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

Study Overview
=================
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).

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

Conditions
-----------------
Retinopathy of Prematurity

Intervention / Treatment
-----------------
* Drug: Ranibizumab
* Procedure: Laser therapy


Participation Criteria
=================
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)
Sexes Eligible for Study
-----------------
All

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

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

Design Details

Primary Purpose: Treatment
Allocation: 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>* Administered as an intravitreal injection<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>* Administered as an intravitreal injection<br>|
| Active Comparator: Laser therapy<br>Laser treatment to each eye on Day 1 (Baseline), with supplementary treatments allowed | Procedure: Laser therapy<br>* Transpupillary diode or frequency-doubled yttrium aluminum garnet (YAG) laser ablative therapy, following anesthesia or sedation<br>|

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 | 

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