A Phase 4 interventional study of RFB002 and Dexamethasone in Retinal Vein Occlusion, sponsored by Novartis Pharmaceuticals. Completed at 37 sites in Germany. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2016-05-17.
Sponsored by Novartis Pharmaceuticals · Phase 4, Interventional, and Treatment
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).
282 studies on the registry are indexed under Retinal Vein Occlusion; 27 are open to participants now.
This study's enrollment of 175 is above the median of 49 across 211 interventional studies indexed under Retinal Vein Occlusion.
Browse Retinal Vein Occlusion studies →Novartis Pharmaceuticals is the lead sponsor of 2,673 studies on the registry; 228 are open to participants now.
Of its 576 completed or terminated interventional studies of FDA-regulated products, 431 (75%) have results posted.
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Exclusion Criteria:
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":
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
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
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.
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
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
Time frame: 6 months
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
Time frame: 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
Time frame: 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.
Time frame: 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,
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: Baseline, month 12
Time to the First Retreatment of Both Treatment Arms
Time to the first retreatment
Time frame: 6 months
A total of 140 patients with (BRVO) completed the core study CRFB002EDE17, and 127 patients with (CRVO) completed the core study CRFB002EDE18. 92 patients with BRVO and 83 patients with CRVO were enrolled into the extension study. A total of 175 patients (113 in the ranibizumab group and 62 in the dexamethasone group) were enrolled
| Milestone | Ranibizumab (BRVO) | Dexamethasone (BRVO) | Ranibizumab (CRVO) | Dexamethasone (CRVO) |
|---|---|---|---|---|
| Started | 52 | 40 | 61 | 22 |
| Completed | 51 | 33 | 57 | 20 |
| Not completed | 1 | 7 | 4 | 2 |
| Withdrew: Lack of efficacy | 0 | 5 | 0 | 1 |
| Withdrew: Withdrawal by subject | 0 | 1 | 1 | 0 |
| Withdrew: Adverse event | 1 | 1 | 1 | 1 |
| Withdrew: Administrative problems | 0 | 0 | 1 | 0 |
| Withdrew: Lost to follow-up | 0 | 0 | 1 | 0 |
The number of participants who experienced Adverse events, serious AE and death
| Participants | Ranibizumab (BRVO) | Dexamethasone (BRVO) | Ranibizumab (CRVO) | Dexamethasone (CRVO) |
|---|---|---|---|---|
| Adverse event | 35 | 28 | 45 | 16 |
| Serious adverse event | 2 | 3 | 6 | 1 |
| Death | 0 | 0 | 0 | 0 |
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
| Letters read correctly | Ranibizumab (BRVO) | Dexamethasone (BRVO) | Ranibizumab (CRVO) | Dexamethasone (CRVO) |
|---|---|---|---|---|
| Baseline | 56.8 ± 10.0 | 58.3 ± 10.8 | 53.8 ± 15.7 | 53.2 ± 16.1 |
| Month 6 | 77.9 ± 10.6 | 69.2 ± 11.9 | 72.6 ± 13.5 | 64.1 ± 24.0 |
| Month 12 | 79.0 ± 10.1 | 70.6 ± 13.9 | 72.6 ± 15.8 | 66.6 ± 22.3 |
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
| Percentage of participants | Ranibizumab (BRVO) | Dexamethasone (BRVO) | Ranibizumab (CRVO) | Dexamethasone (CRVO) |
|---|---|---|---|---|
| Gain≥15 letters | 80.8 | 50.0 | 58.3 | 45.5 |
| Gain ≥10 letters | 88.5 | 65.0 | 75.0 | 68.2 |
| Gain ≥5 letters | 100.0 | 80.0 | 86.7 | 77.3 |
| Loss of ≥15 letters | 0.0 | 7.5 | 0.0 | 4.5 |
| Loss of ≥10 letters | 0.0 | 10.0 | 0.0 | 4.5 |
| Loss of ≥5 letters | 0.0 | 10.0 | 3.3 | 4.5 |
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.
