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

NCT03298867 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: HZNP-TEP-3012017-002763-18
• Study Type: interventional
• Target: 83
• Locations: 3 countries
• Sites: 14

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).

Conditions

Thyroid Eye Disease; Graves' Orbitopathy

Keywords

Proptosis; Human monoclonal antibody; insulin-like growth factor-1 receptor; Thyroid-Associated Ophthalmopathy; Autoimmune Thyroid Disease; Graves' Orbitopathy

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants Who Were Proptosis Responders at Week 24

  Proptosis responders were defined as participants with a ≥2 mm reduction from Baseline in proptosis in the study eye, without deterioration (≥2 mm increase) of proptosis in the fellow eye at Week 24.

  Week 24

Secondary Outcomes (5)

• Percentage of Participants Who Were Overall Responders at Week 24

  Week 24

• Percentage of Participants Who Were CAS Categorical Responders at Week 24 (Study Eye)

  Week 24

• Change From Baseline in Proptosis to Week 24 (Study Eye)

  Baseline, up to Week 24

• Percentage of Participants Who Were Diplopia Responders at Week 24

  Week 24

• Change From Baseline in the Graves' Ophthalmopathy Quality of Life (GO-QoL) Questionnaire Overall Score to Week 24

  Baseline, up to Week 24

Study Arms (2)

Teprotumumab 20 mg/kg

ACTIVE COMPARATOR

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.

Biological: Teprotumumab

Placebo

PLACEBO COMPARATOR

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

Other: Placebo

Interventions

Teprotumumab 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).

Also known as: HZN-001

Teprotumumab 20 mg/kg

Placebo 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).

Also known as: Saline solution

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent.
• Male or female participant between the ages of 18 and 80 years, inclusive, at Screening.
• 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.
• 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.
• Onset of active TED symptoms (as determined by participant records) within 9 months prior to Baseline.
• 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.
• Does not require immediate surgical ophthalmological intervention and is not planning corrective surgery/irradiation during the course of the study.
• 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.
• 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).
• 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.
• 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.
• Participant is willing and able to comply with the study protocol and evaluations for the duration of the study.

You may not qualify if:

• 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 CAS of ≥ 2 points in the study eye between Screening and Baseline.
• Decrease in proptosis of ≥ 2 mm in the study eye between Screening and Baseline.
• Previous orbital irradiation or surgery for TED.
• 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.
• Corticosteroid use for conditions other than TED within 4 weeks prior to Screening (topical steroids for dermatological conditions and inhaled steroids are allowed).
• 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.
• Any previous treatment with rituximab or tocilizumab. Use of any other non-steroid immunosuppressive agent within 3 months prior to Screening.
• Use of an investigational agent for any condition within 60 days prior to Screening or anticipated use during the course of the trial.
• Identified pre-existing ophthalmic disease that, in the judgment of the Investigator, would preclude study participation or complicate interpretation of study results.
• Malignant condition in the past 12 months (except successfully treated basal/squamous cell carcinoma of the skin).
• 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.
• Biopsy-proven or clinically suspected inflammatory bowel disease.

Sponsors & Collaborators

• Amgen: lead

Study Sites (14)

Macro, Llc

Beverly Hills, California, 90212, United States

Location

Cedars-Sinai Medical Center

Los Angeles, California, 90078, United States

Location

The Lennar Foundation Medical

Coral Gables, Florida, 33146, United States

Location

Bascom Palmer Eye Institute

Miami, Florida, 33136, United States

Location

Kellogg Eye Center at University of Michigan

Ann Arbor, Michigan, 48105, United States

Location

Casey Eye Institute at Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Hamilton Eye Institute at University of Tennessee Health Science Center

Memphis, Tennessee, 38163, United States

Location

Eye Wellness Center

Houston, Texas, 77005, United States

Location

Medical College of Wisconsin, The Eye Institute

Milwaukee, Wisconsin, 53226, United States

Location

University Hospital Essen, Department of Ophthalmology

Essen, 45147, Germany

Location

Johannes Gutenberg University Medical Center

Mainz, 55131, Germany

Location

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, 20122, Italy

Location

University of Pisa, Department of Clinical and Experimental Medicine

Pisa, 56100, Italy

Location

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

Pisa, 56124, Italy

Location

Related Publications (2)

• 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.

  PMID: 31971679 RESULT

• 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.

  PMID: 33172865 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Graves Ophthalmopathy; Exophthalmos

Interventions

teprotumumab; Saline Solution

Condition Hierarchy (Ancestors)

Eye Diseases, Hereditary; Eye Diseases; Graves Disease; Orbital Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Goiter; Thyroid Diseases; Endocrine System Diseases; Hyperthyroidism; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Results Point of Contact

• Title: Suzy Hammel
• Organization: Horizon Pharma USA, Inc.

clinicaltrials@horizontherapeutics.com

866-479-6742

Study Officials

• MD

  Amgen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 27, 2017
• First Posted: October 2, 2017
• Study Start: October 4, 2017
• Primary Completion: February 13, 2019
• Study Completion: November 30, 2020
• Last Updated: July 11, 2024
• Results First Posted: March 10, 2020

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.

Locations

IT (3); DE (2); US (9)