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