E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Visual impairment due to vascular endothelial growth factor (VEGF) driven choroidal neovascularization (CNV) |
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E.1.1.1 | Medical condition in easily understood language |
Impaired vision due to abnormal growth of blood vessels in the choroid which is caused by an intrinsic substance, so-called vascular endothelial growth factor (VEGF)
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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 | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060837 |
E.1.2 | Term | Choroidal neovascularization |
E.1.2 | System Organ Class | 10015919 - Eye disorders |
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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 | 10047571 |
E.1.2 | Term | Visual impairment |
E.1.2 | System Organ Class | 10015919 - Eye disorders |
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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 demonstrate that intravitreal injection of 0.5 mg ranibizumab, administered based on individual patient needs has superior efficacy compared to sham treatment in adult patients with visual impairment due to VEGF-driven CNV. The primary objective will be assessed by the best corrected visual acuity (BCVA) change from baseline to Month 2. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of ranibizumab as compared to sham treatment by assessing:
• BCVA change from baseline (BL) by visit up to Month (M) 2
• change in CSFT and CSFV (by OCT) from BL over time to M2
• presence of intra-/sub-retinal fluid (by OCT) /of active chorioretinal leakage (by FA) at M2.
To evaluate the efficacy of ranibizumab by original treatment assignment by assessing:
•average BCVA change from BL to M1 to M6, and to M1 to M12
•change from BL in CSFT&CSFV assessed by OCT by visit
•presence of intra-/subretinal fluid (by OCT) and of active chorioretinal leakage (by FA) at M2, M6 and M12 compared to BL
•proportion of pts with ≥ 1,≥ 5,≥ 10 and ≥ 15 letters gain or reaching 84 letters, from BL at M2, 6&12 / 1, > 5, > 10 and > 15 letters loss at M2, M6 and M12.
To assess the No of (re-)treatments by M2, M6 and M12
To evaluate the safety as assessed by type, frequency and severity of ocular and non-ocular AE up to M2, M6 and M12, and reasons for treatment decision. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Diagnosis of active CNV secondary to any causes (for adult patients: except wAMD, PCV or PM), with the CNV or its sequelae affecting the fovea, confirmed by at least one of the three following criteria:
a) Presence of posterior pole changes compatible with active CNV seen by fundus ophthalmoscopy and/or biomicroscopy
b) Presence of leakage from CNV seen by fluorescein angiography (FA)
c) Presence of intra- or subretinal fluid seen by optical coherence tomography (OCT)
• At least one of the following CNV lesion types present in the study eye:
a) Subfoveal (presence of abnormal neovasculature in the avascular central fovea)
b) Juxtafoveal (presence of abnormal neovasculature not under the center of the fovea but within 200 μm from the center) with involvement of the central macular area
c) Extrafoveal (presence of abnormal neovasculature more than 200 μm from the center of the fovea) with involvement of the central macular area
d) Margin of the optic disc (presence of abnormal neovasculature at peripapillary area) with involvement of the central macular area
• BCVA must be between ≥ 24 and ≤ 83 letters tested at 4 meters starting distance using ETDRS-like visual acuity charts (approximate Snellen chart equivalents of 20/25 and 20/320) in the study eye
• Visual loss in the study eye should mainly be due to the presence of any eligible types of CNV (for adult patients: non-wAMD and non-PM) based on ocular clinical, as well as FA and/or OCT findings |
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E.4 | Principal exclusion criteria |
For both eyes
• Active diabetic retinopathy, active ocular/periocular infectious disease or active severe intra-ocular inflammation (e.g., anterior chamber cells (ACC) >2+ and/or vitreous haze (VH) >2+). Rescreening is permitted after intra-ocular inflammation is successfully treated with antiinflammatory therapy that does not compromise eligibility
• Confirmed intraocular pressure (IOP) ≥ 25 mmHg for any reason
• Neovascularization of the iris or neovascular glaucoma
• Inability to obtain fundus photographs, fluorescein angiograms or OCT images of sufficient quality to be analyzed
For study eye
• CNV secondary to wAMD, PCV or PM (for adult patients only). RAP lesions are exclusionary in patients 50 years of age or older
• Ocular disorders that could confound interpretation of study results, compromise visual acuity or require medical or surgical intervention during the 12-month study period (including retinal detachment, cataract (if causing significant visual impairment), macular hole and preretinal membrane of the macula)
• Any type of ocular advanced, severe or unstable disease or its treatment that could interfere with the primary and/or secondary outcome evaluations.
• CNV- conditions with a high likelihood of spontaneous resolution (e.g., CNV due to choroidal rupture), unless deemed chronic by the Investigator (e.g., lasting for > 2 months or being recurrent). History of laser photocoagulation with involvement of the macular area at any time
• Verteporfin photodynamic therapy (vPDT) at any time
• History of intraocular treatment with any anti-angiogenic drugs within 6 months of the Baseline visit (e.g., bevacizumab [Avastin®], aflibercept [Eylea®], pegaptanib [Macugen®], ranibizumab [Lucentis®])
• History of intravitreal treatment with steroids, e.g., triamcinolone within 6 months of the Baseline visit
• History of treatment with intravitreal implants (e.g., Illuvien®, Ozurdex®, Retisert®) at any time
• History of vitreoretinal surgery at any time (cataract surgery is not an exclusion criterion unless a large removal of vitreous or removal of posterior vitreous has occurred) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Best corrected visual acuity (BCVA) change from baseline to Month 2 |
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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) |
Compared to sham treatment
• BCVA change from baseline by visit up to Month 2 in study eye
• Change in central subfield thickness (CSFT) and central subfield volume (CSFV) in study eye from baseline over time to Month 2
• Presence of intra-/subretinal fluid in study eye at Month 2
• Presence of active chorioretinal leakage assessed by FA at Month 2
• Requirement for rescue treatment at Month 1
By original treatment assigment
• Average BCVA change in study eye from baseline to Month 1 through Month 12
• Change from baseline in CSFT and CSFV in study eye by visit
• Presence of intra-/subretinal fluid in study eye at Month 2, Month 6 and Month 12 compared to Baseline
• Presence of active chorioretinal leakage in study eye at Month 2, Month 6 and Month 12 compared to Baseline
• Proportion of patients with ≥ 1, ≥ 5, ≥ 10 and ≥ 15 letters gain or reaching 84 letters in study eye, from baseline at Month 2, Month 6 and Month 12
• Proportion of patients with > 1, > 5, > 10 and > 15 letters loss at Month 2, Month 6 and Month 12
• Number of ranibizumab treatments and retreatments to study eye by Month 2, Month 6 and Month 12
• Type, frequency and severity of ocular and non-ocular adverse events in the study eye up to Month 2, up to Month 6 and up to Month 12
• Reasons for treatment decision by investigator clinical judgement and investigator-assessed evidence of disease activity from OCT and FA images |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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 | 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) | 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 | Yes |
E.8.1.7.1 | Other trial design description |
Open label group for adolescents. Not applicable for Lithuania. |
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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 injection (adults only) |
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 49 |
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 |
Australia |
Belgium |
Brazil |
Canada |
Czech Republic |
Denmark |
France |
Germany |
Greece |
Hong Kong |
Hungary |
India |
Italy |
Korea, Republic of |
Latvia |
Lithuania |
Peru |
Poland |
Portugal |
Russian Federation |
Singapore |
Slovakia |
South Africa |
Spain |
Switzerland |
Turkey |
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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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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 | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
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 |
E.8.9.2 | In all countries concerned by the trial days | 0 |