TEPEZZA® (Teprotumumab-trbw) Post-Marketing Requirement Study

Thyroid Eye Disease Clinical Trial

Official title:

A Phase 3b/4, Double-masked, Randomized, International, Parallel-assignment, Multicenter Trial in Patients With Thyroid Eye Disease to Evaluate the Safety and Tolerability of Different Dosing Durations of Teprotumumab

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05002998
• Other study ID #: HZNP-TEP-402
• Secondary ID: 2020-005999-36
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: September 16, 2021
• Est. completion date: October 2025

Study information

• Verified date: May 2024
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a double-masked, randomized, parallel-assignment, multicenter trial examining the safety and tolerability of teprotumumab in the treatment of Thyroid Eye Disease (TED) in adult participants. This international, Phase 3b/4 trial is being conducted to fulfill an FDA post-marketing requirement for a descriptive trial to evaluate the safety, efficacy and need for re-treatment of 3 different teprotumumab treatment durations for TED. In addition, serum samples from participants with a Baseline Clinical Activity Score (CAS) ≥3 will be evaluated for biomarkers of disease.

Description:

Participants will be screened for eligibility within 4 weeks prior to the Baseline (Day 1) Visit. Approximately 300 participants who meet the trial eligibility criteria will be randomized on Day 1 in a 1:1:1 ratio in a double-masked fashion (stratified by CAS(clinical activity score) [≥3 (active) or <3 (inactive)] and disease severity [severe disease, defined as both proptosis above normal for race and gender with binocular diplopia at Baseline vs. non-severe disease]) to receive: - 4 infusions of teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for the remaining 3 infusions) (Cohort 1) followed by 4 infusions of: - Placebo if a participants is a treatment responder at Week 12 or - Teprotumumab 20 mg/kg if a participant is a treatment non-responder at Week 12 - 8 infusions of teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for the remaining 7 infusions) (Cohort 2) - 16 infusions of teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for the remaining 15 infusions) (Cohort 3) Three weeks following the final infusion of the Initial Treatment Period, there will be a comprehensive End-of-Initial Treatment Visit at Week 24 (Cohorts 1 and 2)/Week 48 (Cohort 3). At this visit, all participants will be assessed for treatment response. Proptosis responders in all cohorts and non-responders in Cohorts 1 and 2 who choose not to receive a second treatment course, will enter a 52 week Initial Follow-up Period. Proptosis non-responders in Cohorts 1 and 2 who choose to receive a second treatment course (8 infusions) of teprotumumab will receive an infusion q3W. Proptosis non-responders in Cohort 3 are not eligible for a second treatment course following initial treatment. Participants in any of the 3 cohorts who are proptosis responders following the Initial Treatment Period and who flare during the Initial Follow up Period will be eligible to receive re treatment. Acquired from Horizon in 2024

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 313
• Est. completion date: October 2025
• Est. primary completion date: October 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Written informed consent.

2. Male or female between the ages of 18 and 80 years, inclusive, at Screening.

3. Initial diagnosis of TED within 7 years prior to Screening.

4. Proptosis =3 mm from baseline (prior to diagnosis of TED), as estimated by treating physician, and/or proptosis >3 mm above normal for race and gender.

5. Participants must be euthyroid with the baseline disease under control or have mild hypo or hyperthyroidism (defined as free thyroxine and free triiodothyronine 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 duration of the trial.

6. Does not require immediate surgical ophthalmological intervention and is not planning corrective surgery/irradiation during the course of the trial.

7. Diabetic participants must have HbA1c =8.0% at Screening.

8. Participants with a history of IBD (ulcerative colitis or Crohn's disease) must be in clinical remission for at least 3 months, with no history of bowel surgery within 6 months prior to Screening and no planned surgery during the trial. Concomitant stable therapies for IBD without modifications in the 3 months prior to Screening are allowed.

9. 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 time points (i.e., prior to each dose and throughout the participant's participation in 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, 1 of which is recommended to be hormonal, such as an oral contraceptive. Hormonal contraception must be started at least 1 full cycle prior to Baseline and continue for 180 days after the last dose of teprotumumab. Highly effective contraceptive methods (with a failure rate <1% per year), when used consistently and correctly, include implants, injectables, combination oral contraceptives, some intrauterine devices, tubal ligation, sexual abstinence or vasectomized partner.

10. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial.

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 proptosis of =2 mm in the study eye between Screening and Baseline.

4. Prior orbital irradiation, orbital decompression or strabismus surgery.

5. Planned eyelid surgery during the course of the trial.

6. Alanine aminotransferase or aspartate aminotransferase >3 × the upper limit of normal or estimated glomerular filtration rate =30 mL/min/1.73m2 at Screening.

7. Use of any steroid (intravenous [IV], oral, steroid eye drops) for the treatment of TED or other conditions within 3 weeks prior to Screening. Steroids cannot be initiated during the trial. Exceptions include topical and inhaled steroids, as well as steroids used to treat infusion reactions.

8. Any treatment with rituximab (Rituxan® or MabThera®) within 12 months prior to the first infusion of teprotumumab or tocilizumab (Actemra® or Roactemra®) within 6 months prior to the first infusion of teprotumumab. Use of any other non-steroid immunosuppressive agent within 3 months prior to the first infusion of teprotumumab.

9. Any previous treatment with teprotumumab, including previous enrollment in this trial or participation in a prior teprotumumab trial.

10. Treatment with any mAb within 3 months prior to Screening.

11. Identified pre-existing ophthalmic disease that, in the judgment of the Investigator, would preclude trial participation or complicate interpretation of trial results.

12. Use of an investigational agent for any condition within 60 days or 5 half-lives, whichever is longer, prior to Screening or anticipated use during the course of the trial.

13. Malignant condition in the past 5 years (except successfully treated basal/squamous cell carcinoma of the skin or cervical cancer in situ).

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. Known hypersensitivity to any of the components of teprotumumab or prior hypersensitivity reactions to mAbs.

17. Human immunodeficiency virus, untreated or positive viral load for hepatitis C or hepatitis B infections.

18. Any other condition that, in the opinion of the Investigator, would preclude inclusion in the trial.

19. After 150 participants with a CAS <3 at Baseline have been randomized, an additional exclusion criterion will apply: CAS <3 at Baseline.

Related Conditions & MeSH terms

• Eye Diseases
• Graves Ophthalmopathy
• Thyroid Eye Disease

Intervention

Drug:
• 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 containing, in addition to the drug substance, 20 mmol/L histidine-histidine chloride, 250 mmol/L trehalose and 0.01% polysorbate 20 (w/w). Prior to administration, each vial containing 500 mg teprotumumab freeze-dried powder will be reconstituted with 10 mL of sterile water for injection. The resulting solution will have a concentration of 47.6 mg/mL teprotumumab-trbw antibody. The reconstituted teprotumumab solution must be further diluted in 0.9% (w/v) sodium chloride (NaCl) solution prior to administration
• Placebo
Placebo will consist of a normal saline (0.9% NaCl) solution and will be administered in 100 mL or 250 mL infusion bags, as appropriate, per weight-based dosing volumes.

Locations

Country	Name	City	State
France	Hopital Jean Minjoz	Besançon	Doubs
France	Hôpital Louis Pradel	Bron	Rhône
France	Hôpital Claude Huriez	Lille
France	Centre Hospitalier National D'ophtalmologie Des Quinze Vingts	Paris
Germany	Universitätsklinikum Essen	Essen
Germany	University Medicine Göttingen Germany	Göttingen	Niedersachsen
Germany	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz	Rheinland-Pfalz
Germany	Universitätsklinikum Münster	Münster
Germany	Universitätsklinikum Tübingen	Tübingen	Baden-Württemberg
Italy	Azienda Ospedaliera Di Rilievo Nazionale E Di Alta Specializzazione Garibaldi	Catania	Sicilia
Italy	Azienda Ospedaliera Universitaria Federico II	Napoli	Campania
Italy	Azienda Ospedaliero Universitaria Pisana	Pisa	Toscana
Italy	University of Pisa	Pisa	Toscana
Italy	ASST dei Sette Laghi - Ospedale Di Circolo E Fondazione Macchi	Varese	Lombardia
Spain	Hospital La Arruzafa	Córdoba
Spain	Hospital Universitario Ramon Y Cajal	Madrid
Spain	Hospital Universitario Virgen Macarena	Sevilla
United Kingdom	University Hospital of Cardiff	Cardiff	Wales
United Kingdom	Imperial College Healthcare NHS Trust	London	London, City Of
United Kingdom	Moorfields Eye Hospital	London	London, City Of
United Kingdom	Royal Victoria Infirmary, Newcastle Eye Centre	Newcastle Upon Tyne
United Kingdom	Southampton Eye Unit	Southampton
United States	University of Colorado - Eye Center	Aurora	Colorado
United States	UCLA Health, Beverley Hills Primary & Specialty care	Beverly Hills	California
United States	USC Roski Eye Institute - Los Angeles	Los Angeles	California
United States	Bascom Palmer Eye Institute	Miami	Florida
United States	The Medical College of Wisconsin, Inc.	Milwaukee	Wisconsin
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Stanford University	Palo Alto	California
United States	Casey Eye Institute - OHSU	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University in St. Louis	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Countries where clinical trial is conducted

United States,  France,  Germany,  Italy,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants who experience at least 1 treatment-emergent adverse event (TEAE) and the percentage of participants who experience at least 1 treatment emergent AESI during treatment with teprotumumab	Treatment emergent adverse events and treatment emergent adverse events of special interest will be evaluated from the beginning of the study until follow up.	Screening to End of Study (last visit possible is Week 136)
Primary	Percentage of Participants who receive re-treatment	Participants who are not proptosis responders after initial treatment or participants who are proptosis responders after initial treatment but who have flared during follow-up (relapsed).	Week 27 to Week 136

External Links

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