Treatment of Graves' Orbitopathy (Thyroid Eye Disease) to Reduce Proptosis With Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study
Condition: Thyroid Eye Disease; Graves' Orbitopathy
MeSH terms: Eye Diseases; Graves Ophthalmopathy; Thyroid Diseases
Intervention: Teprotumumab; Placebo
Intervention description: 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).; 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).
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 83.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Proptosis; Human monoclonal antibody; insulin-like growth factor-1 receptor; Thyroid-Associated Ophthalmopathy; Autoimmune Thyroid Disease; Graves' Orbitopathy

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).
    

Eligibility criteria:

        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.