A Double-masked, Randomized, Parallel-group Study to Investigate the Pharmacodynamics, Safety, and Systemic Pharmacokinetics of Pazopanib Drops, Administered for 28 Days to Adult Subjects With Neovascular Age-related Macular Degeneration.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 70
- 试验地点
- 1
- 主要终点
- Mean Change From Baseline in Central Retinal/Lesion Thickness (CRLT) as Measured by the Carl Zeiss Meditec Stratus Optical Coherence Tomography (OCT) Scanner at Day 29
研究概览
简要总结
This is a 28 day study to evaluate the pharmacodynamic effect of pazopanib eye drops on the central retinal thickness of AMD patients
详细描述
Pazopanib has been formulated as an eye drop for the topical treatment of age-related macular degeneration (AMD). Safety, tolerability and pharmacokinetics have been evaluated in a first study conducted in healthy volunteers (MD7108238). In the present study, three dosing regimens of pazopanib eye drops, administered for 28 days, will be evaluated in subjects with occult or minimally classic subtypes of choroidal neovascularization due to AMD. This study is designed to measure pharmacological activity of topically administered pazopanib in target tissues (choroid and retina) of patients with AMD by weekly evaluation of central retinal thickness as measured by optical coherence tomography (OCT). Evaluation of efficacy will be performed on an exploratory basis by weekly measurement of visual acuity. The ocular and systemic safety and systemic pharmacokinetics of pazopanib treatment for 28 days will also be evaluated.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
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
- •Age-related macular degeneration patients diagnosed with subfoveal choroidal neovascularization in the study eye, with all of the following characteristics required:
- •central subfield thickness > 300 microns on investigator-determined OCT (inclusive of subretinal fluid)
- •active subfoveal leakage as determined by investigator-determined fluorescein angiography
- •minimally classic or occult with no classic CNV lesion
- •lesion size no greater than 12 disc areas
- •CNV > 50% of lesion area
- •< 50% of lesion area with blood
- •= 25% of lesion area with fibrosis
- •Best-corrected ETDRS visual acuity in the study eye between 80 to 24 letters inclusive (approximately 20/25 and 20/320 or 4/5 to 4/63) at screening
- •Female subjects must be of non-childbearing potential.
排除标准
- •Additional eye disease in the study eye that could compromise best corrected visual acuity (i.e. glaucoma with documented visual field loss, clinically significant diabetic retinopathy, ischemic optic neuropathy, or retinitis pigmentosa).
- •CNV in the study eye due to other causes unrelated to age-related macular degeneration.
- •The presence of retinal angiomatous proliferation (RAP) in the study eye, as determined by the investigator (confirmation by indocyanine green angiography is not required).
- •Geographic atrophy involving the center of the fovea in the study eye.
- •Anterior segment and vitreous abnormalities in the study eye that would preclude adequate observation of the fundus for photographs, fluorescein angiography and OCT.
- •Vitreous, subretinal or retinal hemorrhage in the study eye that is unrelated to AMD.
- •More than one prior photodynamic therapy (PDT) treatment in the study eye.
- •PDT treatment in the study eye < 12 weeks prior to dosing.
- •Previous treatment in the study eye with ranibizumab (Lucentis) or bevacizumab (Avastin) without resolution of exudation (intraretinal and subretinal fluid as documented by OCT).
- •Use of any treatment, either approved or experimental, for AMD in the study eye within 60 days of first dose of investigational product.
- •Intraocular surgery in the study eye within 3 months of dosing.
- •Aphakia or total absence of the posterior capsule (Yttrium aluminum garnet (YAG) capsulotomy permitted) in the study eye.
- •History of vitrectomy in the study eye.
- •Use of topical ocular medications in the study eye within 7 days of first dose of investigational product or expected use of topical ocular medications during the treatment period, with the exception of artificial tears (refer to Section 9.1)
- •Active treatment in the fellow eye, with the exception of preservative-free artificial tears.
- •Current use of medications known to be toxic to the retina, lens or optic nerve (e.g. desferoximine, chloroquine/hydrochloroquine, chlorpromazine, phenothiazines, tamoxifen, nicotinic acid, and ethambutol).
- •Use of systemic steroids (>10 mg prednisone or equivalent/day) within 14 days of first dose.
- •An unwillingness to refrain from wearing contact lenses starting from the screening visit, through the follow-up visit
- •Medical history or condition:
- •Uncontrolled Diabetes Mellitus, with hemoglobin A1c (HbA1c) > 10%.
- •Myocardial infarction or stroke within 12 months of screening.
- •Active bleeding disorder.
- •Major surgery within 1 month of screening.
- •Hepatic impairment.
- •Uncontrolled hypertension
研究组 & 干预措施
Arm 1
Pazopanib eye drops formulation 5 mg/mL daily for 28 days
干预措施: Pazopanib (Drug)
Arm 2
Pazopanib eye drop formulation 5mg/mL TID for 28 days
干预措施: Pazopanib (Drug)
Arm 3
Pazopanib eye drop formulation 2mg/mL TID for 28 days
干预措施: Pazopanib (Drug)
结局指标
主要结局
Mean Change From Baseline in Central Retinal/Lesion Thickness (CRLT) as Measured by the Carl Zeiss Meditec Stratus Optical Coherence Tomography (OCT) Scanner at Day 29
时间窗: Baseline (Day -3 to -1) and Day 29
CRLT was measured by the Carl Zeiss Meditec Stratus OCT scanner based on the manual measurement of the distance between the inner and outer retina, inclusive of subretinal fluid and any choroidal neovascularization (CNV) as measured in the central 1 millimeter (mm) area of the 7 mm Posterior Pole Scan. OCT scans/images were collected by trained and certified photographer and analyzed by investigator. Two datasets were used for analysis namely Last observation carried forward (LOCF) which included missing assessment for a participant who completed at least 7 days of pazopanib eye drop replaced by the last non-missing assessment post 7 days of pazopanib eye drop treatment. OC dataset included a missing assessment at any scheduled time was considered unevaluable and was not imputed. Baseline was defined as the assessments performed between Day -3 to -1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-randomization value at Day 29.
次要结局
- Number of Participants With Complete Ophthalmic Examination Values of Potential Clinical Concern(Upto follow-up (Day 43))
- Number of Participants With Vital Sign Data for Systolic Blood Pressure and Diastolic Blood Pressure and Heart Rate of Potential Clinical Concern(Up to follow up (Day 46))
- Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings(Day 15 and follow-up (Day 43))
- Number of Participants With Clinical Chemistry and Hematology Data of Potential Clinical Concern(Up to follow-up Day 43)
- Number of Participants With Abnormal Urinalysis Data by Dipstick Analysis(Day 29 and follow-up (Day 43))
- Number of Participants With Ocular Adverse Events, Non-ocular Adverse Events, Serious Ocular Adverse Events and Serious Non-ocular Adverse Events(Up to follow-up (Day 43))
- Plasma Pharmacokinetic Parameter Time of Occurrence of Cmax (Tmax)(Day 15 and Day 22)
- Change From Baseline in Best Corrected Visual Acuity (BCVA) [Number of Letter Read on Standardized Early Treatment of Diabetic Retinopathy Study (ETDRS) Charts at Day 29(Baseline (Day -3 to -1) and Day 29)
- Number of Participants With Change in Characteristics (Fibrosis, Atrophy, Blood) as Measured by Fundus Photography (FP)(Day 29)
- Number of Participants With Change in Retinal Morphology (Cystoid Spaces, Subretinal Fluid and Retinal Pigment Epithelial Detachment) as Determined by OCT(Day 29)
- Change From Baseline in Neovascular Size, Total Lesion Size, Fluorescein Angiography (FA) Leakage Area of Measurement, FA Blood Area of Measurement as Measured by FA at Day 29(Baseline (Day -3 to -1) and Day 29)
- Plasma Pharmacokinetic Parameter Area Under Concentration Time-curve From Time Zero to 6 Hours (AUC [0-6)](Day 15 and Day 22)
- Plasma Pharmacokinetic Parameter Maximum Observed Concentration (Cmax)(Day 15 and Day 22)