 
Best-corrected visual acuity will be assessed at Screening, Day I and Weeks 6, 12, 18, and 24 (or 
PWl) and at Weeks 30, 36, 42 and 48 (or PW2) (non-responders who elect to receive open-label 
TEPEZZA) (sec Section 2.1 ). 
If significant abnormalities arc noted compared with previous visits, including a loss of2 lines or 
more of vision or other abnormalities not otherwise specified but of concern to the 
ophthalmologist, further investigations of visual function will be conducted according to the 
ophthalmologist's decision. 
New findings reported from on-trial visual acuity assessments will not be reported as AEs if, 
according to the Investigator, the abnormalities are unequivocally due to disease progression and 
should only be reported as AEs if they fulfill any of the SAE criteria or are the reason for 
discontinuation of trial drug. 
9.5.3. 7 Clinical Laboratory Safety Tests 
With the exception of urine pregnancy tests. a central laboratory will be used for all 
protocol-specified clinical laboratory parameters. Details of timing concerning the collection of 
the.se samples are presented in Section 2.1 . 
lnstn.1<.:tions for the collection, handling and analysis of clinical laboratory samples will be 
provided to the site prior to site initiation. 
9.5.3.8 l mmunogenicity Testing 
Blood samples ,:,,,jll be collected in a 5-mL serum separator collection tube for immunogenicity 
testing (anti-drug antibody [ADA] and possibly neutralizing antibodies) from all patients prior to 
dosing on Day 1, and Weeks 3, 12 and 24 (or P\Vl) (all patients) and Weeks 27, 36 and 48 (or 
PW2) (non-responders who elect to receive open-label TEPEZZA). 
Detailed timing of sample collection for immunogenicity evaluations is described in Section 2.1. 
Samples will be collected, processed and stored at 2:-70°C at the site until shipment to the central 
laboratory 
. The central laboratory will store the samples at 2:-70°C 
' 
I 
until shipm 
oratory for testing. If a patient tests positive for ADA after 
.. . 
I 
.. • I I. I I 
• 
.. 
• I 
PRIVATE AND CONFIDENTIAL rNFORMA TIOJ\ OF IIORJZON THERAPEUTICS U.S.A., INC. 
Page 69 of99 


lk11iwn rhcr,1pcu11.:s U.S.A .. l11,. 
O.\lc: l Q t\lay 2t12-: 
rl:l'E/./.,\ oil' (1<.:prolumu1m1b-1rbw; I !ZN-00 I) 
l'rolO\;OI: IIZN P- rFP-403 
\\;r~ion 5.0. Amc11eJrnt.:11I 4 
c0nfin11at0ry and reactive titer testing. the s::imple will he tested for ncutr::ilizing antibodies. lfthe 
r arient tesrs posiriw for neutralizing antib0dics, the patient may be followed until levels either 
remm r0 Bnsclinc or rhe patient's level dccre:.iscs or remains stubk . AD/\ sampks will bc 
c0lk crcd during any \'isit triggered by suspected immunologicdly related A Es. 
In:-tructions for processing. handling, st(1ri11g an<l shipping of inunuuogcnicity samples will be 
derailed in a lab,1rarory manual that will be pn.widcJ to each site prior to site initiation. 
ln:-trnctions for pr0ccssing. h;mdling, st0ring and shipping ufsamplt's will be detailed in a 
lat,or:itory mamrnl that will be provided to each :;ite prior lo site initiation. 
9.5.5 
Appropriateness of l\tcnsuremcnts 
This nial, which is a randomized, double-masked. placebo-controlled. mulcicenter trial, is 
designed a~cordi.ug lo standard principles for adequate and well-controlled t1ials. 
The measurements used in this t1ial for the efficacy endpoints (proptosis, 
nd 
GO-QoL questionnaire) are established and have been shown to conelate significantly with 
TED. 
9.5.6 
Trial Procedures 
9 .5.6.1 Screening 
Due to the number of screening assessments. the Screening Visit may be completed in more than 
l day,clinic visit provided consent is obtained first and all assessments are completed within the 
designated window. During the Screening Visit, potential trial patients will be informed fully 
regarding the nature of the trial and possible AEs and will receive a copy of the ICF for review. 
Potential t1ial patients must read the ICF and sign the document after the Investigator or designee 
has answered all questions to the trial candidate's satisfaction. Further procedures can begin only 
after the ICF has been signed. The original signed ICF will be retained by the lnvestigator and a 
copy will be given to the patient 
PR[\' A TE A. ' ID CO'.'.'Fm E:--:TIAL 1:-JFORMATION OF HORIZON D IERAPEUT!CS U.S.A, INC. 
Page 70 of99 


I lorizon Therapeutics U.S.A., In.:. 
Date: 19 May 202.l 
TEl'J (i'.I.A'" (tcprotumumab-trhw; I IZN-00 I J 
1'10101,;ol: IIZNl'-TFP-403 
Vcn,ion 5 .0, J\1111;nd111cnt 4 
Trial candidates will be evaluated for crial entry acc,xding to the seated inclusion and exclusion 
criteria tSection 9 .3 ). The Investigator will evaluate the results of all examinations, including 
clinical labt, ratory rest.~. and will detem,ine each candidate's suitabilicy for the trial. The 
TnYestigator mmt review the results of all screening tests before detennining that a candidate is 
d igi r-le for ,rial drug treatment. The scmm pregnancy test perfom1ed at Screening on all female 
candidates of childbearing potential must be negative for those patients to be eligible for 
i.I.litiation of treaunent. All screening procedures must be completed within 28 days prior to 
Day 1 (i e .. t11e first day of administration of trial drug). The following procedures will be 
performc>d during Screening to establish each candidate's general health and eligibilicy for 
enrollment into the trial: 
• 
Obtain signed, written informed consent, including pennission to use Protected Health 
Infom1ation tin accordance with the Health Insurance Portability and Accountability 
Act), with an optional con.sent to being photographed. Refusal to provide permission for 
photographing does not exclude an individual from eligibility for trial participation. 
Record date and time informed consent was given and who co11d11cted the process. 
• 
Collect medical history, including tobacco, alcohol and other substance use history and 
thyroid disease history and treatment. Ensure TED is stable, chronic (inactive) (not 
progressing, 11011-sigln-thrcatcning but with an appreciabk impact on daily lift:) and 
diagnosed 2::2 years but < I U years prior to Screening. 
• 
Determine trial eligibility through review oflhe inclusion/exdusion criteria (sec 
Section 9.3). 
• 
Obtain demographics. 
• 
Inquire about prior medications ( see Table 9 .1 for resriictions regarding medications). 
• 
Perform visual acuity assessment. Patients 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. 
• 
Record vital signs (blood pressure, heart rate, respiratory rate and temperature) and 
weight. These measurements will be performed according to standardized instructions. 
• 
Complete the following efficacy assessments: proptosis, 
• 
Complete CAS. 
• 
Query patients regarding signs and symptoms. 
PRIVATE AN'D CONFIDENTIAL TNFQR.i\,IATION OF I IORIZON TifERAPEUTICS U.S.A., INC. 
Page 71 of99 


H('ti2,,n rltnJp~uti,·s U.S.A .. In,·. 
0:11<:: 19 i\ b, 202~ 
1'1:f'EZZ:\ ® ltcproturnumab-trbw; l-lZN-00 I) 
!'n,tm:ol: llZNl'-TEl'-403 
Y crsion 5.0. /\mtnJmcnt 4 
• 
Obtain blood samples for hematology and fasting chemistry (including thyroid and 
HbAlc) analysis for all patients (see Section 9.3 for details concerning test results and 
trial panicipation) and pregnancy testing for females of childbearing potential. 
• 
Enter Screening Visit data in the FDC system. 
9.5.6.2 Double-masked Treatment Period 
9.5.6.2.1 Day l 
On Day l, patients will rdnm ro the clinic for Baseline assessments and the first dose of trial 
drug. 
• 
Determine trial eligibility through review of the inclusion/exclusion criteria (see 
Section 9.3). 
• 
ReYie,v medical histo1y. 
• 
Obtain signed. written infonrn:.·d consent for optional photographic analysis it' not 
L1bt~1ined at Screening; the consent must be obtained prior to photographs being obtained. 
• 
Obtain prcdosc blood samples for hern:nology and fasting chemistry ( including thyroid 
and HbAlc) analysis. 
• 
Collect predose blood samples for PK analysis, immunogenicity and -
esting. 
• 
Collect predose urine sample for a pregnancy test for females of childbearing potential; 
che pregnancy test must be negative for the patient to receive trial drng. 
• 
Inquire about A.Es and prior medication use (see Table 9.1 for restrictions regarding 
medi-:arions). 
• 
Perfonn predose visual acuity assessment. 
• 
Perfom1 predose Baseline efficacy assessments (proptosis. 
-
and GO-QoL questiomrnire). 
• 
Perform pre.dose Baseline CAS. 
• 
Take predose photograph of the patient's eyes for those patients who have consented. 
• 
Record, ital signs prior to and at the end of the infusion. Additional Yitai sign monitoring 
may be perfmmed in the event of infusion-associated A.Es (see Section 9.5.3.4 for 
details). 
PRIVATE A'-.'D CONFIDEJ\T IAL INFORMA1!01' OF HORIZON TIIERAPEUTICS U.S.A., INC. 
Page 72 of99 


I lorizon Therapeutics lJ.S.A., Inc. 
Uatc: 19 May 20.lJ 
TEl'EZZN"' (tcprotumumab-trbw; HZN-00 I) 
l'rolocol: l lZNl'-TEl'-403 
Version 5.0, Amcn<lmcnl 4 
• 
Register enrollment in F:DC in order for the unmasked site personnel to ohtain 
nmdomization assignment, calculated trial drug dose, vial assignment (if applicable) and 
volume of trial drug to be administered. 
• 
Administer trial drug and record date, volume and start/stop times of the infusion. 
Monitor the patient for any AEs during the infusion and for 60 minutes after the 
completion of the infusion. 
• 
Collect post-dose blood samples for PK analyses following the end of the infusion. 
• 
Enter visit data in the EDC system. 
Patients will be discharged from the site after all Day I procedures have been completed, 
instructed to return for a clinic visit in 3 weeks and contacted the following day to perfonn a 
safety check following the first infosion. 
'>.5.6.2.2 Week 3 
• 
Collect predose urine sample for a pregnancy test for females of childbearing potential; 
the pregnancy test must he negative for the patient to receive trial drng. 
• 
Inquire about AFs and concomitant medication use. 
• 
Collect predose blood samples for PK analysis, immunogenicity and 
• 
Perfo,m efficacy assessments (proptosis, 
• 
Record vital signs prior to and at the end of the infusion . Additional vital sign monitoring 
may be perfonned in the event of infusion-associated AEs (see Section 9.5.3.4 for 
details). 
• 
Obtain calculated trial drug dose, vial assignment (if applicable) and volume of trial drug 
to be administered from the EDC system. 
• 
Administer trial drug and record dale:\ volume and start/stop times of the infusion. 
Monitor the patient for any AEs during the infusion and for 60 minutes after the 
completion of the infusion. 
• 
Collect post-dose blood samples for PK analyses following the end of the infusion. 
• 
Enter visit data in the EDC system. 
PRIVATE AND CONFIDENTIAL rNFORMATION OF IIORIZON THERAPEUTICS U.S.A., INC. 
Page 73 of99 


ill'ri20n ri1rmpcun..:s U.S.A. In,'. 
D11cc-: I 9 \l:,y 202_• 
TEPEZZA ~ tteprotumumab-trbw; I ILN-00 I) 
l'rotm:ol: HZN P-TL:1'-40] 
V cr~ion 5.0. !\1m:nd111cnt 4 
Patient~ will be di$charged from the site :ifter all procedures have been completed. instmcted to 
remm for a clinic Yi sit in 3 weeks and ecmtaeted the following day to perform a safety check 
following thr second infusion. 
9.5.6.2.3 Weeks 6. 12 and 18 
• 
Collect r redosc urine sample for a pregnancy test for females of childbearing potential; 
the pregnancy test must be negative for the patiem to receive trial c.irug. 
• 
Obtain predose blood samples for hcmawlogy and fasting chemistry (including thyroid 
and HbA le a1 ·w eek 12 only). 
• 
Inquire about A Es and concomitant medication use. 
• 
Perform predose , isual acuity assessment. 
• 
Perforn1 predose efficacy assessmencs (proptosis. 
and GO-Qol questionnaire [Weeks b and 12 only]). 
• 
Perfom, predose C'AS at Week 12 only. 
• 
Record\ ital signs prior to the infusion. Additional vital sign monito1ing may be 
perfom1ed in the eYent of infusion-associated AEs (see Section 9.5 .3 .4 for details). 
• 
Collect pn.:dose blood samples for PK analysis, immunogenicity and 
Week 12 only. 
• 
Obtain calculated trial drug dose, vial assignment (if applicable) and volume of trial drug 
co be administered from the EDC system. 
• 
Administer trial drug and record date, volume and start/stop times of the infusion. 
Monitor the patient for any AEs during the infosion and for 60 minutes (Week 6) or 
3 0 minutes (Week 12 and Week 1 8) after the completion of the infusion. 
• 
Collect post-dose blood ~amples for PK analyses following the end of the infusion at 
Week 12 only. 
• 
Enter visit data in the EDC system. 
Patients will be discharged from the site after all procedures have been completed and instructed 
to return for a clinic visit in 3 weeks. 
PRJ\.'A TE A'lD CO'lFIDENTl.:..L NFORMATIOl\ OF HORIZON Tl!ERAPEVTTCS U.S.A., NC. 
Page 74 of99 


