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

NCT ID: NCT03298867

Last Updated: 2024-07-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 83 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-10-04
• Study Completion Date: 2020-11-30

Brief 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).

Detailed Description

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.

Study acquired from Horizon in 2024.

Conditions

Thyroid Eye Disease; Graves' Orbitopathy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Teprotumumab 20 mg/kg

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.

Group Type: ACTIVE_COMPARATOR

Teprotumumab

Intervention Type: BIOLOGICAL

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

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

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).

Interventions

Teprotumumab

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).

Intervention Type: BIOLOGICAL

Placebo

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).

Intervention Type: OTHER

Other Intervention Names

HZN-001; Saline solution

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Amgen

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

MD

Role: STUDY_DIRECTOR

Amgen

Locations

Macro, Llc

Beverly Hills, California, United States

Cedars-Sinai Medical Center

Los Angeles, California, United States

The Lennar Foundation Medical

Coral Gables, Florida, United States

Bascom Palmer Eye Institute

Miami, Florida, United States

Kellogg Eye Center at University of Michigan

Ann Arbor, Michigan, United States

Casey Eye Institute at Oregon Health and Science University

Portland, Oregon, United States

Hamilton Eye Institute at University of Tennessee Health Science Center

Memphis, Tennessee, United States

Eye Wellness Center

Houston, Texas, United States

Medical College of Wisconsin, The Eye Institute

Milwaukee, Wisconsin, United States

University Hospital Essen, Department of Ophthalmology

Essen, , Germany

Johannes Gutenberg University Medical Center

Mainz, , Germany

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, , Italy

University of Pisa, Department of Clinical and Experimental Medicine

Pisa, , Italy

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

Pisa, , Italy

Countries

United States; Germany; Italy

References

Douglas RS, Kahaly GJ, Patel A, Sile S, Thompson EHZ, Perdok R, Fleming JC, Fowler BT, Marcocci C, Marino M, Antonelli A, Dailey R, Harris GJ, Eckstein A, Schiffman J, Tang R, Nelson C, Salvi M, Wester S, Sherman JW, Vescio T, Holt RJ, Smith TJ. Teprotumumab for the Treatment of Active Thyroid Eye Disease. N Engl J Med. 2020 Jan 23;382(4):341-352. doi: 10.1056/NEJMoa1910434.

Reference Type: RESULT

PMID: 31971679 (View on PubMed)

Jain AP, Gellada N, Ugradar S, Kumar A, Kahaly G, Douglas R. Teprotumumab reduces extraocular muscle and orbital fat volume in thyroid eye disease. Br J Ophthalmol. 2022 Feb;106(2):165-171. doi: 10.1136/bjophthalmol-2020-317806. Epub 2020 Nov 10.

Reference Type: DERIVED

PMID: 33172865 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://www.tepezza.com/

Related Info

Other Identifiers

2017-002763-18

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

HZNP-TEP-301

Identifier Type: -

Identifier Source: org_study_id