Study to Compare study drug (AVT06) with marketed product (EU-Eylea) in patients who has neovascular age-related macular degeneration
Scientific Title of Study
A randomized, double-masked, parallel-group, multicenter clinical study to evaluate the efficacy and safety of AVT06 compared with EU-Eylea® in subjects with neovascular (wet) age-related macular degeneration
Advanced Eye Centre, Post Graduate Institute of Medical education and Research
Room 242, 2nd floor, Sector-12, Madhya Marg, Chandigarh-160012, India Chandigarh
9878011253
bansalreema2022@gmail.com
Dr Rodney John Morris
Aravind Eye Hospital
Avinashi Road, study room, near ROP department,
Civil Aerodrome Post,
Kalapatti/
Coimbatore corporation east Coimbatore
9443128169
rodneyjmorris@gmail.com
Dr Sandeep Saxena
Department of Ophthalmology, King George’s Medical University
Shahmina Road, Chowk, Lucknow- 226003, Uttar Pradesh, India Lucknow
9415160528
sandeepsaxena2020@yahoo.com
Dr Punit Kumar Singh
Dhiraj Hospital SBKS MI & RC Sumandeep Vidyapeeth
Department of Ophthalmology,
Block B, Ground Floor Deemed to be University & Dhiraj Hospital
At & Po Piparia, Waghodia-391760, Gujarat, India Vadodara
9879946599
punitsinghdr@yahoo.com
Dr Lional Raj
Dr. Agarwal’s Eye Hospital
Room no: 38, 3rd floor, Clinical research department
No.15, South bypass road, Vannarpettai
Tirunelveli – 627002, Tamilnadu India Tirunelveli
87544-11261
drlionalraj@dragarwal.com
Dr Virendra Agrawal
Dr. Virendra Laser, Phaco Surgery Centre
First Floor, room no. 108,
Tonk Phatak, Tonk road, Gandhi Nagar, Jaipur- 302015, Rajasthan, India Jaipur
9314017147
virendravlpsc1@gmail.com
Dr Neepa Ratilal Gohil
Government Medical College & Sir Takhtasinhji Hospital
Department of Ophthalmology
5th floor
New OPD Building
Sir T Hospital Campus Bhavnagar- 364001, Gujarat, India Bhavnagar
9909978072
solankineepa@hotmail.com
Dr Santosh Kumar Mahapatra
JPM Rotary Eye Hospital CDA
Room No-119, 1st Floor, Near Retina Department,
Sector-VI, Market nagar, Cuttack - 753014, Orissa, India Cuttack
9437017762
santosh74mahapatra@gmail.com
Dr Vivek Pravin Dave
LV Prasad Eye Institute
First floor Room No. 124, Suven Clinical Research Department, GPR building, Kallam Anji Reddy Campus, L V Prasad Marg, Banjara Hills Road No. 02Hyderabad – 500034, Telangana, India Hyderabad
7680859900
vivekdave@lvpei.org
Dr Chaitra Jayadev
Narayana Nethralaya
121/C, Chord Rd, Near Iskcon Temple, 1st R Block, Rajajinagar, Bengaluru-560010, Karnataka, India Bangalore
9740021362
drchaitra@hotmail.com
Dr Kishore Tulsidas Pahuja
Natasha Eye Care and Research Centre
Department of Ophthalmology, Retina Division, Room # 01, Shiv Sai Lane, Building A, Sai Saheb Society, Opposite Lotus Hospital, Pune- 411027, Maharashtra, India Pune
9890086862
kishorepahuja@gmail.com
Dr Parth Jagdishkumar Rana
Netralaya Super Speciality Eye Hospital
Room no: R3,
Clinical Research Department,
1st Floor, Kay Dee House, Above Union Bank of India, Opp. Gujarat Gas, Parimal Garden Cross Road, CG Road, Ahmedabad -380006, Gujarat, India Ahmadabad
7999999344
dr.parth.rana@gmail.com
Dr Urmil Shah
Pagrav Multispeciality Hospital & ICU
512/1 Near G-6 Circle, opp. SBI Bank, Sector 23, Gandhinagar-382023, Gujarat Gandhinagar
AVT06 will be provided as single-dose vials.
Route of Administration - Intravitreal.
Unit Dose Strength(s)/Dosage Level(s): 2 mg (0.05 mL).
Dosage Formulation: 40 mg/mL.
In the study eye, subjects will receive 2 mg (0.05 mL) intravitreal injection of AVT06 every 4 weeks for 3 consecutive monthly visits (Day 1, Week 4, and Week 8) followed by every 8 weeks throughout the remaining treatment period (at Weeks 16, 24, 32, 40, and 48).
Study Duration - 56 weeks
Comparator Agent
EU-Eylea
Eylea will be provided as single-dose prefilled syringes.
Route of Administration - Intravitreal.
Unit Dose Strength(s)/Dosage Level(s): 2 mg (0.05 mL).
Dosage Formulation: 40 mg/mL.
