MANUSCRIPT CITATION

Stahl A, Lepore D, Fielder A, Fleck B, Reynolds JD, Chiang MF, Li J, Liew M, Maier R, Zhu Q, Marlow N. Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW). Lancet 2019; 394:1551-59. PMID: 31522845

REVIEWED BY

Elizabeth Allen, Neonatal Advanced Trainee
Department of Neonatal Medicine, Women’s and Children’s Hospital, North Adelaide, South Australia

Amy Keir, Consultant Neonatologist
Department of Neonatal Medicine, Women’s and Children’s Hospital, North Adelaide, South Australia
Healthy Mothers, Babies and Children Theme, South Australian Health and Medical Institute, North Adelaide, South Australia
Robinson Research Institute and the Adelaide Medical School, the University of Adelaide, Adelaide, South Australia

TYPE OF INVESTIGATION

Treatment

QUESTION

(P) In infants with birthweights less than 1500g and a diagnosis of bilateral retinopathy of prematurity (ROP) Zone I stage 1+, 2+, 3 or 3+, Zone II stage 3+ or aggressive posterior ROP, (I) is ranibizumab superior to (C) laser therapy in (O) treatment of ROP (T) up to 24 weeks after treatment?

METHODS

• Design: Open-label multi-centre superiority, three-arm parallel group randomised controlled trial
• Allocation: 1:1:1 ratio with random allocation stratified by ROP zone of the worst eye. Stratification of geographical region occurred with dynamic block allocation. 
• Blinding: Neither treatment nor outcomes were masked
• Follow-up period: Infants were followed up from enrolment until 24 weeks after treatment.
• Setting: Conducted in 87 Neonatal and Ophthalmic Centres in 26 countries between 31 December 2015 and 29 June 2017.
• Patients:
  • Inclusion criteria
    • Birthweight less than 1500g
    • Diagnosis of bilateral ROP satisfying one of the following
      • Zone I stage 1+, 2+, 3 or 3+
      • Zone II stage 3+
      • Aggressive posterior ROP
    • Exclusion criteria
      • Ocular and neurological co-morbidities
      • Active ocular infection within 5 days before investigational treatment
      • Unilateral cases in which only one eye met treatment criteria
    • Note: Patients with zone II stage 2+ disease were not included as treatment was considered controversial
• Intervention: Patients were randomised to one of three groups
  • Higher dose ranibizumab group: Intravitreal treatment was a single dose of 0.2mg ranibizumab applied to both eyes.
  • Lower dose ranibizumab group: Intravitreal treatment was a single dose of 0.1mg ranibizumab applied to both eyes.
  • Laser therapy group: Laser treatment was administered per local practice
  • In the laser group, supplementary treatment to skip lesions was allowed up to day 11.
  • In the ranibizumab groups, up to two additional treatments with ranibizumab were allowed in each eye at a minimum of 28 day intervals.
  • A switch to a different treatment method was considered as treatment failure.
  • The retina was assessed at baseline and at each study visit up to 169 days (24 weeks)
• Outcomes:
  • Primary outcome: Survival with no active retinopathy, no unfavourable structural outcomes, or need for a different treatment modality at or before 24 weeks post initial treatment.
  • Secondary outcomes: Efficacy of ranibizumab 0.1mg relative to 0.2mg or to laser therapy; time to intervention with second modality for ROP; development of unfavourable outcome or death; recurrence of ROP requiring any post-baseline intervention up to 24 weeks post initial treatment; ocular and systemic safety of intravitreal ranibizumab; pharmacokinetics of intravitreal ranibizumab; and systemic VEGF levels.
• Analysis and Sample Size: The study initially aimed to recruit 80 patients per treatment to be able to provide 90% power to show superiority of ranibizumab. Due to slow enrolment the recruitment target was modified to 60 patients per treatment group with an associated reduction in the expected power of the study to 80%. Analysis was performed by intention to treat. Single confirmatory post-hoc exploratory logistic regression analysis for the primary outcome adjusting for three potential confounders—gestational age, geographical region, and infant sex.
• Patient follow-up: 218/225 patients (97%) received baseline treatment with 201/225 (89%) completing the study. Primary outcome was known in 214 patients (95%). There was significant cross over between groups with 34/225 patients (15%) receiving both ranibizumab and laser therapy during the study period.

