A Phase III, Multicenter, Randomized, Visual Assessor-Masked, Active-comparator Study of the Efficacy, Safety, and Pharmacokinetics of the Port Delivery System With Ranibizumab in Patients With Diabetic Macular Edema (Pagoda)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 672
- 试验地点
- 161
- 主要终点
- Change in BCVA Score From Baseline Averaged Over Weeks 60 and 64 as Measured Using the ETDRS Chart in the Efficacy Population Using a Treatment Policy Strategy for all Intercurrent Events
研究概览
简要总结
This study will evaluate the efficacy, safety, and Pharmacokinetics (PK) of the PDS with ranibizumab in participants with DME when treated every 24 weeks (Q24W) compared with intravitreal (IVT) ranibizumab 0.5 milligrams (mg) every 4 weeks (Q4W).
The substudy will evaluate safety of re-implanting the updated PDS with ranibizumab and the refill-exchange procedures following re-implantation in participants with DME who were previously enrolled in the main study, GR40550. Up to 100 participants from the main study will be enrolled and followed for a maximum of 72 weeks post-re-implantation in the substudy.
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
- Single (Outcomes Assessor)
盲法说明
The substudy is a non-randomized, open-label study.
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
- •Age ≥18 years at time of signing informed consent form (ICF)
- •Documented diagnosis of diabetes mellitus (Type 1 or Type 2)
- •Glycated haemoglobin (HbA1c) level of ≤10% within 2 months prior to screening or at screening
- •Macular thickening secondary to DME involving the center of the fovea with CST ≥325 micrometer (µm) on SD-OCT at screening
- •BCVA score of 78 to 25 letters (20/32 to 20/320 approximate Snellen equivalent)
排除标准
- •High-risk PDR
- •Active intraocular inflammation (grade trace or above)
- •Suspected or active ocular or periocular infection of either eye
- •Uncontrolled ocular hypertension or glaucoma and any such condition the investigator determines may require a glaucoma-filtering surgery during a patient's participation in the study
- •Cerebrovascular accident or myocardial infarction within 6 months prior to randomization
- •Atrial fibrillation diagnosis or worsening within 6 months prior to randomization
- •Uncontrolled blood pressure
- •Inclusion Criteria:
- •Having experienced a septum dislodgement in the original implant while in the main study or after exiting the main study
- •Sufficiently clear ocular media and adequate pupillary dilation to allow for analysis and grading by central reading center
- •Exclusion Criteria (Cohort 1 Only):
- •Recent history (in the last 3 months prior to enrollment) of other disease, other non-diabetic metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a condition that contraindicates the use of ranibizumab or surgical placement of the PDS implant; that might affect interpretation of the results of the study; or that renders the participant at high risk for treatment complications
- •Active cancer within the last 12 months, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or prostate cancer
- •Current systemic treatment for a confirmed active systemic infection
- •Participation in an investigational trial that involves treatment with any drug or device (with the exception of vitamins and minerals or enrollment in Study GR40550) within 6 months prior to enrollment
- •Use of antimitotic or antimetabolite therapy within 30 days
- •Ocular Exclusion Criteria for Study Eye:
- •Any ocular condition that may render the participant at high risk for surgical or treatment complications
- •Intraocular surgery (including cataract surgery) within 1 month preceding the enrollment visit
- •Any use of medicated intraocular implants (other than the PDS implant), at any time prior to enrollment
- •History of rhegmatogenous retinal tears or peripheral retinal breaks within 3 months prior to the enrollment visit
- •Any concurrent ocular condition that would require surgical intervention during the study to prevent or treat visual loss
- •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 refill-exchange procedure of the PDS implant
- •Ongoing ocular complications that might affect participant safety Ocular Exclusion Criteria for Either Eye
- •Suspected or active ocular or periocular infection (e.g., infectious conjunctivitis or endophthalmitis)
- •Any history of uveitis
- •Active blepharitis
研究组 & 干预措施
PDS Arm
Participants randomized to the PDS arm will receive IVT ranibizumab injection Q4W (loading phase) and will then have the PDS implant (pre-filled with ranibizumab) surgically inserted. PDS implant refill-exchange procedures will be performed on a fixed interval Q24W thereafter.
干预措施: PDS Implant Pre-Filled with 100 mg/mL Ranibizumab (Drug)
Substudy: Cohort 1
Participants will undergo re-implantation with the updated PDS implant (pre-filled with ranibizumab 100 milligrams per milliliter [mg/mL]) on Day 1 (or enrollment visit) and then will have two refill-exchanges (ranibizumab 100 mg/mL) Q24W up to 48 weeks.
干预措施: PDS Implant Pre-Filled with 100 mg/mL Ranibizumab (Drug)
Substudy: Cohort 2a
Participants who received an updated PDS implant, have < 24 weeks post-re-implantation follow-up and no scheduled refill-exchange visit in the main study, will undergo two refill-exchange procedures (ranibizumab 100 mg/mL) Q24W, post main study re-implantation visit.
干预措施: Ranibizumab refill exchange (Drug)
Substudy: Cohort 2b
Participants who received an updated PDS implant, have < 48 weeks post-re-implantation follow-up and one refill exchange visit in the main study, regardless of whether the refill exchange was administered or the visit was missed, will undergo one refill-exchange procedure (ranibizumab 100 mg/mL) Q24W, post main study re-implantation visit.
干预措施: Ranibizumab refill exchange (Drug)
Intravitreal Arm
Participants randomized to the intravitreal arm will receive IVT ranibizumab injection Q4W until they receive the PDS implant (pre-filled with ranibizumab). PDS implant refill-exchange procedures will be performed on a fixed interval Q24W thereafter.
干预措施: Intravitreal Ranibizumab 0.5 mg Injection (Drug)
Intravitreal Arm
Participants randomized to the intravitreal arm will receive IVT ranibizumab injection Q4W until they receive the PDS implant (pre-filled with ranibizumab). PDS implant refill-exchange procedures will be performed on a fixed interval Q24W thereafter.
干预措施: Ranibizumab refill exchange (Drug)
PDS Arm
Participants randomized to the PDS arm will receive IVT ranibizumab injection Q4W (loading phase) and will then have the PDS implant (pre-filled with ranibizumab) surgically inserted. PDS implant refill-exchange procedures will be performed on a fixed interval Q24W thereafter.
干预措施: Ranibizumab refill exchange (Drug)
Substudy: Cohort 1
Participants will undergo re-implantation with the updated PDS implant (pre-filled with ranibizumab 100 milligrams per milliliter [mg/mL]) on Day 1 (or enrollment visit) and then will have two refill-exchanges (ranibizumab 100 mg/mL) Q24W up to 48 weeks.
干预措施: Ranibizumab refill exchange (Drug)
结局指标
主要结局
Change in BCVA Score From Baseline Averaged Over Weeks 60 and 64 as Measured Using the ETDRS Chart in the Efficacy Population Using a Treatment Policy Strategy for all Intercurrent Events
时间窗: Baseline to Week 64
BCVA = Best-Corrected Visual Acuity ETDRS = Early Treatment Diabetic Retinopathy Study A vision score of 20/20 vision is considered normal. A score of 20/200 is considered being legally blind.
Substudy: Number of Participants With Ocular and Systemic (Non-ocular) Adverse Events (AEs) and Severity of Ocular and Systemic AEs
时间窗: Baseline to Week 72
Substudy: Number of Participants With Adverse Events of Special Interests (AESIs) and Severity of AESIs
时间窗: Baseline to Week 72
Substudy: Number of Participants With Ocular AESIs and Severity of Ocular AESIs During the Post-operative Period
时间窗: Up to Day 37 post re-implantation
Substudy: Number of Participants With Ocular AESIs and Severity of Ocular AESIs During the Follow-up Period
时间窗: > 37 days post-implantation (up to approximately 72 weeks)
Substudy: Duration of Ocular AESIs During the Post-operative Period
时间窗: Up to Day 37 post re-implantation
Substudy: Duration of Ocular AESIs During the Follow-up Period
时间窗: > 37 days post-implantation (up to approximately 72 weeks)
Substudy: Number of Participants With Adverse Device Effects (ADEs) and Severity of ADEs
时间窗: Baseline to Week 72
Substudy: Number of Participants With Anticipated Serious ADEs
时间窗: Baseline to Week 72
Substudy: Duration of Serious ADEs
时间窗: Baseline to Week 72
Substudy: Number of Device Deficiencies
时间窗: Baseline to Week 72
Change in BCVA Score From Baseline Averaged Over Weeks 60 and 64 as Measured Using the ETDRS Chart in the Efficacy Population Using a Treatment Policy Strategy for all Intercurrent Events
时间窗: Baseline to Week 64
BCVA = Best-Corrected Visual Acuity ETDRS = Early Treatment Diabetic Retinopathy Study A vision score of 20/20 vision is considered normal. A score of 20/200 is considered being legally blind.
Substudy: Number of Participants With Ocular and Systemic (Non-ocular) Adverse Events (AEs) and Severity of Ocular and Systemic AEs
时间窗: Baseline to Week 72
Substudy: Number of Participants With Adverse Events of Special Interests (AESIs) and Severity of AESIs
时间窗: Baseline to Week 72
Substudy: Duration of AESIs
时间窗: Baseline to Week 72
Substudy: Number of Participants With Ocular AESIs and Severity of Ocular AESIs During the Post-operative Period
时间窗: Up to Day 37 post re-implantation
Substudy: Number of Participants With Ocular AESIs and Severity of Ocular AESIs During the Follow-up Period
时间窗: > 37 days post-implantation (up to approximately 72 weeks)
Substudy: Duration of Ocular AESIs During the Post-operative Period
时间窗: Up to Day 37 post re-implantation
Substudy: Duration of Ocular AESIs During the Follow-up Period
时间窗: > 37 days post-implantation (up to approximately 72 weeks)
Substudy: Number of Participants With Adverse Device Effects (ADEs) and Severity of ADEs
时间窗: Baseline to Week 72
Substudy: Number of Participants With Anticipated Serious ADEs
时间窗: Baseline to Week 72
Substudy: Duration of Serious ADEs
时间窗: Baseline to Week 72
Substudy: Number of Device Deficiencies
时间窗: Baseline to Week 72
次要结局
- Change in BCVA Score From Baseline Averaged Over Weeks 60 and 64 as Measured With Use of the ETDRS Chart in the Modified Intent-to-treat (mITT) Population Using a Treatment Policy Strategy for All Intercurrent Events(Baseline to Week 64)
- Change in BCVA Score From Baseline Averaged Over Weeks 60 and 64 as Measured With Use of the ETDRS Chart in the mITT Population Using a Hypothetical Strategy for All Intercurrent Events(Baseline to Week 64)
- Percentage of Participants With a ≥2-step Improvement From Baseline on the ETDRS-DRSS at Week 64 in the Efficacy Population(Baseline to Week 64)
- Percentage of Participants With a ≥2-step Improvement From Baseline on the ETDRS-DRSS at Week 64 in the mITT population(Baseline to Week 64)
- Change from Baseline in BCVA as Measured on the ETDRS Chart Over Time(Baseline up to Week 120)
- Percentage of Participants Who Lose <15, <10, and <5 letters in BCVA From Baseline Over Time(Baseline up to Week 120)
- Percentage of Participants Who Gain ≥15, ≥10, ≥5, ≥0 Letters in BCVA From Baseline Over Time(Baseline up to Week 120)
- Percentage of Participants With a BCVA Snellen Equivalent of 20/40 or Better Over Time(Baseline up to Week 120)
- Percentage of Participants With a BCVA Snellen Equivalent of 20/200 or Worse Over Time(Baseline up to Week 120)
- Percentage of Participants With a ≥2-step Improvement From Baseline on the ETDRS-DRSS Over Time(Baseline up to Week 120)
- Percentage of Participants With a ≥3-step Improvement From Baseline on the ETDRS-DRSS Over Time(Baseline up to Week 120)
- Time to ≥2-step Worsening From Baseline on the ETDRS-DRSS(Baseline up to Week 120)
- Time to ≥3-step Worsening From Baseline on the ETDRS-DRSS(Baseline up to Week 120)
- Change From Baseline in ETDRS-DRSS Score Over Time(Baseline up to Week 120)
- Change From Baseline in Central Subfield Thickness (CST) as Measured on Spectral Domain Optical Coherence Tomography (SD-OCT) Over Time(Baseline up to Week 120)
- Change From Baseline in Total Macular Volume as Measured on SD-OCT Over Time(Baseline up to Week 120)
- Percentage of Participants With Absence of Intraretinal Fluid (IRF) Over Time (IRF as Measured in the Central 1 mm Subfield)(Baseline up to Week 120)
- Percentage of Participants With Absence of Subretinal Fluid (SRF) Over Time (SRF as Measured in the Central 1 mm Subfield)(Baseline up to Week 120)
- Percentage of Participants With Absence of IRF and SRF Over Time(Baseline up to Week 120)
- Time to PDR (Defined as a Score ≥60 on the ETDRS-DRSS)(Baseline up to Week 120)
- Percentage of Participants Who do not Undergo Supplemental Treatment With IVT Ranibizumab Within Each Refill-exchange Interval(Baseline up to Week 120)
- Percentage of Participants Who Report Preferring PDS Treatment Compared With IVT Ranibizumab Treatment(Baseline to Week 64)
- Percentage of Participants Who Report Preferring PDS Treatment Compared With IVT Ranibizumab Treatment, as Measured by the PPPQ at Week 64(Baseline to Week 64)
- Participant-reported Vision-related Functioning and Health-Related Quality of Life (HRQoL) Among Participants in Both Treatment Arms, as Measured by Changes From Baseline(, Baseline Week 48, Week 96)
- Participant-reported Vision-related Functioning and HRQoL, as Measured by the Proportion of Participants With a ≥ 4-Point Improvement From Baseline in the NEI VFQ-25 Composite Score at Weeks 48 and 96 Among Participants in Both Treatment Arms(Baseline, Week 48, Week 96)
- Incidence and Severity of Ocular AEs(Baseline up to Week 120)
- Incidence and Severity of Non-ocular AEs(Baseline up to Week 120)
- Incidence, Severity, and Duration of AEs of Special Interest(Baseline up to Week 120)
- Serum Concentration of Ranibizumab Observed Over Time(Baseline up to Week 120)
- PK Parameter: Value Area Under the Concentration- Time Curve Over 24 weeks (AUC24W)(Baseline to Week 24)
- PK Parameter: Maximum Serum Concentration (Cmax)(Baseline up to Week 120)
- PK Parameter: Minimum Serum Concentration (Cmin)(Baseline up to Week 120)
- Time of Maximum Observed Serum Concentration (Tmax) After PDS Implant Insertion(Baseline up to Week 120)
- Prevalence of Anti-drug Antibodies (ADAs) at Baseline and Incidence of ADAs During the Study(Baseline up to Week 120)
- Prevalence of Neutralizing Antibodies at Baseline and Incidence of Neutralizing Antibodies During the Study(Baseline up to Week 120)
- Reported Incidence of Device Deficiencies(Baseline up to Week 120)
- Incidence, Severity, and Duration of AESIs(Baseline up to Week 120)
- Incidence, Severity, and Duration of Ocular AESIs During the Postoperative Period (up to 37 Days After Initial Implantation) and Follow-up Period (> 37 days After Implantation Surgery)(Baseline up to Week 120)
- Incidence and Severity of ADEs(Baseline up to Week 120)
- Incidence, Causality, Severity, and Duration of Anticipated Serious ADEs(Baseline up to Week 120)
- Substudy: Number of Participants With Ocular AESIs and Severity of Ocular AESIs After Refill-exchange Procedure(Up to approximately 72 weeks)
- Substudy: Duration of AESIs After Refill-exchange Procedure(Up to approximately 72 weeks)
- Substudy: Number of Participants With ADEs and Severity of ADEs After Refill-exchange Procedure(Up to approximately 72 weeks)
- Substudy: Number of Participants With Anticipated Serious ADEs After Refill-exchange Procedure(Up to approximately 72 weeks)
- Substudy: Duration of Serious ADEs After Refill-exchange Procedure(Up to approximately 72 weeks)
- Substudy: Number of Device Deficiencies After Refill-exchange Procedure(Up to approximately 72 weeks)
- Change From Baseline in ETDRS-DRSS Score Over Time(Baseline up to Week 120)
- Time to ≥3-step Worsening From Baseline on the ETDRS-DRSS(Baseline up to Week 120)
- Percentage of Participants With Absence of IRF and SRF Over Time(Baseline up to Week 120)
- Change in BCVA Score From Baseline Averaged Over Weeks 60 and 64 as Measured With Use of the ETDRS Chart in the Modified Intent-to-treat (mITT) Population Using a Treatment Policy Strategy for All Intercurrent Events(Baseline to Week 64)
- Change in BCVA Score From Baseline Averaged Over Weeks 60 and 64 as Measured With Use of the ETDRS Chart in the mITT Population Using a Hypothetical Strategy for All Intercurrent Events(Baseline to Week 64)
- Percentage of Participants With a ≥2-step Improvement From Baseline on the ETDRS-DRSS at Week 64 in the Efficacy Population(Baseline to Week 64)
- Percentage of Participants With a ≥2-step Improvement From Baseline on the ETDRS-DRSS at Week 64 in the mITT population(Baseline to Week 64)
- Change from Baseline in BCVA as Measured on the ETDRS Chart Over Time(Baseline up to Week 120)
- Percentage of Participants Who Lose <15, <10, and <5 letters in BCVA From Baseline Over Time(Baseline up to Week 120)
- Percentage of Participants Who Gain ≥15, ≥10, ≥5, ≥0 Letters in BCVA From Baseline Over Time(Baseline up to Week 120)
- Percentage of Participants With a BCVA Snellen Equivalent of 20/40 or Better Over Time(Baseline up to Week 120)
- Percentage of Participants With a BCVA Snellen Equivalent of 20/200 or Worse Over Time(Baseline up to Week 120)
- Percentage of Participants With a ≥2-step Improvement From Baseline on the ETDRS-DRSS Over Time(Baseline up to Week 120)
- Percentage of Participants With a ≥3-step Improvement From Baseline on the ETDRS-DRSS Over Time(Baseline up to Week 120)
- Time to ≥2-step Worsening From Baseline on the ETDRS-DRSS(Baseline up to Week 120)
- Change From Baseline in Central Subfield Thickness (CST) as Measured on Spectral Domain Optical Coherence Tomography (SD-OCT) Over Time(Baseline up to Week 120)
- Change From Baseline in Total Macular Volume as Measured on SD-OCT Over Time(Baseline up to Week 120)
- Percentage of Participants With Absence of Intraretinal Fluid (IRF) Over Time (IRF as Measured in the Central 1 mm Subfield)(Baseline up to Week 120)
- Percentage of Participants With Absence of Subretinal Fluid (SRF) Over Time (SRF as Measured in the Central 1 mm Subfield)(Baseline up to Week 120)
- Percentage of Participants With Absence DME (Defined as CST ≥325 μm on SD-OCT) Over Time(Baseline up to Week 120)
- Time to PDR (Defined as a Score ≥60 on the ETDRS-DRSS)(Baseline up to Week 120)
- Percentage of Participants Who do not Undergo Supplemental Treatment With IVT Ranibizumab Within Each Refill-exchange Interval(Baseline up to Week 120)
- Percentage of Participants Who Report Preferring PDS Treatment Compared With IVT Ranibizumab Treatment(Baseline to Week 64)
- Percentage of Participants Who Report Preferring PDS Treatment Compared With IVT Ranibizumab Treatment, as Measured by the PPPQ at Week 64(Baseline to Week 64)
- Participant-reported Vision-related Functioning and Health-Related Quality of Life (HRQoL) Among Participants in Both Treatment Arms, as Measured by Changes From Baseline(, Baseline Week 48, Week 96)
- Participant-reported Vision-related Functioning and HRQoL, as Measured by the Proportion of Participants With a ≥ 4-Point Improvement From Baseline in the NEI VFQ-25 Composite Score at Weeks 48 and 96 Among Participants in Both Treatment Arms(Baseline, Week 48, Week 96)
- Incidence and Severity of Ocular AEs(Baseline up to Week 120)
- Incidence and Severity of Non-ocular AEs(Baseline up to Week 120)
- Incidence, Severity, and Duration of AEs of Special Interest(Baseline up to Week 120)
- Serum Concentration of Ranibizumab Observed Over Time(Baseline up to Week 120)
- PK Parameter: Value Area Under the Concentration- Time Curve Over 24 weeks (AUC24W)(Baseline to Week 24)
- PK Parameter: Maximum Serum Concentration (Cmax)(Baseline up to Week 120)
- PK Parameter: Minimum Serum Concentration (Cmin)(Baseline up to Week 120)
- Time of Maximum Observed Serum Concentration (Tmax) After PDS Implant Insertion(Baseline up to Week 120)
- Prevalence of Anti-drug Antibodies (ADAs) at Baseline and Incidence of ADAs During the Study(Baseline up to Week 120)
- Prevalence of Neutralizing Antibodies at Baseline and Incidence of Neutralizing Antibodies During the Study(Baseline up to Week 120)
- Reported Incidence of Device Deficiencies(Baseline up to Week 120)
- Incidence, Severity, and Duration of AESIs(Baseline up to Week 120)
- Incidence, Severity, and Duration of Ocular AESIs During the Postoperative Period (up to 37 Days After Initial Implantation) and Follow-up Period (> 37 days After Implantation Surgery)(Baseline up to Week 120)
- Incidence and Severity of ADEs(Baseline up to Week 120)
- Incidence, Causality, Severity, and Duration of Anticipated Serious ADEs(Baseline up to Week 120)
- Substudy: Number of Participants With Ocular AESIs and Severity of Ocular AESIs After Refill-exchange Procedure(Up to approximately 72 weeks)
- Substudy: Duration of AESIs After Refill-exchange Procedure(Up to approximately 72 weeks)
- Substudy: Number of Participants With ADEs and Severity of ADEs After Refill-exchange Procedure(Up to approximately 72 weeks)
- Substudy: Number of Participants With Anticipated Serious ADEs After Refill-exchange Procedure(Up to approximately 72 weeks)
- Substudy: Duration of Serious ADEs After Refill-exchange Procedure(Up to approximately 72 weeks)
- Substudy: Number of Device Deficiencies After Refill-exchange Procedure(Up to approximately 72 weeks)
- Incidence and Severity of Ocular AEs(Baseline to Week 120)