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 macular edema (ME) |
|
E.1.1.1 | Medical condition in easily understood language |
Impaired vision due to increased accumulation of fluid in the back of the
eye (macula) caused by an intrinsic substance, so-called vascular
endothelial growth factor (VEGF) |
|
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 | PT |
E.1.2 | Classification code | 10025415 |
E.1.2 | Term | Macular oedema |
E.1.2 | System Organ Class | 10015919 - Eye disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
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 |
|
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 an individualized regimen of intravitreal injection of
0.5 mg ranibizumab has superior efficacy compared to sham treatment
in adult patients with visual impairment due to VEGF-driven ME.
The primary objective will be assessed by the BCVA change from
baseline to Month 2. |
|
E.2.2 | Secondary objectives of the trial |
• BCVA change from baseline by visit up to Month 2
• change in CSFT and CSFV (by OCT) from baseline to Month 2
• presence of intra-/sub-retinal fluid assessed by OCT at Month 2
• presence of active ME leakage (by FA) at Month 2
• requirement for rescue treatment at Month 1
• average BCVA change from baseline to M1 through M6 and to M1 through
M12
• change from baseline in CSFT and CSFV by visit
• presence of intra-/sub-retinal fluid
• presence of active ME leakage compared to baseline
Assessing the proportion of patients with:
• ≥ 1, ≥ 5, ≥ 10 and ≥ 15 letters gain or reaching 84 letters
• > 1, > 5, > 10 and > 15 letters loss
• To assess whether treatment with ranibizumab was given by visit
• To assess the number of ranibizumab treatments and re-treatments
• To evaluate the safety of ranibizumab |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
To describe the efficacy and safety of ranibizumab in adolescent patients |
|
E.3 | Principal inclusion criteria |
• Diagnosis of active ME secondary to any causes (for adult patients: except DME, AMD and
RVO) that is primary, chronic (i.e., ME is present for > 3 months) or recurrent, confirmed by
at least one of three following criteria::
• Presence of posterior pole changes compatible with active ME seen by fundus
ophthalmoscopy, biomicroscopy and fundus photography
• Presence of leakage from ME seen by fluorescein angiography (FA)
• Presence of intra-retinal fluid/cysts seen by optical coherence tomography (OCT)
• 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 be mainly due to the presence of any eligible types of ME
(for adult patients: non-DME, non-AMD and non-RVO) based on ocular clinical, as well as FA
and OCT findings |
|
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 anti-inflammatory 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
• ME secondary to DME, AMD or RVO (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. These
include for example:
• Presence or history of retinal detachment, macular hole, epi-retinal membrane (if the
membrane is involving the fovea)
• Presence of cataract, leading to marked visual impairment and/or requiring surgery
during the study
• Presence of vitreomacular traction (VMT) as the primary reason for the ME in the
opinion of the investigator
• Diagnosis of retinitis pigmentosa (RP)
• Diagnosis of Central Serous Chorioretinopathy (CSC, CSR)
• Any type of advanced, severe or unstable ocular disease or its treatment, that could
interfere with the primary and/or secondary outcome evaluations including any medical
condition that could be expected to progress, recur, or change to such an extent that it
could bias the assessment of the clinical status of the patient to a significant degree or put
the patient at special risk.
• ME with a high likelihood of spontaneous resolution (e.g., central serous chorioretinopathy
(CSC) or pseudophakic ME) unless the ME persists for > 3 months or has not improved
upon topical treatment with steroids or NSAIDsHistory 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 prior to
baseline
• History of treatment with intravitreal implants (e.g., Illuvien®, Ozurdex®, Retisert®) at any
time |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Best corrected visual acuity (BCVA) change from baseline to Month 2 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
1) BCVA change from baseline by visit up to Month 2 in study eye (ranibizumab as compared to sham treatment)
2) Change in central subfield thickness (CSFT) and central subfield
volume (CSFV) in study eye from baseline over time to
Month 2
3) Presence of intra-/subretinal fluid in study eye at Month 2
4) Presence of active ME leakage assessed by fluorescein angiography
(FA) at Month 2
5) Requirement for rescue treatment at Month 1
6) Average BCVA change in study eye from baseline to Month 1 through
Month 12
7) Change from baseline in CSFT and CSFV in study eye by visit
8) Presence of intra-/subretinal fluid in study eye at Month 2, Month 6,
and Month 12 compared to Baseline
9) Presence of active ME leakage in study eye at Month 2, Month 6, and
Mon th 12 compared to Baseline
10) Proportion of patients with 1 ≥ 5≥ 10 ≥ and 15 ≥ letters gain or
reaching 84 letters, at Month 2, Month 6 and
Month 12
11) Proportion of patients with > 1, > 5, > 10 and > 15 letters loss at
Month 2, Month 6 and Month 12
12) Number of ranibizumab treatments and retreatments to study eye by
Month 2, Month and Month 12
13) Type, frequency and severity of ocular and non-ocular adverse
events in the study eye up Month 2, up to
Month 6 and up to Month 12 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 |
|
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) |
|
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 | 4 |
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 |
Canada |
Czech Republic |
France |
Germany |
Hungary |
Ireland |
Israel |
Italy |
Korea, Republic of |
Latvia |
Netherlands |
Russian Federation |
Singapore |
Slovakia |
South Africa |
Spain |
Switzerland |
Turkey |
United Kingdom |
|
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
|
|
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 |