Assessment of lower doses of intravitreous bevacizumab for retinopathy of prematurity a phase 1 dosing study

David K. Wallace, Raymond T. Kraker, Sharon F. Freedman, Eric R. Crouch, Amy K. Hutchinson, Amit R. Bhatt, David L. Rogers, Michael B. Yang, Kathryn M. Haider, Deborah K. Van Der Veen, R. Michael Siatkowski, Trevano W. Dean, Roy W. Beck, Michael X. Repka, Lois E. Smith, William V. Good, Mary Elizabeth Hartnett, Lingkun Kong, Jonathan M Holmes

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Abstract

IMPORTANCE: Intravitreous bevacizumab (0.25 to 0.625 mg) is increasingly used to treat type 1 retinopathy of prematurity (ROP), but there remain concerns about systemic toxicity. A much lower dose may be effective while reducing systemic risk. OBJECTIVE: To find a dose of intravitreous bevacizumab that was lower than previously used for severe ROP, was effective in this study, and could be tested in future larger studies. DESIGN, SETTING, AND PARTICIPANTS: Between May 2015 and September 2016, 61 premature infants with type 1 ROP in 1 or both eyes were enrolled in a masked, multicenter, phase 1 dose de-escalation study. One eye of 10 to 14 infants received 0.25 mg of intravitreous bevacizumab. If successful, the dose was reduced for the next group of infants (to 0.125 mg, then 0.063 mg, and finally 0.031 mg). Diluted bevacizumab was delivered using 300 μL syringes with 5/16-inch, 30-gauge fixed needles. INTERVENTIONS: Bevacizumab injections at 0.25 mg, 0.125 mg, 0.063 mg, and 0.031 mg. MAIN OUTCOMES AND MEASURES: Success was defined as improvement in preinjection plus disease or zone I stage 3 ROP by 5 days after injection or sooner, and no recurrence of type 1 ROP or severe neovascularization requiring additional treatment within 4 weeks. RESULTS: Fifty-eight of 61 enrolled infants had 4-week outcomes completed; mean birth weight was 709 g and mean gestational age was 24.9 weeks. Success was achievedin 11 of 11 eyes at 0.25 mg, 14 of 14 eyes at 0.125 mg, 21 of 24 eyes at 0.063 mg, and 9 of 9 eyes at 0.031 mg. CONCLUSIONS AND RELEVANCE: A dose of bevacizumab aslow as 0.031 mgwas effectivein 9 of 9 eyes in this phase 1 study and warrants further investigation. Identifying a lower effective dose of bevacizumab may reduce the risk for neurodevelopmental disability or detrimental effects on other organs.

Original languageEnglish (US)
Pages (from-to)654-656
Number of pages3
JournalJAMA Ophthalmology
Volume135
Issue number6
DOIs
StatePublished - Jun 1 2017

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Retinopathy of Prematurity
Injections
Syringes
Bevacizumab
Birth Weight
Premature Infants
Gestational Age
Needles
Recurrence

ASJC Scopus subject areas

  • Ophthalmology

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Assessment of lower doses of intravitreous bevacizumab for retinopathy of prematurity a phase 1 dosing study. / Wallace, David K.; Kraker, Raymond T.; Freedman, Sharon F.; Crouch, Eric R.; Hutchinson, Amy K.; Bhatt, Amit R.; Rogers, David L.; Yang, Michael B.; Haider, Kathryn M.; Van Der Veen, Deborah K.; Siatkowski, R. Michael; Dean, Trevano W.; Beck, Roy W.; Repka, Michael X.; Smith, Lois E.; Good, William V.; Hartnett, Mary Elizabeth; Kong, Lingkun; Holmes, Jonathan M.

In: JAMA Ophthalmology, Vol. 135, No. 6, 01.06.2017, p. 654-656.

Research output: Contribution to journalArticle

Wallace, DK, Kraker, RT, Freedman, SF, Crouch, ER, Hutchinson, AK, Bhatt, AR, Rogers, DL, Yang, MB, Haider, KM, Van Der Veen, DK, Siatkowski, RM, Dean, TW, Beck, RW, Repka, MX, Smith, LE, Good, WV, Hartnett, ME, Kong, L & Holmes, JM 2017, 'Assessment of lower doses of intravitreous bevacizumab for retinopathy of prematurity a phase 1 dosing study', JAMA Ophthalmology, vol. 135, no. 6, pp. 654-656. https://doi.org/10.1001/jamaophthalmol.2017.1055
Wallace, David K. ; Kraker, Raymond T. ; Freedman, Sharon F. ; Crouch, Eric R. ; Hutchinson, Amy K. ; Bhatt, Amit R. ; Rogers, David L. ; Yang, Michael B. ; Haider, Kathryn M. ; Van Der Veen, Deborah K. ; Siatkowski, R. Michael ; Dean, Trevano W. ; Beck, Roy W. ; Repka, Michael X. ; Smith, Lois E. ; Good, William V. ; Hartnett, Mary Elizabeth ; Kong, Lingkun ; Holmes, Jonathan M. / Assessment of lower doses of intravitreous bevacizumab for retinopathy of prematurity a phase 1 dosing study. In: JAMA Ophthalmology. 2017 ; Vol. 135, No. 6. pp. 654-656.
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abstract = "IMPORTANCE: Intravitreous bevacizumab (0.25 to 0.625 mg) is increasingly used to treat type 1 retinopathy of prematurity (ROP), but there remain concerns about systemic toxicity. A much lower dose may be effective while reducing systemic risk. OBJECTIVE: To find a dose of intravitreous bevacizumab that was lower than previously used for severe ROP, was effective in this study, and could be tested in future larger studies. DESIGN, SETTING, AND PARTICIPANTS: Between May 2015 and September 2016, 61 premature infants with type 1 ROP in 1 or both eyes were enrolled in a masked, multicenter, phase 1 dose de-escalation study. One eye of 10 to 14 infants received 0.25 mg of intravitreous bevacizumab. If successful, the dose was reduced for the next group of infants (to 0.125 mg, then 0.063 mg, and finally 0.031 mg). Diluted bevacizumab was delivered using 300 μL syringes with 5/16-inch, 30-gauge fixed needles. INTERVENTIONS: Bevacizumab injections at 0.25 mg, 0.125 mg, 0.063 mg, and 0.031 mg. MAIN OUTCOMES AND MEASURES: Success was defined as improvement in preinjection plus disease or zone I stage 3 ROP by 5 days after injection or sooner, and no recurrence of type 1 ROP or severe neovascularization requiring additional treatment within 4 weeks. RESULTS: Fifty-eight of 61 enrolled infants had 4-week outcomes completed; mean birth weight was 709 g and mean gestational age was 24.9 weeks. Success was achievedin 11 of 11 eyes at 0.25 mg, 14 of 14 eyes at 0.125 mg, 21 of 24 eyes at 0.063 mg, and 9 of 9 eyes at 0.031 mg. CONCLUSIONS AND RELEVANCE: A dose of bevacizumab aslow as 0.031 mgwas effectivein 9 of 9 eyes in this phase 1 study and warrants further investigation. Identifying a lower effective dose of bevacizumab may reduce the risk for neurodevelopmental disability or detrimental effects on other organs.",
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AU - Wallace, David K.

AU - Kraker, Raymond T.

AU - Freedman, Sharon F.

AU - Crouch, Eric R.

AU - Hutchinson, Amy K.

AU - Bhatt, Amit R.

AU - Rogers, David L.

AU - Yang, Michael B.

AU - Haider, Kathryn M.

AU - Van Der Veen, Deborah K.

AU - Siatkowski, R. Michael

AU - Dean, Trevano W.

AU - Beck, Roy W.

AU - Repka, Michael X.

AU - Smith, Lois E.

AU - Good, William V.

AU - Hartnett, Mary Elizabeth

AU - Kong, Lingkun

AU - Holmes, Jonathan M

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N2 - IMPORTANCE: Intravitreous bevacizumab (0.25 to 0.625 mg) is increasingly used to treat type 1 retinopathy of prematurity (ROP), but there remain concerns about systemic toxicity. A much lower dose may be effective while reducing systemic risk. OBJECTIVE: To find a dose of intravitreous bevacizumab that was lower than previously used for severe ROP, was effective in this study, and could be tested in future larger studies. DESIGN, SETTING, AND PARTICIPANTS: Between May 2015 and September 2016, 61 premature infants with type 1 ROP in 1 or both eyes were enrolled in a masked, multicenter, phase 1 dose de-escalation study. One eye of 10 to 14 infants received 0.25 mg of intravitreous bevacizumab. If successful, the dose was reduced for the next group of infants (to 0.125 mg, then 0.063 mg, and finally 0.031 mg). Diluted bevacizumab was delivered using 300 μL syringes with 5/16-inch, 30-gauge fixed needles. INTERVENTIONS: Bevacizumab injections at 0.25 mg, 0.125 mg, 0.063 mg, and 0.031 mg. MAIN OUTCOMES AND MEASURES: Success was defined as improvement in preinjection plus disease or zone I stage 3 ROP by 5 days after injection or sooner, and no recurrence of type 1 ROP or severe neovascularization requiring additional treatment within 4 weeks. RESULTS: Fifty-eight of 61 enrolled infants had 4-week outcomes completed; mean birth weight was 709 g and mean gestational age was 24.9 weeks. Success was achievedin 11 of 11 eyes at 0.25 mg, 14 of 14 eyes at 0.125 mg, 21 of 24 eyes at 0.063 mg, and 9 of 9 eyes at 0.031 mg. CONCLUSIONS AND RELEVANCE: A dose of bevacizumab aslow as 0.031 mgwas effectivein 9 of 9 eyes in this phase 1 study and warrants further investigation. Identifying a lower effective dose of bevacizumab may reduce the risk for neurodevelopmental disability or detrimental effects on other organs.

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