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临床试验/NCT03481660
NCT03481660已完成3 期

A Two-Year, Two-Arm, Randomized, Double Masked, Multicenter, Phase III Study Assessing the Efficacy and Safety of Brolucizumab Versus Aflibercept in Adult Patients With Visual Impairment Due to Diabetic Macular Edema

Novartis Pharmaceuticals1 个研究点 分布在 1 个国家目标入组 360 人开始时间: 2018年7月27日最近更新:
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适应症
干预措施
相关药物

试验速览

阶段
3 期
状态
已完成
入组人数
360
试验地点
1
主要终点
Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) at Week 52 for the Study Eye
研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

This was a Phase III, randomized, double-masked, multi-center, active-controlled, two-arm study designed to evaluate the efficacy and safety of brolucizumab 6 mg compared to the active control, aflibercept 2 mg used per authorized label, in subjects with visual impairment due to diabetic macular edema (DME).

详细描述

The study included a screening period of up to 2 weeks to assess eligibility, followed by a double-masked treatment period (Day 1 to Week 96). The baseline visit was defined as Day 1/Visit 1, and end of treatment visit as Visit 27 (Week 96). After the last treatment visit, there was a post-treatment follow-up period from Week 96 to Week 100 and an exit visit at Week 100. Subjects were assigned to one of two treatment arms in a 1:1 ratio: brolucizumab 6 mg/0.05 mL (5 loading doses each administered every 6 weeks (q6w) during loading phase then q12w/q8w during maintenance phase with an option to extend treatment interval by 4 weeks during the second year) or aflibercept 2 mg/0.05 mL (5 loading doses each administered every 4 weeks (q4w) during loading phase then q8w during maintenance phase).

Disease activity assessments (DAAs) were conducted by the masked investigator for both treatment arms at Week 32 and Week 36, i.e., 8 and 12 weeks after the end of the loading phase for subjects receiving brolucizumab, and at Week 48, Week 60 and Week 72 (i.e., every 12 weeks). In the brolucizumab arm, subjects who qualified for q12w during this initial q12w interval continued on a q12w treatment frequency unless disease activity was identified at any of the subsequent DAA visits, in which case subjects were switched to a q8w treatment interval until Week 72.

A one-time disease stability assessment was performed by the masked investigator at Week 72 in both treatment arms with the purpose of evaluating the potential for treatment interval extension by 4 weeks. The subjects in the brolucizumab arm who demonstrated disease stability in the one-time assessment at Week 72 under their current assigned treatment regimen (q12w or q8w) were considered for treatment interval extension. To evaluate the adequacy of the individualized q8w, q12w or q16w treatment intervals in the brolucizumab arm, DAAs were performed at every visit from Week 72 up to and including Week 96 (i.e., every 4 weeks) and subjects had their treatment interval modified accordingly. If after Week 72 disease activity had been identified by the masked investigator at a scheduled treatment visit (according to the subject specific treatment schedule q12w or q16w) the subject was assigned to q8w treatment schedule.

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
Double (Participant, Investigator)

入排标准

年龄范围
18 Years 至 —（Adult, Older Adult）
性别
All
接受健康志愿者
否

入选标准

  • •Patients must give written informed consent before any study related assessments are performed
  • •Patients with type 1 or type 2 diabetes mellitus and HbA1c of =< 10% at screening
  • •Medication for the management of diabetes must have been stable within 3 months prior to randomization and is expected to remain stable during the course of the study
  • •Visual impairment due to DME with:
  • •BCVA score between 78 and 23 letters, inclusive, using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at a testing distance of 4 meters (approximate Snellen equivalent of 20/32 to 20/320), at screening and baseline
  • •DME involving the center of the macula, with central subfield retinal thickness (measured from RPE to ILM inclusively) of >= 320 micrometers (μm) on SD-OCT at screening If both eyes are eligible, the eye with the worse visual acuity will be selected for study eye. However, the investigator may select the eye with better visual acuity, based on medical reasons or local ethical requirements.

排除标准

  • •Previous treatment with any anti-VEGF drugs or investigational drugs in the study eye
  • •Active proliferative diabetic retinopathy in the study eye as per the investigator
  • •Concomitant conditions or ocular disorders in the study eye at screening or baseline which could, in the opinion of the investigator, prevent response to study treatment or may confound interpretation of study results, compromise visual acuity or require medical or surgical intervention during the first 12-month study period (e.g., cataract, vitreous hemorrhage, retinal vascular occlusion, retinal detachment, macular hole, or choroidal neovascularization of any cause)
  • •Any active intraocular or periocular infection or active intraocular inflammation (e.g., infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis, uveitis) in study eye at screening or baseline
  • •Structural damage of the fovea in the study eye at screening likely to preclude improvement in visual acuity following the resolution of macular edema, including atrophy of the retinal pigment epithelium, subretinal fibrosis, laser scar(s), epiretinal membrane involving fovea or organized hard exudate plaques
  • •Uncontrolled glaucoma in the study eye defined as intraocular pressure (IOP) > 25 millimeters mercury (mmHg) on medication or according to investigator's judgment, at screening or baseline
  • •Neovascularization of the iris in the study eye at screening or baseline
  • •Evidence of vitreomacular traction in the study eye at screening or baseline which, in the opinion of the investigator, affect visual acuity

研究组 & 干预措施

Brolucizumab 6 mg

Experimental

Brolucizumab 6 mg/0.05 mL, 5 loading doses, with subsequent doses per protocol-specified maintenance schedule

干预措施: Brolucizumab (Drug)

Aflibercept 2 mg

Active Comparator

Aflibercept 2 mg/0.05 mL, as labeled, 5 loading doses, with subsequent doses every 8 weeks

干预措施: Aflibercept (Drug)

结局指标

主要结局

Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) at Week 52 for the Study Eye

时间窗: Baseline, Week 52

Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 4 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. The overall BCVA score (number of letters read correctly by the patient) was calculated using the BCVA worksheet 0-100 letter score, with higher score indicating improvement in acuity. A positive change from baseline is a favorable outcome. BCVA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

次要结局

  • Average Mean Change From Baseline in BCVA Over the Period Week 40 Through Week 52 for the Study Eye(Baseline, period Week 40 through Week 52)
  • (Brolucizumab Treatment Arm Only): Percentage of Participants Maintained at q12w up to Week 52 and up to q12w/q16w up to Week 100.(Week 52, Week 100)
  • (Brolucizumab Treatment Arm Only): Percentage of Participants Maintained at q12w up to Week 52 Within Those Patients That Qualified for q12w at Week 36(Week 36, Week 52)
  • (Brolucizumab Treatment Arm Only): Percentage of Participants Maintained at q12w/q16w up to Week 100, Within Those Patients That Qualified for q12w at Week 36(Week 36, Week 100)
  • (Brolucizumab Treatment Arm Only): Percentage of Participants Maintained on q16w up to Week 100 Within the Patients on q12w at Week 68 and on q16w at Week 76(Week 68, Week 76, Week 100)
  • (Brolucizumab Treatment Arm Only): Percentage of Participants Re-assigned and Maintained on q12w up to Week 100 Within the Patients on q8w at Week 68 and on q12w at Week 80(Week 68, Week 80, Week 100)
  • Average Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Over the Period Week 20 to Week 52/100 and Week 28 to Week 52/100 for the Study Eye(Baseline, period Week 20 through Week 52, period Week 20 through Week 100, period Week 28 through Week 52, period Week 28 through Week 100)
  • Average Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Over the Period Week 88 to 100 for the Study Eye(Baseline, period Week 88 through Week 100)
  • (Brolucizumab Treatment Arm Only): Number of Participants With Injections Per Planned Dosing Regimen (Every 8, 12 or 16 Weeks)(Week 100)
  • Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Each Visit up to Week 100 for the Study Eye(Baseline, Week 4, Week 6, Week 8, Week 12, Week 16, Week 18, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, Week 52, Week 56, Week 60, Week 64, Week 68, Week 72, Week 76, Week 80, Week 84, Week 88, Week 92, Week 96, Week 100)
  • Average Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Over the Period Week 4 to Week 52/100 for the Study Eye(Baseline, period Week 4 through Week 52, period Week 4 through Week 100)
  • Percentage of Participants Who Gained >= 5 Letters in BCVA From Baseline or Reached BCVA >= 84 Letters at Each Post-baseline Visit for the Study Eye(Baseline, Week 4, Week 6, Week 8, Week 12, Week 16, Week 18, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, Week 52, Week 56, Week 60, Week 64, Week 68, Week 72, Week 76, Week 80, Week 84, Week 88, Week 92, Week 96, Week 100)
  • Percentage of Participants Who Gained >= 10 Letters in BCVA From Baseline or Reached BCVA >= 84 Letters at Each Post-baseline Visit for the Study Eye(Baseline, Week 4, Week 6, Week 8, Week 12, Week 16, Week 18, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, Week 52, Week 56, Week 60, Week 64, Week 68, Week 72, Week 76, Week 80, Week 84, Week 88, Week 92, Week 96, Week 100)
  • Percentage of Participants Who Lost >= 10 ETDRS Letters in Best Corrected Visual Acuity (BCVA) From Baseline at Each Post-baseline Visit for the Study Eye(Baseline, Week 4, Week 6, Week 8, Week 12, Week 16, Week 18, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, Week 52, Week 56, Week 60, Week 64, Week 68, Week 72, Week 76, Week 80, Week 84, Week 88, Week 92, Week 96, Week 100)
  • Percentage of Participants Who Gained >= 15 Letters in BCVA From Baseline or Reached BCVA >= 84 Letters at Each Post-baseline Visit for the Study Eye(Baseline, Week 4, Week 6, Week 8, Week 12, Week 16, Week 18, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, Week 52, Week 56, Week 60, Week 64, Week 68, Week 72, Week 76, Week 80, Week 84, Week 88, Week 92, Week 96, Week 100)
  • Percentage of Participants Who Lost >= 5 ETDRS Letters in Best Corrected Visual Acuity (BCVA) From Baseline at Each Post-baseline Visit for the Study Eye(Baseline, Week 4, Week 6, Week 8, Week 12, Week 16, Week 18, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, Week 52, Week 56, Week 60, Week 64, Week 68, Week 72, Week 76, Week 80, Week 84, Week 88, Week 92, Week 96, Week 100)
  • Percentage of Participants Who Lost >= 15 ETDRS Letters in Best Corrected Visual Acuity (BCVA) From Baseline at Each Post-baseline Visit for the Study Eye(Baseline, Week 4, Week 6, Week 8, Week 12, Week 16, Week 18, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, Week 52, Week 56, Week 60, Week 64, Week 68, Week 72, Week 76, Week 80, Week 84, Week 88, Week 92, Week 96, Week 100)
  • Percentage of Participants With an Absolute Best Corrected Visual Acuity (BCVA) >= 73 ETDRS Letters at Each Post-baseline Visit for the Study Eye(Baseline, Week 4, Week 6, Week 8, Week 12, Week 16, Week 18, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, Week 52, Week 56, Week 60, Week 64, Week 68, Week 72, Week 76, Week 80, Week 84, Week 88, Week 92, Week 96, Week 100)
  • Mean Change From Baseline in Central Subfield Thickness (CSFT) at Each Post-baseline Visit for the Study Eye(Baseline, Week 4, Week 6, Week 8, Week 12, Week 16, Week 18, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, Week 52, Week 56, Week 60, Week 64, Week 68, Week 72, Week 76, Week 80, Week 84, Week 88, Week 92, Week 96, Week 100)
  • Average Mean Change From Baseline in Central Subfield Thickness (CSFT) Over the Period Week 40 Through Week 52 / Week 88 Through Week 100 for the Study Eye(Baseline, period Week 40 through Week 52, period Week 88 through Week 100)
  • Average Mean Change From Baseline in CSFT Over the Period Week 4 to Week 52 / 100 for the Study Eye(Baseline, period Week 4 through Week 52, period Week 4 through Week 100)
  • Percentage of Participants With Normal CSFT Thickness (<280 Micrometers) at Each Post-baseline Visit for the Study Eye(Baseline, Week 4, Week 6, Week 8, Week 12, Week 16, Week 18, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, Week 52, Week 56, Week 60, Week 64, Week 68, Week 72, Week 76, Week 80, Week 84, Week 88, Week 92, Week 96, Week 100)
  • Percentage of Patients With Presence of Subretinal Fluid (SRF) in the Study Eye at Each Post-baseline Visit(Week 4, Week 6, Week 8, Week 12, Week 16, Week 18, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, Week 52, Week 56, Week 60, Week 64, Week 68, Week 72, Week 76, Week 80, Week 84, Week 88, Week 92, Week 96, Week 100)
  • Percentage of Patients With Presence of Intraretinal Fluid (IRF) in the Study Eye at Each Post-baseline Visit(Week 4, Week 6, Week 8, Week 12, Week 16, Week 18, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, Week 52, Week 56, Week 60, Week 64, Week 68, Week 72, Week 76, Week 80, Week 84, Week 88, Week 92, Week 96, Week 100)
  • Percentage of Patients With Presence of Subretinal Fluid (SRF) and/or Intraretinal Fluid (IRF) in the Study Eye at Each Post-baseline Visit(Week 4, Week 6, Week 8, Week 12, Week 16, Week 18, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, Week 52, Week 56, Week 60, Week 64, Week 68, Week 72, Week 76, Week 80, Week 84, Week 88, Week 92, Week 96, Week 100)
  • Percentage of Participants With Presence of Leakage on Fluorescein Angiography (FA) at Weeks 52 and 100(Week 52, Week 100)
  • Percentage of Participants With With >=2-step Improvement From Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) Score(Baseline, Week 28, Week 52, Week 76, Week 100)
  • Percentage of Participants With With >=3-step Improvement From Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) Score(Baseline, Week 28, Week 52, Week 76, Week 100)
  • Percentage of Participants With With >=2-step Worsening From Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) Score(Baseline, Week 28, Week 52, Week 76, Week 100)
  • Percentage of Participants With With >=3-step Worsening From Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) Score(Baseline, Week 28, Week 52, Week 76, Week 100)
  • Percentage of Participants With Progression to Proliferative Diabetic Retinopathy (PDR) as Assessed by ETDRS-DRSS Score of at Least 61 by Week 100(Week 100)
  • Number of Participants With Ocular and Non-ocular Adverse Events (AEs)(From randomization till 30 days safety follow-up, assessed up to 35 months.)
  • Change From Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): Composite Score(Baseline, Week 28, Week 52, Week 76, Week 100)
  • Change From Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): Subscale Score - General Vision(Baseline, Week 28, Week 52, Week 76, Week 100)
  • Change From Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): Subscale Score - Ocular Pain(Baseline, Week 28, Week 52, Week 76, Week 100)
  • Change From Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): Subscale Score - Near Activities(Baseline, Week 28, Week 52, Week 76, Week 100)
  • Change From Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): Subscale Score - Mental Health(Baseline, Week 28, Week 52, Week 76, Week 100)
  • Change From Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): Subscale Score - Role Difficulties(Baseline, Week 28, Week 52, Week 76, Week 100)
  • Change From Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): Subscale Score - Dependency(Baseline, Week 28, Week 52, Week 76, Week 100)
  • Change From Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): Subscale Score - Driving(Baseline, Week 28, Week 52, Week 76, Week 100)
  • Change From Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): Subscale Score - Color Vision(Baseline, Week 28, Week 52, Week 76, Week 100)
  • Change From Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): Subscale Score - Peripheral Vision(Baseline, Week 28, Week 52, Week 76, Week 100)
  • Change From Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): Subscale Score - Distance Activities(Baseline, Week 28, Week 52, Week 76, Week 100)
  • Change From Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): Subscale Score - Social Functioning(Baseline, Week 28, Week 52, Week 76, Week 100)
  • Change From Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): General Health Rating(Baseline, Week 28, Week 52, Week 76, Week 100)
  • Systemic Brolucizumab Concentration(Up to Week 24)
  • Distribution of Integrated Anti-Drug Antibody (ADA) Status in the Brolucizumab Arm(Up to Week 100)
  • Distribution of Integrated Anti-Drug Antibody (ADA) Status in the Brolucizumab Arm - Adjusted for Pre-existing ADA Status(Up to Week 100)
  • Pre-existing ADA Status and Incidence of Adverse Event of Special Interest (AESI) in the Study Eye(Up to Week 100)
  • Integrated ADA Status up to Week 100 and Incidence of Adverse Event of Special Interest (AESI) in the Study Eye.(Up to Week 100)

研究者

申办方类型
Industry
责任方
Sponsor

研究点 (1)

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