Dose Ranging Study of Pazopanib to Treat Neovascular Age-Related Macular Degeneration

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and efficacy of different dosage regimens of pazopanib eye drops for the treatment of neovascular age-related macular degeneration.

Detailed Description
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MD7110852 is a Phase 2b dose-ranging study designed to demonstrate the 1 year efficacy and safety of pazopanib eye drops for the treatment of neovascular age related macular degeneration (AMD) in subjects whose disease is currently managed with anti-VEGF (vascular endothelial growth factor) injection therapy. Eye drop regimens are double-masked with placebo eye drops and will have access to open-label ranibizumab intravitreal (IVT) injection if needed. The ranibizumab IVT injection every 4 weeks control arm is open-label.

Official Title
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MD7110852, A Phase 2b Dose-Ranging Study of Pazopanib Eye Drops Versus Ranibizumab Intravitreal Injections for the Treatment of Neovascular Age-Related Macular Degeneration

Conditions
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Macular Degeneration

Intervention / Treatment
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* Drug: pazopanib eye drops
* Drug: placebo
* Biological: ranibizumab intravitreal injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged ≥50 years. Active subfoveal choroidal neovascularization (CNV) lesion secondary to AMD in study eye: Total lesion area ≤12 disc areas with CNV ≥50% total lesion area. Anti-Vascular endothelial growth factor (VEGF) intravitreal injection experienced and in need of re-treatment. Best-corrected visual acuity of at least 24 letters (equates to approximately 20/320 Snellen equivalents or better). Exclusion Criteria: Prior ocular investigational drug/device for choroidal neovascularization, photodynamic therapy, radiation, subfoveal or juxtafoveal focal laser photocoagulation. Prior failure to anti-VEGF intravitreal injection therapy. Recent ocular investigational drug/device for non-CNV condition. Prior ocular surgeries (vitrectomy, scleral buckle, or glaucoma filtering/shunt surgery). Cataract surgery permitted if ≥3 months and has posterior chamber intraocular lens. Center-fovea involvement of any of the following: fibrosis, atrophy, serous retinal pigment epithelial detachment, or retinal pigment epithelial tear. CNV in either eye due to other causes. Clinical evidence of diabetic retinopathy or diabetic macular edema. Recent myocardial infarction or cerebrovascular accident. Uncontrolled hypertension in spite of antihypertensive medications.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: investigational arm 1<br>5 mg/mL pazopanib eye drops TID with allowance for as-needed ranibizumab injection | Drug: pazopanib eye drops<br>* A tyrosine kinase inhibitor of multiple receptors including vascular endothelial growth factor receptors and platelet-derived growth factor receptors.<br>|
| Experimental: investigational arm 2<br>5 mg/mL pazopanib eye drops QID with allowance for as-needed ranibizumab injection | Drug: pazopanib eye drops<br>* A tyrosine kinase inhibitor of multiple receptors including vascular endothelial growth factor receptors and platelet-derived growth factor receptors.<br>|
| Experimental: investigational arm 3<br>10 mg/mL pazopanib eye drops BID with allowance for as-needed ranibizumab injection | Drug: pazopanib eye drops<br>* A tyrosine kinase inhibitor of multiple receptors including vascular endothelial growth factor receptors and platelet-derived growth factor receptors.<br>|
| Experimental: investigational arm 4<br>10 mg/mL pazopanib eye drops TID with allowance for as-needed ranibizumab injection | Drug: pazopanib eye drops<br>* A tyrosine kinase inhibitor of multiple receptors including vascular endothelial growth factor receptors and platelet-derived growth factor receptors.<br>|
| Experimental: investigational arm 5<br>10 mg/mL pazopanib eye drops QID with allowance for as-needed ranibizumab injection | Drug: pazopanib eye drops<br>* A tyrosine kinase inhibitor of multiple receptors including vascular endothelial growth factor receptors and platelet-derived growth factor receptors.<br>|
| Placebo Comparator: placebo control arm<br>Placebo eye drops QID with allowance for as-needed ranibizumab injection | Drug: placebo<br>* placebo eye drops<br>|
| Active Comparator: active open-label control arm<br>Ranibizumab intravitreal injection every 4 weeks | Biological: ranibizumab intravitreal injection<br>* Humanized recombinant monoclonal antibody fragment targeted against human vascular endothelial growth factor A<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Best-corrected Visual Acuity (BCVA) as Measured by the Number of Letters Read on the Early Treatment of Diabetic Retinopathy Study (ETDRS) Grading Charts at a Starting Distance of 4 Meters at Week 52 | BCVA was measured in the study eye using the ETDRS grading charts starting at a test distance of 4 meters. The ETDRS grading chart was of at least 24 to 78 letters. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. There were seven cut off points in change from baseline visual acuity on ETDRS grading chart which are, 15 to 29, 10 to 14, 5 to 9, -4 to 4, -5 to -9, -10 to -14 and -15 to -29 letters. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. If either the baseline or post-randomization value was missing, the change from baseline was set to missing as well. Day 1 values are considered as Baseline in this study. | Day 1 and 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Ranibizumab Re-injections Received Over 28 and 52 Weeks | The investigator interpreted each Week 4 to Week 52 Optical coherence tomography (OCT) scan, BCVA score, and available Fluorescein angiography (FA)/Fundus photography (FP) and re-injected if one or more criteria were met. The criteria were: Evidence of Intraretinal (IR) (with or without cysts) fluid or Subretinal (SR) fluid, a serous retinal pigment epithelial detachment, a notable decline in Visual Acuity, new SR or IR macular hemorrhage that the investigator judges is associated with Choroidal neovascularization, increased lesion size on FA relative to the last angiogram as judged by the investigator or leakage on FA that the investigator judges would benefit from re-injection. Injection rate over 52 weeks was computed by taking the number of injections received divided by the number of visits for the participant. Likewise for 28 weeks it was estimated as the number of post baseline injections received divided by the number of post baseline visits at or before the week 28 visit. | Up to 52 weeks | 
| Number of Participants With BCVA Over Time | BCVA was measured in the study eye using the ETDRS grading charts starting at a test distance of 4 meters. The ETDRS grading chart was of at least 24 to 78 letters. There were seven cut off points in change from baseline visual acuity on ETDRS grading chart which are, 15 to 29, 10 to 14, 5 to 9, -4 to 4, -5 to -9, -10 to -14 and -15 to -29 letters. | Up to Week 52 | 
| Number of Participants Analyzed for Visual Acuity (VA) Response Over Time | VA was measured in the study eye using the ETDRS grading charts starting at a test distance of 4 meters.The ETDRS grading chart was of at least 24 to 78 letters. There were seven cut off points in change from baseline visual acuity on ETDRS grading chart which are, 15 to 29, 10 to 14, 5 to 9, -4 to 4, -5 to -9, -10 to -14 and -15 to -29 letters. This outcome measure contains the number of participants who were analyzed for VA response. | Week 52 | 
| Change From Baseline in Center Point Thickness (CPT) Over Time | CPT was the inner limiting membrane to the beginning of the retinal pigment epithelium (RPE) inclusive of SR fluid. The outer boundary included the outer segment of the photoreceptors and not included the RPE. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. If either the baseline or post-randomization value was missing, the change from baseline was set to missing as well. Day 1 values are considered as Baseline in this study. In amendment 3, inclusion criterion number 5 was revised to remove the required quantitative OCT component. OCT examination was used to supplement FA findings and provided qualitative (presence of SR and/or IR fluid) and quantitative (a CPT that is at least 250 microns) evidence of an active subfoveal lesion. Hence data for pre and post amendment have been provided separately. | Baseline and Week 52 | 
| Number of Participants That Met Criteria for Re-injection | The investigator interpreted each Week 4 to Week 52 Optical coherence tomography (OCT) scan, BCVA score, and available Fluorescein angiography (FA)/Fundus photography (FP) and re-injected if one or more criteria were met. The criteria were: Evidence of Intraretinal (IR) (with or without cysts) fluid or Subretinal (SR) fluid, a serous retinal pigment epithelial detachment, a notable decline in Visual Acuity, new SR or IR macular hemorrhage that the investigator judges is associated with Choroidal neovascularization, increased lesion size on FA relative to the last angiogram as judged by the investigator or leakage on FA that the investigator judges would benefit from re-injection. | Up to Week 52 | 
| Change From Baseline in the Area of Choroidal Neovascularisation (CNV) | Choroidal neovascularisation is progressive worsening of vision that can cause hemorrhage and exudation, and finally disciform scarring and retinal atrophy. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. If either the baseline or post-randomization value was missing, the change from baseline was set to missing as well. Day 1 values are considered as Baseline in this study. | Day 1, Week 28 and Week 52 | 
| Change From Baseline in the Area of the CNV Lesion Complex (i.e. CNV, Blood, PED, and Fibrosis) | CNV is progressive worsening of vision that can cause hemorrhage and exudation, and finally disciform scarring and retinal atrophy. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. If either the baseline or post-randomization value was missing, the change from baseline was set to missing as well. Day 1 values are considered as Baseline in this study. | Day 1, Week 28 and Week 52 | 
| Change From Baseline in the Area of Fluorescein Leakage | Fluorescein angiograms was performed at the Screening, Week 12, Week 28, and Week 52 Visits. All images, including any that were performed at the investigator's medical discretion, were transferred to the FPRC. Fluorescein was injected intravenously according to usual clinic procedures. Dose response was also examined under different aspects of re-injection, such as time to first injection, the percentage of participants that required an injection by Week 28, as well as the estimation of the probability of reinjection. FA assessments of area of fluorescein leakage, CNV area and area of CNV lesion complex were also examined for dose differentiation. | Day 1, Week 28 and Week 52 | 
| Change in Area of Serous Sensory Retinal Detachment (SSRD) | This is an Optical coherence tomography (OCT) parameter used to manually measure thickness along any scan. OCT was performed at week 28 and week 52. | Day 1, Week 28 and Week 52 | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is 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 SAE is 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, or is a congenital anomaly/birth defect. | Up to 52 Weeks | 
| Summary of Potentially Clinically Important Findings for Ophthalmic Examinations | Opthalmicexaminations were done on Ocular alignment and motility, pupillary function, and visual fields by confrontation. Slit-lamp biomicroscopic examination of the anterior segment structure was performed. Fundus slit-lamp biomicroscopic examination, including use of accessory diagnostic lenses, to view the vitreous, retina (including posterior pole and periphery), macula, vasculature, and optic nerve was also performed. These examinations were performed on the study eye (SE) and the Fellow eye (FE). Participants with abnormal findings are listed here. | Up to Week 52 | 
| Summary of Intraocular Pressure Exam Findings | Intraocular pressure (IOP) measurement was done with Goldmann tonometer. Intraocular pressure was measured prior to dilating the pupil and, to account for diurnal variation, at approximately the same time of day for every visit. | Up to week 52 | 
| Number of Participants With Vital Sign Values Outside of Clinical Concern Range | Vital signs including systolic and diastolic blood pressure and heart rate were measured throughout the study. Number of participants with vital signs outside of clinical concern Range were summarized. 'High' denotes above normal range and 'Low' denotes below normal range for all the categories. The potential clinical importance ranges (low and high) of the vital sign parameters were for systolic blood pressure (<85 and >160 millimeter of mercury [mmHg]), diastolic blood pressure (<45 and >100 mmHg) and 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 vital parameter findings at any visit were reported. | Up to Week 52 | 
| Summary of Abnormal Electrocardiogram (ECG) Findings | 12-Lead ECGs were performed in triplicate and were obtained on Weeks 4 to Week 28 and Week 52. The on-treatment ECGs were used to ascertain any risk of QTc interval prolongation at extremely low pazopanib exposures compared to what was routinely observed in participants with cancer. The on-treatment ECG data collected from participants assigned to one of the control arms also provided ECG background rate data for participants not exposed to pazopanib. Participants with Clinically significant abnormal ECGs are included here. | Week 4, Week 28, Week 44 and Week 52 | 
| Summary of Hematology and Clinical Chemistry Parameters Data of Clinical Concern | The Laboratory Parameters included Alanine Amino Transferase (ALT), Albumin, Alkaline Phosphatase, Aspartate Amino Transferase (AST), Calcium, Bicarbonate, Creatinine, Glucose, Hemoglobin, Lymphocytes, Platelet count, Potassium, Sodium, Thyroid Stimulating Hormone (TSH), Total Bilirubin, Total Neutrophils, Blood Urea Nitrogen (BUN) and White Blood Cell count (WBC). Number of participants with Laboratory outside of clinical concern Range were summarized here. Data of high and low from the clinical concern range has been provided here. Here 'High' denotes above normal range and 'Low' denotes below normal range for all the categories. | Up to Week 52 | 
| Number of Participants With Laboratory Data of Clinical Concern for Urine Protein | Urine Samples were collected from Day 1 to Week 28 and Week 52 for analyses. In this dipstick test, the level of protein in urine samples was recorded as negative (Neg), trace (tr), 1+, 2+, and 3+ (the plus sign increases with a higher level of proteins in the urine: 1+=slightly positive, 2+=positive, 3+=high positive). Neg indicated no proteinuria and 3+(high positive) indicated worst proteinuria. | Day 1 to Week 28 and Week 52 | 
| Plasma Concentrations of Pazopanib | All participants in the eye drop containing arms had a single blood sample drawn for assessment of pazopanib plasma concentration at the Week 4, Week 24 and Week 24. The sample was drawn without restriction for the time interval between blood draw and the last dose of IP eye drops. | Week 4, Week 24 and Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ranibizumab, wet AMD, MD7110852, age related macular degeneration, age-related macular degeneration, macular degeneration, pazopanib