| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Visual impairment due to diabetic macula edema |
|
| E.1.1.1 | Medical condition in easily understood language |
| Impaired vision due to an edema in the area of the macula 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 | 17.0 |
| 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 |
| To compare systemic VEGF-A protein levels following monthly intravitreal injections of 0.5 mg ranibizumab versus 2 mg aflibercept as measured by the area under the curve (AUC) from baseline to study week 12. |
|
| E.2.2 | Secondary objectives of the trial |
To compare systemic VEGF-A protein levels in patients switching from monthly 2 mg aflibercept injections to monthly 0.5 mg ranibizumab compared to patients treated with monthly 0.5 mg ranibizumab from baseline as measured by the AUC from study week 12 to week 24.
To explore whether systemic VEGF-A levels of patients switching from aflibercept to ranibizumab will adjust to levels comparable to baseline or to levels comparable as in patients treated from baseline with ranibizumab from study week 12, over time up to week 24. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria for patient:
1. Male or female patients, ≥ 18 years of age.
2. Written informed consent must be obtained before any study-related assessment is performed.
Inclusion criteria for study eye:
3. Type 1 or Type 2 diabetes mellitus according to ADA (2014) and/or WHO (2006) classifications (see Appendix 2, Table A2-2) with glycosylated hemoglobin (HbA1c) ≤ 10% (≤ 86 mmol/mol) at screening. Patients should be on diet, exercise and/or pharmacological treatment for diabetes, which must have been stable for at least 3 months.
4. Visual impairment predominantly due to DME. |
|
| E.4 | Principal exclusion criteria |
Exclusion criteria for systemic medical history and conditions:
1. Any type of systemic disease or its treatment, including any medical condition (controlled or uncontrolled) 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.
2. Stroke or myocardial infarction less than 3 months prior to screening.
3. Presence of uncontrolled systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg at the time of screening or baseline.
4. Renal failure requiring dialysis or renal transplant or renal insufficiency with creatinine levels >2.0 mg/dl at screening.
5. Untreated diabetes mellitus
6. Known hypersensitivity to any of the study drugs or to drugs with similar chemical structures or to fluorescein or any other component of fluorescein formulation.
Exclusion criteria for ocular medical history and conditions:
For either eye:
7. Any active periocular or ocular infection or inflammation at the time of screening or baseline
8. Uncontrolled glaucoma (intraocular pressure [IOP] ≥30 mm Hg on medication or according to investigator’s judgment) at the time of screening or baseline.
9. Neovascularization of the iris or neovascular glaucoma at the time of screening or baseline.
For study eye:
10. Atrophy or fibrosis involving the center of the fovea at the time of screening or baseline.
11. Cataract (if causing significant visual impairment), planned cataract surgery during the study period, vitrectomy, aphakia, glaucoma surgery, severe vitreous hemorrhage, rhegmatogenous retinal detachment, proliferative retinopathy or choroidal neovascularization or macular edema of any other cause than DME at the time of screening or baseline.
12. Irreversible structural damage within 0.5 disc diameter of the center of the macula (e.g., vitreomacular traction, epiretinal membrane, scar, laser burn, macular hole) at the time of screening or baseline that in the investigator’s opinion could preclude visual function improvement with treatment.
For fellow eye:
13. Retinal or choroidal neovascularization or macula edema of any cause at the time of screening or baseline or the anticipation of development of the above mentioned medical conditions within 3 months past screening or baseline.
Exclusion criteria for prior or current systemic medication:
14. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives from screening, whichever is longer.
15. Use of any systemic anti-VEGF drugs (e.g., bevacizumab [Avastin®], ziv-aflibercept [Zaltrap®]).
16. Use of systemic or inhaled corticosteroids for at least 30 consecutive days within 3 months prior to screening.
17. Current or planned use of systemic medications known to be toxic to the lens, retina or optic nerve, including deferoxamine, chloroquine/hydroxychloroquine (Plaquenil®), tamoxifen, phenothiazines and ethambutol.
Exclusion criteria for prior or current ocular treatment:
For study eye:
18. Panretinal laser photocoagulation within 6 months prior to randomization.
19. Focal/grid laser photocoagulation within 3 months prior to randomization.
20. Any intraocular procedure (including cataract surgery, Yttrium-Aluminum-Garnet capsulotomy) within 3 months prior to baseline or anticipated within the next 6 months following baseline.
21. Topical ocular corticosteroids administered for at least 30 consecutive days within 3 months prior to screening.
22. Application of intravitreal corticosteroids (incl. corticosteroid releasing implant, e.g. Ozurdex®) in vitreous within 6 months prior to screening. Prior application of fluocinolonacetonid releasing implant (Iluvien®) in vitreous within 36 months prior to screening.
For either eye:
23. History of treatment with any anti-angiogenic drugs (including any anti-VEGF agents, e.g., bevacizumab [Avastin®]).
Exclusion criteria for patient:
24. Inability to comply with study or follow-up procedures.
25. Inability to give full informed consent.
26. Women
o who are 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)).
o who are menstruating and capable of becoming pregnant* and not practicing a medically approved method of contraception (Pearl Index <1**) during and up to at least 3 months after the end of treatment. A negative pregnancy test (serum) for all women and for girls entering menarche is required with sufficient lead time before inclusion.
27. Patients, who have already been randomized into this trial earlier must not be included a second time.
28. Study personnel or first degree relatives of investigator(s) must not be included in the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Comparison of systemic VEGF-A protein levels following monthly intravitreal injections of 0.5 mg ranibizumab versus 2 mg aflibercept as measured by the area under the curve (AUC).
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Comparison of systemic VEGF-A protein levels in patients switching from monthly 2 mg aflibercept injections to monthly 0.5 mg ranibizumab compared to patients treated with monthly 0.5 mg ranibizumab from baseline as measured by the AUC from study week 12 to week 24.
Exploration whether systemic VEGF-A levels of patients switching from aflibercept to ranibizumab will adjust to levels comparable to baseline or to levels comparable as in patients treated from baseline with ranibizumab from study week 12, over time up to week 24. |
|
| 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 | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| 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 | No |
| 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 |
|
| 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 | 7 |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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