OPTIC: Treatment of Graves' Orbitopathy (Thyroid Eye Disease) to Reduce Proptosis With Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study

• Sponsor: Horizon Pharma USA, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03298867
• Collaborator: (none)
• Enrollment: 83
• Locations: 14
• Arms: 2
• Actual Duration (Months): 37.9
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The overall objective is to investigate the efficacy, tolerability, and safety of teprotumumab (a fully human monoclonal antibody [mAb] inhibitor of the insulin-like growth factor-1 receptor [IGF-1R]) administered once every 3 weeks (q3W) for 21 weeks with a final assessment at Week 24, in comparison to placebo, in the treatment of participants with moderate-to-severe active thyroid eye disease (TED).

Condition or Disease	Intervention/Treatment	Phase
Thyroid Eye Disease; Graves' Orbitopathy	Biological: Teprotumumab; Other: Placebo	Phase 3

Detailed Description

This is a randomized, double-masked, placebo-controlled, parallel-group, multicenter study. Approximately 76 participants (38/group) who meet the study eligibility criteria will be randomized on Day 1 in a 1:1 ratio (stratified by tobacco use status) to receive 8 infusions of teprotumumab or placebo q3W. All participants will enter a 24-week double-masked Treatment Period, during which study drug will be infused on Day 1 (Baseline), and Weeks 3, 6, 9, 12, 15, 18, and 21 (with a final visit at Week 24). All study drug dosing will be performed at the clinic under the supervision of clinic staff. On each dosing day, scheduled assessments (except for adverse event [AE] and concomitant medication use monitoring, which will be monitored throughout the clinic visit) will be completed prior to study drug dosing.

At the end of the double-masked Treatment Period (Week 24), participants who are proptosis non-responders (study eye has < 2 mm decrease in proptosis) will be eligible to enter an open-label extension study in which participants receive 8 infusions of teprotumumab in an open-label fashion.

At Week 24, proptosis responders, as well as non-responders who choose not to enroll in the open-label extension study, will enter a 48-week Follow-Up Period, during which study drug will not be administered and clinic visits are scheduled for Weeks 28, 36, 48, 60, and 72. Participants who are considered responders at Week 24 but who meet criteria for re-treatment due to relapse during the Follow-Up Period may enroll in the open-label extension study.

Participants who complete the Week 72 Visit will be contacted 6 and 12 months later via phone or email by research staff to enquire if any treatment for TED has been received since last study contact.

Study Design

• Study Type: Interventional
• Actual Enrollment: 83 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-Masked, Placebo-Controlled, Parallel-Group, Multicenter Study Evaluating Teprotumumab (HZN-001) Treatment in Subjects With Active Thyroid Eye Disease
• Actual Study Start Date: Oct 4, 2017
• Actual Primary Completion Date: Feb 13, 2019
• Actual Study Completion Date: Nov 30, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Teprotumumab 20 mg/kg Approximately 38 participants will receive 8 infusions of teprotumumab q3W for a total of 21 weeks. Teprotumumab 10 mg/kg will be administered on Day 1 and teprotumumab 20 mg/kg will be administered q3W for the remaining 7 infusions.	Biological: Teprotumumab; Teprotumumab is a fully human anti-IGF-1R mAb. Teprotumumab will be provided in single-dose 20 mL glass vials as a freeze-dried powder. Each vial of teprotumumab must be reconstituted with 10 mL of water for injection. Reconstituted teprotumumab solution must be further diluted in 0.9% (w/v) sodium chloride (NaCl) solution prior to administration. Teprotumumab will be administered in 100 mL or 250 mL infusion bags (100 mL infusion bags for doses up to 1800 mg and 250 mL infusion bags for doses > 1800 mg).; Other Names: HZN-001
Placebo Comparator: Placebo Approximately 38 participants will receive 8 infusions of placebo q3W for a total of 21 weeks.	Other: Placebo; Placebo will consist of normal saline (0.9% NaCl) solution and will be administered in 100 mL or 250 mL infusion bags, as would be appropriate, per weight-based dosing volumes (100 mL infusion bags for doses up to 1800 mg and 250 mL infusion bags for doses > 1800 mg).; Other Names: Saline solution

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Were Proptosis Responders at Week 24 [Week 24]

   Proptosis responders were defined as participants with a ≥2 mm reduction from Baseline in proptosis in the study eye, without deterioration (≥2 mm increase) of proptosis in the fellow eye at Week 24.

Secondary Outcome Measures

1. Percentage of Participants Who Were Overall Responders at Week 24 [Week 24]

   Overall responders were defined as participants with a ≥2 mm reduction in proptosis AND a ≥2 point reduction in Clinical Activity Score (CAS) from Baseline in the study eye, without deterioration (≥2 mm increase in proptosis or ≥2 point increase in CAS) in the fellow eye at Week 24. The CAS is a 7-item description of clinical activity, including: 1. Spontaneous orbital pain; 2. Gaze evoked orbital pain; 3. Eyelid swelling that is considered to be due to active (inflammatory phase) thyroid eye disease/ Graves' Ophthalmopathy or Orbitopathy (TED/GO); 4. Eyelid erythema; 5. Conjunctival redness that is considered to be due to active (inflammatory phase) TED/GO (ignore "equivocal" redness); 6. Chemosis; 7. Inflammation of caruncle or plica. Each item is scored (1=present; 0=absent) and scores for each item are summed for total score of 0 (no clinical activity) to 7 (most clinical activity).

2. Percentage of Participants Who Were CAS Categorical Responders at Week 24 (Study Eye) [Week 24]

   CAS categorical responders were defined as participants with a reduction to a CAS of 0 or 1 (no or minimal inflammatory symptoms) in study eye. The CAS is a 7-item description of clinical activity, including: 1. Spontaneous orbital pain; 2. Gaze evoked orbital pain; 3. Eyelid swelling that is considered to be due to active (inflammatory phase) thyroid eye disease/ Graves' Ophthalmopathy or Orbitopathy (TED/GO); 4. Eyelid erythema; 5. Conjunctival redness that is considered to be due to active (inflammatory phase) TED/GO (ignore "equivocal" redness); 6. Chemosis; 7. Inflammation of caruncle or plica. Each item is scored (1=present; 0=absent) and scores for each item are summed for total score of 0 (no inflammatory symptoms) to 7 (most inflammatory symptoms).

3. Change From Baseline in Proptosis to Week 24 (Study Eye) [Baseline, up to Week 24]

4. Percentage of Participants Who Were Diplopia Responders at Week 24 [Week 24]

   Diplopia responders were defined as participants with Baseline diplopia Subjective Diplopia Score grade >0 in the study eye who had a reduction of ≥1 grade with no corresponding deterioration (≥1 grade worsening) in the fellow eye at Week 24. Denominator is the number of subjects with diplopia at Baseline. The Subjective Diplopia Score is a clinical measure of diplopia severity on a grade scale of 0 to 3: 0=no diplopia; 1=intermittent (diplopia in primary position of gaze, when tired or when first awakening); 2=inconstant (diplopia at extremes of gaze); 3=constant (continuous diplopia in primary or reading position).

5. Change From Baseline in the Graves' Ophthalmopathy Quality of Life (GO-QoL) Questionnaire Overall Score to Week 24 [Baseline, up to Week 24]

   The GO-QoL is a 16-item self-administered questionnaire divided into 2 subsets and used to assess the perceived effects of TED by the subjects on (i) their daily physical activity as it relates to visual function, and (ii) psychosocial functioning. The range of the GO-QoL overall transformed scores is 0 to 100, where higher values correspond to better quality of life.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Written informed consent.

2. Male or female participant between the ages of 18 and 80 years, inclusive, at Screening.

3. Clinical diagnosis of Graves' disease associated with active TED with a Clinical Activity Score (CAS) ≥ 4 (on the 7-item scale) for the most severely affected eye at Screening and Baseline.

4. Moderate-to-severe active TED (not sight-threatening but has an appreciable impact on daily life), usually associated with one or more of the following: lid retraction ≥ 2 mm, moderate or severe soft tissue involvement, exophthalmos ≥ 3 mm above normal for race and gender, and/or inconstant or constant diplopia.

5. Onset of active TED symptoms (as determined by participant records) within 9 months prior to Baseline.

6. Participants must be euthyroid with the baseline disease under control or have mild hypo- or hyperthyroidism (defined as free thyroxine [FT4] and free triiodothyronine [FT3] levels < 50% above or below the normal limits) at Screening. Every effort should be made to correct the mild hypo- or hyperthyroidism promptly and to maintain the euthyroid state for the full duration of the clinical trial.

7. Does not require immediate surgical ophthalmological intervention and is not planning corrective surgery/irradiation during the course of the study.

8. Alanine aminotransferase (ALT) or AST ≤ 3 times the upper limit of normal (ULN) or serum creatine <1.5 times the ULN according to age at Screening.

9. Diabetic participants must have well-controlled stable disease (defined as HbA1C < 9.0% with no new diabetic medication [oral or insulin] or more than a 10% change in the dose of a currently prescribed diabetic medication within 60 days prior to Screening).

10. Women of childbearing potential (including those with an onset of menopause <2 years prior to Screening, non-therapy-induced amenorrhea for <12 months prior to Screening, or not surgically sterile [absence of ovaries and/or uterus]) must have a negative serum pregnancy test at Screening and negative urine pregnancy tests at all protocol-specified timepoints (i.e., prior to each dose and through Week 48 of the Follow-Up Period); participants who are sexually active with a non-vasectomized male partner must agree to use 2 reliable forms of contraception during the trial, one of which is recommended to be hormonal, such as an oral contraceptive. Hormonal contraception must be started at least one full cycle prior to Baseline and continue for 180 days after the last dose of study drug. Highly effective contraceptive methods (with a failure rate less than 1% per year) when used consistently and correctly, includes implants, injectables, combined oral contraceptives, intrauterine devices (IUDs), sexual abstinence or vasectomized partner.

11. Male participants must be surgically sterile or, if sexually active with a female partner of childbearing potential, must agree to use barrier contraceptive method from Screening through 180 days after the last dose of study drug.

12. Participant is willing and able to comply with the study protocol and evaluations for the duration of the study.

Exclusion Criteria:

1. Decreased best corrected visual acuity due to optic neuropathy as defined by a decrease in vision of 2 lines on the Snellen chart, new visual field defect, or color defect secondary to optic nerve involvement within the last 6 months.

2. Corneal decompensation unresponsive to medical management.

3. Decrease in CAS of ≥ 2 points in the study eye between Screening and Baseline.

4. Decrease in proptosis of ≥ 2 mm in the study eye between Screening and Baseline.

5. Previous orbital irradiation or surgery for TED.

6. Any steroid use (intravenous [IV] or oral) with a cumulative dose equivalent to ≥ 1 g of methylprednisolone for the treatment of TED. Previous steroid use (IV or oral) with a cumulative dose of <1 g methylprednisolone or equivalent for the treatment of TED and previous use of steroid eye drops is allowed if the corticosteroid was discontinued at least 4 weeks prior to Screening.

7. Corticosteroid use for conditions other than TED within 4 weeks prior to Screening (topical steroids for dermatological conditions and inhaled steroids are allowed).

8. Selenium and biotin must be discontinued 3 weeks prior to Screening and must not be restarted during the clinical trial; however, taking a multivitamin that includes selenium and/or biotin is allowed.

9. Any previous treatment with rituximab or tocilizumab. Use of any other non-steroid immunosuppressive agent within 3 months prior to Screening.

10. Use of an investigational agent for any condition within 60 days prior to Screening or anticipated use during the course of the trial.

11. Identified pre-existing ophthalmic disease that, in the judgment of the Investigator, would preclude study participation or complicate interpretation of study results.

12. Bleeding diathesis that in the judgment of the Investigator would preclude inclusion in the clinical trial.

13. Malignant condition in the past 12 months (except successfully treated basal/squamous cell carcinoma of the skin).

14. Pregnant or lactating women.

15. Current drug or alcohol abuse, or history of either within the previous 2 years, in the opinion of the Investigator or as reported by the participant.

16. Biopsy-proven or clinically suspected inflammatory bowel disease.

17. Known hypersensitivity to any of the components of teprotumumab or prior hypersensitivity reactions to mAbs.

18. Any other condition that, in the opinion of the Investigator, would preclude inclusion in the study.

19. Previous enrollment in this study or participation in a prior teprotumumab clinical trial.

20. Human immunodeficiency virus (HIV), hepatitis C or hepatitis B infections.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Macro, Llc	Beverly Hills	California	United States	90212
2	Cedars-Sinai Medical Center	Los Angeles	California	United States	90078
3	The Lennar Foundation Medical	Coral Gables	Florida	United States	33146
4	Bascom Palmer Eye Institute	Miami	Florida	United States	33136
5	Kellogg Eye Center at University of Michigan	Ann Arbor	Michigan	United States	48105
6	Casey Eye Institute at Oregon Health and Science University	Portland	Oregon	United States	97239
7	Hamilton Eye Institute at University of Tennessee Health Science Center	Memphis	Tennessee	United States	38163
8	Eye Wellness Center	Houston	Texas	United States	77005
9	Medical College of Wisconsin, The Eye Institute	Milwaukee	Wisconsin	United States	53226
10	University Hospital Essen, Department of Ophthalmology	Essen		Germany	45147
11	Johannes Gutenberg University Medical Center	Mainz		Germany	55131
12	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milan		Italy	20122
13	University of Pisa, Department of Clinical and Experimental Medicine	Pisa		Italy	56100
14	University of Pisa,Department of Clinical and Experimental Medicine, Endocrinology Unit	Pisa		Italy	56124

Sponsors and Collaborators

• Horizon Pharma USA, Inc.

Investigators

• Principal Investigator: Raymond Douglas, MD, PhD, Cedars-Sinai Medical Center
• Principal Investigator: George Kahaly, MD, PhD, Johannes Gutenberg University Medical Center

Study Documents (Full-Text)

• Study Protocol - Jan 31, 2019
• Statistical Analysis Plan - Feb 8, 2019

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Horizon Pharma USA, Inc.
• ClinicalTrials.gov Identifier: NCT03298867
• Other Study ID Numbers: HZNP-TEP-301; 2017-002763-18
• First Posted: Oct 2, 2017
• Last Update Posted: Feb 7, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Horizon Pharma USA, Inc.: Proptosis; Human monoclonal antibody; insulin-like growth factor-1 receptor; Thyroid-Associated Ophthalmopathy; Autoimmune Thyroid Disease; Graves' Orbitopathy
• Additional relevant MeSH terms: Eye Diseases; Graves Ophthalmopathy; Thyroid Diseases

