The Study of Drug 601 in Patients With Wet Age-related Macular Degeneration (wAMD)

Study Overview
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Brief Summary
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Multicenter study to evaluate the safety and tolerability in patients with wet Age-related macular degeneration (wAMD) treated with intravitreal recombinant humanized anti-VEGF monoclonal antibody

Detailed Description
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According to the results of preclinical pharmacological research and clinical application of bevacizumab in ophthalmology Case, 601 will be developed as a drug candidate for the treatment of ocular diseases such as wAMD .Observe the safety and tolerability of the single and multiple doses of 601 in wAMD patients; study the pharmacokinetic characteristics of single and multiple doses of 601, Observe the Preliminary efficacy of 601 multiple injections with different doses in the treatment of patients with wAMD.

Official Title
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Phase I Clinical Trial of Recombinant Anti-VEGF Human Monoclonal Antibody in the Treatment of Wet Age-related Macular Degeneration

Conditions
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Wet Age-related Macular Degeneration

Intervention / Treatment
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* Drug: Drug 601
* Drug: Drug 601
* Drug: Drug 601
* Drug: Drug 601
* Drug: Drug 601
* Drug: Drug 601


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sign informed consent form and willing to be visited at the time specified in the trial; Age ≥45 years and age ≤ 80 years; The study eye must meet the following criteria: Diagnosis of wAMD; The presence of an primary or recurrent active choroidal neovascular (CNV) lesions in subfovea and para-fovea secondary to AMD; Total area of all types of lesions ≤30mm2 (12 optic disc areas) Best EDTRS letter score between 19 and 78(Snellen equivalent of 20/400 to 20/32); No optometric media opacity and pupil shrinkage. Best EDTRS letter score ≥19 (Snellen equivalent of 20/400 or better) in the fellow eyes. Exclusion Criteria: Any of the following eye conditions: Any eye has active ocular infections (e.g.,blepharitis, keratitis, scleritis, conjunctivitis); History of vitreous hemorrhage in the study eye within 2 months before screening; scarring, fibrosis, or atrophy below with fovea in the study eye; Received any drug treatment for CNV within 120 days prior to screening; History of any following surgery in the study eye (e.g. PDT, macular transposition, Glaucoma filtration, subfoveal photocoagulation, vitrectomy and transpupular hyperthermia, and other surgery at the submacular or others for AMD) within 3 months before screening; CNV in the study eye associated with other ocular diseases such as pathologic myopia, eye trauma, etc History or present of uncontrolled glaucoma, history of glaucoma filtering surgery in the study eye; Subretinal hemorrhage in the study eye, and the bleeding area ≥ 50% area of the total lesion; History of rhegmatogenous retinal detachment or macular hole retinal detachment (stage 3 or 4) , retinal detachment, retinal pigment epithelium tear or macular area traction and macular area preretinal membrane and PCV in the study eye; The study eye has no lens( except intraocular lens) or posterior capsular rupture of the lens; Any of the following general condition are present: Medicines with toxicity to the lens are being used or may be used during the study period; History of allergy to fluorescein sodium and allergies to protein products for treatment or diagnosis, history of allergy to more than two drugs and/or non-drug factors, or suffering from allergic diseases now. History of surgery within 1 months before screening; and/or unhealed wounds, ulcers or fractures currently; Suffering from systemic infections and requiring oral, intramuscular or intravenous medication; History of stroke, myocardial infarction within 6 months before screening; Active diffuse intravascular coagulation and obvious bleeding tendency within 3 months before screening; Systemic immune diseases; Uncontrolled blood pressure control ; Diabetic patients with uncontrolled blood sugar; Any uncontrolled clinical problems (such as severe mental, neurological, cardiovascular, respiratory and other systemic diseases and malignant tumours); Any of the following laboratory tests abnormalities(23-25): Renal function impairment (Cr is 1.5 times higher than the upper limit of normal values in the local laboratory) Liver dysfunction (ALT or AST is 2 times higher than the upper limit of normal value in the local laboratory). Abnormal coagulation function (prothrombin time >= the upper limit of normal value for 3 seconds) and activated partial thromboplastin time >= the upper limit of normal value for 10 seconds); Patients with childbearing age with any of the following conditions: Those who do not use effective contraceptive measures; The following are not excluded: Pregnancy and lactation women (pregnancy is defined as urinary pregnancy test positive in this study); Any other conditions: Participation in any other drug clinical trials (except vitamins and minerals) in the past 1 month before screening ; Researchers think it needs to be ruled out.

Ages Eligible for Study
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Minimum Age: 45 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 601 dose level 1 treatment<br> | Drug: Drug 601<br>* Recombinant humanized anti-VEGF monoclonal antibody, drug 601(0.375mg), Vitreous injection, injection once;<br>|
| Experimental: 601 dose level 2 treatment<br> | Drug: Drug 601<br>* Recombinant humanized anti-VEGF monoclonal antibody, drug 601(0.75mg), Vitreous injection, injection once;<br>|
| Experimental: 601 dose level 3 treatment<br> | Drug: Drug 601<br>* Recombinant humanized anti-VEGF monoclonal antibody, drug 601(1.25mg), Vitreous injection, injection once;<br>|
| Experimental: 601 dose level 4 treatment<br> | Drug: Drug 601<br>* Recombinant humanized anti-VEGF monoclonal antibody, drug 601(2.5mg), Vitreous injection, injection once;<br>|
| Experimental: 601 dose level 5 treatment<br> | Drug: Drug 601<br>* Recombinant humanized anti-VEGF monoclonal antibody, drug 601(1.25mg), Vitreous injection, injection once every 4 weeks, three times continuously, then injection as needed within 9 months.<br>|
| Experimental: 601 dose level 6 treatment<br> | Drug: Drug 601<br>* Recombinant humanized anti-VEGF monoclonal antibody, drug 601(2.5mg), Vitreous injection, injection once every 4 weeks, three times continuously, then injection as needed within 9 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLT | Incidence of dose-limiting toxicities up to the Day 14 visit | From Day 0 up to Day 14 | 
| MTD | Maximum tolerated dose | From Day 0 up to Day 56/112. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) profile | Study the change of 601 drug concentration in the blood with time by mathematical principles and methods | From Day 0 up to 56/112 days | 
| Cmax | The maximum blood concentration after 601 drug enters the bloodstream | From Day 0 up to 56/112 days | 
| t1/2 | The half-life of drug 601, the time required for the terminal phase 601 drug concentration to drop by half | From Day 0 up to 56/112 days | 
| AUC | Area under the concentration-time curve, reflect the characteristics of the exposure of 601 drug in the body. | From Day 0 up to 56/112 days | 
| Vd | The proportional constant between the amount of 601 drug in the body and the blood concentration when the 601 drug achieves the dynamic balance in the body. | From Day 0 up to 56/112 days | 
| CL | Clearance rate of drug 601 from the central ventricle. | From Day 0 up to 56/112 days | 
| MRT | The average length of time that the 601 drug stays in the body. | From Day 0 up to 56/112 days | 
| λz | the ratio of the amount of elimination of 601 drug from the body per unit time to the total amount in the body | From Day 0 up to 56/112 days | 
| Biomarker | Detection of VEGF concentration. | From Day 0 up to 56/112 days | 
| Immunogenicity | Development of Anti-drug antibodies (ADA) after IVT injection of 601 | From Day 0 up to 56/112 days | 
| CRT | Changes in central retina thickness (CRT) at all time points compared to the baseline | From Day 0 up to 56/364 days | 
| diseased region | Changes in the diseased region at all time points compared to the baseline | From Day 0 up to 56/364 days |