To Evaluate the Pharmacodynamics, Safety, and Pharmacokinetics of Pazopanib Drops in Adult Subjects With Neovascular AMD

Study Overview
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Brief Summary
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This is a 28 day study to evaluate the pharmacodynamic effect of pazopanib eye drops on the central retinal thickness of AMD patients

Detailed Description
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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.

Official Title
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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.

Conditions
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Macular Degeneration

Intervention / Treatment
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* Drug: Pazopanib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 50 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Pazopanib eye drops formulation 5 mg/mL daily for 28 days | Drug: Pazopanib<br>* Pazopanib eye drops formulation<br>|
| Experimental: Arm 2<br>Pazopanib eye drop formulation 5mg/mL TID for 28 days | Drug: Pazopanib<br>* Pazopanib eye drops formulation<br>|
| Experimental: Arm 3<br>Pazopanib eye drop formulation 2mg/mL TID for 28 days | Drug: Pazopanib<br>* Pazopanib eye drops formulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Baseline (Day -3 to -1) and Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Ophthalmic Examination Values of Potential Clinical Concern | A complete eye examination was performed to include the following: Examination of eyelids and lashes (including meibomian glands), Pupil, motility and confrontation visual field examination, Slit lamp evaluation of anterior ocular structures (including conjunctiva, tear film, cornea with fluorescein staining, anterior chamber, iris, lens, and anterior vitreous), intraocular pressure (IOP) measurement and Dilated Fundus Examination (Indirect ophthalmoscopy and slit lamp biomicroscopy). Data has been presented in a consolidated format for the total number of participants with values of potential clinical concern for complete ophthalmic examinations until Day 43. | 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 | Vital sign assessments included systolic blood pressure, diastolic blood pressure and heart rate. The potential clinical concern range for systolic blood pressure was <85 and > 160 millimeters of mercury, diastolic blood pressure <45 and > 100 millimeters of mercury, heart rate <40 and >110 beats per minute. Only those parameters for which at least one value of potential clinical importance was reported are summarized. The number of participants with potential clinical important findings at any visit were reported. | Up to follow up (Day 46) | 
| Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings | Single 12-lead ECGs were to be obtained at each Day 15 and follow-up Day 43 using an ECG machine that automatically calculated the heart rate and measures PR, QRS, QT, and QTc intervals. ECG findings were defined as abnormal-not clinically significant (A-NCS) and abnormal-clinically significant (A-CS). Data has been presented for the number of participants with A-NCS and A-CS findings. | Day 15 and follow-up (Day 43) | 
| Number of Participants With Clinical Chemistry and Hematology Data of Potential Clinical Concern | Clinical chemistry parameters assessed included blood urea nitrogen, potassium, calcium, albumin, creatinine, chloride, sodium, total protein, glucose, total carbon dioxide, aspartate amino transferase, alanine amino transferase, direct bilirubin, total bilirubin, alkaline phosphatase and hematology parameters assessed included platelet count, white blood cell count, red blood cell count, reticulocyte count, hemoglobin, mean corpuscle volume, mean corpuscle hemoglobin, mean corpuscle hemoglobin concentration, total neutrophils, lymphocytes, monocytes, eosinophils, basophils. Data has been presented for the number of participants with values high and low of potential clinical concern for clinical chemistry and hematology. | Up to follow-up Day 43 | 
| Number of Participants With Abnormal Urinalysis Data by Dipstick Analysis | Urinalysis included analysis for urine occult blood, urine glucose, urine ketones and urine proteins via dipstick analysis. Data has been presented for number of participants with abnormal urinalysis results. Only categories with values have been presented. | 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 | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, may jeopardize the participant or require medical or surgical intervention to prevent one of the other outcomes listed in the definition above, or is an event of possible drug-induced liver injury. Data has been presented for number of participants with ocular and non-ocular adverse events and serious adverse event | Up to follow-up (Day 43) | 
| 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 | BCVA was measured in the study eye using the ETDRS grading charts consists of at least 24 to 78 letters placed at a test distance of 4 meters. There were 7 cut off points in visual acuity on ETDRS grading chart: 15 to 29, 10 to 14, 5 to 9, -4 to 4, -5 to -9, -10 to -14 and -15 to -29 letters. Grade 15 to 29 indicates no impairment in vision and grade -15 to -29 indicates worst impairment in vision. Analyses were done for two sub-efficacy-populations. One sub-efficacy population included all participants in the efficacy population with a YES for retinal angiomatous proliferation (RAP)/retinal choroidal anastomosis (RCA) NONE field from Digital angiography reading center (DARC) FA form in study eye. The other included all participants in the efficacy population with a YES for eligible field from DARC FA form in study eye. Baseline was defined as the assessments performed between Day -3 to -1. Change from Baseline calculated as subtracting the Baseline value from the value at Day 29. | Baseline (Day -3 to -1) and Day 29 | 
| Number of Participants With Change in Retinal Morphology (Cystoid Spaces, Subretinal Fluid and Retinal Pigment Epithelial Detachment) as Determined by OCT | OCT was used for the determination of retinal morphology changes in the study eye which included assessments of cystoids spaces (cyst like spaces in the inner layers of the retina), subretinal fluid (an exudate between the retina and choroid from various sources including the vitreous cavity, subarachnoid space, or abnormal vessels) and pigment epithelial detachment (retinal pigment epithelium separates from the underlying Bruch's membrane due to the presence of blood, serous exudate, drusen, or a neovascular membrane). Data has been presented for number of participants with retinal morphology changes in the study eye at Day 29. | Day 29 | 
| Number of Participants With Change in Characteristics (Fibrosis, Atrophy, Blood) as Measured by Fundus Photography (FP) | Fundus photography involves capturing of images of the center of the very back inner wall of the eye - the retina, optic nerve, macula and main retinal blood vessels. The parameters assessment were heme subretinal hemorrhage (absence or presence at the location), heme intraretinal hemorrhage (absence or presence at the location), subretinal fluid (absence or presence at location), fibrosis (absence or presence at location), atrophy (absence or presence of atrophic changes) and pigment ((absence or presence at location). A protocol set of fundus photographs were obtained at Day 29. Images were read by the investigator for eligibility determination, and by a central reading center for determination of PD effect. Data has been presented for number of participants with changes in eye characteristics in the study eye at Day 29. | 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 | FA uses FP to capture images of injected dye circulating throughout the retinal blood vessels to assess leaking, swelling or circulation problems caused by various eye diseases like diabetic retinopathy and wet macular degeneration. The parameters assessed were CNV size, Classic CNV size, FA blood area of measurement, FA leakage area of measurement and total lesion size. A protocol fluorescein angiogram was to be obtained at Day 29. Images were evaluated by investigator for eligibility determination, and by a central reading center for determination of PD effect. Data has been presented for change from baseline in change in eye characteristics in the study eye at Day 29. 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. | Baseline (Day -3 to -1) and Day 29 | 
| Plasma Pharmacokinetic Parameter Maximum Observed Concentration (Cmax) | Blood samples for analysis of plasma pazopanib concentrations were collected over 6 hours after an ocular dose of pazopanib on Day 15 or Day 22. PK analyses of plasma pazopanib concentration-time data were conducted using non-compartmental Model 200 (for extravascular administration) of WinNonlin Professional Edition version 5.2. Data has been presented for pharmacokinetic parameter Cmax at Day 15 and Day 22. | Day 15 and Day 22 | 
| Plasma Pharmacokinetic Parameter Time of Occurrence of Cmax (Tmax) | Blood samples for analysis of plasma pazopanib concentrations were collected over 6 hours after an ocular dose of pazopanib on Day 15 or Day 22. PK analyses of plasma pazopanib concentration-time data were conducted using non-compartmental Model 200 (for extravascular administration) of WinNonlin Professional Edition version 5.2. Data has been presented for pharmacokinetic parameter tmax at Day 15 and Day 22. | Day 15 and Day 22 | 
| Plasma Pharmacokinetic Parameter Area Under Concentration Time-curve From Time Zero to 6 Hours (AUC [0-6)] | Blood samples for analysis of plasma pazopanib concentrations were collected over 6 hours after an ocular dose of pazopanib on Day 15 or Day 22. PK analyses of plasma pazopanib concentration-time data were conducted using non-compartmental Model 200 (for extravascular administration) of WinNonlin Professional Edition version 5.2. Data has been presented for pharmacokinetic parameter AUC (0-6) at Day 15 and Day 22. | Day 15 and Day 22 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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angiogenesis, pazopanib,, age-related macular degeneration (AMD),, vascular endothelial growth factor (VEGF),, choroidal neovascularization (CNV),