A Multi-center, Open-Label, Phase 1, Single- and Multiple Ascending Dose Study to Assess Safety and Tolerability of PMC-403 in Subjects With Neovascular Age-related Macular Degeneration (nAMD).
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 17
- 试验地点
- 4
- 主要终点
- Maximum tolerated dose (MTD)
研究概览
简要总结
This is a Phase 1 study, first-in-human (FIH), open label study to evaluate the safety, tolerability and identify the maximum tolerated dose (MTD) of PMC-403 and determine the recommended phase 2 dose (RP2D).
详细描述
In this study, Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) will be carried out in a sequential manner.
- PART 1- SAD
The SAD part of the study will be conducted in a step-wise manner for a total of 4 dose levels (0.7 mg, 2 mg, 3 mg, 4 mg). To each dose group, 3 subjects at minimum or 6 subjects at maximum will be recruited. In the SAD part, dose escalation will be performed up to 4 mg/eye (50 uL/eye) until the MTD is identified.
In the SAD part, a maximum of 24 participants are to be enrolled.
- PART 2- MAD
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 50 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •To be eligible for study participation, subjects must meet all of the following inclusion criteria.
- •* Criteria for the selection of the study eye
- •If both eyes meet the criteria, the study eye will be selected according to the following criteria:
- •The eye with lower (severer) best corrected visual acuity (BCVA) at baseline will be selected as the study eye.
- •If both eyes have the same BCVA, the right eye will be selected as the study.
- •Male and female ≥50 years of age at the time of written informed consent.
- •Treatment required, based on the judgment of the investigator, due to insufficient therapeutic efficacy despite ≥ 3 repeated doses of anti-vascular endothelial growth factor (anti-VEGF) intravitreal injection (IVT) for nAMD in the study eye, and the subject's agreement to receive the study drug instead of conventional standard therapy
- •>12 weeks must have elapsed since the last dose of anti-VEGF IVT at the time of screening.
- •Active subfoveal or parafoveal choroidal neovascularization (CNV)* confirmed by fundus fluorescein angiography (FFA), spectral domain-optical coherence tomography (SD-OCT), and IndoCyanine Green (ICG) angiography.
- •*Active CNV (confirmed by the central reading center) is defined as the presence of subretinal fluid (SRF) or intraretinal fluid (IRF) in consequence of vascular leakage.
- •The size of the entire lesion in the study eye (including blood, atrophy, fibrosis, and neovascularization) must be ≤ 9-disc areas, and the area of CNV in the study eye must account for ≥ 50% of the total area of the lesion, as confirmed by FFA and ICG angiography.
- •BCVA measured in the study eye must be between ≥ 23 letters and ≤ 78 letters based on the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart (Snellen visual acuity 20/25 - 20/320).
- •Voluntary written informed consent to study participation.
排除标准
- •Subjects who meet any of the following exclusion criteria are not eligible for study participation.
- •At the screening visit:
- •Uncontrolled ocular hypertension (≥ 25 mmHg) despite drug therapy;
- •Retinal pigment epithelium (RPE) tears involving the macula;
- •Improvement in visual acuity is not expected due to scars, fibrosis, or atrophy involving the fovea;
- •Presence of vitreous hemorrhage;
- •Aphakia or absence of posterior capsule (with the exception of pseudophakic eyes treated with laser posterior capsulotomy);
- •Presence of any causes of CNV other than nAMD, such as ocular histoplasmosis, trauma, pathological myopia, angioid streak, choroidal rupture, or uveitis; or
- •Macular pathology that is unrelated to nAMD, but may affect visual acuity or study drug treatment (e.g., macular hole, epiretinal membrane, vitreomacular traction, macular telangiectasia, central serous chorioretinopathy, retinal vascular occlusion, etc.).
- •Any of the following conditions or medical history in either eye:
- •Current or known history of at least moderate diabetic retinopathy or diabetic macular edema;
- •Active intraocular or periocular infections or inflammations (e.g., infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis, etc.); or
- •History of idiopathic or autoimmune uveitis.
- •Any of the following systemic diseases:
- •Unstable or serious cardiovascular disorders such as congestive heart failure (New York Heart Association Functional Class III or IV), ventricular tachycardia requiring continuous treatment, unstable angina pectoris, or critical limb ischemia;
- •Uncontrolled hypertension with systolic or diastolic blood pressure > 160/100 mmHg;
- •Stroke or myocardial infarction within 24 weeks prior to screening;
- •Dementia or neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease) that might affect study results during the study period;
- •History of malignant tumors within 5 years prior to screening; or
- •Weakened immunity or requiring immunotherapy.
