Clinical Studies:

Protocol S, Two-Year Results

Panretinal Photocoagulation vs. Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial

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

Citation:  Writing Committee for the Diabetic Retinopathy Clinical Research Network, Gross JG, Glassman AR, Jampol LM, Inusah S, Aiello LP, Antoszyk AN, Baker CW, Berger BB, Bressler NM, Browning D, Elman MJ, Ferris FL 3rd, Friedman SM, Marcus DM, Melia M, Stockdale CR, Sun JK, Beck RW. Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial. JAMA. 2015 Nov 24;314(20):2137-2146. doi: 10.1001/jama.2015.15217. Erratum in: JAMA. 2016 Mar 1;315(9):944. Erratum in: JAMA. 2019 Mar 12;321(10):1008. PMID: 26565927; PMCID: PMC5567801.

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 2 years, treatment with ranibizumab resulted in visual acuity that was non-inferior to PRP treatment; ranibizumab may be a reasonable treatment alternative, at least through 2 years, for patients with PDR.
  • Objective

    To compare treatment with intravitreous ranibizumab versus PRP over 2 years for PDR.


    Multicenter, randomized, clinical trial


    24 months



Randomized 1:1 to groups receiving treatment with either PRP or with 0.5-mg intravitreous ranibizumab (with PRP if treatment failure). If participants had 2 study eyes, they randomly were assigned to receive ranibuzumab in one eye and PRP in the other.

Eyes in the ranibizumab group received a baseline injection and monthly injections through week 12. 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), and retreatment with ranibizumab was at investigator discretion. Vitrectomy for vitreous hemorrhage was not allowed for the first 8 weeks; vitrectomy for retinal detachment was allowed at investigator discretion.

RESULTS (24 months)

Study population


Major End-Points

Ancillary End-Points

Adverse events