A Study Evaluating TEPEZZA® Treatment in Patients With Chronic (Inactive) Thyroid Eye Disease
A Study Evaluating TEPEZZA® Treatment in Patients With Chronic (Inactive) Thyroid Eye Disease
The overall objective is to investigate the efficacy, safety and tolerability of TEPEZZA® in
 participants with chronic (inactive) TED (thyroid eye disease). Approximately 39 participants
 will be enrolled. There will be a treatment period (through Week 24) and a follow up period
 (where TEPEZZA will not be infused).
This is randomized, double-masked, placebo-controlled, parallel-group, multicenter trial.
 Participants will be screened for the trial within 4 weeks prior to the Baseline (Day 1)
 Visit. Approximately 39 participants 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
 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 participants 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 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 participants will
 return to the clinic at Week 48 for End-of-Treatment assessments, and participants 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 trial drug will not be
 administered. These participants will be contacted by phone/email 30 days after the Week 24
 Visit for safety assessment.

 Participants who prematurely discontinue trial drug dosing prior to Week 21 of the
 double-masked Treatment Period or 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
 as applicable.
Inclusion Criteria:

 1. Written informed consent.

 2. Male or female at least 18 years old at Screening.

 3. Initial diagnosis of TED ≥3 years but <8 years prior to Screening. Clinical diagnosis
 of stable, chronic (inactive) TED, as determined by participant medical records
 indicating a Clinical Activity Score (CAS) ≤1 in both eyes for at least 1 year prior
 to Screening or all of the following:

 1. no progression in proptosis for at least 1 year prior to Screening

 2. if participant has history of diplopia due to TED, no progression in diplopia for
 at least 1 year prior to Screening

 3. no new inflammatory TED symptoms for at least 1 year prior to Screening

 4. CAS ≤1 at the Screening and Baseline Visits.

 5. Proptosis ≥3-mm increase from participant's Baseline (prior to diagnosis of TED), as
 estimated by treating physician and/or proptosis ≥3 mm above normal for race and
 gender.

 6. Participants must be euthyroid with the participant's Baseline disease under control
 or have mild hypo- or hyperthyroidism (defined as free thyroxine and free
 triiodothyronine 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 trial.

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

 8. Diabetic participants must have HbA1c ≤8.0% at Screening.

 9. Participants with 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 during the
 trial. Concomitant stable therapies for inflammatory bowel disease without
 modifications in the 3 months prior to Screening are allowed.

 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 participant's
 participation); participants who are sexually active with a non-vasectomized male
 partner must agree to use 2 reliable forms of contraception during the trial, 1 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 <1% per year), when used consistently and correctly, include implants,
 injectables, combination oral contraceptives, some intrauterine devices, sexual
 abstinence and vasectomized partner.

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

 12. Willing and able to comply with the prescribed treatment protocol and evaluations for
 the duration of the trial.

 Exclusion Criteria:

 1. 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.

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

 4. Prior orbital irradiation, orbital decompression or strabismus surgery.

 5. Alanine aminotransferase or aspartate aminotransferase >3 × the upper limit of normal
 or estimated glomerular filtration rate ≤30 mL/min/1.73 m2 at Screening.

 6. 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.

 7. Any treatment with rituximab (Rituxan® or MabThera®) within 12 months prior to the
 first infusion of trial drug or tocilizumab (Actemra® or Roactemra®) within 6 months
 prior to the first infusion of trial drug. Use of any other non-steroid
 immunosuppressive agent within 3 months prior to the first infusion of trial drug.

 8. Any previous treatment with TEPEZZA, including previous enrollment in this trial or
 participation in a prior teprotumumab trial.

 9. Treatment with any mAb within 3 months prior to Screening.

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

 11. 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.

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

 13. Pregnant or lactating women.

 14. 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.

 15. Known hypersensitivity to any of the components of TEPEZZA or prior hypersensitivity
 reactions to mAbs.

 16. Poorly controlled human immunodeficiency virus infection or untreated or positive
 viral load for hepatitis C or hepatitis B infections.

 17. Any other condition that, in the opinion of the Investigator, would preclude inclusion
 in the trial.