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

• ClinicalTrials.gov Identifier: NCT01868997
• Recruitment Status: Completed
• First Posted: June 5, 2013
• Results First Posted: August 30, 2017
• Last Update Posted: April 25, 2018
• Sponsor: Horizon Pharma USA, Inc.
• Information provided by (Responsible Party): Horizon Pharma USA, Inc.

Study Description

Brief Summary:

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"

Condition or disease	Intervention/treatment	Phase
Thyroid Associated Ophthalmopathies; Thyroid-Associated Ophthalmopathy	Drug: teprotumumab; Drug: normal saline	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 88 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: July 2013
• Actual Primary Completion Date: March 2016
• Actual Study Completion Date: February 22, 2017

Arms and Interventions

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: RV 001; HZN-001

Outcome Measures

Primary Outcome Measures :

1. Responder Status at Week 24 [ Time Frame: 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.

Secondary Outcome Measures :

1. Overall Average Change From Baseline in Graves' Ophthalmopathy Quality of Life (GO-QOL) Scale - Overall to Week 24 (Mixed-Model Repeated Measures [MMRM]) [ Time Frame: Baseline to Week 24 ]
   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).
2. Overall Average Change From Baseline in Proptosis of the Study Eye to Week 24 (MMRM) [ Time Frame: Baseline to Week 24 ]
   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.
3. Overall Average Change From Baseline in CAS to Week 24 (MMRM) [ Time Frame: Baseline to Week 24 ]
   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.
4. Overall Average Change From Baseline in GO-QOL Scale - Visual Functioning to Week 24 (MMRM) [ Time Frame: Baseline to Week 24 ]
   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.
5. Overall Average Change From Baseline in GO-QOL Scale - Appearance to Week 24 (MMRM) [ Time Frame: Baseline to Week 24 ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

Jules Stein Eye Institute at UCLA

Los Angeles, California, United States, 90095

United States, Colorado

University of Denver

Aurora, Colorado, United States, 80045

United States, Georgia

Emory University Department of Ophthalmology

Atlanta, Georgia, United States, 30322

United States, Iowa

University of Iowa Hospitals and Clinics, Department of Ophthalmology

Iowa City, Iowa, United States, 52242

United States, Michigan

Kellogg Eye Center at University of Michigan

Ann Arbor, Michigan, United States, 48105

United States, Missouri

Washington University Department of Ophthalmology

Saint Louis, Missouri, United States, 63110

United States, Nebraska

University of Nebraska Medical Center Department of Ophthalmology

Omaha, Nebraska, United States, 68198

United States, Oregon

Casey Eye Institute at Oregon Health and Science University

Portland, Oregon, United States, 97239

United States, Tennessee

Hamilton Eye Institute at University of Tennessee

Memphis, Tennessee, United States, 38163

United States, Texas

Eye Wellness Center

Houston, Texas, United States, 77005

United States, Wisconsin

Medical College of Wisconsin, The Eye Institute

Milwaukee, Wisconsin, United States, 53226

Germany

Johannes Gutenberg University Medical Center

Mainz, Germany, 55101

Italy

Fondazione Ca' Granda Ospedale Policlinico Graves GO Center

Milan, Italy, 20122

University of Pisa, Azienda Ospedaliera

Pisa, Italy, 56100

United Kingdom

Moorfields Eye Hospital

London, United Kingdom

Sponsors and Collaborators

Horizon Pharma USA, Inc.

Investigators

• Principal Investigator: Raymond S Douglas, MD, PhD; Cedars-Sinai Medical Center

More Information

Publications of Results:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Horizon Pharma USA, Inc.
• ClinicalTrials.gov Identifier: NCT01868997
• Other Study ID Numbers: TED01RV; FD004792-01A1 ( Other Identifier: FDA - Office of Orphan Product Development (OOPD) ); 2014-000113-31 ( EudraCT Number )
• First Posted: June 5, 2013
• Results First Posted: August 30, 2017
• Last Update Posted: April 25, 2018
• Last Verified: March 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Horizon Pharma USA, Inc.:

Thyroid Eye Disease, Graves Orbitopathy, Thyroid Associated; Ophthalmopathy

Additional relevant MeSH terms:

Eye Diseases; Graves Ophthalmopathy; Thyroid Diseases; Endocrine System Diseases; Eye Diseases, Hereditary; Graves Disease; Exophthalmos; Orbital Diseases; Genetic Diseases, Inborn; Goiter; Hyperthyroidism; Autoimmune Diseases; Immune System Diseases