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

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00612456
• Collaborator: (none)
• Enrollment: 70
• Locations: 27
• Arms: 3
• Actual Duration (Months): 15.4
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Macular Degeneration	Drug: Pazopanib	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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.
• Actual Study Start Date: Mar 5, 2008
• Actual Primary Completion Date: Jan 1, 2009
• Actual Study Completion Date: Jun 17, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 Pazopanib eye drops formulation 5 mg/mL daily for 28 days	Drug: Pazopanib; Pazopanib eye drops formulation
Experimental: Arm 2 Pazopanib eye drop formulation 5mg/mL TID for 28 days	Drug: Pazopanib; Pazopanib eye drops formulation
Experimental: Arm 3 Pazopanib eye drop formulation 2mg/mL TID for 28 days	Drug: Pazopanib; Pazopanib eye drops formulation

Outcome Measures

Primary Outcome Measures

1. 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 [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.

Secondary Outcome Measures

1. Number of Participants With Complete Ophthalmic Examination Values of Potential Clinical Concern [Upto follow-up (Day 43)]

   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.

2. 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)]

   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.

3. Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings [Day 15 and follow-up (Day 43)]

   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.

4. Number of Participants With Clinical Chemistry and Hematology Data of Potential Clinical Concern [Up to follow-up Day 43]

   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.

5. Number of Participants With Abnormal Urinalysis Data by Dipstick Analysis [Day 29 and follow-up (Day 43)]

   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.

6. 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)]

   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

7. 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]

   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.

8. Number of Participants With Change in Retinal Morphology (Cystoid Spaces, Subretinal Fluid and Retinal Pigment Epithelial Detachment) as Determined by OCT [Day 29]

   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.

9. Number of Participants With Change in Characteristics (Fibrosis, Atrophy, Blood) as Measured by Fundus Photography (FP) [Day 29]

   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.

10. 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]

    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.

11. Plasma Pharmacokinetic Parameter Maximum Observed Concentration (Cmax) [Day 15 and Day 22]

    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.

12. Plasma Pharmacokinetic Parameter Time of Occurrence of Cmax (Tmax) [Day 15 and Day 22]

    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.

13. Plasma Pharmacokinetic Parameter Area Under Concentration Time-curve From Time Zero to 6 Hours (AUC [0-6)] [Day 15 and Day 22]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Tucson	Arizona	United States	85704
2	GSK Investigational Site	Beverly Hills	California	United States	90211
3	GSK Investigational Site	Pasadena	California	United States	91105
4	GSK Investigational Site	Sacramento	California	United States	95841
5	GSK Investigational Site	Fort Lauderdale	Florida	United States	33334
6	GSK Investigational Site	Winter Haven	Florida	United States	33880
7	GSK Investigational Site	Indianapolis	Indiana	United States	46280
8	GSK Investigational Site	Boston	Massachusetts	United States	02111
9	GSK Investigational Site	Ann Arbor	Michigan	United States	48105
10	GSK Investigational Site	Grand Rapids	Michigan	United States	49525
11	GSK Investigational Site	Toms River	New Jersey	United States	08755
12	GSK Investigational Site	Winston-Salem	North Carolina	United States	27157
13	GSK Investigational Site	Pittsburgh	Pennsylvania	United States	15213
14	GSK Investigational Site	Austin	Texas	United States	78705
15	GSK Investigational Site	Houston	Texas	United States	77030
16	GSK Investigational Site	Salt Lake City	Utah	United States	84132
17	GSK Investigational Site	Sydney	New South Wales	Australia	2145
18	GSK Investigational Site	Sydney	New South Wales	Australia	2150
19	GSK Investigational Site	Melbourne	Victoria	Australia
20	GSK Investigational Site	Perth	Western Australia	Australia	6009
21	GSK Investigational Site	Leuven		Belgium	3000
22	GSK Investigational Site	Trieste	Friuli-Venezia-Giulia	Italy	34129
23	GSK Investigational Site	Milano	Lombardia	Italy	20132
24	GSK Investigational Site	Milano	Lombardia	Italy	20157
25	GSK Investigational Site	Torino	Piemonte	Italy	10122
26	GSK Investigational Site	Firenze	Toscana	Italy	50134
27	GSK Investigational Site	Padova	Veneto	Italy	35128

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00612456
• Other Study ID Numbers: MD7108240
• First Posted: Feb 11, 2008
• Last Update Posted: Nov 20, 2017
• Last Verified: Sep 1, 2017

• Keywords provided by GlaxoSmithKline: angiogenesis; pazopanib,; age-related macular degeneration (AMD),; vascular endothelial growth factor (VEGF),; choroidal neovascularization (CNV),
• Additional relevant MeSH terms: Macular Degeneration

Study Results

Participant Flow

Recruitment Details	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.

Arm/Group Title	Pazopanib 5 mg/mL TID	Pazopanib 2 mg/mL TID	Pazopanib 5 mg/mL Once Daily
Arm/Group Description	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.	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.	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.
Period Title: Overall Study
STARTED	27	27	16
COMPLETED	25	25	16
NOT COMPLETED	2	2	0

Baseline Characteristics

Arm/Group Title	Pazopanib 5 mg/mL TID	Pazopanib 2 mg/mL TID	Pazopanib 5 mg/mL Once Daily	Total
Arm/Group Description	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..	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.	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 of all reporting groups
Overall Participants	27	27	16	70
Age, Customized (Count of Participants)
57 to 88 years	27 100%	27 100%	16 100%	70 100%
Sex: Female, Male (Count of Participants)
Female	20 74.1%	14 51.9%	9 56.3%	43 61.4%
Male	7 25.9%	13 48.1%	7 43.8%	27 38.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	27 100%	27 100%	16 100%	70 100%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	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
Description	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.
Time Frame	Baseline (Day -3 to -1) and Day 29

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Pazopanib 5 mg/mL TID	Pazopanib 2 mg/mL TID	Pazopanib 5 mg/mL Once Daily
Arm/Group Description	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.	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.	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.
Measure Participants	26	24	14
CRLT as measued by OCT, LOCF data	7.5 (110.34)	10.0 (83.78)	31.2 (85.72)
CRLT as measued by OCT, OC data	7.5 (110.34)	3.0 (85.16)	9.1 (69.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 5 mg/mL TID
	Comments	Comparison between Baseline value and Day 29 value.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means using the LOCF dataset.
Statistical Test of Hypothesis	p-Value	0.6241
	Comments	If the estimates of change from baseline in CRLT were negative, then the one-sided p-values were the two-sided t-test of each treatment arm from this analysis divided by 2. If the estimates of change from baseline in CRLT were positive, then the one
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.83
	Confidence Interval	(2-Sided) 95%; -31.05 to 42.71
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.332
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 2 mg/mL TID
	Comments	Comparison between Baseline value and Day 29 value.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means using the LOCF dataset.
Statistical Test of Hypothesis	p-Value	0.7315
	Comments	If the estimates of change from baseline in CRLT were negative, then the one-sided p-values were the two-sided t-test of each treatment arm from this analysis divided by 2. If the estimates of change from baseline in CRLT were positive, then the one
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	11.87
	Confidence Interval	(2-Sided) 95%; -26.52 to 50.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 19.081
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 5 mg/mL TID
	Comments	Comparison between Baseline value and Day 29 value.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means using the OC dataset.
Statistical Test of Hypothesis	p-Value	0.6212
	Comments	If the estimates of change from baseline in CRLT were negative, then the one-sided p-values were the two-sided t-test of each treatment arm from this analysis divided by 2. If the estimates of change from baseline in CRLT were positive, then the one
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.76
	Confidence Interval	(2-Sided) 95%; -31.65 to 43.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.566
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 2 mg/mL TID
	Comments	Comparison between Baseline value and Day 29 value.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means using the OC dataset.
Statistical Test of Hypothesis	p-Value	0.5987
	Comments	If the estimates of change from baseline in CRLT were negative, then the one-sided p-values were the two-sided t-test of each treatment arm from this analysis divided by 2. If the estimates of change from baseline in CRLT were positive, then the one
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.20
	Confidence Interval	(2-Sided) 95%; -36.44 to 46.84
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 20.662
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 5 mg/mL TID
	Comments	LOCF Data excluding potential one outlier participant. Comparison between Baseline value and Day 29 value.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means.
Statistical Test of Hypothesis	p-Value	0.4820
	Comments	If the estimates of change from baseline in CRLT were negative, then the one-sided p-values were the two-sided t-test of each treatment arm from this analysis divided by 2. If the estimates of change from baseline in CRLT were positive, then the one
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.82
	Confidence Interval	(2-Sided) 95%; -37.28 to 35.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.114
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 2 mg/mL TID
	Comments	LOCF Data excluding potential one outlier participant. Comparison between Baseline value and Day 29 value.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means.
Statistical Test of Hypothesis	p-Value	0.8562
	Comments	If the estimates of change from baseline in CRLT were negative, then the one-sided p-values were the two-sided t-test of each treatment arm from this analysis divided by 2. If the estimates of change from baseline in CRLT were positive, then the one
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	19.90
	Confidence Interval	(2-Sided) 95%; -17.33 to 57.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.496
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 5 mg/mL TID
	Comments	OC Data excluding potential one outlier participant. Comparison between Baseline value and Day 29 value.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means.
Statistical Test of Hypothesis	p-Value	0.4880
	Comments	If the estimates of change from baseline in CRLT were negative, then the one-sided p-values were the two-sided t-test of each treatment arm from this analysis divided by 2. If the estimates of change from baseline in CRLT were positive, then the one
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.55
	Confidence Interval	(2-Sided) 95%; -37.46 to 36.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.300
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 2 mg/mL TID
	Comments	OC Data excluding potential one outlier participant. Comparison between Baseline value and Day 29 value.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means.
Statistical Test of Hypothesis	p-Value	0.7556
	Comments	If the estimates of change from baseline in CRLT were negative, then the one-sided p-values were the two-sided t-test of each treatment arm from this analysis divided by 2. If the estimates of change from baseline in CRLT were positive, then the one
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	13.97
	Confidence Interval	(2-Sided) 95%; -26.38 to 54.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 20.008
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants With Complete Ophthalmic Examination Values of Potential Clinical Concern
Description	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.
Time Frame	Upto follow-up (Day 43)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Pazopanib 5 mg/mL TID	Pazopanib 2 mg/mL TID	Pazopanib 5 mg/mL Once Daily
Arm/Group Description	Eligible participants received Pazopanib eye drops topically at a dose of 5 mg/mL TID for 28 days. Participants were instructed to administer drops approximately with a 6-hour interval between daily doses.	Eligible participants received Pazopanib eye drops topically at a dose of 2 mg/mL TID for 28 days. Participants were instructed to administer drops approximately with a 6-hour interval between daily doses.	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.
Measure Participants	27	27	16
Count of Participants [Participants]	0 0%	0 0%	0 0%

3. Secondary Outcome

Title	Number of Participants With Vital Sign Data for Systolic Blood Pressure and Diastolic Blood Pressure and Heart Rate of Potential Clinical Concern
Description	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.
Time Frame	Up to follow up (Day 46)

Outcome Measure Data

Analysis Population Description

Safety population.

Arm/Group Title	Pazopanib 5 mg/mL TID	Pazopanib 2 mg/mL TID	Pazopanib 5 mg/mL Once Daily
Arm/Group Description	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.	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.	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.
Measure Participants	27	27	16
Systolic blood pressure	1 3.7%	4 14.8%	1 6.3%
Diastolic blood pressure	0 0%	1 3.7%	0 0%
Heart rate	0 0%	0 0%	0 0%

4. Secondary Outcome

Title	Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings
Description	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.
Time Frame	Day 15 and follow-up (Day 43)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Pazopanib 5 mg/mL TID	Pazopanib 2 mg/mL TID	Pazopanib 5 mg/mL Once Daily
Arm/Group Description	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.	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.	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.
Measure Participants	27	27	16
Day 15, A-NCS	11 40.7%	11 40.7%	6 37.5%
Day 15, A-CS	1 3.7%	0 0%	0 0%
Follow-up (Day 43), A-NCS	7 25.9%	10 37%	8 50%
Follow-up (Day 43), A-CS	2 7.4%	0 0%	0 0%

5. Secondary Outcome

Title	Number of Participants With Clinical Chemistry and Hematology Data of Potential Clinical Concern
Description	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.
Time Frame	Up to follow-up Day 43

Outcome Measure Data

Analysis Population Description

Safety population.

Arm/Group Title	Pazopanib 5 mg/mL TID	Pazopanib 2 mg/mL TID	Pazopanib 5 mg/mL Once Daily
Arm/Group Description	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.	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.	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.
Measure Participants	27	27	16
Glucose high	4 14.8%	1 3.7%	1 6.3%
Glucose low	2 7.4%	0 0%	0 0%
Calcium low	1 3.7%	0 0%	0 0%
Potassium high	1 3.7%	1 3.7%	0 0%
Total bilirubin high	1 3.7%	0 0%	0 0%
Alkaline phosphatase high	1 3.7%	0 0%	0 0%
Lymphocytes low	1 3.7%	1 3.7%	1 6.3%
Total neutrophils low	0 0%	0 0%	1 6.3%

6. Secondary Outcome

Title	Number of Participants With Abnormal Urinalysis Data by Dipstick Analysis
Description	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.
Time Frame	Day 29 and follow-up (Day 43)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Pazopanib 5 mg/mL TID	Pazopanib 2 mg/mL TID	Pazopanib 5 mg/mL Once Daily
Arm/Group Description	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.	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.	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.
Measure Participants	27	27	16
Urine Occult Blood at Day 29 1 hour, 1+	1 3.7%	1 3.7%	2 12.5%
Urine Occult Blood at Day 29 1 hour, 2+	0 0%	1 3.7%	0 0%
Urine Occult Blood at Follow-up, 1+	1 3.7%	0 0%	0 0%
Urine Glucose at Day 29 1 hour, 1+ OR 1/4	0 0%	1 3.7%	1 6.3%
Urine Glucose at Follow-up, 3+ OR 1 gram/deciliter	0 0%	0 0%	1 6.3%
Urine Protein at Day 29 1 hour, 1+	2 7.4%	2 7.4%	1 6.3%
Urine Protein at Day 29 1 hour, 2+	0 0%	1 3.7%	0 0%
Urine Protein at Follow-up, 1+	0 0%	2 7.4%	0 0%
Urine Protein at Follow-up, 3+	0 0%	1 3.7%	0 0%

7. Secondary Outcome

Title	Number of Participants With Ocular Adverse Events, Non-ocular Adverse Events, Serious Ocular Adverse Events and Serious Non-ocular Adverse Events
Description	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
Time Frame	Up to follow-up (Day 43)

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Pazopanib 5 mg/mL TID	Pazopanib 2 mg/mL TID	Pazopanib 5 mg/mL Once Daily
Arm/Group Description	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.	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.	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.
Measure Participants	27	27	16
Non-Ocular Adverse Events	10 37%	5 18.5%	2 12.5%
Ocular Adverse Events, Fellow eye	2 7.4%	0 0%	1 6.3%
Ocular Adverse Events, Study eye	9 33.3%	2 7.4%	3 18.8%
Non-Ocular Serious Adverse Events	0 0%	1 3.7%	0 0%

8. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline (Day -3 to -1) and Day 29

