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

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ClinicalTrials.gov Identifier: NCT03298867
Recruitment Status : Recruiting
First Posted : October 2, 2017
Last Update Posted : June 1, 2018
Sponsor:
Information provided by (Responsible Party):
Horizon Pharma USA, Inc.

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).

Condition or disease Intervention/treatment Phase
Thyroid Eye Disease Graves' Orbitopathy Biological: Teprotumumab Other: Placebo Phase 3

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 may receive up to 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 76 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 3, Randomized, Double-Masked, Placebo-Controlled, Parallel-Group, Multicenter Study Evaluating Teprotumumab (HZN-001) Treatment in Subjects With Active Thyroid Eye Disease
Actual Study Start Date : October 24, 2017
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : June 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Teprotumumab 20 mg/kg
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).
Biological: Teprotumumab
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.
Other Name: HZN-001

Placebo Comparator: 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).
Other: Placebo
Approximately 38 participants will receive 8 infusions of placebo q3W for a total of 21 weeks.
Other Name: Saline solution




Primary Outcome Measures :
  1. Effect of teprotumumab versus placebo on the proptosis responder rate at Week 24 [ Time Frame: Week 24 ]
    The percentage of participants with a ≥ 2 mm reduction from Baseline in the study eye without deterioration [≥ 2 mm increase] of proptosis in the fellow eye.


Secondary Outcome Measures :
  1. Effect of teprotumumab versus placebo on the overall responder rate at week 24 [ Time Frame: Week 24 ]
    The percentage of participants with ≥ 2-point reduction in Clinical Activity Score [CAS] AND ≥ 2 mm reduction in proptosis from Baseline, provided there is no corresponding deterioration [≥ 2-point/mm increase] in CAS or proptosis in the fellow eye.

  2. Effect of teprotumumab versus placebo on the percentage of participants with a CAS value of 0 or 1 at Week 24 in the study eye [ Time Frame: Week 24 ]
  3. Effect of teprotumumab versus placebo on the mean change from Baseline to Week 24 in proptosis measurement in the study eye [ Time Frame: Week 24 ]
  4. Effect of teprotumumab versus placebo on the mean change from Baseline to Week 24 in the Graves' Ophthalmopathy Quality of Life (GO-QoL) questionnaire overall score [ Time Frame: Week 24 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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 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 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. HIV, hepatitis C or hepatitis B infections.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03298867


Contacts
Contact: OPTIC Help Desk 855-451-3746 info@opticstudy.com

Locations
United States, California
Macro, Llc Recruiting
Beverly Hills, California, United States, 90212
Contact: Ronnie Zocks    310-991-1407    rzocks@macrotrials.com   
Principal Investigator: Raymond Douglas, MD, PhD         
Cedars-Sinai Medical Center Recruiting
Los Angeles, California, United States, 90078
Contact: Denice Dubuclet       Denice.Dubuclet@cshs.org   
Principal Investigator: Raymond Douglas, MD, PhD         
United States, Florida
The Lennar Foundation Medical Recruiting
Coral Gables, Florida, United States, 33146
Contact: Cristina Lage-Rodriguez    305-326-6117    CLage@med.miami.edu   
Bascom Palmer Eye Institute Recruiting
Miami, Florida, United States, 33136
Contact: Cristina Lage-Rodriguez    305-326-6117    CLage@med.miami.edu   
Principal Investigator: Sara Wester, MD         
United States, Michigan
Kellogg Eye Center at University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48105
Contact: James Green       greenjw@med.umich.edu   
Principal Investigator: Christine Nelson, MD         
United States, Oregon
Casey Eye Institute at Oregon Health and Science University Recruiting
Portland, Oregon, United States, 97239
Contact: Chad Sorenenson       sorensoc@ohsu.edu   
Principal Investigator: Roger Dailey, MD         
United States, Tennessee
Hamilton Eye Institute at University of Tennessee Health Science Center Recruiting
Memphis, Tennessee, United States, 38163
Contact: Paula McCune       pmccune@uthsc.edu   
Principal Investigator: James Fleming, MD         
United States, Texas
Eye Wellness Center Recruiting
Houston, Texas, United States, 77005
Contact: Alonso Prusmack       aprusmack@neuroeye.com   
Principal Investigator: Rosa Tang, MD         
United States, Wisconsin
Medical College of Wisconsin, The Eye Institute Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Ellie Dorsey       edorsey@mcw.edu   
Principal Investigator: Gerald Harris, MD         
Germany
University Hospital Essen, Department of Ophthalmology Recruiting
Essen, Germany, 45147
Contact: Ulrike Kaiser, MD       Ulrike.Kaiser@uk-essen.de   
Principal Investigator: Anja Eckstein, MD         
Johannes Gutenberg University Medical Center Recruiting
Mainz, Germany, 55131
Contact: Michaela Riedle       michaela.riedl@unimedizin-mainz.de   
Principal Investigator: George Kahaly, MD, PhD         
Italy
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Recruiting
Milan, Italy, 20122
Contact: Danila Covelli       Danila.covelli@alice.it   
Principal Investigator: Mario Salvi, MD         
University of Pisa, Department of Clinical and Experimental Medicine Recruiting
Pisa, Italy, 56100
Contact: Poupak Fallahi, MD       poupak@int.med.unipi.it   
Principal Investigator: Alessandro Antonelli, MD         
University of Pisa,Department of Clinical and Experimental Medicine, Endocrinology Unit Recruiting
Pisa, Italy, 56124
Contact: Michele Marino, MD       michele.marino@med.unipi.it   
Principal Investigator: Claudio Marcocci, MD         
Sponsors and Collaborators
Horizon Pharma USA, Inc.
Investigators
Principal Investigator: Raymond Douglas, MD, PhD Cedars-Sinai Medical Center
Principal Investigator: George Kahaly, MD, PhD Johannes Gutenberg University Medical Center

Responsible Party: Horizon Pharma USA, Inc.
ClinicalTrials.gov Identifier: NCT03298867     History of Changes
Other Study ID Numbers: HZNP-TEP-301
2017-002763-18 ( EudraCT Number )
First Posted: October 2, 2017    Key Record Dates
Last Update Posted: June 1, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Horizon Pharma USA, Inc.:
Proptosis
Human monoclonal antibody
insulin-like growth factor-1 receptor
Thyroid-Associated Ophthalmopathy
Hyperthyroidism
Autoimmune Thyroid Disease

Additional relevant MeSH terms:
Thyroid Diseases
Eye Diseases
Graves Ophthalmopathy
Endocrine System Diseases
Eye Diseases, Hereditary
Graves Disease
Exophthalmos
Orbital Diseases
Goiter
Hyperthyroidism
Autoimmune Diseases
Immune System Diseases
Pharmaceutical Solutions
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs