| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Neovascular (Wet) Age-Related Macular Degeneration (AMD)
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| E.1.1.1 | Medical condition in easily understood language |
Age-related macular degeneration (AMD) is a progressive neurodegenerative disease and a leading cause of visual loss in elderly patients
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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 | 27.0 |
| 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 establish therapeutic equivalence of Intas Ranibizumab versus Ranibizumab-Ref with respect to the change in best-corrected visual acuity (BCVA) from Baseline to Week 8 using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale in adult patients with wet AMD.
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| E.2.2 | Secondary objectives of the trial |
• To compare the efficacy of Intas Ranibizumab versus Ranibizumab-Ref at week 24 and 52
• To compare the efficacy of Intas Ranibizumab with Ranibizumab-Ref based on central foveal thickness, area of choroidal neovascularization and leakage from choroidal neovascular lesion.
• To assess the safety and tolerability Intas Ranibizumab relative to Ranibizumab-Ref
• To compare the systemic levels of Intas Ranibizumab with Ranibizumab-Ref
• To compare immunogenicity of Intas Ranibizumab with Ranibizumab-Ref
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female participants aged 50 years or more at the time of screening.
2. Written informed consent at Screening must be obtained before any assessment is performed.
3. Willingness and ability to undertake all scheduled visits and assessments.
4. Newly diagnosed, treatment naïve patients with active subfoveal choroid neovascularization
(CNV) lesion secondary to neovascular (wet) age-related macular degeneration (AMD) in the study eye at Screening and confirmed by the Central Reading Center (CRC).
Note: Active CNV indicates the presence of leakage as evidenced by Fluorescein Angiography
(FA) and intra- or subretinal fluid as evidenced by Optical Coherence Tomography (OCT) and
must involve central subfield:
a. The area of CNV must be ≥50% of the total lesion area in the study eye confirmed by
the CRC, and
b. Total lesion area ≤9 Disc Areas (DA) in size (including blood, scars and
neovascularization) as assessed by FA in the study eye.
c. All subtypes of nAMD CNV lesions are permissible (i.e., classic CNV, occult CNV, or
with some classic CNV component)
5. Good health as determined by past medical history, physical examination, vital signs, and
laboratory tests at screening.
6. BCVA of 20/40 to 20/200 (≤ 73 and ≥ 34 ETDRS letter score) in the study eye using ETDRS
chart at a distance of 4 meters at Screening and Baseline.
7. Fellow eye should not be expected to need any anti-VEGF treatment during the initial 8 weeks
period of study participation.
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| E.4 | Principal exclusion criteria |
1. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant with exceptions described in the protocol
2. Fertile males, defined as all males physiologically capable of conceiving offspring UNLESS,
a. the participant agrees to comply with two highly effective contraceptive methods comprising a barrier method (condom or occlusive cap plus spermicide) for the entire duration of the study, up to the Study Completion visit, and refrain from fathering a child for at least three (3) months following the last study drug administration.
3. Pregnant or nursing (lactating) women.
4. Central subfield of the study eye affected by fibrosis or geographic atrophy assessed by color fundus photography and confirmed by the CRC at Screening.
5. Total area of scarring ≥50% of the total lesion in the study eye at Screening and confirmed by the CRC, in the study eye.
6. Subretinal hemorrhage in the study eye that involves the center of the fovea and/or the size of the hemorrhage is either >50% of the total area of the lesion or ≥1-disc area in size at screening as confirmed by CRC.
7. Any infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis in either eye within 4 weeks prior to Baseline.
8. Any active intraocular inflammation (grade trace or above) in the study eye within 4 weeks prior to Baseline.
9. History of idiopathic or autoimmune-associated uveitis in either eye.
10. CNV in either of the two eyes due to causes other than AMD such as DME, RVO, histoplasmosis, trauma, multifocal choroiditis, angioid streaks, history of choroidal rupture or pathologic myopia (spherical equivalent of –6 diopters or more negative).
11. Prior interventions in the study eye described in the protocol
12. Prior treatment with
a. Any prior anti-VEGF including Ranibizumab, Bevacizumab, Aflibercept and Pegaptanib (intravitreal or systemic) in either eye
b. Any prior intraocular use of corticosteroids in the study eye
c. Use of topical ocular corticosteroids in the study eye for 60 or more consecutive days within the 90 days period prior to Baseline
d. Use of systemic corticosteroids in the past 6 months.
13. Known hypersensitivity to ranibizumab or any of the components of study medication (histidine HCl, α-trehalose dihydrate or polysorbate) or to drugs of similar chemical class or to fluorescein or any other component of fluorescein formulation or to topical anesthetics, mydriatic medications.
14. Current or planned use of systemic medications known to be toxic to the lens, retina or optic nerve.
15. History or evidence of the following in the study eye at Screening and/or baseline visit.
16. Use of other investigational drugs (excluding vitamins, minerals) within 30 days (or as per local regulation) or 5 half-lives prior to Baseline whichever is longer, and for neovascular AMD (other than vitamin supplements) in the study eye at any time.
17. History of drug or alcohol abuse within the 12 months prior to baseline.
18. Significant illness within two (2) weeks prior to baseline.
19. History of immunodeficiency diseases, including a positive HIV (ELISA or Western blot) test result. A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result.
20. Presence of uncontrolled systolic blood pressure >160 mmHg or uncontrolled diastolic blood pressure >100 mmHg based on the average of 3 readings taken with the patient in a resting state
21. Documented medical history of thromboembolic events, stroke, congestive heart failure or recent (within 6 months of screening) myocardial infarction, uncontrolled atrial fibrillation.
22. Documented medical history of bleeding disorders, including platelet disorders, acquired or hereditary coagulations disorders, and acquired or hereditary vascular disorders.
23. History of active malignancy except for appropriately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, and prostate cancer with a Gleason score of < 6 and a stable prostate-specific antigen for > 12 months.
24. Any history or evidence of a concurrent intraocular condition in the study eye, including retinal diseases other than neovascular AMD, that in the judgment of the Investigator, could either require medical or surgical intervention during the course of the study to prevent or treat visual loss that might result from that condition or that limits the potential to gain visual acuity upon treatment with the investigational product.
25. History of a medical condition (disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding) that, in the judgment of the Investigator, would preclude scheduled study visits, completion of the study, or a safe administration of investigational product, affect interpretation of the results of the study, or renders the patient at high risk of treatment complications.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Mean change in BCVA in the study eye from baseline to Week 8 using the ETDRS protocol.
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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. Mean change from baseline in BCVA in the study eye up to 52 weeks using the ETDRS protocol
2. Proportion of patients who gained ≥5, ≥10 and ≥15 letters in the study eye using ETDRS protocol up to 52 weeks
3. Proportion of patients who lost ≥5, ≥10 and ≥15 letters in the study eye using ETDRS protocol up to 52 weeks
4. Mean change from baseline in the total area of leakage from CNV measured by fluorescein angiography (FA) at Weeks 8 and 52
5. Mean change from baseline in total area of CNV measured by FA at Weeks 8 and 52 in the study eye
6. Mean change from baseline in central retinal thickness (foveal center point (FCP) retinal thickness and foveal central subfield (FCS) retinal thickness) as in the study eye measured by SD-OCT (optical coherence tomography) up to 52 weeks
7. Incidence of ocular adverse events over 52 weeks
8. Incidence of non-ocular adverse events over 52 weeks
9. Systemic blood levels of ranibizumab
10. Incidence of anti-drug antibodies |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At Day 1, 8, 15, 29, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365
2. At Day 1, 8, 15, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365
3. At Day 1, 8, 15, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365
4. At Day 57, 365
5. At Day 57, 365
6. At Day 1, 8, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365
7. Throughout the study
8. Throughout the study
9. Only in selected participants
• Day 1: Pre-dose and post-dose at 8.000, 12.000, 16.000, 20.000, 24.000, 28.000 and 32.000 hours
• Week 24: Pre-dose and post-dose at 8.000, 12.000, 16.000, 20.000, 24.000, 28.000 and 32.000 hours
10. At Week 2, 4, 8, 12, 24, 36 and at 52 |
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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 | Yes |
| 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 |
| Tolerability, immunogenicity |
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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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 24 |
| 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 |
| Ukraine |
| India |
| Russian Federation |
| Czechia |
| Estonia |
| Hungary |
| Latvia |
| Poland |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| 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 | 6 |
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