A Clinical Study to Evaluate the Efficacy and Safety of IBI311 in Subjects With Inactive Thyroid Eye Disease

A Multicenter, Randomized, Double-masked, Placebo-controlled Phase III Clinical Study to Evaluate the Efficacy and Safety of IBI311 in Subjects With Inactive Thyroid Eye Disease

A multicenter clinical study to evaluate the efficacy and safety of IBI311 in subjects with inactive thyroid eye disease. The study consists of two parts, with a maximum duration of approximately 64 weeks.

This study is a multicenter, randomized, double-masked, placebo-controlled Phase III clinical study in inactive TED subjects. Approximately 111 eligible subjects will be randomly assigned to the IBI311 group and the placebo group in a 2:1 ratio on Day 1. The study consists of two parts, with a maximum duration of approximately 64 weeks. Part 1 includes a screening period and a double-masked treatment period, lasting for a total of approximately 28 weeks. Part 2 is a follow-up/open treatment period, lasting for up to approximately 36 weeks.

Inclusion Criteria:

1.At screening and baseline, the following diagnostic criteria for inactive TED were met:

1. CAS of both eyes ≤ 2 points during the screening period and baseline;
2. According to the subject's medical history, CAS of both eyes ≤ 2 points at least 6 months before screening, or according to the subject's chief complaint or medical history, with all of the following characteristics: no progression of proptosis and no new diplopia caused by TED at least 6 months before screening or no progression of diplopia caused by TED and no new inflammatory TED symptoms;
3. According to the subject's chief complaint or medical history, the first TED diagnosis before screening was ≥ 2 years and < 10 years.

2.At baseline, the proptosis of the study eye was ≥20 mm. 3.If the subject is a female, she should be infertile or have a negative blood pregnancy test during the screening period and agree to take contraceptive measures from the screening period to 120 days after the last medication. If the subject is a male, he should agree to take contraceptive measures from the screening period to 120 days after the last medication.

Exclusion Criteria:

Subjects who meet any of the following conditions will not be eligible to participate in this study:

1. At baseline, the eyeball protrusion of the study eye decreased by ≥2 mm compared with the screening period;
2. Subjects who have been previously diagnosed with DON, or who are determined by the investigator to have DON during screening (defined as: orbital MRI/CT showing orbital apex crowding or optic nerve compression, and at least 2 of the following ophthalmological examination abnormalities that cannot be explained by other reasons: ① best corrected visual acuity [BCVA] < 0.8 or BCVA decreased by ≥ 2 lines compared with before the onset; ② abnormal pupillary light reflex or relative pupillary afferent disorder; ③ color vision abnormalities; ④ optic disc edema and optic disc pallor on fundus examination; ⑤ visual field loss; ⑥ visual evoked potential with prolonged latency and/or decreased amplitude);
3. Patients with corneal ulcers that are judged by the researchers to have no relief after treatment;
4. Planned to receive orbital radiotherapy or surgical treatment for TED (including orbital decompression, strabismus correction, eyelid correction, etc.) at any time before baseline or during the study period;
5. Poorly controlled thyroid function, defined as free triiodothyronine (FT3) or free thyroxine (FT4) deviating from the normal reference value range of the local research center laboratory by more than 50% during screening;
6. Any other diseases, metabolic disorders, abnormal physical examination or clinical laboratory test results, and there is reason to suspect that there may be diseases or conditions that may lead to contraindications to the use of the trial drug, affect the interpretation of the study results, or put the subjects at high risk of treatment complications, including but not limited to: confirmed or clinically suspected inflammatory bowel disease, coagulation disorders, history of acute cardiovascular and cerebrovascular diseases or treatment history within 180 days before screening(including but not limited to: cerebrovascular accident, transient ischemic attack, acute myocardial infarction, unstable angina, coronary artery bypass grafting, percutaneous coronary intervention [except diagnostic angiography], severe arrhythmia, etc.), history of malignant tumors treated or untreated in the past 5 years (except for skin squamous cell carcinoma, basal cell carcinoma, cervical carcinoma in situ, prostate carcinoma in situ or thyroid papillary carcinoma that have been successfully removed and have no evidence of metastasis), severe systemic infection, proptosis not caused by TED, etc.;
7. During the screening period, any ear has: tinnitus or other history of hearing loss; or abnormal pure tone audiometry results (defined as average bone conduction hearing threshold ≥25 dB at 0.5, 1, 2, 4 kHz or bone conduction hearing threshold ≥40 dB at any frequency);
8. At screening, aspartate aminotransferase (AST) or alanine aminotransferase (ALT)>3×ULN, or with active hepatitis B (defined as HBsAg positive with HBV-DNA load>1000 IU/mL), or receiving anti-hepatitis B virus treatment;
9. At screening, glomerular filtration rate (GFR) <30 ml/min/1.73m2 (MDRD formula: GFR = 186 × serum creatinine (mg/dl) - 1.154 × (age) - 0.203 × (0.742 [if female]), serum creatinine unit conversion: 1 μmol/L = 0.0113 mg/dL);
10. Poorly controlled diabetes at screening (defined as glycated hemoglobin ≥8.0% at screening);
11. At screening, patients have poorly controlled hypertension, with systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg; renal artery stenosis; or evidence of unstable blood pressure (including orthostatic hypotension, etc.);
12. During screening, the 12-lead ECG shows a heart rate of <50 beats/min or >100 beats/min, the ECG indicates active heart disease, or the investigator believes that the ECG abnormality during screening will interfere with the interpretation of the ECG results during subsequent follow-up, especially excluding QTcF>500 ms;
13. HIV antibody or HCV antibody positive or active syphilis (defined as non-specific syphilis antibody positive or requiring anti-syphilis treatment after consultation with the infectious disease department);
14. Oral or intravenous glucocorticoids within 30 days before screening;
15. Use of glucocorticoid eye drops/eye ointment, or non-steroidal immunosuppressant eye drops within 30 days before screening;
16. Periorbital/periorbital injection of glucocorticoids within 90 days before screening;
17. Any other non-steroidal immunosuppressants taken orally or intravenously within 90 days before screening;
18. Received interleukin-6 receptor (IL-6R) antibody treatment within 180 days before screening;
19. Received CD20 antibody treatment within 1 year before screening;
20. Received IBI311 or TEPEZZA treatment at any time before screening;
21. Have received any other TED treatment drugs under development at any time before screening (including but not limited to biological agents targeting IGF-1R, FcRn, and TSHR);
22. Use of any other monoclonal antibody treatment within 90 days before screening;
23. Participated in other interventional clinical trials within 90 days before screening (for drugs, within 5 half-lives, whichever is longer; excluding vitamins and minerals), or attempted to participate in other clinical trials during the study;
24. Female subjects who are pregnant or lactating;
25. Those who are known to be allergic to the study drug ingredients, or have a history of allergies to other monoclonal antibodies; Those who are considered by the researchers to be unsuitable for participating in this clinical trial due to other reasons.