E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
visual impairment due to macular edema following central retinal vein occlusion (CRVO) |
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E.1.1.1 | Medical condition in easily understood language |
visual impairment due to macular edema following central retinal vein occlusion |
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E.1.1.2 | Therapeutic area | Diseases [C] - Eye Diseases [C11] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054467 |
E.1.2 | Term | Macular edema |
E.1.2 | System Organ Class | 100000004853 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to show that ranibizumab (administered in an individualized treatment regimen) has superior efficacy and safety compared to Dexamethasone implant (Ozurdex®) over a 6 months period. |
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E.2.2 | Secondary objectives of the trial |
•To compare the mean BCVA change at Month 6 from Baseline in patients treated with Ozurdex® versus patients treated with ranibizumab
•To compare the percentage of patients gaining / losing >= 15, >= 10 and >= 5 letters after the 6-month treatment of ranibizumab versus Ozurdex® compared to baseline.
•To compare the time to achieve a significant improvement >= 15 letters under treatment of ranibizumab versus Ozurdex®
•To evaluate whether ranibizumab has a higher change over time in BCVA compared with Ozurdex® from Baseline to Month 6
•To compare the change over time of the central retinal thickness after the 6-month treatment
•To compare changes in the quality of life according to NEI-VFQ 25, SF36 and EQ-5D questionnaires under treatment of ranibizumab versus Ozurdex® from Baseline to Month 6
•To compare the increase rate of the internal ocular pressure under the treatment of ranibizumab versus Ozurdex®
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male and female patients aged >= 18 years
2. Patients diagnosed with visual impairment due to macular edema following CRVO; diagnosis of CRVO at maximum 6 months prior to Screening
The following definition of CRVO will be used for the purposes of this study:
An eye that has retinal hemorrhages or other biomicroscopic evidence of CRVO (e.g. telangiectatic capillary bed) and a dilated venous system (or previously dilated venous system) in three quadrants or more of the retina drained by the affected vein. The presence of a CRVO will be centrally assessed by fluorescein angiography.
3. BCVA using ETDRS charts of 20/40 (6/12 in metres)to 20/400(6/120 in metres) in the study eye
4. Signed Informed Consent
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E.4 | Principal exclusion criteria |
1. Media clarity, pupillary dilation and patient cooperation not sufficient for adequate fundus photographs
2. Central retinal thickness (CRT) < 250 µm in the study eye
3. Prior episode of RVO in the study eye
4. History of radial optic neurotomy or sheathotomy in the study eye
5. History or presence of AMD (dry or wet form) in the study eye
6. Active neovascularization in the study eye
7. Aphakia in the study eye
8. Anti-VEGF-treatment in the study or the fellow eye 3 months prior to Baseline
9. Panretinal scatter photocoagulation or sector laser photocoagulation within 3 months prior to Baseline or anticipated within the next 4 months following randomization
10. Intraocular corticosteroid use within 6 months prior to Baseline
11. History of pars plana vitrectomy
12. Intraocular surgery within 2 months prior to Baseline or anticipated within the next 6 months following randomization
13. Yttrium-aluminium-garnet (YAG) capsulotomy performed within 2 months prior to Baseline
14. Combined arterio-venous occlusion
15. Previous filtration surgery in the study eye
16-19 History of herpetic ocular infection, ocular toxoplasmosis, macular detachment or central serous chorioretinopathy
20. Evidence upon examination of vitreoretinal interface disease (e.g. vitreomacular traction, epiretinal membrane), either on clinical examination or OCT, thought to be contributing to macular edema
21. An eye that, in the investigator’s opinion, would not benefit from resolution of macular edema, such as eyes with foveal atrophy, dense pigmentary changes, or dense subfoveal hard exudates
22. Any active infection in either eye (internal or external)
23. IOP >= 30mmHg or uncontrolled glaucoma; patients may be re-screened after 1 month if they have undergone glaucoma treatment
24. Known steroid responders
25. Any ocular condition that, in the opinion of the investigator, would alter the study outcome (e.g. uveitis or other ocular inflammatory disease, neovascular glaucoma, Irvine-Gass syndrome, or prior macula-off rhegmatogenous retinal detachment)
26. Visually significant hemorrhage obscuring the fovea and felt to be a major contributor to visual acuity. The patient should be followed and when the hemorrhage in the fovea clears to the point that it is not longer considered to be a major contributor to reduced visual acuity, the patient may be screened for the study.
27. Presence of a substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by 3 lines or more (i.e. a 20/40 cataract)
28. Evidence upon examination of pseudoexfoliationglaucom
29. Evidence upon examination of any diabetic retinopathy, defined as eyes of diabetic patients with more than one microaneurysm outside the area of the vein occlusion (includes the study eye as well as the partner eye)
30. Relevant ocular disease that may be associated with increased intraocular VEGF levels (namely uveitis, neovascular glaucoma, neovascular AMD, diabetic retinopathy, diabetic maculopathy, or ocular ischemic syndrome)
31. History of cerebral vascular accident or myocardial infarction within 12 months prior to Baseline
32. Improvement of > 10 letters on BCVA between Screening and Baseline.
33. Relevant systemic disease that may be associated with increased systemic VEGF levels (namely all active malignancies; history of successfully treated malignancies is not an exclusion criterion)
34. Uncontrolled blood pressure (defined as a systolic value of > 180 mmHg and a diastolic value of > 110 mmHg).
If a patient’s initial reading exceeds these values, a second reading may be taken 30 minutes (or more) later. Patients with uncontrolled blood pressure should be referred to a specialist for cardiovascular diseases. If a patient’s blood pressure needs to be controlled by antihypertensive medication, the patient can become eligible if medication is taken continuously for at least 30 days prior to Baseline.
35. Women who are pregnant or breast feeding or menstruating and capable of becoming pregnant and not practicing a medically approved method of contraception during and up to at least 4 weeks after the end of treatment.
36. Current or anticipated use of systemic steroids or anticoagulants (e.g. coumadin, warfarin or heparin; the use of aspirin or clopidogrel is not excluded)
37. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer
38-9 History of hypersensitivity to any of the study drugs or to drugs with similar chemical structures or allergy to fluorescein
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective of this study is to demonstrate the superiority of ranibizumab regarding the change in BCVA from baseline to month 6 compared to dexamethasone implant. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
For the binary secondary endpoints (VA gain/loss ≥ 15/10letters), the absolute and relative frequencies will be tabulated. For treatment comparisons, the difference in proportions and the Odds Ratio will be calculated with the respective confidence intervals and p-values. The time courses of BCVA changes will be displayed graphically (LS-means and treatment contrasts with confidence limits at each measurement time). Time to VA gain ≥ 15 will be analyzed by the Kaplan-Maier-Method. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 70 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 15 |