| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Neovascular (Wet) Age-related Macular Degeneration (nAMD) |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with Neovascular (Wet) Age-related Macular Degeneration (nAMD) |
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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 | LLT |
| E.1.2 | Classification code | 10075568 |
| E.1.2 | Term | Wet age-related macular degeneration |
| 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 |
Primary Objective
• To assess the safety, tolerability, and efficacy of a single intravitreal (IVT) injection of ADVM-022 in anti-VEGF treatment-experienced patients with Neovascular (Wet) Age-related Macular Degeneration (nAMD)
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives
• To evaluate the effect of ADVM-022 on Best Corrected Visual Acuity (BCVA) using an ETDRS visual acuity chart
• To assess the durability of a single IVT injection of ADVM-022
• To evaluate the effect of ADVM-022 on Central Subfield Thickness (CST)
• To assess the effectiveness of prophylactic corticosteroid treatment regimens on minimizing post-prophylactic inflammation events |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Ability and willingness to provide informed consent to participate in the study requirements and visits prior to any study procedure
2. Male or female participants, age ≥ 50 years of age
3. Have CST of at least 275 µm in the study eye at the Screening Visit (Baseline) as assessed by SD-OCT, confirmed by the CRC, and agreed upon by the Investigator
4. Prior to the Screening Visit (Baseline), received a minimum of 2 anti-VEGF injections in the previous 4 months for the treatment of CNV secondary to nAMD, will have received anti-VEGF injections for no more than 3 calendar years (36 months) prior to the Screening Visit, and no anti-VEGF injection in the 28 days
5. Vision of the study eye at Baseline: BCVA in the range of 25 – 78 ETDRS letters, inclusive (approximate Snellen equivalent visual acuity range of 20/32 – 20/320)
6. Vision of the non-study eye at Baseline: BCVA ≥ 50 ETDRS letters (approximate Snellen equivalent of 20/100 or better)
7. Demonstrate a meaningful anatomic response 7 to 14 days after IVT aflibercept injection administered at the Screening Visit (Baseline) as measured by SC-OCT images, confirmed by the CRC, and defined as:
a) Reduction in CST by ≥ 10% (values will be rounded to the nearest whole number), or
b) Reduction of 10% in thickest paracentral subfield within ETDRS 3 mm grid (values will be rounded to the nearest whole number), or
c) No anatomical evidence of SRF or IRF if either were present at Baseline
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|
| E.4 | Principal exclusion criteria |
1. Serum anti-AAV.7m8 neutralizing antibody titer levels of 1:125 or higher determined from blood drawn during the Screening Period (Day -21 to Day -14)
2. History of other disease, metabolic dysfunction, physical examination finding (such as, but not limited to, participant exhibiting disorientation, muscle paresis or paralysis, vital sign abnormalities, evidence of active infectious disease, or evidence of a mass or other lesion), or clinical laboratory findings giving reasonable suspicion of a condition that contraindicates the use of ADVM-022, contraindicates the use of systemic prednisone or prednisolone for 10 weeks, compromises the participant’s ability to comply with the planned study activities, or that might affect the interpretation of the results of the study or render the participant at high risk for treatment complications in the opinion of the Investigator
3. Ocular or periocular infection (e.g., conjunctivitis, chalazion, significant blepharitis) or intraocular inflammation (grade trace or above by standardization of uveitis nomenclature (SUN) criteria) in either eye within 1 month prior to or at the Randomization Visit (Day -7) (mild anticipated post-operative inflammation subsequent to the aflibercept injection administered at the Screening Visit that resolved is acceptable)
4. Received any prior gene therapy at any time or any investigational treatment or medical device within 3 months of the Screening Visit or 5 half-lives of the investigational medicinal product (IMP) (whichever is longer) (observational studies involving over the counter (OTC) vitamins, supplements, or diets are not exclusionary)
5. Evidence of poorly controlled diabetes or HbA1c ≥ 7.0 % within the Screening period
6. History or evidence of significant uncontrolled concomitant disease within 6 months of the Screening Visit such as cardiovascular disease (i.e. acute coronary syndrome, myocardial infarction or coronary artery revascularization or CVA), hypertension (defined as blood pressure systolic over 180 mmHg or diastolic over 100 mmHg), or nervous system, pulmonary, renal, hepatic, endocrine, or gastrointestinal disorders
7. History of allergy or hypersensitivity and the presence of contraindications to any product or its excipients administrated within this protocol including aflibercept, corticosteroid (i.e. Ozurdex, Durezol, and Prednisone / Prednisolone), or fluorescein dye or sodium fluorescein used in angiography (mild allergy amenable to treatment is allowable)
8. Any history of ongoing bleeding disorders or INR >3.0 (the use of aspirin or other anticoagulants [e.g., Factor Xa inhibitors] is not an exclusion)
9. Use of systemic corticosteroids or other systemic immunosuppressive treatments, or any systemic anti-VEGF therapy within 3 months prior to the Randomization Visit (Day -7). Patients with previous solid organ or bone marrow transplant are also excluded.
