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 (neovascularization) 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 | 16.1 |
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 the effectiveness of two treatment regimens by assessing the average BCVA change from Month 4 to Month 12 compared to Month 3 based on both, BCVA stability in each treatment group and comparison of the two treatment groups. For the analysis of these objectives a reference margin of two letters will be applied.
A treatment regimen will be considered a relevant option if stability is achieved and non-inferiority compared to the other group is demonstrated.
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of the two treatment regimens by assessing
•time course of BCVA from baseline (BL),
•improvement of BCVA ≥1, ≥5, ≥10, and ≥15 letters from BL, at M12 and 24,
•loss of BCVA <5, <10, and <15 letters from BL, at M12 and 24,
•BCVA ≥73 letters at M12 and 24,
•average BCVA change from M4 to M24 compared to M3,
•average BCVA change from M1 to M12, and to M24 compared to BL.
To assess treatment exposure and patterns of the two treatment regimens over time based on
•frequency,
•reason,
•compliance
•duration of treatment-free intervals
•duration of active treatment-phases.
To evaluate the retinal anatomy by
•change in central subfield retinal thickness and central subfield volume from BL, over time,
•proportion of patients achieving a dry retina at M12 and M24,
•change in lesion size and morphology at M12 and M24.
To evaluate the change in VFQ-25 composite and subscale scores over time.
To evaluate the safety of ranibizumab over 12 and 24 months.
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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 study-related assessment is performed.
2. Male or female patients, ≥50 years of age.
Inclusion criteria for study eye
3. Visual impairment predominantly due to neovascular AMD
4. Active, newly diagnosed, angiographically documented CNV (i.e. leakage on fluorescein angiography plus intraretinal, subretinal or sub RPE fluid on OCT) secondary to AMD in an eye previously untreated with verteporfin PDT, external-beam radiation, subfoveal or extrafoveal focal laser photocoagulation, transpupillary thermotherapy, submacular surgery, or any other surgical intervention for wAMD, any anti-VEGF compound or any investigational treatment, intravitreal or subtenon corticosteroid injection (within 90 days prior to screening) or device implantation
5. CNV or sequelae of the CNV (i.e., pigment epithelium detachment, subretinal or sub-RPE hemorrhage, blocked fluorescence, macular edema, or subretinal, sub-RPE or intraretinal fluid) involving the center of the fovea.
6. BCVA score at both Screening and Baseline between 78 and 23 letters inclusive (approximate Snellen equivalent of 20/32 and 20/320) as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS)-like charts at 4 meters.
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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. 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.
5. Stroke or myocardial infarction less than 3 months prior to Screening.
6. Uncontrolled blood pressure defined as systolic value of >160 mm Hg or diastolic value of >100 mm Hg at Screening or Baseline.
7. Known hypersensitivity to ranibizumab or any component of the ranibizumab formulation, or fluorescein.
Exclusion criteria for ocular medical history and conditions
For either eye
8. Any active periocular or ocular infection or inflammation (e.g., blepharitis, conjunctivitis, keratitis, scleritis, uveitis, endophthalmitis) at the time of Screening or Baseline.
9. Uncontrolled glaucoma (intraocular pressure [IOP] ≥30 mm Hg on medication or according to investigator’s judgment) at the time of Screening or Baseline.
10. Neovascularization of the iris or neovascular glaucoma at the time of Screening or Baseline.
11. Inability to obtain optical coherence tomography (OCT) images of sufficient quality to be analyzed.
For study eye
12. Cataract (if causing significant visual impairment), aphakia, severe vitreous hemorrhage, rhegmatogenous retinal detachment, proliferative retinopathy or choroidal neovascularization of any other cause than wet AMD (e.g., ocular histoplasmosis, pathologic myopia) at the time of Screening or Baseline.
13. Irreversible structural damage within 0.5 disc diameter of the center of the macula (e.g., vitreomacular traction, epiretinal membrane, scar, laser burn, macular hole) at the time of Screening or Baseline that in the investigator’s opinion could substantially impact visual function improvement with treatment.
14. Atrophy or fibrosis involving the center of the fovea.
15. Total area of fibrosis comprising more than 50% of the lesion area.
Exclusion criteria for prior or current systemic medication
16. Use of other investigational drugs within 30 days or 5 half-lives from Baseline, whichever is longer.
17. Use of any systemic anti-VEGF drugs within 3 months prior to Baseline (e.g., bevacizumab [Avastin®]).
18. Use of systemic corticosteroids for at least 30 consecutive days within 3 months prior to screening.
19. Current or planned use of systemic medications known to be toxic to the lens, retina or
optic nerve, including deferoxamine, chloroquine/ hydroxychloroquine (Plaquenil®), tamoxifen, phenothiazines and ethambutol.
Exclusion criteria for prior or current ocular treatment
For fellow eye
20. Treatment with any anti-angiogenic drugs (including any anti-VEGF agents) within 3 months prior to Baseline in either eye (e.g., bevacizumab [Avastin®]).
For study eye
21. Any intraocular procedure (including Yttrium-Aluminum-Garnet capsulotomy) within 2 months prior to Baseline or anticipated within the next 6 months following Baseline.
22. Topical ocular corticosteroids administered for at least 30 consecutive days within 3 months prior to Screening.
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E.5 End points |
E.5.1 | Primary end point(s) |
Average Visual Acuity change from Month 3 to Month 4 through Month 12 |
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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) |
Change from Baseline in Visual Acuity (Letters) of the Study Eye over time
Gain of equal or more than 1, 5, 10, or 15 letters in Visual Acuity of the Study Eye from baseline, at Month 12/24
Loss of less than 5, 10, and 15 letters in Visual Acuity in the Study Eye from baseline, at Month 12/24
Visual Acuity of 73 letters or more in the Study Eye at Month 12/24
Average Visual Acuity change from Month 3 to Month 4 through Month 24 in the Study Eye
Average Visual Acuity change from baseline to Month 1 through Month 12/24 in the Study Eye
Change from Baseline in Central Sub-Field Thickness (CSFT) and Central Sub-Field Volume (CSFV) of the Study Eye over time
Dry retina in the Study Eye on OCT at Month 12/24
Change from baseline in lesion size and morphology based on fluorescein angiography at Month 12/24
Treatment patterns over time in both treatment arms
Change from Baseline in the National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) scores over time
Frequency and severity of ocular and non-ocular adverse events over time
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline to Month 12/24
Month 12/24
Month 3 to Month 24
Screening to Month 12/24
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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 | 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.8.2.4 | 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 | 82 |
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 |
Canada |
France |
Greece |
Ireland |
Italy |
Austria |
Netherlands |
Portugal |
Slovakia |
Sweden |
Argentina |
Brazil |
Colombia |
Czech Republic |
Finland |
Germany |
Guatemala |
Hungary |
Lithuania |
Spain |
Venezuela, Bolivarian Republic of |
Mexico |
Panama |
Switzerland |
Turkey |
United Kingdom |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |