Clinical Study to Investigate Safety and Efficacy of GSK933776 in Adult Patients With Geographic Atrophy Secondary to 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 GSK933776 in the treatment of geographic atrophy secondary to age-related macular degeneration.

Detailed Description
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This is a Phase 2a proof of concept study designed to evaluate the safety and efficacy of GSK933776 for the treatment of geographic atrophy secondary to age-related macular degeneration. This is a placebo-controlled parallel-group study that is double masked.

Official Title
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A Phase 2, Multi-centre, Randomised, Double-masked, Placebo-controlled, Parallel-group Study to Investigate the Safety, Tolerability, Efficacy, Pharmacokinetics and Pharmacodynamics of GSK933776 in Adult Patients With Geographic Atrophy (GA) Secondary to Age-related Macular Degeneration (AMD)

Conditions
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Atrophy, Geographic

Intervention / Treatment
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* Drug: GSK933776
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients ≥55 years of age inclusive Evidence of AMD confirmed by the presence of at least 1 druse ≥125 μm diameter Well-demarcated GA due to AMD of total area 1.9-17 mm2 measured in the study eye Best-corrected visual acuity score of ≥ 35 letters (approximately 20/200 Snellen VA equivalent or better) in the study eye Exclusion Criteria: Additional eye disease in the study eye that could compromise assessment of best-corrected visual acuity or imaging of the posterior pole History of CNV secondary to AMD in the study eye Any previous treatment for AMD in the study eye, approved or investigational, with the exception of dietary supplements Risk of cerebrovascular disease, cerebral hemorrhage or stroke History of systemic autoimmune disease Use of platelet anti-aggregants or anti-coagulants (aspirin up to 325 mg/day is allowable, or in subjects allergic or intolerable to aspirin, clopidogrel up to 75 mg/day is allowable) Use of chronic corticosteroids Uncontrolled hypertension in spite of antihypertensive medications Renal or hepatic insufficiency or clinically significant anemia More than moderate MRI white matter changes

Ages Eligible for Study
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Minimum Age: 55 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: GSK933776 3 mg/kg<br>3 mg/kg administration of GSK933776 via intravenous infusion | Drug: GSK933776<br>* GSK933776<br>|
| Experimental: GSK933776 6 mg/kg<br>6 mg/kg administration of GSK933776 via intravenous infusion | Drug: GSK933776<br>* GSK933776<br>|
| Placebo Comparator: Placebo<br>Placebo via intravenous infusion | Drug: Placebo<br>* Placebo<br>|
| Experimental: GSK933776 15 mg/kg<br>15 mg/kg administration of GSK933776 via intravenous infusion | Drug: GSK933776<br>* GSK933776<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Area of Geographic Atrophy (GA) Assessed by Color Fundus Photographs (FP) in the Study Eye | Atrophic age-related macular degeneration (AMD) also called GA is characterized by thinning of the retinal pigment epithelium (RPE) and underlying choriocapillaris, as well as overlying photoreceptors in the macula. GA was evaluated by color FP at the indicated time points: screening, 6 months, 12 months and 18 months. Change from BL: (screening, month 6, 12 or 18 value minus BL value. Note screening occurs prior to BL). Only participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Efficacy Population: all participants in the Intent-to-Treat (ITT) Population who met the protocol defined inclusion criterion for area of GA assessed by color FP in the study eye in at least one visit from screening visit through BL visit, inclusive and had data of area of GA assessed by fundus autofluorescence images in the study eye for at least 75% of the visits (>=14 visits) from post-BL treatment month 2 visit to treatment month 19 visit. | Baseline (BL), 6 months, 12 months and 18 months | 
| Number of Participants With Ocular or Non-ocular Adverse Events (AEs) During the Treatment Period | An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. It includes:1. Any abnormal laboratory test results or other safety assessments including those that worsen from Baseline, and felt to be clinically significant in the medical and scientific judgment of the Investigator 2.Exacerbation (increase in frequency/intensity) of a chronic or intermittent pre-existing condition 3. New conditions detected or diagnosed after screening visit 4. Signs, symptoms, or the clinical sequelae of a suspected interaction/suspected overdose of investigational product or a concomitant medication. AEs were presented as non-ocular and ocular AEs. | Up to 21 months | 
| Number of Participants With Ocular or Non-ocular Serious Adverse Events (SAEs) During the Treatment Period |  | Up to 21 months | 
| Number of Participants With Vital Signs of Potential Clinical Importance (PCI) During the Treatment Period: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Vital signs included SBP and DBP of Potential Clinical Importance (PCI) at the indicated time points: Baseline, month 0, month 1, month 2, month 3, month 4, month 5, month 6, month 7, month 8, month 9, month 10, month 11, month 12, month 13, month 14, month 15, month 16, month 17, month 18, early withdrawal and at follow-up visit in sitting position. 'General' is an assessment time not relative to dosing. SBP was defined as: low: <85 millimeter of mercury (mmHg) and high: >160 mmHg and DBP was defined as: low:<45 mmHg and high: >100 mmHg. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Only categories with at least one PCI value are presented. | Up to 21 months | 
| Number of Participants With Vital Signs of Potential Clinical Importance (PCI) During the Treatment Period: Heart Rate (HR) | Vital signs included HR of CCR at the indicated time points: Baseline, Month 0, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 7, Month 8, Month 9, Month 10, Month 11, Month 12, Month 13, Month 14, Month 15, Month 16, Month 17, Month 18, early withdrawal and at follow-up visit in sitting position. 'General' is an assessment time not relative to dosing. HR was defined as: low:< 40 beats per minute (bpm) and high: >100 bpm. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Only categories with at least one PCI value are presented. | Baseline, Month 0, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 7, Month 8, Month 9, Month 10, Month 11, Month 12, Month 13, Month 14, Month 15, Month 16, Month 17, Month 18, early withdrawal and at follow-up visit | 
| Number of Participants With 12-lead Electrocardiogram (ECG) of Potential Clinical Importance (PCI) | 12-lead ECG was obtained after 10 minutes rest in a supine position using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT interval corrected using the Fridericia's formula (QTcF). Abnormal-clinically significant (CS) ECG measurements are presented at indicated time points: Baseline, Month 6, Month 12, Month 18, early withdrawal and at follow-up visit. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline, Month 6, Month 12, Month 18, early withdrawal and at follow-up visit | 
| Number of Participants With Abnormal Laboratory Parameter Values of Potential Clinical Importance (PCI) | The following laboratory parameters were assessed: Hematology: Platelet Count, Red Blood Cell Count, White Blood Cell (WBC) Count, Reticulocyte Count, Hemoglobin, Hematocrit, Prothrombin time-International Normalized Ratio, Activated partial thromboplastin time, Mean corpuscular volume, Mean corpuscular haemoglobin, Mean corpuscular hemoglobin concentration, Neutrophils (ANC), Lymphocytes, Monocytes, Eosinophils, and Basophils. Clinical chemistry: Blood urea nitrogen, Potassium, Aspartate aminotransferase, Total and direct bilirubin Creatinine, Chloride, Alanine aminotransferase, Uric Acid, Glucose (fasting), Total Carbon dioxide , Gamma glutamyltransferase, Albumin, Sodium, Calcium, Alkaline phosphatase, Total Protein, and HbA1c. Urine: Specific gravity, pH, glucose, protein, blood and ketones and Microscopic examination. Only those with PCIs are displayed. | At any point from Baseline through follow-up visit. | 
| Number of Participants With Abnormal Magnetic Resonance Imaging (MRI) | Magnetic Resonance Imaging (MRI) was used as a safety assessment to monitor for amyloid related imaging abnormalities (ARIA) events in the brain. MRIs were performed at Baseline and before dose 2, before dose 3, before dose 4, before dose 6, before dose 12, before dose 18 and at follow-up. ARIA-edema/effusions (ARIA-E) and ARIA hemosiderin deposition (ARIA-H) events at any visit are reported. | Month 2, Month 3, Month 4, Month 6, Month 12, Month 18 and at early withdrawal | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Area of GA Assessed by Fundus Autofluorescence Images (hypoAF) Corresponding to GA in Study Eye | Atrophic AMD also called as GA is characterized by thinning of the retinal pigment epithelium (RPE) and underlying choriocapillaris, as well as overlying photoreceptors in the macula. GA was evaluated by fundus autofluorescence images in the study eye at the indicated time points: screening, 6 months, 12 months and at 18 months. Change from Baseline: (months 6, 12,18 value minus Baseline value, respectively. Note screening occurs before baseline). Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline, 6 months, 12 months and 18 months | 
| Change From Baseline in Area of Total hypoAF in Study Eye | Atrophic AMD also called as GA is characterized by thinning of the retinal pigment epithelium (RPE) and underlying choriocapillaris, as well as overlying photoreceptors in the macula. GA was evaluated by fundus autofluorescence at the indicated time points: screening, 6 months, 12 months and at 18 months. Change from Baseline: (Month 6, 12, 18 value minus Baseline value, respectively. Note screening occurs before baseline). Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline, 6 months, 12 months and 18 months | 
| Number of Participants Losing Letters in Early Treatment Diabetic Retinopathy Study (ETDRS)-Best Corrected Visual Acuity (BCVA) Score at Month 12 and Month 18 for Each Eye | Participants enrolled into the study were required to have a best-corrected ETDRS visual acuity score of at least 35 letters as determined by ETDRS-BCVA evaluation. ETDRS-BCVA score was assessed at the indiated time points at: Month 12 and Month 18 with categorical changes in the number of participants losing >30, >=15, >=10, >=5 and <5 letters. | Month 12 and Month 18 | 
| Mean Change in ETDRS-BCVA Score From Baseline at Every Month up to Month 18 | Participants enrolled into the study were required to have a best-corrected ETDRS visual acuity score of at least 35 letters as determined by ETDRS-BCVA evaluation. ETDRS-BCVA score was assessed as change from baseline in the mean best-corrected ETDRS visual acuity score at 18 months. Change from Baseline is defined as post-dose visit value minus Baseline value. Note that screening occurs before baseline. Values were truncated to one decimal place and negative sign retained where value is negative and the truncated value is zero. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline and every month up to Month 18 | 
| Area Under the Plasma Concentration-time Curve From Time 0 to the End of Dosing Interval at Steady-state (AUC0-28d) of GSK933776 in Geographic Atrophy Participants | Area under the plasma concentration-time curve from time 0 to the end of dosing interval at steady-state; derived from dose and clearance parameters was evaluated. Blood samples were collected at the indicated time points on Day 56, Day 63, 70 or 77, Day 84, Day 112, Day 140, Day 224, Day 308, Day 392 and Day 476. | Day 56, Day 63, 70 or 77, Day 84, Day 112, Day 140, Day 224, Day 308, Day 392 and Day 476 | 
| Maximum Observed Plasma Concentration (Cmax) and Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ctau) of GSK933776 in Geographic Atrophy Participants | Blood samples were collected at the indicated time points on Day 56, Day 63, 70 or 77, Day 84, Day 112, Day 140, Day 224, Day 308, Day 392 and Day 476 | Day 56, Day 63, 70 or 77, Day 84, Day 112, Day 140, Day 224, Day 308, Day 392 and Day 476 | 
| Clearance (CL) of GSK933776 in Geographic Atrophy Participants | Blood samples were collected at the indicated time points on Day 56, Day 63, 70 or 77, Day 84, Day 112, Day 140, Day 224, Day 308, Day 392 and Day 476. | Day 56, Day 63, 70 or 77, Day 84, Day 112, Day 140, Day 224, Day 308, Day 392 and Day 476 | 
| Estimation of Terminal Phase Half-life (T1/2) of GSK933776 in Geographic Atrophy Participants | Blood samples were collected at the indicated time points on Day 56, Day 63, 70 or 77, Day 84, Day 112, Day 140, Day 224, Day 308, Day 392 and Day 476. | Day 56, Day 63, 70 or 77, Day 84, Day 112, Day 140, Day 224, Day 308, Day 392 and Day 476 | 
| Volume of Distribution at Steady-state (Vdss) of GSK933776 in Geographic Atrophy Participants Estimated From Population PK Modeling | Blood samples were collected at the indicated time points on Day 56, Day 63, 70 or 77, Day 84, Day 112, Day 140, Day 224, Day 308, Day 392 and Day 476. | Day 56, Day 63, 70 or 77, Day 84, Day 112, Day 140, Day 224, Day 308, Day 392 and Day 476 | 
| The Pharmacodynamic Effects of GSK933776 Total (Bound and Unbound) Plasma Total Amyloid Beta (Abeta42), and Amyloid Beta Fragments (Abeta18-35), if Possible, Unbound Plasma Aβ Fragments (Abeta1-22) | Blood samples were collected at the indicated time points on Baseline, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15 and Month 18. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15 and Month 18 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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age-related macular degeneration, geographic atrophy, dry AMD