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Port Delivery System with Ranibizumab Outperforms Monitoring in Preventing Progression of Nonproliferative Diabetic Retinopathy: Pavilion Trial Results

  • Study Overview:
    • Phase 3, multicenter, randomized clinical trial (Pavilion) evaluating the Port Delivery System (PDS) with ranibizumab (100 mg/mL, refilled every 36 weeks, PDS Q36W) versus monitoring (control) in moderately severe to severe nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME).
    • Conducted at 50 US sites from August 2020 to October 2022, with 174 participants (106 PDS Q36W, 68 control).
    • Participants: Adults ≥18 years with NPDR (Diabetic Retinopathy Severity Scale [DRSS] level 47 or 53) due to type 1 or 2 diabetes, BCVA ≥69 letters (20/40 Snellen equivalent), and no prior DR/DME treatment.
  • Intervention Details:
    • PDS Q36W: Two intravitreal ranibizumab 0.5-mg loading doses (day 1, week 4), followed by PDS implantation (1–14 days post-second dose) with ranibizumab 100 mg/mL, refilled every 36 weeks.
    • Control: Monthly monitoring without PDS; both groups could receive intravitreal ranibizumab 0.5 mg if CI-DME, proliferative diabetic retinopathy (PDR), or anterior segment neovascularization (ASNV) developed.
    • Unmasked trial due to surgical intervention, but VA examiners and reading center graders masked to minimize bias.

 

  • Primary Outcome:
    • Proportion with ≥2-step ETDRS-DRSS improvement at week 52:
      • PDS Q36W: 80.1% vs Control: 9.0% (difference: 71.1%, 95% CI: 61.0%–81.2%, P<.001).
      • Analyzed using Cochran-Mantel-Haenszel test, stratified by baseline DRSS (47 vs 53) and intraretinal/subretinal fluid status.

 

  • Key Secondary Outcomes:
    • Rate of developing CI-DME, PDR, or ASNV through week 52:
      • PDS Q36W: 7.1% vs Control: 47.0% (hazard ratio [HR]: 0.12, 95% CI: 0.05–0.28, P<.001).
      • CI-DME alone: 7.1% (PDS) vs 47.0% (control, HR: 0.12, P<.001).
      • PDR/ASNV: 1.0% (PDS) vs 42.4% (control, HR: 0.02, P<.001).
    • ≥2-step DRSS worsening: 3.0% (PDS) vs 46.4% (control, HR: 0.05, P<.001).
    • ≥3-step DRSS worsening: 3.0% (PDS) vs 45.1% (control, HR: 0.05, P<.001).
    • ≥3-step DRSS improvement: 15.1% (PDS) vs 0% (control, P<.001).
    • BCVA change at week 52: PDS: +1.4 letters (95% CI: -0.5 to 3.3) vs Control: -2.6 letters (95% CI: -5.0 to -0.1), difference: 4.0 letters (95% CI: 0.9–7.1, P=.01).
    • Transient BCVA decrease post-PDS implantation: -7.4 letters at week 4 (95% CI: -10.3 to -4.5), resolving by week 12.

 

  • Anatomic Outcomes:
    • Central subfield thickness (CST): PDS Q36W showed a reduction (-18.8 μm) vs control (+7.8 μm) at week 52 (difference: -26.6 μm, 95% CI: -38.0 to -15.2, P<.001).
    • Transient CST increase in PDS group (weeks 4–8) post-implantation, then declined below baseline.

 

  • Safety Profile:
    • Ocular adverse events of special interest (AESIs) in PDS Q36W (16.2% of 105 participants):
      • Cataract: 7 (6.7%), Vitreous hemorrhage: 6 (5.7%), Conjunctival bleb/retraction/hyphema: 2 each (1.9%), Conjunctival erosion/retinal detachment: 1 each (1.0%).
      • No endophthalmitis or implant dislocation reported through week 52.
    • Serious AESIs: 2 (1.9%)—retinal detachment and vitreous hemorrhage (1 each).
    • Most AESIs occurred within 37 days post-implantation; cataracts more frequent after 37 days.

 

  • PDS Device Context:
    • FDA-approved for neovascular AMD and DME; under investigation for DR/DME.
    • Voluntary recall (October 2022) due to septum dislodgement, lifted April 2024 after implant/needle updates; FDA approval for updated implant in July 2024.

 

  • Clinical Implications:

    • PDS reduces treatment burden by providing continuous ranibizumab delivery, improving DRSS and preventing vision-threatening complications (CI-DME, PDR, ASNV) compared to monitoring.

    • Transient BCVA reduction post-implantation (4–12 weeks) must be weighed against long-term benefits.

    • Suitable for patients at risk of lapses in care, preventing progression to severe complications.

 

  • Limitations:
    • Frequent monitoring in control group not reflective of clinical practice.
    • Unmasked design due to surgical intervention, though mitigated by masked graders.
    • Limited to 1-year follow-up; long-term safety/efficacy data pending.
    • Did not assess visit burden reduction, as all participants had monthly visits.
  • Future Directions:
    • Longer-term studies to evaluate sustained efficacy and safety.
    • Real-world studies to assess PDS impact on visit/treatment burden.
    • Comparison with standard intravitreal anti-VEGF injections.
  • Comparison to Other Trials:
    • PANORAMA and Protocol W: Showed anti-VEGF injections reduce NPDR progression but require frequent dosing. PDS offers similar benefits with less frequent interventions.
    • PDS aligns with continuous delivery, potentially improving adherence in high-risk NPDR patients.

Citation

Pieramici, D. J., Awh, C. C., Chang, M., Emanuelli, A., Holekamp, N. M., Hu, A. Y., Suñer, I. J., Wykoff, C. C., Brittain, C., Howard, D., Quezada-Ruiz, C., Santhanakrishnan, A., & Latkany, P. (2025). Port Delivery System With Ranibizumab vs Monitoring in Nonproliferative Diabetic Retinopathy Without Macular Edema: The Pavilion Randomized Clinical Trial. JAMA Ophthalmology, 143(4), 317–326. doi:10.1001/jamaophthalmol.2025.0001