E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderately severe to very severe non-proliferative diabetic retinopathy (NPDR) |
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E.1.1.1 | Medical condition in easily understood language |
Eye problems caused by diabetes (called 'diabetic retinopathy') |
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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 | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054109 |
E.1.2 | Term | Non-proliferative diabetic retinopathy |
E.1.2 | System Organ Class | 100000004853 |
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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 assess the efficacy and safety of up to 3 intravitreal injections of ocriplasmin (0.0625mg or 0.125mg), in subjects with moderately severe to very severe NPDR, to induce total PVD in order to reduce the risk of disease progression to PDR |
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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 aged 18 years or older - BCVA of 65 letters read or greater (Snellen equivalent of 20/50 or better) in the study eye - BCVA of 20 letters read or greater (Snellen equivalent of 20/400 or better) in the fellow eye - Clear ocular media for adequate fundus imaging in the study eye - HbA1c ≤ 12%, as assessed by the central laboratory - Moderately severe to very severe NPDR as per ETDRS Severity Scale (Levels 47B-53E), based on 7 standard field colour fundus photograph, as assessed by the central reading centre (CRC) - No evidence of total PVD in the study eye, based on both B-scan ultrasound and SD-OCT, as assessed by the B-scan expert reader and the CRC, respectively - Written informed consent obtained from the subject prior to screening procedures
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E.4 | Principal exclusion criteria |
- History of or current ocular condition in the study eye that may interfere with the assessment of the progression to PDR (e.g. exudative AMD, retinal vein occlusion [branch or central vein], uveitis, angioid streaks, histoplasmosis, toxoplasmosis, rhegmatogenous retinal detachment, retinal tear, fibrovascular proliferation, lattice degeneration, macular hole, ocular tumours) - Clinically significant centre-involving DME in the study eye, based on SD-OCT, as assessed by the CRC - Clinically significant CME in the study eye, based on SD-OCT, as assessed by the CRC - Significant ocular trauma in the study eye within 6 months prior to screening (including corneo scleral laceration, lens subluxation, cryo-retinopexy) - Corneal, lenticular, or ocular media abnormalities in the study eye that preclude observation with the slit lamp or accurate readings with a tonometer - Presence of epiretinal membrane in the study eye, based on SD-OCT, as assessed by the CRC - Presence of foveal ischemia, macular vascularisation or peripheral non-perfusion in the study eye, based on fluorescein angiograph, as assessed by the CRC - Presence of pre-retinal or vitreous haemorrhage in the study eye - Presence of iris or angle neovascularisation in the study eye - Any active ocular / intraocular infection or inflammation in either eye (e.g. blepharitis, infectious conjunctivitis, keratitis, scleritis, endophthalmitis, uveitis) - Open angle glaucoma or uncontrolled glaucoma in the study eye (uncontrolled glaucoma is defined as intraocular pressure [IOP] ≥ 26mmHg despite treatment with anti-glaucoma medication) - More than 8D high myopia in the study eye (axial length of > 26.0mm on A-scan ultrasound) - Aphakic study eye - Previous treatments / procedures in the stydy eye as follows: vitrectomy, PRP and Steroid implants [any time] // Intraocular surgery and Intravitreal and peri-ocular steroids [4 months] // Focal / grid laser photocoagulation and Intravitreal anti-VEGF [3 months] // Topical ocular steroids [1 month] [excluded period period to randomisation] - Uncontrolled hypertension in the opinion of the Investigator (e.g. systolic blood pressure > 160mmHg or diastolic blood pressure > 100mmHg for at least 30 days prior to screening despite antihypertensive treatment, or any finding in the Investigator’s opinion suggesting hypertensive retinopathy) - Pseudoexfoliation, Marfan’s syndrome, phacodonesis or any other finding in the Investigator’s opinion suggesting lens / zonular instability - Current use of or possible need for systemic medications known to be toxic to the lens, retina or optic nerve, including Deferoxamine, Chloroquine / hydroxychloroquine (Plaquenil), Tamoxifen, Phenothiazines and Ethambutol - Known hypersensitivity to ocriplasmin, its excipients or any of the medications that will be used for study procedures (e.g. fluorescein, antibiotics, anaesthetic eye drops, eye drops for pupil dilation) - Pregnant or lactating female, or female of child-bearing potential not utilising an adequate form of contraception, or male of reproductive potential not utilising contraception (where 1 method is barrier at the minimum) - Previous ocriplasmin injection in the study eye - History and / or current evidence of a systemic medical condition or any other reason that may, in the Investigator’s opinion, preclude adherence to the scheduled study visits / assessments and safe participation in the study - Concurrent participation in another clinical study, at any time during the entire study period, in which the subject has been or will be exposed to an investigational or a non investigational product (pharmaceutical product or device) - Use of any investigational, non-registered or off-label product within 30 days prior to screening, or planned use during the entire study period
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E.5 End points |
E.5.1 | Primary end point(s) |
Total PVD by the Month 3 visit, confirmed on both B-scan ultrasound and SD-OCT (6mm), as assessed by the masked B-scan expert reader and the masked CRC, respectively |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Principal safety endpoints: - Ocular TEAEs in the study eye Safety will be further assessed through reported TEAEs, full ophthalmic examination, BCVA assessment, assessment of colour vision (subset), SD-OCT, ffERG (subset) and assessment of immunogenicity |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From the time of providing consent until the end of the study. |
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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 | Yes |
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) | 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 | 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 |
Sham empty vials, no penetration of the globe, Investigator to mimic the test injection procedure |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 20 |
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 | No |
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 |
Belgium |
Czech Republic |
France |
Germany |
Italy |
Netherlands |
Poland |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 (LVLS) unless the data monitoring committee (DMC) recommends premature termination of the trial as a 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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 21 |
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 | 21 |