Trial Outcomes & Findings for To Evaluate the Pharmacodynamics, Safety, and Pharmacokinetics of Pazopanib Drops in Adult Subjects With Neovascular AMD (NCT NCT00612456)

NCT ID: NCT00612456

Last Updated: 2017-11-20

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 70 participants
• Primary outcome timeframe: Baseline (Day -3 to -1) and Day 29
• Results posted on: 2017-11-20

Participant Flow

This study was conducted at 22 centers in the United States, Belgium, Italy and Australia between 18 February 2008 and 27 January 2009. A total of 70 participants with Age-related macular degeneration (AMD) were randomized to the study.

Participant milestones

Measure	Pazopanib 5 mg/mL TID Eligible participants received Pazopanib eye drops topically at a dose of 5 milligrams per milliliter (mg/mL) three time daily (TID) for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 2 mg/mL TID Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 5 mg/mL Once Daily Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL once daily for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.
Overall Study STARTED	27	27	16
Overall Study COMPLETED	25	25	16
Overall Study NOT COMPLETED	2	2	0

Reasons for withdrawal

Measure	Pazopanib 5 mg/mL TID Eligible participants received Pazopanib eye drops topically at a dose of 5 milligrams per milliliter (mg/mL) three time daily (TID) for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 2 mg/mL TID Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 5 mg/mL Once Daily Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL once daily for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.
Overall Study Adverse Event	1	0	0
Overall Study Lack of Efficacy	1	1	0
Overall Study Withdrawal by Subject	0	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Pazopanib 5 mg/mL TID n=27 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses..	Pazopanib 2 mg/mL TID n=27 Participants Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 5 mg/mL Once Daily n=16 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL once daily for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Total n=70 Participants Total of all reporting groups
Age, Customized 57 to 88 years	27 Participants n=5 Participants	27 Participants n=7 Participants	16 Participants n=5 Participants	70 Participants n=4 Participants
Sex: Female, Male Female	20 Participants n=5 Participants	14 Participants n=7 Participants	9 Participants n=5 Participants	43 Participants n=4 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	13 Participants n=7 Participants	7 Participants n=5 Participants	27 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) White	27 Participants n=5 Participants	27 Participants n=7 Participants	16 Participants n=5 Participants	70 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline (Day -3 to -1) and Day 29

Population: Pharmacodynamics (PD) parameters population comprised of all participants in the Safety Population and had Choroidal Neovascularization (CNV) present as detected by Fluorescein Angiography (FA). LOCF and OC dataset were used for analysis. Only those participants with data available at the indicated time point were included for analysis.

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.

Outcome measures

Measure	Pazopanib 5 mg/mL TID n=26 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 2 mg/mL TID n=24 Participants Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 5 mg/mL Once Daily n=14 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL once daily for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.
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 as measued by OCT, LOCF data	7.5 Microns Standard Deviation 110.34	10.0 Microns Standard Deviation 83.78	31.2 Microns Standard Deviation 85.72
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 as measued by OCT, OC data	7.5 Microns Standard Deviation 110.34	3.0 Microns Standard Deviation 85.16	9.1 Microns Standard Deviation 69.12

SECONDARY outcome

Timeframe: Upto follow-up (Day 43)

Population: Safety population comprised of all participants who received at least one dose of investigational product.

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.

Outcome measures

Measure	Pazopanib 5 mg/mL TID n=27 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 2 mg/mL TID n=27 Participants Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 5 mg/mL Once Daily n=16 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL once daily for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.
Number of Participants With Complete Ophthalmic Examination Values of Potential Clinical Concern	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to follow up (Day 46)

Population: Safety population.

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.

Outcome measures

Measure	Pazopanib 5 mg/mL TID n=27 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 2 mg/mL TID n=27 Participants Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 5 mg/mL Once Daily n=16 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL once daily for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.
Number of Participants With Vital Sign Data for Systolic Blood Pressure and Diastolic Blood Pressure and Heart Rate of Potential Clinical Concern Systolic blood pressure	1 Participants	4 Participants	1 Participants
Number of Participants With Vital Sign Data for Systolic Blood Pressure and Diastolic Blood Pressure and Heart Rate of Potential Clinical Concern Diastolic blood pressure	0 Participants	1 Participants	0 Participants
Number of Participants With Vital Sign Data for Systolic Blood Pressure and Diastolic Blood Pressure and Heart Rate of Potential Clinical Concern Heart rate	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Day 15 and follow-up (Day 43)

Population: Safety population. Only those participants available at the specified time points were analyzed.

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.

Outcome measures

Measure	Pazopanib 5 mg/mL TID n=27 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 2 mg/mL TID n=27 Participants Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 5 mg/mL Once Daily n=16 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL once daily for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.
Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings Day 15, A-NCS	11 Participants	11 Participants	6 Participants
Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings Day 15, A-CS	1 Participants	0 Participants	0 Participants
Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings Follow-up (Day 43), A-NCS	7 Participants	10 Participants	8 Participants
Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings Follow-up (Day 43), A-CS	2 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to follow-up Day 43

Population: Safety population.

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.

Outcome measures

Measure	Pazopanib 5 mg/mL TID n=27 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 2 mg/mL TID n=27 Participants Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 5 mg/mL Once Daily n=16 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL once daily for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.
Number of Participants With Clinical Chemistry and Hematology Data of Potential Clinical Concern Potassium high	1 Participants	1 Participants	0 Participants
Number of Participants With Clinical Chemistry and Hematology Data of Potential Clinical Concern Glucose high	4 Participants	1 Participants	1 Participants
Number of Participants With Clinical Chemistry and Hematology Data of Potential Clinical Concern Glucose low	2 Participants	0 Participants	0 Participants
Number of Participants With Clinical Chemistry and Hematology Data of Potential Clinical Concern Calcium low	1 Participants	0 Participants	0 Participants
Number of Participants With Clinical Chemistry and Hematology Data of Potential Clinical Concern Total bilirubin high	1 Participants	0 Participants	0 Participants
Number of Participants With Clinical Chemistry and Hematology Data of Potential Clinical Concern Alkaline phosphatase high	1 Participants	0 Participants	0 Participants
Number of Participants With Clinical Chemistry and Hematology Data of Potential Clinical Concern Lymphocytes low	1 Participants	1 Participants	1 Participants
Number of Participants With Clinical Chemistry and Hematology Data of Potential Clinical Concern Total neutrophils low	0 Participants	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Day 29 and follow-up (Day 43)

Population: Safety population. Only those participants available at the specified time points were analyzed.

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.

Outcome measures

Measure	Pazopanib 5 mg/mL TID n=27 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 2 mg/mL TID n=27 Participants Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 5 mg/mL Once Daily n=16 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL once daily for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.
Number of Participants With Abnormal Urinalysis Data by Dipstick Analysis Urine Glucose at Day 29 1 hour, 1+ OR 1/4	0 Participants	1 Participants	1 Participants
Number of Participants With Abnormal Urinalysis Data by Dipstick Analysis Urine Protein at Follow-up, 3+	0 Participants	1 Participants	0 Participants
Number of Participants With Abnormal Urinalysis Data by Dipstick Analysis Urine Occult Blood at Day 29 1 hour, 1+	1 Participants	1 Participants	2 Participants
Number of Participants With Abnormal Urinalysis Data by Dipstick Analysis Urine Occult Blood at Day 29 1 hour, 2+	0 Participants	1 Participants	0 Participants
Number of Participants With Abnormal Urinalysis Data by Dipstick Analysis Urine Occult Blood at Follow-up, 1+	1 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Urinalysis Data by Dipstick Analysis Urine Glucose at Follow-up, 3+ OR 1 gram/deciliter	0 Participants	0 Participants	1 Participants
Number of Participants With Abnormal Urinalysis Data by Dipstick Analysis Urine Protein at Day 29 1 hour, 1+	2 Participants	2 Participants	1 Participants
Number of Participants With Abnormal Urinalysis Data by Dipstick Analysis Urine Protein at Day 29 1 hour, 2+	0 Participants	1 Participants	0 Participants
Number of Participants With Abnormal Urinalysis Data by Dipstick Analysis Urine Protein at Follow-up, 1+	0 Participants	2 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to follow-up (Day 43)

Population: Safety population

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

Outcome measures

Measure	Pazopanib 5 mg/mL TID n=27 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 2 mg/mL TID n=27 Participants Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 5 mg/mL Once Daily n=16 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL once daily for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.
Number of Participants With Ocular Adverse Events, Non-ocular Adverse Events, Serious Ocular Adverse Events and Serious Non-ocular Adverse Events Non-Ocular Adverse Events	10 Participants	5 Participants	2 Participants
Number of Participants With Ocular Adverse Events, Non-ocular Adverse Events, Serious Ocular Adverse Events and Serious Non-ocular Adverse Events Ocular Adverse Events, Fellow eye	2 Participants	0 Participants	1 Participants
Number of Participants With Ocular Adverse Events, Non-ocular Adverse Events, Serious Ocular Adverse Events and Serious Non-ocular Adverse Events Ocular Adverse Events, Study eye	9 Participants	2 Participants	3 Participants
Number of Participants With Ocular Adverse Events, Non-ocular Adverse Events, Serious Ocular Adverse Events and Serious Non-ocular Adverse Events Non-Ocular Serious Adverse Events	0 Participants	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline (Day -3 to -1) and Day 29

Population: Efficacy population comprised of all participants in the Safety Population who completed at least 7 days of pazopanib eye drop treatment and provided VA measurements and had CNV present as detected by FA. Only those participants available at the specified time points were included for analysis.

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.

Outcome measures

Measure	Pazopanib 5 mg/mL TID n=26 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 2 mg/mL TID n=24 Participants Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 5 mg/mL Once Daily n=14 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL once daily for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.
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 at Day 29	4.3 Scores on scale Standard Deviation 5.95	0.8 Scores on scale Standard Deviation 8.38	0.0 Scores on scale Standard Deviation 2.05
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 YES for RAP/RCA NONE field from DARC FA at Day 29	4.8 Scores on scale Standard Deviation 5.67	1.7 Scores on scale Standard Deviation 7.43	-0.1 Scores on scale Standard Deviation 2.13
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 YES for eligible field from DARC FA form at Day 29	3.5 Scores on scale Standard Deviation 5.26	0.8 Scores on scale Standard Deviation 7.39	0.3 Scores on scale Standard Deviation 1.38

SECONDARY outcome

Timeframe: Day 29

Population: PD Parameter Population. Only those participants with data available at the indicated time point were analyzed.

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.

Outcome measures

Measure	Pazopanib 5 mg/mL TID n=26 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 2 mg/mL TID n=21 Participants Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 5 mg/mL Once Daily n=11 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL once daily for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.
Number of Participants With Change in Retinal Morphology (Cystoid Spaces, Subretinal Fluid and Retinal Pigment Epithelial Detachment) as Determined by OCT Cystoid spaces at Day 29	9 Participants	10 Participants	5 Participants
Number of Participants With Change in Retinal Morphology (Cystoid Spaces, Subretinal Fluid and Retinal Pigment Epithelial Detachment) as Determined by OCT Pigment epithelial detachment at Day 29	1 Participants	2 Participants	1 Participants
Number of Participants With Change in Retinal Morphology (Cystoid Spaces, Subretinal Fluid and Retinal Pigment Epithelial Detachment) as Determined by OCT Subretinal fluid at Day 29	2 Participants	4 Participants	2 Participants

SECONDARY outcome

Timeframe: Day 29

Population: PD Parameter Population. Only those participants with data available at the indicated time point were analyzed.

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.

Outcome measures

Measure	Pazopanib 5 mg/mL TID n=26 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 2 mg/mL TID n=22 Participants Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 5 mg/mL Once Daily n=11 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL once daily for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.
Number of Participants With Change in Characteristics (Fibrosis, Atrophy, Blood) as Measured by Fundus Photography (FP) Heme subretinal hemorrhage at Day 29	14 Participants	14 Participants	7 Participants
Number of Participants With Change in Characteristics (Fibrosis, Atrophy, Blood) as Measured by Fundus Photography (FP) Subretinal fluid at Day 29	26 Participants	22 Participants	11 Participants
Number of Participants With Change in Characteristics (Fibrosis, Atrophy, Blood) as Measured by Fundus Photography (FP) Atrophy at Day 29	6 Participants	6 Participants	5 Participants
Number of Participants With Change in Characteristics (Fibrosis, Atrophy, Blood) as Measured by Fundus Photography (FP) Pigment at Day 29	23 Participants	20 Participants	11 Participants
Number of Participants With Change in Characteristics (Fibrosis, Atrophy, Blood) as Measured by Fundus Photography (FP) Heme intraretinal hemorrhage at Day 29	7 Participants	1 Participants	1 Participants
Number of Participants With Change in Characteristics (Fibrosis, Atrophy, Blood) as Measured by Fundus Photography (FP) Fibrosis at Day 29	2 Participants	2 Participants	1 Participants

SECONDARY outcome

Timeframe: Baseline (Day -3 to -1) and Day 29

Population: PD Parameter Population. Only those participants available at the specified time point were analyzed.

