Rainbow Extension Study

Study Overview
=================
Brief Summary
-----------------
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)

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.

Official Title
-----------------
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

Conditions
-----------------
Retinopathy of Prematurity (ROP)

Intervention / Treatment
-----------------
* Drug: Ranibizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 5 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ranibizumab 0.2 mg<br>1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required | Drug: Ranibizumab<br>* 1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required<br>|
| Experimental: Ranibizumab 0.1 mg<br>1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required | Drug: Ranibizumab<br>* 1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required<br>|
| No Intervention: Laser therapy<br>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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
open-label,, long-term,, extension study,, intravitreal ranibizumab,, laser ablation therapy,, retinopathy of prematurity,, preterm infants,, RAINBOW