| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Male and female patients >18 years of age with either type 1 or type 2 diabetes mellitus with stable HbA1c levels between 6.5 and 10% and diabetic macular edema with center involvement in at least one eye. |
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| MedDRA Classification |
| 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 explore whether the activity of ranibizumab (6 and/or 10 mg/ml) treatment is superior to sham treatment in reducing macular edema from baseline to Month 6 in patients diagnosed with DME with center involvement. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to explore the effect of ranibizumab treatment on visual acuity and retinal structure, and the need for photocoagulation. Additional secondary objectives are to evaluate the safety of ranibizumab administered as multiple doses to patients diagnosed with DME involving the center of the macula, based on rates of ocular and non-ocular adverse events.
The exploratory objectives:
to be assessed at selected sites include an assessment of the effect of ranibizumab treatment on visual function encompassing contrast sensitivity and reading performance, as well as patient reported outcome measures. Additional exploratory endpoints performed at selected sites include an assessment of ranibizumab treatment effects on the Early Treatment Diabetic Retinopathy Severity Score and the area of retinal capillaries loss. |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| 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 diagnosed ≥24 months prior to screening and a documented history of stable HbA1c ≥6.5% and ≤9.5% at the time of screening (stable HbA1c values are defined as those that do not differ at monthly assessments by more than 0.5% HbA1c). Any one of the following will be considered to be sufficient evidence that diabetes is present
•Current regular use of insulin for the treatment of diabetes
•Current regular use of oral antihyperglycemia agents for the treatment of diabetes
•Documented diabetes by ADA and/or WHO criteria
3.Patients with diabetic macular edema with center involvement in at least one eye, including those with focal or diffuse DME, as demonstrated with stereoscopic fundus photography, fluorescein angiography and optical coherence tomography within 28 days of the baseline treatment. For this eye to achieve eligibility statue it must fulfill the following three criteria at Visit 1:
•The central macular thickness must be ≥300 µm in the center subfield, as assessed by OCT and confirmed by the central reading center;
•BCVA score between 69 and 39 letters, inclusively, using ETDRS-like visual acuity testing charts at a testing distance of 4 meters (approximate Snellen equivalent of 20/40 to 20/160);
•Decrease in vision is due to foveal thickening from DME and not due to other causes, in the opinion of the investigator.
4.Patients with DME without previous laser photocoagulation or who have been treated at least 6 months preceding Day 1 with mild focal laser photocoagulation consisting of no more than 30 laser burns that are at least 500 µm from the center of the fovea will be allowed to enter the study.
5.Only one eye will be selected for study treatment (study eye). If both eyes are eligible, the one 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 candidate for study treatment. The medical reason for selecting the study eye having the better visual acuity must be described in the eCRF
6.Patients for whom, in the opinion of the investigator, laser photocoagulation in the study eye can be withheld for at least 3 months after randomization
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| E.4 | Principal exclusion criteria |
1.A condition that in the opinion of the investigator would preclude a patient’s participation in the study, e.g., unstable medical status including glycemic control and blood pressure. Patients in poor glycemic control who, within the last 4 months, initiated intensive insulin treatment (a pump or multiple daily injections) or plan to do so in the next 4 months should not be enrolled. Patients with hypertension for whom a change in antihypertensive treatment was initiated within 2 months preceding Day 1 should not be enrolled unless blood pressure is maintained for at least 1 month prior Day 1 below 150/95 mm Hg by antihypertensive treatment
2.History of systemic (e.g., oral, IV, IM, epidural, bursal) corticosteroids within 4 months prior to randomization or topical, rectal, or inhaled corticosteroids in current use more than 2 times per week
3.Panretinal grid or scatter laser photocoagulation or macular laser photocoagulation attempting to resolve macular edema in the study eye. This criterion may become void if results of interim analyses support the inclusion of patients whose study eye has undergone previous laser photocoagulation
4.Known duration of macular edema involving the center of more than 9 months
5.Proliferative diabetic retinopathy in the study eye, with the exception of tufts of neovascularization less than one disc area with no vitreous hemorrhage. Proliferative diabetic retinopathy in the study eye for which only focal, peripheral retinal areas were treated with photocoagulation with fewer than 30 laser burns performed at least 6 months preceding Day 1 is permitted
6.Area of retinal ischemia ≥500 µm and located ≤500 µm from the center of the macula of the study eye as assessed by fluorescein angiography at Visit 1 and confirmed by a central reading center
7.Any active infection involving ocular adnexa including infectious conjunctivitis, keratitis, scleritis, endophthalmitis, as well as idiopathic or autoimmune-associated uveitis in either eye
8.Cataract surgery in the study eye within the past 6 months, Yttrium-Aluminum-Garnet (YAG) laser capsulotomy within the past 6 months, or any intraocular surgery within the past 6 months preceding Day 1
9.Aphakia or absence of the posterior capsule in the study eye
10.History of uncontrolled glaucoma (defined as intraocular pressure ≥25 mm Hg despite treatment with anti-glaucoma medication) or low tension glaucoma in the study eye
11.Blood pressure: Systolic ≥ 150 mmHg and/or Diastolic ≥ 95 mmHg .If blood pressure is brought and maintained for at least 1 month prior Day 1 below 150/95 mm Hg by antihypertensive treatment, patient can become eligible
12.History of chronic renal failure requiring dialysis or kidney transplant
13.Pre-menopausal women not using adequate contraception. The following are considered effective means of contraception: surgical sterilization; use of oral contraceptives; barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel; an IUD; or contraceptive hormone implant or patch
14.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 laboratory test (>5 mIU/ml)
15.Current treatment for active systemic infection
16.Use of anticoagulants during the study, e.g., coumadin, warfarin, heparin. The use of aspirin is not an exclusion
17.History of allergy to fluorescein, not amenable to treatment
18.History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin
19.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 objective is to explore whether ranibizumab (6 and/or 10 mg/ml) treatment is superior to non-treatment in reducing macular edema from baseline to Month 6 in patients diagnosed with DME with center involvement. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| 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.8.6 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 | Information not present in EudraCT |
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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