An Extension to Study MD7108240

Study Overview
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Brief Summary
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This is a two month study to allow continued treatment with pazopanib eye drops. Study may be extended to 5 months.

Official Title
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An Extension Study to Protocol MD7108240: Pazopanib Eye Drops in Subjects With Neovascular Age-related Macular Degeneration

Conditions
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Macular Degeneration

Intervention / Treatment
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* Drug: Pazopanib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who participated in Phase IIa study MD7108240 and who did not experience AMD disease progression requiring rescue therapy during pazopanib treatment or require discontinuation of pazopanib eye drops for safety reasons Best-corrected ETDRS visual acuity in the study eye of 23 letters (20/320 or 4/63) or better at screening. QTcB or QTcF < 450msec; or QTc < 480msec in subjects with Bundle Branch Block. Subject is willing and able to return for all study visits, and is willing and able to comply with all protocol requirements and procedures. Subject is capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. 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 person administering the consent, a family member or legally acceptable representative. If the subject is unable to provide written informed consent due to visual impairment, then written informed consent on behalf of the subject must be provided by a legally acceptable representative. (Note: Consent by legally acceptable representative is allowed where this is in accordance with local laws, regulations and ethics committee policy.) Exclusion Criteria: 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. Intraocular surgery in the study eye within 3 months of dosing. Use of topical ocular medications (other than pazopanib) 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. 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). An unwillingness to refrain from wearing contact lenses starting from the screening visit, through the follow-up visit ALT or AST above the upper limit of normal or total bilirubin ≥ 1.5 times the upper limit of normal at baseline. Note: Laboratory tests outside of the normal range may be repeated at the discretion of the Investigator. Medical history or condition: Uncontrolled Diabetes Mellitus, with hemoglobin A1c (HbA1c) > 10%. Myocardial infarction or stroke within 6 months of screening. Active bleeding disorder. Major surgery within 1 month of screening. Hepatic impairment. Uncontrolled hypertension, based on criteria provided in the protocol. Note: Initiation or adjustment of antihypertensive medications is permitted prior to study entry provided the referenced criteria are met. Use of prohibited medications listed in the protocol within the restricted timeframe relative to the first dose of study medication. A condition or situation which, in the opinion of the investigator, may result in significant risk to the subject, 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 5 mg/ml TID<br>eligible participants received 5 mg/ml Pazopanib eye drops three times daily (TID) | Drug: Pazopanib<br>* 5 mg/ml TID, 2 mg/ml TID or 5 mg/ml QD<br>|
| Experimental: 2 mg/ml TID<br>eligible participants received 2 mg/ml Pazopanib eye drops three times daily | Drug: Pazopanib<br>* 5 mg/ml TID, 2 mg/ml TID or 5 mg/ml QD<br>|
| Experimental: 5 mg/ml QD<br>eligible participants received 5 mg/ml Pazopanib eye drops once daily (QD) | Drug: Pazopanib<br>* 5 mg/ml TID, 2 mg/ml TID or 5 mg/ml QD<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline (Day 1) in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Over Period | Change from Baseline is the value at indicated time point minus the Baseline value. Baseline measurement was recorded at Day 1. SBP and DBP were recorded from Baseline up to 6 months. At screening and Baseline, if the single measured value of blood pressure was above 150 millimeters of mercury (mm Hg) systolic or 95 mm Hg diastolic, then blood pressure measurement could not be repeated. If, the SBP was <80 or >140 mm Hg and DBP was <40 or >90 mm Hg, then measurement of BP was repeated. Three consecutive blood pressure readings that were less than 150 mmHg systolic and 95 mmHg diastolic were taken with each measurement separated by at least 1 hour. | Baseline (Day 1) and approximately up to 6 months | 
| Change From Baseline (Day 1) in Heart Rate Over Period | Heart rate was measured over 6 months. Baseline value was recorded on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value. Heart rate measurement were repeated in case it was in range < 50 beats per minute (bpm) or >110 bpm. | Baseline (Day 1) and approximately up to 6 months | 
| Change From Baseline (Day 1) in Albumin and Hemoglobin Over Period | Albumin and hemoglobin values were recorded at Baseline, Month2, and till follow-up (Month 6). Baseline was recorded on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value. | Baseline (Day 1), Month 2, 5 and approximately up to Month 6 | 
| Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferases (ALT), and Aspartate Aminotransferases (AST) Over Period | ALP, ALT and AST values were measured over 5 months and till the follow-up period. Baseline value was recorded pre-dose Day 1. Change from Baseline is the value at indicated time point minus the Baseline value. | Baseline (Day 1) and approximately up to 6 months | 
| Change From Baseline (Day 1) in Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets, and White Blood Cell Count Over Period | Change from Baseline is the value at indicated time point minus the Baseline value. Baseline measurement was recorded at Day 1. The above mentioned hematological parameters were recorded from Baseline up to 5 months. | Baseline (Day 1) and approximately up to 6 months | 
| Change From Baseline (Day 1) in Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Over Period | Change from Baseline is the value at indicated time point minus the Baseline value. Over here, the change is % Basophils at month x - % Basophils at Baseline. Baseline measurement was recorded at Day 1. Percentage change in the hematological parameter mentioned above was recorded from Baseline up to 5 months. | Baseline (Day 1) and approximately up to 6 months | 
| Change From Baseline (Day 1) in Direct Bilirubin, Total Bilirubin, and Creatinine Over Period | Change from Baseline is the value at indicated time point minus the Baseline value. Baseline measurement was recorded at Day 1. Direct bilirubin, total bilirubin, and creatinine were recorded from Baseline up to 6 months | Baseline (Day 1) and approximately up to 6 months | 
| Change From Baseline in Calcium, Chloride, Carbon di Oxide Equivalent Content, Glucose, Potassium, Sodium, and Urea Blood Urea Nitrogen (BUN) Over Period | Change from Baseline (Day 1) is the value at indicated time point minus the Baseline value. Baseline measurement was recorded at Day 1. Calcium, chloride, carbon di oxide equivalent content (CO2), glucose, potassium, sodium, and urea/blood urea nitrogen (BUN) was recorded from Baseline up to Follow-up. | Baseline (Day 1) and approximately up to 6 months | 
| Change From Baseline (Day 1) in Mean Corpuscular Volume (MCV) Over Period | Change from Baseline is the value at indicated time point minus the Baseline value. Baseline measurement was recorded at Day 1. MCV was recorded from Baseline up to Follow-up. | Baseline (Day 1) and approximately up to 6 months | 
| Change From Baseline (Day 1) in Intra-ocular Pressure Assessment Over Period | Change from Baseline is the value at indicated time point minus the Baseline value. Baseline measurement was recorded at Day 1. Intra-ocular pressure was recorded from Baseline up to Follow-up. | Baseline (Day 1) and approximately up to 6 months | 
| Number of Participants With Blood Occult, Urine Glucose, Urine Ketones, and Urine Proteins by Dip Stick Analysis | In this dipstick test, the level of blood occult and glucose, ketones, protein in urine samples were recorded as negative, trace, 1+, 2+, and 3+ (the plus sign increases with a higher level of glucose, ketones, or proteins in the urine: 1+=slightly positive, 2+=positive, 3+=high positive). | Approximately up to 6 months (up to follow-up) | 
| Number of Participants With Adverse Events (AEs)and Serious Adverse Events (SAEs) | Number of participants with ocular and non-ocular AEs and SAEs were separately recorded. An AE is an unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain time period after the study has ended. This change may or may not be caused by the intervention being studied. An SAE is an adverse event that results in death, is life-threatening, requires inpatient hospitalization or extends a current hospital stay, results in an ongoing or significant incapacity or interferes substantially with normal life functions, or causes a congenital anomaly or birth defect. Medical events that do not result in death, are not life-threatening, or do not require hospitalization may be considered serious adverse events if they put the participant in danger or require medical or surgical intervention to prevent one of the results listed above. | Approximately up to 6 months | 
| Number of Participants With Abnormal Visual Acuity of Potential Clinical Concern (PCI) | Visual acuity was measured over 5 months and also during follow-up period. Visual acuity was measured using standardized early treatment of diabetic retinopathy study (ETDRS) visual acuity charts. Visual acuity measurement was performed by an examiner that had been appropriately trained. Screening, Month 2 and Month 5 data were considered as Best Corrected Visual Acuity (BCVA) data. A loss of greater than or equal to 15 letters in BCVA from Baseline was considered of PCI. Data for number of participants who met the criteria for PCI have been presented. | Approximately up to 6 months | 
| Number of Participants With Abnormal Pupil Examination of PCI | Pupil abnormalities were of different types. Meibomian gland dysfunction was measured as obvious inspissation (debris). Mild injection, no trichiasis (lid thickening), or two step worsening was analyzed. Afferent pupillary defect, motility examination, PERRL, confrontation visual field was measured as a new definite abnormality. Left and right both eyes were examined. | Up to follow-up (approximately 6 months) | 
| Number of Participants With Abnormal Conjunctival Examination of PCI | A two step worsening in the conjunctival examination was considered a value of PCI. Participants were analyzed for conjunctival examination up to follow-up (6 months). | Up to follow-up (approximately 6 months) | 
| Number of Participants With Abnormal Anterior Chamber Examination of PCI | A two step worsening in the anterior chamber examination was considered a value of PCI. The participants were examined for any anterior chamber abnormality. Fibrinous response and obvious aqueous haze were considered abnormalities related to anterior chamber examination. | Approximately up to 6 months | 
| Number of Participants With Abnormal Corneal Examination of PCI | A two step change in any of the lens opacity categories was categorized as of PCI. Corneal epithelium was defined as abnormal when punctate keratopathy was measured as mild, moderate, severe; epithelial edema was measured as subtle epithelial haze, mild patchy microcystic changes, diffuse microcystic changes, and/or investigator determined abnormality. Stromal opacity/ edema was measured by investigator when stroma identifies opacity or edema. Corneal staining was measured as obvious (<=20) localized or diffuse punctate staining areas, severe localized or diffuse punctate staining. Participants were analyzed for any of the mentioned abnormality over 6 weeks (up to follow-up period). | Approximately up to 6 months | 
| Number of Participants With Abnormal Lens Opacity of PCI Using Age Related Eye Disease Study (AREDS) Scale | A two step change in any of the lens opacity categories was considered a value of PCI. Aphakia (surgical removal of lens) or pseudophakia was noted if any. Stroma opacity or edema was measured by investigator when it was detected as edema or opacity in stroma. | Approximately up to 6 months | 
| Number of Participants With Abnormal Tear Films of PCI | Tear film abnormalities were based on the clinical judgment of investigator. Tear film thickness was analyzed and it was reported whether the film was increased or decreased or was normal. Presence of debris or mucus was also reported. Other test were tear lake analysis and checking of discharge from eyes. | Approximately up to 6 months | 
| Number of Participants With Any Grade 2 Plus Worsening of Meibomian Gland Function | Meibomian gland dysfunction was measured as obvious insipisation/debris, mild injection, no trichiasis or lid thickening; inspisation, debris, obvious injection, lid thickening, may have trsichiasis; or a two step worsening. Any 2+ worsening of Meibomian gland function was considered a value of PCI. | Approximately up to 6 months | 
| Number of Participants With Abnormal (Dilated) Fundus Examination | Dilation of fundus was examined post dosing up to 6 months. Number of participants with abnormal change from Baseline indicating dilation of fundus of eye was reported. Change from Baseline was the value at indicated time point minus the Baseline value. The abnormalities were posterior vitreous separation, pale optic nerve, fluid in the posterior pole, drusen, thick arterio-venous changes, pigment changes, cystoids, macular edema, drying of posterior fluid or sub-retinal fluid, underlying central atrophy, and retinal pigment epithelial changes etc. Refraction measurement were determined at the screening and 2 month/5 month visits in order to determine BCVA. | Approximately up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline (Screening Visit) in BCVA at Month 2 and 5 | Change from Baseline in BCVA is the value at indicated time point minus the Baseline value. BCVA at screening visit was used as statistical Baseline. Only data before post-dose intravitreal injection of Avastin/ Lucentis (IVT) has been presented. Arithmetic mean was presented as data values; however statistical analysis is based on means of observed case (OC) data. The screening was used as a Baseline visit that was within or at 14 days of Day 1. Screening visit BCVA values were used to perform statistical comparison at month 2 and 5. | From Baseline (screening visit), Month 2, and Month 5 | 
| Change From Baseline (Screening Visit) in Optical Coherence Tomography (OCT) Central Subfield Over 5 Months | The OCT effect is a pharmacodynamics (PD) measure of daily repeated dosing of Pazopanib. The anatomic effects of pazopanib treatment were limited to investigator determined assessment of OCT central subfield retinal thickness due to heterogeneity of participant population and the low likelihood of utility of central reading center determination. The OCT equipment used was approved by central OTC reading center. OCT scans were collected at indicated time points and were evaluated by Investigator. Thus, grading of further secondary objectives was not performed as per the study team. Change from Baseline is the value at indicated time point minus the Baseline value. The screening was used as a Baseline visit that was within or at 14 days of Day 1. Screening visit BCVA values were used to perform statistical comparison at month 2 and 5. | From Baseline (Screening visit) and up to 5 months | 
| Change in Neo-vascular Size and Lesion Size Over Period | The analysis was planned to be performed up to 6 months; however, due to heterogeneity of the population and the low likelihood of the utility of the data, the anatomic effects of the pazopanib treatment in this treatment were limited to investigator determined assessment of OCT central subfield retinal thickness. Thus, the study team decided not to have DARC (central reading center) perform the grading for the secondary PD outcomes like lesion size and change with respect to time were not analyzed. Thus, data was not collected for this outcome measure. | Up to 6 weeks | 
| Number of Participants With Lesion Types Over Period | Number of participants with type of lesion were reported as determined by Investigator. Occult and minimally classic were the two types of lesions reported. | Up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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age-related macular degeneration (AMD), choroidal neovascularization (CNV), vascular endothelial growth factor (VEGF), pazopanib, angiogenesis