N/A

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Horizon Therapeutics USA Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Eye Diseases [C11]

Trial duration

10 May 2022 → 20 Dec 2025

Decision date (initial)

2024-07-04

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-515090-96-00

EudraCT number

2020-005999-36

WHO UTN

U1111-1308-4576

ClinicalTrials.gov

NCT05002998

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Others, Pharmacokinetic, Safety

"The overall objective is to investigate the safety, tolerability and need for re-treatment of 3 different teprotumumab treatment durations in patients with Thyroid Eye Disease (TED)."

Secondary objectives 15

1. Change in proptosis measurement in the study eye
2. Proptosis responder rate
3. The overall responder rate
4. Binocular diplopia responder rate
5. Binocular diplopia resolution rate
6. Change from Baseline in Graves' Ophthalmopathy QoL quest appearance and visual functioning subscales
7. Rate of flare at end of the Initial FU Period
8. Time to proptosis response during the Initial Treatm. Period
9. CAS: - % pts with a CAS of 0 or 1 who had active disease (CAS ≥3) at Baseline - % pts who improve on the following CAS items: Spontaneous orbital pain & gaze-evoked orbital pain
10. Durab of complete response at the end of the Initial FU Period
11. Durab of response at the last assessment in the Initial FU-Period
12. % pts with at least 1TEAE assessed as Grade 3 or higher
13. % pts with at least 1 post-baseline abnormal lab result of Grade 3 or higher
14. Effect of teprotumumab the mean change from Baseline over time in serum biomarkers for pts with a Baseline CAS ≥3
15. For the complete secondary objectives, please refer to the study protocol.

Conditions and MedDRA coding

Thyroid Eye Disease

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

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. 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 (Note: For sites in France: Normal values for proptosis do vary by gender and race [de Juan et al, 1980; Fledelius and Stubgaard, 1986; Kashkouli et al, 2008]).
5. Patients 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 patients must have HbA1c ≤8.0% at Screening.
8. Patients 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 patient's participation in the Follow-up Period); patients 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, bilateral tubal ligation, combination oral contraceptives, some intrauterine devices, vasectomized partner or sexual abstinence. Abstinence should only be used as a contraceptive method if it is in line with the patient's usual and preferred lifestyle and periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) is not an acceptable method of contraception. Periodic abstinence, withdrawal (coitus interruptus) or spermicides only are not acceptable methods of contraception. For sites in France, highly effective contraceptive methods (with a failure rate <1% per year), when used consistently and correctly, include: • combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral intravaginal transdermal • progestogen-only hormonal contraception associated with inhibition of ovulation: oral injectable implantable • intrauterine device (IUD) • intrauterine hormone-releasing system (IUS) • bilateral tubal ligation • vasectomized partner • sexual abstinence (Abstinence should only be used as a contraceptive method if it is in line with the patient's usual and preferred lifestyle; periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] is not an acceptable method of contraception.)
10. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial.

Exclusion criteria 19

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. Any systemic use of any steroid (intravenous [IV] or oral), or steroid eye drops for the treatment of TED or other conditions within 3 weeks prior to Screening. Such steroids cannot be initiated during the trial. Exceptions include local administration [excluding steroid eye drops], eg, topical (for skin only), intraarticular, and inhaled steroids, as well as allowance for systemic steroids (IV or oral) 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 monoclonal antibody 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 patient.
16. Known hypersensitivity to any of the components of teprotumumab or prior hypersensitivity reactions to monoclonal antibodies.
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 patients with a CAS <3 at Baseline have been randomized, an additional exclusion criterion will apply: CAS <3 at Baseline.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The percentage of patients who experience at least 1 TEAE and the percentage of patients who experience at least 1 treatment-emergent AESI during treatment with teprotumumab. . The percentage of patients who receive re-treatment

Secondary endpoints 16

1. Mean change from Baseline in proptosis measurement in the study eye.
2. Proptosis responder rate (percentage of patients with a ≥2-mm reduction from Baseline in proptosis in the study eye, without deterioration [≥2-mm increase] of proptosis in the fellow eye).
3. The overall responder rate (percentage of patients with ≥2-point reduction in CAS AND ≥2-mm reduction in proptosis from Baseline in the study eye, provided there is no corresponding deterioration [≥2 point/mm increase] in CAS or proptosis in the fellow eye).
4. The binocular diplopia responder rate (percentage of patients with baseline binocular diplopia >0 who have a reduction of ≥1 grade).
5. The binocular diplopia resolution rate (percentage of patients with baseline binocular diplopia >0 who have no binocular diplopia).
6. Mean change from Baseline in the GO-QoL questionnaire appearance and visual functioning sub-scales.
7. Rate of flares at the end of the Initial Follow-up Period.
8. Time to proptosis response from the first infusion until the end of the Initial Treatment Period.
9. CAS: - Proportion of patients with a CAS ≥3 at Baseline who have a CAS of 0 or 1 at the end of the Initial Treatment Period - Proportion of patients who improve on individual questions on the CAS for - spontaneous orbital pain - gaze-evoked orbital pain.
10. Proportion of patients with complete response at the end of the Initial Follow-up Period, as defined by durability of complete response
11. Proportion of patients with response at the last assessment in the Initial Follow-up Period, as defined by durability of response at the last assessment in the Initial Follow-up Period.
12. Mean change from Baseline over time in disease biomarkers for patients with a Baseline CAS ≥3.
13. "All other endpoints, except the time to proptosis response, rate of flares at the end of the Initial Follow-up Period, durability of complete response and durability of response at the last assessment in the Initial Follow-up Period, will be assessed by randomized cohort at the end of the Initial Treatment Period, at the end of the Initial Follow-up Period.
14. For patients who require re-treatment, the same endpoints will be estimated at the end of the 24-week Re-treatment Period.
15. Safety and Tolerability Endpoints 1. Incidence of TEAEs, SAEs, TEAEs resulting in premature discontinuation of treatment and treatment-emergent AESIs (infusion reactions, hyperglycemia, hearing impairment, new onset IBD and exacerbation of IBD). "
16. 2. Incidence of ≥Grade 3 TEAEs. 3. Incidence of ≥Grade 3 laboratory evaluations, in which CTCAE grading is available. 4. The results of best-corrected visual acuity. PK and ADA Endpoints 1. Peak and trough concentrations of teprotumumab. 2. ADA incidence and titers."

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Horizon Therapeutics USA Inc.

Sponsor organisation

Horizon Therapeutics USA Inc.

Address

1 Horizon Way

City

Deerfield

Postcode

60015-3888

Country

United States

Scientific contact point

Organisation

Horizon Therapeutics USA Inc.

Contact name

Medical Director

Public contact point

Organisation

Horizon Therapeutics USA Inc.

Contact name

Medical Director

Third parties 8

Locations

4 EU/EEA countries · 17 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 21 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications