12 Week Patient Study in Neovascular Age-related Macular Degeneration (AMD)

Study Overview
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Brief Summary
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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
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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.

Official Title
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An Open-label, Phase 2a Study to Evaluate Pazopanib Eye Drops Administered for 12 Weeks to Patients With Neovascular Age-related Macular Degeneration

Conditions
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Macular Degeneration

Intervention / Treatment
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* Drug: pazopanib eye drops


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pazopanib eye drops<br>pazopanib topical ocular administration | Drug: pazopanib eye drops<br>* 10 mg/mL (1 drop) four times daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Central Retinal Lesion Thickness (CRT) as Measured by Optical Coherence Tomography (OCT) at Day 29 | CRT was the distance between the inner limiting membrane of the retina and the inner border of the retinal pigment epithelium/choriocapillaris band, inclusive of sub retinal fluid, measured in the central 1 millimeter (mm) of the Cube scan. OCT assessments were performed using SPECTRALIS spectral domain OCT. Images were evaluated by investigator for safety monitoring, and by a central reading center for eligibility determination and pharmacodynamics (PD) effects. Observed case (OC) data set was used for analysis in this analysis dataset, a missing assessment at any scheduled time point was considered unevaluable, was not imputed and was not included in data analysis. 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. | Baseline (Week 0) and Day 29 | 
| 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 | BCVA was measured in the study eye using the EVA chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the participant. A decrease in the BCVA score indicates a worsening of vision while higher scores indicates improvement of VA. 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. | Baseline (Day -3 to -1) and Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Central Retinal Lesion Thickness (CRLT) Over Time | CRLT was the manual measurement of the distance between the inner limiting membrane of the retina and the inner border of the choriocapillaris, inclusive of subretinal or sub-retinal pigment epithelium fluid collections and of the thickness of any observable choroidal neovascular membrane or scar tissue, evaluated in the central 1 mm of the Cube scan. OCT assessments were performed using SPECTRALIS spectral domain OCT. 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. | Baseline (Week -3 to -1) Up to Follow-up (Day 102) | 
| Change From Baseline in Intraretinal (IR) or Subretinal (SR) Fluid Thickness, Intraretinal Cysts or Serous Retinal Pigment Epithelial Detachment (PED Thickness) Over Time | OCT was used for the determination of retinal morphology changes in the study eye which included assessments of SR fluid (an exudate between the retina and choroid from various sources including the vitreous cavity, subarachnoid space, or abnormal vessels) and PED (retinal pigment epithelium separates from the underlying Bruch's membrane due to the presence of blood, serous exudate, drusen, or a neovascular membrane). 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. | Baseline (Week -3 to -1) Up to Follow-up (Day 102) | 
| Change From Baseline in BCVA Over Time | BCVA was measured in the study eye using the EVA chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the participant. A decrease in the BCVA score indicates a worsening of vision while higher scores indicates improvement of VA. 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. | Baseline (Week -3 to -1) Up to Follow-up (Day 102) | 
| 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 | CNV was the measurement of the combined classic and occult neovascular lesion including areas of classic neovascularization, late staining of undetermined origin and fibrovascular PED. CNV total lesion complex size was the measurement of the entire lesion including classic and occult neovascular components as well as contagious blood and/or blocked fluorescence and/or serous PED. FA uses fundus photography (FP) to capture images of injected dye circulating throughout the retinal blood vessels to assess leaking, swelling/circulation problems caused by various eye diseases like diabetic retinopathy and wet macular degeneration. A fluorescein angiogram was obtained at Day 29. Images were evaluated by investigator for eligibility and by a central reading center for determination of PD effect. 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. | Baseline (Day -3 to -1) and Day 29 | 
| Number of Participants With Change in Charactertsics (Atrophy, Pigment, SR Hemorrhage, IR Hemorrhage, SR Fluid and Fibrosis) as Measured by 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 SR hemorrhage (absence or presence at the location), heme IR hemorrhage (absence or presence at the location), SR 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. | Day 29 | 
| Number of Participants Who Received Rescue Medication | At any time during the study, including the follow-up period, rescue treatment (standard of care) was given based on the clinical judgment of the investigator. Rescue treatment was to be strongly considered for participants whose center subfield thickness had increased by >50 microns from the lowest value on study or whose BCVA decreased by more than 5 letters compared to baseline and who also had persistent fluid by OCT. Data has been reported for the number of participants with their percentages who required any rescue medication administration until follow-up. | Up to follow-up (Day 102) | 
| Number of Participants With Ocular Adverse Events (AEs), Non-ocular AEs, Serious Ocular AEs and Serious Non-ocular AEs | 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. | Until Follow-up (Day 102) | 
| Number of Participants With Values of Potential Clinical Concern for Ocular Assessments on General Ophthalmic Examination | 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 102. | Up to Follow-up (Day 102) | 
| Number of Participants With Vital Sign Data 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. Data has been presented in a consolidated format for the total number of participants with values of potential clinical concern for systolic blood pressure, diastolic blood pressure and heart rate until Day 102. | Up to Follow-up (Day 102) | 
| Number of Participants With Clinical Chemistry and Hematology Data of Potential Clinical Concern | Clinical chemistry parameters included albumin, alkaline phosphatase, alanine amino transferase, aspartate amino transferase, direct bilirubin, total bilirubin, calcium, chloride, carbon dioxide, creatinine, thyroxine (T3 free), gamma glutamyl transferase, glucose, potassium, sodium, total protein, total T3, urea, uric acid while hematology included basophils, eosinophils, hemoglobin, hematocrit, lymphocytes, mean corpuscle hemoglobin concentration, mean corpuscle hemoglobin, mean corpuscle volume, monocytes, segmented neutrophils, total neutrophils, platelet count, red blood cell count, reticulocytes and white blood cell count. The potential clinical concern ranges were as follows: glucose-low <3 and high >9 millimoles per liter (mmol/L), carbon dioxide-low <18 and high >34 mmol/L, lymphocyte-low <0.8 giga per liter (G/L) and platelet count was <100 and high >550 G/L. Data has been presented for the number of participants with values high and low of potential clinical concern. | Up to Follow-up (Day 102) | 
| Number of Participants With Abnormal Urinalysis Data by Urine Microscopy and Dipstick Analysis | Urinalysis measurements included assessments for red blood cells and white blood cells via microscopic examination while assessments for urine protein by standard dipstick analysis. Data has been presented for the number of participants with abnormal urinalysis results. | Up to Follow-up (Day 102) | 
| Summary of Plasma Pazonib Concentration | Throughout the study, 1 to 4 blood samples (2 mL) were collected from each participants for the analysis of plasma pazopanib concentrations between 0.55 to 10.83 hours post-dose on Weeks 2, 3, 4, 6 (unplanned), 8 (unplanned) and 12. The concentrations from the three blood samples per participant were averaged and then the values were averaged through all the participants. Blood samples were collected without restriction for the time interval between blood draw and the last dose of pazopanib eye drops. | Up to Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Age-related Macular Degeneration