Thyroid Eye Disease
Conditions
Brief summary
This is a multicenter, randomized, double-masked, placebo-controlled, single/multiple-dose-escalation trial conducted in Chinese participants with Thyroid Eye Disease (TED), aiming to evaluate the safety and tolerability of IBI3031 administered via subcutaneous or intravenous injection.
Detailed description
IBI3031 is an IGF-1R(Insulin-like growth factor 1 receptor)/TSHR(Thyroid-stimulating hormone receptor) bispecific antibody with potential synergistic therapeutic efficacy in TED and modulatory effects on thyroid function. As the first-in-human trial of IBI3031, this study evaluates the safety, tolerability, PK(Pharmacokinetics)/PD(Pharmacodynamics) profiles, immunogenicity, and efficacy of IBI3031 in TED participants. The trial is conducted in two stages: Stage 1- a single-ascending-dose (SAD) study involving single SC or IV administration of IBI3031; Stage 2- a multiple-ascending-dose (MAD) study involving three SC administrations of IBI3031. Approximately 66 TED participants are planned for enrollment: 36 in Stage 1 (allocated at a 3:1 ratio) and 30 in Stage 2 (allocated at a 4:1 ratio).
Interventions
DRUGIBI3031
subcutaneous injection or intravenous infusion.
DRUGplacebo
subcutaneous injection or intravenous infusion.
Sponsors
Innovent Biologics (Suzhou) Co. Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Written informed consent. 2. Aged between 18 and 75 years at screening. 3. Weight between 45 kg and 100 kg. 4. Moderate-to-severe active TED: * CAS ≥ 3 in the study eye at screening and baseline; * Usually associated with at least two of the following: lid retraction ≥ 2 mm, moderate or severe soft tissue involvement, exophthalmos ≥ 3 mm above normal, and/or inconstant or constant diplopia; * ≤ 12 months since the onset of active TED symptoms according to subjects' chief complaint or medical record at screening; 5. Exophthalmos ≥ 18 mm in the study eye at baseline. (Only applicable to Stage 2) 6. Participants must be clinically and biochemically euthyroid, or have mild hypothyroidism or mild-to-moderate hyperthyroidism at screening. 7. Positive for Thyrotrophin Receptor Antibody (TRAb) at screening. 8. No prior treatment with antithyroid medications and/or thyroid hormone replacement therapy, or having taken antithyroid medications and/or thyroid hormone replacement therapy on a stable dose for at least 6 weeks prior to the first dose, or having not been treated with antithyroid medications and/or thyroid hormone replacement therapy due to intolerable side effects for at least 6 weeks prior to the first dose. 9. Infertile female participants or fertile female participants with negative blood pregnancy test results during the screening period and agree to take contraceptive measures from screening to 120 days after the last dose; male participants should agree to use contraceptive measures from screening to 120 days after the last dose. Key
Exclusion criteria
Participants to be excluded (Participants meeting any of the following criteria will be regarded as ineligible): 1. The CAS of the study eye at baseline is reduced by ≥ 2 points compared with that at screening, or the proptosis of the study eye at baseline is reduced by ≥ 2 mm compared with that at screening; 2. Participants previously diagnosed with dysthyroid optic neuropathy (DON), or with DON as determined by the investigator at screening; 3. Patients with corneal ulcers that are not relieved after treatment at the investigator's discretion; 4. Presence of other non-TED ophthalmic diseases that may affect the interpretation of study results or the safety of participants as determined by the investigator (e.g., proptosis not primarily caused by TED); 5. At screening, clinical or laboratory evidence of significant hypothyroidism (presence of clinical symptoms of hypothyroidism, or FT3 or FT4 (Free Thyroxine)\<0.5×lower limit of normal \[LLN\], or TSH\>1.5×upper limit of normal \[ULN\]); or severe hyperthyroidism during the screening period (FT3 and FT4(Free Thyroxine)\>2×ULN, or presence of thyroid storm). 