Clinical trial NCT02434328: Efficacy and Safety of RTH258 Versus Aflibercept - Study 2
Official title: A Two-year, Randomized, Double-masked, Multicenter, Two-arm Study Comparing the Efficacy and Safety of RTH258 6 mg Versus Aflibercept in Subjects With Neovascular Age-related Macular Degeneration
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Neovascular Age-Related Macular Degeneration
Choroidal Neovascularization
Keywords: AMD
CNV
IVT
Lead sponsor: Alcon Research
Sponsor class: INDUSTRY
First posted: 2015-05-05
Enrollment: 1048
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare brolucizumab (RTH258) ophthalmic solution for intravitreal (IVT) injection (6 mg) to aflibercept ophthalmic solution for IVT injection (2 mg) in subjects with untreated active choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) in the study eye.

Detailed description: Subjects were randomized to brolucizumab 6 mg and aflibercept 2 mg in a 1:1 ratio. Subjects in both treatment arms received 3 monthly loading doses (Day 0, Week 4 and Week 8), followed by a maintenance regimen, until the end of the study (Week 96/Exit). All subjects attended pre-specified visits every 4 weeks.

Subjects in the brolucizumab 6 mg arm followed a q12w/q8w maintenance regimen. Within the q12w/q8w regimen, the initial treatment after the loading phase was q12w (1 injection every 12 weeks). If disease activity was identified by the masked investigator at any of the disease activity assessments, dosing was adjusted to q8w (1 injection every 8 weeks) ("q12w/q8w regimen"). Once subjects were adjusted to the q8w interval, they stayed on that interval until the end of the study.

Subjects in the aflibercept 2 mg arm followed a q8w maintenance regimen until the end of the study.

Results reported up to Week 48 are based on the database locked for the primary analysis at Week 48. Results reported after Week 48 are based on the database locked at the end of study (final analysis).

Eligibility criteria: Key Inclusion Criteria:

* Provide written informed consent;
* Active CNV lesions secondary to AMD that affected the central subfield in the study eye at Screening;
* Total area of CNV \> 50% of the total lesion area in the study eye at Screening;
* Intraretinal and/or subretinal fluid affecting the central subfield of the study eye at Screening;
* Best corrected visual acuity (BCVA) between 78 and 23 letters, inclusive, in the study eye at Screening and Baseline using Early Treatment Diabetic Retinopathy Study (ETDRS) testing.

Key Exclusion Criteria:

* Any active intraocular or periocular infection or active intraocular inflammation in either eye at Baseline;
* Central subfield of the study eye affected by fibrosis or geographic atrophy or total area of fibrosis ≥ 50% of the total lesion in the study eye at Screening;
* Subretinal blood affecting the foveal center point and/or ≥ 50% of the lesion of the study eye at Screening;
* Any approved or investigational treatment for neovascular age-related macular degeneration (nAMD) in the study eye at any time;
* Retinal pigment epithelial rip/tear in the study eye at Screening or Baseline or current vitreous hemorrhage or history of vitreous hemorrhage in the study eye within 4 weeks prior to Baseline;
* Pregnant or nursing women; women of child-bearing potential;
* Stroke or myocardial infarction in the 6-month period prior to Baseline.

Primary outcomes:
measure: Change From Baseline in Best Corrected Visual Acuity (BCVA) (Letters Read) at Week 48 - Study Eye
timeFrame: Baseline, Week 48
Secondary outcomes:
measure: Average Change From Baseline in BCVA (Letters Read) Over the Period Week 36 Through Week 48 - Study Eye
timeFrame: Baseline, Weeks 36, 40, 44, 48
measure: Proportion of Subjects With Positive q12 (Every 12 Weeks) Treatment Status at Week 48
timeFrame: Weeks 16, 20, 28, 32, 40, 44, 48
measure: Proportion of Subjects With Positive q12 Treatment Status at Week 48 Within the Subjects With no q8 (Every 8 Weeks) Treatment Need During the Initial q12w Cycle (Week 16, Week 20)
timeFrame: Weeks 16, 20, 28, 32, 40, 44, 48
measure: Proportion of Subjects With Positive q12 Treatment Status up to Week 96
timeFrame: Weeks 16, 20, 28, 32, 40, 44, 52, 56, 64, 68, 76, 80, 88, 92, 96
measure: Proportion of Subjects With Positive q12 Treatment Status at Week 96 Within the Subjects With no q8 Treatment Need During the Initial q12w Cycle (Week 16, Week 20)
timeFrame: Weeks 16, 20, 28, 32, 40, 44, 52, 56, 64, 68, 76, 80, 88, 92, 96
measure: Change From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
measure: Average Change From Baseline in BCVA (Letters Read) Over the Period Week 4 to Week 48/96 - Study Eye
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
measure: Average Change From Baseline in BCVA (Letters Read) Over the Period Week 12 to Week 48/96 - Study Eye
timeFrame: Baseline, Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
measure: Average Change From Baseline in BCVA (Letters Read) Over the Period Week 84 to Week 96 - Study Eye
timeFrame: Baseline, Weeks 84, 88, 92, 96
measure: Percentage of Subjects With >=15 Letter Gain From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
measure: Percentage of Subjects With >=10 Letter Gain From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
measure: Percentage of Subjects With >=5 Letter Gain From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
measure: Percentage of Subjects With >=15 Letter Loss From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
measure: Percentage of Subjects With >=10 Letter Loss From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
measure: Percentage of Subjects With >=5 Letter Loss From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
measure: Percentage of Subjects With BCVA of 73 Letters Read or More at Each Visit - Study Eye
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
measure: Change From Baseline in Central Subfield Thickness (CSFT) at Each Post-baseline Visit - Study Eye
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
measure: Average Change From Baseline in CSFT Over the Period Week 36 Through Week 48 - Study Eye
timeFrame: Baseline, Weeks 36, 40, 44, 48
measure: Average Change From Baseline in CSFT Over the Period Week 84 Through Week 96 - Study Eye
timeFrame: Baseline, Weeks 84, 88, 92, 96
measure: Average Change From Baseline in CSFT Over the Period Week 4 Through Week 48/96 - Study Eye
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
measure: Change From Baseline in Choroidal Neovascularization (CNV) Lesion Size at Week 12, Week 48, and Week 96 - Study Eye
timeFrame: Baseline, Weeks 12, 48, 96
measure: Change From Baseline in Central Subfield Neurosensory Retinal Thickness (CSFTns) at Each Post-baseline Visit - Study Eye
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
measure: Percentage of Subjects With Presence of Subretinal Fluid at Each Post-baseline Visit - Study Eye
timeFrame: Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
measure: Percentage of Subjects With Presence of Intraretinal Fluid at Each Post-baseline Visit - Study Eye
timeFrame: Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
measure: Percentage of Subjects With Presence of Sub-retinal Pigment Epithelium (RPE) Fluid at Each Post-baseline Visit - Study Eye
timeFrame: Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
measure: Percentage of Subjects With Presence of Subretinal and/or Intraretinal Fluid (Central Subfield) at Each Post-baseline Visit - Study Eye
timeFrame: Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
measure: Percentage of Subjects With Disease Activity Present (q8 Treatment Need = "Yes") at Week 16 - Study Eye
timeFrame: Week 16
measure: Change From Baseline in Visual Function Questionnaire (VFQ-25) Composite Score at Week 24, Week 48, Week 72, and Week 96
timeFrame: Baseline, Weeks 24, 48, 72, 96
measure: Percentage of Subjects With Induced or Boosted Anti-drug Antibody (ADA) Status at Week 48 (Brolucizumab Only)
timeFrame: Week 48
measure: Percentage of Subjects With Intraretinal Hemorrhage (Central Subfield) Present at the Visit While Absent at Baseline at Each Treatment - Study Eye
timeFrame: Baseline, Weeks 12, 48, 96
measure: Percentage of Subjects With Subretinal Hemorrhage (Central Subfield) Present at the Visit While Absent at Baseline at Each Treatment - Study Eye
timeFrame: Baseline, Weeks 12, 48, 96
Other outcomes:
Locations:
Study officials:
affiliation: Novartis Pharmaceuticals
name: Group Trial Lead
role: STUDY_DIRECTOR
References:
citation: Singh RP, Jhaveri C, Wykoff CC, Gale RP, Staurenghi G, Iida T, Koh A, B G, Gedif K, Singer M. Efficacy Outcomes of Brolucizumab Versus Aflibercept in Neovascular Age-Related Macular Degeneration Patients with Early Residual Fluid. Ophthalmol Retina. 2022 May;6(5):377-386. doi: 10.1016/j.oret.2021.12.014. Epub 2021 Dec 27.
citation: Mones J, Srivastava SK, Jaffe GJ, Tadayoni R, Albini TA, Kaiser PK, Holz FG, Korobelnik JF, Kim IK, Pruente C, Murray TG, Heier JS. Risk of Inflammation, Retinal Vasculitis, and Retinal Occlusion-Related Events with Brolucizumab: Post Hoc Review of HAWK and HARRIER. Ophthalmology. 2021 Jul;128(7):1050-1059. doi: 10.1016/j.ophtha.2020.11.011. Epub 2020 Nov 15.
citation: Dugel PU, Koh A, Ogura Y, Jaffe GJ, Schmidt-Erfurth U, Brown DM, Gomes AV, Warburton J, Weichselberger A, Holz FG; HAWK and HARRIER Study Investigators. HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2020 Jan;127(1):72-84. doi: 10.1016/j.ophtha.2019.04.017. Epub 2019 Apr 12.