Clinical Study of the Safety and Efficacy of BAT5906 Injection

Study Overview
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Brief Summary
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This study is a multi-center, open, multiple-dose phase Ib/IIa clinical study evaluating the efficacy and safety of BAT5906 injection in patients with diabetic macular edema. BAT5906's phase I study on w-AMD shows that it is safe from 0.3-4.0 mg, and the higher dose (2.5 mg and 4 mg) may maintain the effect for longer; the same target drugs (such as brolucizumab and Abecip ) It has also been found in clinical studies that high doses can extend the dosing interval and reduce the dosing frequency. Therefore, in this study, two safe and effective doses were selected, and the optimal clinical effective dose and frequency of BAT5906 in DME were initially explored.

Official Title
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Phase Ib/IIa Clinical Study of the Safety and Efficacy of BAT5906 Injection in Patients With Diabetic Macular Edema With Multiple Changes of Intravitreal Two Doses

Conditions
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Diabetic Macular Edema

Intervention / Treatment
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* Drug: 2.5mg of BAT5906
* Drug: 4.0mg of BAT5906


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Only the following criteria are met: Sign the informed consent voluntarily, willing and capable to follow the procedures of outpatient visits and research at the time specified in the trial Diagnosed with type 1 or type 2 diabetes, aged 18 to 80 years old; The drug treatment to control diabetes must be stable within 3 months before randomization and is expected to remain stable during the study period; Macular edema secondary to diabetes, and found to be involved in the macular center (fovea) of the research eye by OCT examination, confirmed by the reading center during screening; The CRT of the research eye evaluated by OCT examination is ≥300 μM, confirmed by the reading center during screening; The BCVA of the research eye is 73-24 letters (using the ETDRS table, including the boundary value, which is equivalent to the Snellen visual acuity score of the research eye equal to 20/40 -20/400); Contralateral eye BCVA ≥ 34 letters (using ETDRS table, equivalent to snellen vision ≥ 20/200). Note: If both eyes meet the inclusion criteria, the eye with poor baseline vision is selected as the research eye; At the time of screening and baseline, the investigator judged that the contralateral eye was expected to not require any anti-VEGF treatment within 3 months (PK group only). Exclusion Criteria: If a patient meets any of the following conditions, they cannot enter the study: Eye exclusion criteria: There is structural damage to the center of the macula in the eye, and the best corrected vision may not be improved after the macular edema resolves, including atrophy of retinal pigment epithelial cells, subretinal fibrosis or scarring, and obvious macular ischemia (FFA suggests arching Obvious damage), macular anterior membrane involving fovea or organic hard exudate (as confirmed by the reading center before randomization); The research eye has iris lesions and neovascular glaucoma; Those who have no eye lens (except intraocular lens); The study eye has active hyperplastic diabetic retinopathy (PDR); The research eye has anyone other than diabetic macular edema that may confuse macular assessment or vision testing (retinal vascular occlusion, retinal detachment, vitreous macular traction, macular hole, preretinal fibrosis involving the macula, choroidal neovascularization, age Related macular degeneration, etc.); The research eye is accompanied by poorly controlled glaucoma, which is defined as the intraocular pressure still ≥21mmHg after treatment with anti-glaucoma drugs, or according to the judgment of the investigator; The research eye has undergone or may have undergone anti-glaucoma surgery during the study period (including trabeculectomy, sclerectomy and non-penetrating trabecular surgery, etc.); The research eye has undergone vitreoretinal surgery or scleral buckling; At the time of screening and baseline, the study eye had received laser photocoagulation (total retina or macular laser photocoagulation) within 90 days (including 90 days) or during the study period; At the time of screening and baseline, the study eye had any intraocular or perocular surgery within 90 days (including 90 days) (except for yttrium-aluminum-garnet (YAG) lens capsule incision and eyelid surgery for more than 30 days) ; A history of uveitis in any eye; Any eye has active ocular inflammation or infection (bacterial, viral, parasitic or fungal infection); At the time of screening and baseline, any eye had received intraocular anti-VEGF treatment within the first 90 days (including 90 days), such as ranibizumab, bevacizumab, abercept, compacept, etc.; At the time of screening and baseline, any eye has received intraocular, periocular, and subconjunctival corticosteroid treatment within the first 90 days (including 90 days); Exclusion criteria for abnormal conditions in laboratory inspection: Abnormal liver and kidney function (this test specifies that ALT and AST should not be higher than the upper limit of the normal value of the laboratory in the center by 2.5 times; Crea and BUN should not be higher than the upper limit of the normal value of the laboratory in the center by 2 times); Abnormal blood coagulation function (prothrombin time ≥ upper limit of normal value 3 seconds, activated partial thromboplastin time ≥ upper limit of normal value 10 seconds); Any one of the infected patients: active hepatitis B (if HBsAg(+) requires HBV DNA must be> 500 IU/mL or the hospital maximum limit), hepatitis C, AIDS or syphilis (positive RPR test); Other exclusion criteria: Myocardial infarction or stroke occurred within 6 months before the first dose; Poorly controlled diabetes [defined as glycated hemoglobin (HbA1c)>9%)]; Accompanied by uncontrollable hypertension (defined as blood pressure >150/100 mmHg after treatment with antihypertensive drugs); Patients who took large doses of oral or injectable corticosteroids and other hormonal drugs (>10 mg prednisolone or the same dose/day) within 6 months before screening, but patients who used steroid drugs for inhalation, nasal cavity or local skin small doses except; Those who have undergone surgery within 1 month and have not healed, or according to the investigator's judgment; There is a history of contraindications to the study drug, metabolic dysfunction, physical examination results, or a disease or symptom that is reasonably suspected of being based on clinical laboratory results is a contraindication to the study drug, which may affect the judgment of the study results, or make the subject suffer Higher risk of complications; Allergy or contraindications to known research drugs or their ingredients, fluorescein or povidone iodine; Those who participated in clinical trials of any drugs (except vitamins and minerals) or devices 90 days before the first dose (including 90 days); Women who are pregnant, pregnant or breastfeeding (pregnancy is defined as a positive blood/urine pregnancy test in this trial); male or female subjects of fertility do not agree to the entire study period and within 3 months after the end of the visit period Take appropriate contraceptive measures (such as IUD, birth control pills or condoms, etc.). For women who have not been menopausal or have been menopausal but have not met the menopause time continuously for more than 12 months, and have not undergone sterilization surgery (ovarian and/or hysterectomy), they are defined as having fertility. The definition of fertility may be adjusted according to local standards in each region. Note: High-efficiency contraception methods include total abstinence, IUD, double barrier method (eg condom + diaphragm with spermicides, implanted contraceptives, hormonal contraceptives [contraceptives, implanted contraceptives, transdermal Patches, hormone-vaginal devices or sustained-release injections], or the partner has undergone a vasectomy and is confirmed to have no sperm); The researchers believe that there are other conditions that need to be excluded.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: one investigational medicine with two different dose groups
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2.5mg of BAT5906<br>Specification: 10mg/0.2ml/piece; route of administration: intravitreal injection; dose: 2.5mg/eye/time, 50μl; medication duration: once every 4 weeks, 6 consecutive times, then every 4 weeks Followed up once (the investigator judged to administer the drug as needed) and observed until the 48th week. | Drug: 2.5mg of BAT5906<br>* Specification: 2.5mg of BAT5906<br>|
| Experimental: 4mg of BAT5906<br>Specification: 16mg/0.2ml/piece; route of administration: intravitreal injection; dose: 4mg/eye/time, 50μl; medication duration: once every 4 weeks, 3 consecutive times, then every 4 weeks Followed up once (the investigator judged to administer the drug as needed) and observed until the 48th week. | Drug: 4.0mg of BAT5906<br>* Specification: 4.0mg of BAT5906<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vital signs（ body temperature） | the patient's body temperature (axillary temperature) Any clinically significant abnormality should be reported as an adverse event and recorded in the original | After patient resting for more than 3 minutes | 
| Vital signs（heart rate/pulse） | heart rate/pulse Any clinically significant abnormality should be reported as an adverse event and recorded in the original | After patient resting for more than 3 minutes | 
| Vital signs（respiratory rate） | respiratory rate Any clinically significant abnormality should be reported as an adverse event and recorded in the original | After patient resting for more than 3 minutes | 
| Vital signs（blood pressure） | blood pressure Any clinically significant abnormality should be reported as an adverse event and recorded in the original | After patient resting for more than 3 minutes | 
