Diabetic Retinopathy
Conditions
Keywords
Port Delivery System; ranibizumab; Diabetic Retinopathy; anti-VEGF, nonproliferative diabetic retinopathy, retina, vision loss, retinal disease, eye disease
Brief summary
Study GR41675 is a Multicenter, Randomized Study in Participants with Diabetic Retinopathy (DR) Without Center-Involved Diabetic Macular Edema (CI-DME) to Evaluate the Efficacy, Safety of the Port Delivery System with Ranibizumab (PDS) Relative to the Comparator Arm
Interventions
Will be administered as per the schedule described in individual arm.
Will be administered as per the schedule described in individual arm.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
The visual acuity examiner will only conduct refraction and visual acuity assessments and will be masked, as best as possible, to the following items: study eye assignment; study visit type; and treatment assignment.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥18 years at time of signing Informed Consent Form * Documented diagnosis of diabetes mellitus (Type 1 or Type 2) * HbA1c level of ≤12% within 2 months prior to screening or at screening Inclusion Criteria for Study Eye * Moderately severe or severe NPDR (ETDRS-DRSS level 47 or 53) * BCVA score of ≥ 69 letters (20/40 approximate Snellen equivalent or better)
Exclusion criteria
* Uncontrolled blood pressure * Cerebrovascular accident or myocardial infarction within 6 months prior to randomization * Atrial fibrillation diagnosis or worsening within 6 months prior to randomization * Current systemic treatment for a confirmed active systemic infection * Renal failure requiring renal transplant, hemodialysis, or peritoneal dialysis, or anticipated to require hemodialysis or peritoneal dialysis at any time during the study * History 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 patient at high risk for treatment complications in the opinion of the investigator or Sponsor Ocular
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a ≥2-Step Improvement From Baseline on the Early Treatment Diabetic Retinopathy Study-Diabetic Retinopathy Severity Scale (ETDRS-DRSS) at Week 52 | Baseline, Week 52 | ETDRS-DRSS classifies diabetic retinopathy (DR) into 12 severity steps ranging from absence of retinopathy to advanced proliferative diabetic retinopathy (PDR). DRSS grades= 10 (DR absent) - 85 (very advanced PDR), DRSS 90 = ungradable. All DRSS values are converted into a 12-level scale, from 1 (DR absent) to 12 (very advanced PDR), allowing derivation of ≥2-step change from baseline for post-baseline assessment. A lower score represents less advanced diabetic retinopathy. The Cochran-Mantel Haenszel (CMH) method was used for analysis and weighted percentage of participants are estimated and reported in this outcome measure. Participants receiving supplemental treatments, prohibited therapy, or panretinal photocoagulation (PRP) were considered non-responders. Missing values not preceded by these intercurrent events were imputed using the last observation carried forward method. SD OCT= spectral-domain optical coherence tomography. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Participants Developing a Vision-Threatening Complication or Center-involved Diabetic Macular Edema (CI-DME) Through Week 52 | From Baseline through Week 52 | A vision threatening complication is defined as proliferative DR (PDR) or anterior segment neovascularization (ASNV) or center-involved diabetic macular edema (CI-DME). CI-DME is defined as central foveal thickness (CST) ≥325 micrometres (μm) on spectral-domain optical coherence tomography (SD-OCT). Composite strategy (i.e., considered to be an event) was applied to participants who received supplemental or prohibited therapy or PRP in the study eye. The rate of participants was calculated using the Kaplan-Meier (KM) method. |
| Rate of Participants Developing PDR or ASNV Through Week 52 | From Baseline through Week 52 | The KM method was used for analysis, and estimates are in terms of event rate. Composite strategy (i.e., considered to be an event) was applied to participants who received supplemental or prohibited therapy or PRP in the study eye. |
| Rate of Participants Developing CI-DME Through Week 52 | From Baseline through Week 52 | CI-DME is defined as CST ≥325 μm on SD-OCT. The KM method was used for analysis, and estimated in terms of event rate. Composite strategy (i.e., considered to be an event) was applied to participants who received supplemental or prohibited therapy or PRP in the study eye. |
| Rate of Participants Developing a ≥ 2-Step Worsening From Baseline on the ETDRS-DRSS Through Week 52 | From Baseline through Week 52 | ETDRS-DRSS classifies diabetic retinopathy (DR) into 12 severity steps ranging from absence of retinopathy to advanced proliferative diabetic retinopathy (PDR). DRSS grades= 10 (DR absent) - 85 (very advanced PDR ), DRSS 90 = ungradable. All DRSS values are converted into a 12-level scale, from 1 (DR absent) to 12 (very advanced PDR), allowing derivation of ≥2-step change from baseline for post-baseline assessment. A lower score represents less advanced diabetic retinopathy. Composite strategy (i.e., considered to be an event) was applied to participants who received supplemental or prohibited therapy or PRP in the study eye. The rate of participants developing ≥ 2-step worsening on the ETDRS-DRSS was calculated using the KM method. |
| Percentage of Participants With a ≥ 3-Step Improvement From Baseline on the ETDRS-DRSS at Week 52 | Week 52 | ETDRS-DRSS classifies diabetic retinopathy (DR) into 12 severity steps ranging from absence of retinopathy to advanced proliferative diabetic retinopathy (PDR). DRSS grades= 10 (DR absent) - 85 (very advanced PDR ), DRSS 90 = ungradable. All DRSS values are converted into a 12-level scale, from 1 (DR absent) to 12 (very advanced PDR), allowing derivation of ≥2-step change from baseline for post-baseline assessment. A lower score represents less advanced diabetic retinopathy. Participants receiving supplemental treatments, prohibited therapy, or panretinal photocoagulation (PRP) were considered non-responders. Missing values not preceded by these intercurrent events were imputed using the last observation carried forward method. Percentages are rounded off to the nearest decimal point. |
| Rate of Participants Developing a ≥ 3-Step Worsening From Baseline on the ETDRS-DRSS Through Week 52 | From Baseline through Week 52 | ETDRS-DRSS classifies diabetic retinopathy (DR) into 12 severity steps ranging from absence of retinopathy to advanced proliferative diabetic retinopathy (PDR). DRSS grades= 10 (DR absent) - 85 (very advanced PDR ), DRSS 90 = ungradable. All DRSS values are converted into a 12-level scale, from 1 (DR absent) to 12 (very advanced PDR), allowing derivation of ≥2-step change from baseline for post-baseline assessment. A lower score represents less advanced diabetic retinopathy. Composite strategy (i.e., considered to be an event) was applied to participants who received supplemental or prohibited therapy or PRP in the study eye. The rate of participants developing ≥ 3-step worsening on the ETDRS-DRSS was calculated using the KM method. |
| Percentage of Participants With a ≥ 2-Step Improvement From Baseline on the ETDRS-DRSS Over Time | Baseline up to Week 112 | ETDRS-DRSS classifies diabetic retinopathy (DR) into 12 severity steps ranging from absence of retinopathy to advanced proliferative diabetic retinopathy (PDR). DRSS grades= 10 (DR absent) - 85 (very advanced PDR), DRSS 90 = ungradable. All DRSS values are converted into a 12-level scale , from 1 (DR absent) to 12 (very advanced PDR), allowing derivation of ≥2-step change from baseline for post-baseline assessment. A lower score represents less advanced diabetic retinopathy. |
| Percentage of Participants With a ≥ 3-step Improvement From Baseline on the ETDRS-DRSS Over Time | Baseline up to Week 112 | ETDRS-DRSS classifies diabetic retinopathy (DR) into 12 severity steps ranging from absence of retinopathy to advanced proliferative diabetic retinopathy (PDR). DRSS grades= 10 (DR absent) - 85 (very advanced PDR ), DRSS 90 = ungradable. All DRSS values are converted into a 12-level scale , from 1 (DR absent) to 12 (very advanced PDR), allowing derivation of ≥2-step change from baseline for post-baseline assessment. A lower score represents less advanced diabetic retinopathy. |
| Time to First Development of Either PDR, ASNV, or CI-DME | Baseline up to Week 112 | — |
| Time to First Development of PDR or ASNV | Baseline up to Week 112 | — |
| Time to First Development of CI-DME | Baseline up to Week 112 | CI-DME is defined as CST ≥325 μm on SD-OCT. |
| Time to First Development of a ≥ 2-Step Worsening From Baseline on the ETDRS-DRSS | Baseline up to Week 112 | ETDRS-DRSS classifies diabetic retinopathy (DR) into 12 severity steps ranging from absence of retinopathy to advanced proliferative diabetic retinopathy (PDR). DRSS grades= 10 (DR absent) - 85 (very advanced PDR), DRSS 90 = ungradable. All DRSS values are converted into a 12-level scale, from 1 (DR absent) to 12 (very advanced PDR), allowing derivation of ≥2-step change from baseline for post-baseline assessment. A lower score represents less advanced diabetic retinopathy. |
| Time to First Development of a ≥ 3-Step Worsening From Baseline on the ETDRS-DRSS | Baseline up to Week 112 | ETDRS-DRSS classifies diabetic retinopathy (DR) into 12 severity steps ranging from absence of retinopathy to advanced proliferative diabetic retinopathy (PDR). DRSS grades= 10 (DR absent) - 85 (very advanced PDR), DRSS 90 = ungradable. All DRSS values are converted into a 12-level scale, from 1 (DR absent) to 12 (very advanced PDR), allowing derivation of ≥2-step change from baseline for post-baseline assessment. A lower score represents less advanced diabetic retinopathy. |
| Change From Baseline in Best-Corrected Visual Acuity (BCVA) as Measured on the ETDRS Chart Over Time | Baseline up to Week 112 | BCVA was measured at a starting test distance of 4 meters using a set of three Precision Vision\^TM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R). The BCVA letter score ranges from 0 to 100 (best score attainable), and a higher score indicates better visual acuity. |
| Percentage of Participants Who Lost <15, <10 and <5 Letters in BCVA From Baseline Over Time | Baseline up to Week 112 | BCVA was measured at a starting test distance of 4 meters using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R). The BCVA letter score ranges from 0 to 100 (best score attainable), and a higher score indicates better visual acuity. |
| Percentage of Participants With a BCVA Score of 69 Letters (20/40 Approximate Snellen Equivalent) or Better Over Time | Baseline up to Week 112 | BCVA is measured using the ETDRS visual acuity chart starting at a test distance of 4 meters. The number of letters read correctly, Snellen fraction are converted to a decimal scale. There are 11 lines on a standard Snellen chart ranging from 0.1 (20/200) at worst to 2.0 (20/10) at best. 20/20 on the decimal scale is equal to 1.0. The higher the number of letters read correctly (higher number on the decimal scale), the better the vision (or visual acuity). The Snellen equivalent of 20/40 or better is 69 or more letters correctly read in the ETDRS chart. |
| Change From Baseline in CST as Measured on SD-OCT Over Time | Baseline up to Week 112 | CST is defined as the average thickness of the central 1 millimeter (mm) circle of the ETDRS grid centered on the fovea measured between the internal limiting membrane and the Bruch's membrane. CST is measured using spectral domain optical coherence tomography (SD-OCT). A central reading center graded the SD-OCT digital images. A negative change from baseline value represents a reduction in macular edema. |
| Change From Baseline in Total Macular Volume (TMV) as Measured on SD-OCT Over Time | Baseline up to Week 112 | Total macular volume in cubic millimeter (mm\^3), is the calculated volume from the layers of the retina based off OCT imaging. TMV is measured using SD-OCT. |
| Number of Participants With Ocular Adverse Events (AEs) and Severity of Ocular AEs in the PDS Arm | From first dose of study drug through Week 52 | An adverse event is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product,regardless of causal attribution.An adverse event can therefore be any unfavourable \& unintended sign,symptom,or disease temporally associated with the use of a pharmaceutical product,whether considered related to the pharmaceutical product.Preexisting conditions which worsen during a study are also considered as adverse events.Ocular AEs are the events which are localized in the ocular region,graded according to the AE Severity Grading Scale as Mild:discomfort noticed,but no disruption of normal daily activity;Moderate:Discomfort sufficient to reduce or affect normal daily activity;Severe incapacitating with inability to work or to perform normal daily activity.Number of participants with ocular AEs in the study eye are reported in this outcome measure.As prespecified in the protocol, this outcome measure was applicable to participants in the PDS arm only. |
| Number of Participants With Non-ocular AEs in the PDS Arm | From first dose of study drug through Week 52 | An adverse event is any untoward medical occurrence in a clinical investigation participant subject administered a pharmaceutical product, regardless of causal attribution. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. As prespecified in the protocol, this outcome measure was applicable to participants in the PDS arm only. |
| Number of Participants With At Least One Ocular Adverse Events of Special Interest (AESI) in the PDS Arm | From first dose of study drug through Week 52 | An AE is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. Ocular AESI include vitreous hemorrhage; endophthalmitis; retinal detachment; conjunctival retraction; conjunctival erosion; conjunctival bleb or conjunctival filtering bleb leak; hyphema; cataract; device dislocation. As prespecified in the protocol, this outcome measure was applicable to participants in the PDS arm only. |
| Number of Participants With At Least One Ocular AESI During the Postoperative Period in the PDS Arm | From Day 1 to Day 37 Postoperative Period | An AE is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. Ocular AESI include vitreous hemorrhage; endophthalmitis; retinal detachment; conjunctival retraction; conjunctival erosion; conjunctival bleb or conjunctival filtering bleb leak; hyphema; cataract; device dislocation. The ocular AESIs in the study eye were categorized based on onset as, Postoperative Period: onset within 37 days post initial implantation. As prespecified in the protocol, this outcome measure was applicable to participants in the PDS arm only. |
| Serum Concentration of Ranibizumab Observed Over Time | Baseline up to week 112 | — |
| Pharmacokinetic (PK) Parameter Value Area Under the Concentration | At Baseline and multiple time points up to week 112 | — |
| Minimum Serum Concentration (Cmin) of Ranibizumab Observed Over Time | Baseline up to week 112 | — |
| Half-Life (t ½) of Ranibizumab Observed Over Time | Baseline up to Week 112 | — |
| Number of Participants With Anti-Drug Antibodies (ADAs) to Ranibizumab | Baseline up to Week 112 | The numbers of ADA-positive participants at baseline and after drug administration were to be summarized for participants exposed to Ranibizumab. PDS patients who were ADA positive at the reference visit and ADA titer increased after implant; in this case, the titer of one or more samples collected after implant must be at least 4-fold greater than the titer of the reference visit sample. These patients are considered to have treatment-enhanced ADA responses. |
| Number of Participants With Neutralizing Antibodies to Ranibizumab | Baseline up to Week 112 | The numbers of neutralizing antibodies positive participants at baseline and after drug administration were to be summarized for participants exposed to Ranibizumab. |
| Percentage of Participants Who do Not Undergo Supplemental Treatment With Intravitreal Ranibizumab Within Each Refill-Exchange Interval | Baseline up to Week 112 | — |
| Percentage of Participants With At Least One AE Related to Study Device or Procedure in the PDS Arm | From first dose of study drug through Week 52 | An AE related to study device or procedure is defined as any adverse event related to the use of an investigational medical device. This includes any adverse events resulting from insufficient or inadequate instructions for use, deployment, implantation, installation, operation, or any malfunction of the investigational medical device and any adverse event resulting from use error or from intentional misuse of the investigational medical device. PDS Device refers to the implant, insertion tool, initial fill needle, refill needle, and explant tool. PDS Procedure refers to the initial fill, implant insertion, refill-exchange, and explantation. As prespecified in the protocol, this outcome measure was applicable to participants in the PDS arm only. Percentages are rounded off to the nearest decimal point. |
| Percentage of Participants With Serious Adverse Effects Related to Study Device or Procedure in the PDS Arm | From Day 1 up to Week 52 | An AE related to study device or procedure is defined as any AE related to the use of an investigational medical device \& includes any AE resulting from insufficient or inadequate instructions for use, deployment, implantation, installation, operation, or any malfunction of the investigational medical device \& any AE resulting from use error or from intentional misuse of the investigational medical device. PDS refers to the implant, insertion tool, initial fill needle, refill needle \& explant tool. PDS procedure refers to the initial fill, implant insertion, refill-exchange, \& explantation. Any AE related to study device or procedure that resulted in any of a serious AE such as death, life-threatening illness or injury or permanent impairment of a body structure or a body function was considered serious. As prespecified in the protocol, this outcome measure was applicable to participants in the PDS arm only. Percentages are rounded off to the nearest decimal point. |
| Percentage of Participants With Absence of Intraretinal Fluid, Subretinal Fluid or Both Over Time | Baseline up to Week 112 | Absence of intraretinal fluid and subretinal fluid are measured in the central 1 mm subfield on SD-OCT. Percentages are rounded off to the nearest decimal point. |
| Percentage of Participants Who Report Preferring PDS Treatment to Intravitreal Ranibizumab Treatment, as Measured by the PDS Patient Preference Questionnaire (PPPQ) at Week 52 | Week 52 | The PPPQ is a 3-item questionnaire that captures a participant's preference for treatment (PDS or intravitreal injections), the strength of their preference (very strong, fairly strong, and not very strong) and the reasons for their preference (less worry or nervousness, requires less time for treatment, less discomfort, fewer treatments and other reason). As prespecified in the protocol, this outcome measure was applicable to participants in the PDS arm only. Percentages are rounded off to the nearest decimal point. |
| Number of Participants With Device Deficiencies | Baseline up to Week 52 | A device deficiency is defined as any inadequacy with respect to labeling, identity, quality, durability, reliability, usability, safety, or performance of an investigational device, including malfunctions, use errors, or inadequacy in information supplied by the manufacturer. As prespecified in the protocol, this outcome measure was applicable to participants in the PDS arm only and device deficiencies were to be recorded in the electronic capture system (EDC) after implementation of protocol Version 2 (i.e., for participants implanted after 14 June 2021). |
Countries
Puerto Rico, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
Participants were enrolled in this study at 50 investigative sites in the United States from 10 August 2020. The study is ongoing. The analyses presented in this results summary are based on a primary completion date (clinical cut-off) of 03 October 2022.
Pre-assignment details
A total of 174 participants with moderately severe or severe non-proliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) were randomized in a 5:3 ratio to either port delivery system (PDS) arm or comparator arm.
Participants by arm
| Arm | Count |
|---|---|
| PDS With Ranibizumab 100 mg/mL Participants received two loading doses of ranibizumab, 0.5 mg, as IVT before the PDS implant procedure. The first loading dose was on Day 1 followed by the second dose at Week 4. The PDS implant (pre-filled with ranibizumab 100 mg/mL) was surgically inserted 1 to 14 days after the second loading dose. Participants underwent PDS implant refill-exchange procedures (ranibizumab 100 mg/mL) Q36W thereafter until the end of study. | 106 |
| Comparator Arm Participants underwent study visits Q4W for observation and comprehensive clinical monitoring for the first 60 weeks. Thereafter, participants received two loading doses of ranibizumab, 0.5 mg, as IVT before the PDS implant procedure. The first loading dose was scheduled at Week 60 followed by the second dose at Week 64. The PDS implant (pre-filled with ranibizumab 100 mg/mL) was surgically inserted 1 to 14 days after the second loading dose. Participants underwent PDS implant refill-exchange procedures (ranibizumab 100 mg/mL) Q36W thereafter until the end of study. | 68 |
| Total | 174 |
Baseline characteristics
| Characteristic | PDS With Ranibizumab 100 mg/mL | Total | Comparator Arm |
|---|---|---|---|
| Age, Continuous | 53.7 years STANDARD_DEVIATION 11.32 | 53.9 years STANDARD_DEVIATION 11.68 | 54.1 years STANDARD_DEVIATION 12.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 43 Participants | 72 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 63 Participants | 102 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 4 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 17 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 18 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 8 Participants | 4 Participants |
| Race (NIH/OMB) White | 73 Participants | 125 Participants | 52 Participants |
| Sex: Female, Male Female | 47 Participants | 74 Participants | 27 Participants |
| Sex: Female, Male Male | 59 Participants | 100 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 106 |
| other Total, other adverse events | 89 / 105 |
| serious Total, serious adverse events | 17 / 105 |
Outcome results
Primary
Percentage of Participants With a ≥2-Step Improvement From Baseline on the Early Treatment Diabetic Retinopathy Study-Diabetic Retinopathy Severity Scale (ETDRS-DRSS) at Week 52
ETDRS-DRSS classifies diabetic retinopathy (DR) into 12 severity steps ranging from absence of retinopathy to advanced proliferative diabetic retinopathy (PDR). DRSS grades= 10 (DR absent) - 85 (very advanced PDR), DRSS 90 = ungradable. All DRSS values are converted into a 12-level scale, from 1 (DR absent) to 12 (very advanced PDR), allowing derivation of ≥2-step change from baseline for post-baseline assessment. A lower score represents less advanced diabetic retinopathy. The Cochran-Mantel Haenszel (CMH) method was used for analysis and weighted percentage of participants are estimated and reported in this outcome measure. Participants receiving supplemental treatments, prohibited therapy, or panretinal photocoagulation (PRP) were considered non-responders. Missing values not preceded by these intercurrent events were imputed using the last observation carried forward method. SD OCT= spectral-domain optical coherence tomography.
Time frame: Baseline, Week 52
Population: ITT Population included all participants who were randomized. Participants were grouped according to treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PDS With Ranibizumab 100 mg/mL | Percentage of Participants With a ≥2-Step Improvement From Baseline on the Early Treatment Diabetic Retinopathy Study-Diabetic Retinopathy Severity Scale (ETDRS-DRSS) at Week 52 | 80.1 percentage of participants |
| Comparator Arm | Percentage of Participants With a ≥2-Step Improvement From Baseline on the Early Treatment Diabetic Retinopathy Study-Diabetic Retinopathy Severity Scale (ETDRS-DRSS) at Week 52 | 9.0 percentage of participants |
p-value: <0.000195.04% CI: [61, 81.2]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Best-Corrected Visual Acuity (BCVA) as Measured on the ETDRS Chart Over Time
BCVA was measured at a starting test distance of 4 meters using a set of three Precision Vision\^TM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R). The BCVA letter score ranges from 0 to 100 (best score attainable), and a higher score indicates better visual acuity.
Time frame: Baseline up to Week 112
Secondary
Change From Baseline in CST as Measured on SD-OCT Over Time
CST is defined as the average thickness of the central 1 millimeter (mm) circle of the ETDRS grid centered on the fovea measured between the internal limiting membrane and the Bruch's membrane. CST is measured using spectral domain optical coherence tomography (SD-OCT). A central reading center graded the SD-OCT digital images. A negative change from baseline value represents a reduction in macular edema.
Time frame: Baseline up to Week 112
Secondary
Change From Baseline in Total Macular Volume (TMV) as Measured on SD-OCT Over Time
Total macular volume in cubic millimeter (mm\^3), is the calculated volume from the layers of the retina based off OCT imaging. TMV is measured using SD-OCT.
Time frame: Baseline up to Week 112
Secondary
Half-Life (t ½) of Ranibizumab Observed Over Time
Time frame: Baseline up to Week 112
Secondary
Minimum Serum Concentration (Cmin) of Ranibizumab Observed Over Time
Time frame: Baseline up to week 112
Secondary
Number of Participants With Anti-Drug Antibodies (ADAs) to Ranibizumab
The numbers of ADA-positive participants at baseline and after drug administration were to be summarized for participants exposed to Ranibizumab. PDS patients who were ADA positive at the reference visit and ADA titer increased after implant; in this case, the titer of one or more samples collected after implant must be at least 4-fold greater than the titer of the reference visit sample. These patients are considered to have treatment-enhanced ADA responses.
Time frame: Baseline up to Week 112
Secondary
Number of Participants With At Least One Ocular Adverse Events of Special Interest (AESI) in the PDS Arm
An AE is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. Ocular AESI include vitreous hemorrhage; endophthalmitis; retinal detachment; conjunctival retraction; conjunctival erosion; conjunctival bleb or conjunctival filtering bleb leak; hyphema; cataract; device dislocation. As prespecified in the protocol, this outcome measure was applicable to participants in the PDS arm only.
Time frame: From first dose of study drug through Week 52
Population: SE Population in the PDS arm included all participants randomized to PDS receiving at least one loading dose, or any participant who received the PDS implant prior to Week 52.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PDS With Ranibizumab 100 mg/mL | Number of Participants With At Least One Ocular Adverse Events of Special Interest (AESI) in the PDS Arm | 17 Participants |
Secondary
Number of Participants With At Least One Ocular AESI During the Postoperative Period in the PDS Arm
An AE is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. Ocular AESI include vitreous hemorrhage; endophthalmitis; retinal detachment; conjunctival retraction; conjunctival erosion; conjunctival bleb or conjunctival filtering bleb leak; hyphema; cataract; device dislocation. The ocular AESIs in the study eye were categorized based on onset as, Postoperative Period: onset within 37 days post initial implantation. As prespecified in the protocol, this outcome measure was applicable to participants in the PDS arm only.
Time frame: From Day 1 to Day 37 Postoperative Period
Population: SE Population in the PDS arm included all participants randomized to PDS receiving at least one loading dose, or any participant who received the PDS implant prior to Week 52.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PDS With Ranibizumab 100 mg/mL | Number of Participants With At Least One Ocular AESI During the Postoperative Period in the PDS Arm | Postoperative Period | 10 Participants |
| PDS With Ranibizumab 100 mg/mL | Number of Participants With At Least One Ocular AESI During the Postoperative Period in the PDS Arm | Follow-up Period | 9 Participants |
Secondary
Number of Participants With Device Deficiencies
A device deficiency is defined as any inadequacy with respect to labeling, identity, quality, durability, reliability, usability, safety, or performance of an investigational device, including malfunctions, use errors, or inadequacy in information supplied by the manufacturer. As prespecified in the protocol, this outcome measure was applicable to participants in the PDS arm only and device deficiencies were to be recorded in the electronic capture system (EDC) after implementation of protocol Version 2 (i.e., for participants implanted after 14 June 2021).
Time frame: Baseline up to Week 52
Population: SE Population in the PDS arm included all participants randomized to PDS receiving at least one loading dose, or any participant who received the PDS implant prior to Week 52. Overall number analyzed is the number of participants implanted after 14 June 2021.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PDS With Ranibizumab 100 mg/mL | Number of Participants With Device Deficiencies | 9 Participants |
Secondary
Number of Participants With Neutralizing Antibodies to Ranibizumab
The numbers of neutralizing antibodies positive participants at baseline and after drug administration were to be summarized for participants exposed to Ranibizumab.
Time frame: Baseline up to Week 112
Secondary
Number of Participants With Non-ocular AEs in the PDS Arm
An adverse event is any untoward medical occurrence in a clinical investigation participant subject administered a pharmaceutical product, regardless of causal attribution. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. As prespecified in the protocol, this outcome measure was applicable to participants in the PDS arm only.
