RAINBOW Study: RAnibizumab Compared With Laser Therapy for the Treatment of INfants BOrn Prematurely With Retinopathy of Prematurity (RAINBOW)

• ClinicalTrials.gov Identifier: NCT02375971
• Recruitment Status: Completed
• First Posted: March 3, 2015
• Results First Posted: July 31, 2018
• Last Update Posted: November 14, 2018
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: February 18, 2015
• First Posted Date: March 3, 2015
• Results First Submitted Date: June 5, 2018
• Results First Posted Date: July 31, 2018
• Last Update Posted Date: November 14, 2018
• Actual Study Start Date: December 30, 2015
• Actual Primary Completion Date: December 14, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 3, 2018)

Percentage of Participants With Absence of Active ROP and Absence of Unfavorable Structural Outcomes in Both Eyes at Week 24 [ Time Frame: Week 24 ]

To achieve this outcome, patients must fulfill all the following criteria, 1) survival, 2) no intervention with a second modality for ROP, 3) absence of active ROP and 4) absence of unfavorable structural outcome. Retinopathy of prematurity (ROP) is a pathologic process that occurs in the incompletely vascularized, developing retina of low birth-weight preterm neonates.

Original Primary Outcome Measures (submitted: February 24, 2015)

Absence of active Retinopathy of Prematurity (ROP) and unfavorable structural outcome [ Time Frame: 24 weeks after starting investigational treatment ]

To achieve this outcome, patients must fulfill all the following criteria, 1) survival, 2) no intervention with a second modality for ROP, 3) absence of active ROP and 4) absence of unfavorable structural outcome

Current Secondary Outcome Measures (submitted: July 3, 2018)

• Percentage of Participants Requiring Interventions With a Second Modality for ROP at Week 24 [ Time Frame: Week 24 ]
  Intervention for ROP in either eye at or before the 24-week assessment visit with a treatment modality other than the modality of the first study treatment. Only descriptive analysis done.
• Number of Participants Experiencing an Event, From the First Study Treatment to the Last Study Visit [ Time Frame: Day 1 (after initiation of study treatment) up to study exit (Day 169) ]
  An event was defined as death, treatment switch, or the first occurrence of unfavorable structural outcomes in either eye. Only descriptive analysis done.
• Percentage of Participants Having Recurrent ROP and Receiving Any Post-baseline Intervention at or Before Week 24 [ Time Frame: Week 24 ]
  Recurrence of ROP is defined as subjects receiving any post-baseline intervention in either eye at or before 24 weeks (ranibizumab re-treatment or switch to laser in the ranibizumab groups, switch to ranibizumab treatment in the laser group). Zone I consists of a circle, the radius of which extends from the center of the optic disc to twice the distance from the center of the optic disc to the center of the macula. Zone II extends centrifugally from the edge of zone I to the nasal ora serrata. Only descriptive analysis done.
• Percent of Participants With Ocular Adverse Events by Primary System Organ (SOCs) at Week 24 [ Time Frame: Week 24 ]
  Percent of Participants with Ocular Adverse Events regardless of Study Treatment and Procedure Relationship by Primary System Organ (SOCs) reported categorically (Mild, Moderate, Severe) 24 weeks after the first study treatment. Only descriptive analysis done.
• Mean Change in Ranibizumab Concentration in Pharmacokinetic Serum Samples Over Time at Day 1, Day 15 and Day 29 [ Time Frame: Day 1 (Baseline), Day 15 and Day 29 ]
  Blood samples for the determination of ranibizumab concentrations were collected in the Ranibizumab treatment arms only at the following time points: within 24 hours after the first administration of ranibizumab, at Day 15 and at Day 29. Only descriptive analysis done.
• Mean Change in Vascular Endothelial Growth Factor (VEGF) Levels Over Time at Day 1, Day 15 and Day 29 [ Time Frame: Day 1 (Baseline), Day 15 and Day 29 ]
  Blood samples for the determination of systemic VEGF levels were collected at the following time points: before the first investigational treatment, at Day 15 and at Day 29. Only descriptive analysis done.
• Total Number of Ranibizumab Injections Received at Week 24 [ Time Frame: Week 24 ]
  Patients randomized to receive Ranibizumab 0.1 mg or 0.2 mg received a single dose of intravitreal Ranibizumab to each eye on Day 1 (Baseline). Only descriptive analysis done.
• Percent of Participants With Non-Ocular Adverse Events by Primary System Organ (SOCs) at Week 24 [ Time Frame: Week 24 ]
  Percent of Participants with Non-Ocular Adverse Events regardless of Study Treatment and Procedure Relationship by Primary System Organ (SOCs) reported categorically (Mild, Moderate, Severe) 24 weeks after the first study treatment. Only descriptive analysis done.
• Mean Change From Baseline in Vital Signs (Body Length, Head Circumference and Knee to Heel Length) at Day 85 and Day 169 [ Time Frame: Baseline, Day 85, Day 169 ]
  Body Length, Head Circumference and Knee to Heel Length were assessed. Only descriptive analysis done.
• Mean Change From Baseline in Vital Signs (Weight) at Day 85 and Day 169 [ Time Frame: Baseline, Day 85, Day 169 ]
  Body weight was measured. Only descriptive analysis done.
• Mean Change From Baseline in Vital Signs (Sitting Blood Pressure) at Day 85 and Day 169 [ Time Frame: Baseline, Day 85, Day 169 ]
  Blood Pressure measurements were not required by the protocol. Instead, the most recent Systolic and Diastolic Blood Pressure expressed in millimeters of mercury (mmHg) measured as part of the routine clinical care were used. Only descriptive analysis done.

Original Secondary Outcome Measures (submitted: February 24, 2015)

• Requirement for intervention with a second modality for ROP [ Time Frame: 24 weeks after starting investigational treatment ]
• Time to intervention with a second modality for ROP or development of unfavorable structural outcome or death [ Time Frame: 24 weeks after starting investigational treatment ]
• Recurrence of ROP [ Time Frame: 24 weeks after starting investigational treatment ]
• Number of patients having any ocular Adverse Event [ Time Frame: 24 weeks after starting investigational treatment ]
• Systemic ranibizumab levels [ Time Frame: Within 24 hours, 14 days and 28 days after ranibizumab treatment ]
• Systemic Vascular Endothelial Growth Factor (VEGF) levels [ Time Frame: Before investigational treatment, 14 days and 28 days after investigational treatment ]
• Number of ranibizumab administrations [ Time Frame: 24 weeks after starting investigational treatment ]
• Number of patients having any systemic Adverse Event [ Time Frame: 24 weeks after starting investigational treatment ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: RAINBOW Study: RAnibizumab Compared With Laser Therapy for the Treatment of INfants BOrn Prematurely With Retinopathy of Prematurity
• Official Title: RAINBOW Study: a Randomized, Controlled Study Evaluating the Efficacy and Safety of RAnibizumab Compared With Laser Therapy for the Treatment of INfants BOrn Prematurely With Retinopathy of Prematurity
• Brief Summary: The purpose of this study was to determine if intravitreal ranibizumab is superior to laser ablation therapy in the treatment of retinopathy of prematurity (ROP).
• Detailed Description: The study consisted of a screening period (screening and randomization could occur up to 3 days before the administration of the first investigational treatment), followed by a treatment and follow-up period (Day 1 to Day 169).
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Retinopathy of Prematurity

Intervention

• Drug: Ranibizumab
  Administered as an intravitreal injection
• Procedure: Laser therapy
  Transpupillary diode or frequency-doubled yttrium aluminum garnet (YAG) laser ablative therapy, following anesthesia or sedation

Study Arms

• Experimental: Ranibizumab 0.2 mg
  1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required
  Intervention: Drug: Ranibizumab
• Experimental: Ranibizumab 0.1 mg
  1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required
  Intervention: Drug: Ranibizumab
• Active Comparator: Laser therapy
  Laser treatment to each eye on Day 1 (Baseline), with supplementary treatments allowed
  Intervention: Procedure: Laser therapy

Publications *

• Fleck BW, Reynolds JD, Zhu Q, Lepore D, Marlow N, Stahl A, Li J, Weisberger A, Fielder AR; RAINBOW Investigator Group. Time Course of Retinopathy of Prematurity Regression and Reactivation After Treatment with Ranibizumab or Laser in the RAINBOW Trial. Ophthalmol Retina. 2022 Jul;6(7):628-637. doi: 10.1016/j.oret.2022.02.006. Epub 2022 Feb 22.
• 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): an open-label randomised controlled trial. Lancet. 2019 Oct 26;394(10208):1551-1559. doi: 10.1016/S0140-6736(19)31344-3. Epub 2019 Sep 12.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 29, 2017): 224
• Original Estimated Enrollment (submitted: February 24, 2015): 300
• Actual Study Completion Date: December 14, 2017
• Actual Primary Completion Date: December 14, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• preterm infants with a birth weight of less than 1500 g
• bilateral ROP with one of the following retinal findings in each eye: Zone I, stage 1+, 2+, 3 or 3+ disease, or Zone II, stage 3+ disease, or Aggressive posterior retinopathy of prematurity (AP-ROP)

Exclusion Criteria:

• ROP disease characteristic in either eye other than that listed above at the time of the first investigational treatment
• A history of hypersensitivity (either the patient or the mother) to any of the investigational treatments or to drugs of similar chemical classes
• Had received any previous surgical or nonsurgical treatment for ROP (e.g., ablative laser therapy or cryotherapy, vitrectomy)
• Had been previously exposed to any intravitreal or systemic anti-VEGF agent (either the patient or the mother during this child's pregnancy)
• Had used (either the patient or the mother) other investigational drugs as part of another clinical study (other than vitamins and minerals) within 30 days or within 5 half-lives of the other investigational drug, whichever was longer
• Had ocular structural abnormalities that were assessed by the Investigator to have had a clinically significant impact on study assessments
• Had active ocular infection within 5 days before or on the day of first investigational treatment
• Had a history of hydrocephalus requiring treatment
• Had a history of any other neurological conditions that are assessed by the Investigator to have a significant risk of severe impact on visual function
• Had any other medical conditions or clinically significant comorbidities or personal circumstances that were assessed by the Investigator to have a clinically relevant impact on study participation, any of the study procedures, or on efficacy assessments (e.g., poor life expectancy, pupil not able to be adequately dilated, unable to comply with the visit schedule)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Belgium, Croatia, Czechia, Denmark, Egypt, Estonia, France, Germany, Greece, Hungary, India, Italy, Japan, Lithuania, Malaysia, Mexico, Poland, Romania, Russian Federation, Saudi Arabia, Slovakia, Taiwan, Turkey, United Kingdom, United States
• Removed Location Countries: Canada, Chile, Colombia, Czech Republic, Finland, Sweden, United Arab Emirates

Administrative Information

• NCT Number: NCT02375971
• Other Study ID Numbers: CRFB002H2301; 2014-003041-10 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided
• Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: October 2018