6. Other medical history and abnormal test results during the screening period that are judged by the investigator to be clinically significant, may cause the participant to fail to comply with the study protocol or complete the trial, or endanger safety, including but not limited to: * History of hepatic insufficiency (Child-Pugh Class B or C) or liver cirrhosis; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 2 × ULN at screening; * Glomerular filtration rate (GFR) \< 60 ml/min/1.73 m2; * Poorly controlled diabetes mellitus or hypertension; * Confirmed or clinically suspected inflammatory bowel disease, gastrointestinal bleeding, or peptic ulcer disease. * History of of chronic or recurrent infections; opportunistic infection within 180 days prior to screening; * Positive for human immunodeficiency virus antibody (HIV Ab), hepatitis C virus antibody (HCV Ab), non-specific syphilis antibody (e.g., RPR(Rapid Plasma Reagin), TRUST), hepatitis B virus surface antigen (HBsAg) or e-antigen (HBeAg), or interferon-gamma release assay (IGRA). * History of tinnitus or other hearing impairment in either ear during the screening period; or abnormal pure tone audiometry results (defined as an average bone conduction hearing threshold of ≥ 25 dB(decibe) at 0.5, 1, 2, and 4 kHz(kilohertz), or a bone conduction hearing threshold of ≥ 40 dB at any frequency); 7. Scheduled radioactive iodine therapy or thyroidectomy at any time before screening or during the study; 8. Scheduled orbital radiotherapy at any time before screening or during the study, or surgical treatment for TED, including orbital decompression, strabismus surgery, and eyelid surgery; 9. Cumulative dose of glucocorticoids used to treat TED ≥ 1 g of methylprednisolone equivalents within 90 days prior to screening; 10. Oral or intravenous glucocorticoids within 30 days prior to screening; 11. Peribulbar/periorbital injection of glucocorticoids within 90 days prior to screening; 12. Oral or intravenous administration of any other non-steroidal immunosuppressants within 90 days prior to screening; 13. Use of glucocorticoid eye drops/ointments or use of non-steroidal immunosuppressant eye drops within 14 days prior to screening; 14. Received antibody therapy targeting IGF-1R, TSHR, CD20(cluster of differentiation antigen 20), IL-6, or IL-6 receptor (IL-6R) at any time before screening; 15. Received any other TED therapeutic drugs under development (including but not limited to biologics targeting IGF-1R, FcRn(neonatal Fc recepto), IL-6, or IL-6R) at any time before screening; 16. Use of any other monoclonal antibody within 90 days prior to screening; 17. Have received live vaccines within 180 days prior to screening, or plan to receive live vaccines during the study; 18. Female participants in pregnancy or lactation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number, incidence rate, severity, and association with the study drug of Adverse Events (AEs) | up to Day 85 for SAD;up to Day 337 for MAD | The number, incidence rate, severity, and association with the study drug of all AEs occurring throughout the trial will be summarized. |
| Number, incidence rate, severity, and association with the study drug of Treatment-Emergent Adverse Events (TEAEs) | up to Day 85 for SAD;up to Day 337 for MAD | The number, incidence rate, severity, and association with the study drug of all TEAEs after study drug administration will be summarized. |
| Number, incidence rate, severity, and association with the study drug of Serious Adverse Events (SAEs) | up to Day 85 for SAD;up to Day 337 for MAD | The number, incidence rate, severity, and association with the study drug of all SAEs will be summarized. |
| Change in systolic and diastolic blood pressure after dosing in each dose group(Unit of Measure: mmHg) | up to Day 85 for SAD;up to Day 337 for MAD | Systolic and diastolic blood pressure will be measured and recorded at each specified time point |
| Number of participants with clinically significant abnormal findings in complete physical examination(Unit of Measure: participants) | up to Day 85 for SAD;up to Day 337 for MAD | A complete physical examination will be performed at each specified time point, including assessment of general appearance, respiratory system, cardiovascular system, abdomen, skin, head and neck (including ears, nose, and throat), lymph nodes, thyroid gland, musculoskeletal system (including spine and extremities), and neurological system. Any finding that is new or worsened from baseline and deemed clinically significant by the investigator will be |
| Changes in hematology laboratory parameters before and after dosing in each dose group | up to Day 85 for SAD;up to Day 337 for MAD | Changes in hematology parameters including white blood cell count, red blood cell count, hemoglobin, and platelet count will be recorded. |
| Changes in blood chemistry laboratory parameters before and after dosing in each dose group | up to Day 85 for SAD;up to Day 337 for MAD | Changes in blood chemistry parameters including liver and renal function, electrolytes, and blood glucose will be recorded. |
| Changes in urinalysis laboratory parameters before and after dosing in each dose group | up to Day 85 for SAD;up to Day 337 for MAD | Changes in urinalysis parameters including urine protein, urine occult blood, and urine leukocytes will be recorded. |
| Changes in thyroid function laboratory parameters before and after dosing in each dose group | up to Day 85 for SAD;up to Day 337 for MAD | Changes in thyroid function parameters including thyroid-stimulating hormone, free triiodothyronine, and free thyroxine will be recorded. |
| Number of subjects with abnormal ECG changes before and after administration in each dose group | up to Day 85 for SAD;up to Day 337 for MAD | — |
| Changes in pure-tone audiometry results before and after dosing in each dose group | up to Day 85 for SAD;up to Day 337 for MAD | Changes in hearing thresholds at each frequency (500 Hz, 1000 Hz, 2000 Hz, 4000 Hz) will be recorded. |
| Change in heart rate after dosing in each dose group (Unit of Measure: beats per minute) | up to Day 85 for SAD;up to Day 337 for MAD | Heart rate will be measured and recorded at each specified time point. |
| Change in body temperature after dosing in each dose group(Unit of Measure: °C) | up to Day 85 for SAD;up to Day 337 for MAD | Body temperature will be measured and recorded at each specified time point. |
| Change in respiratory rate after dosing in each dose group( Unit of Measure: breaths per minute) | up to Day 85 for SAD;up to Day 337 for MAD | Respiratory rate will be measured and recorded at each specified time point. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC) of the serum concentration-time profile | up to Day 85 for SAD;up to Day 337 for MAD | — |
| Maximum Concentration (Cmax) of the drug in serum | up to Day 85 for SAD;up to Day 337 for MAD | — |
| Clearance (CL) | up to Day 85 for SAD;up to Day 337 for MAD | — |
| Volume of Distribution (Vd) | up to Day 85 for SAD;up to Day 337 for MAD | — |
| Elimination Half-life (t1/2) | up to Day 85 for SAD;up to Day 337 for MAD | — |
| Production of anti-drug antibodies (ADAs) and/or neutralizing antibodies (NAbs) in serum | up to Day 85 for SAD;up to Day 337 for MAD | — |
| Proportion of participants with proptosis response | Day 8, Day 29, Day 57, and Day 85 for single ascending dose (SAD) stage; Week 5, Week 9, Week 13, Week 17, Week 21, Week 29, Week 37, and Week 49 for multiple ascending dose (MAD) stage | Defined as a ≥2 mm reduction in proptosis in the study eye from baseline, without a ≥2 mm increase in proptosis in the fellow eye |
| Proportion of participants with overall response | Day 8, Day 29, Day 57, and Day 85 for single ascending dose (SAD) stage; Week 5, Week 9, Week 13, Week 17, Week 21, Week 29, Week 37, and Week 49 for multiple ascending dose (MAD) stage | Defined as a ≥2-point reduction in the Clinical Activity Score (CAS) from baseline in the study eye, a ≥2 mm reduction in proptosis in the study eye from baseline, and no worsening in the fellow eye (worsening defined as a ≥2-point increase in CAS or a ≥2 mm increase in proptosis) |
| Number of subjects with changes in proptosis from baseline after dosing | Day 8, Day 29, Day 57, and Day 85 for single ascending dose (SAD) stage; Week 5, Week 9, Week 13, Week 17, Week 21, Week 29, Week 37, and Week 49 for multiple ascending dose (MAD) stage | — |
| Proportion of participants with CAS = 0 or 1 | Day 8, Day 29, Day 57, and Day 85 for single ascending dose (SAD) stage; Week 5, Week 9, Week 13, Week 17, Week 21, Week 29, Week 37, and Week 49 for multiple ascending dose (MAD) stage | — |
| CAS change from baseline | Day 8, Day 29, Day 57, and Day 85 for single ascending dose (SAD) stage; Week 5, Week 9, Week 13, Week 17, Week 21, Week 29, Week 37, and Week 49 for multiple ascending dose (MAD) stage | — |
| Proportion of participants with diplopia response | Day 8, Day 29, Day 57, and Day 85 for single ascending dose (SAD) stage; Week 5, Week 9, Week 13, Week 17, Week 21, Week 29, Week 37, and Week 49 for multiple ascending dose (MAD) stage | Defined as a ≥1-point reduction in diplopia |
| Total score of the Graves' Ophthalmopathy Quality of Life | Day 8, Day 29, Day 57, and Day 85 for single ascending dose (SAD) stage; Week 5, Week 9, Week 13, Week 17, Week 21, Week 29, Week 37, and Week 49 for multiple ascending dose (MAD) stage | The effect of thyroid eye disease on social activities and appearance during the past 1 week. |
Countries
China
Contacts
CONTACTZhongyan shan
CONTACTfunan liu
Outcome results
None listed