Watch VBS members discuss this study on New Retina Radio Journal Club

With Aleksandra Rachitskaya, MD; Mrinali Gupta, MD; Eric Nudleman, MD, PhD; and Aris Thanos, MD

STUDY SUBJECTS

Major inclusion criteria:

• neovascular AMD with documented history of anti-VEGF responsiveness in the preceding 9 months

RANDOMIZATION SCHEME AND INTERVENTIONS

Randomized 3:3:3:2 to:

• (a) PDS filled with ranibizumab 10 mg/mL
• (b) PDS filled with ranibizumab 40mg/mL
• (c) PDS filled with ranibizumab 100 mg/mL
• (d) Monthly ranibizumab 0.5mg injections

Randomization stratified by ETDRS letters (≤65 letters vs >66 letters) and # of prior anti-VEGF injections (≤3 or >3 injections)

PDS Procedure

Conjunctival peritomy, full thickness stab incision through sclera/pars plana with 3.2mm slit knife, followed by implantation of PDS implant, then conjunctival closure. Partway through the study, the procedure was amended to reduce vitreous hemorrhage risk to peritomy followed by layer-by-layer incision through sclera, then laser ablation of the exposed pars plana, followed by incision with the 3.2mm slit knife, etc.

Monitoring

All patients were monitored monthly. PDS patients underwent refill (full exchange/refill) procedures in the office under topical anesthesia based on one or more prespecified criteria including:

• 1) OCT
  • increase in CFT of ≥75 µm compared to the avg CFT from the last 2 available measurements OR
  • increase in CFT of ≥100 µm compared to the lowest CFT measurement in the study
• 2) BCVA
  • decrease in ≥5 letters compared to the avg BCVA from the last 2 available visits
  • decrease in ≥10 letters compared to the best BCVA from the study
• 3) New macular hemorrhage

Intravitreal ranibizumab injections were also available to PDS patients if vitreous hemorrhage occurred with BCVA loss with inability to assess macula or SD-OCT, if lack of clinical efficacy criteria met, or if progressively worsening BCVA or CFT on 2 consecutive visits due to nAMD that did not hit threshold for refill. If lack of clinical efficacy criteria met, implant was retained, received intravitreal ranibizumab 0.5mg injection and mandatory refill of implant with ranibizumab 100mg/mL at the next monthly visit (and all future refills were 100mg/mL).

After the primary LADDER study analysis, all patients continued their assigned treatment until PORTAL (open label PDS extension study) initiated. If patients did not rollover into PORTAL, PDS was removed

RESULTS (24 months)

Study population

• 220 patients total
• Mean baseline vision 20/40

Study Duration

• Total duration 38 months, but varied from patient to study (10.8-37.6 months in PDS, 7-37.3 months in monthly ranibizumab), with a mean duration of 22 months across both arms
• Study completion was 91.1% PDS, 87.8% ranibizumab injection
• 96.6% of PDS patients rolled over into PORTAL

Time to refill analysis

• Median time to refill (those without any refill were included in the study with the duration listed as the overall study period) was:

PDS-ranibizumab 10mg/mL: 8.7 months

PDS-ranibizumab 40mg/mL: 13 months

PDS-ranibizumab 100mg/mL: 15.8 months

(significantly better for 40 and 100mg/mL compared to 10mg/mL)

• Most common cause for first refill was CFT increase from baseline, across all arms

Additional refill analysis

• Overall, % of PDS patients with need for any refill across the study period was:

PDS-ranibizumab 10mg/mL: 65.5%

PDS-ranibizumab 40mg/mL: 54.8%

PDS-ranibizumab 100mg/mL: 52.5%

In this subset, mean time to refill was:

PDS-ranibizumab 10mg/mL: 6.4 months

PDS-ranibizumab 40mg/mL: 5.6 months

PDS-ranibizumab 100mg/mL: 8.8 months

In this subset, time from first to second refill was:

PDS-ranibizumab 10mg/mL: 3.3 months

PDS-ranibizumab 40mg/mL: 5.9 months

PDS-ranibizumab 100mg/mL: 8.8 months

Vision outcomes:

• At month 22, mean BCVA change from baseline was

PDS-ranibizumab 10mg/mL: -4.6 letters

PDS-ranibizumab 40mg/mL: -2.3 letters

PDS-ranibizumab 100mg/mL: +2.9 letters

monthly ranibizumab 0.5mg injection: +2.7 letters

• % maintaining vision at month 22 was

PDS-ranibizumab 10mg/mL: 57.7%

PDS-ranibizumab 40mg/mL: 80%

PDS-ranibizumab 100mg/mL: 87.5%

monthly ranibizumab 0.5mg injection: 88.9%

Anatomic outcomes

• CFT was generally stable over time in all arms and results were comparable between PDS 100mg/mL and the ranibizumab arm across all time points
• Similar rates of macular atrophy

Adverse outcomes

• Ocular serious adverse events in 9.5% of PDS eyes (17 eyes), 0% of ranibizumab eyes, most commonly vitreous hemorrhage (3.9%, 7 eyes; 6 of 7 prior to the amendment in the implantation surgery technique and 1 occurring after the amendment but after the postoperative procedure).
• Overall 19 eyes had vitreous hemorrhage (of which 7 were serious as outlined above), 11 prior to technique optimization and 8 (rate 5.1%) after optimization. Vitreous hemorrhages tended to be mild to moderate and resolved, with duration ranging 8-902 days
• There were 3 cases of endophthalmitis (1.7%) and 4 cases of rhegmatogenous retinal detachment in the PDS group. Conjunctival complications included blebs/erosions (6.8%) or filtering bleb leaks/retraction (2.3%).