A Multicenter, Randomized Study in Participants With Diabetic Retinopathy Without Center-involved Diabetic Macular Edema To Evaluate the Efficacy, Safety, and Pharmacokinetics of Ranibizumab Delivered Via the Port Delivery System Relative to the Comparator Arm

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.

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.

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.

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.

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.

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.

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.

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.

CI-DME is defined as CST ≥325 μm on SD-OCT.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The numbers of neutralizing antibodies positive participants at baseline and after drug administration were to be summarized for participants exposed to Ranibizumab.

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.

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.

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.

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.

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).