E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Neovascular age-related macular degeneration (nAMD)
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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 efficacy of ranibizumab 100 mg/mL delivered via the port delivery system with ranibizumab (PDS) every 36 weeks (Q36W) compared with every 24 weeks (Q24W) on the basis of change from baseline in best-corrected visual acuity (BCVA) score averaged over Weeks 68 and 72 |
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E.2.2 | Secondary objectives of the trial |
● Efficacy of ranibizumab 100 mg/mL delivered via PDS Q36W versus Q24W on basis of change from baseline in BCVA score over time, proportion of patients with BCVA score of 69 letters/better/ 38 letters/ worse over time, proportion of patients who prefer ranibizumab delivered via PDS compared with intravitreal treatment (IVT), proportion of patients with bilateral disease who report preferring ranibizumab delivered via PDS compared with fellow eye IVT, proportion of patients who lose <1, <5, or gain >= 0 letters in BCVA score from baseline over time, change from baseline in center point thickness (CPT), proportion of patients who do not undergo supplemental treatment with intravitreal ranibizumab, mean overall treatment satisfaction ● Safety, tolerability of ranibizumab delivered via PDS, and device and procedure related safety ● Pharmacokinetic profile of ranibizumab delivered via PDS ● Formation of anti-drug antibodies (ADAs) to ranibizumab delivered via PDS |
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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 |
REMOTE VISION MONITORING DATA COLLECTION SUBSTUDY IN ASSOCIATION WITH STUDY WR42221: A PHASE IIIb, GLOBAL, MULTICENTER, RANDOMIZED, VISUAL ASSESSOR-MASKED STUDY OF THE EFFICACY, SAFETY, AND PHARMACOKINETICS OF A 36-WEEK REFILL REGIMEN FOR THE PORT DELIVERY SYSTEM WITH RANIBIZUMAB IN PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION (VELODROME) |
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E.3 | Principal inclusion criteria |
General Inclusion criteria ●Age >= 50 years ●For women of childbearing potential: agreement to remain abstinent or use contraception and must remain abstinent or use contraceptive methods with a failure rate of <1% per year during the study, within 3 months after the final intravitreal ranibizumab injection and for 1 year after the final implant refill-exchange procedure or implantation of the PDS Ocular inclusion criteria ●Initial diagnosis 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 prior to the first anti-VEGF treatment for nAMD until the time of study enrollment ●BCVA of 34 letters or better, using Early Treatment Diabetic Retinopathy Study (ETDRS) chart at a starting distance of 4 meters at screening and enrollment visits ●With any subtype of nAMD lesions o 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 analysis and grading by the central reading center of fundus photography, fluorescein angiography, fundus autofluorescence image and OCT images |
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E.4 | Principal exclusion criteria |
Prior Ocular Treatment o Study Eye ● History of vitrectomy surgery, submacular surgery, or other surgical intervention for AMD ● Prior treatment with Visudyne®, external-beam radiation therapy, or transpupillary thermotherapy ● Previous treatment with corticosteroid intravitreal injection, intraocular device implantation, previous laser used for AMD treatment ● Treatment with anti-VEGF agents other than ranibizumab within 1 month prior to the enrollment visit ● 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 the PDS implant o Either Eye ●Prior treatment with brolucizumab (at any time prior to the screening visit) ●Prior gene therapy for nAMD ●Prior participation in a clinical trial involving any therapies for nAMD, within 9 months from the time of nAMD diagnosis, CNV Lesion Characteristics ● Patients who meet any of the following exclusion criteria related to CNV lesion o Study Eye ● Subretinal hemorrhage that involves the center of the fovea, if the hemorrhage is greater than 0.5 disc area in size at screening ● Subfoveal fibrosis or subfoveal atrophy o Either Eye ● CNV due to other causes, such as ocular histoplasmosis, trauma, central serous chorio-retinopathy, or pathologic myopia Concurrent Ocular Conditions ● Patients who meet any of the following exclusion criteria related to concurrent ocular conditions o Study Eye ● Retinal pigment epithelial tear ● 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 ● History of vitreous hemorrhage, rhegmatogenous retinal detachment, pars plana vitrectomy surgery, rhegmatogenous retinal tears or peripheral retinal breaks within 3 months prior to the enrollment visit ● Aphakia or absence of the posterior capsule ● Spherical equivalent of the refractive error demonstrating more than 8 diopters of myopia ● Preoperative refractive error that exceeded 8 diopters of myopia, for patients who have undergone prior refractive or cataract surgery in the study eye ● Intraocular surgery within 3 months preceding the enrollment visit ● Uncontrolled ocular hypertension or glaucoma and any such condition the investigator determines may require a glaucoma-filtering surgery during a patient's participation in the study ● History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma surgery ● History of corneal transplant ● Non-functioning fellow (non-study) eye o Either Eye Patients who meet the following exclusion