| physical examination | Physical examination should include at least general conditions, head and face, skin, lymph nodes, ears, nose, throat, respiratory system, cardiovascular system, abdomen (including liver and spleen), genitourinary system, musculoskeletal system, nervous system, and mental condition | The investigator or other authorized and qualified investigator shall perform the prescribed physical examination according to the evaluation schedule. During the visit, the investigator performed a physical examination as indicated by symptoms | 
| laboratory examination（blood routine） | In the test process will be carried out in accordance with the testing program flow chart of blood routine, the laboratory testing results of the subjects to evaluate the change of relative to the baseline, the each evaluate clinical significance of abnormal experimental value, the researchers don't think with basic diseases related to abnormal subjects as AE record | Screening period，Week 12, Week 24, Week 48 of the last visit | 
| laboratory examination（outine urine） | In the test process will be carried out in accordance with the testing program flow chart of routine urine , the laboratory testing results of the subjects to evaluate the change of relative to the baseline, the each evaluate clinical significance of abnormal experimental value, the researchers don't think with basic diseases related to abnormal subjects as AE record | Screening period，Week 12, Week 24, Week 48 of the last visit | 
| laboratory examination（blood biochemical examination） | In the test process will be carried out in accordance with the testing program flow chart of blood biochemical examination, the laboratory testing results of the subjects to evaluate the change of relative to the baseline, the each evaluate clinical significance of abnormal experimental value, the researchers don't think with basic diseases related to abnormal subjects as AE record | Screening period，Week 12, Week 24, Week 48 of the last visit | 
| laboratory examination（blood coagulation function） | In the test process will be carried out in accordance with the testing program flow chart of blood coagulation function, the laboratory testing results of the subjects to evaluate the change of relative to the baseline, the each evaluate clinical significance of abnormal experimental value, the researchers don't think with basic diseases related to abnormal subjects as AE record | Screening period，Week 12, Week 24, Week 48 of the last visit | 
| electrocardiogram（12- Lead ECG） | During the trial, the examination of the electrocardiogram (ecg) method must be consistent, and to evaluate the clinical significance of the results, will any researchers to make judgment for clinical significance of abnormal as adverse events were reported, and recorded in the original records and case report form, the subjects in the process of the entire study if there is clinical indications by researchers to determine whether the need for ecg examination. | Screening period of the first visit: Week 12 of the fifth visit, Week 24 of the eighth visit, and Week 48 of the last visit | 
| anti-drug antibody (ADA) | Plasma samples for anti-drug antibody (ADA) detection were collected to detect the positive incidence of ADA associated with plasma levels of BAT5906 | 24 hours before 1, 2, 3, 4 dosing, 5 dosing to last visit, each dosing before and 24 hours before the last visit as needed | 
| ocular and non-ocular adverse events (AE) and serious adverse events (SAE) | Any adverse medical event that occurs after a subject participates in a clinical trial and receives the investigational drug, but is not necessarily cause-and-effect with the treatment. An adverse event can be any adverse or unexpected sign (including abnormal laboratory tests), symptom, or disease, whether or not it is drug related. | Adverse events were collected from the time the patient signed the informed consent to the time 28 days after the last dication | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effectiveness evaluation | Main efficacy indicators (study eye) At week 24, Change in BCVA from baseline At week 24, the mean change of BCVA from baseline. Secondary efficacy indicators (research eyes): At 12th and 48th week, the mean change of BCVA from baseline; At week 12, week 24 and week 48, the average change of CRT from baseline after OCT examination; At Week 12, 24 and 48, the proportion of subjects whose BCVA increased ≥10 letters from baseline, BCVA increased ≥15 letters from baseline, and BCVA decreased ≥15 letters from baseline; The average number of BAT5906 injections in 24 weeks and 48 weeks. The definition of CRT is: the average thickness of the central retina with the fixation point as the center and a diameter of 1 mm. | Week 24 | 
| Effectiveness evaluation | Secondary efficacy indicators (study eye) At week 12 and 48, the mean change of BCVA from baseline. | Week 12 and 48 | 
| Effectiveness evaluation | Changes in CRT from baseline were examined by OCT CRT:The mean thickness of the central retina with a diameter of 1mm, centered on the fixed point of view | at weeks 12, 24, and 48 | 
| Effectiveness evaluation | Percentage of subjects whose BCVA increased by ≥10 letters from baseline, increased by ≥15 letters from baseline, and decreased by ≥15 letters from baseline; | at weeks 12, 24, and 48 | 
| Effectiveness evaluation | Average number of injections for BAT5906 | 24 weeks and 48 weeks |