Hori-zon Thcrapcuti-:s U.S.A., lni.:. 
Date: l 9 May :lO.lJ 
9.5.6.2.4 \Vccks 9, 15 and 21 
TEPE1/ZA'1v (lcprolumumab-trbw; I IZN-00 I) 
1'1olornl. IIZNP-Tl:l'-'10:I 
Version 5.0, A111c.;11<lnic n1 4 
• 
Collect rredosc urine sample for a pregnancy test for females of childbearing potential; 
the pregnancy test must be negative for the patient to receive trial drug. 
• 
Inquire about AEs and concomitant medication use. 
• 
Measme predose weight (Week 9 only). 
• 
Record vital signs prior to the infusion. Additional vital sign monitoring may be 
performed in the event of infusion-associated AEs (see Section 9.5.3.4 for details). 
• 
Obtain calculated trial drug dose, vial assignment (if applicable) and volume of trial drng 
to be administered from the EDC system. 
• 
Administer trial drug and record date, volume and start/stop times of the infusion. 
Monitor the patient for any AEs during the infusion and for 30 minutes after the 
completion of the infusion. 
• 
Enter visit data in the EDC system. 
Patients will be discharged from the site after all procedures have been completed and instructed 
to return for a clinic visit in 3 weeks. 
9.5.6.2.5 Week 24/End-of-Treatment 1/First Infusion of Open-label Treatment Period 
Week 24 is the final visit of the double-masked Treatment Period. Trial drug is not administered 
for responders and non-responders who elect not to receive open-label TEPEZZA. For proptosis 
non-responders who elect to receive open-label TEPEZZA, the infusion will be perfonned at 
Week 24 (first of 8 infusions): all Week 24 procedures except AE and concomitant medication 
monitoring, post-infusion PK sample collection and 24-hour post-dose phone/email contact must 
be completed prior to TEPEZZA infusion. 
• 
Perform cfficac assessments (proptosis, 
and GO-QoL questionnaire). The~vill not need to be 
performed on the same day as other Weck 24 assessments as long as it is performed 
within the visit window and prior to the first open-label infusion (proptosis 
non-responders who elect to receive open-label TEPEZZA). 
• 
Perform CAS. 
• 
Perform treatment response assessment, including whether the patient is a proptosis 
responder or non-responder, and enter data in EDC. 
PR IV A TE AND CONFIDENTIAL INFORMATION OF HORIZON TifERAPEUTICS U.S.A , INC. 
Page 75 of99 


Hl,ri,011 Thcrnr•nll11:s lJ.:S.A .. In.:. 
D:l!c: l'l i\bv :zo~; 
l'l:Pl •:IZA <to l tcprotumu111ab-trbw; IIZN-00 l) 
Protocol: 1 IZNP-TFP-40] 
Vcrsio11 5.0. Amcmlmcnt 4 
• 
Obtain Hood samples for hemat0logy nnd fasting chemistry (including thyroid and 
HbA le) :inalysis. 
• 
Col!ect urine sample for a pregnancy test for females of childbearing potential. 
• 
Perform visua.1 a-:-uiry assessment. 
• 
fr:isw·c weight. 
• 
R,YorJ \·i1al signs lj)rior to and at the end of the infusion tor non-responders who elect to 
rel.'ei\·e op-:n-label TEPEZZA). Additional vital sign monitoring may be performed in the 
cwnt of inti.1sio11-associatc-d AEs (sec:: Scccion 9 5.34 for details). 
• 
Collt'('l bl00d samplt'" for irnmHn0genicity and 
(NOTF: C'olkction 
,-h0uld be prior to do:-e t~ir n0n-rc>sp0nder~ who 
m,:; open-label T F,PF77.t\.) 
Colic-ct a single blood samp le for PK analyses (proptosis responders and 
responders who elect not to rl:'ceive open-label TEPEZZA). NOTE: 
• 
Inquire abouc A Es and concomitant medication use. 
• 
Take photograph of the patient's eyes for those patients who have consented. 
• 
Obtain calculated dose. vial assignment and volume ofTEPEZZA ro he administered 
from the EDC system for non-responders who elect to receive open-label TEPEZZA 
l~nly. 
• 
C'ollecr blood samples for PK analy~es prior to and at the end of the infusion 
lnon-respondc>rs who elect lo receive open-label TEPEZZA only). 
• 
Administer TEPEZZA and record date. volume> and start/stop times of the infusion 
lnon-responders who elect to receive open-label T EPEZZA only). 
• 
Enter remaining visit data in the EDC system. 
Patients will be discharged from the site after all procedures have been completed. Patients who 
are proptosis responders. as well as non-responders who elect not to receive open-label 
TEPEZZA, will enter the Follow-up Period and will be contacted via phone or email in 30 days. 
Patients in the open-label Treatment Period will be instructed to return for a clinic v isit in 
3 weeks and will be contacted the fo llowing day to perform a safety check following the first 
open-label infusion. 
PRl\'A TE A:'-ID CO:----FfDEKTIAL r.--.TfORJ'v!AT!OJ\ OF I IORIZON TIJERAPEUTICS U.S.A., lNC. 
Page 76 of99 


I lo1i7.011 Thcraptulics U.S.A., Inc. 
Dalt'.: I <,I May 2023 
TEl'EZI.A'" (tcprotumurnab-trbw; 11 ZN-00 I ) 
l'rolui:ol: HZNl'-T[l'-403 
Vcrsion 5.0, Amcmlnicnl '1 
9.5.6.3 Open-label Trealrnmt Period Visits After Week 24 - Proptosis '.'Ion-responders 
Who Choose to Receive Open-label TF:PEZZA 
Proptosis non-responders who elect to receive open-label TEPEZZA during the open-label 
Treatment Period will receive additional infusions at Weeks 27, 30, 33, 36, 39, 42 and 45. 
9.5.6.3.1 Weck 27 
• 
Collect predose urine sample for a pregnancy test for females of childbearing potential; 
the pregnancy test must be negative for the patient to receive TEPEZZA. 
• 
Perform efficacy assessments (proptosis, 
• 
Inquire about A Es and concomitant medication use. 
• 
Collect blood samples for PK analyses prior to and at the end of the infusion . 
• 
Collect predose blood sample for immunogenicity testing. 
• 
Record 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 9.5.3.4 for 
details). 
• 
Obtain calculated dose, vial assignment and volume ofTFPEZZ/\ to he administered 
from the EDC system. 
• 
Administer TF.PEZZ/\ and record date, volume and start/stop times of the infusion. 
Monitor the palient for any AEs during the infusion and for 60 minutes aflcr the 
completion of the infusion. 
• 
Enter visit data in the EDC system. 
Patients will be discharged from the site after all procedures have been wmplctcd, instructed to 
return for a clinic visit in 3 weeks and contacted the following day to perforn1 a safety check 
following the second open-label infusion. 
9.5.6.3.2 Weeks 30, 36 and 42 
• 
Collect predose urine sample for a pregnancy test for females of childbearing potential; 
the pregnancy test must be negative for the patient to receive TEPEZZA. 
• 
Obtain predose blood samples for hematology and fasting chemistry (including thyroid 
and HbAlc at Week 36 only). 
• 
Inquire about AEs and concomitant medication use. 
PRIVATE AND CONFIDE1'TIAL INFORJvlATION OF HORIZON THERAPEUTICS U.SA., rNC. 
Page 77 of99 


ll,1ri,,111 l'h<-r:1pnH1...:s l.1.::;.A., Im·. 
n~tt:: l 9 l\ fav 2t)2., 
• 
Perfonn predose visual acuity assessment. 
l'El'EZZA >1-' l leprotumumab-!Tbw; HZN-00 I) 
l'rntocol: l lZNl'-Tl' P-403 
Ycrsion 5.0, Amcnc..1111,;nt 4 
• 
Perfonn predose efficacy assessments (proptosis. 
1.i as well as GO-QoL questionnaire [\Veeks 30 and 36 only]). 
• 
Perform predose CAS at Week 36 only. 
• 
Collect predose blood s:unples for PK analysis and immunogenicity testing at Vhck 36 
only. 
• 
Re~ord vital signs prior co the infusion. Additional vital sign monitoring may be 
perfom1ed in the event of infusion-associated AEs (see Section 9.5.3.4 for details). 
• 
Obtain calculated dose, vial assignment and volume of TEPEZZA to be administered 
from the EDC system. 
• 
.-\dminister TEPEZZA and record date, volume and start/stop times of the infusion. 
\lonicur the palicnt for any ,\Es during lhe infusion and for oO minutes (Week 30) or 
30 minutes (\Vcck 36 and Week-42) afkr the completion of the infusion. 
• 
Ema visit data in the EDC system. 
Patients will be disdnrgl.'d from the site after dll procedures have been completed and instructed 
to rerum for a clinic Yisit in 3 weeks. 
9.5.6.3.3 Weeks 33, 39 and 45 
• 
Coll~ct predose urin~ sample for a pregnancy test for females of childbearing potential; 
the pregnancy test must be negative for the patient to receive TEPF.ZZA. 
• 
Inquire about AEs and concomitant medication use. 
• 
~frasme predose weighc (Week 33 only). 
• 
Re-cord \'it.11 signs prior to chc int'u1;ion. Additional viral sign monitoring may be 
perfonned in tht' event 0finfosiL1n-associated AEs (see Section 9.5.3.4 for details). 
• 
Obtain c:ikulatcd dose:,\ ial assignment anJ volume ofTEPEZZA to be administered 
fr0111 the EDC system. 
• 
Administer TEPEZZA and record date, volume and start/stop times of the infusion. 
Monitor the patient for any AEs during the infusion and for 30 minutes after the 
completion of the infusion. 
PRf\ .ATE Ai'l"D CO'JHDENTIAL NFORMA TION OF IIORIZON THERP.PEUTICS U.S.A., NC. 
Page 78 of99 


Horizon Therapeutics U.S.A., Inc. 
Date: 19 May 202J 
• 
Enter visit data in the EOC system. 
TEl'EZZA<t<' (tcprotumumab-lrbw; l lZN-00 I) 
l'rotoi:ol HZNl'-TEP-403 
Version 5.0, Amendment 4 
Patients will be disclu rged from the site after all procedures have heen completed and instructed 
to return for a clinic visit in 3 weeks. 
9.5.6.3.4 Week 48/F.nd-of-Trcatmcnt 2 
Weck 48 is the final visit of the open-label Treatment Period. Trial drug is not administered. 
• 
Obtain blood samples for hematology and fasting chemistry (including thyroid and 
HbA I c) analysis. 
• 
Collect urine sample for a pn;gnancy test for females of childbearing potential. 
• 
Perfon11 visual acuity assessment. 
• 
Measure weight. 
• 
Perform efficacy assessments (proptosis, 
an<l CiO-QoL questionnaire). The ·-
wi ll nol need to be 
perlormcd on t 1c same ay as other Wc:ek 48 assessments as long as it is performed 
within the visit w indow. 
• 
Perfonn CAS. 
• 
Record vital signs. 
• 
Collect blood samples for immunogenicity testing. Collect a single blood sample for PK 
analyses. 
• 
Inquire about AEs and concomitant medication use. 
• 
Take photograph of the patient's eyes for those patients who have consented. 
• 
Enter visit data in the EDC system. 
Patients will be discharged from the site after all procedures have been completed and enter the 
Follow-up Period. 
9.5.6.4 Follow-up Period (End-of-Study/Trfal) 
All patients will be contacted via phone or email 30 days after the Week 24 (responders and non-
responders who choose not to receive open-label TEPEZZA) or Week 48 (non-responders who 
receive open-label TEPEZZA) Visit. Inquire about AEs and concomitant medication use. 
PRIVATE AND CONFIDENTIAL INFORMATION OF JIORIZO'N TIIERAPEUTJCS U.S.A., INC. 
Page 79 of99 


Horizon Thn::ipcur,..:s U.S.A .. In,·. 
Da!e: 19 1\ luy 2023 
TEPEZZA~ {lt::protumumnb-trbw; HZN-00 I) 
l'rotornl: H/.Nl'-TEP-4UJ 
Yi.:rsion 5.0, J\1m.:nJ mcnt 4 
The end of the trial is defined as the date of the last patient contact at the end of the Follow-up 
Peri0d. 
9.6 
Statistical Methods and Determination of Sample Size 
9.6.1 
Fndpoints 
9.6.1.1 Primary Endpoint 
The primary efficacy endpoint is the change from Baseline at Weck 24 in proptosis in the study 
eye. 
9.6.l.2 Other F.fficacy Endpoints 
I. The proptosis responder rate (percentage of patients with a ~2-mm reduction from 
Baseline in proprnsis in the study eye, without deterioration [>2-mm increase] of 
proptosis in the fellow eye) at Week 24. 
2. The change from Baseline at Week 24 in the GO-QoL questionnaire appearance and 
3. 
4. 
5. 
9.6.1.3 Pharmacokinetic and Anti-drug Antibody Endpoints 
l . The peak and trough concentrations of TEPEZZA. 
2. The ADA incidence and titers. 
9.6.1.4 Safety and Tolerability Endpoints 
I. The incidence of TEA Es, SAE.s, TEAEs resulting in premature discontinuation of 
treatment and AESls (infusion reactions, hyperglycemia, hearing impairment, new onset 
inflammatory bowel disease and exacerbation of inflammatory bowel disease). 
2. The incidence of ~Grade 3 TEA£:;. 
3. The change from Baseline to each scheduled visit in viral signs (blood pressure, heart 
rate, respiratory rate and temperarure). 
4. The results of best-corrected visual acuity. 
5. The incidence of~Grade 3 fasting glucose values. 
6. The change from Baseline to each scheduled visit in laboratory evaluations (hematology 
and fasting chemistry [including thyroid panel and HbAlc]). 
PRIVATE A~D CONFmENTIAL INFOR,\·lA TION OF HORIZON Ti fERAPEUTICS U.S.A., INC. 
Page 80 of99 


llo1izon Thcrapcutics U.S.A., Inc. 
IJale: l 9 t-fay 2023 
9.6.1.5 F.xplorntory Rndpoint 
9.6.2 
Analysis Sets 
TEPEZZA <JI) (tcprolumumab-trbw; l lZN-00 I) 
Protocol: IIZNP-TEl'-40J 
Version 5.0, Amcm.lmcnl 4 
Efficacy analyses will be performed on the intent-to-treat (ITT) analysis set, consisting of 
patients who are randomized to trial drug (either TEPEZZA or placebo). Safety analyses will be 
peiformed on the safety set. consisting of patients who receive at least 1 dose of trial drug. The 
PK analysis set will include all patients who receive at least l dose of trial drug and have at least 
I post-dose PK sample. 
9.6.3 
Primary Efficacy Endpoint Analysis 
The primary efficacy analysis will be conducted on the ITT analysis set. A Mixed-Model for 
Repeated-Measures (MMRM) analysis of covariance model filling to the individual change from 
Baseline scores for Lhe study eye will be used for the analysis of change from Baseline in 
proptosis. The model includes Baseline score, treatment group, visit, visit-by-treatment and visit-
by-Baseline score as covariates. The unstructured covariance will be used. The treatment 
difference (TEPEZZA minus placebo) based on the estimated least squares (LS) means at Week 
24 will be presented with associated standard error (SE), 95% confidence interval (CI) and p-
value. 
9.6.4 
Other Efficacy Endpoints Analyses 
The otb~r endpoints of the proptosis responder rate, 
-
· A 95¾ exact CI will be provided for each risk differcnc.:c observed between the treatment 
groups. Patients whose Weck 24 evaluation is missing will be considered treatment failures 
(non-responders) for the responder analysis. 
PRIVATE AND CONFIDE1'TIAL INFORMATION OF I-IORIZON THERAPEUTICS U.S.A., INC. 
Page 81 of99 


I ll1ri'.ll't1 Thrr:lpeu!11:s U.S.A. In..:. 
Date: l 9 1\IHy 202.., 
TEPEZZA"" (teprotumumab-trbw; IIZN-O0 I) 
Protoc0l: HZNP-TEP-403 
Version 5.0. J\111c11Jmcnl 4 
Rem'.lining ocher or exploratory endpoints analyzing change from Baseline (such as in GO-QoL, 
will use the same MMRM method ~pecified for Lhc primary 
cfric'.lcy endpoint. 
9.6.5 
Safety and Tolerability Analyses 
ll1e number and percentage of patients experiencing at least 1 occurrence of a TFAF, SAE, 
TEAE resulting in premature discontinuation of treatment and AESI for each unique System 
Organ Class and Preferred Tenn will be summarized by treatment group. TEAEs and SAEs will 
also be rnrnmarized 'by severity and relationship to trial drng. as assessed by the Tnvestigntor. 
Gmde 3 and higher TF AFs. as graded hy the Nationnl Cancer fnstitutc Common Tc1111inology 
Crireria for Adwrse Fvents (NCT-CTCAF.). will al.so he summ::irizcd for each unique System 
Organ Clnss and Preferred Term. 
The number and percentage of patients in each treatment group u~ing concomitant medications 
will he summarized by Anatomical Thcmpcutic Chemical Level 4 term ::ind PrcfctTed Term. 
For besr-c0rTectc-d \·isual acuity, shift tables will be presented providing the count of paticnls in 
each rre3tment group with e3ch type of finding (normal, abnonnul - not clinically significant. or 
abnomul - clinically significant) ai Baseline compared to each postbaseline visit. 
Descriprivc- summaries of obserYed and cha.age from Baseline values will be presented for each 
\"ital sign par;.1meter by treatment group and visit. A shift table for vital signs by NCI-CTCAE 
grade and\ isit will be generated by treatment group. 
Safety laboratory (hematology and fasting chemistry [including thyroid panel and HbAlc]) 
\·alues and change from Baseline will be summarized by visit and treatment group using 
descriptive statistics. The laboratory assessment will be categorized as low, normal or high based 
on nonnal ranges and graded using the NCJ-CTCAE grading scale, when available. Shift tables 
using categories of low, no1mal and high from Baseline to each visit will be generated by 
treatment group. Additionally, a shift table for glucose by NCI-CTCAE grade and visit will be 
generJted by crcatmt:m group. Summaries will be provided separately for hyperglycemia. 
The rate: and citer ofposirivc ADA sampk ~ will lie summarized hy visir and treatment group 
using kscriptiw stati:-:tics. Teprotumum:ib peak :ind trough (i.e., prior ro dose) concentrations 
will also be summarized by visit using descriptive statistics. 
?RIVA TE .-\~ I) co:--FJDENT!AL N:'OR.\f A TIO,\' OF HOR!ZO:'-1 THERAPEUTICS U.S.A., INC. 
P;lgc 82 of99 


Horizon Therapeutics U.S.A., Inc. 
Date: 19 May 2023 
9.6.6 Interim Analyses 
No interim analyses are planned. 
9.6.7 Sample Size and Power Considerations 
TEPEZZA ® (teprotumumab-trbw; HZN-00 I) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
A total of 57 patients (38 in the TEPEZZA group and 19 in the placebo group) will be enrolled in 
the trial to detect at least a 2-mm mean difference between the 2 treatment groups in the change 
from Baseline of proptosis values at Week 24 in order to have 81 % power at the 2-sided 
0.05 level of significance. The sample size was determined assuming that the mean difference in 
proptosis change between the 2 groups is at least 2.0 mm (clinically relevant) and the standard 
deviation of proptosis change values is 2.5 for both groups (larger than observed in Phase 2 and 
Phase 3 active TED trials). 
9.7 
Changes in the Conduct of the Trial 
If any modifications in the trial design, dosages, parameters, patient 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 w ill be accomplished through formal 
amendments to this protocol by the Sponsor that will be approved by the appropriate IRB. 
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 the eCRF. In the event of a protocol deviation, the 
Investigator and Sponsor's Medical Monitor will determine whether the patient should continue 
participation in the trial. 
The Sponsor has a legal responsibility to report fully to regulatory authorities all results of 
administration of investigational drugs to humans. No investigational procedures other than those 
described in this protocol will be undertaken on the enrolled patients without the agreement of 
the IRB and Sponsor. 
PRIVATE AND CONFIDEN'TTAL INFORMATION OF I IORIZON TIIERAPEUTICS U.S.A., INC. 
Page 83 of99 


I ll11T,:,,n Thcr:1p1.·u1i..:s U.:-.A.. In.:. 
Dale l 9 l\la v 20~] 
TEPEZ.lA"" llcproturnumab-trbw; I 11.N-OO I) 
l'rotocol: HZNl'-TEP-40.1 
Vcrsiu11 5.0. A1m:nJ111cn1 4 
10 SOURCE DOCUl\lENTATION AND fNYRSTlGATOR FILES 
The lnwst.igator must maintain adequate and accurate records to document fully the conduct of 
the trial and to ensure th:-it trial data can be subsequently verified. These documents should be 
classified in 2 separate c-atc-gories: ( l) lm·cstig:1tor trial file and (2) patient clinical source 
documents that c01Tobornte data collected in the eCRfs. Pali.:nl clinical source Jo-.:umcnls 
include, :is appl icable. original hospital/clinic patient records; physicians' and nurses· notes; 
appoinrmcm book; original laboratory, ekctrocardiogr;m1, dectroenccphalog:ram, radiology, 
pathology :md special assessment reports; dispensing records; signed lCFs; consultant letters; 
3nd pa1icnt screening and enrollment logs. 
In order 10 comply w ith regulatory requirements, it is the policy of the Sponsor that, at a 
minimum, the following be do-:umentc'd in source documenls at the site: 
• 
l'vfeJica l history/physical condition and diagnosis of the patient before involvement in the 
tTial sutlicient to verify that the patient meets protocol entry criteria. 
• 
Trial number, 3ssig11ed patient number and vcrilication that written infonned consent(s) 
was(werc) obtained (each recorded in dated and signed progress notes). 
• 
Progress notes or cquivalenl source documemation for each patient visit and contact 
(each dated and signed). 
• 
Records of each !Tia! visit including each trial assessment and the identity of the staff 
member perfonning the assessment. 
• 
Trial drug dispensing and return. 
• 
Review by the Investigator or qualified pers0nnel oflaboratory test results. 
• 
AEs (~tart and stop date, description. relationship to trial drug, action taken and 
resolution). 
• 
Investigator or sub-investigator's signed assessment of each AE. 
• 
Concomitant medications (start and stop dates, reason for use). 
• 
C'ondirion of patient upon completion of, or PW from, the trial. 
?Rl\'A TE A~D CONFIDENTL·\ L I'-ITOR\fA TIO\ OF l:ORIZON TJIERAPEUTICS t;.S.A , INC. 
Page 84 of99 


I lorizon Therapcutics U.S.A., Inc. 
IJate: I 9 May 2023 
11 CASE RF:PORT FORMS 
TEPEZZA ® (teprotumumab•trbw; l lZN-00 I) 
Protocol: HZNP-TEl'-403 
Version 5.0, Amendment 4 
An eCRF is required for every patient who signs an ICF. Required data must be entered on tbe 
eCRF within the required time period, which will be outlined within each site agreement, after 
data collection or the availability oftest results. Separate source records arc required to support 
all eCRF entries. Data capture<l on the eCRF and requested anonyrnized copies of supporting 
documents will be transferred to the Sponsor at trial completion. 
TI1c Investigator will ensure that Lhe eCRFs arc accurate, complete, legible and timely and will 
review and provide an electronic signature for the eCRF according to the standard operating 
proc<.:dure of tbe Data Management System. Final cCRFs will be provided to the Investigator and 
Sponsor by Data Management. 
PRTV A TE AND CONFIDENTIAL fl\"FORMA TION OF llORJZON THERAPEUTICS U.S.A., INC. 
Page 85 of99 


H0riz011 rht'r:ipc:uti..:s U.S.A.. Im·. 
Once-: tQi\fay 2(l~~ 
12 TRIAL MOl\ITORING 
TL:PEZZA. ,io (tt:protumurnab-trbw; HZN-00 I) 
l'rococol: HZN P-TEP-403 
\"nsion 5.0. J\mrndmcnt 4 
The lnwstigator will ensure that the trial is conducted in accordance with all regulations 
governing the protection of human subjects and \Vil! adhere to the basic principles of GCP as 
outlined in Title 21 of the CFR. Part 312. Subpart D, '·Responsibilities of Sponsors and 
In\'esrig:itors:" ~ 1 CFR, Part 50, "Protection of Human Subjects;" 21 CFR, Pari 56, "Institutional 
Review Boards;·' 21 CFR, Par1 54 "Financi:il Disclosure by Clinical Investigators;'' and the TCH 
guideline entitled '·Good Clinical Practicc: Consolidated Guidance.'· Additionally, this trial will 
be conduc1cd in .:ompliance with the Dedaration of Hdsin.k.i and with all local laws and 
reguL.ltions. 
The Investigawr will ensure that all ',\,'Ork 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 In\'estigator will provide 
copies of the trial protocol and Investigator's Brochure to all sub-Investigators, phannacists and 
other staff responsible for trial conduct. 
.-\11 aspe.:ts ot' the trial will be monitored by qualified individuals designated by the Sponsor. The 
Sponsor will ensure that the tiial is monitored adequately in accordance with GCP guidelines. 
Prior co initiation of the rrial, the Sponsor's representatives will review with site personnel 
infonnation regarding the investigational drug, protocol requirements, monitoring requirements 
and reporting of SAEs. 
At imcrYals during the trial. as well as after the completion of patient enrollment, the site will be 
mon.itored by the Sponsor or designee for compliance. During these visits. the monitor will 
discuss trial progress, verify adherence to the protocol and the completeness. consistency and 
accuracy of the data being entered on the eCRF (source data verification), oversee the resolution 
of outstanding data discrepancies and check on various aspects of trial conduct (e.g., drug 
accountability. sample swrage). The Investigator agrees to allow monitors access to the clinical 
:;upplies. dispensing and storage areas and clinical records of the trial patients 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 \'isits are resolved. 
A secondary audit may be conducted by Quality Assurance designated by tbc Sponsor. The 
Investig:itor 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 representatiYcs of other regulatory autho1ities may also 
conduct an inspection of the trial at the site. Tf informed of such an inspection, the Investigator 
should notify the Sponsor imnH~diatcly. 
Evc-1-y dTurt will be rmde tu maintain the anonymity and confidentiality of patients participat.ing 
in this trial. HoweYer, the Investigator agrees to allow representatives of the Sponsor, its 
designated agents and authorized employees of the appropriate regulatory agencies to inspect the 
facilities used in this trial and to have direct access to inspect, for purposes of verification, the 
?R[\'ATE ,4.]',;1) CO\fFIDE:',-:-JAL r,,.."FQ~ lATJOt-' OF HORIZON THERAPEUTICS U.S.A., INC. 
Page 86 of99 


Ho1izon Therapeutics U.S.A., Inc. 
Date: 19 May 2023 
TEPEZZA"" ( teproturnumab-trbw; HZN-00 I) 
l'rotocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
hospital or clinical records of all patients enrolled in this trial. A statement to this effect should 
be included in the TCF. 
PR!V A TE ANO CONFTOENTIAL fNFORMATION OF HORIZON THERAPEUTICS U.S.A., INC. 
Page 87 of99 


Horizon Therapeutics U.S.A., Inc. 
Date: 19 May 2023 
13 DATA MANAGEMENT 
TEPEZZA ® (teprotumumab-trbw; HZN-00 I) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
Daca will be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures will be applied to ensure the validity and accuracy of the 
clinical database. Data will be reviewed and checked for omissions, apparent errors and values 
requiring further clarification using computerized and manual procedures. Data queries requiring 
clarification will be communicated to the investigational site for resolution. Only authorized 
personnel will make corrections to the clinical database, and all corrections will be docwnented 
in an audit trail. 
The coding of .AE, medical history and concomitant medication tem1s will be performed by a 
qualified medical coder and reviewed and approved by the Sponsor. Concomitant medications 
will be coded using the World Health Organization Drug Dictionary and AE/medical 
history/surgery/non-drug therapy terms will be coded using the Medical Dictionary for 
Regulatory Activities. 
PRIVATE A'ID CO\l'fDENTIAL Tl\TORMATjQ:'- OF HORIZON TIIERAPEUTICS U.S.A., NC. 
Page 88 of 99 


Horizon Therapeutics U.S.A., Jnc. 
Date: 19 May 2023 
14 RETENTION OF RECORDS 
TEPEZZA® (teprotumumab-trbw; HZN-001) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
No trial documents at the site should be destroyed without prior written agreement between the 
Sponsor and the Investigator. All patient medical records, the Investigator's copy of the eCRF, 
other supporting data, records of drug dispensing and accountability, signed ICFs, IRB 
correspondence and correspondence with the Sponsor must be kept by the Investigator for at 
least 2 years or as required by 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. The Sponsor must be notified prior to the 
disposal of any trial-related files. If the Investigator leaves the practice or institution during the 
required retention period, it is important that arrangements be made for continued record 
retention. In that event, the records generally will be retained at the institution at which the trial 
was conducted. 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS U.SA., INC. 
Page 89 of99 


Hori:l.l,11 Thempcult,·s U.S.A .. In,. 
Dale: l O ]\[av 2023 
15 PUBUC'A TIOJ\' 
TEPt:::ZZA ® (teprolumumab-trbw; HZN-00 I) 
f'ro1ocol: HZNl'-TEP-403 
Version 5.0. /\mcm.lmcnt 4 
To aYoid disclosures that could jeopard in proprietary 1ights. 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. 
PRIVATE AND CONFIDENTIAL INFORMATION Of HORIZON TITERAPEUTICS U.S.A., INC. 
Page 90 of99 


Ho1izon Therapeutics U.S.A .. In..:. 
Dale: 19 May 2023 
16 REFERENCES 
TEPEZZ/\® (tcprotumumab-trbw; HZN-00 I) 
Protocol: I IZN P-TEP-40J 
Vt:r.\ion 5.0, A1m;ndmcn1 4 
Abraham-Nordling M. Rystrom K, Torring 0 , et al. Incidence of hyperthyroidism in Sweden. 
European Journal of Endocrinology. 20 11 ; 165(6):899-90:S. 
Bahn RS. Graves' ophthalmopathy. The New England Journal of Medicine. 20 I 0;362(8):726-38. 
Bartalcna L, Baldeschi L, Dickinson A, et al. Consensus statement of the European Group on 
Graves' orbitopathy (EUGOGO) on management of GO. European Journal of Endocrinology. 
2008; 158(3):273-85. 
Bartley GB. The cpidemiologic characteristics and clinical course of ophthalmopathy associated 
with autoimmune thyroid disease in Olmsted County, Minnesota. Transactions of the American 
Ophthalmological Society. l 994;92:477-588. 
Bartley GB, Fatoureclti V, Kadrmas EF, ct al. Long-term follow-up of Graves ophthalmopathy in 
an incidence cohort. Ophthalmology. 1996; I 03(6):958-62. 
Boschi A, Daumcric C, Spiritus M, et al. Quanli Ii cation of cells expressing the thyrotropin 
receptor in cxlraocular muscles in thyroid associated orbitopalhy. The 13rilish Journal of 
Ophthalmology. 2005;89(6):724-9. 
Burch IIB, Wartofsky L. Graves' ophthalrnopathy: current corn.:epts regarding pathogenesis and 
management. Endocrine Reviews. 1993; 14(6):747-93 . 
Coulter I, Frew in S, Krassas GE, et al. Psychological implications of Graves' orbitopathy. 
European Journal of Endocrinology. 2007; 157(2): 127-31. 
Dickinson AJ. (20 17). Clinical manift:stalions. In W. M. W iersinga & G. J. Kahaly (Eds.), 
Graves' orbitopathy: a multidisciplinary approach - questions and answers (3rd ed.): Karger 
Basel. 
Douglas RS, Kahaly GJ, Patel A, et al. Teprotumumab for the lrealment of active thyroid eye 
disease. New England Journal of Medicine. 2020;382( 4):341-52. 
Gerding MN, Terwee CB, Dekker FW, et al. Quality of life in patients with Graves' 
ophthalmopathy is markedly decreased: measurement by the medical outcomes study instrument. 
Thyroid: official journal of the American Thyroid Association. 1997;7(6):885-9. 
Kahaly GJ, Petrak F, Hardt J, et al. Psychosocial morbidity of Graves' orbitopathy. Clinical 
Endocrinology. 2005;63(4):395-402. 
Mallika P, Tan A, Aziz S, et al. Thyroid associated ophthalmopathy - a review. Malaysian family 
Physician : the official jownal of the Academy of Family Physicians of Malaysia. 
2009;4(1 ):8-14. 
PRIVATE AND CONFIDEKTIAL INFORMATION OF IIORIZON THERAPEUTICS U.S.A., fNC. 
Page 91 of99 


Horizon Therapeutics U.S.A., Inc. 
Date: !9 May 2023 
TEPEZZA ~ (teprotumumab-trbw; HZN-00 I) 
Protocol: HZNP-TEP-403 
Version 5.0, Amendment 4 
Marcovecchio, L. (201 7). Complications of acute and chronic hyperglycemia. US 
Endocrinology, 13 (1), 17-2 1. 
Mostbeck A, Galvan G, Bauer P, ct al. The incidence ofhyperthyrnidism in Austria from 1987 to 
1995 before and after an increase in salt iodization in 1990. European Journal of Nuclear 
Medicine. 1998;25(4):367-74. 
Maurits MP, Koomneef L. Wiersinga WM, et al. Clinical criteria for the assessment of disease 
activity in Graves' ophthalmopathy: a novel approach. The British Journal of Ophthalmology. 
I 989;73(8):639-44. 
Noth D, Gebauer M, Muller B, et al. Graves' ophthalmopathy: natural history and treatment 
outcomes. Swiss Medical Weekly. 2001;131(41-42):603-9. 
Prummel l\ff, Wiersinga WM. Smoking and risk of Graves· disease. Journal of the American 
Medical Association. l 993;269(4):479-82. 
Smith TJ. T11suli11-likr gmv.th fa..:tor-I rc~ulati011 0fi111111u11c fu11ctio11: a J)l)lc11tial Ll11.:rapeutic 
L1rg~·1 in au1oin111rn11c diseases'' Phar111,1cologic1I Reviews. 20 I 0;62(2): 191)-23(1. 
Sn1ith TJ. Kahaly GJ. E.:::ra DG. c't al. Tcprotumumab forThyroid-/\sso1.:iated Ophth;1l111opathy. 
The-
1cw f-11gbnd .loum;1I l)f 1\.frdici11c. 20 I 7;3 7o( IS): I 7-l8-6 I. 
Ta11da ML Pial1laniJn E. Liparull) Let al. Prcvakn-.:e and natural history or Graves' orbitopathy 
in :1 L1rg.e sail·s Lif pa[ic111s with newly di~1guoscd graves' hyperthyroidism seen at a single center. 
The Juurna.l or-Clinical Endocrinology and !Vktabolism. 2013;98t4): 1443-9. 
T erwee C, Wakdbmp I. Tan S, d al. Long-1em1 effects of Graves' ophthalmopathy on health-
related quality of life. European Journal ofl::ndocrinology. 2002;146(6):751-7. 
Tcrwee CB. Gerding \ttN, Dekker F\\.', et al. DeYeloprnent of a disease specific quality of life 
questionnaire for patients with Graves' ophthalmopathy: the GO-QOL. The British Journal of 
Ophthalmology. l 998;82(7):77 3-9. 
Ullrich.-\., Gray A, Tarn A \V, et al. lnsulin-likc growth factor I receptor primary structure: 
comparison with insulin receptor suggests structural detenninants that define functional 
sp~cificity. The E!viBO Journal. 1986;5( 10):2503-12. 
Wi.!rsinga W.\tl, Pen·os P, 1'.ahaly GJ, et al. Clinical assessment of patients with Graves' 
orbitopathy: the European Group on Graves' Orbitopathy recommendations to generalists, 
specialists and clinical researchers. European Journal of Endocrinology. 2006; 155(3):387-9. 
?RIVA E A:'m CO:--IFJDEJ-;T[AL NFORMA no . OF HORIZON THERAPEUTICS U.S.A., INC. 
Page 92 of99 


Horizon Therapeutics U.S.A., Inc. 
Dale: 19 May 2023 
17 APPENDICES 
TEPEZZA® (leprutumumab-trbw; I IZN-00 I) 
l'rolocol: I IZNl'-T El'-403 
Version 5.0, Amcmlmcnt 4 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS U.S.A , INC. 
Page 93 of99 


I i..,ri;:011 T hcr~1peu1i..:s U.S .A .. Inc. 
0:!!c 19 !\fay :20z..; 
TEPEZZA ® ( teprotumumab-trbw; 1 IZN-00 I) 
Protocul: I IZNP-T EP-403 
Vt:r~ion 5.0, Amendment 4 
17.1 Adminisrrativc Appendi..'\. 
Th.is :lppendix proYidcs names and contact information for the trial administrative structure. The 
IRB must be notified of ch:mgcs that are mad~ to this section, but IRB review or approval of 
these change.s is not required. Changes made in this section will be dated but will not be assigned 
a protocol amendment number. 
Mcdica.l Monitor 
Sponsor 
Representative 
Sponsor Contact for 
SAE Reporting 
PPD 
I Horizon Way 
Deerfield, IL 60015 
Mobile telephone number: 'PD 
Email: ...., _____________ _ 
PPD 
1 onzon Way 
Deerfield, IL 60015 
Office telephone number: 
Mobile tele hone number:~ ;P;Po~ ==~ 
Email: PD 
---------------
? Rl\'ATE A'-1D CO:SfflDENT IAL l'lFORMA TlON OF IIORIZON THERAPEUTICS U.S.A., fNC. 
Page 94 of99 


Horizon Therapeutics U.S.A., In.:. 
Date: l 9 May 20.lJ 
17.2 
TEPEZZA ® (lcprotumumab-lrbw; 1 IZN-00 I) 
Protocol: HZNP-TF.P-403 
Version 5.0, Amendment 4 
PRIVATE AND CONFIDENTIAL fNFORMA TION OF HORIZON THERAPEUTICS U.S.A., INC. 
Page 95 of99 


H,,n7,,n Th-:r:1prn111.:s U.S.:\ .. In,·. 
Dtirc: 19 ;\fay 202_; 
TEPEZZA ® lfcprotumumab-lrbw; IIZN-00 I) 
f)rnlocol: HZN 1'-TEP-403 
\\.:rsiun 5.0. Amrndrncnt 4 
17.3 Sampson Criteria for Anaphylactic Reaction 
AlUlphyl•.x;. i:s highly likely ...t>en ony one of the lollowing J c,iteria are fuffihd: 
I. A.urc o.o..<el of :ill i~< (mIDLIICS Ill SC\'trdl hoor.;) wilh invol\\.."ltlcnt of the skin. 1D11cosal tissue. or both (cg. generalized hives, pnritus or 
rlush111g. s"ollro l,ps-roogu,:,u\'ulu) 
/l/\'D AT /FAST CNF: OF THE F0/./0\VfNG 
a. Respiratory compromise (cg. dy,;int.1. wb=-1:rord,o,-pa.<m. <trirlor, rcducrd PEF. hypo, cmia) 
b. Rcdu:cd BP or :i.ssocittd symptoms cf cnd-orgllll dysfuOC1Jon (cg, hypo!Ooia [t'Ollapsci syncope. inrootincncc) 
! . Tv. o or more of th: following lhsl occur rapidly afier cxpo,,-urc 10 a Iii.el)' alkrsm for that parien1 (minutes !O several hours): 
tl lnvc,l',,·rn,cm of <Ile <kio•muro."11 tis.sue 1cg. g<e.ncnila:cd hiv~. 1lch-tlush. swollen lips-rmguc-uvul:!) 
b. Re1;>ir.ucry romiromi;or (eg. rly,:pnoi.. "'bccze,h<ond,ospa.sm, strider. n.-<luccrl PEF, hypoxcmia) 
c. Reduced BP or associated S')'lTIJXoms (cg. bypora:ua fcoQip:;c:J, synrupc. i.oronLincncc) 
d. l'tnislCl'l g1:,troiotcstinal S)'ll'41IOms (cg. ,T.unµy abdominal p:u1, vomiting) 
3. Rn.Lero BP lifter r.,posurc to .trw•·11 <ilcrycn for t!w.J parirru (minua;s 10 several bows): 
a lnfunr.s :il1d childn,n: low sysiolic BP (a~c- spccilic) or ~.!let' than 30~ de<.-rc= in sy,1olic BP• 
b. Adu]Ls: SJ,•.g o lic BP of less rhan 90 rnn Hg or greater Lhan 30% ch:rca.«c from Iha! pcn;<n 's ba,ctinc 
f'EF. f"eal: «p•"Ol<)() ilo..-: Bf. bl'Od prc:s<ure. 
' l o"' ;ysiolr blood fl"'<""" fnr chil<.tr«l i< defi"'-'<f 15 ""' dLO:\ 70 """ "s from I mMll, to I year. le<< lhl>l\ (70 mm Hg • (2 >< -sell &om I IO 10 you,, 
;10,j ~~ th.cl 90 mm Hg from 11 J.:, 17 yeu-1. 
!'RIYA \'l:: A:-lO ( (.1:"IFiDll\T IAL l)ff('Rlll:\ 1 101'\ OF HORIZON Tl IERAPEllrn:s l.'..S,A., INC. 
Page 96 of99 


