| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Wet Age-related Macular Degeneration (wAMD)
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with wet Age-related Macular Degeneration in need of treatment |
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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 |
Part 1 (Safety Run-in Portion):
To evaluate the safety and tolerability of HLX04-O in patients with wAMD.
Part 2 (Non-inferiority Study):
To evaluate the efficacy of HLX04-O at Month 9 compared with ranibizumab in patients with wAMD.
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| E.2.2 | Secondary objectives of the trial |
Part 1 (Safety Run-in Portion):
To evaluate the efficacy of HLX04-O at Months 3, 9 and 12 in patients with wAMD.
To assess the safety of HLX04-O.
To characterize the systemic pharmacokinetics of HLX04-O IVT administration.
Part 2 (Non-inferiority Study):
To evaluate the efficacy of HLX04-O at Months 3, 9 and 12 compared with ranibizumab in patients with wAMD.
To evaluate the safety and tolerability of HLX04-O compared with ranibizumab in patients with wAMD.
To characterize the systemic pharmacokinetics of HLX04-O IVT administration.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Capable to read, understand, and sign the informed consent form (ICF) which includes compliance with the requirements and restrictions.
2. Women or men aged ≥50 years when signing the ICF.
3. In the Investigator’s judgment, willing and able to complete all visits and assessments adhering to the prohibitions and restrictions specified in the protocol.
4. Infertile women or men must meet either of the following ones: 1) menopause (≥12 continuous months of amenorrhea with no identified cause other than menopause before screening); 2) surgically sterilized. Fertile women or men must meet either of the following ones: 1) women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of the study intervention, and should not breastfeed; 2) agreement to remain abstinent (refrain from heterosexual intercourse) or use effective contraceptive methods from signed ICF to at least 6 months following the last dose of study intervention. Effective contraceptive methods include bilateral tubal ligation, male sterilization, established, proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices (IUDs), and copper IUDs.
5. Newly diagnosed, angiographically documented, previously untreated, active subfoveal CNV lesions secondary to age-related macular degeneration in the study eye. Active CNV was defined as leakage on fluorescein angiography (FA) and subretinal or intraretinal fluid on optical coherence tomography (OCT) with confirmation of the reading center during screening. Only one eye will be enrolled as the study eye in the study. If both eyes are eligible, the participant and study ophthalmologist will select the study eye for entry (usually a severe eye).
6. The total lesion area (including bleeding, scar and neovascularization) of the study eye ≤12 disc area (DA) with confirmation of the reading center before randomization and meet the requirements of fundus photography.
7. The BCVA by E-ETDRS score for the study eye must be between 20/40 and 20/320 (Snellen equivalent).
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| E.4 | Principal exclusion criteria |
1. Macular-related retinal pigment epithelial tears in the study eye, fibrosis or atrophy involving the center of the fovea, or CNV due to other causes in either eye (e.g., ocular histoplasmosis, trauma, or pathological myopia, etc.) on FA with confirmation of the reading center.
2. The area of subretinal hemorrhage involving fovea ≥50% of the total lesion area or >1 DA (2.54 mm2 ) in size in the study eye.
3. Aphakia (except intraocular lens) or posterior capsular rupture of the lens (except yttrium-aluminium-garnet (YAG) laser postcapsulorhexis after intraocular lens implantation ≥30 days prior to first dose) in the study eye.
4. Active or recent (28 days prior to randomization) intraocular, extraocular or periocular infection (including conjunctivitis, keratitis, scleral or endophthalmitis), or history of idiopathic or autoimmune-associated uveitis in either eye.
5. Current vitreous hemorrhage in the study eye.
6. Corneal dystrophy or history of corneal transplantation, scleral softening or history of scleral softening, history of rhegmatogenous retinal detachment or macular hole (Stage 3 or 4) in the study eye.
7. Uncontrolled glaucoma in the study eye (defined as intraocular pressure [IOP] ≥25 mmHg despite treatment with antiglaucoma medication), and/or glaucoma filtering surgery (e.g., trabeculectomy, scleral nipping, non-penetrating trabeculectomy, etc.)
8. Equivalent spherical diopter of the study eye ≥−8D. For participants who had undergone refractive correction or cataract surgery, the equivalent spherical diopter of the study eye before surgery ≥−8D.
9. Any concurrent intraocular condition in the study eye that may require medical or surgical intervention or contribute to vision loss within 1 year estimated by the Investigator.
10. Any concurrent intraocular condition in the fellow eye that may require anti-VEGF therapy within 3 months after randomization estimated by the Investigator. No other anti-VEGF treatments than HLX04-O or ranibizumab as per treatment arm are allowed for both eyes during the study period.
11. Previous treatment with AMD therapy in the study eye.
12. Previous systemic anti-VEGF therapy or IVT injection of any anti-VEGF drug into either eye.
13. Underwent internal eye surgery (including cataract extraction, vitrectomy, laser photocoagulation in macular area, etc.) within 90 days, or external eye surgery within 30 days before the first dose in the study eye.
14. Treated with corticosteroids either intraocular or systemic within 90 days or peripherally within 30 days before the first dose in the study eye.
15. Participated in any drug (other than vitamins and minerals) or device clinical trials within 30 days before the first dose and have used the test drug or received device treatment.
16. Pregnancy or lactation, or fertile men or women not willing to use effective contraception from the day when ICF was signed to at least 6 months following the last dose of study intervention.
17. In the Investigator’s judgment, there is evidence of a disease or condition that contraindicates the use an investigational drug or that might affect interpretation of the results of the study or render the participant at high risk for treatment complications (e.g. stroke or myocardial infarction within 6 months prior to screening, uncontrolled hypertension (systolic blood pressure >160 mmHg, or diastolic blood pressure >100 mmHg), etc.).
18. Evidence of significant uncontrolled concomitant diseases such as cardiovascular diseases, nervous system diseases, respiratory system diseases, urinary system diseases, digestive system diseases and endocrine diseases.
19. Current treatment for active systemic infection, or history of recurrent significant infections.
20. Known active or suspected autoimmune diseases, requiring systemic immunosuppressive therapy.
21. Hepatitis B (hepatitis B virus antigen [HBsAg] positive, and hepatitis B virus [HBV] deoxyribonucleic acid [DNA] test result suggests viral replication); hepatitis C (hepatitis C virus [HCV] antibody positive, and HCV ribonucleic acid [RNA] test result suggests viral replication); participants with co-infection with hepatitis B and C (HBsAg and HCV antibody positive). Positive for syphilis screening test human immunodeficiency virus (HIV) infection or positive for HIV screening test.
22. Known allergy to any component of the study intervention or history of allergy to fluorescein or indocyanine green.
23. In the Investigator’s judgment, other conditions considered not amenable to this study.
24. Participant who has been diagnosed to be COVID-19 within 14 days prior to screening.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1 (Safety Run-in Portion)
Safety events: toxicity and causality (related, possibly related, unknown) associated with the treatment of HLX04-O that occurs within 30 days
after the first treatment (single administration) including:
• Ocular AEs
➢ Severe clinically significant inflammation and visual impairment;
➢ Ophthalmic abnormalities uncommon in wAMD patients, such as acute retinal detachment, intravitreal or and diffuse retinal hemorrhage, etc;
➢ BCVA: Loss of 10 letters; Baseline BCVA of less than 20/500 switched to light perception or hand motion;
➢ IOP: IOP be 20 mmHg higher than baseline measured at two tests at least 1 day apart, or be 30 mmHg lasted for 1 week despite medication;
➢ FA: Significant retinal or choroidal vascular abnormalities not seen at baseline, such as: Arteriovenous circulation time delay (>15 seconds) and retinal artery or vein occlusion (any deviation from baseline).
• Non-ocular AEs
➢ Hematological toxicity Grade ≥4
➢ Non-hematological toxicity Grade ≥3
Part 2 (Non-inferiority Study)
• Mean change from baseline in BCVA at Month 9. |
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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) |
Part 1 (Safety Run-in Portion)
• Mean change from baseline in BCVA at Months 3, 9 and 12;
• Mean change in the BCVA over time;
➢ Proportion of patients gaining at least 15 letters in the BCVA at Months 3, 9, and 12;
➢ Proportion of patients gaining at least 10 letters in the BCVA at Months 3, 9, and 12;
➢ Proportion of patients gaining at least 5 letters in the BCVA at Months 3, 9, and 12;
• Mean change from baseline in size of CNV on FA at Months 3, 9, and 12 (as measured by the Fundus Photograph Reading Center);
• Mean change from baseline in size of leakage from CNV on OCT at Months 3, 9, and 12 (as measured by the OCT Reading Center);
• Change from baseline in NEI VFQ-25 scale score at Months 3, 9, and 12.
• Percentage and severity of ocular AEs (IVT procedure related and Investigation Medication related), non-ocular AEs; laboratory abnormalities; vital sign, physical examination abnormalities, etc.
• Incidence of ADAs and NAbs against HLX04-O following IVT administration.
• HLX04-O systemic PK parameters following IVT administration of Dose 1 and Dose 4:
➢ AUC(0-τ): Area under the serum concentration-time curve during the dosage interval;
➢ Cmax: Maximum drug concentration;
➢ Cmin: Minimum drug concentration;
➢ Tmax: Time to Cmax;
➢ t1/2: Elimination half-life, as data permit;
➢ CL/F: Apparent total body clearance;
➢ Accumulation ratios (Dose 4/Dose 1) for AUC(0-τ), Cmax and Cmin.
Part 2 (Non-inferiority Study)
• Mean change from baseline in BCVA at Months 3 and 12;
• Mean change in the BCVA over time;
• Proportion of patients gaining at least 15 letters in the BCVA at Months 3, 9, and 12;
• Proportion of patients gaining at least 10 letters in the BCVA at Months 3, 9, and 12;
• Proportion of patients gaining at least 5 letters in the BCVA at Months 3, 9, and 12;
• Mean change from baseline in size of CNV on FA at Months 3, 9, and 12 (as measured by the Fundus Photograph Reading Center);
• Mean change from baseline in size of leakage from CNV on OCT at Months 3, 9, and 12 (as measured by the OCT Reading Center);
• Change from baseline in NEI VFQ-25 scale score at Months 3, 9, and 12.
• Percentage and severity of ocular AEs (IVT procedure related and Investigation Medication related), non-ocular AEs; laboratory abnormalities; vital sign, physical examination abnormalities, etc.
• Incidence of ADAs and NAbs against HLX04-O following IVT administration.
• Minimum HLX04-O concentrations prior to Dose 1, Dose 2, Dose 6, Dose 9 and Dose 12 as data permit.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Months 3, 9, and 12
Throughout the duration of the study
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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 | 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 | Yes |
| 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 |
| Two-part Study: Open-label Followed by Randomized Double-masked Active Controlled |
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| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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 |
| Australia |
| China |
| Russian Federation |
| Serbia |
| Singapore |
| Hungary |
| Latvia |
| Poland |
| Spain |
| Czechia |
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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 | 26 |
| 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 | 1 |
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