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.

Outcome measures

Measure	Pazopanib 5 mg/mL TID n=26 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 2 mg/mL TID n=24 Participants Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 5 mg/mL Once Daily n=14 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL once daily for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.
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 CNV size at Day 29	0.6 millimeters Standard Deviation 1.67	0.44 millimeters Standard Deviation 2.04	0.7 millimeters Standard Deviation 1.96
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 Classic CNV size at Day 29	0.2 millimeters Standard Deviation 0.90	1.5 millimeters Standard Deviation 1.62	0.7 millimeters Standard Deviation 0.81
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 blood area of measurement at Day 29	-0.2 millimeters Standard Deviation 0.75	1.0 millimeters Standard Deviation 1.87	0.4 millimeters Standard Deviation 0.82
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 leakage area of measurement at Day 29	0.8 millimeters Standard Deviation 1.77	0.8 millimeters Standard Deviation 2.06	0.6 millimeters Standard Deviation 1.88
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 Total lesion size	0.5 millimeters Standard Deviation 1.57	1.2 millimeters Standard Deviation 2.37	0.7 millimeters Standard Deviation 1.86

SECONDARY outcome

Timeframe: Day 15 and Day 22

Population: The pharmacokinetic population included all participants in the Safety Population who received at least one dose of active treatment and a PK sample was obtained and analyzed. Only those participants available at the specified time points were used for analysis.

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.

Outcome measures

Measure	Pazopanib 5 mg/mL TID n=24 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 2 mg/mL TID n=24 Participants Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 5 mg/mL Once Daily Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL once daily for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.
Plasma Pharmacokinetic Parameter Maximum Observed Concentration (Cmax) Day 15	56.104 nanograms per milliliter Geometric Coefficient of Variation 85.38	21.142 nanograms per milliliter Geometric Coefficient of Variation 75.53	—
Plasma Pharmacokinetic Parameter Maximum Observed Concentration (Cmax) Day 22	—	17.680 nanograms per milliliter Geometric Coefficient of Variation NA Geometric coefficient variation could not be calculated as only a single participant was analyzed.	—

SECONDARY outcome

Timeframe: Day 15 and Day 22

Population: Pharmacokinetic population. Only those participants available at the specified time points were used for analysis.

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.

Outcome measures

Measure	Pazopanib 5 mg/mL TID n=24 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 2 mg/mL TID n=24 Participants Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 5 mg/mL Once Daily Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL once daily for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.
Plasma Pharmacokinetic Parameter Time of Occurrence of Cmax (Tmax) Day 15	3.000 hour Interval 0.0 to 6.0	2.970 hour Interval 0.0 to 6.42	—
Plasma Pharmacokinetic Parameter Time of Occurrence of Cmax (Tmax) Day 29	—	3.000 hour Interval 3.0 to 3.0	—

SECONDARY outcome

Timeframe: Day 15 and Day 22

Population: Pharmacokinetic population. Only those participants available at the specified time points were used for analysis.

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.

Outcome measures

Measure	Pazopanib 5 mg/mL TID n=24 Participants Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 2 mg/mL TID n=24 Participants Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 5 mg/mL Once Daily Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL once daily for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.
Plasma Pharmacokinetic Parameter Area Under Concentration Time-curve From Time Zero to 6 Hours (AUC [0-6)] Day 15	312.17998 nanograms per hour per milliliter Geometric Coefficient of Variation 87.87	124.57714 nanograms per hour per milliliter Geometric Coefficient of Variation 77.00	—
Plasma Pharmacokinetic Parameter Area Under Concentration Time-curve From Time Zero to 6 Hours (AUC [0-6)] Day 22	—	96.13500 nanograms per hour per milliliter Geometric Coefficient of Variation NA Geometric coefficient variation could not be calculated as only a single participant was analyzed.	—

Adverse Events

Pazopanib 5 mg/mL TID

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Pazopanib 2 mg/mL TID

Serious events: 1 serious events

Other events: 1 other events

Deaths: 0 deaths

Pazopanib 5 mg/mL Once Daily

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Measure	Pazopanib 5 mg/mL TID n=27 participants at risk Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 2 mg/mL TID n=27 participants at risk Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 5 mg/mL Once Daily n=16 participants at risk Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL once daily for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.
Cardiac disorders Atrial fibrillation	0.00% 0/27 • Up to follow-up (Day 43) Safety population was used for analysis.	3.7% 1/27 • Up to follow-up (Day 43) Safety population was used for analysis.	0.00% 0/16 • Up to follow-up (Day 43) Safety population was used for analysis.

