Evaluation of AGN-150998 in Exudative Age-related Macular Degeneration (AMD)

Study Overview
=================
Brief Summary
-----------------
This study is conducted in 3 stages. Stage 1 is an open-label, dose-escalation assessment of the safety of AGN-150998 administered as a single intravitreal injection to patients with advanced exudative Age-related Macular Degeneration (AMD). Stage 2 and Stage 3 are randomized, double-masked, comparisons of the safety and treatment effects on retinal edema and best-corrected visual acuity (BCVA) of AGN-150998 and ranibizumab in treatment-naive patients with exudative AMD. Study medication is administered as needed in Stage 2 and with a fixed-dosing schedule in Stage 3. The study objectives are (1) to identify the highest tolerated dose of AGN-150998, (2) to assess the safety and duration of treatment effects on retinal edema and BCVA, and (3) to characterize the systemic pharmacokinetic profile of AGN-150998.

Conditions
-----------------
Age-related Macular Degeneration

Intervention / Treatment
-----------------
* Drug: AGN-150998
* Drug: ranibizumab
* Other: Sham Injection


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Exudative age-related macular degeneration Best-corrected visual acuity between 20/32 and 20/320 in the study eye Exclusion Criteria: Near-sightedness of 8 diopters or more Uncontrolled glaucoma in the study eye Cataract surgery or Lasik within the last 3 months Any active ocular infection or inflammation

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1: AGN-150998 4.2 mg<br>Stage 1: AGN-150998 4.2.mg given as a single intravitreal injection. | Drug: AGN-150998<br>* AGN-150998 Intravitreal injection.<br>|
| Experimental: Stage 1: AGN-150998 3.0 mg<br>Stage 1: AGN-150998 3.0 mg given as a single intravitreal injection. | Drug: AGN-150998<br>* AGN-150998 Intravitreal injection.<br>|
| Experimental: Stage 1: AGN-150998 2.0 mg<br>Stage 1: AGN-150998 2.0 mg given as a single intravitreal injection. | Drug: AGN-150998<br>* AGN-150998 Intravitreal injection.<br>|
| Experimental: Stage 1: AGN-150998 1.0 mg<br>Stage 1: AGN-150998 1.0 mg given as a single intravitreal injection. | Drug: AGN-150998<br>* AGN-150998 Intravitreal injection.<br>|
| Experimental: Stage 2: AGN-150998 4.2 mg<br>Stage 2: AGN-150998 4,2 mg (highest tolerated dose from Stage 1) given as a single intravitreal injection at baseline. A second intravitreal injection will be given by week 16. | Drug: AGN-150998<br>* AGN-150998 Intravitreal injection.<br>|
| Experimental: Stage 2: AGN-150998 3.0 mg<br>Stage 2: AGN-150998 3.0 mg (one dose below highest tolerated dose) from Stage 1 given as a single intravitreal injection at baseline. A second intravitreal injection will be given by week 16. | Drug: AGN-150998<br>* AGN-150998 Intravitreal injection.<br>|
| Active Comparator: Stage 2: ranibizumab 0.5 mg<br>Stage 2: ranibizumab 0.5 mg given as a single intravitreal injection at baseline. A second intravitreal injection will be given by week 16. | Drug: ranibizumab<br>* Ranibizumab 0.5 mg given by intravitreal injection.<br>* Other names: Lucentis®;|
| Experimental: Stage 3: AGN-150998 2.0 mg<br>Stage 3: AGN-150998 2.0 mg given as intravitreal injections at Baseline, Weeks 4 and 8, followed by sham injections at Weeks 12 and 16. | Drug: AGN-150998<br>* AGN-150998 Intravitreal injection.<br>Other: Sham Injection<br>* Stage 3: Sham injection at Weeks 12 and 16.<br>|
| Experimental: Stage 3: AGN-150998 1.0 mg<br>Stage 3: AGN-150998 1.0 mg given as intravitreal injections at Baseline, Weeks 4 and 8, followed by sham injections at Weeks 12 and 16. | Drug: AGN-150998<br>* AGN-150998 Intravitreal injection.<br>Other: Sham Injection<br>* Stage 3: Sham injection at Weeks 12 and 16.<br>|
| Active Comparator: Stage 3: ranibizumab 0.5 mg<br>Stage 3: ranibizumab 0.5 mg given as intravitreal injections every 4 weeks for 16 weeks. | Drug: ranibizumab<br>* Ranibizumab 0.5 mg given by intravitreal injection.<br>* Other names: Lucentis®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Highest Tolerated Dose (HTD) of AGN-150998 | Stage 1 evaluated the safety of a single intravitreal injection of AGN-150998 with doses ranging from 1.0 to 4.2 mg. | 24 Weeks | 
| Stage 1: Change From Baseline in Central Retinal Thickness (CRT) in the Study Eye | CRT was assessed using spectral domain optical coherence tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. SD-OCT was performed in the study eye after pupil dilation. A negative change from Baseline indicated improvement. | Baseline, Week 4 | 
| Stage 2: Time Between Baseline Treatment and Recurrence of Active Disease | Recurrence of Active Disease was based on Best Corrected Visual Acuity (BCVA), Central Retinal Thickness (CRT) values as evaluated by the Central Reading Center (CRC) and the investigator assessments of haemorrhage. | Baseline, Week 16 | 
| Stage 3: Change From Baseline in Best Corrected Visual Acuity (BCVA) in the Study Eye | BCVA is measured using an eye chart and is reported as the number of letters read correctly (ranging from 0 to 100 letters) in the study eye. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. | Baseline, Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 2: Time Between Second Treatment and Recurrence of Active Disease | Recurrence of active disease is defined as the time in days to escape to standard of care. Time is calculated as (date of Escaping to Standard of Care/Censoring minus the date of the Second Injection) +1. | 32 Weeks | 
| Stage 2: Change From Baseline in Central Retinal Thickness (CRT) in the Study Eye | CRT was assessed using spectral domain optical coherence tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. SD-OCT was performed in the study eye after pupil dilation. A negative change from Baseline indicated improvement. | Baseline, Week 4 | 
| Stage 2: Change From Baseline in Best Corrected Visual Acuity (BCVA) in the Study Eye | BCVA is measured using an eye chart and is reported as the number of letters read correctly (ranging from 0 to 100 letters) in the study eye. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. | Baseline, Week 4 | 
| Stage 3: Change From Baseline in Central Retinal Thickness (CRT) in the Study Eye | CRT was assessed using spectral domain optical coherence tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. SD-OCT was performed in the study eye after pupil dilation. A negative change from Baseline indicated improvement. | Baseline, Week 4 | 
| Stage 3: Change From Baseline in BCVA in the Study Eye | BCVA is measured using an eye chart and is reported as the number of letters read correctly (ranging from 0 to 100 letters) in the study eye. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. | Baseline, Week 4 |