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Randomized, Double-Masked, Active-Controlled, Phase 3 Study of the Efficacy and Safety of Aflibercept 8 mg in Macular Edema Secondary to Retinal Vein Occlusion (QUASAR)

Efficacy and Safety of High Dose Aflibercept in Macular Edema Secondary to Retinal Vein Occlusion (QUASAR)

892

The overall proportion of male and female subjects was 52.2% and 47.8%, respectively. The mean age was 65.9 years (range 23 to 95 years) overall. Most subjects were White (59.2%) or Asian (32.4%) and of Not Hispanic or Latino (89.0%) ethnic origin.

The study was conducted at 237 centers in Europe, America, Japan, and Asia-Pacific between 15-May-2023 (first participant first visit) and 27-May-2025 (last participant last visit) In total 1282 participants were screened, of whom 388 participants were screen failures. Overall, 892 participants were randomized and treated. Of these, 795 participants completed the treatment phase through Week 64.

The overall incidences of non-ocular treatment-emergent adverse events (TEAEs) reported up to Week 64 were similar across the treatment groups, while the incidences of ocular TEAEs in the study eye was slightly higher in the 8q8/3 group (45.7%) compared to the 8q8/5 group (39.6%) or the 2q4 group (42.2%). Most of the reported TEAEs were mild or moderate in intensity and were resolved or resolving within the observation period with no need to permanently discontinue the study intervention. Ocular TEAEs in the study eye that resulted in discontinuation of the study intervention affected few subjects: 2 (0.7%) subjects in the 8q8/5 group and 1 (0.3%) subject in the 2q4 group, and no subjects in the 8q8/3 group. Similarly, non-ocular TEAEs resulted in discontinuation of the study intervention in few subjects: 7 (1.2%) subjects in the All 8 mg groups and 4 (1.3%) subjects in the 2q4 group. Arm/Reporting group details - 2q4 group: Participants receive 9 intravitreal (IVT) injections of aflibercept 2 mg every 4 weeks, after which the dosing interval is adjusted according to treatment response. - 8q8/3 group: Participants receive 3 IVT injections of aflibercept 8 mg every 4 weeks, followed by dosing every 8 weeks, after which the dosing interval is adjusted according to treatment response. - 8q8/5 group: Participants receive 5 IVT injections of aflibercept 8 mg every 4 weeks, followed by dosing every 8 weeks, after which the dosing interval is adjusted according to treatment response. A total of 10 deaths were reported in this study, and all were associated with a serious adverse events (SAE). One event of Myocardial ischemia in an elderly subject in the 8q8/5 group who had a medical history of dyslipidemia and hypertension was assessed as related to the study intervention. All other events were assessed as not related to study intervention, intravitreal (IVT) injection procedure or protocol-required procedure. The deaths reported were consistent with concurrent medical conditions and the complications of these conditions associated with an older population. The incidences of ocular or non-ocular serious TEAEs were low and comparable across the treatment groups. Most of the serious TEAEs were reported in single subjects only.

Primary endpoint result: - The least square (LS) mean change from baseline in best-corrected visual acuity (BCVA) at Week 36 was 17.5 letters in the Aflibercept 2q4 arm, 17.4 letters in the Aflibercept 8q8/3 arm and 18.3 letters in the Aflibercept 8q8/5 arm. Key secondary endpoint result: - The LS mean number of active injections from baseline to Week 64 was 11.7 active injections in the Aflibercept 2q4 arm, 8.5 active injections in the Aflibercept 8q8/3 arm and 9.5 active injections in the Aflibercept 8q8/5 arm. Secondary endpoint results: - The LS mean number of active injections from baseline to Week 36 was 8.8 active injections in the Aflibercept 2q4 arm, 6.1 active injections in the Aflibercept 8q8/3 arm and 6.9 active injections in the Aflibercept 8q8/5 arm. - At Week 44, the LS mean change from baseline in BCVA was 17.8 letters in the Aflibercept 2q4 arm and 18.8 letters in the Aflibercept 8q8/5 arm. At Week 64, the LS mean change from baseline in BCVA was 17.3 letters in the Aflibercept 2q4 arm, 17.8 letters in the Aflibercept 8q8/3 arm and 18.1 letters in the Aflibercept 8q8/5 arm. - At Week 36, the proportion of subjects gaining at least 15 letters in BCVA from baseline was 59.8% in the Aflibercept 2q4 arm, 58.8% in the Aflibercept 8q8/3 arm, and 64.9% in the Aflibercept 8q8/5 arm. At Week 64, the corresponding proportions were 60.4%, 61.7%, and 67.1% respectively. - The proportion of subjects achieving a BCVA letter score of at least 69, the rates at Week 36 was 67.8% in the Aflibercept 2q4 arm, 72.7% in the Aflibercept 8q8/3 arm, and 76.2% in the Aflibercept 8q8/5 arm. At Week 64, the corresponding proportions were 70.2%, 70.4%, and 75.4%, respectively. - The proportion of subjects having no intraretinal fluid (IRF) and no subretinal fluid (SRF) in the central subfield was similar across treatment groups, ranging from 81.2% to 83.7% at Week 36. At Week 64, the proportions were 66.0% in the Aflibercept 2q4 arm, 76.3% in the Aflibercept 8q8/3 arm, and 71.3% in the Aflibercept 8q8/5 arm. - At Week 36, the LS mean change from baseline in central subfield thickness (CST) was -370.8 um in the Aflibercept 2q4 arm, -370.9 um in the Aflibercept 8q8/3 arm and -369.5 um in the Aflibercept 8q8/5 arm. Similar LS mean decreases from baseline were observed in all treatment groups at Week 64, (- 353.7, -361.1 and -353.3 um in 2q4, 8q8/3 and 8q8/5 groups, respectively). - At Week 36, the LS mean change from baseline in National Eye Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25) was 6.27 points in the Aflibercept 2q4 arm, 5.91 points in the Aflibercept 8q8/3 arm and 6.92 points in the Aflibercept 8q8/5 arm. At Week 64, the LS mean change from baseline in NEI-VFQ-25 was 7.21 points in the 2q4 arm, 6.10 points in the 8q8/3 arm, and 6.67 points in the 8q8/5 arm. - A total of 501 (90.9%) subjects in the All 8 mg group were able to maintain every 8 weeks dosing through Week 36. - In subjects completing Week 64, the last completed dosing interval was >=Q12 in 81.4% and 78.5% of subjects in the 8q8/3 and 8q8/5 groups, respectively. Due to the study design, only subjects in the 8q8/3 group could complete a Q16 dosing interval, which was achieved in 56.1% of subjects. In subjects completing Week 64 in the 2q4 group, the last completed dosing interval was >=Q12 in 67.8% of subjects. - In subjects completing Week 64, the last intended dosing interval was >=Q12 in 86.2% and 85.5% of subjects in the 8q8/3 and 8q8/5 arms, respectively, and was >=Q16 in 64.3% and 62.1% of subjects, respectively. Due to the study design, only subjects in the 8q8/3 group could be assigned to a Q20 dosing interval, which was achieved in 40.5% of subjects. In subjects completing Week 64 in the 2q4 group, the last intended dosing interval was >=Q12 in 77.8% of subjects and was >=Q16 in 50.0% of subjects. - Through Week 36, similar proportions of subjects experienced TEAEs: 360 (60.9%) subjects in the All 8 mg group (184 [62.8%] in the aflibercept 8q8/3 arm and 176 [59.1%] in the aflibercept 8q8/5 arm) and 188 (62.5%) in the aflibercept 2q4 arm. Regarding TESAEs, 49 (8.3%) subjects in the All 8 mg group (23 [7.8%] in the aflibercept 8q8/3 arm and 26 [8.7%] in the aflibercept 8q8/5 arm) and 32 (10.6%) in the aflibercept 2q4 arm experienced TESAEs. Through Week 64, 431 (73.0%) subjects in the All 8 mg group (220 [75.1%] in the 8q8/3 group and 211 [70.8%] in the 8q8/5 group) and 226 (75.1%) in the 2q4 group experienced TEAEs. Regarding TESAEs, 75 (12.7%) subjects in the All 8 mg group (37 [12.6%] in the aflibercept 8q8/3 arm and 38 [12.8%] in the aflibercept 8q8/5 arm) and 44 (14.6%) in the aflibercept 2q4 arm experienced TESAEs.

Treatment with aflibercept 8 mg at >=8-week intervals (with 3 or 5 initial monthly doses) provided noninferior BCVA gains at Week 36 vs aflibercept 2 mg Q4W. Week 64 results were consistent. Outcomes achieved with fewer injections in 8q8/3 and 8q8/5 vs 2q4. ~90% of subjects completing Week 64 maintained >8-week intervals while preserving visual and anatomic outcomes. Robust efficacy and safety in all RVO types (BRVO, CRVO/HRVO). No new safety signals; safety profile consistent with established aflibercept.

July. 31, 2026

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2031230147

Myoishi Masafumi

Bayer Yakuhin, Ltd.

2-4-9 Umeda, Kita-ku, Osaka, Osaka

byl_ct_contact@bayer.com

Dedicated contact

Bayer Yakuhin, Ltd.

2-4-9 Umeda, Kita-ku, Osaka, Osaka

+81-6-6133-6363

byl_ct_contact@bayer.com

Complete

June. 16, 2023

Interventional

randomized controlled trial

double blind

active control

parallel assignment

treatment purpose

- Adult >=18 years of age (or countrys legal age of adulthood if the legal age is >18 years) at the time of signing the informed consent.
- Treatment-naive macular edema involving the foveal center secondary to RVO (BRVO, HRVO, or CRVO) diagnosed within 16 weeks (112 days) before the screening visit in the study eye.
- Early Treatment Diabetic Retinopathy Study BCVA letter score of 73 to 24 (20/40 to 20/320) at screening and baseline visits in the study eye.- Decrease in BCVA determined to be primarily the result of RVO in the study eye.
- Mean CST >=00 um on optical coherence tomography (OCT) if excluding Bruchs membrane (e.g., Cirrus or Topcon) or >=320 um if including Bruchs membrane (e.g., Heidelberg Spectralis), confirmed by the reading center at the screening visit and by the site at baseline visit in the study eye.
- Capable of giving signed informed consent form (ICF) by study participant or legally acceptable representative, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.- US participants will be required to have a Health Insurance Portability and Accountability Act (HIPAA) authorization; in other countries, as applicable according to national laws.
- Women of childbearing potential (WOCBP) or men who are sexually active with partners of childbearing potential must agree to use highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 4 months after the last administration of study intervention. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for participation in clinical studies and fulfil the conditions set on Section 10.4.2.

- Concurrent disease that causes substantial decrease of BCVA, is expected to limit BCVA recovery or is likely to require medical or surgical intervention during the study in the study eye.
- Presence or history of the following ocular conditions:
1. Advanced age-related macular degeneration (neovascular AMD or geographic atrophy) in the study eye.
2. Diabetic macular edema or diabetic retinopathy, defined in diabetic participants as diabetic retinopathy lesions outside the area of the vein occlusion in the study eye and anywhere in the retina in the fellow eye.
3. Anterior segment neovascularization, vitreous hemorrhage, retinal detachment in the study eye.
4. Vitreomacular traction, epiretinal membrane or structural damage to the macula that is considered by the Investigator to significantly affect central vision or preclude improvement in vision in the study eye.
5. Macular hole of stage 2 and above in the study eye.
6. Myopia of a spherical equivalent of at least 8 diopters prior to any refractive or cataract surgery in the study eye.
7. Corneal transplant or corneal dystrophy in the study eye.
8. Idiopathic or autoimmune uveitis in the study or in the fellow eye.
- Presence of the following ocular conditions at screening or baseline visit:
1. Significant media opacities, including cataract, that interfere with BCVA, or imaging assessments (e.g., fundus photography [FP], OCT) in the study eye.
2. Aphakia, or pseudophakia with absence of posterior capsule (unless it occurred as a result of a yttrium-aluminum-garnet [YAG] posterior capsulotomy performed more than 30 days before the screening visit), in the study eye.
3. Uncontrolled glaucoma (defined as IOP >25 mmHg despite treatment with anti-glaucoma medication); or history or likely future need of glaucoma surgery in the study eye.
4. Intraocular inflammation/infection (including trace, or above, cells in the anterior chamber and/or vitreous) within 12 weeks (84 days) of the screening visit in the study or in the fellow eye.
5. Extraocular or periocular infection or inflammation (including infectious blepharitis, keratitis, scleritis, or conjunctivitis) in the study or in the fellow eye.
- Uncontrolled blood pressure (defined as systolic >160 mmHg or diastolic >95 mmHg) at the screening visit or baseline visit.
- Uncontrolled diabetes mellitus, defined by hemoglobin A1c (HbA1c) >12% at the screening visit.
- History of cerebrovascular accident or myocardial infarction within 24 weeks (168 days) before the screening visit or between screening and baseline visits.
- Renal failure requiring dialysis, or renal transplant at screening or potentially during the study.
- Any prior or concomitant ocular or systemic treatment (with an investigational or approved, anti-VEGF or other agent) or surgery for RVO in the study eye.
- Previous administration of systemic anti-angiogenic medications for any condition.
- Prior treatment of the study eye with any of the following drugs (any route of ophthalmic administration) or procedures:
1. Anti-angiogenic drugs at any time including investigational therapy (e.g., with anti-angiopoietin/anti-VEGF bispecific monoclonal antibodies).
2. Previous use topical steroids within 4 weeks (28 days) from the screening visit, or intraocular or periocular steroids within 16 weeks (112 days) from the screening visit, or steroid implants at any time.
3. Previous treatment with intraocular or periocular implant, gene therapy, or cell therapy at any time.
4. Treatment with ocriplasmin at any time.
5. Vitreoretinal surgery (including scleral buckling) at any time.
6. Any intraocular surgery, including cataract surgery, within 12 weeks (84 days) before the screening visit.
7. Previous treatment with retinal laser photocoagulation.
- Prior treatment of the fellow eye with any of the following:
a. Gene therapy, or cell therapy in the fellow eye at any time.

Both

Macular Edema Secondary to Retinal Vein Occlusion

Drug: Aflibercept, VEGF Trap-Eye(Eylea, BAY86-5321)_higher dose Intravitreally (IVT) injection.
Drug: Aflibercept, VEGF Trap-Eye(Eylea, BAY86-5321)_2 mg Intravitreally (IVT) injection.
Drug: Sham, Sham procedure will be given on visits when an active injection is not planned.
Diagnostic Test: Fluorescein, Fluorescein 100 mg/mL solution for injection is a dye that makes the retinal vessels visible during FA examinations, and as such, it will be used as an auxiliary medicinal product (AxMP) in this periodic ophthalmic examination. This medicine is for diagnostic use only. It is not used to treat any condition.

Change from baseline in BCVA measured by the ETDRS letter score at Week 36 [ Time Frame: At Week 36 ]

+81-3-3815-5411

April. 20, 2023

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