Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase 1 Trial of Bevacizumab Treatment for Severe Retinopathy of Prematurity

Conditions
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Retinopathy of Prematurity

Intervention / Treatment
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* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Maximum Age: 6 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bevacizumab 0.250 mg<br>Dosage of injected Bevacizumab to be studied | Drug: Bevacizumab<br>* Varying dosages in 10µl<br>* Other names: Avastin;|
| Experimental: Bevacizumab 0.125 mg<br>Dosage of injected Bevacizumab to be studied | Drug: Bevacizumab<br>* Varying dosages in 10µl<br>* Other names: Avastin;|
| Experimental: Bevacizumab 0.063 mg<br>Dosage of injected Bevacizumab to be studied | Drug: Bevacizumab<br>* Varying dosages in 10µl<br>* Other names: Avastin;|
| Experimental: Bevacizumab 0.031 mg<br>Dosage of injected Bevacizumab to be studied | Drug: Bevacizumab<br>* Varying dosages in 10µl<br>* Other names: Avastin;|
| Experimental: Bevacizumab 0.016 mg<br>Dosage of injected Bevacizumab to be studied | Drug: Bevacizumab<br>* Varying dosages in 10µl<br>* Other names: Avastin;|
| Experimental: Bevacizumab 0.008 mg<br>Dosage of injected Bevacizumab to be studied | Drug: Bevacizumab<br>* Varying dosages in 10µl<br>* Other names: Avastin;|
| Experimental: Bevacizumab 0.004 mg<br>Dosage of injected Bevacizumab to be studied | Drug: Bevacizumab<br>* Varying dosages in 10µl<br>* Other names: Avastin;|
| Experimental: Bevacizumab 0.002 mg<br>Dosage of injected Bevacizumab to be studied | Drug: Bevacizumab<br>* Varying dosages in 10µl<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 4 weeks post-injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 2 weeks post-injection | 
| 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. | 4 weeks post-injection | 
| 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. | 2 weeks post-injection | 
| 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. | 4 weeks post-injection | 
| 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 | 12-month corrected age | 
| 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 | 12-month corrected age | 
| Visual Fixation Status at 12 Months | 12-month corrected age calculated as the estimated date of confinement (EDC), or due date, plus 12 months | 12-month corrected age | 
| 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 | Enrollment to 12-month corrected age | 
| 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 | Enrollment to 12-month corrected age | 
| 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. | Enrollment to 12-month corrected age | 
| 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 | Enrollment to 12-month corrected age | 
| 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. | 24-month corrected age | 
| 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 | 12-month corrected age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Retinopathy of Prematurity, Bevacizumab, ROP