ROP1: Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity

Sponsor

Jaeb Center for Health Research (Other)

Overall Status

Completed

CT.gov ID

NCT02390531

Collaborator

Pediatric Eye Disease Investigator Group (Other), National Eye Institute (NEI) (NIH)

121

Enrollment

Locations

Arm

72.4

Actual Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to find a dose of intravitreal bevacizumab that is lower than currently used for severe retinopathy of prematurity (ROP), is effective in this study, and can be tested in future larger studies.

Condition or Disease	Intervention/Treatment	Phase
Retinopathy of Prematurity	Drug: Bevacizumab	Phase 1

Detailed Description

Despite promising initial results using empirical doses of bevacizumab based on half the adult dose for treatment of acute severe ROP, little is known about lower doses of bevacizumab for ROP. An increasing number of ophthalmologists are treating premature infants with severe ROP using bevacizumab. Given the potential systemic and ocular adverse effects of intravitreal bevacizumab injections, determining a lower effective dose of bevacizumab is an important next step. The proposed study will test progressively lower doses to find a dose to take forward to a future larger study.

Study Design

Study Type:

Interventional

Actual Enrollment :

121 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity

Actual Study Start Date :

Apr 28, 2015

Actual Primary Completion Date :

Jun 4, 2019

Actual Study Completion Date :

May 11, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bevacizumab Dosage if injected Bevacizumab to be studied	Drug: Bevacizumab Varying dosages in 10µl Other Names: Avastin

Arm

Intervention/Treatment

Experimental: Bevacizumab

Dosage if injected Bevacizumab to be studied

Drug: Bevacizumab

Varying dosages in 10µl

Other Names:

Avastin

Outcome Measures

Primary Outcome Measures

Successful Treatment of ROP [4 weeks post-injection]
Success is defined as improvement* by the 4-day exam and no recurrence of type 1 ROP or severe neovascularization requiring additional treatment within 4 weeks of injection. * For infants with plus disease, improvement by the 4-day post-injection exam is defined as plus disease no longer being present. For infants with type 1 ROP without plus disease (i.e., zone I, stage 3), improvement by the 4-day post-injection exam is defined as: (1) a significant reduction in severity and/or extent of extraretinal neovascularization, and, (2) if pre-plus was present pre-injection, reduction in the degree of abnormal vascular dilation and/or tortuosity. A dose will be considered effective if it successfully treats at least 80% of subjects.

Secondary Outcome Measures

Distribution of VEGF Levels [2 weeks post-injection]
The parents of each infant enrolled in the study will be given the option to participate in a study to measure levels of vascular endothelial growth factor (VEGF) and Avastin in the plasma. Participants in this optional study will have blood collected for analysis The distribution of VEGF and Avastin levels (median, range, and quartiles) will be described before injection, and at 2 weeks and 4 weeks post-injection. For each dosage level, at 2, and 4-weeks post-injection, the change from pre-injection will be calculated, and a 95% confidence interval calculated for the change.
Distribution of VEGF Levels [4 weeks post-injection]
The parents of each infant enrolled in the study will be given the option to participate in a study to measure levels of VEGF and Avastin in the plasma. Participants in this optional study will have blood collected for analysis The distribution of VEGF and Avastin levels (median, range, and quartiles) will be described before injection, and at 2 weeks and 4 weeks post-injection. For each dosage level, at 2, and 4-weeks post-injection, the change from pre-injection will be calculated, and a 95% confidence interval calculated for the change.
Distribution of Avastin Levels [2 weeks post-injection]
The parents of each infant enrolled in the study will be given the option to participate in a study to measure levels of VEGF and Avastin in the plasma. Participants in this optional study will have blood collected for analysis The distribution of VEGF and Avastin levels (median, range, and quartiles) will be described before injection, and at 2 weeks and 4 weeks post-injection. For each dosage level, at 2, and 4-weeks post-injection, the change from pre-injection will be calculated, and a 95% confidence interval calculated for the change.
Distribution of Avastin Levels [4 weeks post-injection]
The parents of each infant enrolled in the study will be given the option to participate in a study to measure levels of VEGF and Avastin in the plasma. Participants in this optional study will have blood collected for analysis The distribution of VEGF and Avastin levels (median, range, and quartiles) will be described before injection, and at 2 weeks and 4 weeks post-injection. For each dosage level, at 2, and 4-weeks post-injection, the change from pre-injection will be calculated, and a 95% confidence interval calculated for the change.
Number of study eye and fellow eyes requiring additional treatment/s for ROP, and if retreated, type of treatment [12-month corrected age]
12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months
Any adverse events or complications since the 4-week exam [12-month corrected age]
12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months
Assessment of vision [12-month corrected age]
12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months
Proportion of infants for whom at least one event was reported [Enrollment to 12-month corrected age]
Adverse events reported at any time during the study will be tabulated for all enrolled infants and coded using the MedRA system. For each dosage level, an estimate and 95% confidence interval of the proportions will be obtained using the exact binomial method 12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months
Proportion of infants with an adverse event thought by investigator to be related to study drug [Enrollment to 12-month corrected age]
Adverse events reported at any time during the study will be tabulated for all enrolled infants and coded using the MedRA system. For each dosage level, an estimate and 95% confidence interval of the proportions will be obtained using the exact binomial method 12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months
Proportion of infants for whom at least one serious adverse event was reported [Enrollment to 12-month corrected age]
Adverse events reported at any time during the study will be tabulated for all enrolled infants and coded using the MedRA system. For each dosage level, an estimate and 95% confidence interval of the proportions will be obtained using the exact binomial method
Proportion of infant deaths [Enrollment to 12-month corrected age]
Adverse events reported at any time during the study will be tabulated for all enrolled infants and coded using the MedRA system. For each dosage level, an estimate and 95% confidence interval of the proportions will be obtained using the exact binomial method 12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months
24-Month Extended Follow Up Exam [24-month corrected age]
A subset of infants enrolled in ROP1 will have extended follow up consisting of one additional office exam with developmental testing. This testing will provide a cross-sectional evaluation of visual acuity, refractive error, and development at the adjusted age 24-month visit. 24-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 24 months.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 6 Months

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Type 1 ROP; defined as:

Zone I, any stage ROP with plus disease, or
Zone I, stage 3 ROP without plus disease, or
Zone II, stage 2 or 3 ROP with plus disease

No previous treatment for ROP in the study eye; no previous bevacizumab treatment in the non-study eye

Exclusion Criteria:

The following exclusions apply to the study eye:

Nasolacrimal duct obstruction
Major ocular anomalies (e.g., cataract, coloboma)
Any opacity that precludes an adequate view of the retina

If purulent ocular discharge is present in either eye, then the infant is ineligible.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Emory Eye Center	Atlanta	Georgia	United States	30322
2	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
3	Wilmer Institute	Baltimore	Maryland	United States	21287
4	Boston Children's Hospital	Boston	Massachusetts	United States	02115
5	Duke University Eye Center	Durham	North Carolina	United States	27710
6	Cincinnati Children's Hospital	Cincinnati	Ohio	United States	45229
7	Pediatric Ophthalmology Associates, Inc.	Columbus	Ohio	United States	43205
8	Dean A. McGee Eye Institute, University of Oklahoma	Oklahoma City	Oklahoma	United States	73104
9	Texas Children's Hospital - Dept. Of Ophthalmology	Houston	Texas	United States	77030
10	University of Utah Moran Eye Center	Salt Lake City	Utah	United States	84132
11	Virginia Pediatric Eye Center	Norfolk	Virginia	United States	23502