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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00612456




Registration number
NCT00612456
Ethics application status
Date submitted
29/01/2008
Date registered
11/02/2008
Date last updated
20/11/2017

Titles & IDs
Public title
To Evaluate the Pharmacodynamics, Safety, and Pharmacokinetics of Pazopanib Drops in Adult Subjects With Neovascular AMD
Scientific 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.
Secondary ID [1] 0 0
MD7108240
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Macular Degeneration 0 0
Condition category
Condition code
Eye 0 0 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Pazopanib

Experimental: Arm 1 - Pazopanib eye drops formulation 5 mg/mL daily for 28 days

Experimental: Arm 2 - Pazopanib eye drop formulation 5mg/mL TID for 28 days

Experimental: Arm 3 - Pazopanib eye drop formulation 2mg/mL TID for 28 days


Treatment: Drugs: Pazopanib
Pazopanib eye drops formulation

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Mean Change From Baseline in Central Retinal/Lesion Thickness (CRLT) as Measured by the Carl Zeiss Meditec Stratus Optical Coherence Tomography (OCT) Scanner at Day 29 - CRLT was measured by the Carl Zeiss Meditec Stratus OCT scanner based on the manual measurement of the distance between the inner and outer retina, inclusive of subretinal fluid and any choroidal neovascularization (CNV) as measured in the central 1 millimeter (mm) area of the 7 mm Posterior Pole Scan. OCT scans/images were collected by trained and certified photographer and analyzed by investigator. Two datasets were used for analysis namely Last observation carried forward (LOCF) which included missing assessment for a participant who completed at least 7 days of pazopanib eye drop replaced by the last non-missing assessment post 7 days of pazopanib eye drop treatment. OC dataset included a missing assessment at any scheduled time was considered unevaluable and was not imputed. Baseline was defined as the assessments performed between Day -3 to -1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-randomization value at Day 29.
Timepoint [1] 0 0
Baseline (Day -3 to -1) and Day 29
Secondary outcome [1] 0 0
Number of Participants With Complete Ophthalmic Examination Values of Potential Clinical Concern - A complete eye examination was performed to include the following: Examination of eyelids and lashes (including meibomian glands), Pupil, motility and confrontation visual field examination, Slit lamp evaluation of anterior ocular structures (including conjunctiva, tear film, cornea with fluorescein staining, anterior chamber, iris, lens, and anterior vitreous), intraocular pressure (IOP) measurement and Dilated Fundus Examination (Indirect ophthalmoscopy and slit lamp biomicroscopy). Data has been presented in a consolidated format for the total number of participants with values of potential clinical concern for complete ophthalmic examinations until Day 43.
Timepoint [1] 0 0
Upto follow-up (Day 43)
Secondary outcome [2] 0 0
Number of Participants With Vital Sign Data for Systolic Blood Pressure and Diastolic Blood Pressure and Heart Rate of Potential Clinical Concern - Vital sign assessments included systolic blood pressure, diastolic blood pressure and heart rate. The potential clinical concern range for systolic blood pressure was <85 and > 160 millimeters of mercury, diastolic blood pressure <45 and > 100 millimeters of mercury, heart rate <40 and >110 beats per minute. Only those parameters for which at least one value of potential clinical importance was reported are summarized. The number of participants with potential clinical important findings at any visit were reported.
Timepoint [2] 0 0
Up to follow up (Day 46)
Secondary outcome [3] 0 0
Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings - Single 12-lead ECGs were to be obtained at each Day 15 and follow-up Day 43 using an ECG machine that automatically calculated the heart rate and measures PR, QRS, QT, and QTc intervals. ECG findings were defined as abnormal-not clinically significant (A-NCS) and abnormal-clinically significant (A-CS). Data has been presented for the number of participants with A-NCS and A-CS findings.
Timepoint [3] 0 0
Day 15 and follow-up (Day 43)
Secondary outcome [4] 0 0
Number of Participants With Clinical Chemistry and Hematology Data of Potential Clinical Concern - Clinical chemistry parameters assessed included blood urea nitrogen, potassium, calcium, albumin, creatinine, chloride, sodium, total protein, glucose, total carbon dioxide, aspartate amino transferase, alanine amino transferase, direct bilirubin, total bilirubin, alkaline phosphatase and hematology parameters assessed included platelet count, white blood cell count, red blood cell count, reticulocyte count, hemoglobin, mean corpuscle volume, mean corpuscle hemoglobin, mean corpuscle hemoglobin concentration, total neutrophils, lymphocytes, monocytes, eosinophils, basophils. Data has been presented for the number of participants with values high and low of potential clinical concern for clinical chemistry and hematology.
Timepoint [4] 0 0
Up to follow-up Day 43
Secondary outcome [5] 0 0
Number of Participants With Abnormal Urinalysis Data by Dipstick Analysis - Urinalysis included analysis for urine occult blood, urine glucose, urine ketones and urine proteins via dipstick analysis. Data has been presented for number of participants with abnormal urinalysis results. Only categories with values have been presented.
Timepoint [5] 0 0
Day 29 and follow-up (Day 43)
Secondary outcome [6] 0 0
Number of Participants With Ocular Adverse Events, Non-ocular Adverse Events, Serious Ocular Adverse Events and Serious Non-ocular Adverse Events - An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, may jeopardize the participant or require medical or surgical intervention to prevent one of the other outcomes listed in the definition above, or is an event of possible drug-induced liver injury. Data has been presented for number of participants with ocular and non-ocular adverse events and serious adverse event
Timepoint [6] 0 0
Up to follow-up (Day 43)
Secondary outcome [7] 0 0
Change From Baseline in Best Corrected Visual Acuity (BCVA) [Number of Letter Read on Standardized Early Treatment of Diabetic Retinopathy Study (ETDRS) Charts at Day 29 - BCVA was measured in the study eye using the ETDRS grading charts consists of at least 24 to 78 letters placed at a test distance of 4 meters. There were 7 cut off points in visual acuity on ETDRS grading chart: 15 to 29, 10 to 14, 5 to 9, -4 to 4, -5 to -9, -10 to -14 and -15 to -29 letters. Grade 15 to 29 indicates no impairment in vision and grade -15 to -29 indicates worst impairment in vision. Analyses were done for two sub-efficacy-populations. One sub-efficacy population included all participants in the efficacy population with a YES for retinal angiomatous proliferation (RAP)/retinal choroidal anastomosis (RCA) NONE field from Digital angiography reading center (DARC) FA form in study eye. The other included all participants in the efficacy population with a YES for eligible field from DARC FA form in study eye. Baseline was defined as the assessments performed between Day -3 to -1. Change from Baseline calculated as subtracting the Baseline value from the value at Day 29.
Timepoint [7] 0 0
Baseline (Day -3 to -1) and Day 29
Secondary outcome [8] 0 0
Number of Participants With Change in Retinal Morphology (Cystoid Spaces, Subretinal Fluid and Retinal Pigment Epithelial Detachment) as Determined by OCT - OCT was used for the determination of retinal morphology changes in the study eye which included assessments of cystoids spaces (cyst like spaces in the inner layers of the retina), subretinal fluid (an exudate between the retina and choroid from various sources including the vitreous cavity, subarachnoid space, or abnormal vessels) and pigment epithelial detachment (retinal pigment epithelium separates from the underlying Bruch's membrane due to the presence of blood, serous exudate, drusen, or a neovascular membrane). Data has been presented for number of participants with retinal morphology changes in the study eye at Day 29.
Timepoint [8] 0 0
Day 29
Secondary outcome [9] 0 0
Number of Participants With Change in Characteristics (Fibrosis, Atrophy, Blood) as Measured by Fundus Photography (FP) - Fundus photography involves capturing of images of the center of the very back inner wall of the eye — the retina, optic nerve, macula and main retinal blood vessels. The parameters assessment were heme subretinal hemorrhage (absence or presence at the location), heme intraretinal hemorrhage (absence or presence at the location), subretinal fluid (absence or presence at location), fibrosis (absence or presence at location), atrophy (absence or presence of atrophic changes) and pigment ((absence or presence at location). A protocol set of fundus photographs were obtained at Day 29. Images were read by the investigator for eligibility determination, and by a central reading center for determination of PD effect. Data has been presented for number of participants with changes in eye characteristics in the study eye at Day 29.
Timepoint [9] 0 0
Day 29
Secondary outcome [10] 0 0
Change From Baseline in Neovascular Size, Total Lesion Size, Fluorescein Angiography (FA) Leakage Area of Measurement, FA Blood Area of Measurement as Measured by FA at Day 29 - FA uses FP to capture images of injected dye circulating throughout the retinal blood vessels to assess leaking, swelling or circulation problems caused by various eye diseases like diabetic retinopathy and wet macular degeneration. The parameters assessed were CNV size, Classic CNV size, FA blood area of measurement, FA leakage area of measurement and total lesion size. A protocol fluorescein angiogram was to be obtained at Day 29. Images were evaluated by investigator for eligibility determination, and by a central reading center for determination of PD effect. Data has been presented for change from baseline in change in eye characteristics in the study eye at Day 29. Baseline was defined as the assessments performed between Day -3 to -1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-randomization value at Day 29.
Timepoint [10] 0 0
Baseline (Day -3 to -1) and Day 29
Secondary outcome [11] 0 0
Plasma Pharmacokinetic Parameter Maximum Observed Concentration (Cmax) - Blood samples for analysis of plasma pazopanib concentrations were collected over 6 hours after an ocular dose of pazopanib on Day 15 or Day 22. PK analyses of plasma pazopanib concentration-time data were conducted using non-compartmental Model 200 (for extravascular administration) of WinNonlin Professional Edition version 5.2. Data has been presented for pharmacokinetic parameter Cmax at Day 15 and Day 22.
Timepoint [11] 0 0
Day 15 and Day 22
Secondary outcome [12] 0 0
Plasma Pharmacokinetic Parameter Time of Occurrence of Cmax (Tmax) - Blood samples for analysis of plasma pazopanib concentrations were collected over 6 hours after an ocular dose of pazopanib on Day 15 or Day 22. PK analyses of plasma pazopanib concentration-time data were conducted using non-compartmental Model 200 (for extravascular administration) of WinNonlin Professional Edition version 5.2. Data has been presented for pharmacokinetic parameter tmax at Day 15 and Day 22.
Timepoint [12] 0 0
Day 15 and Day 22
Secondary outcome [13] 0 0
Plasma Pharmacokinetic Parameter Area Under Concentration Time-curve From Time Zero to 6 Hours (AUC [0-6)] - Blood samples for analysis of plasma pazopanib concentrations were collected over 6 hours after an ocular dose of pazopanib on Day 15 or Day 22. PK analyses of plasma pazopanib concentration-time data were conducted using non-compartmental Model 200 (for extravascular administration) of WinNonlin Professional Edition version 5.2. Data has been presented for pharmacokinetic parameter AUC (0-6) at Day 15 and Day 22.
Timepoint [13] 0 0
Day 15 and Day 22

Eligibility
Key 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.
Minimum age
50 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC,WA
Recruitment hospital [1] 0 0
GSK Investigational Site - Sydney
Recruitment hospital [2] 0 0
GSK Investigational Site - Melbourne
Recruitment hospital [3] 0 0
GSK Investigational Site - Perth
Recruitment postcode(s) [1] 0 0
2145 - Sydney
Recruitment postcode(s) [2] 0 0
2150 - Sydney
Recruitment postcode(s) [3] 0 0
- Melbourne
Recruitment postcode(s) [4] 0 0
6009 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Florida
Country [4] 0 0
United States of America
State/province [4] 0 0
Indiana
Country [5] 0 0
United States of America
State/province [5] 0 0
Massachusetts
Country [6] 0 0
United States of America
State/province [6] 0 0
Michigan
Country [7] 0 0
United States of America
State/province [7] 0 0
New Jersey
Country [8] 0 0
United States of America
State/province [8] 0 0
North Carolina
Country [9] 0 0
United States of America
State/province [9] 0 0
Pennsylvania
Country [10] 0 0
United States of America
State/province [10] 0 0
Texas
Country [11] 0 0
United States of America
State/province [11] 0 0
Utah
Country [12] 0 0
Belgium
State/province [12] 0 0
Leuven
Country [13] 0 0
Italy
State/province [13] 0 0
Friuli-Venezia-Giulia
Country [14] 0 0
Italy
State/province [14] 0 0
Lombardia
Country [15] 0 0
Italy
State/province [15] 0 0
Piemonte
Country [16] 0 0
Italy
State/province [16] 0 0
Toscana
Country [17] 0 0
Italy
State/province [17] 0 0
Veneto

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
GlaxoSmithKline
Address
Country

Ethics approval
Ethics application status

Summary
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
Trial website
https://clinicaltrials.gov/show/NCT00612456
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications