Clinical trial NCT01362348: 12 Week Patient Study in Neovascular Age-related Macular Degeneration (AMD)
Official title: An Open-label, Phase 2a Study to Evaluate Pazopanib Eye Drops Administered for 12 Weeks to Patients With Neovascular Age-related Macular Degeneration
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Macular Degeneration
Keywords: Age-related Macular Degeneration
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2011-05-30
Enrollment: 19
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this 12 week, open-label study is to investigate the safety and efficacy of a single dose regimen of pazopanib eye drop for neovascular AMD.

Detailed description: MD7114987 is a Phase 2a study designed to determine whether pazopanib eye drops have the potential to reduce retinal edema and maintain or improve visual acuity in persons with a previously untreated subfoveal choroidal neovascularization (CNV) lesion secondary to age-related macular degeneration (AMD) and to further characterize the safety and tolerability of pazopanib eye drops administered over a 12-week period.

Eligibility criteria: Inclusion Criteria:

Subjects eligible for enrolment in the study must meet all of the following criteria:

* Consent: Subject understands the procedures, agrees to participate in the study (including participation in the CFH Y402H pharmacogenetic research), and has signed and dated the informed consent form prior to the initiation of any study-related activities. If the subject is unable to read the consent form due to visual impairment then the consent must be read to the subject verbatim by the person administering the consent, a family member, or legally acceptable representative. (Note: Consent by legally acceptable representative is allowed where this is in accordance with local laws, regulations, and ethics committee policy.)
* Age-related macular degeneration: For each subject enrolled in the study, only one eye (study eye) will be treated, and eligibility criteria apply to the study eye. All of the following characteristics are required and must be confirmed by the central reading center:
* CNV caused by AMD that extends under the geometric center of the foveal avascular zone
* Center subfield thickness (inclusive of subretinal fluid) \> 320 microns on OCT \[SPECTRALIS® (Heidelberg)\]
* Total lesion area ≤12 disc areas on fluorescein angiography, where the lesion complex includes CNV, blood, blocked florescence not from blood, and serous detachment of the retinal pigment epithelium
* CNV comprises \< 50% of lesion area
* classic CNV comprises \< 50% of the lesion area
* fibrosis comprises ≤ 25% of lesion area
* if no evidence of classic CNV, then presumed to have recent disease progression based on deterioration (≥ 5 letter decrease in vision or evidence of growth of a CNV lesion on fluorescein angiography ) within the last 3 months or evidence of hemorrhage from CNV
* Visual acuity: Best-corrected visual acuity score by electronic ETDRS in the study eye of between 25 and 73 letters (approximately equivalent to Snellen VA of 20/320 to 20/32) at screening
* Gender and age: Subject is a male or female adult 50 years of age or older.
* Non-childbearing potential: Female subject is of non-childbearing potential defined as being physiologically incapable of becoming pregnant. This includes any female who is post-menopausal (12 months of spontaneous amenorrhea) or who is surgically post-menopausal (via documented hysterectomy or bilateral tubal ligation). In questionable cases of postmenopausal status, a blood sample with simultaneous follicle stimulating hormone (FSH) \>40 MIU/mL and estradiol \<40 pg/mL (\<140 pmol/L) \[or equivalent values based on local laboratory criteria\] is confirmatory. Refer to the SPM for more information.
* Study Compliance: Subject is able and willing to comply with the study requirements and is able and willing to attend all scheduled visits.
* Liver function tests: Subject has liver chemistry values that are within normal limits or clinically insignificant as evidenced by serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<2xULN; alkaline phosphatase and bilirubin \<1.5xULN (isolated bilirubin \>1.5xULN is acceptable, if bilirubin is fractionated and direct bilirubin is \< 35%).
* QT interval: Subject has a QTcF value \< 450 msec, or \< 480 msec for subjects with Bundle Branch Block. \[Note: subjects with paced rhythms may be considered pending discussion with the medical monitor.\]

Exclusion Criteria:

Subjects meeting any of the following criteria must not be enrolled in the study:

Study Eye:

* Additional eye disease in the study eye that could compromise best-corrected visual acuity (e.g. glaucoma with documented visual field loss, clinically significant diabetic retinopathy, ischemic optic neuropathy, infection or retinitis pigmentosa)
* CNV in the study eye due to other causes unrelated to age-related macular degeneration
* 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 spectral-domain OCT
* Vitreous, subretinal or retinal hemorrhage in the study eye that is unrelated to AMD
* Presence of an RPE tear in the study eye
* 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
* Intraocular surgery in the study eye within 3 months prior to treatment
* Any previous treatment in the study eye for neovascular AMD, approved or investigational

Fellow Eye:

* Current intravitreal anti-VEGF therapy in the fellow eye
* Best-corrected visual acuity score by electronic ETDRS \< 56 letters in the fellow eye at screening

Concurrent Conditions or Concomitant Medications:

* Subject has uncontrolled glaucoma (intraocular pressure \> 25 mmHg) despite treatment with anti-glaucoma medication.
* A known, positive test for Hepatitis B surface antigen or Hepatitis C antibody within 3 months of screening
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
* Active bleeding disorder or a history of hemoptysis, cerebral or clinically significant gastrointestinal hemorrhage within 6 months of screening
* Significant uncontrolled or unstable cardiovascular, nervous system, pulmonary, renal, endocrine, or gastrointestinal disease for example:
* Uncontrolled diabetes mellitus, with hemoglobin A1c (HbA1c) \> 10%
* Myocardial infarction or stroke within 6 months of screening
* Major surgery within 3 months of screening
* Clinically relevant thyroid disease
* Uncontrolled hypertension:

Systolic blood pressure \> 160 mmHg Diastolic blood pressure \> 100 mmHg Note: Initiation or adjustment of antihypertensive medications is permitted prior to study entry provided the referenced criteria are met (See Section 4.4.3).

