E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diabetic Macular Edema (DME) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10057934 |
E.1.2 | Term | Diabetic macular edema |
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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 of this study is to demonstrate superiority of ranibizumab 0.5 mg as adjunctive or mono-therapy to laser treatment in the mean change from baseline in BCVA over a 12-month treatment period. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are •to evaluate whether ranibizumab (0.5 mg) as adjunctive or mono-therapy is superior to laser treatment -in the number of patients with visual acuity above 73 letters and -in the number of patients with improvement in BCVA. •to evaluate the time course of BCVA changes on ranibizumab (0.5 mg) adjunctive and mono-therapy relative to laser treatment •to evaluate the effects of ranibizumab (0.5 mg) adjunctive and mono-therapy on central retinal thickness and other anatomical changes relative to laser treatment •to evaluate the effects of ranibizumab (0.5 mg) adjunctive and mono-therapy on patient-reported outcomes (PROs) relative to laser treatment •to evaluate the safety of intravitreal injections of ranibizumab (0.5 mg) as adjunctive and mono-therapy in patients with DME overall and relative to laser treatment.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female patients >18 years of age who have signed an informed consent 2. Patients with Type 1 or Type 2 diabetes mellitus (according to ADA or WHO Guidelines) with HbA1c not more than 10.0% at screening (Visit 1). Patients should be on diet, exercise, and/or pharmacological treatment for diabetes. 3. Patients with visual impairment due to focal or diffuse DME in at least one eye who are eligible for laser treatment in the opinion of the investigator. If both eyes are eligible, the eye with the worse visual acuity, as assessed at Visit 1, will be selected for study treatment, unless, based on medical reasons, the investigator deems the other eye the more appropriate to receive study treatment. The study eye must fulfill the following criteria at Visit 1: • BCVA score between 78 and 39 letters, inclusively, using ETDRS-like visual acuity testing charts at a testing distance of 4 meters (approximate Snellen equivalent of 20/32 to 20/160) • Decrease in vision is due to DME and not due to other causes, in the opinion of the investigator 4. Medication for the management of diabetes must have been stable within 3 months prior to randomization and is expected to remain stable during the course of the study. |
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E.4 | Principal exclusion criteria |
Ocular concomitant conditions/ diseases 1. Concomitant conditions in the study eye which could, in the opinion of the investigator, prevent the improvement of visual acuity on study treatment 2. Active intraocular inflammation (grade trace or above) in either eye 3. Any active infection (e.g. conjunctivitis, keratitis, scleritis, uveitis, endophthalmitis) in either eye 4. History of uveitis in either eye 5. Structural damage within 0.5 disc diameter of the center of the macula 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), epiretinal membrane involving fovea or organized hard exudate plaques 6. Ocular disorders in the study eye that may confound interpretation of study results, compromise visual acuity or require medical or surgical intervention during the 12-month study period, including cataract, retinal vascular occlusion, retinal detachment, macular hole, or choroidal neovascularization of any cause (e.g., AMD, ocular histoplasmosis, or pathologic myopia) 7. Uncontrolled glaucoma in either eye (e.g. IOP > 24 mmHg on medications, or according to investigator’s judgement) 8. Neovascularization of the iris in either eye 9. Evidence of vitreomacular traction in either eye 10. Active proliferative diabetic retinopathy in the study eye 11. 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
Ocular treatments 12. Panretinal laser photocoagulation in the study eye within 6 months prior to or during the study 13. Focal/grid laser photocoagulation in the study eye within 3 months prior to study entry 14. Treatment with anti-angiogenic drugs (pegaptanib sodium, anecortave acetate, bevacizumab, ranibizumab, etc.) in study eye within 3 months prior to randomization 15. Any intraocular surgery in the study eye within 3 months prior to randomization 16. History of vitrectomy in study eye 17. History of intravitreal corticosteroid treatment in phakic study eye 18. Intravitreal corticosteroids in post-cataract surgical study eyes (aphakic or pseudophakic without damaged posterior capsule) within 3 months prior to randomization 19. Ocular conditions in the study eye that require chronic concomitant therapy with topical ocular or systemically administered corticosteroids
Systemic conditions or treatments 20. History of stroke 21. Renal failure requiring dialysis or renal transplant OR renal insufficiency with creatinine levels > 2.0 mg/dl 22. Untreated diabetes mellitus 23. Blood pressure systolic > 160 mmHg or diastolic > 100 mmHg 24. Untreated hypertension or change in antihypertensive treatment within 3 months preceding Baseline 25. 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 26. Known hypersensitivity to ranibizumab or any component of the ranibizumab formulation or fluorescein 27. Any type of advanced, severe or unstable disease or it`s treatment, that could interfere with primary and/or secondary outcome evaluations including any medical condition that could be expected to progress, recur, or change to such an extend that it may bias the assessment of the clinical status of the patient to a significant degree or put the patient at special risk
Compliance/ Administrative 28. Previous participation in any clinical studies of investigational drugs (excluding vitamins and minerals) within 1 month (or a period corresponding to 5 half-lives of the investigational drug, whatever is longer) prior to randomization 26. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant. including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods. The two methods can be a double barrier method or a barrier method plus a hormonal method. Adequate barrier methods of contraception include: diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide. Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent. 27. Pregnant or nursing (lactating) women 28. Inability to comply with study or follow-up procedures. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary variable will be the difference between the average level of BCVA (letters) over all monthly post-baseline assessments from Month 1 to Month 12 and the baseline level of BCVA. |
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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 | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Information not present in EudraCT |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 63 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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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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Provided in the protocol. |
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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 | |
E.8.9.1 | In the Member State concerned days | |
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 | 10 |