Study Results

Participant Flow

Arm/Group Title	Placebo	Teprotumumab 20 mg/kg
Arm/Group Description	Eight infusions of placebo every 3 weeks (q3W) for a total of 21 weeks.	Eight infusions of teprotumumab every q3W for a total of 21 weeks. Teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.
Period Title: Double-Masked 24-Week Treatment Period
STARTED	42	41
COMPLETED	40	39
NOT COMPLETED	2	2
Period Title: Double-Masked 24-Week Treatment Period
STARTED	4	36
COMPLETED	3	20
NOT COMPLETED	1	16
Period Title: Double-Masked 24-Week Treatment Period
STARTED	3	20
COMPLETED	3	19
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Placebo	Teprotumumab 20 mg/kg	Total
Arm/Group Description	Eight infusions of placebo q3W for a total of 21 weeks.	Eight infusions of teprotumumab q3W for a total of 21 weeks. Teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.	Total of all reporting groups
Overall Participants	42	41	83
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.9 (12.96)	51.6 (12.63)	50.2 (12.79)
Age, Customized (Count of Participants)
<65 years	38 90.5%	32 78%	70 84.3%
≥65 years	4 9.5%	9 22%	13 15.7%
Sex: Female, Male (Count of Participants)
Female	31 73.8%	29 70.7%	60 72.3%
Male	11 26.2%	12 29.3%	23 27.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 2.4%	2 4.9%	3 3.6%
Not Hispanic or Latino	41 97.6%	39 95.1%	80 96.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Asian	1 2.4%	2 4.9%	3 3.6%
Black or African American	2 4.8%	4 9.8%	6 7.2%
White	37 88.1%	35 85.4%	72 86.7%
More Than 1 Race	2 4.8%	0 0%	2 2.4%
Tobacco use status - as randomized (Count of Participants)
Non-User	33 78.6%	32 78%	65 78.3%
User	9 21.4%	9 22%	18 21.7%
Tobacco use status - actual (Count of Participants)
Non-User	34 81%	32 78%	66 79.5%
User	8 19%	9 22%	17 20.5%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Were Proptosis Responders at Week 24
Description	Proptosis responders were defined as participants 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.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: all randomized participants.

Arm/Group Title	Placebo	Teprotumumab 20 mg/kg
Arm/Group Description	Eight infusions of placebo q3W for a total of 21 weeks.	Eight infusions of teprotumumab q3W for a total of 21 weeks. Teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.
Measure Participants	42	41
Number [percentage of participants]	9.5 22.6%	82.9 202.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teprotumumab 20 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Two-sided p-value calculated assuming the test statistic was distributed as a standard normal random variable.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Stratified difference in percentages
	Estimated Value	73.45
	Confidence Interval	(2-Sided) 95%; 58.89 to 88.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.43
	Estimation Comments	Stratified difference (teprotumumab - placebo) is a weighted average of the difference within each stratum. Estimates from the 2 strata (tobacco user, tobacco non-user) were combined with Cochran-Mantel-Haenszel (CMH) weights.

2. Secondary Outcome

Title	Percentage of Participants Who Were Overall Responders at Week 24
Description	Overall responders were defined as participants with a ≥2 mm reduction in proptosis AND a ≥2 point reduction in Clinical Activity Score (CAS) from Baseline in the study eye, without deterioration (≥2 mm increase in proptosis or ≥2 point increase in CAS) in the fellow eye at Week 24. The CAS is a 7-item description of clinical activity, including: 1. Spontaneous orbital pain; 2. Gaze evoked orbital pain; 3. Eyelid swelling that is considered to be due to active (inflammatory phase) thyroid eye disease/ Graves' Ophthalmopathy or Orbitopathy (TED/GO); 4. Eyelid erythema; 5. Conjunctival redness that is considered to be due to active (inflammatory phase) TED/GO (ignore "equivocal" redness); 6. Chemosis; 7. Inflammation of caruncle or plica. Each item is scored (1=present; 0=absent) and scores for each item are summed for total score of 0 (no clinical activity) to 7 (most clinical activity).
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: all randomized participants.

Arm/Group Title	Placebo	Teprotumumab 20 mg/kg
Arm/Group Description	Eight infusions of placebo q3W for a total of 21 weeks.	Eight infusions of teprotumumab q3W for a total of 21 weeks. Teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.
Measure Participants	42	41
Number [percentage of participants]	7.1 16.9%	78.0 190.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teprotumumab 20 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Two-sided p-value calculated assuming the test statistic was distributed as a standard normal random variable.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Stratified difference in percentages
	Estimated Value	70.82
	Confidence Interval	(2-Sided) 95%; 55.89 to 85.75
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.62
	Estimation Comments	Stratified difference (teprotumumab - placebo) is a weighted average of the difference within each stratum. Estimates from the 2 strata (tobacco user, tobacco non-user) were combined with CMH weights.

3. Secondary Outcome

Title	Percentage of Participants Who Were CAS Categorical Responders at Week 24 (Study Eye)
Description	CAS categorical responders were defined as participants with a reduction to a CAS of 0 or 1 (no or minimal inflammatory symptoms) in study eye. The CAS is a 7-item description of clinical activity, including: 1. Spontaneous orbital pain; 2. Gaze evoked orbital pain; 3. Eyelid swelling that is considered to be due to active (inflammatory phase) thyroid eye disease/ Graves' Ophthalmopathy or Orbitopathy (TED/GO); 4. Eyelid erythema; 5. Conjunctival redness that is considered to be due to active (inflammatory phase) TED/GO (ignore "equivocal" redness); 6. Chemosis; 7. Inflammation of caruncle or plica. Each item is scored (1=present; 0=absent) and scores for each item are summed for total score of 0 (no inflammatory symptoms) to 7 (most inflammatory symptoms).
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: all randomized participants.

Arm/Group Title	Placebo	Teprotumumab 20 mg/kg
Arm/Group Description	Eight infusions of placebo q3W for a total of 21 weeks.	Eight infusions of teprotumumab q3W for a total of 21 weeks. Teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.
Measure Participants	42	41
Number [percentage of participants]	21.4 51%	58.5 142.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teprotumumab 20 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Two-sided p-value calculated assuming the test statistic was distributed as a standard normal random variable.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Stratified difference in percentages
	Estimated Value	36.03
	Confidence Interval	(2-Sided) 95%; 17.39 to 54.67
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.51
	Estimation Comments	Stratified difference (teprotumumab - placebo) is a weighted average of the difference within each stratum. Estimates from the 2 strata (tobacco user, tobacco non-user) were combined with CMH weights.

4. Secondary Outcome

Title	Change From Baseline in Proptosis to Week 24 (Study Eye)
Time Frame	Baseline, up to Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: all randomized participants.

Arm/Group Title	Placebo	Teprotumumab 20 mg/kg
Arm/Group Description	Eight infusions of placebo q3W for a total of 21 weeks.	Eight infusions of teprotumumab q3W for a total of 21 weeks. Teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.
Measure Participants	42	41
Least Squares Mean (Standard Error) [mm]	-0.54 (0.192)	-2.82 (0.191)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teprotumumab 20 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Results obtained from an MMRM with an unstructured covariance matrix including the following terms: Baseline value, tobacco use status, treatment group, visit, visit-by-treatment interaction and visit-by-Baseline-value interaction.
	Method	mixed model for repeated measures (MMRM)
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-2.28
	Confidence Interval	(2-Sided) 95%; -2.77 to -1.80
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.244
	Estimation Comments

5. Secondary Outcome

Title	Percentage of Participants Who Were Diplopia Responders at Week 24
Description	Diplopia responders were defined as participants with Baseline diplopia Subjective Diplopia Score grade >0 in the study eye who had a reduction of ≥1 grade with no corresponding deterioration (≥1 grade worsening) in the fellow eye at Week 24. Denominator is the number of subjects with diplopia at Baseline. The Subjective Diplopia Score is a clinical measure of diplopia severity on a grade scale of 0 to 3: 0=no diplopia; 1=intermittent (diplopia in primary position of gaze, when tired or when first awakening); 2=inconstant (diplopia at extremes of gaze); 3=constant (continuous diplopia in primary or reading position).
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: all randomized participants with diplopia at baseline in the study eye.

Arm/Group Title	Placebo	Teprotumumab 20 mg/kg
Arm/Group Description	Eight infusions of placebo q3W for a total of 21 weeks.	Eight infusions of teprotumumab q3W for a total of 21 weeks. Teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.
Measure Participants	28	28
Number [percentage of participants]	28.6 68.1%	67.9 165.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teprotumumab 20 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	Two-sided p-value calculated assuming the test statistic was distributed as a standard normal random variable.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Stratified difference in percentages
	Estimated Value	39.29
	Confidence Interval	(2-Sided) 95%; 15.55 to 63.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.11
	Estimation Comments	Stratified difference is a weighted average of the difference within each stratum. Estimates from the 2 strata (tobacco user, tobacco non-user) were combined with CMH weights.