Time frame: From first dose of study drug through Week 52
Population: Safety Evaluable (SE) Population in the PDS arm included all participants randomized to PDS receiving at least one loading dose, or any participant who received the PDS implant prior to Week 52.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PDS With Ranibizumab 100 mg/mL | Number of Participants With Non-ocular AEs in the PDS Arm | 59 Participants |
Secondary
Number of Participants With Ocular Adverse Events (AEs) and Severity of Ocular AEs in the PDS Arm
An adverse event is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product,regardless of causal attribution.An adverse event can therefore be any unfavourable & unintended sign,symptom,or disease temporally associated with the use of a pharmaceutical product,whether considered related to the pharmaceutical product.Preexisting conditions which worsen during a study are also considered as adverse events.Ocular AEs are the events which are localized in the ocular region,graded according to the AE Severity Grading Scale as Mild:discomfort noticed,but no disruption of normal daily activity;Moderate:Discomfort sufficient to reduce or affect normal daily activity;Severe incapacitating with inability to work or to perform normal daily activity.Number of participants with ocular AEs in the study eye are reported in this outcome measure.As prespecified in the protocol, this outcome measure was applicable to participants in the PDS arm only.
Time frame: From first dose of study drug through Week 52
Population: Safety Evaluable Population in the PDS arm included all participants randomized to PDS receiving at least one loading dose, or any participant who received the PDS implant prior to Week 52.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PDS With Ranibizumab 100 mg/mL | Number of Participants With Ocular Adverse Events (AEs) and Severity of Ocular AEs in the PDS Arm | Ocular AEs | 84 Participants |
| PDS With Ranibizumab 100 mg/mL | Number of Participants With Ocular Adverse Events (AEs) and Severity of Ocular AEs in the PDS Arm | Ocular AEs: Mild | 55 Participants |
| PDS With Ranibizumab 100 mg/mL | Number of Participants With Ocular Adverse Events (AEs) and Severity of Ocular AEs in the PDS Arm | Ocular AEs: Moderate | 21 Participants |
| PDS With Ranibizumab 100 mg/mL | Number of Participants With Ocular Adverse Events (AEs) and Severity of Ocular AEs in the PDS Arm | Ocular AEs: Severe | 8 Participants |
Secondary
Percentage of Participants Who do Not Undergo Supplemental Treatment With Intravitreal Ranibizumab Within Each Refill-Exchange Interval
Time frame: Baseline up to Week 112
Secondary
Percentage of Participants Who Lost <15, <10 and <5 Letters in BCVA From Baseline Over Time
BCVA was measured at a starting test distance of 4 meters using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R). The BCVA letter score ranges from 0 to 100 (best score attainable), and a higher score indicates better visual acuity.
Time frame: Baseline up to Week 112
Secondary
Percentage of Participants Who Report Preferring PDS Treatment to Intravitreal Ranibizumab Treatment, as Measured by the PDS Patient Preference Questionnaire (PPPQ) at Week 52
The PPPQ is a 3-item questionnaire that captures a participant's preference for treatment (PDS or intravitreal injections), the strength of their preference (very strong, fairly strong, and not very strong) and the reasons for their preference (less worry or nervousness, requires less time for treatment, less discomfort, fewer treatments and other reason). As prespecified in the protocol, this outcome measure was applicable to participants in the PDS arm only. Percentages are rounded off to the nearest decimal point.
Time frame: Week 52
Population: ITT Population included all participants who were randomized. Overall number analyzed is the number of participants who completed the questionnaire.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PDS With Ranibizumab 100 mg/mL | Percentage of Participants Who Report Preferring PDS Treatment to Intravitreal Ranibizumab Treatment, as Measured by the PDS Patient Preference Questionnaire (PPPQ) at Week 52 | 76.6 percentage of participants |
Secondary
Percentage of Participants With a ≥ 2-Step Improvement From Baseline on the ETDRS-DRSS Over Time
ETDRS-DRSS classifies diabetic retinopathy (DR) into 12 severity steps ranging from absence of retinopathy to advanced proliferative diabetic retinopathy (PDR). DRSS grades= 10 (DR absent) - 85 (very advanced PDR), DRSS 90 = ungradable. All DRSS values are converted into a 12-level scale , from 1 (DR absent) to 12 (very advanced PDR), allowing derivation of ≥2-step change from baseline for post-baseline assessment. A lower score represents less advanced diabetic retinopathy.
Time frame: Baseline up to Week 112
Secondary
Percentage of Participants With a ≥ 3-Step Improvement From Baseline on the ETDRS-DRSS at Week 52
ETDRS-DRSS classifies diabetic retinopathy (DR) into 12 severity steps ranging from absence of retinopathy to advanced proliferative diabetic retinopathy (PDR). DRSS grades= 10 (DR absent) - 85 (very advanced PDR ), DRSS 90 = ungradable. All DRSS values are converted into a 12-level scale, from 1 (DR absent) to 12 (very advanced PDR), allowing derivation of ≥2-step change from baseline for post-baseline assessment. A lower score represents less advanced diabetic retinopathy. Participants receiving supplemental treatments, prohibited therapy, or panretinal photocoagulation (PRP) were considered non-responders. Missing values not preceded by these intercurrent events were imputed using the last observation carried forward method. Percentages are rounded off to the nearest decimal point.
Time frame: Week 52
Population: ITT Population included all participants who were randomized. Participants were grouped according to treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PDS With Ranibizumab 100 mg/mL | Percentage of Participants With a ≥ 3-Step Improvement From Baseline on the ETDRS-DRSS at Week 52 | 15.1 percentage of participants |
| Comparator Arm | Percentage of Participants With a ≥ 3-Step Improvement From Baseline on the ETDRS-DRSS at Week 52 | 0 percentage of participants |
p-value: 0.000395.04% CI: [8.3, 21.9]Fisher Exact
Secondary
Percentage of Participants With a ≥ 3-step Improvement From Baseline on the ETDRS-DRSS Over Time
ETDRS-DRSS classifies diabetic retinopathy (DR) into 12 severity steps ranging from absence of retinopathy to advanced proliferative diabetic retinopathy (PDR). DRSS grades= 10 (DR absent) - 85 (very advanced PDR ), DRSS 90 = ungradable. All DRSS values are converted into a 12-level scale , from 1 (DR absent) to 12 (very advanced PDR), allowing derivation of ≥2-step change from baseline for post-baseline assessment. A lower score represents less advanced diabetic retinopathy.
