Intravitreal Ranibizumab Injection for Aggressive Versus Type 1 Prethreshold Retinopathy of Prematurity
Condition: Retina Disease; Retinopathy of Prematurity; Ranibizumab
MeSH terms: Retinal Diseases; Retinopathy of Prematurity; Premature Birth; Aggression
Study type: Interventional
Phase: Phase 3

Summary: 
      Despite advances in the neonatal intensive care units, retinopathy of prematurity (ROP) has
      become a common reason for blindness and visual disabilities in premature infants so that it
      accounts for about 5% and 30% of such complications in developed and developing countries.
      The pathophysiology of ROP is multifactorial. Supplemental oxygen demand and lower
      gestational age (GA) and birth weight (BW) are among the major risk factors for the
      occurrence and progression of ROP.

      Anti-vascular endothelial growth factor (anti-VEGF) agents are a promising modality of
      treatment for ROP, as laser therapy is associated with disadvantages such as complications
      from undertreatment or overtreatment, anterior segment burns, hemorrhage, or ischemia, and
      potentially higher rates of myopia. Ranibizumab is the first approved anti-VEGF treatment for
      the management of retinopathy, and is a promising alternative to laser therapy.

      Ranibizumab is a humanized monoclonal recombinant antibody fragment with a shorter half-life
      and less systemic toxicity than bevacizumab. Its binding affinity is nearly tenfold that of
      bevacizumab.

      The plasma half-life of bevacizumab is 17-21 days, while that of ranibizumab is 3 days.
      Greater systemic absorption of bevacizumab is thought to lead to greater systemic suppression
      of VEGF. These data may explain the better safety profile of ranibizumab. Type I ROP is
      defined as any stage of ROP with plus disease in zone I, stage 3 ROP in zone I and stage 2 or
      3 ROP with plus disease in zone II . The hallmark of Aggressive-ROP (previously known as
      Aggressive posterior-ROP) is rapid development of pathological neovascularization and severe
      plus disease without progression being observed through the typical stages of ROP. It may
      occur in larger preterm infants and beyond the posterior retina.

      The aim of this prospective study is to compare the efficacy of intravitreal ranibizumab for
      type 1 ROP and A-ROP as regard acute ROP regression, recurrence profile, peripheral retinal
      vascularization and the need for further ablative therapy.
    

Detailed description: 
      A prospective randomized study of 37 eyes of 30 infants, who received intravitreal injections
      of ranibizumab in one eye (the most severe) or both eyes, were included. A-ROP group included
      18 eyes of 15 infants and type 1 ROP group included 19 eyes of 15 infants. The primary
      outcome measure was the number of eyes that achieved regression of ROP without additional
      treatment till 55 weeks' post-menstrual age (PMA). The mean follow-up period for A-ROP group
      was 11.44 months and 13.95 months for type 1 ROP group.

      Treatment was performed within 72 hours once treatment criteria were detected. Intravitreal
      injection (IVI) was performed under topical anesthesia in standard ophthalmic operating room.
      5% povidone-iodine disinfection and topical antibiotic were instilled. Ranibizumab (0.25
      mg/0.025 mL) was injected into the vitreous cavity with a 31-gauge needle, aiming the needle
      directly toward the optic nerve in direction of visual axis 1.0 mm posterior to the
      corneoscleral junction at the inferotemporal quadrant. The intraocular pressure and central
      artery perfusion were then checked. Topical antibiotics were given for 7 days
      postoperatively. All infants were followed up on the next day, third day, then weekly until
      the regression of ROP, after that every (2-4) weeks until a minimum of 55 weeks' post
      menstrual age (PMA) or retinal vascularization achieved zone III without an active component
      such as hemorrhage or exudation or clinically significant tractional elements, which came
      earlier. Each examination evaluated disease regression (via indirect fundoscopic analysis),
      recurrence, the presence of tractional elements and peripheral vascularization. Then follow
      up was continued monthly for at least 6 months following treatment.

      Successful treatment was defined as remission of plus disease, good pupil dilation and
      reduced disease grade. Outcomes were further classified as insufficient regression
      (persistence of plus disease and neovascularization at 3-5 days' post-injection), progression
      (post-injection intravitreal hemorrhage, increased neovascularization and formation of
      tractional components) and recurrence requiring treatment (recurrence of plus disease,
      recurrent neovascularization, reformation of a ridge or extraretinal fibrovascular
      proliferation, despite initial regression post injection) Once insufficient regression or ROP
      recurrence requiring treatment was determined, rescue therapy of IVR was applied.

      Cases with no recurrence or recurrence not requiring treatment (stage 1 or 2 eyes, with Zone
      2 or Zone 3 localisation, not accompanied by plus disease) were closely monitored until
      peripheral retinal vascularization was completed.

      In case of failed peripheral retinal vascularization to approach zone III until 55 weeks'
      PMA, an indirect infrared diode laser (IRIDEX, Iris Medical SL laser with laser indirect
      ophthalmoscope (LIO) Ophthalmic Laser, 810 nm, USA) was used to apply photocoagulation
      through a +20/+28 diopter condensing lens under sedation or general anesthesia in the
      operating room to reduce the risk of late ROP reactivation.

      Follow-up examinations were made weekly for the first month after laser photocoagulation and
      at 3-4-week intervals thereafter until the ROP findings receded. Follow-up examinations were
      continued at 3-4-month intervals after the patients turned 1-year old.
    

Intervention name(s): Ranibizumab (0.25 mg/0.025 mL)
Intervention type(s): Drug
Intervention description(s): Intravitreal injection (IVI) was performed under topical anesthesia in standard ophthalmic operating room. 5% povidone-iodine disinfection and topical antibiotic were instilled. Ranibizumab (0.25 mg/0.025 mL) was injected into the vitreous cavity with a 31-gauge needle, aiming the needle directly toward the optic nerve in direction of visual axis 1.0 mm posterior to the corneoscleral junction at the inferotemporal quadrant. The intraocular pressure and central artery perfusion were then checked.
Other intervention name(s): Lucentis
Intervention MeSH terms: Ranibizumab
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Aggressive ROP; Ranibizumab; Type 1 ROP; anti-VEGF; Laser photocoagulation