E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Visual impairment due to diabetic macular edema |
|
E.1.1.1 | Medical condition in easily understood language |
Impaired vision due to vessels leakage in the retina which is caused by an intrinsic substance, so-called vascular endothelial growth factor (VEGF) |
|
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 | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012689 |
E.1.2 | Term | Diabetic retinopathy |
E.1.2 | System Organ Class | 10015919 - Eye disorders |
|
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 demonstrate that the mean average change of BCVA in patients with DME treated with ranibizumab injections at the discretion of the investigator (DI) and in accordance with disease activity criteria is non-inferior to current standard of care (PRN). |
|
E.2.2 | Secondary objectives of the trial |
To evaluate:
• Mean change of visual acuity by comparing change of BCVA in ETDRS letters between baseline and month 12
• Frequency of visits and injections, treatment free and visit intervals
• mean change of central subfield retinal thickness (CSRT) and foveal center point thickness from baseline will be evaluated by central reading center assessing OCT images
• change in DRS retinopathy scale evaluated by central reading center scoring fundus photography
• Influence of relevant HbA1c-, blood pressure and blood lipid levels changes on primary objective (ANCOVA Analysis)
|
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
optional pharmacogenetic sub-studies:
• Pharmacogenetic Evaluations
• Contrast Sensitivity
• Microperimetry (visual field assessment) incl. QOL-assessment (NEI VFQ-25)
• Functional parameters with autofluoerescence assessment
• Functional parameters with near infrared assessment
• Functional parameters with Multi-Color assessment
• Movement-patterns and pedometry incl. QOL-assessment (NEI VFQ-25)
|
|
E.3 | Principal inclusion criteria |
Patient:
1. Male or female patients > 18 years of age giving written Informed Consent and who are willing and capable to comply with all study procedures.
2. Patients with Type 1 or Type 2 diabetes mellitus with glycosylated hemoglobin (HbA1c) ≤ 12.0% (107 mmol/mol) at screening (Visit 1).
Inclusion criteria for the study eye at screening:
3. Patients with visual impairment due to DME in at least one eye. If both eyes are eligible, the one with the worse visual acuity, as assessed at Visit 1, will be selected by the investigator as the study eye.
4. BCVA ≥ 24 and ≤ 78 letters in the study eye, using ETDRS-like visual acuity testing charts at a testing distance of 4 resp. 1 meters (approximate Snellen equivalent of 20/32 to 20/320) at screening.
5. Concomitant conditions in the study eye are only permitted if, they do not prevent improvement of visual acuity on study treatment
|
|
E.4 | Principal exclusion criteria |
Patient Compliance/ Administrative:
1. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG test.
2. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment.
Ocular medical history:
3. Active intraocular inflammation (grade trace or above) in either eye at enrollment.
4. Any active infection (e.g. conjunctivitis, keratitis, scleritis, endophthalmitis) in either eye at the time of enrollment.
5. History of uveitis (any cause) in either eye at any time.
6. Structural damage within 0.5 disc diameter of the center of the macular in the study eye likely to preclude improvement in visual acuity following the resolution of macular edema, including atrophy of the retinal pigment epithelium, subretinal fibrosis, laser scar(s).
7. Patients with both, a BCVA score of > 73 letters and a central subfield thickness (CSFT) of < 300 μm in the study eye.
8. Uncontrolled glaucoma in either eye at screening (IOP > 24 mmHg on medication or according to investigator’s judgment).
9. Neovascularization of the iris in either eye.
10. Vitreous hemorrhage impairing the adequate diagnosis of DME in the study eye
11. Evidence of clinically relevant vitreofoveal adhesion in the opinion of the investigator, vitreofoveal traction with foveal involvement or epiretinal membrane with foveal involvement in the study eye that is likely to prevent improvement of BCVA loss due to DME.
12. Proliferative vitreoretinopathy in study eye.
13. History of retinal detachment, retinal tear or macular hole in the study eye.
14. Neovascularization covering an area of ≥ 2 disc areas within the macula (defined as area with 6mm diameter centered on the fovea), originating either from neovascularization of the disc or multiple neovascularization’s elsewhere in study eye.
15. Patients who are monocular or have a BCVA score in the non-study eye (fellow eye) < 24 letters (approximate Snellen equivalent of 20/320) at Visit 1.
Prior and planned Ocular treatments:
16. Any intraocular surgery in the study eye within 4 months prior to randomization.
17. Vitrectomy/vitreoretinal surgery
a. In the medical history or planned for study eye
b. planned vitrectomy or vitrectomy in last 3 months in fellow eye
18. Planned medical or surgical intervention during the 12-months study period likely to interfere with study schedule or outcomes.
19. Panretinal laser or focal/grid laser photocoagulation in the study eye within 3 months prior to randomization unless sufficient documentation of laser photocoagulation in that period of time is available.
20. Treatment with anti-angiogenic drugs (pegaptanib sodium, anecortave acetate, bevacizumab, ranibizumab, VEGF-Trap, etc.)
- within 3 months prior to randomization for study eye
- within 1 month prior randomization for fellow eye.
21. Use of other investigational drugs at the time of enrollment, or within 3 months or 5 half-lives from enrollment, whichever is longer.
22. History of intravitreal corticosteroid treatment in phakic study eye.
23. Intravitreal corticosteroids in post-cataract surgery study eye (aphakic or pseudophakic, without damaged posterior capsule) within 3 months or 6 months for dexamethasone implant (Ozurdex®) or 3 years for fluocinolone implant (Iluvien®) prior to randomization.
24. Ocular conditions in the study eye that require chronic concomitant therapy with topical ocular corticosteroids.
Systemic conditions or treatments
25. History of stroke within 4 months prior to enrollment.
26. Renal failure requiring dialysis or renal transplant.
27. Untreated diabetes mellitus.
28. Blood pressure systolic > 160 mmHg or diastolic > 100 mmHg at screening and/or randomization.
29. Conditions that require chronic concomitant therapy with systemically administered corticosteroids.
30. Current use of or likely need for systemic medications known to be toxic to the lens, retina or optic nerve, including Deferoxamine, Chloroquine/ hydroxychloroquine (Plaquenil), Tamoxifen, Phenothiazines and Ethambutol.
31. Use of any systemic anti-VEGF drugs within 3 months prior to Screening (e.g. bevacizumab [Avastin®], ziv-aflibercept [Zaltrap®]).
32. Known hypersensitivity to fluorescein or ranibizumab or any component thereof or drugs of similar chemical classes.
33. Any type of advanced, severe or unstable disease or its treatment, that may interfere with primary and/or secondary variable evaluations including any medical condition that could be expected to progress, recur, or change to such an extent that it may bias the assessment of the clinical status of the patient to a significant degree or put the patient at special risk. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
To demonstrate that the mean average change of BCVA in patients with DME treated with ranibizumab injections at the discretion of the investigator (DI) and in accordance with disease activity criteria is non-inferior to current standard of care (PRN). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Evaluation of:
• Mean change of visual acuity by comparing change of BCVA in ETDRS letters between baseline and month 12
• Frequency of visits and injections, treatment free and visit intervals
• mean change of central subfield retinal thickness (CSRT) and foveal center point thickness from baseline will be evaluated by central reading center assessing OCT images
• change in DRS retinopathy scale evaluated by central reading center scoring fundus photography
• Influence of relevant HbA1c-, blood pressure and blood lipid levels changes on primary objective (ANCOVA Analysis)
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | No |
E.6.5 | Efficacy | No |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
standard Lucentis treatment regimen |
|
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 | 40 |
E.8.5 | The trial involves multiple Member States | No |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |