E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Visual impairment due to neovascular AMD |
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E.1.1.1 | Medical condition in easily understood language |
Impaired vision due to growth of new vessels (neovascularisation) in the choroid which is caused by an intrinsic substance, so-called vascular enothelial 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 | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060837 |
E.1.2 | Term | Choroidal neovascularization |
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 |
The primary objective is to evaluate whether treatment with intravitreal ranibizumab is associated with improvement (i.e. reduction at Day 90 from Baseline) in central subfield retinal thickness (CSRT) as determined by spectral domain/high definition optical coherence tomography (SD/HD-OCT) after 3 monthly injections of ranibizumab.
The CSRT represents the average retinal thickness (μm) of the circular area within 1 mm diameter around the foveal center. |
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E.2.2 | Secondary objectives of the trial |
To evaluate whether treatment with intravitreal ranibizumab is associated with improvements in various retinal morphology parameters as determined by SD/HD-OCT at various time points over a period of 6 months and evaluated by the Central Reading Centre (CRC) including:
- The change in subfoveal retinal thickness (SRT), central subfield retinal thickness (CSRT) and central subfield retinal volume (CSRV).
- The proportion of patients with subretinal fluid (SF), intra-retinal cystoid changes (IRC), pigment epithelial detachments (PEDs), or dry retina.
- The change in size (height or volume as appropriate) of various anatomical parameters including SF, IRC, and PEDs.
To evaluate changes from Baseline BCVA at various time points over a period of 6 months including changes in BCVA between 3 and 6 months.
To evaluate ocular and systemic safety by determining the incidence of ocular and systemic adverse events (AEs) up to Day 180.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria for patient
1. Written informed consent must be obtained before any assessment is performed.
2. Age ≥50 years.
3. BCVA ≥23 ETDRS letters, at both the Screening Visit and Baseline Visit in the Study eye.
4. Active, angiographically documented CNV lesion in study eye (e.g. leakage on fluorescein angiography plus intraretinal, subretinal or sub-retinal pigment epithelium (RPE) fluid on SD/HD-OCT) secondary to AMD at Screening.
5. Evidence of active CNV involving the center of the fovea in the study eye (e.g. pigment epithelium detachment, subretinal or sub-RPE hemorrhage, macular edema, or subretinal, sub-RPE or intraretinal fluid) at Baseline.
6. The total area of fibrosis in the study eye comprising less than 50% of the lesion area.
Patient subgroup specific inclusion criteria
Patients need to meet all the criteria for one of the following two groups:
Group 1. Primary treatment failure
7. No prior anti-VEGF treatment prior to initiating aflibercept.
8. Received no more than 3 injections of aflibercept into the study eye prior to the Screening Visit.
9. Historical OCT volume scan acquired <= 28 days before the first aflibercept injection was administered to the study eye.
10. Initiated treatment with aflibercept <130 days prior to the Screening Visit.
11. Last injection of aflibercept was ≥28 days but ≤40 days prior to the Baseline visit.
12. No increase in BCVA (≥5 letters) since commencing treatment with aflibercept.
13. Disease activity has never been controlled in the study eye after initiating aflibercept as defined by at least one of the following observed on a historical OCT volume scan acquired after a minimum of 2 aflicerpt injections: evidence of unchanged or increasing retinal or sub-retinal fluid; new PED; unchanged or increasing size of pre-existing
PED.
Group 2. Suboptimal treatment response
14. No prior anti-VEGF treatment prior to initiating aflibercept.
15. Aflibercept commenced ≥6 months prior to the Screening Visit.
16. Received ≥3 aflibercept injections into the study eye within 6 months of the Screening Visit.
17. Historical OCT volume scan acquired <= 28 days before the first aflibercert injection was administered to the study eye.
18. Evidence of previous reduced disease activity in the study eye after initiating aflibercept as defined by reduction of ≥50µm in central subfield retinal thickness observed on a historical OCT volume scan after a minimum of 2 aflibercept injections.
19. Last injection of aflibercept was ≥28 days but ≤70 days prior to the Baseline visit.
20. At Screening Visit, disease activity has worsened (as defined by increasing retinal* or sub-retinal fluid, or new or increasing size of PED) in the study eye compared to prior visits.
*Evidence of increasing retinal fluid may include increased number, size or total volume of IRCs, or increased central retinal or foveal thickness, or similar quantitative retinal imaging data recorded within the individual patient record. |
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E.4 | Principal exclusion criteria |
Exclusion criteria for patient
1. Inability to comply with study or follow-up procedures.
2. 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.
3. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment.
Exclusion criteria for systemic medical history and conditions
4. History of cerebrovascular accident, transient ischemic attack or myocardial infarction within 3 months of the Screening visit.
5. Any type of systemic disease or its treatment, including any medical condition (controlled or uncontrolled) that could be expected to progress, recur, or change to such an extent that it may bias the assessment of the clinical status of the patient to a significant degree or put the patient at special risk.
6. Uncontrolled blood pressure defined as a persistent systolic value of >160 mm Hg or persistent diastolic value of >100 mm Hg at Screening or Baseline.
7. Simultaneous participation in any other clinical study for the duration of this study.
8. Use of other investigational drugs (excluding vitamins and minerals) or participation in any other clinical study within 90 days or 5 half-lives of the Screening visit, or until the expected pharmacodynamic effect has resolved, whichever is longer.
9. History of hypersensitivity to either ranibizumab (or any component of the ranibizumab formulation), or fluorescein, or indocyanine green, or to drugs of similar chemical classes.
Exclusion criteria for ocular medical history and conditions
For either eye
10. Any active periocular or ocular infection or inflammation (e.g., blepharitis, conjunctivitis, keratitis, scleritis, uveitis, endophthalmitis) at the time of Screening or Baseline.
11. Uncontrolled glaucoma (intraocular pressure [IOP] ≥30 mm Hg on medication or
according to Investigator’s judgment) at the time of Screening or Baseline.
12. Evidence of bilateral active CNV during the Screening Period or at Baseline requiring bilateral anti-VEGF injections. Patients with active CNV in the study eye with quiescent CNV in the fellow eye who may have received IVT aflibercept or ranibizumab injections into the fellow eye >40 days prior to the Screening visit are not excluded from the study; however, should the fellow eye require anti-VEGF treatment during the study only ranibizumab may be utilized.
13. Prior intravitreal injection of ranibizumab or bevacizumab into the study eye and/or prior intravitreal injection of bevacizumab into the fellow eye
Study eye exclusion criteria
14. At Baseline, intraocular surgery was performed within the previous 28 days or intraocular surgery is planned at any time during the 6 month study period.
15. Cataract (if causing significant visual impairment), aphakia, severe vitreous hemorrhage, rhegmatogenous retinal detachment, proliferative retinopathy or choroidal neovascularization of any other cause for CNV other than wet AMD (e.g., ocular histoplasmosis, pathologic myopia (≥-8 dioptres)) at the time of Screening and Baseline.
16. Irreversible structural damage involving the center of the fovea (e.g. advanced fibrosis or geographic atrophy) which in the opinion of the Investigator is sufficient to irreversibly impair visual acuity.
17. Polypoidal choroidal vasculopathy (PCV), RPE tear, central serous retinopathy (CSR), or significant vitreomacular traction identified during Screening period or within 4 months of Baseline visit. Note that small vitreomacular adhesions that do not result in deformity of the retina are permitted.
18. Any other ocular abnormality unrelated to AMD that is in the Investigator’s opinion is likely to contribute to progressive deterioration in visual acuity over the next 6 months.
19. Prior laser therapy or use of verteporfin photodynamic therapy.
20. Prior use of intra- or peri-ocular corticosteroids within 6 months of Screening.
21. Unable to obtain at Screening SD/HD-OCT images of sufficient quality to be analyzed.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective is to demonstrate that the mean change from baseline in CSRT (as determined by OCT) at Day
90 is less than zero. The primary variable is the difference from baseline to Day 90 in CSRT. |
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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) |
To determine whether ranibizumab treatment is associated with improvements in various retinal morphology parameters as determined by OCT over a period of 6 months including:
o The change in subfoveal retinal thickness (SRT), central subfield retinal thickness (CSRT) and central subfield retinal volume (CSRV).
o The proportion of patients with subretinal fluid (SF), intra-retinal cystoid changes (IRC), pigment epithelial detachments (PEDs), or dry retina.
o The change in size (height or volume as appropriate) of various anatomical parameters including SF, IRC, and PEDs.
To evaluate changes from Baseline BCVA at various time points over a period of 6 months including changes in BCVA between 3 and 6 months.
To evaluate ocular and systemic safety by determining the incidence of ocular and systemic adverse events (AEs). |
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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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 38 |
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 | No |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 3 |