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Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity (ROP1)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02390531
Recruitment Status : Completed
First Posted : March 17, 2015
Last Update Posted : November 8, 2021
Sponsor:
Collaborators:
Pediatric Eye Disease Investigator Group
National Eye Institute (NEI)
Information provided by (Responsible Party):
Jaeb Center for Health Research

Tracking Information
First Submitted Date  ICMJE February 17, 2015
First Posted Date  ICMJE March 17, 2015
Last Update Posted Date November 8, 2021
Actual Study Start Date  ICMJE April 28, 2015
Actual Primary Completion Date June 4, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 20, 2015)
Successful Treatment of ROP [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 10, 2015)
  • Successful Treatment of ROP at 0.25mg [ Time Frame: 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.
  • Successful Treatment of ROP at 0.125mg [ Time Frame: 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.
  • Successful Treatment of ROP at 0.0625mg [ Time Frame: 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.
  • Successful Treatment of ROP at 0.03125mg [ Time Frame: 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 12, 2017)
  • Distribution of VEGF Levels [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 10, 2015)
  • Distribution of VEGF Levels [ Time Frame: 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 VEGF Levels [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
  • Time Since Initial Discharge [ Time Frame: 12-month corrected age ]
    12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months
  • Number of Times Re-hospitalized by 12 months [ Time Frame: 12-month corrected age ]
    12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months
  • Number of infants with an increase in oxygen requirement prior to injection [ Time Frame: 12-month corrected age ]
    12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months
  • Number of infants with periventricular leukomalacia [ Time Frame: 12-month corrected age ]
    12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months
  • Number of study eye and fellow eyes requiring additional treatment/s for ROP, and if retreated, type of treatment [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 12-month corrected age ]
    12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months
  • Most recent head circumference [ Time Frame: 12-month corrected age ]
    12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months Most recent head circumference (in centimeters), reported by z scores
  • Most recent weight [ Time Frame: 12-month corrected age ]
    12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months Most recent weight (in grams), reported by z scores
  • Proportion of infants for whom at least one event was reported [ Time Frame: Enrollment to completion ]
    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 infants with an adverse event thought by investigator to be related to study drug [ Time Frame: Enrollment to completion ]
    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 infants for whom at least one serious adverse event was reported [ Time Frame: Enrollment to completion ]
    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 [ Time Frame: Enrollment to completion ]
    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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity
Official Title  ICMJE Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Retinopathy of Prematurity
Intervention  ICMJE Drug: Bevacizumab
Varying dosages in 10µl
Other Name: Avastin
Study Arms  ICMJE Experimental: Bevacizumab
Dosage if injected Bevacizumab to be studied
Intervention: Drug: Bevacizumab
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 1, 2019)
121
Original Estimated Enrollment  ICMJE
 (submitted: March 10, 2015)
112
Actual Study Completion Date  ICMJE May 11, 2021
Actual Primary Completion Date June 4, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. 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
  2. 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:

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

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 6 Months   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02390531
Other Study ID Numbers  ICMJE ROP1
2U10EY011751 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
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.
Time Frame: Data will be made available after publication of each primary manuscript.
Access Criteria: Users accessing the data must enter an email address.
Responsible Party Jaeb Center for Health Research
Study Sponsor  ICMJE Jaeb Center for Health Research
Collaborators  ICMJE
  • Pediatric Eye Disease Investigator Group
  • National Eye Institute (NEI)
Investigators  ICMJE
Study Chair: David K Wallace, MD, MPH Duke Eye Center
PRS Account Jaeb Center for Health Research
Verification Date November 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP