TEPEZZA® (Teprotumumab-trbw) Post-Marketing Requirement Study

Study Overview
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Brief Summary
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This is a double-masked, randomized, parallel-assignment, multicenter trial examining the safety and tolerability of teprotumumab in the treatment of Thyroid Eye Disease (TED) in adult participants. This international, Phase 3b/4 trial is being conducted to fulfill an FDA post-marketing requirement for a descriptive trial to evaluate the safety, efficacy and need for re-treatment of 3 different teprotumumab treatment durations for TED. In addition, serum samples from participants with a Baseline Clinical Activity Score (CAS) ≥3 will be evaluated for biomarkers of disease.

Detailed Description
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Participants will be screened for eligibility within 4 weeks prior to the Baseline (Day 1) Visit. Approximately 300 participants who meet the trial eligibility criteria will be randomized on Day 1 in a 1:1:1 ratio in a double-masked fashion (stratified by CAS(clinical activity score) [≥3 (active) or <3 (inactive)] and disease severity [severe disease, defined as both proptosis above normal for race and gender with binocular diplopia at Baseline vs. non-severe disease]) to receive: 4 infusions of teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for the remaining 3 infusions) (Cohort 1) followed by 4 infusions of: Placebo if a participants is a treatment responder at Week 12 or Teprotumumab 20 mg/kg if a participant is a treatment non-responder at Week 12 8 infusions of teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for the remaining 7 infusions) (Cohort 2) 16 infusions of teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for the remaining 15 infusions) (Cohort 3) Three weeks following the final infusion of the Initial Treatment Period, there will be a comprehensive End-of-Initial Treatment Visit at Week 24 (Cohorts 1 and 2)/Week 48 (Cohort 3). At this visit, all participants will be assessed for treatment response. Proptosis responders in all cohorts and non-responders in Cohorts 1 and 2 who choose not to receive a second treatment course, will enter a 52 week Initial Follow-up Period. Proptosis non-responders in Cohorts 1 and 2 who choose to receive a second treatment course (8 infusions) of teprotumumab will receive an infusion q3W. Proptosis non-responders in Cohort 3 are not eligible for a second treatment course following initial treatment. Participants in any of the 3 cohorts who are proptosis responders following the Initial Treatment Period and who flare during the Initial Follow up Period will be eligible to receive re treatment.

Official Title
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A Phase 3b/4, Double-masked, Randomized, International, Parallel-assignment, Multicenter Trial in Patients With Thyroid Eye Disease to Evaluate the Safety and Tolerability of Different Dosing Durations of Teprotumumab

Conditions
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Thyroid Eye Disease