Other adverse events

Measure	Pazopanib 5 mg/mL TID n=27 participants at risk Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 2 mg/mL TID n=27 participants at risk Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.	Pazopanib 5 mg/mL Once Daily n=16 participants at risk Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL once daily for 28 days. Participants were instructed to administer drops with a 6-hour interval between daily doses.
Eye disorders Retinal disorder	3.7% 1/27 • Up to follow-up (Day 43) Safety population was used for analysis.	0.00% 0/27 • Up to follow-up (Day 43) Safety population was used for analysis.	6.2% 1/16 • Up to follow-up (Day 43) Safety population was used for analysis.
Eye disorders Vision blurred	3.7% 1/27 • Up to follow-up (Day 43) Safety population was used for analysis.	0.00% 0/27 • Up to follow-up (Day 43) Safety population was used for analysis.	6.2% 1/16 • Up to follow-up (Day 43) Safety population was used for analysis.
Eye disorders Detachment of retinal pigment epithelium	0.00% 0/27 • Up to follow-up (Day 43) Safety population was used for analysis.	0.00% 0/27 • Up to follow-up (Day 43) Safety population was used for analysis.	6.2% 1/16 • Up to follow-up (Day 43) Safety population was used for analysis.
Eye disorders Myodesopsia	0.00% 0/27 • Up to follow-up (Day 43) Safety population was used for analysis.	0.00% 0/27 • Up to follow-up (Day 43) Safety population was used for analysis.	6.2% 1/16 • Up to follow-up (Day 43) Safety population was used for analysis.
Eye disorders Visual acuity reduced	0.00% 0/27 • Up to follow-up (Day 43) Safety population was used for analysis.	0.00% 0/27 • Up to follow-up (Day 43) Safety population was used for analysis.	6.2% 1/16 • Up to follow-up (Day 43) Safety population was used for analysis.
Eye disorders Visual impairment	0.00% 0/27 • Up to follow-up (Day 43) Safety population was used for analysis.	0.00% 0/27 • Up to follow-up (Day 43) Safety population was used for analysis.	6.2% 1/16 • Up to follow-up (Day 43) Safety population was used for analysis.
Nervous system disorders Headache	11.1% 3/27 • Up to follow-up (Day 43) Safety population was used for analysis.	3.7% 1/27 • Up to follow-up (Day 43) Safety population was used for analysis.	0.00% 0/16 • Up to follow-up (Day 43) Safety population was used for analysis.
Respiratory, thoracic and mediastinal disorders Cough	7.4% 2/27 • Up to follow-up (Day 43) Safety population was used for analysis.	0.00% 0/27 • Up to follow-up (Day 43) Safety population was used for analysis.	0.00% 0/16 • Up to follow-up (Day 43) Safety population was used for analysis.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	3.7% 1/27 • Up to follow-up (Day 43) Safety population was used for analysis.	0.00% 0/27 • Up to follow-up (Day 43) Safety population was used for analysis.	6.2% 1/16 • Up to follow-up (Day 43) Safety population was used for analysis.
Gastrointestinal disorders Nausea	7.4% 2/27 • Up to follow-up (Day 43) Safety population was used for analysis.	0.00% 0/27 • Up to follow-up (Day 43) Safety population was used for analysis.	0.00% 0/16 • Up to follow-up (Day 43) Safety population was used for analysis.
Vascular disorders Hypertension	3.7% 1/27 • Up to follow-up (Day 43) Safety population was used for analysis.	0.00% 0/27 • Up to follow-up (Day 43) Safety population was used for analysis.	6.2% 1/16 • Up to follow-up (Day 43) Safety population was used for analysis.

Additional Information

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Phone: 866-435-7343

Results disclosure agreements

• Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
• Publication restrictions are in place

Restriction type: OTHER