Clinical Studies:

Protocol S, Five-Year Results

Five-Year Outcomes of Panretinal Photocoagulation vs. Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy

Summarized by Michael J. Venincasa, MD (Bascom Palmer Eye Institute of Miami, FL)

Citation:  Gross JG, Glassman AR, Liu D, Sun JK, Antoszyk AN, Baker CW, Bressler NM, Elman MJ, Ferris FL 3rd, Gardner TW, Jampol LM, Martin DF, Melia M, Stockdale CR, Beck RW; Diabetic Retinopathy Clinical Research Network. Five-Year Outcomes of Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial. JAMA Ophthalmol. 2018 Oct 1;136(10):1138-1148. doi: 10.1001/jamaophthalmol.2018.3255. Erratum in: JAMA Ophthalmol. 2019 Apr 1;137(4):467. PMID: 30043039; PMCID: PMC6233839.

Key Points

  • Protocol S was a multicenter, randomized clinical trial of patients with proliferative diabetic retinopathy (PDR) that compared treatment with intravitreal ranibizumab to pan-retinal photocoagulation (PRP).
  • At 5 years, severe vision loss and serious PDR complications were uncommon with both ranibizumab and PRP, but the ranibizumab group had lower rates of vision-impairing diabetic macular edema and less visual field loss.
  • These findings support either anti-vascular endothelial growth factor therapy or PRP treatment for patients with PDR.
  • Objective

    To evaluate efficacy and safety of 0.5-mg intravitreous ranibizumab versus PRP over 5 years for PDR.


    Multicenter, randomized, clinical trial


    60 months



Randomized 1:1 to either 0.5-mg intravitreous ranibizumab or PRP. If participants had 2 study eyes, they randomly received ranibuzumab in one eye and PRP in the other.

Eyes in the ranibizumab group received a baseline injection and monthly injections through week 24. At weeks 16 and 20, deferral of injections was allowed if neovascularization (NV) was resolved. Starting at week 24, injections could be deferred if all NV was resolved or if NV became and remained stable after 2 consecutive injections. If NV worsened, injections were resumed. If an eye met failure or futility criteria, PRP was permitted.

Eyes in the PRP group received PRP—either full or completed over several sittings—at baseline. Additional PRP was performed if the amount of NV increased.

Both groups required ranibizumab injections at baseline for diabetic macular edema (DME). Vitrectomy for vitreous hemorrhage was not allowed for the first 8 weeks; vitrectomy for retinal detachment was allowed at investigator discretion.


Study population


Major End-Points

Ancillary End-Points

Adverse events