Teprotumumab (RV 001) Treatment in Patients With Active Thyroid Eye Disease

A Multicenter, Double-Masked, Placebo-Controlled, Efficacy And Safety Study Of RV 001, An Insulin-Like Growth Factor-1 Receptor (IGF-1R) Antagonist Antibody (Fully Human), Administered Every 3 Weeks (q3W) By Intravenous (IV) Infusion In Patients Suffering From Active Thyroid Eye Disease (TED)

The primary objective of this study is to investigate the efficacy, safety, and tolerability of RV 001 (teprotumumab), a fully human anti-IGF1R antibody, administered q3W for 6 months, in comparison to placebo, in the treatment of participants suffering from active TED.

"Funding Source - FDA OOPD"

Study Overview

• Status: Completed
• Conditions: Thyroid-Associated Ophthalmopathy; Thyroid Associated Ophthalmopathies
• Intervention / Treatment: Drug: normal saline; Drug: teprotumumab

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Mainz, Germany, 55101
    • Johannes Gutenberg University Medical Center
• Italy
  • Milan, Italy, 20122
    • Fondazione Ca' Granda Ospedale Policlinico Graves GO Center
  • Pisa, Italy, 56100
    • University of Pisa, Azienda Ospedaliera
• United Kingdom
  • London, United Kingdom
    • Moorfields Eye Hospital
• United States
  • California
    • Los Angeles, California, United States, 90095
      • Jules Stein Eye Institute at UCLA
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Denver
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Department of Ophthalmology
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics, Department of Ophthalmology
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • Kellogg Eye Center at University of Michigan
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University Department of Ophthalmology
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center Department of Ophthalmology
  • Oregon
    • Portland, Oregon, United States, 97239
      • Casey Eye Institute at Oregon Health and Science University
  • Tennessee
    • Memphis, Tennessee, United States, 38163
      • Hamilton Eye Institute at University of Tennessee
  • Texas
    • Houston, Texas, United States, 77005
      • Eye Wellness Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin, The Eye Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Clinical diagnosis of Graves' disease associated with active TED and a clinical activity score of ≥ 4
• Fewer than 9 months from onset of TED
• No previous medical or surgical treatment, excluding local supportive measures and oral steroids if the maximum cumulative dose is less than 1000 mg methylprednisolone or equivalent with at least 6 weeks between last administration of oral steroids and randomization
• Euthyroid or with mild hypo or hyperthyroidism defined as free thyroxine (FT4) and free triiodothyronine (FT3) levels less than 50% above or below the normal limits (every effort should be made to correct the mild hypo- or hyperthyroidism promptly)

Exclusion Criteria:

• Optic neuropathy
• Corneal decompensation unresponsive to medical management
• Oral or IV steroid treatment for any non-TED reason in the preceding 3 months
• Poorly controlled diabetes
• Platelets < 100 x 10^9/L
• Hemoglobin concentration > 2 g/dL below the lower limit of normal

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; A placebo infusion (normal saline) administered q3W by IV infusion over a period of 24 weeks for a total of 8 infusions.	Drug: normal saline
Experimental: Teprotumumab; Teprotumumab administered q3W by IV infusion over a period of 24 weeks for a total of 8 infusions. All participants start treatment at a dose of 10 mg/kg. At Week 3, the dose is escalated to 20 mg/kg and kept constant for the remainder of the study.	Drug: teprotumumab; Other Names: HZN-001; RV 001

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Responder Status at Week 24	Number of participants classified as responders and non-responders at Week 24. Responders were defined as participants with a reduction in clinical activity score (CAS, see Outcome Measure 4 description for details) of ≥ 2 points, and a reduction in proptosis (amount of protrusion of the eye from the orbital rim) of ≥ 2 mm in the study eye, and no deterioration (increase in CAS of ≥ 2 points or increase in proptosis of ≥ 2 mm) in the non-study eye. Participants who had no assessment at 24 weeks were considered non-responders.	Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Average Change From Baseline in Graves' Ophthalmopathy Quality of Life (GO-QOL) Scale - Overall to Week 24 (Mixed-Model Repeated Measures [MMRM])	The GO-QOL is a 16-item self-administered questionnaire used to assess the perceived effects of thyroid eye disorder (TED) by the participants on their daily physical and psychosocial functioning. Two subscales of the 16-question GO-QOL have been defined: Visual Functioning and Appearance, with 8 questions comprising each subscale. The transformed overall score is the sum of scores from all 16 questions to a scale of 0 (worst health) to 100 (best health).	Baseline to Week 24
Overall Average Change From Baseline in Proptosis of the Study Eye to Week 24 (MMRM)	Proptosis is the amount of protrusion of the eye from the orbital rim. Measurements were recorded using the Hertel exophthalmometer. Participants with a decrease ≥ 2 mm were considered improving, those with an increase or decrease < 2 mm were considered remaining stable, and those with an increase ≥ 2 mm were considered worsening.	Baseline to Week 24
Overall Average Change From Baseline in CAS to Week 24 (MMRM)	The 7-item European Group on Graves' Ophthalmopathy (EUGOGO) amended CAS was used to evaluate clinical activity. For each of the following items, one point is given: spontaneous orbital pain, gaze evoked orbital pain, eyelid swelling that is considered to be due to active (inflammatory phase) Graves' ophthalmopathy (GO), eyelid erythema, conjunctival redness that is considered to be due to active (inflammatory phase) GO, chemosis, and inflammation of caruncle or plica. The sum of these points is the total score, with 0 indicating no clinical activity and 7 indicating the most severe clinical activity.	Baseline to Week 24
Overall Average Change From Baseline in GO-QOL Scale - Visual Functioning to Week 24 (MMRM)	The GO-QOL is a 16-item self-administered questionnaire used to assess the perceived effects of TED by the participants on their daily physical and psychosocial functioning. Two subscales of the 16-question GO-QOL have been defined: Visual Functioning and Appearance, with 8 questions comprising each subscale. Transformed Visual Functioning score is the sum of scores from following 8 questions to a scale of 0 (worst health) to 100 (best health): bicycling, driving, moving around the house, walking outdoors, reading, watching television (TV), hobby or pastime, feel hindered.	Baseline to Week 24
Overall Average Change From Baseline in GO-QOL Scale - Appearance to Week 24 (MMRM)	The GO-QOL is a 16-item self-administered questionnaire used to assess the perceived effects of TED by the participants on their daily physical and psychosocial functioning. Two subscales of the 16-question GO-QOL have been defined: Visual Functioning and Appearance, with 8 questions comprising each subscale. Transformed Appearance score is the sum of scores from the following 8 questions to a scale of 0 (worst health) to 100 (best health): feel appearance has changed, feel being stared at, feel people react unpleasantly, influence on self-confidence, feel socially isolated, influence on making friends, appear less often on photos, try to mask changes in appearance.	Baseline to Week 24

Collaborators and Investigators

• Sponsor: Horizon Pharma USA, Inc.
• Investigators: Principal Investigator: Raymond S Douglas, MD, PhD, Cedars-Sinai Medical Center

Publications and helpful links

General Publications

• Smith TJ, Kahaly GJ, Ezra DG, Fleming JC, Dailey RA, Tang RA, Harris GJ, Antonelli A, Salvi M, Goldberg RA, Gigantelli JW, Couch SM, Shriver EM, Hayek BR, Hink EM, Woodward RM, Gabriel K, Magni G, Douglas RS. Teprotumumab for Thyroid-Associated Ophthalmopathy. N Engl J Med. 2017 May 4;376(18):1748-1761. doi: 10.1056/NEJMoa1614949.
• Xin Y, Xu F, Gao Y, Bhatt N, Chamberlain J, Sile S, Hammel S, Holt RJ, Ramanathan S. Pharmacokinetics and Exposure-Response Relationship of Teprotumumab, an Insulin-Like Growth Factor-1 Receptor-Blocking Antibody, in Thyroid Eye Disease. Clin Pharmacokinet. 2021 Aug;60(8):1029-1040. doi: 10.1007/s40262-021-01003-3. Epub 2021 Mar 26.
• Wang Y, Smith TJ. Current concepts in the molecular pathogenesis of thyroid-associated ophthalmopathy. Invest Ophthalmol Vis Sci. 2014 Mar 20;55(3):1735-48. doi: 10.1167/iovs.14-14002.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2013
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): February 22, 2017

Study Registration Dates

• First Submitted: May 2, 2013
• First Submitted That Met QC Criteria: May 30, 2013
• First Posted (Estimate): June 5, 2013

Study Record Updates

• Last Update Posted (Actual): April 25, 2018
• Last Update Submitted That Met QC Criteria: March 27, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Thyroid Eye Disease, Graves Orbitopathy, Thyroid Associated; Ophthalmopathy
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Genetic Diseases, Inborn; Eye Diseases, Hereditary; Graves Disease; Exophthalmos; Orbital Diseases; Goiter; Hyperthyroidism; Eye Diseases; Graves Ophthalmopathy; Thyroid Diseases
• Other Study ID Numbers: TED01RV; FD004792-01A1 (Other Identifier: FDA - Office of Orphan Product Development (OOPD)); 2014-000113-31 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided