A Study of IBI311 in Subjects With Steroid-resistant, Thyroid Associated Ophthalmopathy

This is an exploratory study of the efficacy and safety of IBI311, a modified anti-IGF-1R antibody, in patients with steroid-resistant, thyroid associated ophthalmopathy (TAO). This study includes two stages. Stage I is a single-center, single-arm, open-label clinical study designed to evaluate the safety and tolerability of IBI311 in subjects with TAO. Approximately 10 subjects meeting the study eligibility criteria will be enrolled. Stage II is a single-center, randomized, double-masked, placebo-controlled clinical trial designed to evaluate the efficacy and safety of IBI311 in subjects with steroid-resistant TAO. Approximately 54 subjects meeting the study eligibility criteria will be randomly assigned to IBI311 or placebo on day 1 (D1) in a 2:1 ratio stratified by disease activity.


Eligibility Criteria:
Inclusion Criteria:

1. Written informed consent.
2. Male or female subject between 18 and 80 years (inclusive) at Screening.
3. Steroid-resistant TAO, defined as poor response to steroid after completing a 3-month steroid pulse therapy (4.5g to 8.0g methylprednisolone) or 3-6 months of oral glucocorticoids treatment (i.e., CAS decreased by \< 2 points, or proptosis decreased by \< 2mm, or no improvement in diplopia), or relapse of TAO after steroid withdrawal (CAS increased by ≥2 points and CAS≥3 points \[7-item scale\] in either eye, or proptosis increased by ≥2 mm, or Gorman diplopia score increased by ≥1 point).
4. Moderate-to-severe active TAO or chronic TAO at screening:

   Inclusion criteria for subjects with moderate-to-severe active TAO:
   * Active TAO, with CAS ≥3 in the study eye during the screening period;
   * Proptosis ≥18 mm in the study eye;
   * Moderate to severe active TAO, usually associated with at least two of the following manifestations: eyelid retraction ≥ 2 mm, moderate or severe soft tissue involvement, proptosis ≥ 3 mm above upper limit of normal (ULN), inconstant or constant diplopia (Gorman subjective diplopia score 2-3);

   Inclusion criteria for subjects with chronic TAO:
   * CAS ≤2 in both eyes during the screening period;
   * Proptosis ≥18 mm in the study eye;
   * A clinical diagnosis of chronic non-active TAO at screening was defined as CAS ≤2 in both eyes for at least 6 months prior to screening, or having all of the following characteristics: no progression of proptosis, no newly onset diplopia or diplopia progression induced by TED at least 6 months prior to screening, and no new inflammatory TAO symptoms.
5. Infertile female subjects or fertile female subjects with negative blood pregnancy test results during the screening period and agrees to take contraceptive measures from screening to 120 days after the last dose; male subjects should agree to use contraceptive measures from screening to 120 days after the last dose.

Exclusion Criteria:

Subjects will be ineligible for study participation if they meet any of the following criteria:

1. Decreased best-corrected visual acuity due to optic neuropathy (defined as a ≥ 2-line decrease in best-corrected visual acuity due to optic neuropathy within the past 180 days), newly emerging visual field defects or color vision impairment secondary to optic nerve damage;
2. Subjects with corneal ulcer;
3. Immediate orbital radiotherapy or orbital decompression as judged by investigators;
4. Orbital radiation therapy or surgical treatment for TAO, including orbital decompression, strabismus diorthosis and eyelid diorthosis, at any time before baseline, or planned to have the aforementioned treatments during the study;
5. Subjects with poorly controlled thyroid function, defined as FT3 or FT4 levels deviating from the normal reference ranges of the local study site laboratories by more than 50% at screening;
6. Receiving Teprotumumab or IBI311 at any time before baseline;
7. Receiving anti-CD20 antibody or interleukin-6 receptor antibody treatment within 180 days prior to baseline;
8. Oral or intravenous administration of any other non-steroid immunosuppressant within 90 days prior to baseline