| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Neovascular Age-Related Macular Degeneration (AMD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Age-related macular degeneration (AMD) is the leading cause of severe vision loss in individuals over the age of 50 years. |
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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 |
|
| 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 Port Delivery System with ranibizumab (PDS) Q36W compared with aflibercept T&E through the change from baseline in best corrected visual acuity (BCVA) score averaged over Weeks 76 (or 78) and 80, as assessed using the early treatment diabetic retinopathy study (ETDRS) visual acuity chart at a starting distance of 4 meters and treatment burden as assessed by the treatment frequency up to Week 80 |
|
| E.2.2 | Secondary objectives of the trial |
● To evaluate the effectiveness of PDS Q36W compared with aflibercept T&E on the basis of proportion of subjects with BCVA score of 69 letters or better and with BCVA score of 38 letters or worse averaged over Weeks 76 (or 78) and 80; proportion of subjects who lose <15, < 10, or < 5 letters in BCVA score from baseline averaged over Weeks 76 (or 78) and 80; change from baseline in center point thickness (CPT) and center subfield thickness (CST); proportion of subjects randomized to PDS Q36W who do not undergo supplemental treatment with intravitreal ranibizumab 0.5 mg before each refill-exchange procedure
● To evaluate the safety of PDS Q36W and aflibercept T&E
● To evaluate the device and procedure-related safety
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
General inclusion criteria
•Age >=50 years
● For women of childbearing potential: agreement to remain abstinent 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 Neovascular age-related macular degeneration (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
● 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 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 ETDRS chart at a starting distance of 4 meters at screening and randomization visits
● With any subtype of nAMD lesions. Exudative nAMD lesions at the time of diagnosis must involve the macula
● 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 treatm. with Visudyne®, external-beam radiation therapy, transpupillary thermotherapy or with corticosteroid intravitreal injection
● Previous intraocular device implantation and surgery within 3 months of randomization
● Previous laser used for AMD or diabetic retinopathy treatment
● History of vitreous hemorrhage and rhegmatogenous retinal detachment
● Concurrent conjunctival, Tenon's capsule, and/or scleral condition in the supero-temporal quadrant of the eye that may affect the implantation, subsequent tissue coverage, and refill-exchange procedure of PDS implant
● Histo. of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma surgery
● Histo. of corneal transplant and conjunctival surgery in the superotemporal quadrant
Either Eye
● Histo. of a severe allergic reaction or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of the ranibiz. or afliber. injections, study-related procedure preparations, dilating drops, or any of the anesthetic and antimicrobial preparations used by a subject during the study
● Any contraindication to afliberc. as per local label
● Prior participation in a clinical trial involving any therapies for nAMD any time prior to screening visit
● Prior treatm. with brolucizumab or gene therapy for nAMD and with external-beam radiation therapy or brachytherapy
MNV (choroidal neovascularization -CNV) Lesion Characteris.
Study Eye
● Subretinal hemorrhage that involv. the center of fovea
● Subfoveal fibrosis or subfoveal atrophy
Either Eye
● CNV due to other causes
● 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 that would either require surgical intervention during the study to prevent or treat visual loss that might result from that condition or affect interpretation of study results
● Active intraocular inflammation
● Rhegmatogenous retinal tears or peripheral retinal breaks on depressed fundus exam that are untreated, or treated within 3 months prior to the randomization visit
● Aphakia or absence of the posterior capsule (Previous violation of the posterior capsule is unless it occurred as a result of yttrium-aluminum garnet (YAG) laser posterior capsulotomy in associat. with prior, posterior chamber intraocular lens implantations)
● 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 or exceeds 5 diopters of hyperopia
● Spherical equivalent of the refractive error demonstrating more than 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
● Histo. 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 and active or history of facial nerve palsy/paresis
Fellow (Non-Study) Eye
● BCVA of hand motion or worse
● No physical presence of non-study eye
Either Eye
● Any active or history of uveitis
● Active or histo. of keratitis, scleritis, endophthalmitis, or chronic blepharitis
● Suspected or active ocular or periocular infectious conjunctivitis or endophthalmitis
● Active or histo. of Sjogrens syndrome, keratoconjunctivitis sicca, floppy eyelid syndrome and chronic eye rubbing
● Active thyroid eye disease
Concurrent Systemic Conditions
● Uncontrolled blood pressure
● Active or histo. of autoimmune diseases
● Histo. of stroke and myocardial infarction, atrial fibrillation diagnosed or worsened within the last 3 mths prior to informed consent
● Histo. of other disease, metabolic dysfunction, or clinical laboratory finding
● Confirmed active systemic infection
● Use of any systemic a-VEGF agents
● Chronic use of oral corticoster.
● Active cancer within 12 months of randomization
● 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
● Requirem. for continuous use of any medications or treatments prohibited in the study
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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
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Baseline (Day 1) to Weeks 76 (or 78) and 80
2. Up to Week 80
|
|
| 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 (or Week 78) 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 up to Week 80
6. Up to Week 80
7-8. Up to Week 80
9. During the postoperative period (≤ 37 days of initial implantation) and follow-up period (> 37 days after implantation surgery)
10-11. Up to Week 80
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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 |
|
| 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 |
|
| 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 | 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 |
| Argentina |
| Brazil |
| Canada |
| Chile |
| Hong Kong |
| Israel |
| Singapore |
| Thailand |
| United Arab Emirates |
| Austria |
| Finland |
| France |
| Poland |
| Netherlands |
| Spain |
| Switzerland |
| Czechia |
| Germany |
| Greece |
| Italy |
| Denmark |
| Hungary |
| Ireland |
| Norway |
| Portugal |
| United Kingdom |
|
| 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
|
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. |
|
| 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 | 2 |
| 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 |
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