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Pazopanib 5 mg/mL TID	Pazopanib 2 mg/mL TID	Pazopanib 5 mg/mL Once Daily
Arm/Group Description	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.	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.	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.
Measure Participants	26	24	14
BCVA at Day 29	4.3 (5.95)	0.8 (8.38)	0.0 (2.05)
YES for RAP/RCA NONE field from DARC FA at Day 29	4.8 (5.67)	1.7 (7.43)	-0.1 (2.13)
YES for eligible field from DARC FA form at Day 29	3.5 (5.26)	0.8 (7.39)	0.3 (1.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 5 mg/mL TID
	Comments	Comparison between Baseline value and Day 29 value.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means based on efficacy population.
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.32
	Confidence Interval	(2-Sided) 95%; 1.74 to 6.91
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.290
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 2 mg/mL TID
	Comments	Comparison between Baseline value and Day 29 value.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means based on efficacy population.
Statistical Test of Hypothesis	p-Value	0.5921
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; -2.05 to 3.57
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.403
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 5 mg/mL Once Daily
	Comments	Comparison between Baseline value and Day 29 value.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means based on efficacy population.
Statistical Test of Hypothesis	p-Value	0.9646
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 95%; -3.89 to 4.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.988
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 5 mg/mL TID
	Comments	Comparison between Baseline value and Day 29 value.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means based on participants with a 'YES' for RCA NONE field from DARC FA form in study eye at screening.
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.75
	Confidence Interval	(2-Sided) 95%; 2.32 to 7.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 2 mg/mL TID
	Comments	Comparison between Baseline value and Day 29 value.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means based on participants with a 'YES' for RCA NONE field from DARC FA form in study eye at screening.
Statistical Test of Hypothesis	p-Value	0.2208
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.64
	Confidence Interval	(2-Sided) 95%; -1.02 to 4.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.326
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 5 mg/mL Once Daily
	Comments	Comparison between Baseline value and Day 29 value.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means based on participants with a 'YES' for RCA NONE field from DARC FA form in study eye at screening.
Statistical Test of Hypothesis	p-Value	0.9847
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -3.90 to 3.83
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.927
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 5 mg/mL TID
	Comments	Comparison between Baseline value and Day 29 value.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means based on participants with a 'YES' for eligible field from DARC FA form in study eye at screening.
Statistical Test of Hypothesis	p-Value	0.0142
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.53
	Confidence Interval	(2-Sided) 95%; 0.75 to 6.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.376
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 2 mg/mL TID
	Comments	Comparison between Baseline value and Day 29 value.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means based on participants with a 'YES' for eligible field from DARC FA form in study eye at screening.
Statistical Test of Hypothesis	p-Value	0.5547
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; -2.02 to 3.71
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.419
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 5 mg/mL Once Daily
	Comments	Comparison between Baseline value and Day 29 value.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means based on participants with a 'YES' for eligible field from DARC FA form in study eye at screening.
Statistical Test of Hypothesis	p-Value	0.9114
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.26
	Confidence Interval	(2-Sided) 95%; -4.37 to 4.88
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.287
	Estimation Comments

9. Secondary Outcome

Title	Number of Participants With Change in Retinal Morphology (Cystoid Spaces, Subretinal Fluid and Retinal Pigment Epithelial Detachment) as Determined by OCT
Description	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.
Time Frame	Day 29

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Pazopanib 5 mg/mL TID	Pazopanib 2 mg/mL TID	Pazopanib 5 mg/mL Once Daily
Arm/Group Description	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.	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.	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.
Measure Participants	26	21	11
Cystoid spaces at Day 29	9 33.3%	10 37%	5 31.3%
Pigment epithelial detachment at Day 29	1 3.7%	2 7.4%	1 6.3%
Subretinal fluid at Day 29	2 7.4%	4 14.8%	2 12.5%

10. Secondary Outcome

Title	Number of Participants With Change in Characteristics (Fibrosis, Atrophy, Blood) as Measured by Fundus Photography (FP)
Description	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.
Time Frame	Day 29

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Pazopanib 5 mg/mL TID	Pazopanib 2 mg/mL TID	Pazopanib 5 mg/mL Once Daily
Arm/Group Description	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.	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.	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.
Measure Participants	26	22	11
Heme subretinal hemorrhage at Day 29	14 51.9%	14 51.9%	7 43.8%
Heme intraretinal hemorrhage at Day 29	7 25.9%	1 3.7%	1 6.3%
Subretinal fluid at Day 29	26 96.3%	22 81.5%	11 68.8%
Fibrosis at Day 29	2 7.4%	2 7.4%	1 6.3%
Atrophy at Day 29	6 22.2%	6 22.2%	5 31.3%
Pigment at Day 29	23 85.2%	20 74.1%	11 68.8%

11. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline (Day -3 to -1) and Day 29

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Pazopanib 5 mg/mL TID	Pazopanib 2 mg/mL TID	Pazopanib 5 mg/mL Once Daily
Arm/Group Description	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.	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.	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.
Measure Participants	26	24	14
CNV size at Day 29	0.6 (1.67)	0.44 (2.04)	0.7 (1.96)
Classic CNV size at Day 29	0.2 (0.90)	1.5 (1.62)	0.7 (0.81)
FA blood area of measurement at Day 29	-0.2 (0.75)	1.0 (1.87)	0.4 (0.82)
FA leakage area of measurement at Day 29	0.8 (1.77)	0.8 (2.06)	0.6 (1.88)
Total lesion size	0.5 (1.57)	1.2 (2.37)	0.7 (1.86)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 5 mg/mL TID
	Comments	Comparison between Baseline value and Day 29 value for FA Leakage Area of measurement.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means.
Statistical Test of Hypothesis	p-Value	0.0534
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; -0.01 to 1.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.383
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 2 mg/mL TID
	Comments	Comparison between Baseline value and Day 29 value for FA Leakage Area of measurement.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means.
Statistical Test of Hypothesis	p-Value	0.0508
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; -0.00 to 1.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.409
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 5 mg/mL Once Daily
	Comments	Comparison between Baseline value and Day 29 value for FA Leakage Area of measurement.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means.
Statistical Test of Hypothesis	p-Value	0.3141
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; -0.60 to 1.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 5 mg/mL TID
	Comments	Comparison between Baseline value and Day 29 value for FA Blood Area of measurement.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means.
Statistical Test of Hypothesis	p-Value	0.6018
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -1.04 to 0.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.395
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 2 mg/mL TID
	Comments	Comparison between Baseline value and Day 29 value for FA Blood Area of measurement.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0509
	Comments	Statistics has been presented for least square means.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; -0.00 to 2.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.476
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 5 mg/mL Once Daily
	Comments	Comparison between Baseline value and Day 29 value for FA Blood Area of measurement.
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means.
Statistical Test of Hypothesis	p-Value	0.3976
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.49
	Confidence Interval	(2-Sided) 95%; -0.70 to 1.68
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.566
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 5 mg/mL TID
	Comments	Comparison between Baseline value and Day 29 value for Total Lesion size
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means.
Statistical Test of Hypothesis	p-Value	0.2410
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95%; -0.32 to 1.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.385
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 2 mg/mL TID
	Comments	Comparison between Baseline value and Day 29 value for Total Lesion size
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means.
Statistical Test of Hypothesis	p-Value	0.0032
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.27
	Confidence Interval	(2-Sided) 95%; 0.44 to 2.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.412
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 5 mg/mL Once Daily
	Comments	Comparison between Baseline value and Day 29 value for Total Lesion size
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means.
Statistical Test of Hypothesis	p-Value	0.3185
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 95%; -0.58 to 1.75
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.581
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 5 mg/mL TID
	Comments	Comparison between Baseline value and Day 29 value for CNV Size
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means.
Statistical Test of Hypothesis	p-Value	0.1074
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; -0.14 to 1.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.377
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 2 mg/mL TID
	Comments	Comparison between Baseline value and Day 29 value for CNV Size
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means.
Statistical Test of Hypothesis	p-Value	0.0403
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.04 to 1.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.402
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Pazopanib 5 mg/mL Once Daily
	Comments	Comparison between Baseline value and Day 29 value for CNV Size
	Type of Statistical Test	Superiority or Other
	Comments	Statistics has been presented for least square means.
Statistical Test of Hypothesis	p-Value	0.2490
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; -0.50 to 1.88
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.594
	Estimation Comments

12. Secondary Outcome

Title	Plasma Pharmacokinetic Parameter Maximum Observed Concentration (Cmax)
Description	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.
Time Frame	Day 15 and Day 22

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Pazopanib 5 mg/mL TID	Pazopanib 2 mg/mL TID
Arm/Group Description	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.	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.
Measure Participants	24	24
Day 15	56.104 (85.38)	21.142 (75.53)
Day 22	17.680 (NA)

13. Secondary Outcome

Title	Plasma Pharmacokinetic Parameter Time of Occurrence of Cmax (Tmax)
Description	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.
Time Frame	Day 15 and Day 22

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Pazopanib 5 mg/mL TID	Pazopanib 2 mg/mL TID
Arm/Group Description	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.	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.
Measure Participants	24	24
Day 15	3.000	2.970
Day 29	3.000

14. Secondary Outcome

Title	Plasma Pharmacokinetic Parameter Area Under Concentration Time-curve From Time Zero to 6 Hours (AUC [0-6)]
Description	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.
Time Frame	Day 15 and Day 22

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Pazopanib 5 mg/mL TID	Pazopanib 2 mg/mL TID
Arm/Group Description	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.	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.
Measure Participants	24	24
Day 15	312.17998 (87.87)	124.57714 (77.00)
Day 22	96.13500 (NA)

Adverse Events

Time Frame	Up to follow-up (Day 43)
Adverse Event Reporting Description	Safety population was used for analysis.
Arm/Group Title	Pazopanib 5 mg/mL TID		Pazopanib 2 mg/mL TID		Pazopanib 5 mg/mL Once Daily
Arm/Group Description	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.		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.		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.
All Cause Mortality
	Pazopanib 5 mg/mL TID		Pazopanib 2 mg/mL TID		Pazopanib 5 mg/mL Once Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/27 (0%)		0/16 (0%)
Serious Adverse Events
	Pazopanib 5 mg/mL TID		Pazopanib 2 mg/mL TID		Pazopanib 5 mg/mL Once Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		1/27 (3.7%)		0/16 (0%)
Cardiac disorders
Atrial fibrillation	0/27 (0%)		1/27 (3.7%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	Pazopanib 5 mg/mL TID		Pazopanib 2 mg/mL TID		Pazopanib 5 mg/mL Once Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/27 (25.9%)		1/27 (3.7%)		3/16 (18.8%)
Eye disorders
Retinal disorder	1/27 (3.7%)		0/27 (0%)		1/16 (6.3%)
Vision blurred	1/27 (3.7%)		0/27 (0%)		1/16 (6.3%)
Detachment of retinal pigment epithelium	0/27 (0%)		0/27 (0%)		1/16 (6.3%)
Myodesopsia	0/27 (0%)		0/27 (0%)		1/16 (6.3%)
Visual acuity reduced	0/27 (0%)		0/27 (0%)		1/16 (6.3%)
Visual impairment	0/27 (0%)		0/27 (0%)		1/16 (6.3%)
Gastrointestinal disorders
Nausea	2/27 (7.4%)		0/27 (0%)		0/16 (0%)
Nervous system disorders
Headache	3/27 (11.1%)		1/27 (3.7%)		0/16 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	2/27 (7.4%)		0/27 (0%)		0/16 (0%)
Oropharyngeal pain	1/27 (3.7%)		0/27 (0%)		1/16 (6.3%)
Vascular disorders
Hypertension	1/27 (3.7%)		0/27 (0%)		1/16 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.