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)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 191
- 试验地点
- 1
- 主要终点
- Change From Baseline in the Area of Geographic Atrophy (GA) Assessed by Color Fundus Photographs (FP) in the Study Eye
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 55 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
GSK933776 3 mg/kg
3 mg/kg administration of GSK933776 via intravenous infusion
干预措施: GSK933776 (Drug)
GSK933776 6 mg/kg
6 mg/kg administration of GSK933776 via intravenous infusion
干预措施: GSK933776 (Drug)
Placebo
Placebo via intravenous infusion
干预措施: Placebo (Drug)
GSK933776 15 mg/kg
15 mg/kg administration of GSK933776 via intravenous infusion
干预措施: GSK933776 (Drug)
结局指标
主要结局
Change From Baseline in the Area of Geographic Atrophy (GA) Assessed by Color Fundus Photographs (FP) in the Study Eye
时间窗: Baseline (BL), 6 months, 12 months and 18 months
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.
Number of Participants With Vital Signs of Potential Clinical Importance (PCI) During the Treatment Period: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
时间窗: Up to 21 months
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.
Number of Participants With Ocular or Non-ocular Adverse Events (AEs) During the Treatment Period
时间窗: Up to 21 months
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.
Number of Participants With Vital Signs of Potential Clinical Importance (PCI) During the Treatment Period: Heart Rate (HR)
时间窗: 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
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.
Number of Participants With Ocular or Non-ocular Serious Adverse Events (SAEs) During the Treatment Period
时间窗: Up to 21 months
Number of Participants With Abnormal Laboratory Parameter Values of Potential Clinical Importance (PCI)
时间窗: At any point from Baseline through follow-up visit.
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.
Number of Participants With 12-lead Electrocardiogram (ECG) of Potential Clinical Importance (PCI)
时间窗: Baseline, Month 6, Month 12, Month 18, early withdrawal and at follow-up visit
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).
Number of Participants With Abnormal Magnetic Resonance Imaging (MRI)
时间窗: Month 2, Month 3, Month 4, Month 6, Month 12, Month 18 and at early withdrawal
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.
次要结局
- Clearance (CL) of GSK933776 in Geographic Atrophy Participants(Day 56, Day 63, 70 or 77, Day 84, Day 112, Day 140, Day 224, Day 308, Day 392 and Day 476)
- Change From Baseline in Area of GA Assessed by Fundus Autofluorescence Images (hypoAF) Corresponding to GA in Study Eye(Baseline, 6 months, 12 months and 18 months)
- Estimation of Terminal Phase Half-life (T1/2) of GSK933776 in Geographic Atrophy Participants(Day 56, Day 63, 70 or 77, Day 84, Day 112, Day 140, Day 224, Day 308, Day 392 and Day 476)
- Change From Baseline in Area of Total hypoAF in Study Eye(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(Month 12 and Month 18)
- Mean Change in ETDRS-BCVA Score From Baseline at Every Month up to Month 18(Baseline and every month up to Month 18)
- Maximum Observed Plasma Concentration (Cmax) and Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ctau) of GSK933776 in Geographic Atrophy Participants(Day 56, Day 63, 70 or 77, Day 84, Day 112, Day 140, Day 224, Day 308, Day 392 and Day 476)
- 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(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)(Baseline, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15 and Month 18)
- Volume of Distribution at Steady-state (Vdss) of GSK933776 in Geographic Atrophy Participants Estimated From Population PK Modeling(Day 56, Day 63, 70 or 77, Day 84, Day 112, Day 140, Day 224, Day 308, Day 392 and Day 476)