Horizon Therapeutics U.S.A., Inc. 
Date: 19 May 2023 
17.4 Proptosis (Exophthalmometry) Method 
TEPEZZA ® (teprotumumab-trbw; HZN-00 I) 
Protocol: HZNl'-TEP-403 
Version 5.0, Amendment 4 
l . Choose a Hertel exophthalmometer provided by the Trial 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 . 
• 
• 
( 
move adjustable part to left side of 
patient only when right size is 
stabilised firmly in position 
5. Position left foot of Hertel against the patient's right lateral orbital rim, at level oflateral 
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. ln 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 instrwnent 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 
nikr. This is Hertel value. 
8. To record the left eye, hold the instrument stationary and move your head. Then use your 
1ight 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. 
PRIVATE ANO CONFIDENTIAL TNFORMATION OF HORIZON TIIERAPEUTICS U.S.A., !NC. 
Page 97 of99 


l·l(,riz,m Thrrnpcur1~·s U.S.A .. lnr. 
D:itc 19 ~la\' 2()~_; 
rl.:PE/.Z:\ ® (tcprohum1malHrbw; I lZN-001) 
Protocol: HZN l'-TEP-403 
Ycr~iun 5.0. Amc1uJmc11t 4 
CJ 
The distance along the borizonal bar. as <ldineJ by the location of tl1e feer on the lateral 
-:amhi. is also re.:ordcd us tl1e base Sll t.har the rnn-icrs will be set at the same base at 
subsequent readings for l'Ompnrison of the forward protrusion of each eye in relation to 
the bony orbit. 
PRN A TE A~ CONFIDE1'1l.-'\L T\rORMATION Of HORIZON TIIERAPEUTTCS U.S.A., INC. 
Page 98 of99 


Horizon Therapeutics U.S.A., Inc. 
Date: I 9 May 2023 
17.5 
Directions: 
TEPEZZA ~> (teprotumumab-trbw; HZN-00 I) 
Protocol: HZN'P-TEP-403 
Version 5.0, Amendment 4 
• 
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. 
The following questions deal with your thyroid eye disease in general. 
PRIVATE AND CONFIDENTIAL fNFORMA TION OF I JORlZON THERAPEUTICS U.S.A, NC. 
Page 99 of99 



SAP_001.pdf: 


Horizon Therapeutics U.S.A., Inc
                                                Statistical Analysis Plan, Version 6.0
HZNP-TEP-403
  Date Issued: 02OCT2023
Page 2
Approved by
Date: ___/___/___
Horizon Therapeutics U.S.A., Inc.
Approved by:
Date: ___/___/___
Horizon Therapeutics U.S.A., Inc.
PPD
PPD
PPD






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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................... 8 
1. 
INTRODUCTION .......................................................................................................... 10 
2. 
OBJECTIVES ................................................................................................................. 11 
2.1 
PRIMARY OBJECTIVE ........................................................................................................ 11 
2.2 
OTHER OBJECTIVES .......................................................................................................... 11 
2.3 
PHARMACOKINETIC AND ANTI-DRUG ANTIBODY OBJECTIVES ......................................... 11 
2.4 
SAFETY AND TOLERABILITY OBJECTIVES ......................................................................... 11 
2.5 
EXPLORATORY OBJECTIVE ............................................................................................... 12 
3 
INVESTIGATIONAL PLAN ........................................................................................ 12 
3.1 
OVERALL STUDY DESIGN AND PLAN ................................................................................ 12 
3.2 
STUDY ENDPOINTS ........................................................................................................... 13 
3.2.1 
Primary Endpoint...................................................................................................... 13 
3.2.2 
Other Efficacy Endpoints .......................................................................................... 13 
3.2.3 
Pharmacokinetic and Anti-drug Antibody Endpoints ............................................... 13 
3.2.4 
Safety and Tolerability Endpoints ............................................................................. 14 
3.2.5 
Exploratory Endpoints .............................................................................................. 14 
3.3 
STUDY EYE ....................................................................................................................... 14 
4 
TYPE OF PLANNED ANALYSIS ................................................................................ 14 
4.1 
INTERIM ANALYSIS ........................................................................................................... 14 
4.2 
PRIMARY ANALYSIS ......................................................................................................... 14 
4.3 
FOLLOW-UP ANALYSIS ..................................................................................................... 14 
5 
GENERAL STATISTICAL CONSIDERATIONS ..................................................... 15 
5.1 
SAMPLE SIZE .................................................................................................................... 15 
5.2 
RANDOMIZATION, STRATIFICATION, AND MASKING ......................................................... 16 
5.3 
ANALYSIS SET .................................................................................................................. 16 
5.3.1 
Intent-to-Treat (ITT) ................................................................................................. 16 
5.3.2 
Modified Intent-to-Treat (mITT) ............................................................................... 16 
5.3.3 
Per Protocol (PP) ..................................................................................................... 16 
5.3.4 
Safety ......................................................................................................................... 17 
5.3.5 
PK ............................................................................................................................. 17 
5.4 ASSESSMENT WINDOWS ....................................................................................................... 17 
5.5 MISSING DATA ALGORITHMS ............................................................................................... 19 
5.6 
MULTIPLICITY .................................................................................................................. 21 
6. PATIENT DISPOSITION ..................................................................................................... 21 
6.1 DISPOSITION ......................................................................................................................... 21 
6.2 PROTOCOL DEVIATIONS ........................................................................................................ 21 
7. DEMOGRAPHICS AND BASELINE CHARACTERISTICS .......................................... 22 
7.1 SUBSTANCE USE ................................................................................................................... 23 
7.2 MEDICAL HISTORY ............................................................................................................... 23 


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7.3 INCLUSION AND EXCLUSION CRITERIA ................................................................................. 23 
8. TREATMENTS AND MEDICATIONS ............................................................................... 23 
8.1 PRIOR AND CONCOMITANT MEDICATIONS ............................................................................ 23 
8.2 CONCOMITANT PROCEDURES ................................................................................................ 24 
8.3 RESTRICTED MEDICATIONS AND SURGICAL PROCEDURES .................................................... 24 
8.4 STUDY TREATMENTS ............................................................................................................ 25 
8.4.1 Extent of Exposure ........................................................................................................ 25 
8.4.2 Treatment Compliance and Modifications .................................................................... 25 
9. EFFICACY ANALYSIS ......................................................................................................... 25 
9.1 INTERCURRENT EVENT HANDLING STRATEGY FOR ESTIMANDS ........................................... 26 
9.2 PRIMARY EFFICACY ENDPOINT ............................................................................................. 26 
9.2.1 Primary Analysis Method .............................................................................................. 26 
9.2.2 Sensitivity Analysis Method ........................................................................................... 27 
9.2.3 Supplementary Analysis ................................................................................................ 29 
9.2.4 Subgroup Analysis ......................................................................................................... 29 
9.2.5 Exploratory Analysis ..................................................................................................... 29 
9.3 OTHER EFFICACY ENDPOINTS ............................................................................................... 30 
9.3.1 Proptosis Responder Rate at Week 24 .......................................................................... 30 
9.3.1.1 Primary Analysis Method ....................................................................................... 30 
9.3.1.2 Sensitivity Analysis Method ................................................................................... 31 
9.3.2 Change from Baseline at Week 24 in the GO-QoL Questionnaire Appearance and 
Visual Functioning Subscales ................................................................................................ 31 
9.3.3 
 ............................................................. 32 
9.3.4 
 .......................................................... 33 
9.3.5 
.......................................... 33 
9.4 EXPLORATORY ENDPOINTS ................................................................................................... 34 
9.4.1 
 ....................................................... 34 
9.4.2 
 
 ........................ 34 
9.4.3 
 .............................................. 34 
9.4.4 Clinical Activity Score ................................................................................................... 34 
10. SAFETY ANALYSIS ........................................................................................................... 34 
10.1 ADVERSE EVENTS ............................................................................................................... 35 
10.1.1 Incidence of Adverse Events ........................................................................................ 35 
10.1.2 Relationship of Adverse Events to Study Drug............................................................ 36 
10.1.3 Severity of Adverse Event ............................................................................................ 36 
10.1.4 Serious Adverse Events ............................................................................................... 36 
10.1.5 Adverse Events Leading to Treatment Discontinuation .............................................. 36 
10.1.6 Adverse Events of Special Interest (AESI) .................................................................. 37 
10.2 CLINICAL LABORATORY EVALUATIONS ............................................................................. 37 
10.3 VITAL SIGN AND WEIGHT MEASUREMENTS ........................................................................ 38 
10.4 OTHER SAFETY DATA ......................................................................................................... 38 
11. IMMUNOGENICITY: ANTI-DRUG ANTIBODY .......................................................... 38 
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12. PHARMACOKINETICS ..................................................................................................... 39 
13. CHANGES IN THE PLANNED ANALYSIS .................................................................... 39 
14. REFERENCES ...................................................................................................................... 41 
15. APPENDICES ....................................................................................................................... 42 
15.1 SCHEDULE OF ASSESSMENTS .............................................................................................. 42 
15.2 UNIT CONVERSION ............................................................................................................. 46 
15.3 GRAVES  OPHTHALMOPATHY QUALITY OF LIFE QUESTIONNAIRE ...................................... 47 
15.4 
 
 ........................................................................ 48 
15.5 
 
 
 
 
 
 
 
 .................................................................................................................................. 49 
15.5.1 
 ..................................................................................................... 49 
15.5.2 
 ........................................................................................................................ 50 
15.5.3 
............................................................................................................... 50 
15.6 
 
 
 
 
 ... 52 
15.6.1 
 ..................................................................................................... 52 
15.6.2 
 ......................................................................................................... 52 
15.6.3 
.............................................................................................................. 53 
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List of Abbreviations 
 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
best corrected visual acuity 
BMI 
body mass index  
CAS 
Clinical Activity Score 
CI 
confidence interval 
eCRF 
electronic case report form 
FCS 
full conditional specification 
FDA 
Food and Drug Administration 
FT3 
free triiodothyronine 
FT4 
free thyroxine 
GO-QoL 
 
HbA1c 
glycated hemoglobin 
HLT 
high level term 
ICE 
intercurrent event 
IGF 
insulin-like growth factor 
IGF-1R 
insulin-like growth factor-1 receptor 
ITT 
intent-to-treat 
IV 
intravenous(ly) 
kg 
kilogram 
LOCF 
last observation carried forward 
LS 
least squares 
mAb 
monoclonal antibody 
MCAR 
missing completely at random 
MedDRA
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MI 
multiple imputation 
mITT 
modified intent-to-treat 
MMRM 
Mixed-Model for Repeated-Measures 
 
 
NAb 
neutralizing antibody 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
PP 
Per Protocol 
PT 
preferred term 
PK 
pharmacokinetic 
PW 
premature withdrawal 
PW1 
premature withdrawal during the double-masked treatment 
period 
PW2 
premature withdrawal during the open-label treatment 
period 
Q1 
first quartile 
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Q3 
third quartile 
q3W 
once every 3 weeks 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
SMQ 
standard MedDRA query 
TEAE 
treatment-emergent adverse events 
TED 
thyroid eye disease 
TEPEZZA  
teprotumumab-trbw; HZN-001 
TLF 
tables, listings, and figures 
TSH 
thyroid stimulating hormone 
U.S.A./US 
United States of America 
VAS 
visual analog scale 
W 
week 
WHO 
World Health Organization 
 
 
 


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1. Introduction 
 
Thyroid eye disease (TED), also termed 
-
associated ophthalmopathy, is a serious, debilitating and painful autoimmune disease that can, in 
hyperthyroidism/disease, but also occurs in a proportion of patients with other autoimmune 
 
TEPEZZA ® (teprotumumab-trbw, HZN-001), hereafter referred to as TEPEZZA) is a fully 
human immunoglobulin G1 monoclonal antibody (mAb) directed against human insulin-like 
growth factor -1 receptor (IGF-1R). The IGF-1R is a tyrosine kinase cell surface receptor that 
shares ~50% overall homology with the insulin receptor [Ullrich et al, 1986]. TEPEZZA binds 
with high affinity and selectivity to the extracellular domain of IGF-1R and prevents its 
activation by the endogenous ligands, IGF-1 and IGF-2. 
TEPEZZA was approved by the US Food and Drug Administration (FDA) on 21 January 2020 
for the treatment of TED. 
Previous teprotumumab clinical trials for the TED indication include 2 independent, randomized, 
double-masked, placebo-controlled, parallel-group, multicenter trials (Phase 2 Trial TED01RV 
[Smith et al, 2017] and Phase 3 Trial HZNP-TEP-301 [Douglas et al, 2020]). In these 2 trials, 
teprotumumab resulted in statistically significant and clinically relevant improvements in 
measures that assessed multiple facets of TED (proptosis, inflammation as measured by Clinical 
Activity Score [CAS], diplopia and quality of life). In addition, the persistence of effect was 
demonstrated after approximately 1 year off treatment. Consistent results were shown across all 
efficacy endpoints and all subpopulations.  
In the Phase 2 trial, the majority of reported adverse events (AEs) were mild, required no 
treatment and resolved while patients remained on drug. Hyperglycemia, which was monitored 
by assessing blood glucose and glycated hemoglobin (HbA1c), was the only mechanism-based 
anticipated AE clearly identified as related to teprotumumab.  
In the Phase 3 trial, teprotumumab was well tolerated and demonstrated an acceptable safety 
profile, replicating the results of the Phase 2 trial.   
This phase 4 study is a randomized, double-masked, placebo-controlled, parallel-group, 
multicenter trial study. The dose of either TEPEZZA (10 mg/kg for the first infusion and 20 
mg/kg for the remaining 7 infusions) or placebo will be administered to patients with chronic 
(inactive) TED. 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, listings, and figures (TLFs) of the primary analysis and follow-
up analysis for Study HZNP-TEP-403. The primary analysis is planned after all patients 
complete the week 24 visit 
 in the double-masked treatment period or withdraw from 
the study prior to Week 24. The follow-up analysis is planned after all patients complete the 30-
day follow-up period or terminate early from the study during the follow-up period. The SAP is 


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based on protocol: administrative change 1 to Protocol number: HZNP-TEP-403 V4.0 
(Amendment 3.0), dated on 15 December 2022 by Horizon Therapeutics U.S.A., Inc. 
2. Objectives 
 
The overall objective is to investigate the efficacy, safety and tolerability of TEPEZZA® in 
comparison to placebo in treating patients with chronic (inactive) TED. 
2.1 Primary Objective 
 
The primary objective is to evaluate the effect of TEPEZZA versus placebo on the change of 
proptosis measurements in the study eye from Baseline at Week 24 in patients with chronic 
(inactive) TED.  
2.2 Other Objectives 
1. To evaluate the effect of TEPEZZA versus placebo on the proptosis responder rate (i.e., 
the percentage of patients 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. 
2. To evaluate the effect of TEPEZZA versus placebo on the change from Baseline at Week 
24 in the Graves' Ophthalmopathy Quality of Life (GO-QoL) questionnaire appearance 
and visual functioning subscales. 
3. To evaluate the effect of TEPEZZA versus placebo on the 
 
 
4. To evaluate the effect of TEPEZZA versus placebo on the 
 
 
 
. 
5. To evaluate the effect of TEPEZZA versus placebo on the 
 
 
. 
2.3 Pharmacokinetic and Anti-drug Antibody Objectives 
1. To evaluate the pharmacokinetic (PK) of TEPEZZA. 
2. To evaluate the immunogenicity of TEPEZZA.   
2.4 Safety and Tolerability Objectives 
 
To assess safety and tolerability of TEPEZZA versus placebo based on: 
1. Adverse events (AEs) 
2. AEs of special interest (AESIs) (infusion reactions, hyperglycemia, hearing impairment, 
new onset inflammatory bowel disease and exacerbation of inflammatory bowel disease) 
3. Vital signs 
4. Visual acuity 
5. Clinical safety laboratory evaluations (hematology, chemistry, thyroid function tests and 
glycated hemoglobin [HbA1c])  
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2.5 Exploratory Objective 
1. To evaluate the effect of TEPEZZA versus placebo on the 
 
  
2. To evaluate the effect of TEPEZZA versus placebo on the 
 
 
 
 
3. To evaluate the effect of TEPEZZA vs placebo on the 
 
 
3 Investigational Plan 
3.1 Overall Study Design and Plan 
 
This is a randomized, double-masked, placebo-controlled, parallel-group, multicenter trial. 
Patients will be screened for the trial within 4 weeks prior to the Baseline (Day 1) Visit. 
Approximately 57 patients who meet the trial eligibility criteria will be randomized on Day 1 in a 
2:1 ratio to receive 8 infusions of TEPEZZA (10 mg/kg for the first infusion and 20 mg/kg for 
the remaining 7 infusions) or placebo once every 3 weeks (q3W). All patients will enter a 24-
week double-masked treatment period, during which trial 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 of the 24-week 
treatment period). 
At the end of the double-masked treatment period (Week 24), all patients will be assessed for 
treatment response. The primary treatment response is assessed based on the change in proptosis 
from Baseline. Proptosis responders were defined as patients with a 2 mm or greater reduction in 
proptosis from Baseline in the study eye, without deterioration (i.e., 2 mm or great increase) of 
proptosis in the fellow eye.  Proptosis non-responders who have completed the double-masked 
treatment period may choose to receive 8 infusions of TEPEZZA (10 mg/kg for the first infusion 
and 20 mg/kg for the remaining 7 infusions) in an open-label fashion q3W at Weeks 24, 27, 30, 
33, 36, 39, 42 and 45. These patients will return to the clinic at Week 48 for End-of-Treatment 
assessments, and patients will be contacted by phone/email 30 days after the Week 48 Visit for 
safety assessment. Proptosis responders, as well as non-responders who choose not to receive 
TEPEZZA in an open-label fashion, will enter a 30-day Follow-up Period, during which study 
drug will not be administered. These patients will be contacted by phone/email 30 days after the 
Week 24 Visit for safety assessment. 
An overview of the trial design is presented in Figure 1, and details of trial activities are 
presented in Section 15.1, Schedule of Assessments.   
 
 
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Figure 1    Schematic of Trial Design 
 
* Infusion of trial drug (TEPEZZA or placebo in double-masked treatment period and open-label TEPEZZA in open-label 
treatment period). 
BL=Baseline; q3W=once every 3 weeks; W=Week. 
1. Patients will be randomized in a 2:1 ratio to receive: 
a. TEPEZZA (10 mg/kg on Day 1 followed by 20 mg/kg q3W for the remaining 7 infusions); or 
b. Placebo (placebo q3W for all 8 infusions). 
2. Visit windows are ±3 days for Weeks 3, 6, 9, 12, 15, 18 and 21 of double-masked treatment period and Weeks 27, 30, 33, 36, 
39, 42 and 45 of open-label treatment period, and ±7 days for Week 24 of double-masked treatment period, Week 48 of open-
label treatment period and 30-day Follow-up Period. 
3.  All patients will be contacted by phone/email the day after infusion for the first and second infusions during the  
double-masked treatment period and during the open-label treatment period, and thereafter as deemed appropriate; additional 
phone/email contacts will occur the day after any clinic visit where a patient experiences an infusion-related adverse event. 
4. Patients who are proptosis non-responders at Week 24 of the double-masked treatment period will be offered the option to 
receive 8 infusions of TEPEZZA (10 mg/kg on Day 1 followed by 20 mg/kg for the remaining 7 infusions) in an open-label 
fashion. 
5.  All patients will be contacted via phone or email 30 days (±7 days) following the Week 24 (responders and non-responders 
who choose not to receive open-label TEPEZZA) or Week 48 (non-responders who receive open-label TEPEZZA) Visit. 
 
3.2 Study Endpoints 
3.2.1 Primary Endpoint 
 
The primary efficacy endpoint is the change from Baseline at Week 24 in proptosis in the study 
eye. 
3.2.2 Other Efficacy Endpoints 
1. The proptosis responder rate (percentage of patients 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.  
2. The change from Baseline at Week 24 in the GO-QoL questionnaire appearance and 
visual functioning subscales.  
3.2.3 Pharmacokinetic and Anti-drug Antibody Endpoints 
1. The peak and trough concentrations of TEPEZZA. 
2. The anti-drug antibody (ADA) incidence and titers.   
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3.2.4 Safety and Tolerability Endpoints 
1. The incidence of treatment-emergent adverse events (TEAEs,) serious adverse events 
(SAEs), TEAEs resulting in premature discontinuation of treatment and AESIs (infusion 
reactions, hyperglycemia, hearing impairment, new onset inflammatory bowel disease 
and exacerbation of inflammatory bowel disease). 
2. The incidence of Grade 3 TEAEs. 
3. The change from Baseline to each scheduled visit in vital signs (blood pressure, heart 
rate, respiratory rate and temperature). 
4. The results of best-corrected visual acuity.  
5. 
de 3 fasting glucose values. 
6. The change from Baseline to each scheduled visit in laboratory evaluations (hematology 
and chemistry [including thyroid panel and HbA1c]). 
3.2.5 Exploratory Endpoints 
3.3 Study Eye 
 
be identified. If both e
eyes will be assessed for efficacy, but the study eye will be used to assess the primary efficacy 
endpoint. 
4 Type of Planned Analysis 
4.1 Interim Analysis 
 
 
4.2 Primary Analysis 
 
 
4.3 Follow-up Analysis 
 
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1. 
 
2. 
supplementary 
 
3. 
 
 
5 General Statistical Considerations 
 
The primary efficacy endpoint will be tested at the level of significance of 0.05 two-sided. Other 
efficacy endpoints will be tested in a sequential order as listed in Section 3.2.2 only when 
statistical significance is achieved for the primary efficacy endpoint and the other preceding 
endpoint in the prespecified order is statistically significant at the 0.05 significant level (two-
sided).  
In general, continuous data will be summarized by treatment group using descriptive statistics 
(number, mean, standard deviation (SD), minimum, 25th (Q1) percentile, median, 75th (Q3) 
percentile, and maximum). Categorical data will be summarized by treatment group using 
frequency tables (frequencies and percentages). SD will be presented to two decimal places 
beyond the precision with which the data was captured. Mean, median, Q1, and Q3 will be 
presented to one decimal places beyond the precision with which the data was captured. 
Minimum and maximum will be presented to the precision with which the data was captured. 
When count data are presented, the percentage will be suppressed when the count is zero in order 
to draw attention to the non-
tabulations where specified on the shells to account for dropouts and missing values. The 
denominator for all percentages will be the number of patients (including the missing category) 
in that treatment group within the analysis set of interest, unless otherwise specified. P-values 
will be rounded to 4 decimal places. If a p-value is less than 0.0001 it will be reported as 
-
 
All study-related raw data that support the corresponding tables and figures will be presented in 
data listings. Unless otherwise noted, all data listings will be sorted by treatment group and 
patient number. 
5.1 Sample Size 
 
A total of 57 patients (38 in the TEPEZZA group and 19 in the placebo group) will be enrolled in 
the trial to detect at least a 2-mm mean difference between the 2 treatment groups in the change 
from Baseline of proptosis values at Week 24 in order to have 81% power at the two-sided 0.05 
level of significance. The sample size was determined assuming that the mean difference in 


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proptosis change between the 2 groups is at least 2.0 mm (clinically relevant) and the standard 
deviation of proptosis change values is 2.5 for both groups (larger than the observed in Phase 2 
and Phase 3 active TED trials). 
5.2 Randomization, Stratification, and Masking 
 
TEPEZZA
 
 
 
 
5.3 Analysis Set 
5.3.1 Intent-to-Treat (ITT) 
 
 
5.3.2 Modified Intent-to-Treat (mITT) 
 
The modified intent-to-treat (mITT) analysis set will include all ITT 
 who receive at least 
one dose of study drug and have at least one post-baseline measurement of the primary efficacy 
endpoint. The mITT analysis set will be used to perform a supplementary analysis of the primary 
efficacy analysis for the double-masked treatment period. Patients will be analyzed according to 
their randomized treatment assignment. If the ITT analysis set is the same as the mITT analysis 
set because all randomized patients have met the mITT definition, then analysis results based the 
mITT analysis set will not be provided. 
5.3.3 Per Protocol (PP) 
 
The per protocol (PP) analysis set includes all mITT patients who complete the double-masked 
treatment period and do not incur any major protocol violations that would challenge the validity 
of their data. The PP analysis set will also be used to conduct as a supplementary analysis of the 
primary efficacy analysis. Patients will be analyzed according to treatment received. Major 
protocol violations that challenge the validity of the data will be identified by a masked review 


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on a regular basis while the study is ongoing and the review for major protocol deviations will be 
completed prior to the Week 24 database lock for the primary analysis. 
5.3.4 Safety 
 
 
5.3.5 PK 
 
 
5.4 Assessment Windows           
5.4.1 Study Day and TEPEZZA Study Day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.4.2 Baseline and TEPEZZA Baseline 
 
 
 
 


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5.4.3 Visit Windows for Analysis 
 
For analyses that present visit-based data, the variables will be summarized based on the 
scheduled visits with derived analysis visit windows, with the exception of PK data, anti-drug 
antibody (ADA)/neutralizing antibody (NAb) data, and 
, which will be 
analyzed based on nominal visits.  For the visits on and after the first dose date, the actual visit 
date will be mapped to the derived analysis visit windows based on the study day. 
 
 
 
 
 
 
 
 
 
 
 
 
hematology  
 For postbaseline visits, if there are multiple records with the same time or no time 
recorded on the same day, the value with the worst severity within the window will be 
selected (e.g., abnormal will be selected over normal for hematology). 
The Analysis Visit Window for the primary endpoint (change of proptosis), other endpoints 
(
) and exploratory endpoint (
) is shown in 
. The details for 
the other analysis visit window rules will be included in the TLF shell document. 
 
 
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 If day is missing, and the month and year match the month and the year of the first dose 
date, the day of the first dose date will be imputed and the AE will be considered 
treatment emergent. Otherwise, the first of the month will be used and the treatment-
emergent status will be assessed relative to the dosing start date. 
 If the day and month are missing, and the year matches the year of the first dose date, the 
month and the day of the first dose date will be imputed, and the AE will be considered 
treatment emergent. Otherwise, January 1 will be used and the treatment emergent status 
will be assessed relative to the dosing start date. 
 If the start date is completely missing, the AE will be considered treatment emergent 
unless the stop date is complete and prior to the first dose or provides enough partial 
information to rule out a treatment-emergent status. 
 If the stop date is complete and the imputed start date is after the actual stop date, then 
the start date will be imputed as the stop date and the treatment-emergent status will be 
assessed relative to the dosing start date. 
 
Any missing intensity 
 
 
5.5.4 Medication Dates 
 
For prior and concomitant medications with incomplete dates, the following rules will be used to 
impute start and/or stop dates for the purposes of determining if a medication is prior or 
concomitant only. Imputed dates will not be presented in the data listings. 
 
For partial or missing start dates: 
 
 If day is missing, and the month and year match the month and the year of the first dose 
date, the day of the first dose date will be imputed. Otherwise, the first of the month will 
be used.  
 If day and month are missing and the year matches the year of the first dose date, the 
month and the day of the first dose date will be imputed. Otherwise, January 1 will be 
used.  
 If the start date is completely missing, the start date will not be imputed. If the stop date 
is after first dose date, the medication will be considered to be concomitant. If the stop 
date is prior to the first dose date, the medication will be considered to be prior.  
 If the stop date is complete and the imputed start date is after the actual stop date, then 
the start date will be imputed as the stop date.  
 
For partial or missing stop dates: 
 For stop dates, if the day is missing, then the last day of the month will be used.  
 If the month is missing, then December will be used.  
 If the stop date is completely missing, then the latest date available in the dataset for the 
patient will be used.  
 All medications with a missing stop date will be considered as concomitant. 


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5.6 Multiplicity 
 
 
1. 
percentage of patients 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 
2. 
appearance and visual 
functioning subscales 
 
6. Patient Disposition 
6.1 Disposition 
 
 
 
6.2 Protocol Deviations 
 
deviation 
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 and treatment period for ITT analysis set
 
7. Demographics and Baseline Characteristics 
 
, and time since diagnosis of TED [in years])
, and time since diagnosis of TED
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
during the double-masked treatment period and for the ITT analysis set 
during the open-label treatment period
If mITT and 
safety analysis sets are the same as the ITT analysis set, then summaries based on mITT and 
safety analysis sets will not be presented. For the open-label treatment period, baseline values 
will be recalculated based on the TEPEZZA Baseline.
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s such as 
 
7.1 Substance Use 
 
 
7.2 Medical History 
 
version 24.0  
 
 
7.3 Inclusion and Exclusion Criteria 
 
 
8. Treatments and Medications 
8.1 Prior and Concomitant Medications 
 
 
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during the follow-up period are defined as all medications that start after 21 days of the last dose 
of study drug through completion of follow-up period, or medications that start before 21 days of 
the last dose of study drug and continue during the follow-up period. 
All medications will be mapped to the preferred terms according to WHODrug dictionary 
version March 2021. 
The number and percentage of patients in each treatment group using prior medications and 
concomitant medications will be summarized by Anatomical Therapeutic Chemical (ATC) Level 
4 term and Preferred Term. At each level of report, a patient will be counted only once even if 
the patient has taken more than one medication in the level. 
All prior and concomitant medications (including concomitant medications during the follow-up 
period) will be presented in a by-subject listing with an indicator to identify whether their use is 
prior and /or concomitant.   
8.2 Concomitant Procedures 
 
All concomitant procedures performed during the trial will be presented in a by-subject listing 
for all patients enrolled. 
8.3 Restricted Medications and Surgical Procedures 
 
 Restricted surgical procedures are (1 category): 
- 
. This category 
 
 Restricted medications or drugs are (9 categories): 
- 
 s
or Roactemra®)
TEPEZZA
monoclonal 
 
- 
 
 
All restricted medication categories described above are reviewed manually by Horizon patient 
safety and pharmacovigilance. 
The number and percentage of patients who received restricted surgical procedures in each 
treatment group will be summarized by SOC and preferred terms.  
The number and percentage of patients who received restricted medications in each treatment 
group for each treatment period will be summarized by  
 ATC Level 4 term and preferred terms for concomitant medications. 


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 SOC and preferred terms for medical history and adverse event   
A patient who reported the same event more than once will be counted only once in the 
applicable category, SOC (or ATC Level 4), and preferred term for that event. 
All restricted medications and surgical procedures will be presented in a by-subject listing.   
8.4 Study Treatments 
8.4.1 Extent of Exposure 
 
Extent of exposure will be measured and summarized by duration of exposure and total number 
of infusions and presented by treatment period (double-masked treatment period/open-label 
treatment period) and TEPEZZA. 
The duration of exposure (days) for each treatment period will be calculated as:  
The duration of exposure (days) for each treatment period = the last dosing date in each 
treatment period - the first dosing date in each treatment period +1. 
 
The duration of exposure (days) to TEPEZZA will be calculated as the sum of treatment duration 
to TEPEZZA in double-masked treatment period and open-label treatment period. 
The total number of infusions given is the sum of actual infusions received by patient for each 
treatment period. 
The total number of infusions to TEPEZZA is the sum of TEPEZZA infusions received in 
double-masked treatment period and open-label treatment period 
8.4.2 Treatment Compliance and Modifications 
 
All doses of study drug will be administered and recorded by study site personnel, and any 
administration records will be listed for each patient with study drug administered, start date and 
 
Summaries will be provided for the count and percentages of patients with each of the following 
by treatment group for each treatment period: 
 Planned doses that were not administered completely 
 Infusion interruptions 
Planned TEPEZZA doses that were not administered completely and infusion interruptions to 
TEPEZZA in double-masked treatment period and open-label treatment period will be 
summarized by treatment group. 
9. Efficacy Analysis 
 


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Efficacy analysis will be conducted for the double-masked period (as the primary analysis) and 
open-label period (as the follow-up analysis) separately based on the ITT analysis set.   Efficacy 
analysis results from the primary analysis (i.e., based on the data collected during the double-
masked period) will be used for comparison between the two treatment groups.  Both study and 
fellow eyes will be used for the efficacy analyses during the primary analysis, but the statistical 
inference will be made based on study eye analysis results only. For the follow-up analysis, 
which will be conducted using subsequent assessments collected during the open-label treatment 
period, only descriptive summaries of efficacy analysis results will be provided.  
9.1 Intercurrent Event Handling Strategy for Estimands 
 
Potential intercurrent events (ICEs) like discontinuing from the treatment may occur. Patients 
who discontinue from the treatment will be encouraged to stay in the trial after those ICEs and 
data will be collected through the planned study completion visit.  
 
In general, treatment policy strategy will be used to account for the ICEs for defining estimands 
corresponding to continuous efficacy endpoints, including the primary efficacy endpoint. All 
efficacy analyses will be based on the observed data except for categorical efficacy endpoints. 
For categorical endpoints, composite strategy will be used.  For binary responder endpoints, 
patients whose Week 24 assessment is missing will be considered treatment failures 
(non responders). For ordinal response endpoint, missing value at Week 24 will be imputed 
using the last assessment value available for patients whose Week 24 assessment is missing. 
9.2 Primary Efficacy Endpoint 
 
The primary efficacy endpoint is the change in proptosis from Baseline at Week 24 in the study 
eye. 
 
Population 
ITT Analysis Set defined as all patients who were randomized in the trial 
Endpoint 
Change from Baseline at Week 24 in proptosis of the study eye 
ICE 
Discontinued from treatment early 
Population-level 
Summary 
Difference (TEPEZZA minus placebo) in least squares means of changes 
from Baseline at Week 24 in proptosis of the study eye between the 
treatment groups 
9.2.1 Primary Analysis Method 
 
 
The primary efficacy endpoint analysis will be conducted based on the ITT analysis set.  
 
A Mixed-Model for Repeated-Measures (MMRM) analysis of covariance model fitting to the 
individual change from Baseline values for the study eye will be used for the analysis of change 
from Baseline in proptosis. The model includes Baseline value, treatment group, visit, visit-by-


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treatment and visit-by-Baseline value as fixed effects, and patient as a random effect as shown 
below: 
 
 
where  
 yt is a vector of change in proptosis from Baseline at visit t 
 visit t is Week 3, 6, 12, 18 or 24 
   is an unknown vector of fixed-effects parameters with known design matrix 
= 
(Baseline value, treatment group, ,  *treatment group,  * Baseline value) 
 
 is an unknown vector of random-effects parameters with known design matrix 
= 
patient, and 
 
is an unknown random error vector. 
 
It is assumed that and  are Gaussian random variables that are uncorrelated and have 
expectations 0 and variances  and , respectively. The variance of  is 
 
where  and  are unstructured covariance.  
 
If there are model convergence issues with an unstructured variance-covariance matrix, the 
following three variance-covariance matrices will be attempted in order until one converges: 
heterogeneous Toeplitz (TOEPH), heterogeneous compound symmetry (CSH), and Toeplitz 
(TOEP). If there are any patients in the ITT analysis set without post-baseline values, a change 
from Baseline value of 0 will be imputed at the first post-baseline visit (in order to avoid 
exclusion of these patients from the MMRM analysis). 
 
The p-values for all terms in the model will be presented, as well as the overall treatment group 
least squares (LS) means and associated standard errors (SE), and their difference, SE of the 
difference, 95% confidence intervals (CIs) for the difference and p-value. The primary analysis 
will be to test the treatment difference at Week 24. Analysis results at Week 24 present the 
estimated LS means, SEs and their difference with the SE, 95% CI for the difference and p-
value.  
 
Further, the analysis will be repeated using assessments obtained from the fellow eye based on 
the ITT analysis set. 
 
Descriptive summaries of change from Baseline in the proptosis for study eye and fellow eye at 
each scheduled visit will be provided by treatment group for each treatment period based on the 
ITT analysis set.  
 
Changes from Baseline in proptosis of the study eye over time during the double-masked 
treatment period will be depicted by treatment group using LS means of change and 
corresponding 95% CI. 
9.2.2 Sensitivity Analysis Method 
 


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9.2.3 Supplementary Analysis 
 
The primary efficacy analysis described in Section 9.2.1 will be repeated using the mITT and PP 
analysis sets on study eye only.  
 
Descriptive summaries of change from Baseline in the proptosis for study eye and fellow eye at 
each scheduled visit will be provided by treatment group for each treatment period using the 
mITT and PP analysis sets.  
9.2.4 Subgroup Analysis 
 
The primary efficacy endpoint will be evaluated for subgroups of interest, including:   
 
 Race (White, Black or African American, Asian, Other) 
 Tobacco use status (Non-user, User) 
 Age (<65 years, >=65 years) 
 Sex (Male, Female) 
 
For race, if the number of patients in any of the race groups is less than 5, we will 
Non-White . For other variables, if the number of 
patients is less than 5 in any subgroup, then subgroup analysis will not be performed. For 
-
eCRF. 
 
9.2.5 Exploratory Analysis 
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responder status at each scheduled visit in open-label treatment period, but no analysis of risk 
difference will be performed. 
 
Line plot of proptosis responder rate over time by treatment group for the study eye based on the 
ITT analysis set will be provided for each treatment period.  
9.3.1.2 Sensitivity Analysis Method 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
9.3.2 Change from Baseline at Week 24 in the GO-QoL Questionnaire Appearance and 
Visual Functioning Subscales 
 
The GO-QoL questionnaire (see Protocol section 17.5) has 
 
 
 
 
 
 
 
 
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9.3.3 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The same primary analyses described in Section 9.3.1.1 will be repeated for this endpoint. 
9.4 Exploratory Endpoints 
9.4.1 
  
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
10. Safety Analysis 
 
Safety parameters include monitoring of TEAEs, SAEs, vital sign measurements, laboratory tests 
and visual acuity. 
Safety data will be summarized and listed with no statistical hypothesis testing performed. 
Continuous variables will be summarized using the mean, the SD, median, 25th percentile, 75th 
percentile, minimum value, and maximum value. Categorical variables will be summarized using 
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frequency counts and percentages. All safety summaries and analyses will be conducted 
separately for each treatment period based on the safety analysis set.  
10.1 Adverse Events 
 
Adverse events will be coded using MedDRA version 24.0. AEs that occur during Screening and 
prior to dosing on Day 1 will be considered pre-treatment AEs. TEAEs for the double-masked 
treatment period is defined as AEs with onset date on or after the first dose of study drug during 
the double-masked treatment period prior to receiving the first dose of TEPEZZA during open-
label treatment period for patients who entered open-label treatment period, or through 3 weeks 
(21 days) after the last dose of study drug during the double-masked treatment period for patients 
who did not enter open-label treatment period. TEAEs for open-label treatment period defined as 
AEs with onset date on or after first dose of TEPEZZA during the open-label treatment period 
through 3 weeks (21 days) after last dose of TEPEZZA during the open-label treatment period. 
All analyses for TEAEs will be split to TEAEs reported during the double-masked treatment 
period and open-label treatment period separately. The follow-up AE reporting period begins 3 
weeks (21 days) after the last dose of study drug through completion of the follow-up period.  
An overall summary of all TEAEs including the number and percentage of patients experiencing 
at least one occurrence of a TEAE, serious TEAEs, treatment-related TEAEs, treatment-related 
serious TEAEs, TEAEs resulting in study drug discontinuation, TEAEs of special interest, 
TEAEs leading to death along with the summary of National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) grade 3 or higher will be provided. 
Additionally, AEs and SAEs reported during the follow-up period after each treatment period 
will be presented by SOC and PT separately. 
All AEs, AEs with CTCAE Grade 3 or higher, SAEs, AEs leading to discontinuation of study 
drug, AE of special interest, and deaths will be presented in separate by-subject listings. 
Signs and symptoms associated with Infusion reaction and anaphylaxis will be recorded and 
included in a by-subject listing. 
10.1.1 Incidence of Adverse Events 
 
