Study of AR-14034 in Participants With Neovascular Age-Related Macular Degeneration (nAMD)

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the safety and durability of single- and repeat administration of AR-14034 Sustained Release (SR) in subjects with neovascular age-related macular degeneration (nAMD).

Detailed Description
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This study will be conducted in two stages. Stage 1 is a 48-week, dose-escalation, open-label evaluation of AR-14034 SR. Two cohorts will be enrolled, for an approximate total of 10 subjects. Subjects in both cohorts will attend visits through Week 48 for assessment of safety and preliminary treatment effects. Stage 2 is a 56-week (plus extension) double-masked, active comparator, randomized, parallel group evaluation of AR-14034 SR compared with aflibercept. Approximately 130 subjects will be enrolled and randomized 2:2:1 to AR-14034 SR lower dose, AR-14034 SR higher dose, or aflibercept dosed as labelled. Subjects will attend visits through Week 56 for assessment of safety and treatment effects. A 16-week open label extension phase will be conducted thereafter.

Official Title
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A Phase 1/2 Two-Stage Dose Escalation and Randomized Parallel-Group Study to Evaluate the Safety, Preliminary Treatment Effects, and Durability of AR-14034 Sustained Release Implant Compared to Intravitreal Anti-Vascular Endothelial Growth Factor Treatment in Participants With Neovascular Age-Related Macular Degeneration

Conditions
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Neovascular Age-related Macular Degeneration (nAMD)

Intervention / Treatment
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* Drug: AR-14034 SR implant lower dose
* Drug: Aflibercept Injection
* Drug: Sham procedure
* Drug: AR-14034 SR implant higher dose


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria [Stage 1 and Stage 2]: Presence of an active choroidal neovascularization (CNV) lesion secondary to age-related macular degeneration (AMD); Best corrected visual acuity (BCVA) between 80 and 35 letters (20/25 to 20/200 Snellen equivalent) in the study eye; BCVA greater than 34 letters (approximately 20/200 Snellen equivalent) in the non-study eye; Media clarity and pupillary dilation in the study eye sufficient for all planned study procedures; 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; Other protocol-specified inclusion criteria may apply. [Stage 1]: Greater than or equal to 3 and less than or equal to 6 prior treatments of an ocular anti-VEGF medication within the 8 months prior to Screening in the study eye, with demonstrated anatomic response, as assessed by the Investigator. [Stage 2]: Treatment-naïve, or initial diagnosis of exudative neovascular age-related macular degeneration (nAMD) in the study eye within 9 months before Screening. Key Exclusion Criteria [Stage 1 and Stage 2]: History or current ocular disease in the study eye other than nAMD, that, might require medical or surgical intervention during the study; Structural damage to the macula that is likely to preclude improvement in visual acuity in the study eye after resolution of the nAMD; Any active intraocular or periocular infection or active intraocular inflammation; Treatment with ocular anti-VEGF product within 28-days before Week -1 [Stage 1] or Baseline [Stage 2]; Uncontrolled glaucoma in the study eye; Uncontrolled blood pressure; Females of child-bearing potential who are pregnant, intending to become pregnant, nursing, or who are not willing to use an acceptable form of contraception for the duration of the study; Other protocol-specified exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Stage 1 will enroll 2 cohorts. Stage 2 will enroll 3 treatment arms.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (Stage 1)<br>One intravitreal (IVT) injection of aflibercept 2 mg at Week -1 and one IVT insertion of AR-14034 SR lower dose at Baseline. Up to one retreatment with AR-14034 SR will be administered between Weeks 4 and 36 according to protocol-specified disease activity criteria. | Drug: AR-14034 SR implant lower dose<br>* AR-14034 SR administered as an intravitreal implant<br>Drug: Aflibercept Injection<br>* Aflibercept administered as a 2 milligram (mg) intravitreal injection<br>|
| Experimental: Cohort 2 (Stage 1)<br>One IVT injection of aflibercept 2 mg at Week -1 and one IVT insertion of AR-14034 SR higher dose at Baseline. Up to one retreatment with AR-14034 SR will be administered between Weeks 4 and 36 according to protocol-specified disease activity criteria. | Drug: Aflibercept Injection<br>* Aflibercept administered as a 2 milligram (mg) intravitreal injection<br>Drug: AR-14034 SR implant higher dose<br>* AR-14034 SR administered as an intravitreal implant<br>|
| Experimental: AR-14034 SR lower dose (Stage 2)<br>One IVT injection of aflibercept 2 mg at Baseline, Week 4, and Week 8, with one IVT insertion of AR-14034 SR lower dose at Week 6. Up to one retreatment of AR-14034 SR will be administered between Weeks 16 and 52 according to protocol-specified disease activity criteria. Sham procedures will be performed between Weeks 16 and 52 except when AR-14034 SR repeat treatment is administered. | Drug: AR-14034 SR implant lower dose<br>* AR-14034 SR administered as an intravitreal implant<br>Drug: Aflibercept Injection<br>* Aflibercept administered as a 2 milligram (mg) intravitreal injection<br>Drug: Sham procedure<br>* Needleless syringe used to simulate an intravitreal injection<br>|
| Experimental: AR-14034 SR higher dose (Stage 2)<br>One IVT injection of aflibercept 2 mg at Baseline, Week 4, and Week 8, with one IVT insertion of AR-14034 SR higher dose at Week 6. Up to one retreatment of AR-14034 SR will be administered between Weeks 16 and 52 according to protocol-specified disease activity criteria. Sham procedures will be performed between Weeks 16 and 52 except when AR-14034 SR repeat treatment is administered. | Drug: Aflibercept Injection<br>* Aflibercept administered as a 2 milligram (mg) intravitreal injection<br>Drug: Sham procedure<br>* Needleless syringe used to simulate an intravitreal injection<br>Drug: AR-14034 SR implant higher dose<br>* AR-14034 SR administered as an intravitreal implant<br>|
| Active Comparator: Aflibercept (Stage 2)<br>One IVT injection of aflibercept 2 mg at Baseline, Week 4, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48. Sham procedures will be performed between Weeks 16 and 52. | Drug: Aflibercept Injection<br>* Aflibercept administered as a 2 milligram (mg) intravitreal injection<br>Drug: Sham procedure<br>* Needleless syringe used to simulate an intravitreal injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change from baseline in ETDRS BCVA at the average across two visits, Weeks 44 and 48 (Stage 2) | Visual acuity will be measured after manifest refraction using Early Treatment of Diabetic Retinopathy Study (ETDRS) letter charts in a 4-meter lane under standard illumination. Best corrected visual acuity (BCVA) will be recorded as the number of letters read correctly. The difference between the average across Weeks 44 and 48, and the baseline visit will be reported. One eye (study eye) will contribute to the analysis. | Baseline, Week 44, Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change from baseline in ETDRS BCVA by visit (Stage 2) | Visual acuity will be measured after manifest refraction using ETDRS letter charts in a 4-meter lane under standard illumination. BCVA will be recorded as the number of letters read correctly. The difference between a given post-baseline visit and the baseline visit will be reported. One eye (study eye) will contribute to the analysis. | Baseline to Week 56 | 
| Mean change from baseline in Central Subfield Thickness (CST) by visit (Stage 2) | Central subfield thickness (CST) will be assessed using spectral domain optical coherence tomography (SD-OCT) imaging and measured in micrometers. The difference between a given post-baseline visit and the baseline visit will be reported. One eye (study eye) will contribute to the analysis. | Baseline to Week 56 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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nAMD, retina, eyes, ophthalmology