- •Clinically significant liver/kidney disease or any of the following hematologic test results:
- •Serum creatinine ≥1.5 x upper limit of normal
- •Aspartate transaminase (AST) or alanine transaminase (ALT) ≥2 x upper limit of normal
- •Treatment with any of the following systemic drug therapy:
- •Systemic anti-VEGF therapy within 12 weeks prior to baseline;
- •Systemic corticosteroids for ≥2 consecutive weeks
- •≤ 10 mg/day prednisolone or equivalent for less than 2 consecutive weeks will be allowed
- •Inhaled, nasal, and topical steroids will also be allowed
- •Ongoing treatment with any drugs with potential toxicity to the lens, retina, and optic nerves (e.g., deferoxamine, chloroquine/hydroxychloroquine, tamoxifen, phenothiazines, vigabatrin, or ethambutol).
- •Any of the following medical history (surgical or procedural):
- •Intraocular or periocular injection of corticosteroids (e.g., triamcinolone acetonide, etc.) to the study eye within 24 weeks prior to screening;
- •Intraocular surgery or laser therapy (e.g., cataract surgery, laser posterior capsulotomy, etc.) to the study eye within 12 weeks prior to screening;
- •Eyelid surgery within 4 weeks prior to screening;
- •History of vitrectomy, glaucoma surgery, macular laser treatment, keratoplasty, or retinal detachment surgery; or
- •History of treatment with radiotherapy around the study eye including radiation retinopathy
- •Any concurrent ophthalmic abnormalities that, based on the judgment of the investigator, may affect the assessment of safety and therapeutic efficacy or may need medical or surgical treatment during the study period (e.g., cloudy ocular media, optic neuropathy, amblyopia, etc.).
- •Hypersensitivity to any of the components of IP or to contrast agents used for FFA and ICG angiography.
- •Pregnant and/or breastfeeding women.
- •Men and women of childbearing potential who are unwilling to use adequate methods of contraception* or who are planning a pregnancy during the study period and for 12 weeks from the last dose of IP
- •Methods of contraception: hormone contraceptives (oral contraceptives, contraceptive patch, etc.), intrauterine device (IUD) (copper IUD, hormonal intrauterine system), double barrier method (both male [condom] and female [diaphragm, vaginal sponge, or cervical cap]), surgical sterilization (tubal sterilization, vasectomy, etc.)
- •Having participated in another clinical trial and treated with an IP within 12 weeks prior to screening
- •Distance vision test result of <0.1 for the fellow eye
- •Other reasons based on which individuals are determined by the investigator to be ineligible for study participation.
研究组 & 干预措施
PART 1- SAD
The SAD part of the study will be conducted in a step-wise manner for a total of 4 dose levels of PMC-403.
- Dose level 1: 0.7 mg/eye, baseline(Day 0)
- Dose level 2: 2 mg/eye, baseline(Day 0)
- Dose level 3: 3 mg/eye, baseline(Day 0)
- Dose level 4: 4 mg/eye, baseline(Day 0)
干预措施: PMC-403 (Drug)
PART 2- MAD
Upon the end of the SAD part of the study, the MAD part is planned to be conducted in a step-wise manner for a total of 2 dose levels.
- Dose level 1: 3 mg/eye, baseline(Day 0), Week 4(Day 28), Week 8(Day 56)
- Dose level 2: 4 mg/eye, baseline(Day 0), Week 4(Day 28), Week 8(Day 56)
干预措施: PMC-403 (Drug)
结局指标
主要结局
Maximum tolerated dose (MTD)
时间窗: Baseline upto 4 weeks
To identify the maximum tolerated dose (MTD), and determine the recommended phase 2 dose (RP2D) of PMC-403 in patients with nAMD. MTD of PMC-403 will be calculated by incidence of DLT at 4 weeks from the first dosing of PMC-403.
Laboratory tests - Hematology
时间窗: Baseline upto 5 months
Hematology will be performed at Visits 1, 2, 5, and 7 and at Follow-up Visits 8 and 9 in the SAD groups and at each visit in the MAD groups. The following Hematology parameters will be recorded: white blood cell (WBC), red blood cell (RBC), hemoglobin, hematocrit, platelet, WBC differential count (neutrophil, lymphocyte, monocyte, eosinophil, basophil) Test results collected will be assessed for change before and after IP dosing and/or change in normal/abnormal findings.
Laboratory tests - Blood coagulation
时间窗: Baseline upto 5 months
Blood coagulation will be performed at Visits 1, 2, 5, and 7 and at Follow-up Visits 8 and 9 in the SAD groups and at each visit in the MAD groups. For continuous variables, values at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum; and change from baseline at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum. Additionally, test results collected will be assessed for change before and after IP dosing and/or change in normal/abnormal findings.
Vital Signs - body temperature
时间窗: Baseline upto 5 months
At each visit, body temperature will be measured. Vital signs collected will be assessed for change before and after IP dosing and/or change in normal/abnormal findings. By dose group, values at each time point will be presented with number of subjects, mean, standard deviation, median, minimum, and maximum; and change from baseline at each time point will be presented with number of subjects, mean, standard deviation, median, minimum, and maximum.
Laboratory tests - Urinalysis
时间窗: Baseline upto 5 months
Urinalysis will be performed at Visits 1, 2, 5, and 7 and at Follow-up Visits 8 and 9 in the SAD groups and at each visit in the MAD groups. For continuous variables, values at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum; and change from baseline at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum. Additionally, test results collected will be assessed for change before and after IP dosing and/or change in normal/abnormal findings.
Ophthalmologic examination - fundus examination
时间窗: Baseline upto 5 months
fundus examination measuring will be performed according to Schedule of Events. For continuous variables, values at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum. The ophthalmologic examination results will be assessed for change in normal/abnormal status before and after IP dosing.
Ophthalmologic examination - spectral domain-optical coherence tomography (SD-OCT)
时间窗: Baseline upto 5 months
SD-OCT will be performed according to Schedule of Events. For continuous variables, values at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum. The ophthalmologic examination results will be assessed for change in normal/abnormal status before and after IP dosing.
Vital Signs - Pulse Rate (beats/min)
时间窗: Baseline upto 5 months
At each visit, pulse rate will be measured. Vital signs collected will be assessed for change before and after IP dosing and/or change in normal/abnormal findings. By dose group, values at each time point will be presented with number of subjects, mean, standard deviation, median, minimum, and maximum; and change from baseline at each time point will be presented with number of subjects, mean, standard deviation, median, minimum, and maximum.
Laboratory tests - Blood chemistry
时间窗: Baseline upto 5 months
Blood chemistry will be performed at Visits 1, 2, 5, and 7 and at Follow-up Visits 8 and 9 in the SAD groups and at each visit in the MAD groups. The following Blood chemistry parameters will be recorded: glucose, aspartate transaminase (AST; SGOT), alanine transaminase (ALT; SGPT), total bilirubin, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total protein, albumin, blood urea nitrogen (BUN), creatinine, uric acid, sodium, potassium, chloride, calcium, phosphorus, C-reactive protein (CRP), HbA1c (to be tested at the screening visit only) Test results collected will be assessed for change before and after IP dosing and/or change in normal/abnormal findings.
Ophthalmologic examination - Slit lamp examination
时间窗: Baseline upto 5 months
Slit lamp examination measuring will be performed according to Schedule of Events. For continuous variables, values at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum. The ophthalmologic examination results will be assessed for change in normal/abnormal status before and after IP dosing.
Adverse events
时间窗: Baseline upto 5 months
For Treatment-emergent adverse events (TEAEs), Adverse Drug Reactions (ADRs), Serious Adverse Events (SAEs), Serious Adverse Drug Reactions (SADRs), and Adverse Events (AEs) leading to study withdrawal, number of subjects, incidence, number of events, and 95% two-sided confidence interval will be presented by dose group.
Vital Signs - systolic/diastolic blood pressure (mmHg)
时间窗: Baseline upto 5 months
At each visit, systolic/diastolic blood pressure will be measured. Vital signs collected will be assessed for change before and after IP dosing and/or change in normal/abnormal findings. By dose group, values at each time point will be presented with number of subjects, mean, standard deviation, median, minimum, and maximum; and change from baseline at each time point will be presented with number of subjects, mean, standard deviation, median, minimum, and maximum.
Electrocardiogram (ECG)
时间窗: Baseline upto 5 months
Test results will be classified into normal/NCS and CS, and change from baseline at each time point and at the last visit will be presented with frequency and percentage in a shift table by dose group. The following ECG parameters will be recorded: heart rate, RR interval, HR interval, QTc interval and QRS interval.
Ophthalmologic examination - intraocular pressure (IOP)
时间窗: Baseline upto 5 months
IOP will be performed according to Schedule of Events. During the study visits involving IP dosing (SAD: Visits 2, MAD: Visits 2, 5, 7), IOP will be measured a total of 3 times (once before dosing and twice after dosing). For continuous variables, values at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum. The ophthalmologic examination results will be assessed for change in normal/abnormal status before and after IP dosing.
次要结局
- Presence of intraretinal fluid (IRF)(Baseline upto 5 months)
- Presence of subretinal fluid (SRF)(Baseline upto 5 months)
- Change in best corrected visual acuity (BCVA)(Baseline upto 5 months)
- Presence of sub-RPE fluid(Baseline upto 5 months)
- Change from baseline in CNV lesion size as measured by ICG angiography(Baseline upto 5 months)
- Change in central retinal thickness (CRT)(Baseline upto 5 months)
- Change from baseline in choroidal neovascularization (CNV) lesion size as measured by Fundus Fluorescein Angiography (FFA)(Baseline upto 5 months)