A Three-part, Phase I/II Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Efficacy of Zifibancimig Following Intravitreal Administration of Multiple Ascending Doses and Continuous Delivery From the Port Delivery in Patients With Neovascular Age-related Macular Degeneration
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 177
- 试验地点
- 39
- 主要终点
- Duration of ASADEs
研究概览
简要总结
This is a first in-human study to investigate the safety, tolerability and efficacy of zifibancimig administered through intravitreal (IVT) injections and via the port delivery (PD) implant in participants with neovascular age-related macular degeneration (nAMD).
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
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
Part 1: Visual Acuity (VA) examiner; Part 2: Participant, Investigator, VA examiner and Sponsor; Part 3: Participant, Investigator, VA examiner and Sponsor.
The sponsor and its agents have been unblinded to treatment assignment in Parts 2 and 3, as of protocol amendment version 12.
入排标准
- 年龄范围
- 50 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Part 1, Part 2 and Part 3
- •Inclusion Criteria:
- •Willing to allow AH collection
- •Part 1 and Part 2
- •Ocular Inclusion Criteria for Study Eye:
- •Choroidal neovascularization (CNV) exclusively due to age-related macular degeneration (AMD)
- •Anti-vascular endothelial growth factor (VEGF) or anti-VEGF/Angiopoietin-2 (Ang-2) IVT treatment-naïve, or pre-treated with anti-VEGF or anti-VEGF/Ang-2 no less than two months prior to Day 1
- •Sufficiently clear ocular media and adequate pupillary dilatation to allow for analysis and grading by the central reading center of fundus photography (FP), fluorescein angiography (FA), fundus autofluorescence (FAF), and spectral domain optical coherence tomography (SD-OCT) images
- •Decreased BCVA attributable primarily to nAMD, with BCVA letter score of 78 to 34 letters (inclusive) on ETDRS-like charts at screening. In case both eyes of a participant are eligible, the eye with the lower BCVA score should become the study eye
- •Ocular Inclusion Criteria for Study Eye:
- •CNV exclusively due to AMD
- •Diagnosis of nAMD within 36 months prior to the screening visit
- •Previous treatment with at least one IVT anti-VEGF or anti-VEGF/Ang-2 administrations IVT for nAMD. The last IVT administration must have occurred at least 21 days prior to the screening visit
- •Demonstrated response to prior IVT anti-VEGF or anti-VEGF/Ang-2 treatment since diagnosis
- •Availability of historical VA data prior to the first anti-VEGF or anti-VEGF/Ang-2 treatment for nAMD
- •Sufficiently clear ocular media and adequate pupillary dilatation to allow for analysis and grading
- •Decreased BCVA attributable primarily to nAMD with letter score of 78 to 34 letters (inclusive) or better on ETDRS-like charts
排除标准
- •for Study Eye:
- •History of vitrectomy surgery, submacular surgery, other intraocular surgery, or any planned surgical intervention during the study period
- •Cataract surgery without complications within three months preceding the screening visit or planned during the study period
- •Aphakia or absence of the posterior capsule. Previous violation of the posterior capsule is also an exclusion criterion, unless it occurred as a result of yttrium-aluminum garnet laser posterior capsulotomy in association with prior, posterior chamber intraocular lens implantation
- •Prior macular treatment with verteporfin, external beam radiation therapy, transpupillary thermotherapy, or any type of laser photocoagulation
- •Prior treatment with IVT corticosteroids or implant (e.g., triamcinolone, ozurdex, iluvien)
- •Subretinal hemorrhage >50% of the total lesion area and/or involving the fovea
- •Subfoveal fibrosis or subfoveal atrophy
- •Retinal pigment epithelial tear involving the macula
- •History of vitreous hemorrhage, rhegmatogenous retinal detachment, glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma surgery, and corneal transplant
- •History of rhegmatogenous retinal tears or peripheral retinal breaks within three months prior to the screening visit
- •Actual or history of myopia >-8 diopters
- •Uncontrolled ocular hypertension or glaucoma (defined as intraocular pressure [IOP] >25 millimeters of mercury (mm Hg) or a cup to disc ratio >0.8, despite treatment with antiglaucoma medication) and any such condition the Investigator determines may require a glaucoma-filtering surgery during a participant's participation in the study
- •Concurrent intraocular conditions (e.g., cataract, diabetic retinopathy, epiretinal membrane with traction, macular hole) that, in the opinion of the Investigator, could either: require medical or surgical intervention during the study period to prevent or treat visual loss that might result from that condition; or likely contribute to loss of BCVA over the study period if allowed to progress untreated; or preclude any visual improvement due to substantial structural damage
- •Concurrent conjunctival, Tenon's capsule, and/or scleral condition in the supero-temporal quadrant of the eye (e.g., scarring, thinning, mass) that may affect the implantation, subsequent tissue coverage, and refill-exchange procedure of the PD implant
- •Prior treatment with any medication for geographic atrophy (GA) during the last 3 months prior to screening
- •Prior treatment with any anti-VEGF-C or anti-VEGF-D inhibitors
- •Exclusion Criteria for Fellow Eye
- •BCVA letter score using ETDRS charts of < 34 letters
- •Treatment with IVT anti-VEGF or anti-VEGF/Ang-2 agents within one week prior to Day 1 (concurrent treatment with SUSVIMO^TM in the fellow eye is not exclusionary)
- •Exclusion Criteria for Either Eye
- •CNV due to causes other than nAMD, such as ocular histoplasmosis, trauma, pathological myopia, angioid streaks, choroidal rupture, uveitis or central serous chorioretinopathy
- •Prior participation in a clinical trial involving anti-VEGF drugs within six months prior to the screening visit, other than ranibizumab, aflibercept, or faricimab including approved biosimilars
- •Active intraocular inflammation (grade trace or above), infectious conjunctivitis, keratitis, scleritis, or endophthalmitis
- •History of uveitis, including history of any intraocular inflammation following intravitreal therapy
- •Prior treatment with brolucizumab
- •Prior gene therapy for nAMD
研究组 & 干预措施
Part 2: PD With High Dose
Zifibancimig administered at a high dose through the PD implant, followed by ranibizumab, 100 milligrams per milliliter (mg/mL), administered through the PD implant.
干预措施: Zifibancimig (Drug)
Part 2: PD With Low Dose
Zifibancimig administered at a low dose through the PD implant, followed by ranibizumab, 100 mg/mL, administered through the PD implant.
干预措施: Zifibancimig (Drug)
Part 3: PD With Low Dose
Zifibancimig administered at a low dose through the PD implant, followed by ranibizumab, 100 mg/mL, administered through PD implant.
干预措施: Zifibancimig (Drug)
Part 3: PD With Ranibizumab
100 mg/mL of ranibizumab administered through the PD implant.
干预措施: Ranibizumab (Drug)
Part 2: PD With Low Dose
Zifibancimig administered at a low dose through the PD implant, followed by ranibizumab, 100 mg/mL, administered through the PD implant.
干预措施: Ranibizumab (Drug)
Part 3: PD With Low Dose
Zifibancimig administered at a low dose through the PD implant, followed by ranibizumab, 100 mg/mL, administered through PD implant.
干预措施: Port Delivery Platform (Device)
Part 3: PD With High Dose
Zifibancimig administered at a high dose through the PD implant, followed by ranibizumab, 100 mg/mL, administered through PD implant.
干预措施: Ranibizumab (Drug)
Part 3: PD With High Dose
Zifibancimig administered at a high dose through the PD implant, followed by ranibizumab, 100 mg/mL, administered through PD implant.
干预措施: Zifibancimig (Drug)
Part 2: PD With High Dose
Zifibancimig administered at a high dose through the PD implant, followed by ranibizumab, 100 milligrams per milliliter (mg/mL), administered through the PD implant.
干预措施: Port Delivery Platform (Device)
Part 1: IVT Injections
Zifibancimig administered in multiple ascending dose levels through IVT injections.
干预措施: Zifibancimig (Drug)
Part 2: PD With High Dose
Zifibancimig administered at a high dose through the PD implant, followed by ranibizumab, 100 milligrams per milliliter (mg/mL), administered through the PD implant.
干预措施: Ranibizumab (Drug)
Part 3: PD With Low Dose
Zifibancimig administered at a low dose through the PD implant, followed by ranibizumab, 100 mg/mL, administered through PD implant.
干预措施: Ranibizumab (Drug)
Part 2: PD With Low Dose
Zifibancimig administered at a low dose through the PD implant, followed by ranibizumab, 100 mg/mL, administered through the PD implant.
干预措施: Port Delivery Platform (Device)
Part 3: PD With High Dose
Zifibancimig administered at a high dose through the PD implant, followed by ranibizumab, 100 mg/mL, administered through PD implant.
干预措施: Port Delivery Platform (Device)
结局指标
主要结局
Duration of ASADEs
时间窗: Parts 2 and 3: Baseline up to Week 48
Percentage of Participants With Adverse Events of Special Interest (AESIs) Including Ocular AESIs
时间窗: Part 1: Baseline up to Week 24; Parts 2 and 3: Baseline up to Week 48
Duration of Ocular AESIs
时间窗: Part 1: Baseline up to Week 24; Parts 2 and 3: Baseline up to Week 48
Percentage of Participants With Adverse Device Effects (ADEs)
时间窗: Parts 2 and 3: Baseline up to Week 48
Duration of ADEs
时间窗: Parts 2 and 3: Baseline up to Week 48
Percentage of Participants With Anticipated Serious ADEs (ASADEs)
时间窗: Parts 2 and 3: Baseline up to Week 48
Percentage of Participants With Ocular and Systemic (Non-ocular) Adverse Events (AEs)
时间窗: Part 1: Baseline up to Week 24; Parts 2 & 3: Baseline up to Week 48
Percentage of Participants With Ocular AEs During the Post-operative and Follow-up Periods
时间窗: Parts 2 and 3: From Day 1 to Week 4 and during follow-up period (up to Week 48)
Percentage of Participants With Adverse Events of Special Interest (AESIs) Including Ocular AESIs
时间窗: Part 1: Baseline up to Week 24; Parts 2 and 3: Baseline up to Week 48
Percentage of Participants With Ocular AESIs During the Post-operative and Follow-up Periods
时间窗: Parts 2 and 3: From Day 1 to Week 4 and during follow-up period (up to Week 48)
Duration of Ocular AESIs
时间窗: Part 1: Baseline up to Week 24; Parts 2 and 3: Baseline up to Week 48
Duration of Ocular AESIs During the Post-operative and Follow-up Periods
时间窗: Parts 2 and 3: From Day 1 to Week 4 and during follow-up period (up to Week 48)
Percentage of Participants With Adverse Device Effects (ADEs)
时间窗: Parts 2 and 3: Baseline up to Week 48
Duration of ADEs
时间窗: Parts 2 and 3: Baseline up to Week 48
Percentage of Participants With Anticipated Serious ADEs (ASADEs)
时间窗: Parts 2 and 3: Baseline up to Week 48
Duration of ASADEs
时间窗: Parts 2 and 3: Baseline up to Week 48
Change From Baseline in Early Treatment Diabetic Retinopathy Study - Best Corrected Visual Acuity (ETDRS-BCVA) Score at Week 48
时间窗: Part 3: Baseline (baseline visit, before implant insertion), and Week 48
ETDRS-BCVA will be used to quantify visual acuity. BCVA is measured using an eye chart and is reported as the number of letters read correctly using the ETDRS Scale (ranging from 0 to 100 letters) in the study eye. 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.
次要结局
- Maximum Observed Concentration (Cmax) of Zifibancimig in Blood and Aqueous Humor (AH)(Part 1: Baseline up to Week 24; Parts 2 and 3: Baseline up to Week 144)
- Time of Maximum Concentration Observed (Tmax) of Zifibancimig in Blood and AH(Part 1: Baseline up to Week 24; Parts 2 and 3: Baseline up to Week 144)
- Concentration at the End of a Dosing Interval Before the Next Dose Administration (Ctrough) of Zifibancimig in Blood and AH(Part 1: Baseline up to Week 24; Parts 2 and 3: Baseline up to Week 144)
- Area Under the Curve (AUC) of Zifibancimig in Blood and AH(Part 1: Baseline up to Week 24; Parts 2 and 3: Baseline up to Week 144)
- Percentage of Participants Who Gained or Lost ≥15, ≥10 ≥5 or ≥0 Letters in ETDRS-BCVA Score From Baseline to Week 48(Part 3: Baseline to Week 48)
- Maximum Observed Concentration (Cmax) of Zifibancimig in Blood and Aqueous Humor (AH)(Part 1: Baseline up to Week 24; Parts 2 and 3: Baseline up to Week 144)
- Time of Maximum Concentration Observed (Tmax) of Zifibancimig in Blood and AH(Part 1: Baseline up to Week 24; Parts 2 and 3: Baseline up to Week 144)
- Concentration at the End of a Dosing Interval Before the Next Dose Administration (Ctrough) of Zifibancimig in Blood and AH(Part 1: Baseline up to Week 24; Parts 2 and 3: Baseline up to Week 144)
- Area Under the Curve (AUC) of Zifibancimig in Blood and AH(Part 1: Baseline up to Week 24; Parts 2 and 3: Baseline up to Week 144)
- Percentage of Participants Who did not Meet Supplemental Treatment Criteria for the PD Implant With Zifibancimig(Part 3: Week 36, Week 40, and Week 44)
- Percentage of Participants Who Gained or Lost ≥15, ≥10 ≥5 or ≥0 Letters in ETDRS-BCVA Score From Baseline to Week 48(Part 3: Baseline to Week 48)
- Change From Baseline in Central Subfield Thickness (CST) at Week 48(Part 3: Baseline, and Week 48)
- Change From Baseline Over Time in CST(Part 3: Baseline to end of follow-up period (up to Week 144))