6. Secondary Outcome

Title	Change From Baseline in the Graves' Ophthalmopathy Quality of Life (GO-QoL) Questionnaire Overall Score to Week 24
Description	The GO-QoL is a 16-item self-administered questionnaire divided into 2 subsets and used to assess the perceived effects of TED by the subjects on (i) their daily physical activity as it relates to visual function, and (ii) psychosocial functioning. The range of the GO-QoL overall transformed scores is 0 to 100, where higher values correspond to better quality of life.
Time Frame	Baseline, up to Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: all randomized participants.

Arm/Group Title	Placebo	Teprotumumab 20 mg/kg
Arm/Group Description	Eight infusions of placebo q3W for a total of 21 weeks.	Eight infusions of teprotumumab q3W for a total of 21 weeks. Teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.
Measure Participants	42	41
Least Squares Mean (Standard Error) [score on a scale]	4.43 (2.102)	13.79 (2.074)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teprotumumab 20 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Results obtained from an MMRM with an unstructured covariance matrix including the following terms: Baseline value, tobacco use status, treatment group, visit, visit-by-treatment interaction and visit-by-Baseline-value interaction.
	Method	mixed model for repeated measures (MMRM)
	Comments
Method of Estimation	Estimation Parameter	Difference in LS mean
	Estimated Value	9.36
	Confidence Interval	(2-Sided) 95%; 4.08 to 14.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.651
	Estimation Comments

Adverse Events

Time Frame	From first dose of study drug through the end of the Double-Masked Treatment Period (up to 24 weeks) plus 3 weeks.
Arm/Group Title	Placebo		Teprotumumab 20 mg/kg
Arm/Group Description	Eight infusions of placebo q3W for a total of 21 weeks.		Eight infusions of teprotumumab q3W for a total of 21 weeks. Teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.
All Cause Mortality
	Placebo		Teprotumumab 20 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/42 (0%)		0/41 (0%)
Serious Adverse Events
	Placebo		Teprotumumab 20 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/42 (2.4%)		2/41 (4.9%)
Injury, poisoning and procedural complications
Infusion related reaction	0/42 (0%)		1/41 (2.4%)
Nervous system disorders
Visual field defect	1/42 (2.4%)		0/41 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumothorax	0/42 (0%)		1/41 (2.4%)
Other (Not Including Serious) Adverse Events
	Placebo		Teprotumumab 20 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/42 (69%)		37/41 (90.2%)
Gastrointestinal disorders
Abdominal Pain Upper	3/42 (7.1%)		2/41 (4.9%)
Diarrhoea	5/42 (11.9%)		5/41 (12.2%)
Nausea	4/42 (9.5%)		6/41 (14.6%)
Stomatitis	1/42 (2.4%)		3/41 (7.3%)
General disorders
Fatigue	1/42 (2.4%)		5/41 (12.2%)
Infections and infestations
Influenza	3/42 (7.1%)		1/41 (2.4%)
Musculoskeletal and connective tissue disorders
Muscle Spasms	4/42 (9.5%)		14/41 (34.1%)
Nervous system disorders
Dizziness	0/42 (0%)		3/41 (7.3%)
Dysgeusia	0/42 (0%)		4/41 (9.8%)
Headache	4/42 (9.5%)		4/41 (9.8%)
Reproductive system and breast disorders
Amenorrhoea	0/42 (0%)		4/41 (9.8%)
Respiratory, thoracic and mediastinal disorders
Cough	3/42 (7.1%)		2/41 (4.9%)
Skin and subcutaneous tissue disorders
Alopecia	5/42 (11.9%)		10/41 (24.4%)
Dry Skin	0/42 (0%)		5/41 (12.2%)
Madarosis	0/42 (0%)		3/41 (7.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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