MAIN RESULTS

• Treatment success occurred in 45 (66%) of 68 infants who received laser therapy and in 56 (80%) of 70 infants who received ranibizumab 0·2 mg
• Odds ratio (OR) of treatment success following ranibizumab 0·2 mg compared with laser therapy was 2·19, 95% Cl 0·99−4·82, p=0·051)
• Treatment success occurred in 57 (75%) of 76 infants who received ranibizumab 0·1 mg
  • OR of treatment success following ranibizumab 0.1mg compared with laser therapy was 1·57, 95% Cl 0·76−3·26;)
  • OR of treatment success following ranibizumab 0.1mg compared with ranibizumab 0·2 mg was 1·35, 95% Cl 0·61−2·98) OR in favour of ranibizumab 0·2 mg versus laser treatment was 2·32 (95% CI 1·04−5·16
• Treatment success was higher for all three groups in zone II than in zone I, and the gradient of effect remained in favour of ranibizumab.
• Among the two ranibizumab groups, full peripheral vascularization assessed by indirect ophthalmoscopy occurred by day 169 in 28 (38%) infants in the ranibizumab 0·2 mg group and 21 (27%) infants in the ranibizumab 0·1 mg group.
• A total of 61 (27%) of 225 infants received additional post-baseline treatments.

CONCLUSION

The proportion of infants with successful outcome was greater following intravitreal ranibizumab 0·2 mg compared with laser therapy and does not exclude the potential superiority of ranibizumab over laser therapy.

COMMENTARY

Retinopathy of prematurity is a vasoproliferative disorder that affects the developing retinal vessels of preterm infants.(1) After preterm birth, there is a halt in the typical development of the retinal vasculature with subsequent pathological compensatory mechanisms leading to abnormal and uncontrolled retinal neovascularisation. This can lead to retinal scarring, retinal detachment, vision impairment and blindness.(2)   Retinopathy of prematurity is a leading cause of preventable childhood blindness, occurring primarily in infants of low birth weight (≤1250 g; mean, 700 g).(3) Most studies report ROP incidence of about 60% for babies under 1500 g.¹ Globally it is estimated that 50,000 infants are blind as a result of ROP.(3)

The disorder is treated primarily by ablation of the avascular retina by cryotherapy or laser therapy.(4) However, use of anti-vascular endothelial growth factor (VEGF) agents is an emerging treatment for acute ROP.(5) To date there has been limited evidence to support their use alone or in combination with laser or cryotherapy for the treatment of ROP.(4) The largest clinical trial compared intravitreal bevacizumab with laser therapy. This study showed fewer re-treatments in the bevacizumab group, but this was isolated to infants with ROP in zone 1.(5)   These agents inhibit VEGF which is an important growth factor in angiogenesis.(6)

The RAINBOW study sought to evaluate the efficacy and safety of Ranibizumab compared to conventional laser therapy. It is an important study because, despite widespread use of anti-VEGF agents, questions regarding ocular efficacy, dosing, and systemic effects have remained unanswered.(7)

The study findings suggest that Ranibizumab has the potential to be a safe and effective treatment for ROP, it is important to acknowledge its limitations. Many of the identified limitations reflect the inherent challenges of research within this area. By necessity, it was an unmasked, open label study with no placebo. Switching to an alternative modality of treatment was common in all three groups. However, the study design allowed for this to minimise the risk of visual impairment and was applied to all three groups. A source of potential bias included that decisions on re-treatment were made on an individual basis and re-treatment with ranibizumab was restricted to intervals of 28 days. The authors note that the study was funded by Novartis and that the funders “had full access to data collection, analysis, and interpretation and was involved in the writing of the manuscript, as well as the decision to submit.” The study was limited by slow enrolment, which led to a modified recruitment target of 60 patients per treatment group, with a subsequent reduction in the power of the study. Instructions for the administration of ranibizumab were provided but training in the use of fundoscopy to evaluate the primary outcome was not widespread. Furthermore, not all centres had access to retinal photography.

The RAINBOW extension trial will explore both the long-term systemic safety profile of Ranibizumab and definitive vision outcomes, which are needed. Currently, evidence regarding efficacy and safety is insufficient to introduce Ranibizumab as an alternative to laser therapy for treatment of ROP.

REFERENCES

1. Zin A, Gole GA. Retinopathy of Prematurity – Incidence Today. Clin Perinatol 40 (2013) 185–200
2. Hellstrom A, Smith EH, Dammann O. Retinopathy of prematurity. Lancet 2013; 382:1445-1457.
3. Gilbert C. Retinopathy of prematurity: a global perspective of the epidemics, population of babies at risk and implications for control. Early Hum Dev2008; 84:77-
4. Sankar MJ, Sankar J, Chandra P. Anti-vascular endothelial growth factor (VEGF) drugs. For treatment of retinopathy of prematurity. Cochran Database Syst Rev 2018:1:CD009734.
5. Mintz-Hittner HA, Kennedy KA, Chuang AZ. Efficacy of Intravitreal Bevacizumab for Stage 3+ Retinopathy of Prematurity. N Engl J Med 2011; 364:603-615
6. Conrady CD, Hartnett ME. The role of anti-vascular endothelial growth factor agents in the management of retinopathy of prematurity. US Ophthalmic Review 2017;10(1):57-63.
7. Chiang MF. How Does the Standard of Care Evolve? Anti-Vascular Endothelial Growth Factor Agents in Retinopathy of Prematurity Treatment as an Example. Ophthalmology 2018; 125:1485-1487.