Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity

Overview

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.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Sequential Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: June 4, 2019

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.

Interventions

  • Drug: Bevacizumab
    • Varying dosages in 10µl

Arms, Groups and Cohorts

  • Experimental: Bevacizumab 0.250 mg
    • Dosage of injected Bevacizumab to be studied
  • Experimental: Bevacizumab 0.125 mg
    • Dosage of injected Bevacizumab to be studied
  • Experimental: Bevacizumab 0.063 mg
    • Dosage of injected Bevacizumab to be studied
  • Experimental: Bevacizumab 0.031 mg
    • Dosage of injected Bevacizumab to be studied
  • Experimental: Bevacizumab 0.016 mg
    • Dosage of injected Bevacizumab to be studied
  • Experimental: Bevacizumab 0.008 mg
    • Dosage of injected Bevacizumab to be studied
  • Experimental: Bevacizumab 0.004 mg
    • Dosage of injected Bevacizumab to be studied
  • Experimental: Bevacizumab 0.002 mg
    • Dosage of injected Bevacizumab to be studied

Clinical Trial Outcome Measures

Primary Measures

  • Number of Participants With 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.

Secondary Measures

  • 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.
  • 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.
  • 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 Eyes Requiring Additional Treatment/s for ROP
    • 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
  • Visual Fixation Status at 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
  • 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
  • Count 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.
  • Number 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. 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
    • 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.
  • Number of Fellow Eyes Requiring Additional Treatment/s for ROP
    • Time Frame: 12-month corrected age
    • 12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: 6 Months

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Jaeb Center for Health Research
  • Collaborator
    • Pediatric Eye Disease Investigator Group
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • David K Wallace, MD, MPH, Study Chair, Indiana University

References

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.

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.

Citations Reporting on Results

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.

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.

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.

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