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

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

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).

Study Overview

• Status: Completed
• Conditions: Retinopathy of Prematurity
• Intervention / Treatment: Drug: Ranibizumab; Procedure: Laser therapy

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
• Enrollment (Actual): 224
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, A-8036
    • Novartis Investigative Site
  • Vienna, Austria, 1090
    • Novartis Investigative Site
• Belgium
  • Brugge, Belgium, 8000
    • Novartis Investigative Site
  • Gent, Belgium, 9000
    • Novartis Investigative Site
• Croatia
  • Osijek, Croatia, 31000
    • Novartis Investigative Site
  • Zagreb, Croatia, 10000
    • Novartis Investigative Site
• Czechia
  • Praha, Czechia, 12808
    • Novartis Investigative Site
  • Czech Republic
    • Ostrava Poruba, Czech Republic, Czechia, 708 52
      • Novartis Investigative Site
    • Praha 4 - Podoli, Czech Republic, Czechia, 14700
      • Novartis Investigative Site
• Denmark
  • Koebenhavn Ø, Denmark, 2100
    • Novartis Investigative Site
• Egypt
  • Alexandria, Egypt, 21131
    • Novartis Investigative Site
• Estonia
  • Tallinn, Estonia, 13419
    • Novartis Investigative Site
• France
  • Amiens Cedex 1, France, 80054
    • Novartis Investigative Site
  • Marseille, France, 13915
    • Novartis Investigative Site
• Germany
  • Bonn, Germany, 53127
    • Novartis Investigative Site
  • Hannover, Germany, 30625
    • Novartis Investigative Site
• Greece
  • Goudi- Athens, Greece, 115 27
    • Novartis Investigative Site
  • GR
    • Ampelokipi, GR, Greece, 115 27
      • Novartis Investigative Site
    • Thessaloniki, GR, Greece, 546 29
      • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, 1125
    • Novartis Investigative Site
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
• India
  • New Delhi, India, 110029
    • Novartis Investigative Site
  • Gujarat
    • Ahmedabad, Gujarat, India, 380016
      • Novartis Investigative Site
  • Maharashtra
    • Mumbai, Maharashtra, India, 400 008
      • Novartis Investigative Site
  • Tamil Nadu
    • Coimbatore, Tamil Nadu, India, 641014
      • Novartis Investigative Site
    • Madurai, Tamil Nadu, India, 625020
      • Novartis Investigative Site
  • Thiruvanantapuram
    • Vanchiyoor, Thiruvanantapuram, India, 695035
      • Novartis Investigative Site
• Italy
  • FI
    • Firenze, FI, Italy, 50139
      • Novartis Investigative Site
  • Lazio
    • Roma, Lazio, Italy, 00168
      • Novartis Investigative Site
  • PG
    • Perugia, PG, Italy, 06100
      • Novartis Investigative Site
  • RM
    • Fiumicino, RM, Italy, 00054
      • Novartis Investigative Site
• Japan
  • Aichi
    • Nagoya, Aichi, Japan, 453-8511
      • Novartis Investigative Site
    • Nagoya, Aichi, Japan, 466 8560
      • Novartis Investigative Site
  • Chiba
    • Yachiyo-city, Chiba, Japan, 276-8524
      • Novartis Investigative Site
  • Fukuoka
    • Fukuoka city, Fukuoka, Japan, 812-8582
      • Novartis Investigative Site
    • Fukuoka-city, Fukuoka, Japan, 814-0180
      • Novartis Investigative Site
    • Kurume city, Fukuoka, Japan, 830-0011
      • Novartis Investigative Site
  • Fukushima
    • Fukushima-city, Fukushima, Japan, 960-1295
      • Novartis Investigative Site
  • Hokkaido
    • Sapporo-city, Hokkaido, Japan
      • Novartis Investigative Site
  • Kagawa
    • Zentsuji-city, Kagawa, Japan, 765-8507
      • Novartis Investigative Site
  • Okinawa
    • Shimajiri-Gun, Okinawa, Japan, 901-1303
      • Novartis Investigative Site
  • Osaka
    • Izumi-city, Osaka, Japan, 594-1101
      • Novartis Investigative Site
  • Shiga
    • Ohtsu-city, Shiga, Japan, 520-2192
      • Novartis Investigative Site
  • Tokyo
    • Fuchu-city, Tokyo, Japan, 183-8561
      • Novartis Investigative Site
    • Ota-ku, Tokyo, Japan, 143 8541
      • Novartis Investigative Site
    • Setagaya-ku, Tokyo, Japan, 157-8535
      • Novartis Investigative Site
    • Sumida-ku, Tokyo, Japan, 130-8575
      • Novartis Investigative Site
    • Toshima-ku, Tokyo, Japan, 170-8476
      • Novartis Investigative Site
• Lithuania
  • LTU
    • Kaunas, LTU, Lithuania, LT-50161
      • Novartis Investigative Site
• Malaysia
  • Sabah
    • Kota Kinabalu, Sabah, Malaysia, 88996
      • Novartis Investigative Site
  • Wilayah Persekutuan
    • Kuala Lumpur, Wilayah Persekutuan, Malaysia, 50586
      • Novartis Investigative Site
• Mexico
  • Querataro, Mexico, 76090
    • Novartis Investigative Site
• Poland
  • Bialystok, Poland, 15-274
    • Novartis Investigative Site
  • Wroclaw, Poland, 51-124
    • Novartis Investigative Site
• Romania
  • Brasov, Romania, 500025
    • Novartis Investigative Site
  • Bucuresti, Romania, 020395
    • Novartis Investigative Site
  • Timisoara, Romania, 300041
    • Novartis Investigative Site
• Russian Federation
  • Cheboksary, Russian Federation, 428028
    • Novartis Investigative Site
  • Kazan, Russian Federation, 420012
    • Novartis Investigative Site
  • Moscow, Russian Federation, 127486
    • Novartis Investigative Site
  • Saint-Petersburg, Russian Federation, 194100
    • Novartis Investigative Site
• Saudi Arabia
  • Riyadh, Saudi Arabia, 11211
    • Novartis Investigative Site
• Slovakia
  • Bratislava, Slovakia, 833 40
    • Novartis Investigative Site
• Taiwan
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
  • Taoyuan, Taiwan, 33305
    • Novartis Investigative Site
• Turkey
  • Ankara, Turkey, 06100
    • Novartis Investigative Site
  • Ankara, Turkey, 06500
    • Novartis Investigative Site
  • Istanbul, Turkey, 34140
    • Novartis Investigative Site
  • Soguksu / Antalya, Turkey, 07100
    • Novartis Investigative Site
  • Zuhuratbaba / Istanbul, Turkey, 34147
    • Novartis Investigative Site
  • Meselik
    • Eskisehir, Meselik, Turkey, 26480
      • Novartis Investigative Site
• United Kingdom
  • Manchester, United Kingdom, M13 9WL
    • Novartis Investigative Site
  • Oxford, United Kingdom, OX3 9DU
    • Novartis Investigative Site
  • Portsmouth, United Kingdom, PO6 3LY
    • Novartis Investigative Site
• United States
  • California
    • Loma Linda, California, United States, 92354
      • Novartis Investigative Site
    • Sacramento, California, United States, 95817
      • Novartis Investigative Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Novartis Investigative Site
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Novartis Investigative Site
  • Kentucky
    • Louisville, Kentucky, United States, 40208
      • Novartis Investigative Site
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Novartis Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Novartis Investigative Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • Novartis Investigative Site
  • New York
    • Rochester, New York, United States, 14642
      • Novartis Investigative Site
  • Texas
    • Austin, Texas, United States, 78705
      • Novartis Investigative Site
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Novartis Investigative Site
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	Drug: Ranibizumab; Administered as an intravitreal injection
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	Drug: Ranibizumab; Administered as an intravitreal injection
Active Comparator: Laser therapy; Laser treatment to each eye on Day 1 (Baseline), with supplementary treatments allowed	Procedure: Laser therapy; Transpupillary diode or frequency-doubled yttrium aluminum garnet (YAG) laser ablative therapy, following anesthesia or sedation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Absence of Active ROP and Absence of Unfavorable Structural Outcomes in Both Eyes at 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.	Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Requiring Interventions With a Second Modality for ROP at 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.	Week 24
Number of Participants Experiencing an Event, From the First Study Treatment to the Last Study Visit	An event was defined as death, treatment switch, or the first occurrence of unfavorable structural outcomes in either eye. Only descriptive analysis done.	Day 1 (after initiation of study treatment) up to study exit (Day 169)
Percentage of Participants Having Recurrent ROP and Receiving Any Post-baseline Intervention at or Before 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.	Week 24
Percent of Participants With Ocular Adverse Events by Primary System Organ (SOCs) at 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.	Week 24
Mean Change in Ranibizumab Concentration in Pharmacokinetic Serum Samples Over Time at Day 1, 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.	Day 1 (Baseline), Day 15 and Day 29
Mean Change in Vascular Endothelial Growth Factor (VEGF) Levels Over Time at Day 1, 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.	Day 1 (Baseline), Day 15 and Day 29
Total Number of Ranibizumab Injections Received at 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.	Week 24
Percent of Participants With Non-Ocular Adverse Events by Primary System Organ (SOCs) at 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.	Week 24
Mean Change From Baseline in Vital Signs (Body Length, Head Circumference and Knee to Heel Length) at Day 85 and Day 169	Body Length, Head Circumference and Knee to Heel Length were assessed. Only descriptive analysis done.	Baseline, Day 85, Day 169
Mean Change From Baseline in Vital Signs (Weight) at Day 85 and Day 169	Body weight was measured. Only descriptive analysis done.	Baseline, Day 85, Day 169
Mean Change From Baseline in Vital Signs (Sitting Blood Pressure) at Day 85 and 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.	Baseline, Day 85, Day 169

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 30, 2015
• Primary Completion (Actual): December 14, 2017
• Study Completion (Actual): December 14, 2017

Study Registration Dates

• First Submitted: February 18, 2015
• First Submitted That Met QC Criteria: February 24, 2015
• First Posted (Estimate): March 3, 2015

Study Record Updates

• Last Update Posted (Actual): November 14, 2018
• Last Update Submitted That Met QC Criteria: October 15, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: intravitreal ranibizumab; laser ablation therapy; retinopathy of prematurity; preterm infants; RAINBOW
• Additional Relevant MeSH Terms: Eye Diseases; Infant, Newborn, Diseases; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Infant, Premature, Diseases; Retinal Diseases; Premature Birth; Retinopathy of Prematurity; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Ranibizumab
• Other Study ID Numbers: CRFB002H2301; 2014-003041-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No