The incidence of AEs will be reported by SOC and PT level for each treatment period. The 
patient will be counted only once in corresponding category if the patient experiences more than 
one event under the same SOC or PT level.  
The total number of TEAEs and the number and percentage of patients with at least one TEAE 
for each SOC and PT will be presented by treatment group. 
Incidence of TEAEs by SOC and PT by the following subgroups for each treatment period will 
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 Race (White, Black or African American, Asian, Other) 
 Tobacco use status (Non-user, User) 
 Age (<65 years, >=65 years) 
 Sex (Male, Female) 
 
-
patients is less than 5 in any subgroup, then subgroup analysis will not be performed. For 
-
eCRF. 
10.1.2 Relationship of Adverse Events to Study Drug 
 
The relationship between study treatment and AE will be captured on the eCRF. The AE records 
with missing relationship information will be summarized as related AEs.  
Summary of all TEAEs and SAEs respectively will be presented by SOC, PT and relationship 
(Unrelated/Related) to study drug. 
10.1.3 Severity of Adverse Event 
 
The severity of AEs will be evaluated by the NCI-CTCAE (v4.03). the grade will be assessed by 
the investigator as mild (Grade 1), moderate (Grade 2), severe (Grade 3), life-threatening (Grade 
4), or fatal (Grade 5). 
For AE grade tables, the patient will be counted once with the highest-grade event if he/she 
experiences more than one event under given SOC or PT level.  
A summary of CTCAE Grade 3 or higher TEAEs by SOC and PT will be presented by treatment 
group.  
Summary of all TEAEs and SAEs respectively will be presented SOC, PT and maximum 
severity of AEs. 
10.1.4 Serious Adverse Events 
 
The SAE is defined as any event that results in death, is immediately life threatening, requires 
inpatient hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability/incapacity, or is a congenital anomaly/birth defect. 
A summary of all SAEs by SOC and PT will be presented by treatment group. 
10.1.5 Adverse Events Leading to Treatment Discontinuation 
 


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AEs leading to treatment discontinuation will be captured in the eCRF AE page. Besides 
treatment discontinuation, other consequences include drug interrupted, dose reduced, delayed, 
and increased will also be collected. 
A summary of TEAEs leading to premature discontinuation of treatment by SOC and PT will be 
presented by treatment group.  
10.1.6 Adverse Events of Special Interest (AESI) 
 
AESIs include infusion reactions, hyperglycemia, hearing impairment, new onset inflammatory 
bowel disease and exacerbation of inflammatory bowel disease.  
Infusion reactions will be collected on the AE eCRF form; hyperglycemia will be captured via 
standard MedDRA query (SMQ) narrow term "Hyperglycaemia/new onset diabetes mellitus"; 
hearing impairment will be captured via sub-SMQ term "Hearing impairment" (under SMQ 
and high level term (HLT) term "Hearing losses"; and new 
onset inflammatory bowel disease and exacerbation of inflammatory bowel disease will be 
captured via HLT term 
. 
A summary of TEAEs of special interest by SOC and PT will be presented and corresponding 
AESI listing will be provided  
10.2 Clinical Laboratory Evaluations 
 
With the exception of urine pregnancy tests, a central laboratory will be used for all protocol-
specified clinical laboratory parameters. Laboratory results reported in conventional units will be 
converted to International System of Units (SI) for all summaries and listings for consistent 
results presentation.  
Safety laboratory including hematology, chemistry, thyroid function tests and HbA1c values and 
change from Baseline values will be summarized by visit and treatment group for each treatment 
period using descriptive statistics. For fasting glucose and HbA1c, means and 95% CI of the test 
results measured at each scheduled visit will be plotted. 
The laboratory assessment will be categorized as low, normal or high based on normal ranges. 
Shift tables using categories of low, normal and high from Baseline (i.e., based on normal 
reference ranges) to each post-baseline visit will be generated by treatment group for each 
treatment period for hematology, chemistry parameters, thyroid function and HbA1c, 
respectively. 
The laboratory assessment will be graded using the NCI-CTCAE (v4.03) grading scale, when 
available. A shift table for glucose by NCI-CTCAE grade and visit will be generated by 
treatment group. Another table with summary of incidence of  Grade 3 glucose will be 
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For those patients who experienced hyperglycemia (per AE reporting), their safety laboratory 
assessment results during the double-masked treatment period will be examined and summarized 
using the similar manner described above. 
10.3 Vital Sign and Weight Measurements 
 
Vital signs measurements will include systolic and diastolic blood pressures, heart rate, 
respiratory rate, height, weight, BMI and temperature.  
Descriptive summaries of observed and change from Baseline values will be presented for each 
vital sign parameter by treatment group and visit for each treatment period.  
A summary table for weight loss and a shift table for hypertension by NCI-CTCAE grade will be 
generated by treatment group and visit for each treatment period. 
10.4 Other Safety Data 
 
Pregnancy test will be performed at each scheduled visit and the data will be included in a by-
subject listing.  
For best-corrected visual acuity (BCVA), shift tables for study and fellow eye each will be 
presented providing the count of patients with each type of finding (i.e., Normal, Mild, Moderate 
Low Vision, Severe Low Vision and Blindness) at each assessment visit by treatment group for 
each treatment period. BCVA findings are categorized as follow: 
 Normal: 20/12 to 20/40 
 Mild: worse than 20/40 to 20/70 
 Moderate Low Vision: worse than 20/70 to 20/200 
 Severe Low Vision: worse than 20/200 to 20/400 
 Blindness: worse than 20/400 
11. Immunogenicity: Anti-drug Antibody 
 
ADA samples will be collected prior to the infusion at scheduled visits. If the ADA test is 
positive after confirmatory and reactive titer testing, the sample will then be tested for 
neutralizing antibodies (NAb). 
Overall positive ADA result for a patient will be defined as at least one post Day 1 confirmed 
positive ADA result. Cumulative negative result will be defined as negative ADA result at all 
available time points for a patient. 
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Titer (Ratio)  
reported value 
Titer (Result)  
converted value 
1:<2 
2 
1:x 
X 
For example, x could be 4, 10, 40, 64, and 100. 
The incidence and titer of positive ADA results will be summarized by visit and treatment group 
using descriptive statistics for the safety analysis set in each treatment period.  
All ADA and NAb test results will be presented in a by-subject listing for the safety analysis set 
in each treatment period.  
12. Pharmacokinetics 
 
Pharmacokinetic samples will be collected pre-dose and at the end of infusion on scheduled 
visits, Day 1, Weeks 3 and 12 of the double-masked treatment period (all patients) and at Weeks 
24, 27 and 36 (non-responders who elect to receive open-label TEPEZZA); a single sample will 
also be collected at Week 24 (or premature withdrawal [PW1]) of the double-masked treatment 
period (proptosis responders and proptosis non-responders who elect not to receive open-label 
TEPEZZA) and Week 48 of the open-label treatment period (non-responders who elect to 
receive open-label TEPEZZA).  
A patient listing of serum concentration-time data will be presented by visit. Teprotumumab 
peak and trough (i.e., prior to dose) concentrations will be summarized by visit and ADA status 
(overall positive vs cumulative negative; only to be performed if more than 2 patients receiving 
TEPEZZA treatment with a positive ADA observed in the trial) using descriptive statistics. The 
analyses will be based on the PK analysis set in each treatment period. 
Further, the mean and CV% (calculated as 100%*SD/mean) of pre-dose serum concentrations 
will be provided by visit in the subset of patients who are confirmed ADA positive, NAb positive 
(if applicable) and ADA negative for each visit. This analysis will be provided for the PK 
Population.  
13. Changes in the Planned Analysis 
 
 To ensure the control of the overall Type I error rate in analyzing multiple efficacy 
endpoints, the process to test individual efficacy endpoints has been added in the SAP 
section 5 and section 9, as an addition to the protocol. 
 
 Baseline is defined in the SAP for analysis relative to baseline in the open-
label treatment period. 
 
 study day is defined in the SAP for analysis relative to first dose date during 
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 To better characterized GO-QoL, analyses of patients with minimal clinically important 
change in the GO-QoL subscales will be provided. 
 Summary and shift tables for chemistry (excluding glucose) will be based on all records 
(fasting and non-fasting records). 
 
 


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14. References 
 
Campbell G, Pennello G, and Yue L. Missing Data in the Regulation of Medical Devices. 
Journal of Biopharmaceutical Statistics. 2011;21(2):180-95. 
 
Douglas RS, Kahaly GJ, Patel A, et al. Teprotumumab for the treatment of active thyroid eye 
disease. New England Journal of Medicine. 2020;382(4):341-52. 
Heitjan DF and Little RJA. Multiple Imputation for the Fatal Accident Reporting System. 
Journal of the Royal Statistical Society, Series C. 1991; 40:13 29. 
 
Lumyongsatien M, Keeratidamkerngsakul B, Pornpanich K, et al.  Development and 
-QOL) 
questionnaire. Journal of Patient-Reported Outcomes. 2019;4(1): 1.   
 
Rubin DB Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & Sons. 
1987. 
Schenker N and Taylor JMG. Partially parametric techniques for multiple imputation. 
Computational Statistics & Data Analysis. 1996; 22:425-446. 
 
Smith TJ, Kahaly GJ, Ezra DG, et al. Teprotumumab for Thyroid-Associated Ophthalmopathy. 
The New England Journal of Medicine. 2017;376(18):1748-61. 
Yan X., Lee S., and Li N.  Missing Data Handling Methods in Medical Device Clinical Trials, 
Journal of Biopharmaceutical Statistics. 2009; 19(6):1085-1098 
 
Yuan Y. Multiple Imputation Using SAS Software. Journal of Statistical Software. 2011; 
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4. Medical history will include tobacco, alcohol and other substance use history and thyroid disease history and treatment. 
5. Thyroid eye disease must be stable, chronic (inactive) (not progressing, non-sight-threatening but with an appreciable impact on daily life), with thyroid eye disease 
 years prior to Screening. 
6. The weight obtained at Screening will be used to calculate dose for Day 1 and Weeks 3, 6 and 9. The weight obtained at Week 9 will be used in dose calculations at 
Weeks 12, 15, 18 and 21. The dose on Weeks 24, 27, 30 and 33 of the open-label Treatment Period will be based on the Week 24 weight; weight measured at Week 
33 will be used in dose calculations at Weeks 36, 39, 42 and 45. 
7. On Day 1, patients will be randomized in a 2:1 ratio to receive either: a) TEPEZZA (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); baseline assessments will be performed prior to dosing.  
8. 
-mm decrease from Screening in proptosis in the study eye are not eligible for randomization. 
9. Response assessment will include whether the patient is a proptosis responder or non-responder; therefore, the proptosis measurement should be one of the first 
assessments completed during the Week 24 Visit.  
10. 
 
 
 
  
11. 
yes at the Screening and Baseline Visits. 
12. 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]), a serum pregnancy test will be performed at Screening and urine pregnancy tests will 
be performed prior to dosing at all other visits, as applicable, and at the End-of-Treatment Visit. 
13. Patients 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. 
14. Vital signs (blood pressure, heart rate, respiratory rate, temperature) will be measured at all clinic visits. Vital signs will be measured pre- and post-infusion on Day 
1 and Week 3 (all patients), pre- and post-infusion at Week 24 and Week 27 (proptosis non-responders who elect to receive open-label TEPEZZA) and pre-infusion 
on all other infusion days. Additional vital signs will be monitored if infusion-associated AEs occur. 
15. Patients 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 
trial. 
16. 
 be eligible for the trial. If the HbA1c is elevated and considered clinically significant at any time point after Screening, it will be repeated 
approximately every 90 days until it returns to normal or Baseline value. 
17. ADA sample will be collected prior to the infusion. If the ADA test is positive after confirmatory and reactive titer testing, the sample will then be tested for NAb. 
vel decreases or remains stable. ADA 
samples will be collected during any visit triggered by suspected immunologically related AEs. 
18. Pharmacokinetic samples will be collected prior to, and at the end of, the infusion on Day 1, Week 3 and Week 12 of the double-masked Treatment Period (all 
patients) and Week 24, Week 27 and Week 36 of the open-label Treatment Period (proptosis non-responders who elect to receive open-label TEPEZZA); a single 
sample will be collected at Week 24 (proptosis responders and proptosis non-responders who elect not to receive open-label TEPEZZA) and Week 48 (proptosis 
non-responders who elect to receive open-label TEPEZZA).  
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19. 
 
 
 
20. Not collected for patients who prematurely discontinue from the double-masked Treatment Period.  
21. 
k 24 (all patients) and Week 48 (non-
responders who elect to receive open-label TEPEZZA).  
22. For non-responders who choose to receive open-label treatment, TEPEZZA infusion will be performed at Week 24 (first of 8 infusions). All Week 24 assessments 
except AE and concomitant medication monitoring, post-infusion PK sample collection and 24-hour post-dose phone/email contact must be completed prior to 
TEPEZZA infusion.  
23. 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 during the 
double-masked Treatment Period and during the open-label Treatment Period, and thereafter as deemed appropriate. In addition, patients 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. 
 
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15.2 Unit Conversion 
 
Quantity 
From SI to Conventional Unit 
From Conventional Unit to SI 
Height 
0.394 x [cm] = [in] 
2.540 x [in]. = [cm] 
Weight 
2.205 x [kg] = [lb] 
0.454 x [lb] = [kg] 
Temperature 
([°C] x 9/5) + 32 = [°F] 
([°F]  32) 5/9 = [°C] 
 
 
 


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15.3 
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. 
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15.5 
  
15.5.1 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
  
 
 
  
 
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15.5.2 
 
  
 
 
 
 
 
  
 
  
 
  
  
 
 
 
15.5.3 
 
 
 
 
 
  
 
 
 
  
 
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15.6 
 
15.6.1 
 
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15.6.3
 
 
 
 
  
    
  
 
  
 
 
 
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