Clinical trial NCT00612456: To Evaluate the Pharmacodynamics, Safety, and Pharmacokinetics of Pazopanib Drops in Adult Subjects With Neovascular AMD
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Macular Degeneration
Keywords: angiogenesis
pazopanib,
age-related macular degeneration (AMD),
vascular endothelial growth factor (VEGF),
choroidal neovascularization (CNV),
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2008-02-11
Enrollment: 70
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: Baseline (Day -3 to -1) and Day 29
Secondary outcomes:
measure: Number of Participants With Complete Ophthalmic Examination Values of Potential Clinical Concern
timeFrame: Upto follow-up (Day 43)
measure: Number of Participants With Vital Sign Data for Systolic Blood Pressure and Diastolic Blood Pressure and Heart Rate of Potential Clinical Concern
timeFrame: Up to follow up (Day 46)
measure: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings
timeFrame: Day 15 and follow-up (Day 43)
measure: Number of Participants With Clinical Chemistry and Hematology Data of Potential Clinical Concern
timeFrame: Up to follow-up Day 43
measure: Number of Participants With Abnormal Urinalysis Data by Dipstick Analysis
timeFrame: Day 29 and follow-up (Day 43)
measure: Number of Participants With Ocular Adverse Events, Non-ocular Adverse Events, Serious Ocular Adverse Events and Serious Non-ocular Adverse Events
timeFrame: Up to follow-up (Day 43)
measure: 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
timeFrame: Baseline (Day -3 to -1) and Day 29
measure: Number of Participants With Change in Retinal Morphology (Cystoid Spaces, Subretinal Fluid and Retinal Pigment Epithelial Detachment) as Determined by OCT
timeFrame: Day 29
measure: Number of Participants With Change in Characteristics (Fibrosis, Atrophy, Blood) as Measured by Fundus Photography (FP)
timeFrame: Day 29
measure: 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
timeFrame: Baseline (Day -3 to -1) and Day 29
measure: Plasma Pharmacokinetic Parameter Maximum Observed Concentration (Cmax)
timeFrame: Day 15 and Day 22
measure: Plasma Pharmacokinetic Parameter Time of Occurrence of Cmax (Tmax)
timeFrame: Day 15 and Day 22
measure: Plasma Pharmacokinetic Parameter Area Under Concentration Time-curve From Time Zero to 6 Hours (AUC [0-6)]
timeFrame: Day 15 and Day 22
Other outcomes:
Locations:
city: Tucson
country: United States
facility: GSK Investigational Site
state: Arizona
city: Beverly Hills
country: United States
facility: GSK Investigational Site
state: California
city: Pasadena
country: United States
facility: GSK Investigational Site
state: California
city: Sacramento
country: United States
facility: GSK Investigational Site
state: California
city: Fort Lauderdale
country: United States
facility: GSK Investigational Site
state: Florida
city: Winter Haven
country: United States
facility: GSK Investigational Site
state: Florida
city: Indianapolis
country: United States
facility: GSK Investigational Site
state: Indiana
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: GSK Investigational Site
state: Michigan
city: Grand Rapids
country: United States
facility: GSK Investigational Site
state: Michigan
city: Toms River
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Winston-Salem
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Pittsburgh
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Salt Lake City
country: United States
facility: GSK Investigational Site
state: Utah
city: Sydney
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Sydney
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Melbourne
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Perth
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Leuven
country: Belgium
facility: GSK Investigational Site
city: Trieste
country: Italy
facility: GSK Investigational Site
state: Friuli-Venezia-Giulia
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Torino
country: Italy
facility: GSK Investigational Site
state: Piemonte
city: Firenze
country: Italy
facility: GSK Investigational Site
state: Toscana
city: Padova
country: Italy
facility: GSK Investigational Site
state: Veneto
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: