Rainbow Extension Study (RainbowExt)

RAINBOW Extension Study: an Extension Study to Evaluate the Long Term 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 evaluate the long term efficacy and safety of intravitreal ranibizumab compared with laser ablation therapy in patients who were treated for retinopathy of prematurity (ROP) in the core study CRFB002H2301 (NCT02375971)

Study Overview

• Status: Completed
• Conditions: Retinopathy of Prematurity (ROP)
• Intervention / Treatment: Drug: Ranibizumab

Detailed Description

This was a multicenter, open-label extension study where the Visual Acuity (VA) assessment at the child's 5th birthday visit was performed. The study had 2 distinct periods (Epochs). Treatment with study ranibizumab (either as retreatment after ranibizumab had already been injected in the same eye or as switch ranibizumab treatment from study laser therapy administered in the core study) was permitted for eligible eyes with recurrence/worsening of ROP up to and including Week 40 from the baseline visit in the core study (Epoch 1). The remainder of the extension study up to the 5th birthday visit (Epoch 2) was observational, with no study treatment planned to be administered.

In the core study, patients were randomized to 1 of the 3 treatment arms (ranibizumab 0.2 mg, ranibizumab 0.1 mg, and laser). Treatment arm assignment and patient identifier in the extension study remained the same as in the core study.

• Study Type: Interventional
• Enrollment (Actual): 180
• 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
  • Zagreb, Croatia, 10000
    • Novartis Investigative Site
• Czechia
  • Praha, Czechia, 12808
    • Novartis Investigative Site
  • Czech Republic
    • Praha 4 - Podoli, Czech Republic, Czechia, 14700
      • Novartis Investigative Site
  • Poruba
    • Ostrava, Poruba, Czechia, 708 52
      • Novartis Investigative Site
• Denmark
  • Koebenhavn Ø, Denmark, 2100
    • Novartis Investigative Site
• Egypt
  • Alexandria, Egypt, 21131
    • Novartis Investigative Site
• Estonia
  • Tallinn, Estonia, 10138
    • Novartis Investigative Site
• France
  • Amiens, France, 80054
    • Novartis Investigative Site
  • Marseille, France, 13915
    • Novartis Investigative Site
• Germany
  • Hannover, Germany, 30625
    • Novartis Investigative Site
• Greece
  • Athens, Greece, 115 27
    • Novartis Investigative Site
  • GR
    • Ampelokipi, GR, Greece, 115 27
      • Novartis Investigative Site
    • Thessaloniki, GR, Greece, 564 03
      • 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
  • PG
    • Perugia, PG, Italy, 06100
      • Novartis Investigative Site
  • RM
    • Fiumicino, RM, Italy, 00054
      • Novartis Investigative Site
    • Roma, RM, Italy, 00168
      • 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
  • 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
• 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
  • Soguksu / Antalya, Turkey, 07100
    • Novartis Investigative Site
  • Bakirkoy
    • Istanbul, Bakirkoy, Turkey, 34140
      • Novartis Investigative Site
  • Eskisehir
    • Meselik, Eskisehir, Turkey, 26480
      • Novartis Investigative Site
• United Kingdom
  • Manchester, United Kingdom, M13 9WL
    • Novartis Investigative Site
  • Portsmouth, United Kingdom, PO6 3LY
    • Novartis Investigative Site
• United States
  • California
    • 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, 40202
      • Novartis Investigative Site
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • 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
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 5 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed informed consent from parent(s) or legal guardian(s), in compliance with local requirements
• The patient successfully completed the core study H2301, as defined by providing assessments at the Visit 112 (the last scheduled visit in the core study) or, if appropriate, at the last of the additional assessment visits as per protocol in H2301, whichever was latest
• The patient received study treatment in both eyes at baseline of study H2301

Exclusion Criteria:

• Patient had a medical condition or personal circumstance which precluded study participation or compliance with study procedures, as assessed by the Investigator
• Patient had been discontinued from the core study H2301 at any time

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

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; 1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required
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; 1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required
NO_INTERVENTION: Laser therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual Acuity (VA) of the Better-seeing Eye at the Participant's Fifth Birthday Visit - Comparison Between Treatment Arms	The VA assessment at the child's 5th birthday visit was performed using Early Treatment Diabetic Retinopathy Study (ETDRS) methodology. VA measurements were taken in a sitting position at an initial test distance of 3 meters using Lea Symbols charts. Scores represented the number of optotypes (Lea symbols) the participant identified and ranged from 0 to 100, with higher scores indicating better visual acuity. VA was tested in each eye, using the child's current refractive index. The better-seeing eye was defined as the eye with the higher ETDRS score at the 5th birthday visit. If both eyes had the same ETDRS score, then the right eye was assigned as the better-seeing eye.	at the participant's fifth birthday visit (maximum 5 years and 4 months post core baseline visit)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Ocular Adverse Events (AEs) Regardless of Study Treatment or Procedure Relationship by Preferred Term	Number of participants with ocular AEs starting during the core study and ongoing at extension baseline, or starting on/after extension baseline were reported.	throughout the study, approximately 5 years
Number of Participants With Non-ocular Adverse Events (AEs) Regardless of Study Treatment or Procedure Relationship (Greater Than or Equal to 3% in Any Arm) by Preferred Term	Number of participants with non-ocular adverse events regardless of study treatment or procedure relationship (greater than or equal to 3% in any arm) by preferred term were reported.	throughout the study, approximately 5 years
Visual Acuity (VA) of the Worse-seeing Eye at the Participant's Fifth Birthday Visit - Comparison Between Treatment Arms	The VA assessment at the child's 5th birthday visit was performed using Early Treatment Diabetic Retinopathy Study (ETDRS) methodology. VA measurements were taken in a sitting position at an initial test distance of 3 meters using Lea Symbols charts. Scores represented the number of optotypes (Lea symbols) the participant identified and ranged from 0 to 100, with higher scores indicating better visual acuity. VA was tested in each eye, using the child's current refractive index. The worse-seeing eye was the eye with a lower ETDRS score at the 5th birthday visit. If both eyes had the same ETDRS score, then the left eye was assigned as the worse-seeing eye.	at the participant's fifth birthday visit (maximum 5 years and 4 months post core baseline visit)
Number of Participants With Absence of Active Retinopathy of Prematurity (ROP) at 40 Weeks Post Core Baseline Visit	The absence of active ROP in both eyes is defined by the absence of all of the following features: (1) Vessel dilatation of plus disease in at least 2 quardrants (some persisting tortuosity is allowed), (2) Extra-retina vessels extending from the retina into the vitreous and judged to be a sign of active ROP disease.	at 40 weeks post core baseline visit
Number of Participants With Absence of Active Retinopathy of Prematurity (ROP) at 52 Weeks Post Core Baseline Visit	The absence of active ROP in both eyes is defined by the absence of all of the following features: (1) Vessel dilatation of plus disease in at least 2 quardrants (some persisting tortuosity is allowed), (2) Extra-retina vessels extending from the retina into the vitreous and judged to be a sign of active ROP disease.	at 52 weeks post core baseline visit
Number of Participants With Absence of All Ocular Structural Abnormalities at or Before 40 Weeks Post Baseline Visit	The absence of all ocular structural abnormalities is defined by the absence of all of the following fundus features in both eyes at or before the given time point: (1) Substantial temporal retinal vessel dragging causing abnormal structural features/macular Ectopia, (2) Retrolental membrane obscuring the view of the posterior pole, (3) Posterior retinal fold involving the macula, (4) Retinal detachment involving the macula	at or before 40 weeks post baseline visit
Number of Participants With Absence of All Ocular Structural Abnormalities at or Before the Participant's Fifth Birthday Visit	The absence of all ocular structural abnormalities is defined by the absence of all of the following fundus features in both eyes at or before the given time point: (1) Substantial temporal retinal vessel dragging causing abnormal structural features/macular Ectopia, (2) Retrolental membrane obscuring the view of the posterior pole, (3) Posterior retinal fold involving the macula, (4) Retinal detachment involving the macula	at or before the participant's fifth birthday visit (up to maximum 5 years and 4 months post core baseline visit)
Number of Participants With Absence of Individual Ocular Structural Abnormalities at or Before 40 Weeks Post Baseline Visit	Number of participants with absence of each structural abnormality in both eyes at or before the given time point: (1) Substantial temporal retinal vessel dragging causing abnormal structural features/macular Ectopia, (2) Retrolental membrane obscuring the view of the posterior pole, (3) Posterior retinal fold involving the macula, (4) Retinal detachment involving the macula, (5) Retinal detachment not involving the macula, (6) Pre-retinal fibrosis	at or before 40 weeks post baseline visit
Number of Participants With Absence of Individual Ocular Structural Abnormalities at or Before the Participant's Fifth Birthday Visit	Number of participants with absence of each structural abnormality in both eyes at or before the given time point: (1) Substantial temporal retinal vessel dragging causing abnormal structural features/macular Ectopia, (2) Retrolental membrane obscuring the view of the posterior pole, (3) Posterior retinal fold involving the macula, (4) Retinal detachment involving the macula, (5) Retinal detachment not involving the macula, (6) Pre-retinal fibrosis, (7) Optic disc pallor, (8) Optic disc swelling, (9) Pigmentary disturbance in the macula, (10) Atrophic changes in the macula	at or before the participant's fifth birthday visit (up to maximum 5 years and 4 months post core baseline visit)
Number of Participants With Absence of All Ocular Structural Abnormalities at or Before Participant's 2 Years Corrected Age Visit	The absence of all ocular structural abnormalities is defined by the absence of all of the following fundus features in both eyes at or before the given time point: (1) Substantial temporal retinal vessel dragging causing abnormal structural features/macular Ectopia, (2) Retrolental membrane obscuring the view of the posterior pole, (3) Posterior retinal fold involving the macula, (4) Retinal detachment involving the macula	at or before participant's 2 years corrected age visit (up to 2 years and 4 months post core baseline visit)
Number of Participants With Absence of Individual Ocular Structural Abnormalities at or Before Participant's 2 Years Corrected Age Visit	Number of participants with absence of each structural abnormality in both eyes at or before the given time point: (1) Substantial temporal retinal vessel dragging causing abnormal structural features/macular Ectopia, (2) Retrolental membrane obscuring the view of the posterior pole, (3) Posterior retinal fold involving the macula, (4) Retinal detachment involving the macula, (5) Retinal detachment not involving the macula, (6) Pre-retinal fibrosis, (7) Optic disc pallor, (8) Optic disc swelling, (9) Pigmentary disturbance in the macula, (10) Atrophic changes in the macula	at or before participant's 2 years corrected age visit (up to 2 years and 4 months post core baseline visit)
Number of Participants With Recurrence of ROP up to 40 Weeks Post Baseline Visit in the Core Study	Recurrence of ROP was defined as ROP receiving any post-baseline intervention after the 1st study treatment in the core study. In the ranibizumab arms, post-baseline interventions were ranibizumab retreatment or switch to laser. In the laser arm, post-baseline interventions were supplementary laser treatments after 11 days post-baseline, or switch to ranibizumab; supplementary laser treatment within 11 days post-baseline was not counted as recurrence.	up to 40 weeks post baseline visit in the core study
Number of Participants With Recurrence of ROP up to 52 Weeks Post Baseline Visit in the Core Study	Recurrence of ROP was defined as ROP receiving any post-baseline intervention after the 1st study treatment in the core study. In the ranibizumab arms, post-baseline interventions were ranibizumab retreatment or switch to laser. In the laser arm, post-baseline interventions were supplementary laser treatments after 11 days post-baseline, or switch to ranibizumab; supplementary laser treatment within 11 days post-baseline was not counted as recurrence. Beyond Week 40, participants did not receive any study intervention and no new data was collected after 40 weeks post core baseline visit.	up to 52 weeks post baseline visit in the core study
