Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial

Abstract

Background: Despite increasing worldwide use of anti-vascular endothelial growth factor agents for treatment of retinopathy of prematurity (ROP), there are few data on their ocular efficacy, the appropriate drug and dose, the need for retreatment, and the possibility of long-term systemic effects. We evaluated the efficacy and safety of intravitreal ranibizumab compared with laser therapy in treatment of ROP.

Methods: This randomised, open-label, superiority multicentre, three-arm, parallel group trial was done in 87 neonatal and ophthalmic centres in 26 countries. We screened infants with birthweight less than 1500 g who met criteria for treatment for retinopathy, and randomised patients equally (1:1:1) to receive a single bilateral intravitreal dose of ranibizumab 0·2 mg or ranibizumab 0·1 mg, or laser therapy. Individuals were stratified by disease zone and geographical region using computer interactive response technology. The primary outcome was survival with no active retinopathy, no unfavourable structural outcomes, or need for a different treatment modality at or before 24 weeks (two-sided α=0·05 for superiority of ranibizumab 0·2 mg against laser therapy). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02375971.

Interpretation: Between Dec 31, 2015, and June 29, 2017, 225 participants (ranibizumab 0·2 mg n=74, ranibizumab 0·1 mg n=77, laser therapy n=74) were randomly assigned. Seven were withdrawn before treatment (n=1, n=1, n=5, respectively) and 17 did not complete follow-up to 24 weeks, including four deaths in each group. 214 infants were assessed for the primary outcome (n=70, n=76, n=68, respectively). Treatment success occurred in 56 (80%) of 70 infants receiving ranibizumab 0·2 mg compared with 57 (75%) of 76 infants receiving ranibizumab 0·1 mg and 45 (66%) of 68 infants after laser therapy. Using a hierarchical testing strategy, compared with laser therapy the odds ratio (OR) of treatment success following ranibizumab 0·2 mg was 2·19 (95% Cl 0·99-4·82, p=0·051), and following ranibizumab 0·1 mg was 1·57 (95% Cl 0·76-3·26); for ranibizumab 0·2 mg compared with 0·1 mg the OR was 1·35 (95% Cl 0·61-2·98). One infant had an unfavourable structural outcome following ranibizumab 0·2 mg, compared with five following ranibizumab 0·1 mg and seven after laser therapy. Death, serious and non-serious systemic adverse events, and ocular adverse events were evenly distributed between the three groups.

Findings: In the treatment of ROP, ranibizumab 0·2 mg might be superior to laser therapy, with fewer unfavourable ocular outcomes than laser therapy and with an acceptable 24-week safety profile.

Funding: Novartis.

Figure 1:. CONSORT diagram detailing enrolment, randomisation, and follow-up of infants in the RAINBOW trial

*Includes four deaths. †Includes four deaths and one treatment switch before withdrawal.

Figure 2:. Progress of infants with retinopathy of prematurity through additional post-baseline study treatments

Flow chart shows the number of infants receiving at least one additional treatment (ranibizumab or laser therapy), either allowed in the protocol (up to 29 days when ranibizumab retreatment was first allowed) or up to 169 days, and treatment switches, which contributed to the primary outcome (shaded pink). Infants might have received one or more additional treatments in one or both eyes. Laser treatments to skip lesions were allowed as part of the baseline treatment but are included because they represent extra treatment episodes. *Allowed in protocol.

Figure 3:. Vascular endothelial growth factor levels following study entry to 35 days for each treatment group

(A) Ranibizumab 0·2 mg. (B) Ranibizumab 0·1 mg. (C) Laser therapy.