| um | Ranibizumab (BRVO) | Dexamethasone (BRVO) | Ranibizumab (CRVO) | Dexamethasone (CRVO) |
|---|---|---|---|---|
| Change in Central Subfield Thickness (CSRT) From Baseline to Month 12 | -288.1 ± 180.6 | -211.5 ± 199.3 | -374.6 ± 239.8 | -360.3 ± 260.2 |
FCPT (foveal center point thickness) was assessed by central reading center to ensure error- corrected measurements of retinal thickness and volumes,
| um | Ranibizumab (BRVO) | Dexamethasone (BRVO) | Ranibizumab (CRVO) | Dexamethasone (CRVO) |
|---|---|---|---|---|
| Change of Foveal Center Point Thickness (FCPT) From Baseline to Month 12 | -341.8 ± 226.2 | -252.6 ± 197.9 | -439.4 ± 279.8 | -432.3 ± 245.8 |
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.
| Scores on a scale | Ranibizumab (BRVO) | Dexamethasone (BRVO) | Ranibizumab (CRVO) | Dexamethasone (CRVO) |
|---|---|---|---|---|
| Overall Composite | 8.1 ± 10.6 | 5.5 ± 11.3 | 9.1 ± 15.5 | 10.0 ± 15.9 |
| General Health | -1.4 ± 15.2 | 6.3 ± 18.6 | 1.7 ± 18.9 | 5.7 ± 20.3 |
| General Vision | 15.0 ± 16.7 | 9.5 ± 16.3 | 20.0 ± 17.7 | 13.6 ± 23.4 |
| Ocular Pain | 5.3 ± 15.7 | 5.3 ± 13.8 | 4.2 ± 20.8 | 3.4 ± 15.0 |
| Near Activities | 13.3 ± 18.9 | 10.8 ± 20.6 | 12.3 ± 20.5 | 12.3 ± 23.2 |
| Distance Activities | 8.9 ± 17.5 | 5.6 ± 15.3 | 7.8 ± 18.3 | 8.3 ± 23.4 |
| Social Functioning | 3.4 ± 16.8 | 2.2 ± 12.0 | 3.3 ± 16.7 | 2.8 ± 21.1 |
| Mental Health | 10.2 ± 14.9 | 2.9 ± 20.4 | 10.7 ± 21.7 | 15.1 ± 18.3 |
| Role Difficulties | 4.8 ± 26.8 | 10.6 ± 20.5 | 14.6 ± 29.9 | 24.4 ± 27.8 |
| Dependency | 3.2 ± 9.2 | 0.4 ± 16.6 | 5.1 ± 16.7 | 4.4 ± 12.8 |
| Driving (BRVO n=44,31) (CRVO n=42,16) | 11.7 ± 23.9 | 4.8 ± 21.3 | 14.2 ± 24.6 | 17.7 ± 25.1 |
| Color Vision(BRVO n=52,39) | 0.5 ± 10.5 | 1.9 ± 10.6 | 0.4 ± 17.5 | -1.1 ± 14.4 |
| Peripheral Vision(BRVO n=51,40) | 10.3 ± 24.1 | 6.9 ± 23.3 | 11.7 ± 25.0 | 14.8 ± 22.7 |
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.
| Score on a scale | Ranibizumab (BRVO) | Dexamethasone (BRVO) | Ranibizumab (CRVO) | Dexamethasone (CRVO) |
|---|---|---|---|---|
| Physical Component(BRVO n=50,39) (CRVO n=58,20) | 1.6 ± 5.0 | 0.2 ± 7.0 | -1.1 ± 8.2 | 1.3 ± 7.2 |
| Mental Component (BRVO n=50,39) (CRVO n=58,20) | 3.3 ± 9.7 | 2.1 ± 13.2 | 2.1 ± 9.3 | 2.4 ± 12.4 |
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).
| Score on a scale | Ranibizumab (BRVO) | Dexamethasone (BRVO) | Ranibizumab (CRVO) | Dexamethasone (CRVO) |
|---|---|---|---|---|
| Change in Euro Quality of Life Questionnaire (EQ-5D) VAS Summary Scores | 3.3 ± 15.2 | 2.6 ± 16.9 | 1.5 ± 16.4 | 0.2 ± 20.4 |
Time to the first retreatment
| Days | Ranibizumab (BRVO) | Dexamethasone (BRVO) | Ranibizumab (CRVO) | Dexamethasone (CRVO) |
|---|---|---|---|---|
| Time to the First Retreatment of Both Treatment Arms | 37 (3 to 56) | NA (328 to NA) | 62 (5 to 67) | NA (309 to NA) |
Non-serious events are listed at a 3% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Ranibizumab (BRVO) | — | 2/52 (3.8%) | 35/52 (67.3%) |
| Dexamethasone (BRVO) | — | 3/40 (7.5%) | 28/40 (70%) |
| Ranibizumab (CRVO) | — | 6/61 (9.8%) | 45/61 (73.8%) |
| Dexamethasone (CRVO) | — | 1/22 (4.5%) | 16/22 (72.7%) |
| Event | Ranibizumab (BRVO) | Dexamethasone (BRVO) | Ranibizumab (CRVO) | Dexamethasone (CRVO) |
|---|---|---|---|---|
| RETINAL DETACHMENT (Study eye)Eye disorders | 0/52 | 0/40 | 0/61 | 1/22 |
| VITREOUS HAEMORRHAGE (Study eye)Eye disorders | 0/52 | 0/40 | 1/61 | 1/22 |
| INTERVERTEBRAL DISC PROTRUSIONMusculoskeletal and connective tissue disorders | 1/52 | 1/40 | 0/61 | 0/22 |
| ROTATOR CUFF SYNDROMEMusculoskeletal and connective tissue disorders | 0/52 | 1/40 | 0/61 | 0/22 |
| LUMBAR RADICULOPATHYNervous system disorders | 0/52 | 1/40 | 0/61 | 0/22 |
| PSORIASISSkin and subcutaneous tissue disorders | 0/52 | 1/40 | 0/61 | 0/22 |
| PULMONARY EMBOLISMRespiratory, thoracic and mediastinal disorders | 1/52 | 0/40 | 0/61 | 0/22 |
| GLAUCOMA (Fellow eye)Eye disorders | 0/52 | 0/40 | 1/61 | 0/22 |
| GLAUCOMA (Study eye)Eye disorders | 0/52 | 0/40 | 1/61 | 0/22 |
| IRIS NEOVASCULARISATION (Study eye)Eye disorders | 0/52 | 0/40 | 1/61 | 0/22 |
| Event | Ranibizumab (BRVO) | Dexamethasone (BRVO) | Ranibizumab (CRVO) | Dexamethasone (CRVO) |
|---|---|---|---|---|
| INTRAOCULAR PRESSURE INCREASED (Study eye)Investigations | 3/52 | 10/40 | 3/61 | 4/22 |
| MACULAR OEDEMA (Study eye)Eye disorders | 9/52 | 3/40 | 14/61 | 3/22 |
| NASOPHARYNGITISInfections and infestations | 9/52 | 3/40 | 12/61 | 3/22 |
| EYE PAIN (Study eye)Eye disorders | 4/52 | 0/40 | 7/61 | 4/22 |
| CONJUNCTIVAL HAEMORRHAGE (Study eye)Eye disorders | 2/52 | 7/40 | 3/61 | 3/22 |
| OCULAR HYPERAEMIA (Study eye)Eye disorders | 7/52 | 3/40 | 4/61 | 3/22 |
| VISUAL ACUITY REDUCED (Study eye)Eye disorders | 4/52 | 4/40 | 8/61 | 1/22 |
| LACRIMATION INCREASED (Study eye)Eye disorders | 6/52 | 2/40 | 2/61 | 2/22 |
| OCULAR DISCOMFORT (Study eye)Eye disorders | 2/52 | 4/40 | 1/61 | 0/22 |
| RETINAL ISCHAEMIA (Study eye)Eye disorders | 5/52 | 4/40 | 2/61 | 0/22 |
| Age, Continuous(Years) | Ranibizumab | Dexamethasone | Total |
|---|---|---|---|
| Mean | 65.6 ± 9.9 | 63.3 ± 10.3 | 64.8 ± 10.1 |
| Sex: Female, Male(Participants) | Ranibizumab | Dexamethasone | Total |
|---|---|---|---|
| Female | 64 | 26 | 90 |
| Male | 49 | 36 | 85 |
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Novartis Pharmaceuticals