In the study eye, subjects will receive 2 mg (0.05 mL) intravitreal injection of Eylea every 4 weeks for 3 consecutive monthly visits (Day 1, Week 4, and Week 8) followed by every 8 weeks throughout the remaining treatment period (at Weeks 16, 24, 32, 40, and 48).
Dose, frequency, route of administration and duration- same as interventional agent
Inclusion Criteria
Age From
50.00 Year(s)
Age To
99.00 Year(s)
Gender
Both
Details
Age
1. Subject must be ≥50 years of age, at the time of signing the informed consent.
Study Eye
2. Subjects must be diagnosed with neovascular (wet) AMD in the study eye.
3. Subjects must have active, treatment naïve, subfoveal CNV lesions secondary to neovascular (wet) AMD, including juxtafoveal lesions with foveal involvement (demonstrated by leakage on FA and/or intraretinal fluid or subretinal fluid on SD-OCT) in the study eye at screening.
4. Subjects with total lesion area ≤9.0 Disc Areas in size (including blood, scars [not involving the center of the fovea], and neovascularization) in the study eye at screening.
5. Subjects with active CNV area must occupy at least 50% of total lesion in the study eye.
6. Subjects with BCVA of 20/40 to 20/200 (between 73 and 34 letters inclusive), in the study eye as assessed by ETDRS letter score at screening and on Day 1 prior to randomization.
7. Presence of intra and/or subretinal fluid as identified in the center subfield by SD-OCT attributable to active CNV in the study eye at screening.
8. Subjects with central retinal thickness of ≥300 μm in the study eye as determined by SD-OCT at screening.
Sex
9. Male or female
a) Male subjects:
A male subject must agree to use contraception as per protocol during the treatment period and for at least 3 months after the last intravitreal injection of study treatment and refrain from donating sperm during this period.
b) Female subjects:
A female subject is eligible to participate if she is not pregnant, not breastfeeding, not intending to become pregnant during the treatment period and for at least 3 months after the last intravitreal injection of study treatment, and at least 1 of the following conditions applies:
i) Not a woman of childbearing potential (WOCBP) as defined protocol. OR
ii) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 3 months after the last intravitreal injection of study treatment.
Informed Consent
10. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
ExclusionCriteria
Details
1. Scar, fibrosis, or atrophy involving the center of the fovea in the study eye
2. History of retinal detachment in the study eye.
3. Presence of RPE tears involving the macula in the study eye.
4. History of any vitreous hemorrhage within 4 weeks before randomization in the study eye.
5. Prior vitrectomy or laser surgery of the macula (including photodynamic therapy or focal laser photocoagulation) in the study eye.
6. Uncontrolled ocular hypertension (defined as IOP ≥25 mmHg despite treatment with anti-glaucoma medication) at screening and randomization visits in the study eye.
7. Any history of macular hole in the study eye.
8. Any concurrent macular abnormality other than wet AMD which could affect central vision or the efficacy of the study treatment in the study eye.
9. Aphakia or absence of the posterior capsule (unless it occurred as a result of a posterior capsulotomy with neodymium-doped yttrium aluminium garnet [YAG] laser following cataract surgery with intraocular lens implantation) in the study eye.
10. Significant media opacities, including cataract or inadequate pupil dilatation, which might interfere with visual acuity or assessment of safety in the study eye.
11. Cataract surgery within 3 months from Day 1.
12. History of corneal transplant, corneal dystrophy, or corneal ectasia (such as either keratoconus or keratoglobus) in the study eye.
13. Subjects with previous ocular (intraocular and peribulbar) corticosteroids injection/implant within 1 year in the study eye prior to randomization.
14. Topical ocular corticosteroids for 30 or more consecutive days within 90 days prior to randomization in the study eye.
15. Previous therapeutic radiation in the region of the study eye.
16. Any prior ocular treatment, including surgery or another investigational product for neovascular AMD (including anti-VEGF therapy), in the study eye, except dietary supplements or vitamins.
17. Concurrent ocular condition which, in the opinion of the Investigator, could require medical or surgical intervention during the study period and/or confound the interpretation of the study results.
Either Eye
18. History or clinical evidence of uveitis, diabetic retinopathy, diabetic macular edema, or any other vascular disease affecting the retina, other than neovascular AMD.
19. Active or suspected ocular or periocular infection, within 2 weeks before randomization.
20. Active scleritis or episcleritis or presence of scleromalacia.
Fellow Eye
21. Any ocular treatment, including surgery or another investigational product for neovascular AMD (including anti-VEGF treatment), in the fellow eye, within 6 months before randomization, except dietary supplements or vitamins.
22. Subjects with BCVA of 20/200 or less (34 letters or less) in the fellow eye as assessed by ETDRS letter score at screening and on Day 1 prior to randomization.
23. Subjects with any diagnosis and/or signs of neovascular AMD requiring intravitreal anti-VEGF in the fellow eye, or in the opinion of the Investigator, are expected to require such treatments before the evaluation of the primary efficacy endpoint (ie, Week 8) and completion of PK sampling (ie, Week 16) for the subjects in the PK sub-study.
Other
24. Any prior systemic treatment with anti-VEGF therapy.
25. History of hypersensitivity or anaphylaxis to study treatments (including any excipient), and/or history of hypersensitivity to fluorescein sodium for injection in angiography or to any other compound used for the study procedures.
26. Prior treatment with any investigational drugs within 30 days or 5 half-lives (whichever is longer) of the previous investigational treatment before initiation of the study treatment or concomitant enrolment in any other clinical study involving an investigational study treatment.
27. Uncontrolled diabetes mellitus with glycosylated hemoglobin (HbA1c) >8%. 28. Uncontrolled cardiovascular disease including hypertension, heart failure, or clinically significant electrocardiogram (ECG) abnormality, including subjects with QT interval corrected using Fridericia’s formula [QTcF] >480 ms at screening, confirmed by repeat assessment.
29. Acute coronary event or stroke within 6 months before randomization.
30. Any condition that, in the Investigator´s opinion, can interfere with full participation in the study, including administration of the study treatment and attending required visits; can pose a significant risk to the participant, or interfere with interpretation of study data.
31. Malignancy diagnosed within 5 years except treated and considered cured cutaneous squamous or basal cell carcinoma, in situ cervical cancer, in situ prostate cancer, or in situ breast ductal carcinoma.
32. Subjects not suitable for participation, whatever the reason, as judged by the Investigator, including medical or psychiatric conditions, or participants potentially at risk of noncompliance to study procedures
Method of Generating Random Sequence
Other
Method of Concealment
Other
Blinding/Masking
Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded
Primary Outcome
Outcome
TimePoints
Objective: To demonstrate the equivalent efficacy of AVT06 to Eylea in subjects with neovascular (wet) age-related macular degeneration (AMD).
Endpoint: Change from baseline to Week 8 in Best-corrected Visual Acuity (BCVA) as measured by Early Treatment Diabetic Retinopathy Study (ETDRS) letter score.
As per clinicaltrial.gov
Change from baseline to Week 8 in Best-corrected Visual Acuity (BCVA) [ Time Frame: Week 8 ]
Week 8
Secondary Outcome
Outcome
TimePoints
Objectives:
To assess immunogenicity of AVT06 compared with Eylea
End-points:
•Proportion of subjects testing positive for anti-drug antibodies (ADAs), including neutralizing ADA (NAb) from baseline to Week 4, Week 8, Week 16, Week 24, and Week 52.
Objectives:
To evaluate the efficacy of AVT06 compared with Eylea in subjects with neovascular (wet) AMD.
End-points:
1.Change from baseline in BCVA as assessed by ETDRS letter score at Week 4, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 52.
2. Gain of ≥5, 10, 15 letter score in BCVA from baseline to Week 4, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 52.
3. Loss of ≥5, 10, 15 letter score in BCVA from baseline to Week 4, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 52.
4. Change from baseline in central subfield thickness (CST) as assessed by spectral domain optical coherence tomography (SD-OCT) at Week 4, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 52.
5. Change from baseline in choroidal neovascularization (CNV) area as assessed by fluorescein angiography (FA) and color fundus photography (FP) at Week 8, Week 24, and Week 52.
Objectives:
To evaluate the safety and tolerability of AVT06 compared with Eylea.
End-points:
1. Incidence of ocular and non-ocular treatment-emergent adverse events (TEAEs), adverse events of special interest (AESIs), and serious adverse events (SAEs).
2.Evaluation of ophthalmic parameters (intraocular pressure [IOP], biomicroscopy, and indirect ophthalmoscopy).
3. Evaluation of routine safety parameters, including safety laboratory, 12-lead electrocardiogram (ECG) results, vital signs, and physical examination.
Objectives:
To evaluate the systemic pharmacokinetics (PK) of AVT06 and Eylea in a subset of subjects
End-points:
•Evaluate systemic PK profile of free and bound aflibercept from baseline (Day 1 predose) to Day 1 (1 to 4 hours postdose), Day 2, Day 3, Week 4, Week 8 Day 1 (predose), Week 8 Day 1 (1 to 4 hours postdose), Week 8 Day 2, Week 8 Day 3, and Week 16
This is a Phase 3, randomized, double-masked, parallel-group, multicenter, therapeutic equivalence study evaluating the efficacy, safety, and immunogenicity of AVT06 compared with Eylea in subjects with neovascular (wet) AMD. The study will also evaluate systemic PK of AVT06 and Eylea in a subset of subjects.
Number of Subjects: Approximately 444 subjects will be randomly assigned to the study treatment in order to obtain approximately 398 evaluable subjects for the analysis of primary endpoint of change from baseline to Week 8 in BCVA.
Treatment Groups and Duration: The study consists of a screening period of up to 4 weeks, a treatment period of 48 weeks, and a follow-up period of 4 weeks until Week 52 (end of study). The total study duration per subject is 56 weeks including screening period.
After completing the screening activities, eligible subjects will be randomized in a 1:1 ratio on Day 1 to either AVT06 or Eylea treatment groups. The randomization will be stratified by geographical origin (Europe, Americas, Japan, Other), baseline BCVA (≤53 letters versus ≥54 letters), and iris color (light irides versus non-light irides).
