E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
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 |
To evaluate the safety and preliminary efficacy of several doses of intravitreal microplasmin in patients with diabetic macular edema. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male or female patients aged > or = 18 - Patients diagnosed with diabetes - Patients with DME involving the center of the macula with a macular thickness (in the central subfield on OCT) of greater than 300 microns in the study eye - No evidence in study eye of complete macular PVD (on biomicroscopy, B-scan or OCT), i.e. attached posterior hyaloid or incomplete PVD with vitreomacular adhesions - BCVA of 20/32 or worse in study eye - BCVA of 20/400 or better in the contralateral eye - In cases where both eyes meet all inclusion and exclusion criteria, the eye with the worst BCVA will be injected as the study eye - Written informed consent obtained from the patient prior to inclusion in the study
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E.4 | Principal exclusion criteria |
- Evidence of fibrocellular proliferation characterized by whitish epimacular tissue (surface wrinkling is not an exclusion criterion) in the study eye - Evidence of foveal ischemia (foveal avascular zone: longest diameter > 1,000 microns) or dense, hard exudates beneath the fovea - Evidence of complete macular PVD in study eye on biomicroscopy, B-scan or OCT prior to planned study drug injection - Any evidence of proliferative retinopathy meeting the definition for PDR in the study eye - Patients with vitreous hemorrhage which precludes either of the following: visualization of the posterior pole by visual inspection OR adequate assessment of the macula by either OCT and/or fluorescein angiogram in the study eye - Patients with rhegmatogenous retinal detachment, PVR, or retinal degenerative changes associated with increased risk of retinal detachment in the study eye. Such retinal degenerative changes include lattice degeneration or cystic retinal tufts. Thorough retinal examination should be performed in all patients to rule out these changes. - Patients with high myopia (axial length > 26.0 mm on A-scan ultrasound) or aphakia in the study eye - Patients with history of rhegmatogenous retinal detachment in the fellow eye - Patients who are considered likely to require intraocular surgery in either eye for any reason in the next three months - Patients who have had ocular surgery in the study eye in the prior three months - Patients who have had a vitrectomy in either eye at any time. - Patients with glaucoma that is not controlled with topical medication or that is associated with severe visual field loss documented by perimetry in the study eye - Patients who have had laser photocoagulation treatment in the study eye in the previous 3 months - Intravitreal injection of any drug in the study eye in the previous 3 months - Patients who are pregnant or of child-bearing potential not utilizing a form of contraception acceptable to the Investigator - Patients who are breastfeeding - Patients who in the investigators view will not complete all visits and investigations, including the last double-masked visit at 6 months - Patients who have participated in an investigational drug study within the past 30 days - Patients with a HbA1c > 10% - Patients with hypertension (either SBP > 170 or DBP > 100 mm Hg) - Patients with a life expectancy less than 6 months - Patients who have previously participated in this trial |
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E.5 End points |
E.5.1 | Primary end point(s) |
EFFICACY EVALUATIONS/CRITERIA
Primary efficacy endpoint:
• Proportion of patients with total PVD (i.e. vitreous detachment to the equator) as determined by masked, Central Reading Center evaluation at day 14 visit imaging (4-quadrant US and OCT) (Central Reading Center representative: Prof. Dr. M. Ulbig, Munich, Germany)
Secondary efficacy endpoint: • Proportion of patients with total PVD as determined by masked, Central Reading Center evaluation of imaging (4-quadrant US and OCT) from study visits other than the day 14 post-injection visit • ME resolution (change from baseline in macular thickness in the central subfield; central foveal thickness [mean thickness at the point of intersection of the 6 radial scans]; and macular volume on OCT) • Change in BCVA • Achievement of >= 2 and >= 3 lines improvement in BCVA without need for alternative therapy (i.e. intravitreal drug injection, laser photocoagulation, or vitrectomy) and time to >= 2 and >= 3 lines improvement in BCVA without need for alternative therapy • Maintenance or gain in vision (no change in number of letters or a gain of one or more letters from baseline) • Moderate visual loss (decrease from baseline of >= 15 letters, i.e. 3 lines), sustained moderate visual loss (moderate visual loss at each of two consecutive visits 3 or more months apart) and severe visual loss (decrease from baseline of >= 30 letters, i.e. 6 lines) and time to moderate, sustained moderate and severe visual loss • VFQ-25 • Need for alternative therapy (either intravitreal drug administration, laser photocoagulation, or vitrectomy) • Progression of DR severity (Masked Central Reading Center): >= 2 step progression; >= 3 step-progression; time to >= 2 step progression; time to >= 3 step-progression
All of the above secondary endpoints will be evaluated at all visits in which the underlying assessments are performed.
SAFETY EVALUATIONS/CRITERIA
The safety profile of the different treatment regimens will be assessed based on:
• Post-injection complications (including worsening visual acuity, worsening macular edema, vitreous hemorrhage, retinal tear or detachments, inflammation [presence, severity, location]*, IOP alterations, cataract formation* • ERG pre and post injection • Fluorescein angiography to assess for leakage from vessels • OCT
*According to criteria defined as follows: - for anterior chamber and vitreous inflammation grading, use scales defined in Appendix 6 - for cataract grading, use LOCS III grading system |
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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 | Yes |
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 | Yes |
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) | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
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 | Information not present in EudraCT |
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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The end of the trial is defined as the last visit of the last subject, unless the Safety Committee recommends premature termination of the trial as result of safety concerns. |
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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 | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |