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.

Approximately 38 participants will receive 8 infusions of placebo q3W for a total of 21 weeks.

Eight infusions of placebo q3W for a total of 21 weeks.

Placebo

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.

Teprotumumab 20 mg/kg

Total

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race/Ethnicity, Customized

Tobacco use status - as randomized

Actual tobacco use status reflects the status as reported on the substance use case report form. One participant was randomized in error to the tobacco user stratum as this subject was reported as a non-user (former tobacco use status) on the substance use case report form.

Tobacco use status – actual

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.

Percentage of Participants Who Were Proptosis Responders at 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).

Percentage of Participants Who Were Overall Responders at Week 24

CAS categorical responders were defined as participants with a reduction to a CAS of 0 or 1 (no or minimal inflammatory symptoms).
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).

Percentage of Participants Who Were CAS Categorical Responders at Week 24

Change From Baseline in Proptosis to 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).

Percentage of Participants Who Were Diplopia Responders at 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.

Change From Baseline in the Graves' Ophthalmopathy Quality of Life (GO-QoL) Questionnaire Overall Score to Week 24

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.

Overall Study

Suzy Hammel

Thyroid Eye Disease

Graves' Orbitopathy

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).

Teprotumumab

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).

Macro, Llc

Cedars-Sinai Medical Center

The Lennar Foundation Medical

Bascom Palmer Eye Institute

Kellogg Eye Center at University of Michigan

Casey Eye Institute at Oregon Health and Science University

Hamilton Eye Institute at University of Tennessee Health Science Center

Eye Wellness Center

Medical College of Wisconsin, The Eye Institute

University Hospital Essen, Department of Ophthalmology

Johannes Gutenberg University Medical Center

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

University of Pisa, Department of Clinical and Experimental Medicine

University of Pisa,Department of Clinical and Experimental Medicine, Endocrinology Unit

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

A Phase 3, Randomized, Double-Masked, Placebo-Controlled, Parallel-Group, Multicenter Study Evaluating Teprotumumab (HZN-001) Treatment in Subjects With Active Thyroid Eye Disease

Horizon Pharma USA, Inc.

12 months treatment with diclofenac 50 mg 1x2 in addition to regular treatment for thyrotoxicosis.

12 months treatment without diclofenac in addition to regular treatment for thyrotoxicosis.

Graves´ Disease

T Diclofenac 50 mg twice daily for 12 months

Diclofenac

Methimazole

L-thyroxin approximately 100 to 200 micrograms/day. The dose is adjusted to reach euthyroidism during concomitant treatment with methimazole for 18 months

L-thyroxin

T Propronalol 40mg 1x1-3 during during 1-3 weeks until the patient has responded to thyrostatics

Propranolol

T Metoprolol 50 mg 1x3 for 1-3 weeks until the patient has responded to thyrostatics

Metoprolol

Departmenty of Endocrinology, Skane University Hospital

Department of Endocrinology, Karolinska Hospital

Department of Internal Medicine, section of Endocrinology, Sodersjukhuset

Adjuvant Treatment of Graves´ Ophthalmopathy With NSAID (aGO Study)

Optic nerve dysfunction 0. No 1. Yes Eye-lid edema 0. No 1. Yes Chemosis 0. No 1. Yes Conjunctival injection 0. No 1. Yes Exophthalmos 0. No 1. Yes Hertel - base right left Eye muscle dysfunction 0. No 1. Yes Corneal ulcers 0. No 1. Yes
Sum:
Ophthalmopathy is present if the patient has one sign or more.

Spontaneous retrobulbar pain 0. No 1. Yes Painfull eye-movements 0. No 1. Yes Eye-lid erythema 0. No 1. Yes Conjunctival injection 0. No 1. Yes Chemosis 0. No 1. Yes Swollen caruncula 0. No 1. Yes Eye-lid edema or swolleness 0. No 1. Yes
Sum:

Criteria for start of steroid treatment are: 1. Risk of corneal ulcers with or without exophthalmos 2. Double vision within 30 degrees 3. Optic nerve dysfunction.

exophthalmos/nicotina

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

Adjuvant Treatment of Graves´ Ophthalmopathy With NSAID (aGO Study)

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