Protocol S, Two-Year Results
Panretinal Photocoagulation vs. Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial
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.
- 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.
To compare treatment with intravitreous ranibizumab versus PRP over 2 years for PDR.
Multicenter, randomized, clinical trial
- Patients who were at least 18 years old, with type 1 or type 2 diabetes, with at least 1 eye with PDR, and best-corrected visual acuity (BCVA) letter score of 24 or better.
Major inclusion criteria:
- Patients who previously underwent PRP
Major exclusion criteria:
RANDOMIZATION SCHEME AND INTERVENTIONS
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)
- The study initially enrolled 394 study eyes (n=191 for ranibizumab, n=203 for PRP) from 305 patients overall
- The 2-year visit was completed for 328 study eyes (86%, excluding 14 deaths) in the ranibizumab (160 [88%]) and PRP (168 [86%]) groups.
- Median (range) age was 52 (44, 59) years in the ranibizumab group and 51 (44, 59) years in the PRP group; 43% and 45% were women, respectively, and 52% and 50% were white.
- Ranibizumab Group: the median (quartiles) number of injections for eyes without DME at baseline were 7 (5, 9) through 1 year and 10 (6, 13) through 2 years. Eyes with DME at baseline received 9 (7, 11) injections through 1 year and 14 (10, 17) through 2 years. Focal/grid laser treatment was required for 15 (8%) eyes, and PRP was required for 12 (6%) eyes (with 8 of these being endolaser during vitrectomy).
- PRP Group: after the initial baseline PRP treatment, at least 1 additional PRP session was administered in 92 (45%) eyes, with the median (quartiles) time to repeat treatment being 221 (116, 386) days. For eyes without DME at baseline, the medan (quartiles) number of injections was 3 (1, 6) and 4 (2, 7) prior to 1 and 2 years, respectively; for eyes with DME at baseline the number of injections was 5 (3, 9) and 9 (4, 15). Focal/grid laser treatment was performed in 21 (10%) eyes.
- Change in Baseline Visual Acuity: At the 2-year mark, visual acuity improved a mean of +2.8 letters in the ranibizumab group and +0.2 letters in the PRP group (non-inferiority P<0.001).
- The mean change in visual acuity letter score (area under the curve) was +4.5 in the ranibizumab group and -0.3 in the PRP group (P<0.001).
- The mean (SD) change in visual field total point score from baseline, combining Humphrey visual field 30-2 and 60-4 test patterns, was -23 (410) dB in the ranibizumab group and -422 (518) dB in the PRP group; the PRP group had significantly lower cumulative visual field total point scores (P<.001).
- At the 5-year visit, among eyes with baseline DME (n=68), the mean (SD) central subfield thickness (CST) decreased from baseline by 153 (129) μm in the ranibizumab group and 48 (124) μm in the PRP group. This difference was statistically significant (P=.035). Among eyes without baseline DME, the cumulative probability of developing central DME with vision impairment by 2 years was 9% in the ranibizumab group and 28% in the PRP group (P<.001).
- Retinal detachment was identified in 6% of ranibizumab eyes and in 10% of PRP eyes (P<.001).
- Vitreous hemorrhage developed in 52 (27%) ranibizumab eyes and 69 (34%) PRP eyes (P=.09).
- Patients without active or with regressed neovascularization at the disc or elsewhere on fundus photographs at 2 years was 35% among the ranibizumab group and 30% among the PRP group (P=.58).
- There were no significant differences identified between groups in the number of participants with a serious adverse event, hospitalization, death, Antiplatelet Trialists’ Collaboration arteriothromboembolic events, or events in each individual MedDRA system organ class. However, there were decreased incidences in 6 of 22 system organ classes in the PRP group that approached significance (defined as P<.01): cardiac disorders (P = .01), endocrine disorders (P=.02), infections/infestations (P=.02), respiratory disorders (P=.04), skin and subcutaneous tissue disorders (P=0.03), and surgical and medical procedures (P=.01).
- Injection-related endophthalmitis occurred in 1 (0.5%) eye in the ranibizumab group injection and no eyes in the PRP group, among 2581 total injections.
- Among eyes with PDR, treatment with ranibizumab resulted in visual acuity that was non-inferior to PRP at 2 years.
- Longer term follow-up is needed, but ranibizumab may be a reasonable treatment alternative to PDR through 2 years for patients with PDR.