A Two-year, Three-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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 566
- 试验地点
- 1
- 主要终点
- Change From Baseline in Best-corrected Visual Acuity (BCVA) at Week 52
研究概览
简要总结
The purpose of this study was to evaluate the efficacy and safety of brolucizumab in treatment of patients with visual impairment due to diabetic macular edema (DME).
详细描述
This was a Phase III, randomized, double-masked, multi-center, active-controlled, three-arm study designed to evaluate the efficacy and safety of brolucizumab 6 mg and 3 mg compared to the active control, aflibercept 2 mg used per authorized label, in subjects with diabetic macular edema (DME). The study included a screening period of up to 2 weeks to assess eligibility, followed by a doublemasked 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, a post-treatment follow-up period was planned from Week 96 to Week 100.
Subjects were assigned to one of three treatment arms in a 1:1:1 ratio: brolucizumab 6 mg/0.05 mL administered 5 x every 6 weeks (q6w) during loading phase then q12w/every 8 weeks (q8w) during maintenance phase, brolucizumab 3 mg/0.05 mL administered 5 x every 6 weeks (q6w) during loading phase then q12w/q8w during maintenance phase or aflibercept 2 mg/0.05 mL administered 5 x every 4 weeks (q4w) during loading phase then q8w during maintenance phase.
Disease Activity Assessments (DAAs) were conducted by the masked investigator for each treatment arm at Week 32 and Week 36, i.e. 8 and 12 weeks after the end of the loading phase for subjects receiving brolucizumab. Assessments were also performed at Week 48, and will then continue to be performed from Week 60 up to Week 96, every 12 weeks. Subjects in the brolucizumab arms who qualified for q12w during the 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 the end of the study.
To fulfil the double-masking requirement, each investigational site had masked and unmasked staff. The investigator who performed the injection was unmasked to the treatments as were any other site personnel who had been delegated responsibility for working with the Investigational Product (IP). The unmasked site personnel and unmasked injecting investigator did not perform Best-corrected visual acuity (BCVA), complete ophthalmic examination (with the exception of post-injection safety assessment), DAAs or administer the Visual Functioning Questionnaire-25 (VFQ-25). Also, the unmasked site personnel and unmasked injecting physician did not perform assessment of any ocular or non-ocular safety parameters, or assess causality of Adverse event (AEs) for subjects during the course of the study except an event reported immediately following Intravitreal treatment (IVT). Once the designated roles were determined, the unmasked investigator/site personnel roles were not switched at any time after randomization to masked role. Every effort was made to limit the number of unmasked study personnel to ensure the integrity of this masked study.
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
- •Written informed consent before any assessment
- •Patients with type 1 or type 2 diabetes mellitus and HbA1c of ≤10% at screening
- •Medication for the management of diabetes stable within 3 months prior to randomization and is expected to remain stable during the course of the study
排除标准
- •Active proliferative diabetic retinopathy in the study eye
- •Active intraocular or periocular infection or active intraocular inflammation in study eye
- •Uncontrolled glaucoma in the study eye defined as intraocular pressure (IOP) > 25 millimeters mercury (mmHg)
- •Previous treatment with anti-VEGF drugs or investigational drugs in the study eye
- •Stroke or myocardial infarction during the 6-month period prior to baseline
- •Uncontrolled blood pressure defined as a systolic value ≥160 mmHg or diastolic value ≥100 mmHg
- •Other protocol-specified inclusion/exclusion criteria may apply
研究组 & 干预措施
Brolucizumab 3 mg
Brolucizumab 3 mg/0.05 mL, 5 loading doses, with subsequent doses per protocol-specified maintenance schedule.
To fulfil the double-masking requirement, each investigational site had masked and unmasked staff. The investigator who performed the injection was unmasked to the treatments as were any other site personnel who had been delegated responsibility for working with the Investigational Product (IP).
干预措施: Brolucizumab (Drug)
Brolucizumab 6 mg
Brolucizumab 6 mg/0.05 mL, 5 loading doses, with subsequent doses per protocol-specified maintenance schedule.
To fulfil the double-masking requirement, each investigational site had masked and unmasked staff. The investigator who performed the injection was unmasked to the treatments as were any other site personnel who had been delegated responsibility for working with the Investigational Product (IP).
干预措施: Brolucizumab (Drug)
Aflibercept 2 mg
Aflibercept 2 mg/0.05 mL, as labeled, 5 loading doses, with subsequent doses every 8 weeks.
To fulfil the double-masking requirement, each investigational site had masked and unmasked staff. The investigator who performed the injection was unmasked to the treatments as were any other site personnel who had been delegated responsibility for working with the Investigational Product (IP).
干预措施: Aflibercept (Drug)
结局指标
主要结局
Change From Baseline in Best-corrected Visual Acuity (BCVA) at Week 52
时间窗: Baseline, Week 52
BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual Function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 78 to 23 (approximate Snellen equivalent of 20/32 to 20/320) in the study eye were included. Min and max possible scores are 0-100 respectively. A higher score represents better visual functioning. This endpoint was analyzed via the pairwise ANOVA method where the 2 dose groups of Brolucizumab are compared to Aflibercept.
次要结局
- BCVA (Letters Read): ANOVA Results for Average Change From Baseline Over the Period Week 88 Through Week 100 for the Study Eye (FAS - LOCF)(Baseline, and Week 88 through Week 100 (average))
- Change From Baseline in Central Subfield Thickness (CSFT) at Each Visit up to Week 52 - Pairwise ANOVA Results(Baseline up to week 52)
- Number of Patients With Presence of Intraretinal Fluid (IRF) at Each Assessment Visit(Baseline, up to Week 52 and Week 100)
- Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS): Number of Subjects With >=3-step Improvement From Baseline in the DRSS Score at Each Assessment Visit for the Study Eye - Number of Subjects(Baseline, Weeks 28, 52, 76, 100)
- Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Dependency(Baseline, Weeks 28, 52, 76, 100)
- Patients Maintained at q12w up to Week 64 (After Three q12w- Treatment Intervals) and Week 100 - Probability of Maintaining on q12w(Baseline (Week 0), Weeks 32, 36, 48, 60, 72, 84, and 96)
- Secondary: Patients Maintained at q12w up to Week 64 (After Three q12w- Treatment Intervals) and Week 100, Within Those Patients That Qualified for q12w at Week 36 - Probability of Maintaining on q12w(Baseline (Week 0), Weeks 32, 36, 48, 60, 72, 84, and 96)
- Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS): Proportion of Subjects With >=3-step Improvement From Baseline in the DRSS Score at Each Assessment Visit for the Study Eye - Percentage Estimates(Baseline, Weeks 28, 52, 76, 100)
- Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Near Activities(Baseline, Weeks 28, 52, 76, 100)
- Patients Maintained at q12w - Probability of Maintaining on q12w(Baseline (Week 0), Weeks 32, 36 and 48)
- Central Subfield Thickness (CSFT) (Micrometers): ANOVA Results for Average Change From Baseline Over the Period Week 88 Through Week 100 for the Study Eye (Full Analysis Set - LOCF)(Baseline, and Week 88 through Week 100 (average))
- Number of Patients With Presence of Leakage on Fluorescein Angiography (FA) at Week 100(Week 100)
- Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS): Number of Subjects With >=2-step Improvement From Baseline in the DRSS Score at Each Assessment Visit for the Study Eye - Number of Subjects(Baseline, Weeks 28, 52, 76, 100)
- Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Mental Health(Baseline, Weeks 28, 52, 76, 100)
- Average Change From Baseline in BCVA Over the Period Week 40 Through Week 52(Baseline and Week 40 through Week 52 (average))
- Patients Maintained at q12w (for Those Patients Who Qualified for q12w at Week 36) - Probability of Maintaining on q12w(Weeks 36 and 48)
- Change From Baseline in BCVA at Each Visit up to Week 52(Baseline (Week 0), Weeks 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, and 52)
- Number of Patients With Presence of Subretinal Fluid (SRF) at Each Assessment Visit(Baseline up to Week 52 and Week 100)
- Number of Patients With Presence of SRF and/or IRF in the Study Eye by Visit(Baseline, up to Week 52 and Week 100)
- Number of Patients With Presence of Leakage on Fluorescein Angiography (FA) at Week 52(Week 52)
- Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS): Proportion of Subjects With >=2-step Improvement From Baseline in the DRSS Score at Each Assessment Visit for the Study Eye - Percentage Estimates(Baseline, Weeks 28, 52, 76, 100)
- Ocular Adverse Events (AEs) (>=2% in Any Treatment Arm) by Preferred Term for the Study Eye(Adverse events were reported from first dose of study treatment until Week 96, plus 30 days post treatment, up to a maximum duration of 100 weeks.)
- Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Composite Score(Baseline, Weeks 28, 52, 76, 100)
- Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - General Vision(Baseline, Weeks 28, 52, 76, 100)
- Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Distance Activities(Baseline, Weeks 28, 52, 76, 100)
- Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Social Functioning(Baseline, Weeks 28, 52, 76, 100)
- Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Driving(Baseline, Weeks 28, 52, 76, 100)
- Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Peripheral Vision(Baseline, Weeks 28, 52, 76, 100)
- Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Ocular Pain(Baseline, Weeks 28, 52, 76, 100)
- Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Color Vision(Baseline, Weeks 28, 52, 76, 100)
- Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - General Health Rating(Baseline, Weeks 28, 52, 76, 100)
- Number of Subjects With Non-ocular Adverse Events (AEs) (>=2% in Any Treatment Arm)(Adverse events were reported from first dose of study treatment until Week 96, plus 30 days post treatment, up to a maximum duration of 100 weeks.)
- Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Role Difficulties(Baseline, Weeks 28, 52, 76, 100)