10. Any febrile illness within 1 week prior to the Randomization Visit (Day -7)
11. History of malignancy within the last 5 years except for the following adequately treated:
a) Local basal cell carcinoma of the skin
b) Carcinoma in situ of the cervix or breast
c) Papillary, noninvasive bladder cancer
d) Prostate cancer Stage 1 and 2 for which observation is clinically indicated with stable prostate-specific antigen for 6 months
e) Any other cancer that has been in complete remission for at least 2 years or considered surgically cured
12. History within the 12 months prior to the Screening Visit or evidence of renal dysfunction (i.e., creatinine clearance ≤ 50 mL/min) or hepatic dysfunction (i.e., AST or ALT ≥ 2.5X ULN) at Screening
13. Positive for human immunodeficiency virus (HIV) infection or hepatitis B or C at Screening (unless having received a documented cure for hepatitis C) or history or documented evidence of the following systemic or ocular or mycobacterial (including active or latent tuberculosis) or fungal (except for benign dermatomycosis) or viral infections: SARS-CoV-2 2019 (COVID-19), or EBV (symptomatic within the prior 3 months), or syphilis, or known to be positive (in either eye) for ocular herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV) infection including viral uveitis, retinitis or keratitis.
14. Women who are currently pregnant or lactating (or intend to become pregnant or breastfeed during the study) and women of childbearing potential unless permanently sterile, unless they are using an appropriate form of contraception for the duration of their study participation. More detail is provided in the protocol. Appropriate forms of contraception are detailed in the protocol.
See protocol for Ocular Exclusion Criteria (Study Eye) |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Incidence and severity of ocular and non-ocular adverse events
• Mean change in BCVA from the Screening Visit (Baseline) at Week 50/ End of Study (EOS)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• On-going basis after intravitreal administration of ADVM-022: days 1, 3 and 8, weeks 2, 4, 6, 8, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46 and 50/EOS.
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| E.5.2 | Secondary end point(s) |
• Percentage of participants who lose/gain at least 5, 10, or 15 letters in BCVA compared with Baseline through Week 50
• Mean change in BCVA from Baseline at Week 26
• Percentage of participants who are supplemental aflibercept injection-free through Week 50
• Percentage reduction in mean rate of anti-VEGF injections over one year relative to the number of anti-VEGF injections received in the year prior to Baseline
• Mean change in CST from baseline through Week 26 and Week 50
• Percentage of participants without CST fluctuations > 50 μm through Week 50
• Percentage of participants without post-prophylactic inflammation through Week 50
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| • On-going basis after intravitreal administration of ADVM-022: days 1, 3 and 8, weeks 2, 4, 6, 8, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46 and 50/EOS. |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 |
| Two different dose of ADVM-022, Four different prophylaxis corticosteroid regimens |
|
| E.8.2.4 | Number of treatment arms in the trial | 8 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
| United States |
| France |
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 7 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
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