Time frame: Baseline up to Week 112
Secondary
Percentage of Participants With a BCVA Score of 69 Letters (20/40 Approximate Snellen Equivalent) or Better Over Time
BCVA is measured using the ETDRS visual acuity chart starting at a test distance of 4 meters. The number of letters read correctly, Snellen fraction are converted to a decimal scale. There are 11 lines on a standard Snellen chart ranging from 0.1 (20/200) at worst to 2.0 (20/10) at best. 20/20 on the decimal scale is equal to 1.0. The higher the number of letters read correctly (higher number on the decimal scale), the better the vision (or visual acuity). The Snellen equivalent of 20/40 or better is 69 or more letters correctly read in the ETDRS chart.
Time frame: Baseline up to Week 112
Secondary
Percentage of Participants With Absence of Intraretinal Fluid, Subretinal Fluid or Both Over Time
Absence of intraretinal fluid and subretinal fluid are measured in the central 1 mm subfield on SD-OCT. Percentages are rounded off to the nearest decimal point.
Time frame: Baseline up to Week 112
Secondary
Percentage of Participants With At Least One AE Related to Study Device or Procedure in the PDS Arm
An AE related to study device or procedure is defined as any adverse event related to the use of an investigational medical device. This includes any adverse events resulting from insufficient or inadequate instructions for use, deployment, implantation, installation, operation, or any malfunction of the investigational medical device and any adverse event resulting from use error or from intentional misuse of the investigational medical device. PDS Device refers to the implant, insertion tool, initial fill needle, refill needle, and explant tool. PDS Procedure refers to the initial fill, implant insertion, refill-exchange, and explantation. As prespecified in the protocol, this outcome measure was applicable to participants in the PDS arm only. Percentages are rounded off to the nearest decimal point.
Time frame: From first dose of study drug through Week 52
Population: SE Population in the PDS arm included all participants randomized to PDS receiving at least one loading dose, or any participant who received the PDS implant prior to Week 52.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PDS With Ranibizumab 100 mg/mL | Percentage of Participants With At Least One AE Related to Study Device or Procedure in the PDS Arm | 70.5 percentage of participants |
Secondary
Percentage of Participants With Serious Adverse Effects Related to Study Device or Procedure in the PDS Arm
An AE related to study device or procedure is defined as any AE related to the use of an investigational medical device & includes any AE resulting from insufficient or inadequate instructions for use, deployment, implantation, installation, operation, or any malfunction of the investigational medical device & any AE resulting from use error or from intentional misuse of the investigational medical device. PDS refers to the implant, insertion tool, initial fill needle, refill needle & explant tool. PDS procedure refers to the initial fill, implant insertion, refill-exchange, & explantation. Any AE related to study device or procedure that resulted in any of a serious AE such as death, life-threatening illness or injury or permanent impairment of a body structure or a body function was considered serious. As prespecified in the protocol, this outcome measure was applicable to participants in the PDS arm only. Percentages are rounded off to the nearest decimal point.
Time frame: From Day 1 up to Week 52
Population: SE Population in the PDS arm included all participants randomized to PDS receiving at least one loading dose, or any participant who received the PDS implant prior to Week 52.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PDS With Ranibizumab 100 mg/mL | Percentage of Participants With Serious Adverse Effects Related to Study Device or Procedure in the PDS Arm | 1.0 percentage of participants |
Secondary
Pharmacokinetic (PK) Parameter Value Area Under the Concentration
Time frame: At Baseline and multiple time points up to week 112
Secondary
Rate of Participants Developing a ≥ 2-Step Worsening From Baseline on the ETDRS-DRSS Through Week 52
ETDRS-DRSS classifies diabetic retinopathy (DR) into 12 severity steps ranging from absence of retinopathy to advanced proliferative diabetic retinopathy (PDR). DRSS grades= 10 (DR absent) - 85 (very advanced PDR ), DRSS 90 = ungradable. All DRSS values are converted into a 12-level scale, from 1 (DR absent) to 12 (very advanced PDR), allowing derivation of ≥2-step change from baseline for post-baseline assessment. A lower score represents less advanced diabetic retinopathy. Composite strategy (i.e., considered to be an event) was applied to participants who received supplemental or prohibited therapy or PRP in the study eye. The rate of participants developing ≥ 2-step worsening on the ETDRS-DRSS was calculated using the KM method.
Time frame: From Baseline through Week 52
Population: ITT Population included all participants who were randomized. Participants were grouped according to treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PDS With Ranibizumab 100 mg/mL | Rate of Participants Developing a ≥ 2-Step Worsening From Baseline on the ETDRS-DRSS Through Week 52 | 3.0 percentage of participants |
| Comparator Arm | Rate of Participants Developing a ≥ 2-Step Worsening From Baseline on the ETDRS-DRSS Through Week 52 | 46.4 percentage of participants |
p-value: <0.000195.04% CI: [0.1, 0.2]Stratified Log-Rank
Secondary
Rate of Participants Developing a ≥ 3-Step Worsening From Baseline on the ETDRS-DRSS Through Week 52
ETDRS-DRSS classifies diabetic retinopathy (DR) into 12 severity steps ranging from absence of retinopathy to advanced proliferative diabetic retinopathy (PDR). DRSS grades= 10 (DR absent) - 85 (very advanced PDR ), DRSS 90 = ungradable. All DRSS values are converted into a 12-level scale, from 1 (DR absent) to 12 (very advanced PDR), allowing derivation of ≥2-step change from baseline for post-baseline assessment. A lower score represents less advanced diabetic retinopathy. Composite strategy (i.e., considered to be an event) was applied to participants who received supplemental or prohibited therapy or PRP in the study eye. The rate of participants developing ≥ 3-step worsening on the ETDRS-DRSS was calculated using the KM method.
