| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Wet Age-related Macular Degeneration (wAMD)
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with wet Age-related Macular Degeneration in need of treatment |
|
| 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 | LLT |
| E.1.2 | Classification code | 10075568 |
| E.1.2 | Term | Wet 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 efficacy of HLX04-O at Week 36 compared with ranibizumab in patients study eyes with wAMD. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of HLX04-O at week 12, 24, 36 and 48 compared with ranibizumab in patients' study eyes 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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Capable to 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. Newly diagnosed, untreated, active CNV lesions secondary to agerelated macular degeneration that affect the central subfield (CSF) 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.
5. The total lesion area (including hemorrage, scar and neovascularization) of the study eye ≤12 disc area (DA) with confirmation of the reading center before randomization.
6. The BCVA letters between 24 and 73, inclusive, in the study eye, using Early Treatment Diabetic Retinopathy Study (ETDRS) charts.
7. Participants' fellow (non-study) eyes must have had a BCVA of 24 letters or better.
8. Clear ocular media and adequate pupillary dilatation to allow acquisition of good quality retinal images to confirm the diagnosis. |
|
| E.4 | Principal exclusion criteria |
1.Macular-related retinal pigment epithelial tears in the study eye; scar,
fibrosis or atrophy involving the fovea, or CNV due to other causes in the
study eye with confirmation of the reading center.
2.The fellow (non study) eye needs anti-VEGF IVT injection in the next 3
months after randomization, in the investigator's judgment.
3.Aphakia (except intraocular lens) or posterior capsular rupture of the
lens (except yttrium aluminium-garnet (YAG) laser posterior
capsulotomy after intraocular lens implantation ≥30 days prior to first
dose) in the study eye.
4.Active or recent (within 1 month prior to dose 1) intraocular,
extraocular or periocular infection (including conjunctivitis, keratitis,
scleritis or endophthalmitis), or history of idiopathic or
autoimmune associated uveitis in either eye.
5.Vitreous hemorrhage in the study eye within 3 months prior to dose 1.
6.Corneal dystrophy or history of corneal transplantation, scleral
softening or history of scleral softening, history of rhegmatogenous
retinal detachment or macular hole (Stage II, III or IV) 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
8.Equivalent spherical diopter of the study eye ≥−8D.
9.Estimated by the Investigator, any concurrent intraocular condition
except wAMD in the study eye that limited the potential to gain visual
acuity upon treatment with the investigational product, or could have
required medical or surgical intervention during the study to prevent or
treat visual loss.
10.Underwent intraocular surgery including verteporfin photodynamic
therapy (PDT), transpupillary thermotherapy, macular
translocation,vitrectomy, laser photocoagulation in macular area, other
surgery in macular area or surgery to treat AMD.
11.Previous extraocular or periocular surgery within 1 month or intraocular surgery (except the surgery mentioned in exclusion 10, such as cataract surgery, etc.) within 3 months prior to dose 1, or current unhealed wound, moderate or severe ulcer or fracture in the study eye.
12.Subconjunctival or intraocular use of corticosteroids within 3 months (including subconjunctival or intraocular long-acting implant within 6 months) prior to dose 1 in the study eye. Use of systemic corticosteroids for 30 or more consecutive days within 3 months prior to dose 1.Inhaled, nasal or dermal steroids are permitted. Topical ocular corticosteroids administered for 30 or more consecutive days in the study eye within 3 months prior to dose 1
13.Previous systemic anti-VEGF therapy or IVT injection of any anti-
VEGF drug into either eye or other ocular use of anti-VEGF drug within 3
months prior to dose 1.
14.Participated in any drug (other than vitamins and minerals) or device
clinical trials 3 months or the duration of 5 half-lives of the study drug
(which is longer) before the first dose and have used the test drug or
received device treatment.
15.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.
16.Infertile women or men fail to meet either of the following ones: 1)
menopause 2) surgically sterilized.
Fertile women or men fail to meet either of the following ones: 1)
women of childbearing potential must have a negative urine or serum
pregnancy test result within 14 days prior to initiation of the study
intervention and should not breastfeed. If the urine pregnancy test is
positive, it must be confirmed by a serum pregnancy test; 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.
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
18.Uncontrolled diabetes (defined as HbA1c≥10.0%).
19.Alanine aminotransferase (ALT) and/or aspartate aminotransferase
(AST) is more than twice the upper limit of normal (ULN), and/or serum
creatinine is 1.2 times more than the ULN, and is clinically significant in
the opinion of the Investigator.
20.Abnormal coagulation function (PT) or International normalized ratio (INR) ≥ 1.5 ×ULN, activated partial thromboplastin time (aPTT) ≥1.5 ×ULN）, and is clinically significant in the opinion of the Investigator.
21.Active disseminated intravascular coagulation and obvious bleeding
tendency within 3 months prior to dose 1. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Mean change from baseline in best-corrected visual acuity (BCVA) at Week 36 based on all randomized participants. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
•Mean change from baseline in BCVA at Week 48. If, and only if, HLX04-O is statistically by proven to be non-inferior to the ranibizumab in the primary efficacy analysis, confirmatory testing will be continued to prove the non-inferiority regard to the key secondary efficacy variable. The assessment method will be the same as the primary efficacy endpoint describing in section 9.4.3;
• Mean change in the BCVA over time;
• Proportion of patients gaining at least 15 letters in the BCVA at Week
12, 24, 36 and 48;
• Proportion of patients gaining at least 10 letters in the BCVA at Week
12, 24, 36 and 48;
• Proportion of patients gaining at least 5 letters in the BCVA at Week
12, 24, 36 and 48;
• Mean change from baseline in size of CNV and the total area of
fluorescein leakage on FA at Week 12, 36 and 48 (as measured by the
Reading Center);
• Mean change from baseline in central retina thickness (CRT) on OCT at
Week 12, 24, 36 and 48 (as measured by the Reading Center);
• Change from baseline in NEI VFQ-25 scale score at Week 12, 36, and
48.
•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 serum concentrations before Dose 1, Dose 2, Dose 6, Dose 9,
Dose 12 and the last visit as data permit.
• HLX04-O systemic PK parameters following IVT administration of Dose
1 and Dose 4, including but not limited to:
➢ 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 following Dose 4 at steady state
➢ Accumulation ratios (Dose 4/Dose 1) for AUC(0-τ), Cmax and Cmin. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints included in above endpoints and throughout the duration of the study |
|
| 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 | 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 | 14 |
| 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 |
| Serbia |
| United States |
| Bulgaria |
| France |
| Germany |
| Hungary |
| Italy |
| Latvia |
| Poland |
| Slovakia |
| Spain |
|
| 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
|
|
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | 18 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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