E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Neovascular Age-Related Macular Degeneration (AMD) |
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E.1.1.1 | Medical condition in easily understood language |
Wet AMD, is a form of advanced AMD that causes central visual loss, and remains a leading cause of visual impairment in the elderly. |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10071129 |
E.1.2 | Term | Neovascular age-related macular degeneration |
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 evaluate the effectiveness of the Port Delivery System (PDS) refilled with ranibizumab every 36 weeks (PDS Q36W) compared with aflibercept intravitreal injections administered per a treat-and-extend strategy (aflibercept T&E) according to (1) change in visual acuity and (2) treatment burden |
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E.2.2 | Secondary objectives of the trial |
•To evaluate the effectiveness of PDS Q36W compared with aflibercept T&E based on (1) best-corrected visual acuity (BCVA) score at end of study or change to BCVA score, (2) change in center point thickness (CPT) and center subfield thickness (CST) •To evaluate the proportion of subjects in PDS group not needing supplemental intravitreal treatment •To evaluate the safety of PDS Q36W and aflibercept T&E •To evaluate the PDS device and PDS procedures-related safety
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
General inclusion criteria •Age >=50 years, at time of signing Informed Consent Form •For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures during the treatment period and for at least 3 months after the final intravitreal injection of ranibizumab or aflibercept, or 1 year after the last implant refill of ranibizumab Ocular Inclusion Criteria •Initial diagnosis of nAMD within 9 months prior to the screening visit •Previous treatment with at least three anti- vascular endothelial growth factor (VEGF) intravitreal injections for nAMD per standard of care within 6 months prior to the screening visit •Demonstrated response to prior anti-VEGF intravitreal treatment since diagnosis, as evidenced by the following: a) Overall decrease in nAMD disease activity detected on SD-OCT, as assessed by the investigator and confirmed by the central reading center and b) Stable or improved BCVA at randomization •Availability of historical visual acuity data obtained at or after nAMD diagnosis and prior to the first anti-VEGF treatment for nAMD •Availability of historical spectral-domain optical coherence tomography (SD-OCT) image data obtained at or after nAMD diagnosis and prior to the first anti-VEGF treatment for nAMD •BCVA of 34 letters or better (20/200 or better approximate Snellen equivalent), using Early Treatment Diabetic Retinopathy Study (ETDRS) chart at a starting distance of 4 meters at screening and randomization visits •With any subtype of nAMD lesions (i.e., type I, type II, type III, or mixed forms per OCT classification, including polypoidal choroidal vasculopathy and retinal angiomatous proliferation). Exudative nAMD lesions at the time of diagnosis must involve the macula (6-mm diameter centered at the fovea) •Sufficiently clear ocular media and adequate pupillary dilation to allow for clinical examination and analysis and grading by the central reading center of fundus photography (FP), fluorescein angiography (FA), fundus autofluorescence (FAF) image, and SD-OCT images
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E.4 | Principal exclusion criteria |
Prior Ocular Treatment Study Eye •History of vitrectomy surgery, submacular surgery, or other surgical intervention for AMD •Prior pars plana vitrectomy surgery •Prior treatment with Visudyne®, external-beam radiation therapy, or transpupillary thermotherapy • corticosteroid intravitreal injection •Previous intraocular device implantation •Previous intraocular surgery within 3 mths of randomization •Previous laser used for AMD or diabetic retinopathy treatment •History of vitreous hemorrhage, rhegmatogenous retinal detachment •Concurrent conjunctival, Tenon's capsule, and/or scleral condition in the supero-temporal quadrant of the eye •History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma surgery, corneal transplant, conjunctival surgery in the superotemporal quadrant Either Eye •History of a severe allergic reaction or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of the ranibizumab or aflibercept injections, study-related procedure preparations, dilating drops, or any of the anesthetic and antimicrobial preparations used by a subject •Any contraindication to aflibercept •Prior participation in a clinical trial involving any anti-VEGF drugs within 6 mths prior to the randomization visit •Prior treatment with brolucizumab, external-beam radiation therapy or brachytherapy Macular neovascularization (MNV) (choroidal neovascularization [CNV]) Lesion Characteristics Study Eye •Subretinal hemorrhage that involves the center of the fovea •Subfoveal fibrosis or subfoveal atrophy Either Eye •CNV due to other causes, such as ocular histoplasmosis, trauma, central serous chorio-retinopathy, or pathologic myopia •CNV masquerading lesions Concurrent Ocular Conditions Study Eye •Subfoveal and/or juxtafoveal retinal pigment epithelial tear •Scleral pathology in the superotemporal quadrant •Conjunctival pathologies in the superotemporal quadrant •Any concurrent intraocular condition •Active intraocular inflammation (grade trace or above) •Rhegmatogenous retinal tears or peripheral retinal breaks on depressed fundus exam that are untreated, or treated within 3 mths prior to the randomization visit •Aphakia or absence of the posterior capsule •Previous violation of the posterior capsule •Spherical equivalent of the refractive error demonstrating more than 8 diopters of myopia or evidence of pathologic myopia on depressed fundus exam •Preoperative refractive error that exceeds 8 diopters of myopia •Spherical equivalent of the refractive error demonstrating more than 5 diopters of hyperopia •Preoperative refractive error that exceeds 5 diopters of hyperopia •Uncontrolled ocular hypertension or glaucoma and any such condition the investigator determines may require a glaucoma-filtering surgery during a subject's participation in the study •History or presence of severe posterior blepharitis, recurrent chalazia or hordeolum, severe dry eye syndrome, or severe allergic conjunctivitis •Ectropion, entropion, in growing lashes, or other impairment of the upper or lower eyelid impacting lid functionality needed to protect the ocular surface from exposure •Trichiasis, Corneal neuropathy, Lagophthalmos or incomplete blink, Active or history of facial nerve palsy/paresis Non-Study (Fellow) Eye •BCVA of hand motion or worse •No physical presence of non-study eye •Legally blind in the subject’s relevant jurisdiction Either Eye •Any active or history of uveitis •Active or history of keratitis, scleritis, endophthalmitis, or chronic blepharitis •for active ocular or periocular infectious conjunctivitis or endophthalmitis •Active or history of Sjogrens syndrome or keratoconjunctivitis sicca, floppy eyelid syndrome, chronic eye rubbing •Active thyroid eye disease Concurrent Systemic Conditions •Uncontrolled blood pressure •Active or history of autoimmune diseases •History of stroke within the last 3 mths prior to informed consent •Atrial fibrillation diagnosed or worsened within the last 3 mths prior to informed consent •History of myocardial infarction within the last 3 mths prior to informed consent •History of other disease, metabolic dysfunction (including uncontrolled diabetes), or clinical laboratory finding •Confirmed active systemic infection •Use of any systemic anti-VEGF agents •use of oral corticoster. •Active cancer within 12 mths of randomiz. •Previous participation in any non-ocular disease studies of investigational drugs within 1 mth preceding the informed consent •Use of antimitotic or antimetabolite therapy within 30 D or 5 elimination half-lives of the randomization visit •Requirement for continuous use of any medications or treatments prohibited in the study •Pregnant or breastfeeding, or intending to become pregnant during the treatment period and for at least 3 mths after the final intravitreal injection of ranibizumab or aflibercept, or 1 Y after the last implant refill-exchange procedure
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E.5 End points |
E.5.1 | Primary end point(s) |
1.Change from baseline in BCVA score averaged over Weeks 76 (or 78*) and 80, as assessed using the ETDRS visual acuity chart at a starting distance of 4 meters 2.Treatment burden as assessed by the treatment frequency up to Week 80
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Baseline, Week 76 and Week 80 2. Up to Week 80
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E.5.2 | Secondary end point(s) |
1.Proportion of subjects with BCVA score of 69 letters (approximate 20/40 Snellen equivalent) or better averaged over Week 76 (Week 78 for some subjects) and Week 80 2.Proportion of subjects with BCVA score of 38 letters (approximate 20/200 Snellen equivalent) or worse averaged over Weeks 76 (or 78) and 80 3.Proportion of subjects who lose <15, < 10, or < 5 letters in BCVA score from baseline averaged over Weeks 76 (or 78) and 80 4.Change from baseline in CPT, defined as the retinal thickness in the center point of the fovea measured between the internal limiting membrane and the inner third of the retinal pigment epithelium layer, on SD-OCT at Week 80 5.Change from baseline in CST, defined as the average thickness of the central 1 mm circle of the ETDRS grid centered on the fovea measured between the internal limiting membrane and the Bruch’s membrane, on SD-OCT at Week 80 6.Proportion of subjects randomized to PDS Q36W who do not undergo supplemental treatment with intravitreal ranibizumab 0.5 mg before each refill-exchange procedure 7.Incidence and severity of ocular and systemic (non-ocular) adverse events 8.Incidence, severity, and duration of adverse events of special interest, including ocular adverse events of special interest 9.Incidence, severity, and duration of ocular adverse events of special interest during the postoperative period (≤ 37 days of initial implantation) and follow-up period (> 37 days after implantation surgery) 10.Incidence and severity of adverse device effects with PDS Q36W 11.Incidence, causality, severity, and duration of anticipated serious adverse device effects with PDS Q36W
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-3. At Weeks 78 and 80 4-5. Baseline and Week 80 6. Up to approximately 40 months 7-8. Up to approximately 40 months 9. During the postoperative period (≤ 37 days of initial implantation) and follow-up period (> 37 days after implantation surgery) 10-11. Up to approximately 40 months
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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 | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
multicenter, randomized, two-arm, visual assessor-masked trial |
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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 |
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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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 108 |
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 | Yes |
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 |
Chile |
Hong Kong |
Singapore |
Thailand |
United Arab Emirates |
Argentina |
Austria |
Brazil |
Canada |
Czechia |
Denmark |
Finland |
Germany |
Greece |
Hungary |
Ireland |
Israel |
Italy |
Netherlands |
Norway |
Poland |
Portugal |
Spain |
Switzerland |
United Kingdom |
France |
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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 this study is defined as the date when the last patient, last visit (LPLV) occurs or safety follow-up is received from the last patient whichever occurs later. |
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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 | 3 |
E.8.9.1 | In the Member State concerned days | 10 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 10 |