* Subject has a history within the past 2 years of alcohol or substance abuse, or psychiatric disorder likely to confound the efficacy or safety assessments.
* Known HIV infection
* Within 6 months prior to the Screening Visit, use of any systemically administered anti angiogenic agent (e.g., bevacizumab, sunitinib, cetuximab, sorafenib, pazopanib), approved or investigational
* Within 6 months prior to the Screening Visit, use of medications known to be toxic to the retina, lens or optic nerve (e.g. desferoximine, chloroquine/hydrochloroquine, chlorpromazine, phenothiazines, tamoxifen, and ethambutol)
* Use of systemic steroids (\>10 mg prednisone or equivalent/day) within 14 days of the start of treatment
* Use of prohibited medications within the restricted timeframe relative to the start of study medication (See Section 5.5.2)
* Use of an investigational drug within 30 days of screening
* History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation
* A condition or situation, which, in the opinion of the investigator, may result in significant risk to the patient, confound the study results or interfere significantly with participation

Primary outcomes:
measure: Change From Baseline in Central Retinal Lesion Thickness (CRT) as Measured by Optical Coherence Tomography (OCT) at Day 29
timeFrame: Baseline (Week 0) and Day 29
measure: Change From Baseline in Best Correct Visual Acuity (BCVA) as Measured by the Number of Letters Determined by Electronic Early Treatment Diabetic Retinopathy [ETDRS] Study Visual Acuity (EVA) at Day 29
timeFrame: Baseline (Day -3 to -1) and Day 29
Secondary outcomes:
measure: Change From Baseline in Central Retinal Lesion Thickness (CRLT) Over Time
timeFrame: Baseline (Week -3 to -1) Up to Follow-up (Day 102)
measure: Change From Baseline in Intraretinal (IR) or Subretinal (SR) Fluid Thickness, Intraretinal Cysts or Serous Retinal Pigment Epithelial Detachment (PED Thickness) Over Time
timeFrame: Baseline (Week -3 to -1) Up to Follow-up (Day 102)
measure: Change From Baseline in BCVA Over Time
timeFrame: Baseline (Week -3 to -1) Up to Follow-up (Day 102)
measure: Change From Baseline in the Area of Choroidal Neovascular (CNV) Size and CNV Total Lesion Complex Size as Measured by Fluorescein Angiography (FA) at Day 29
timeFrame: Baseline (Day -3 to -1) and Day 29
measure: Number of Participants With Change in Charactertsics (Atrophy, Pigment, SR Hemorrhage, IR Hemorrhage, SR Fluid and Fibrosis) as Measured by FP
timeFrame: Day 29
measure: Number of Participants Who Received Rescue Medication
timeFrame: Up to follow-up (Day 102)
measure: Number of Participants With Ocular Adverse Events (AEs), Non-ocular AEs, Serious Ocular AEs and Serious Non-ocular AEs
timeFrame: Until Follow-up (Day 102)
measure: Number of Participants With Values of Potential Clinical Concern for Ocular Assessments on General Ophthalmic Examination
timeFrame: Up to Follow-up (Day 102)
measure: Number of Participants With Vital Sign Data of Potential Clinical Concern
timeFrame: Up to Follow-up (Day 102)
measure: Number of Participants With Clinical Chemistry and Hematology Data of Potential Clinical Concern
timeFrame: Up to Follow-up (Day 102)
measure: Number of Participants With Abnormal Urinalysis Data by Urine Microscopy and Dipstick Analysis
timeFrame: Up to Follow-up (Day 102)
measure: Summary of Plasma Pazonib Concentration
timeFrame: Up to Week 12
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: GSK Investigational Site
state: Arizona
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Winter Haven
country: United States
facility: GSK Investigational Site
state: Florida
city: Decatur
country: United States
facility: GSK Investigational Site
state: Georgia
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Grand Rapids
country: United States
facility: GSK Investigational Site
state: Michigan
city: Cleveland
country: United States
facility: GSK Investigational Site
state: Ohio
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Paris cedex 10
country: France
facility: GSK Investigational Site
city: Paris cedex 12
country: France
facility: GSK Investigational Site
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Bonn
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Muenster
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Leipzig
country: Germany
facility: GSK Investigational Site
state: Sachsen
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Singh R, Wurzelmann JI, Ye L, Henderson L, Hossain M, Trivedi T, Kelly DS. Clinical evaluation of pazopanib eye drops in healthy subjects and in subjects with neovascular age-related macular degeneration. Retina. 2014 Sep;34(9):1787-95. doi: 10.1097/IAE.0000000000000179.