Intervention / Treatment
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* Drug: Teprotumumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent. Male or female between the ages of 18 and 80 years, inclusive, at Screening. Initial diagnosis of TED within 7 years prior to Screening. Proptosis ≥3 mm from baseline (prior to diagnosis of TED), as estimated by treating physician, and/or proptosis >3 mm above normal for race and gender. Participants must be euthyroid with the 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 duration of the trial. Does not require immediate surgical ophthalmological intervention and is not planning corrective surgery/irradiation during the course of the trial. Diabetic participants must have HbA1c ≤8.0% at Screening. Participants with a history of IBD (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 IBD without modifications in the 3 months prior to Screening are allowed. 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 the participant's participation in 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, 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 teprotumumab. Highly effective contraceptive methods (with a failure rate <1% per year), when used consistently and correctly, include implants, injectables, combination oral contraceptives, some intrauterine devices, tubal ligation, sexual abstinence or vasectomized partner. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial. Exclusion Criteria: 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. Corneal decompensation unresponsive to medical management. Decrease in proptosis of ≥2 mm in the study eye between Screening and Baseline. Prior orbital irradiation, orbital decompression or strabismus surgery. Planned eyelid surgery during the course of the trial. Alanine aminotransferase or aspartate aminotransferase >3 × the upper limit of normal or estimated glomerular filtration rate ≤30 mL/min/1.73m2 at Screening. Use of any steroid (intravenous [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, as well as steroids used to treat infusion reactions. Any treatment with rituximab (Rituxan® or MabThera®) within 12 months prior to the first infusion of teprotumumab or tocilizumab (Actemra® or Roactemra®) within 6 months prior to the first infusion of teprotumumab. Use of any other non-steroid immunosuppressive agent within 3 months prior to the first infusion of teprotumumab. Any previous treatment with teprotumumab, including previous enrollment in this trial or participation in a prior teprotumumab trial. Treatment with any mAb within 3 months prior to Screening. Identified pre-existing ophthalmic disease that, in the judgment of the Investigator, would preclude trial participation or complicate interpretation of trial results. 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. Malignant condition in the past 5 years (except successfully treated basal/squamous cell carcinoma of the skin or cervical cancer in situ). Pregnant or lactating women. 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. Known hypersensitivity to any of the components of teprotumumab or prior hypersensitivity reactions to mAbs. Human immunodeficiency virus, untreated or positive viral load for hepatitis C or hepatitis B infections. Any other condition that, in the opinion of the Investigator, would preclude inclusion in the trial. After 150 participants with a CAS <3 at Baseline have been randomized, an additional exclusion criterion will apply: CAS <3 at Baseline.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 4 infusions of teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for the remaining 3 infusions) (Cohort 1) followed by 4 infusions of: Placebo if a participant is a treatment responder at Week 12 or Teprotumumab 20 mg/kg if a participant is a treatment non-responder at Week 12 8 infusions of teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for the remaining 7 infusions) (Cohort 2) 16 infusions of teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for the remaining 15 infusions) (Cohort 3)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Teprotumumab 4 Infusions<br>• 4 infusions of teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for the remaining 3 infusions) (Cohort 1) followed by 4 infusions of: Placebo if a participant is a treatment responder at Week 12 or Teprotumumab 20 mg/kg if a participant is a treatment non-responder at Week 12 | Drug: Teprotumumab<br>* 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 containing, in addition to the drug substance, 20 mmol/L histidine-histidine chloride, 250 mmol/L trehalose and 0.01% polysorbate 20 (w/w). Prior to administration, each vial containing 500 mg teprotumumab freeze-dried powder will be reconstituted with 10 mL of sterile water for injection. The resulting solution will have a concentration of 47.6 mg/mL teprotumumab-trbw antibody. The reconstituted teprotumumab solution must be further diluted in 0.9% (w/v) sodium chloride (NaCl) solution prior to administration<br>* Other names: TEPEZZA;Drug: Placebo<br>* Placebo will consist of a normal saline (0.9% NaCl) solution and will be administered in 100 mL or 250 mL infusion bags, as appropriate, per weight-based dosing volumes.<br>* Other names: Saline Solution;|
| Other: Teprotumumab 8 Infusions<br>8 infusions of teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for the remaining 7 infusions) (Cohort 2) | Drug: Teprotumumab<br>* 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 containing, in addition to the drug substance, 20 mmol/L histidine-histidine chloride, 250 mmol/L trehalose and 0.01% polysorbate 20 (w/w). Prior to administration, each vial containing 500 mg teprotumumab freeze-dried powder will be reconstituted with 10 mL of sterile water for injection. The resulting solution will have a concentration of 47.6 mg/mL teprotumumab-trbw antibody. The reconstituted teprotumumab solution must be further diluted in 0.9% (w/v) sodium chloride (NaCl) solution prior to administration<br>* Other names: TEPEZZA;|
| Other: Teprotumumab 16 Infusions<br>16 infusions of teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for the remaining 15 infusions) (Cohort 3) | Drug: Teprotumumab<br>* 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 containing, in addition to the drug substance, 20 mmol/L histidine-histidine chloride, 250 mmol/L trehalose and 0.01% polysorbate 20 (w/w). Prior to administration, each vial containing 500 mg teprotumumab freeze-dried powder will be reconstituted with 10 mL of sterile water for injection. The resulting solution will have a concentration of 47.6 mg/mL teprotumumab-trbw antibody. The reconstituted teprotumumab solution must be further diluted in 0.9% (w/v) sodium chloride (NaCl) solution prior to administration<br>* Other names: TEPEZZA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants who experience at least 1 treatment-emergent adverse event (TEAE) and the percentage of participants who experience at least 1 treatment emergent AESI during treatment with teprotumumab | Treatment emergent adverse events and treatment emergent adverse events of special interest will be evaluated from the beginning of the study until follow up. | Screening to End of Study (last visit possible is Week 136) | 
| Percentage of Participants who receive re-treatment | Participants who are not proptosis responders after initial treatment or participants who are proptosis responders after initial treatment but who have flared during follow-up (relapsed). | Week 27 to Week 136 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TED