Multicenter 12 Months Clinical Study to Evaluate Efficacy and Safety of Ranibizumab Alone or in Combination With Laser Photocoagulation vs. Laser Photocoagulation Alone in Proliferative Diabetic Retinopathy (PRIDE)

Study Overview
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Brief Summary
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The purpose of this study was to assess the efficacy and safety of the anti-Vascular Endothelial Growth Factor (VEGF) agent ranibizumab (0.5 mg) with or without Panretinal laser photocoagulation (PRP) compared to PRP alone in patients with Proliferative Diabetic Retinopathy (PDR).

Detailed Description
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A 12-month core phase was followed by a 12-month observational follow-up phase (physician's routine), for a planned individual study duration of 24-25 months. A separate informed consent was signed for the 12-month observational follow-up phase. This study was conducted in Germany.

Official Title
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Multicenter Randomized Open-label Three-arms Controlled 12 Months Clinical Proof of Concept Study to Evaluate Efficacy and Safety of Ranibizumab Alone or in Combination With Laser Photocoagulation vs. Laser Photocoagulation Alone in Proliferative Diabetic Retinopathy

Conditions
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Proliferative Diabetic Retinopathy (PDR)

Intervention / Treatment
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* Drug: Ranibizumab 0.5 mg
* Procedure: Panretinal laser photocoagulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Proliferative Diabetic Retinopathy Best Corrected Visual Acuity (BCVA) in study eye of at least 20 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (20/400) Type 1 or type 2 diabetes under medical surveillance / with stabilized treatment Exclusion Criteria: Proliferative vitreoretinopathy in study eye Clinically significant macular edema (CSME) in the study eye Clinically non significant macular edema (CNSME) that is likely to develop to CSME in the study eye Uncontrolled glaucoma in either eye Other protocol-specified conditions

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ranibizumab mono<br>Interventional Core Phase: One intravitreal injection of ranibizumab 0.5 mg to the study eye monthly until stability regarding morphological parameters is confirmed (ie, no further improvement of morphology or no worsening of morphology for 3 consecutive months) | Drug: Ranibizumab 0.5 mg<br>* Pre-filled syringe for intravitreal injection<br>* Other names: RFB002;|
| Active Comparator: PRP mono<br>Interventional Core Phase: Panretinal laser photocoagulation (PRP) treatment administered to the study eye in accordance with the modified diabetic retinopathy study (DRS) guidelines for panretinal laser photocoagulation procedures | Procedure: Panretinal laser photocoagulation<br>* PRP treatment following DRS guidelines<br>* Other names: PRP;|
| Experimental: Ranibizumab+PRP<br>Interventional Core Phase: Ranibizumab 0.5 mg as described for the ranibizumab mono arm and PRP treatment as described for the PRP mono arm until stability regarding morphological parameters is confirmed | Drug: Ranibizumab 0.5 mg<br>* Pre-filled syringe for intravitreal injection<br>* Other names: RFB002;Procedure: Panretinal laser photocoagulation<br>* PRP treatment following DRS guidelines<br>* Other names: PRP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Area of Neovascularizations (NVs) at End of Core Study (EOCS) | The area of neovascularizations (NV) was assessed by a central reading center via fluorescein angiography (FA) images. The area of NV was calculated as the sum of area of neovascularization of the disc (NVD) and neovascularization elsewhere (NVE) and was recorded in square millimeters. A higher positive change value may indicate a greater formation of new, abnormal blood vessels and thus disease progression. One eye (study eye) contributed to the analysis. | Baseline, EOCS | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Area of Neovascularizations (NVs) at Month 3 | The area of neovascularizations (NV) was assessed by a central reading center via fluorescein angiography (FA) images. The area of NV was calculated as the sum of area of neovascularization of the disc (NVD) and neovascularization elsewhere (NVE) and was recorded in square millimeters. A higher positive change value may indicate a greater formation of new, abnormal blood vessels and thus disease progression. One eye (study eye) contributed to the analysis. | Baseline, Month 3 | 
| Best Corrected Visual Acuity (BCVA) (ETDRS Letters) at EOCS | BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS)-like charts at a testing distance of 4 meters. A higher number of ETDRS letters may indicate better visual acuity. One eye (study eye) contributed to the analysis. | EOCS | 
| Percentage of Patients With Change From Baseline in BCVA (ETDRS Letters) at EOCS | BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS)-like charts at a testing distance of 4 meters. No clinically relevant change was defined as <5 letters gain or loss. A higher positive change value may indicate a greater improvement in visual acuity. One eye (study eye) contributed to the analysis. | Baseline, EOCS | 
| Number of Patients With Change From Baseline in ETDRS Severity Grade of Diabetic Retinopathy (DR) at EOCS | The severity level of diabetic retinopathy was determined using the ETDRS severity scale. However, in contrast to the original ETDRS severity scale, wide field fluorescein angiography images were used in addition to color fundus photography for identification of NVs and prior PRP treatment was not considered for determining the severity level. Eyes could be graded in the following classes: DR absent (10), questionable DR (14,15), NPDR (20-53), mild PDR (60-61), moderate PDR (65), high risk PDR (71-75), advanced PDR (81-85) and cannot grade (90). One eye (study eye) contributed to the analysis. No statistical analysis was conducted for ≥ 1 class deterioration or ≥ 2 class deterioration from Baseline at EOCS because ratios could not be calculated in case of zero frequencies in at least one of the three treatment groups. | Baseline, EOCS | 
| Change From Baseline in Central Subfield Thickness at EOCS | Central subfield retinal thickness was assessed by a central reading center using Optical Coherence Tomography images. A positive change value may indicate disease progression. One eye (study eye) contributed to the analysis. | Baseline, EOCS | 
| Change From Baseline in Foveal Center Point Retinal Thickness at EOCS | Foveal center point retinal thickness was assessed by a central reading center using Optical Coherence Tomography images. A positive change value may indicate disease progression. One eye (study eye) contributed to the analysis. | Baseline, EOCS | 
| Number of Ranibizumab Injections Until EOCS | The total number of ranibizumab injections until EOCS was calculated. One eye (study eye) contributed to the analysis. No statistical analysis was conducted. | Baseline to EOCS | 
| Number of PRP Laser Spots Until EOCS | The total number of PRP laser spots from baseline until EOCS was calculated. One eye (study eye) contributed to the analysis. No statistical analysis was conducted. | Baseline to EOCS | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Panretinal photocoagulation, Ranibizumab