Extension Study to Compare Long-term Efficacy and Safety of Ranibizumab Intravitreal Injections Versus Dexamethasone Intravitreal Implant in Patients With RVO

Study Overview
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Brief Summary
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The study is intended to characterize the clinical benefit regarding safety and efficacy of a long term treatment with Lucentis in comparison with Ozurdex over an additional 6 months and a 3-month follow-up period, following the initial 6-month treatment in the respective core studies CRFB002EDE17 (NCT01396057) and CRFB002EDE18 (NCT01396083).

Official Title
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An Open-label, Multi-center, 6-month Extension Study Comparing the Long-term Efficacy and Safety of Lucentis (Ranibizumab) Intravitreal Injections Versus Ozurdex (Dexamethasone) Intravitreal Implant in Patients With Visual Impairment Due to Macular Edema Following Branch Retinal Vein Occlusion (BRVO) or Central Retinal Vein Occlusion (CRVO) Who Have Completed the Respective Core Study (CRFB002EDE17 or CRFB002EDE18)

Conditions
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Retinal Vein Occlusion

Intervention / Treatment
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* Biological: RFB002
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have completed the core study assessments at month 6 of study CRFB002EDE17 or CRFB002EDE18, respectively Exclusion Criteria: Patients who experienced an uncontrollable rise in IOP during the core study CRFB002EDE17 respectively CRFB002EDE18, i.e. IOP could not be decreased to a stable level of < 25mmHg. Use of other investigational drugs Current use or likely need of systemic medications known to be toxic to the lens, retina or optic nerve History of hypersensitivity to Ranibizumab or Ozurdex or any component of the ranibizumab respectively Ozurdey formulation Any type of advanced, severe or unstable disease or its treatment, that could interfere with evaluations or put the patient at special risk Women who were pregnant or breast feeding (pregnancy defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (>5 mIU/mL) who were menstruating and capable of becoming pregnant* and not practicing a medically approved method of contraception (Pearl Index <1**)*** during and up to at least 4 weeks after the end of treatment. A negative pregnancy test (serum) for all women and for girls entering menarche was required with sufficient lead time before randomization definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels >40 mIU/mL or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy examples of particularly reliable methods with Pearl Index (PI) <1, according to guidelines of Deutsche Gesellschaft für Gynäkologie und Geburtshilfe: Combination pill with estrogen and gestagen (no mini-pill, PI=0.1-0.9) Vaginal ring (NuvaRing®, PI=0.65 uncorr.; 0.4 corr.) Contraceptive patch (EVRA®, PI= 0.72 uncorr.; 0.9 corr.) Estrogen-free ovulation inhibitors (Cerazette®, PI=0.14) Progestin-containing contraceptives (Implanon®, PI=0-0.08) Injectable 3-month depot progestins (PI=0.3-1.4; 0.88 corr.) Intra-uterine progestin device (Mirena®, PI=0.16)

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ranibizumab (Arm A)<br>The PRN injection scheme applied in the core study will also be followed during this extension study: Patients should be monitored monthly (starting at V1E) for VA and treatment is to be resumed when monitoring indicates loss of VA due to disease activity. Monthly injections should then be administered until stable VA is reached again for 3 consecutive monthly assessments (implying a minimum of 2 injections during stable VA). The interval between 2 doses should not be shorter than 1 month | Biological: RFB002<br>* 0.5 mg/0.05 mL solution to be injected intravitreally. Ranibizumab was formulated as a sterile solution aseptically filled in a sterile glass vial. Each vial contained ranibizumab in an aqueous solution (pH 5.5) with histidine, trehalose and polysorbate 20.<br>|
| Sham Comparator: Dexamethasone (Arm B)<br>A PRN re-treatment scheme will be applied for the Ozurdex arm during this extension study, i.e. patients may receive an implant at V1E or later as needed: Patients should be monitored monthly and if there is a decline from stable VA stability due to macular edema patients will receive another intravitreal implant. (700 µg; long acting release (LAR)) given that in the opinion of the investigator the patient would benefit from the re-treatment. However, a minimum period of 5 months in between implantations is required. | Drug: Dexamethasone<br>* Ozurdex (Dexamethasone): intravitreal implant as per commercial label (700 µg Dexamethasone; Dexamethasone was formulated as a rod shaped implant to be inserted into the eye by an applicator. The implant as well as the respective applicator were suitable for single use only. Dexamethasone had to be stored according to label instructions and it had to be kept in a secure locked facility<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | The number of participants who experienced Adverse events, serious AE and death | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Raw Mean Best Corrected Visual Acuity (BCVA) by Treatment Group | Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (EDTRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. An ETDRS visual acuity score of 85 is approximately 20/20. The range of BCVA (EDTRS) is 0 to 100 letters. A positive change from baseline of BCVA indicates improvement | Baseline, 6 months and 12 months | 
| Percentage of Patients Gaining / Losing ≥ 15 / 10 / 5 Letters at Month 12 Compared to Baseline | BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An ETDRS visual acuity score of 85 is approximately 20/20. An increased score indicates improvement in acuity. This outcome assessed the percentage of participants who were gaining/losing ≥15, 10 or 5 more letters of visual acuity at month 12 as compared with baseline | 12 month | 
| Change in Central Subfield Thickness (CSRT) From Baseline to Month 12 | High Resolution OCT was performed at every study visit by Spectral Domain OCT (if not available Time Domain OCT was acceptable) and the images were transferred to a digital video disc. These assessments were performed by trained and adequately qualified experts at the sites and prior to any study drug administration. CSFT is the average retinal thickness of the circular area with 1 mm diameter around the foveal center. | Baseline , Month 12 | 
| Change of Foveal Center Point Thickness (FCPT) From Baseline to Month 12 | FCPT (foveal center point thickness) was assessed by central reading center to ensure error- corrected measurements of retinal thickness and volumes, | Baseline, Month 12 | 
| Change in Mean Visual Function Questionnaire (VFQ-25) | The VFQ-25 composite and subscale scores range from 0 to 100, a higher score indicating better functioning. The 12 subscales in the VFQ-25 are general health, general vision, ocular pain, near activities, distance activities, social function, mental health, role difficulties, dependency, driving, color vision, and peripheral vision. The scores on the subscales were added together for a total score, which ranged from 0 to 100. A higher score indicated improvement in quality of life due to vision function. | Baseline, 12 months | 
| Change in SF-36 Summary Scores | The SF-36 measures the impact of disease on overall quality of life and consists of eight subscales (physical function, pain, general and mental health, vitality, social function, physical and emotional health) which can be aggregated to derive a physical-component summary score and a mental-component summary score. Scores for each subscale range from 0 to 10, and the composite scores range from 0 to 100, with higher scores indicating better health. A positive change from Baseline score indicates improvement in quality of life. | Baseline, month 12 | 
| Change in Euro Quality of Life Questionnaire (EQ-5D) VAS Summary Scores | The Euro Quality of Life Questionnaire (EQ-5D) standardized instrument was utilized to measure health outcomes related to mobility, self care, usual activities, pain/discomfort, and anxiety/depression. Participants self-rate their health on a visual, vertical analogue scale from 0 to 100 where the endpoints are labeled Best imaginable health state (100) and worst imaginable health state (0). | Baseline, month 12 | 
| Time to the First Retreatment of Both Treatment Arms | Time to the first retreatment | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Macular Degeneration, Macular Edema, Retinal Vein Occlusion, Choroidal Neovascularization, Signs and Symptoms, Retinal Degeneration, Retinal Diseases, Eye Diseases, Venous Thrombosis Sensation Disorders, Dexamethasone acetate, Dexamethasone, Dexamethasone 21-phosphate, BB 1101, Anti-Inflammatory Agents, Therapeutic Uses, Vision, Low, Signs, Vision Disorders