criterion for the either eye at both the screening and enrollment visits will be excluded from study entry ● Any history of uveitis requiring treatment ● Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis Concurrent Systemic Conditions ● Uncontrolled blood pressure ● History of stroke within the last 3 months prior to informed consent ● Atrial fibrillation diagnosed or worsened within the last 3 months prior to informed consent ● History of myocardial infarction within the last 3 months prior to informed consent, other disease, metabolic dysfunction, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of ranibizumab or placement of the implant and that might affect interpretation of the results of the study or renders the patient at high risk of treatment complications in the opinion of the investigator ● Confirmed active systemic infection ● Use of any systemic anti-VEGF agents ● Active cancer within 12 months of enrollment except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, and prostate cancer with a Gleason score of <= 6 and a stable prostate-specific antigen for > 12 months ● Previous participation in any non-ocular disease studies of investigational drugs within 1 month preceding the informed consent ● Use of antimitotic or antimetabolite therapy within 30 days or 5 elimination half-lives of the enrollment visit ● Pregnant or breastfeeding, or intending to become pregnant during the treatment period or within 1 year after the final refill-exchange procedure
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in BCVA score averaged over Weeks 68 and 72, as assessed using the ETDRS chart starting at a distance of 4 meters |
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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) |
1. Change from baseline in BCVA score over time (up to and including Week 72) 2. Proportion of patients with BCVA score of 69 letters or better averaged over Weeks 68 and 72 3. Proportion of patients with BCVA score of 69 letters or better over time 4. Proportion of patients with BCVA score of 38 letters or worse averaged over Weeks 68 and 72 5. Proportion of patients with BCVA score of 38 letters or worse over time 6. Proportion of patients who report preferring ranibizumab 100 mg/mL delivered via the PDS compared with intravitreal treatment, as measured by the PDS PPPQ at Weeks 24, 40 and 72 7. Proportion of patients with bilateral disease who report preferring ranibizumab 100 mg/mL delivered via the PDS compared with intravitreal treatment, as measured by the PPPQ at Weeks 24, 40 and 72 8. Mean overall treatment satisfaction at Week 40, as measured by the Macular Disease Treatment Satisfaction Questionnaire (MacTSQ) total score in the Q36W arm compared with the Q24W arm 9. Proportion of patients who lose <10, <5, or gain >= 0 letters in BCVA score from baseline averaged over Weeks 68 and 72 10. Change from baseline in CPT up to and including Week 72 11. Change from baseline in central subfield thickness (CST) over time , up to and including Week 72 12. Proportion of patients who do not undergo supplemental treatment with intravitreal ranibizumab 0.5 mg before each refill-exchange procedure 13. Mean overall treatment satisfaction at Week 40, as measured by the Macular Disease Treatment Satisfaction Questionnaire (MacTSQ) total score in the Q36W arm compared with the Q24W arm 14. Incidence and severity of ocular and systemic adverse events in Q36W and Q24W 15. Incidence, severity, and duration of ocular adverse events of special interest during the postoperative period and follow-up period in all enrolled patients 16. Incidence and severity of adverse device effects in the Q36W and Q24W arms 17. Incidence, causality, severity, and duration of anticipated serious adverse device effects in the Q36W and Q24W arms 18. Observed serum concentration of ranibizumab at specified timepoints 19. Incidence of treatment-emergent ADAs to ranibizumab during the study |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to Week 72 2. At Weeks 68 and 72 3. Up to Week 72 4. At Weeks 68 and 72 5. Up to Week 72 6-7. At Weeks 24, 40 and 72 8. At Week 40 9. At Weeks 68 and 72 10. Up to Week 72 11. Baseline (enrolment visit up to 7 days before Day 1) to up to Week 72 12-17. Up to Week 72 18. Day 1, Week 4, 12, 24, at study termination visit and at explanation visit; for Arm A and B (Q36W and Q24W): Week 36, 72 and at early study termination visit and at explanation visit 19. Day 1, Week 4, 24 and at study termination visit, Arm A and B (Q36W and Q24W): Week 36, 72, at early study termination |
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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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
immunogenicity, exploratory biomarker, exploratory patient experience |
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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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 54 |
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 |
Argentina |
Australia |
Brazil |
Canada |
Israel |
Korea, Republic of |
Singapore |
Taiwan |
Austria |
France |
Spain |
Switzerland |
Germany |
Italy |
Belgium |
Turkey |
United Kingdom |
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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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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 | 9 |
E.8.9.1 | In the Member State concerned days | |
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 |