Number of Ranibizumab Injections Received Per Participant Over the Whole Safety Observation Period	Number of ranibizumab injections received in the treatment of participants with ROP up to and including 40 weeks post baseline visit in the core study were reported.	up to and including 40 weeks post baseline visit in the core study
Refraction Status: Summary of Participants at Participant's 2 Years Corrected Age	Summary of participants was reported to evaluate the refraction in each eye at the participant's 2 years corrected age	at participant's 2 years corrected age (maximum 2 years and 4 months post core baseline visit)
Refraction Status: Summary of Participants at the Participant's Fifth Birthday Visit	Summary of participants was reported to evaluate the refraction in each eye at the participant's 2 years' corrected age	at the participant's fifth birthday visit (maximum 5 years and 4 months post core baseline visit)
Change From Baseline in Weight	Subject´s weight was reported to evaluate the physical development.	Baseline of the core study, at the subject's 2 years' corrected age (maximum 2 years and 4 months post core baseline visit) and at the subjects' fifth birthday (maximum 5 years and 4 months post core baseline visit)
Change From Baseline in Head Circumference	Subject´s head circumference was reported to evaluate the physical development.	Baseline of the core study and at the subject's 2 years' corrected age (maximum 2 years and 4 months post core baseline visit)
Change From Baseline in Sitting Diastolic Blood Pressure	Subject´s Sitting Diastolic Blood Pressure was reported to evaluate the physical development.	Baseline of the core study and at the subject's 2 years' corrected age (maximum 2 years and 4 months post core baseline visit)
Change From Baseline in Sitting Systolic Blood Pressure	Subject´s Sitting Systolic Blood Pressure was reported to evaluate the physical development.	Baseline of the core study and at the subject's 2 years' corrected age (maximum 2 years and 4 months post core baseline visit)
Number of Participants With the Summary of Respiratory Function Status	Number of participants with respiratory function status was reported	at the participants' fifth birthday visit (maximum 5 years and 4 months post core baseline visit)
Number of Participants With Hearing Impairment of Any Type	Number of participants with hearing function status was reported	at the participants' fifth birthday visit (maximum 5 years and 4 months post core baseline visit)
Duration of Hospitalization	Duration of hospitalization (from birth to first hospital discharge home) was reported to evaluate the health status of the subject	From baseline of the core study up to 5 years and 4 months post core baseline visit
Weight at the Time of First Hospital Discharge	Weight (gram) at the time of first hospital discharge was reported to evaluate the health status of the subject	From baseline of the core study up to 5 years and 4 months post core baseline visit

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Marlow N, Stahl A, Lepore D, Fielder A, Reynolds JD, Zhu Q, Weisberger A, Stiehl DP, Fleck B; RAINBOW investigators group. 2-year outcomes of ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW extension study): prospective follow-up of an open label, randomised controlled trial. Lancet Child Adolesc Health. 2021 Oct;5(10):698-707. doi: 10.1016/S2352-4642(21)00195-4. Epub 2021 Aug 13.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 16, 2016
• Primary Completion (ACTUAL): April 21, 2022
• Study Completion (ACTUAL): April 21, 2022

Study Registration Dates

• First Submitted: December 1, 2015
• First Submitted That Met QC Criteria: December 23, 2015
• First Posted (ESTIMATE): December 29, 2015

Study Record Updates

• Last Update Posted (ACTUAL): February 13, 2023
• Last Update Submitted That Met QC Criteria: January 18, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: RAINBOW; extension study,; open-label,; long-term,; intravitreal ranibizumab,; laser ablation therapy,; retinopathy of prematurity,; preterm infants,
• 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: CRFB002H2301E1; 2014-004048-36 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

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

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