Back to resultsPhase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity (ROP1)
Primary Purpose
Retinopathy of Prematurity
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Bevacizumab
Sponsored by
About this trial
This is an interventional treatment trial for Retinopathy of Prematurity focused on measuring Retinopathy of Prematurity, Bevacizumab, ROP
Eligibility Criteria
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.
Sites / Locations
- The Emory Eye Center
- Riley Hospital for Children
- Wilmer Institute
- Boston Children's Hospital
- Duke University Eye Center
- Cincinnati Children's Hospital
- Pediatric Ophthalmology Associates, Inc.
- Dean A. McGee Eye Institute, University of Oklahoma
- Texas Children's Hospital - Dept. Of Ophthalmology
- University of Utah Moran Eye Center
- Virginia Pediatric Eye Center
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm 7
Arm 8
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Arm Label
Bevacizumab 0.250 mg
Bevacizumab 0.125 mg
Bevacizumab 0.063 mg
Bevacizumab 0.031 mg
Bevacizumab 0.016 mg
Bevacizumab 0.008 mg
Bevacizumab 0.004 mg
Bevacizumab 0.002 mg
Arm Description
Dosage of injected Bevacizumab to be studied
Dosage of injected Bevacizumab to be studied
Dosage of injected Bevacizumab to be studied
Dosage of injected Bevacizumab to be studied
Dosage of injected Bevacizumab to be studied
Dosage of injected Bevacizumab to be studied
Dosage of injected Bevacizumab to be studied
Dosage of injected Bevacizumab to be studied
Outcomes
Primary Outcome Measures
Number of Participants With Successful Treatment of ROP
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
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.
Distribution of VEGF Levels
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.
Distribution of Avastin Levels
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
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 Eyes Requiring Additional Treatment/s for ROP
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 calculated as the estimated date of confinement (EDC), or due date, plus 12 months
Visual Fixation Status at 12 Months
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
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
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
Count of Infants for Whom at Least One Serious Adverse Event Was Reported
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.
Number of Infant Deaths
Adverse events reported at any time during the study will be tabulated for all enrolled infants and coded using the MedRA system.
12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months
Number of Infants With 24-Month Extended Follow Up Exam
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.
Number of Fellow Eyes Requiring Additional Treatment/s for ROP
12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months
Full Information
NCT ID
NCT02390531
First Posted
February 17, 2015
Last Updated
November 1, 2022
Sponsor
Jaeb Center for Health Research
Collaborators
Pediatric Eye Disease Investigator Group, National Eye Institute (NEI)
1. Study Identification
Unique Protocol Identification Number
NCT02390531
Brief Title
Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity
Acronym
ROP1
Official Title
Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity
Study Type
Interventional
2. Study Status
Record Verification Date
November 2022
Overall Recruitment Status
Completed
Study Start Date
April 28, 2015 (Actual)
Primary Completion Date
June 4, 2019 (Actual)
Study Completion Date
May 11, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Jaeb Center for Health Research
Collaborators
Pediatric Eye Disease Investigator Group, National Eye Institute (NEI)
4. Oversight
Data Monitoring Committee
Yes
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Retinopathy of Prematurity
Keywords
Retinopathy of Prematurity, Bevacizumab, ROP
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Model Description
8 bevacizumab doses were evaluated in this dose de-escalation study in the following dosage amounts: 0.250mg, 0.125mg, 0.063mg, 0.031mg, 0.016mg, 0.008mg, 0.004mg, 0.002mg. Each dose was planned to be used in up to 14 infants to ensure at least 10 infants with 4-week outcomes
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
120 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Bevacizumab 0.250 mg
Arm Type
Experimental
Arm Description
Dosage of injected Bevacizumab to be studied
Arm Title
Bevacizumab 0.125 mg
Arm Type
Experimental
Arm Description
Dosage of injected Bevacizumab to be studied
Arm Title
Bevacizumab 0.063 mg
Arm Type
Experimental
Arm Description
Dosage of injected Bevacizumab to be studied
Arm Title
Bevacizumab 0.031 mg
Arm Type
Experimental
Arm Description
Dosage of injected Bevacizumab to be studied
Arm Title
Bevacizumab 0.016 mg
Arm Type
Experimental
Arm Description
Dosage of injected Bevacizumab to be studied
Arm Title
Bevacizumab 0.008 mg
Arm Type
Experimental
Arm Description
Dosage of injected Bevacizumab to be studied
Arm Title
Bevacizumab 0.004 mg
Arm Type
Experimental
Arm Description
Dosage of injected Bevacizumab to be studied
Arm Title
Bevacizumab 0.002 mg
Arm Type
Experimental
Arm Description
Dosage of injected Bevacizumab to be studied
Intervention Type
Drug
Intervention Name(s)
Bevacizumab
Other Intervention Name(s)
Avastin
Intervention Description
Varying dosages in 10µl
Primary Outcome Measure Information:
Title
Number of Participants With Successful Treatment of ROP
Description
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.
Time Frame
4 weeks post-injection
Secondary Outcome Measure Information:
Title
Distribution of VEGF Levels
Description
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.
Time Frame
2 weeks post-injection
Title
Distribution of VEGF Levels
Description
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.
Time Frame
4 weeks post-injection
Title
Distribution of Avastin Levels
Description
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.
Time Frame
2 weeks post-injection
Title
Distribution of Avastin Levels
Description
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.
Time Frame
4 weeks post-injection
Title
Number of Study Eyes Requiring Additional Treatment/s for ROP
Description
12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months
Time Frame
12-month corrected age
Title
Any Adverse Events or Complications Since the 4-week Exam
Description
12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months
Time Frame
12-month corrected age
Title
Visual Fixation Status at 12 Months
Description
12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months
Time Frame
12-month corrected age
Title
Proportion of Infants for Whom at Least One Event Was Reported
Description
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
Time Frame
Enrollment to 12-month corrected age
Title
Proportion of Infants With an Adverse Event Thought by Investigator to be Related to Study Drug
Description
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
Time Frame
Enrollment to 12-month corrected age
Title
Count of Infants for Whom at Least One Serious Adverse Event Was Reported
Description
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.
Time Frame
Enrollment to 12-month corrected age
Title
Number of Infant Deaths
Description
Adverse events reported at any time during the study will be tabulated for all enrolled infants and coded using the MedRA system.
12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months
Time Frame
Enrollment to 12-month corrected age
Title
Number of Infants With 24-Month Extended Follow Up Exam
Description
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.
Time Frame
24-month corrected age
Title
Number of Fellow Eyes Requiring Additional Treatment/s for ROP
Description
12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months
Time Frame
12-month corrected age
10. Eligibility
Sex
All
Maximum Age & Unit of Time
6 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David K Wallace, MD, MPH
Organizational Affiliation
Indiana University
Official's Role
Study Chair
Facility Information:
Facility Name
The Emory Eye Center
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Riley Hospital for Children
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Wilmer Institute
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Boston Children's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Duke University Eye Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Cincinnati Children's Hospital
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Pediatric Ophthalmology Associates, Inc.
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
Facility Name
Dean A. McGee Eye Institute, University of Oklahoma
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Facility Name
Texas Children's Hospital - Dept. Of Ophthalmology
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Utah Moran Eye Center
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Facility Name
Virginia Pediatric Eye Center
City
Norfolk
State/Province
Virginia
ZIP/Postal Code
23502
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
In accordance with the NIH data sharing policy, a de-identified database is placed in the public domain on the PEDIG public website after the completion of each protocol and publication of the primary manuscript.
IPD Sharing Time Frame
Data will be made available after publication of each primary manuscript.
IPD Sharing Access Criteria
Users accessing the data must enter an email address.
Citations:
PubMed Identifier
28448664
Citation
Wallace DK, Kraker RT, Freedman SF, Crouch ER, Hutchinson AK, Bhatt AR, Rogers DL, Yang MB, Haider KM, VanderVeen DK, Siatkowski RM, Dean TW, Beck RW, Repka MX, Smith LE, Good WV, Hartnett ME, Kong L, Holmes JM; Pediatric Eye Disease Investigator Group (PEDIG). Assessment of Lower Doses of Intravitreous Bevacizumab for Retinopathy of Prematurity: A Phase 1 Dosing Study. JAMA Ophthalmol. 2017 Jun 1;135(6):654-656. doi: 10.1001/jamaophthalmol.2017.1055.
Results Reference
background
PubMed Identifier
34410311
Citation
Kraker RT, Wallace DK, Beck RW, Saunders CT, Lorenzi E, Melia BM, Li Z; Pediatric Eye Disease Investigator Group. Choice of Dose Level for a Randomized Clinical Trial of Low-Dose Bevacizumab vs Laser for Type 1 Retinopathy of Prematurity. JAMA Ophthalmol. 2021 Oct 1;139(10):1143-1144. doi: 10.1001/jamaophthalmol.2021.3192.
Results Reference
background
PubMed Identifier
29887334
Citation
Wallace DK, Dean TW, Hartnett ME, Kong L, Smith LE, Hubbard GB, McGregor ML, Jordan CO, Mantagos IS, Bell EF, Kraker RT; Pediatric Eye Disease Investigator Group. A Dosing Study of Bevacizumab for Retinopathy of Prematurity: Late Recurrences and Additional Treatments. Ophthalmology. 2018 Dec;125(12):1961-1966. doi: 10.1016/j.ophtha.2018.05.001. Epub 2018 Jun 7.
Results Reference
result
PubMed Identifier
31697304
Citation
Crouch ER, Kraker RT, Wallace DK, Holmes JM, Repka MX, Collinge JE, Bremer DL, Gray ME, Smith HA, Steinkuller PG; Writing Committee for Pediatric Eye Disease Investigator Group. Secondary 12-Month Ocular Outcomes of a Phase 1 Dosing Study of Bevacizumab for Retinopathy of Prematurity. JAMA Ophthalmol. 2020 Jan 1;138(1):14-20. doi: 10.1001/jamaophthalmol.2019.4488.
Results Reference
result
PubMed Identifier
32324197
Citation
Wallace DK, Kraker RT, Freedman SF, Crouch ER, Bhatt AR, Hartnett ME, Yang MB, Rogers DL, Hutchinson AK, VanderVeen DK, Haider KM, Siatkowski RM, Dean TW, Beck RW, Repka MX, Smith LE, Good WV, Kong L, Cotter SA, Holmes JM; Pediatric Eye Disease Investigator Group (PEDIG). Short-term Outcomes After Very Low-Dose Intravitreous Bevacizumab for Retinopathy of Prematurity. JAMA Ophthalmol. 2020 Jun 1;138(6):698-701. doi: 10.1001/jamaophthalmol.2020.0334.
Results Reference
result
Links:
URL
http://www.pedig.net
Description
PEDIG Public Website
Learn more about this trial
Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity
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