A Phase 3, Randomized, Double-Masked, Placebo-Controlled, Parallel-Group, Multicenter Trial Evaluating HZN-001 (teprotumumab) Treatment in Japanese Patients with Active Thyroid Eye Disease

JRCT ID: jRCT2031210453

Registered date:26/11/2021

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Active thyroid eye disease
• Date of first enrollment: 27/11/2021
• Target sample size: 50
• Study type: Interventional

Intervention(s)

On Day 1 of the double-masked Treatment Period, patients will be randomized in a 1:1 ratio (stratified by tobacco use status) to receive infusions of either:
1. HZN-001 (10 mg/kg on Day 1 followed by 20 mg/kg q3W for the remaining 7 infusions), or
2. Placebo (q3W for all 8 infusions).
The first and second infusion will be administered over approximately 90 minutes (but not less than 80 minutes). All subsequent infusions will be administered over approximately 60 minutes (but not less than 50 minutes).

Outcome(s)

• Primary Outcome: The primary efficacy endpoint is the proptosis responder rate (defined as the 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) at Week 24.

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: <= 80age old
• Gender: Both

Include criteria

Eligible patients must meet/provide all of the following criteria:
1. Written informed consent.
2. Male or female Japanese patients between the ages of 20 and 80 years, inclusive, at Screening.
3. Clinical diagnosis of Graves' disease associated with active TED with a CAS >= 3 (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 and/or inconstant or constant diplopia.
5. Proptosis >= 3-mm increase from the patient's baseline (prior to diagnosis of TED), as estimated by treating physician. and/or proptosis >= 18mm.
6. Onset of active TED symptoms (as determined by patient records) within 9 months prior to Baseline.
7. Patients 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.
8. Does not require immediate surgical ophthalmological intervention.
9. Diabetic patients must have HbA1C < 8.0% at Screening.
10. Patients with a history of inflammatory bowel disease (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 inflammatory bowel disease without modifications in the 3 months prior to Screening are allowed.
11. 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); patients who are sexually active with a non-vasectomized male partner 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 (failure rate less than 1% per year), when used consistently and correctly, include implants, injectables, combination oral contraceptives, some intrauterine devices, tubal ligation, sexual abstinence and vasectomized partner.
12. Patient is willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the study.

Exclude criteria

Patients will be ineligible for trial participation if they meet any of the following 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 (or equivalent), 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], injected, 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 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 must be discontinued 3 weeks prior to Screening and must not be restarted during the trial; however, taking a multivitamin that includes selenium (less than 100 mcg daily) is allowed.
9. Any previous treatment with rituximab (Rituxan) within the last 12 months or tocilizumab (Actemra) within the last 6 months prior to Screening. 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. Malignant condition in the past 12 months (except successfully treated basal/squamous cell carcinoma of the skin).
13. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >= 3 times the upper limit of normal (ULN) or estimated glomerular filtration rate<= 30 ml/min/1.73 m2 at Screening.
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 HZN-001 or prior hypersensitivity reactions to mAbs.
17. Any other condition that, in the opinion of the Investigator, would preclude inclusion in the study.
18. Previous enrollment in this study or participation.
19. HIV, hepatitis C or hepatitis B infections.

Related Information

• Primary Sponsor: Oyama Fujiyo