Time frame: From Baseline through Week 52
Population: ITT Population included all participants who were randomized. Participants were grouped according to treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PDS With Ranibizumab 100 mg/mL | Rate of Participants Developing a ≥ 3-Step Worsening From Baseline on the ETDRS-DRSS Through Week 52 | 3.0 percentage of participants |
| Comparator Arm | Rate of Participants Developing a ≥ 3-Step Worsening From Baseline on the ETDRS-DRSS Through Week 52 | 45.1 percentage of participants |
p-value: <0.000195.04% CI: [0.1, 0.2]Stratified Log-Rank
Secondary
Rate of Participants Developing a Vision-Threatening Complication or Center-involved Diabetic Macular Edema (CI-DME) Through Week 52
A vision threatening complication is defined as proliferative DR (PDR) or anterior segment neovascularization (ASNV) or center-involved diabetic macular edema (CI-DME). CI-DME is defined as central foveal thickness (CST) ≥325 micrometres (μm) on spectral-domain optical coherence tomography (SD-OCT). Composite strategy (i.e., considered to be an event) was applied to participants who received supplemental or prohibited therapy or PRP in the study eye. The rate of participants was calculated using the Kaplan-Meier (KM) method.
Time frame: From Baseline through Week 52
Population: ITT Population included all participants who were randomized. Participants were grouped according to treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PDS With Ranibizumab 100 mg/mL | Rate of Participants Developing a Vision-Threatening Complication or Center-involved Diabetic Macular Edema (CI-DME) Through Week 52 | 7.1 percentage of participants |
| Comparator Arm | Rate of Participants Developing a Vision-Threatening Complication or Center-involved Diabetic Macular Edema (CI-DME) Through Week 52 | 47.0 percentage of participants |
p-value: <0.000195.04% CI: [0.1, 0.3]Stratified Log-Rank
Secondary
Rate of Participants Developing CI-DME Through Week 52
CI-DME is defined as CST ≥325 μm on SD-OCT. The KM method was used for analysis, and estimated in terms of event rate. Composite strategy (i.e., considered to be an event) was applied to participants who received supplemental or prohibited therapy or PRP in the study eye.
Time frame: From Baseline through Week 52
Population: ITT Population included all participants who were randomized. Participants were grouped according to treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PDS With Ranibizumab 100 mg/mL | Rate of Participants Developing CI-DME Through Week 52 | 7.1 percentage of participants |
| Comparator Arm | Rate of Participants Developing CI-DME Through Week 52 | 47.0 percentage of participants |
p-value: <0.000195.04% CI: [0.1, 0.3]Stratified Log-Rank
Secondary
Rate of Participants Developing PDR or ASNV Through Week 52
The KM method was used for analysis, and estimates are in terms of event rate. Composite strategy (i.e., considered to be an event) was applied to participants who received supplemental or prohibited therapy or PRP in the study eye.
Time frame: From Baseline through Week 52
Population: ITT Population included all participants who were randomized. Participants were grouped according to treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PDS With Ranibizumab 100 mg/mL | Rate of Participants Developing PDR or ASNV Through Week 52 | 1.0 percentage of participants |
| Comparator Arm | Rate of Participants Developing PDR or ASNV Through Week 52 | 42.4 percentage of participants |
p-value: <0.000195.04% CI: [0.1, 0.1]Stratified Log-Rank
Secondary
Serum Concentration of Ranibizumab Observed Over Time
Time frame: Baseline up to week 112
Secondary
Time to First Development of a ≥ 2-Step Worsening From Baseline on the ETDRS-DRSS
ETDRS-DRSS classifies diabetic retinopathy (DR) into 12 severity steps ranging from absence of retinopathy to advanced proliferative diabetic retinopathy (PDR). DRSS grades= 10 (DR absent) - 85 (very advanced PDR), DRSS 90 = ungradable. All DRSS values are converted into a 12-level scale, from 1 (DR absent) to 12 (very advanced PDR), allowing derivation of ≥2-step change from baseline for post-baseline assessment. A lower score represents less advanced diabetic retinopathy.
Time frame: Baseline up to Week 112
Secondary
Time to First Development of a ≥ 3-Step Worsening From Baseline on the ETDRS-DRSS
ETDRS-DRSS classifies diabetic retinopathy (DR) into 12 severity steps ranging from absence of retinopathy to advanced proliferative diabetic retinopathy (PDR). DRSS grades= 10 (DR absent) - 85 (very advanced PDR), DRSS 90 = ungradable. All DRSS values are converted into a 12-level scale, from 1 (DR absent) to 12 (very advanced PDR), allowing derivation of ≥2-step change from baseline for post-baseline assessment. A lower score represents less advanced diabetic retinopathy.
Time frame: Baseline up to Week 112
Secondary
Time to First Development of CI-DME
CI-DME is defined as CST ≥325 μm on SD-OCT.
Time frame: Baseline up to Week 112
Secondary
Time to First Development of Either PDR, ASNV, or CI-DME
Time frame: Baseline up to Week 112
Secondary
Time to First Development of PDR or ASNV
Time frame: Baseline up to Week 112