Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity: A Randomized Clinical Trial

Abstract

Importance: Anti-vascular endothelial growth factor (VEGF) therapies are a novel treatment option in retinopathy of prematurity (ROP). Data on dosing, efficacy, and safety are insufficient.

Objective: To investigate lower doses of anti-VEGF therapy with ranibizumab, a substance with a significantly shorter systemic half-life than the standard treatment, bevacizumab.

Design, setting, and participants: This randomized, multicenter, double-blind, investigator-initiated trial at 9 academic medical centers in Germany compared ranibizumab doses of 0.12 mg vs 0.20 mg in infants with bilateral aggressive posterior ROP; ROP stage 1 with plus disease, 2 with plus disease, or 3 with or without plus disease in zone I; or ROP stage 3 with plus disease in posterior zone II. Patients were recruited between September 2014 and August 2016. Twenty infants were screened and 19 were randomized.

Interventions: All infants received 1 baseline ranibizumab injection per eye. Reinjections were allowed in case of ROP recurrence after at least 28 days.

Main outcomes and measures: The primary end point was the number of infants who did not require rescue therapy at 24 weeks. Key secondary end points included time-to-event analyses, progression of physiologic vascularization, and plasma VEGF levels. Stages of ROP were photodocumented and reviewed by an expert committee.

Results: Nineteen infants with ROP were enrolled (9 [47.4%] female; median [range] postmenstrual age at first treatment, 36.4 [34.7-39.7] weeks), 3 of whom died during the study (1 in the 0.12-mg group and 2 in the 0.20-mg group). Of the surviving infants, 8 (88.9%) (17 eyes [94.4%]) in the 0.12-mg group and 6 (85.7%) (13 eyes [92.9%]) in the 0.20-mg group did not require rescue therapy. Both ranibizumab doses were equally successful in controlling acute ROP (Cochran-Mantel-Haenszel analysis; odds ratio, 1.88; 95% CI, 0.26-13.49; P = .53). Physiologic intraretinal vascularization was superior in the 0.12-mg group. The VEGF plasma levels were not systematically altered in either group.

Conclusions and relevance: This pilot study demonstrates that ranibizumab is effective in controlling acute ROP and that 24% of the standard adult dose (0.12 mg) appears equally effective as 40% (0.20 mg). Superior vascularization of the peripheral retina with 0.12 mg of ranibizumab indicates that the lower dose may be favorable. Unchanged plasma VEGF levels point toward a limited systemic drug exposure after ranibizumab.

Trial registration: clinicaltrials.gov Identifier: NCT02134457 and clinicaltrialsregister.eu Identifier: 2013-002539-13.

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1.. Flow of Patients in Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity Study

Over a 2-year recruitment window, 20 patients were screened and 19 randomized for CARE-ROP (representing the full analysis set). All patients received the intervention as allocated. Three patients died during the course of the study. No major protocol violations were noted in the remaining infants. The per protocol set at 24 weeks thus comprises 16 infants. All infants were treated bilaterally with study medication. aAll enrolled patients were considered for analysis of primary end point.

Figure 2.. Treatment Response to Ranibizumab Therapy

A, Representative images of treatment response to ranibizumab. Two eyes from 1 infant are shown before baseline ranibizumab injection (left) and at 24 weeks (right). Staging of retinopathy of prematurity (ROP) at baseline was stage 3, posterior zone II, moderate plus disease in the right eye and stage 3, zone I, moderate plus disease in the left eye. Note the significant retinal hemorrhages in both eyes. At week 24, all plus disease, hemorrhages, and preretinal ridge had fully resolved. OD indicates right eye, OS, left eye. B-E, Time-to-event analyses for first resolution of plus disease (B), active proliferation (C), preretinal ridge (D), and any ROP (E). These plots represent the time to first occurrence of the respective event and illustrate the dynamics of the initial treatment response. Later recurrences of the respective item are not captured here. Censored values represent eyes in which the respective event did not occur before the last study visit or before the first rescue or reinjection. Plus disease and active proliferations showed rapid response to treatment in almost all patients. Resolution of the preretinal ridge and all ROP stages were slower to occur.

Figure 3.. Recurrences of Retinopathy of Prematurity (ROP)

A, Representative images of initial response to treatment (left image) and response to retreatment after recurrence of acute ROP at 10 weeks (right image). The initial preretinal ridge is marked with a white arrow. The secondary ridge forming at the time of recurrence is marked with a black arrow. The initial ridge is fully resolved at week 4 (second image from left) but reappears together with the new ridge at the time of recurrence (second image from right). Four weeks after retreatment, both the initial and the secondary ridge have flattened but are still visible as flat demarcation lines in the vascularized retina (right image). Physiologic intraretinal blood vessels can be seen proceeding beyond the secondary ridge. B-E, Time-to-event analyses for first recurrence of plus disease (B), active proliferation (C), preretinal ridge (D), or any ROP (E). These plots represent the time to first recurrence of the respective event. Note that recurrences can only occur in patients who had prior resolution of the respective item. Number of patients at risk and proportional values therefore vary between graphs. Time to first recurrence is calculated from time of full resolution for each item. Censored values represent eyes in which the respective event did not occur before the last study visit.