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Open Access 01-12-2022 | Tropicamide | Study protocol

Efficacy and safety of Mydriatic Microdrops for Retinopathy Of Prematurity Screening (MyMiROPS): study protocol for a non-inferiority crossover randomized controlled trial

Authors: Aikaterini K. Seliniotaki, Anna-Bettina Haidich, Maria Lithoxopoulou, Helen Gika, Eleftheria Boutou, Christina Virgiliou, Martha Nikolaidou, Aristides Dokoumetzidis, Nikolaos Raikos, Elisavet Diamanti, Nikolaos Ziakas, Asimina Mataftsi

Published in: Trials | Issue 1/2022

Abstract

Background

Retinopathy of prematurity (ROP) eye examination screening presupposes adequate mydriasis for an informative fundoscopy of preterm infants at risk, on a weekly basis. Systemic absorption of the instilled mydriatic regimens has been associated with various adverse events in this fragile population. This report aims to present the fully developed protocol of a full-scale trial for testing the hypothesis that the reduced mydriatic drop volume achieves adequate mydriasis while minimizing systemic adverse events.

Methods

A non-inferiority crossover randomized controlled trial will be performed to study the efficacy and safety of combined phenylephrine 1.67% and tropicamide 0.33% microdrops compared with standard drops in a total of 93 preterm infants requiring ROP screening. Primary outcome will be the pupil diameter at 45 (T45) min after instillation. Pupil diameter at T90 and T120 will constitute secondary efficacy endpoints. Mixed-effects linear regression models will be developed, and the 95% confidence interval approach will be used for assessing non-inferiority. Whole blood samples will be analyzed using hydrophilic liquid chromatography–tandem mass spectrometry method (HILIC–MS/MS), for gathering pharmacokinetic (PK) data on the instilled phenylephrine, at nine specific time points within 3 h from mydriasis. Pooled PK data will be used due to ethical restrictions on having a full PK profile per infant. Heart rate, oxygen saturation, blood pressure measurements, and 48-h adverse events will also be recorded.

Discussion

This protocol is designed for a study powered to assess non-inferiority of microdrops compared with standard dilating drops. If our hypothesis is confirmed, microdrops may become a useful tool in ROP screening.

Trial registration

ClinicalTrials.govNCT05043077. Registered on 2 September 2021

Available only for authorised users

Hellström A, Smith LEH, Dammann O. Retinopathy of prematurity. Lancet. 2013;382(9902):1445–57. https://doi.org/10.1016/S0140-6736(13)60178-6.CrossRefPubMedPubMedCentral

Fierson WM. Screening examination of premature infants for retinopathy of prematurity. Pediatrics. 2013;131(1):189–95. https://doi.org/10.1542/peds.2012-2996.CrossRefPubMed

Mitchell AJ, Green A, Jeffs DA, Paula K, Roberson P. Physiologic effects of retinopathy of prematurity screening examinations. Adv Neonatal Care. 2011;11(4):291–7. https://doi.org/10.1097/ANC.0b013e318225a332.CrossRefPubMedPubMedCentral

Lux AL, Degoumois A, Barjol A, Mouriaux F, Denion E. Combination of 5% phenylephrine and 0.5% tropicamide eyedrops for pupil dilation in neonates is twice as effective as 0.5% tropicamide eyedrops alone. Acta Ophthalmol. 2017;95(2):165–9. https://doi.org/10.1111/aos.13175.CrossRefPubMed

Kremer LJ, Reith DM, Medlicott N, Broadbent R. Systematic review of mydriatics used for screening of retinopathy in premature infants. BMJ Paediatr Open. 2019;3(1):e000448. https://doi.org/10.1136/bmjpo-2019-000448.CrossRefPubMedPubMedCentral

Seliniotaki AK, Prousali E, Lithoxopoulou M, Kokkali S, Ziakas N, Soubasi V, et al. Alternative mydriasis techniques for retinopathy of prematurity screening. Int Ophthalmol. 2020;40(12):3613–9. https://doi.org/10.1007/s10792-020-01542-x.CrossRefPubMed

Alcorn J, McNamara PJ. Pharmacokinetics in the newborn. Adv Drug Deliv Rev. 2003;55(5):667–86. https://doi.org/10.1016/S0169-409X(03)00030-9.CrossRefPubMed

Lynch MG, Brown RH, Goode SM, Schoenwald RD, Chien S. Reduction of phenylephrine drop size in infants achieves equal dilation with decreased systemic absorption. Arch Ophthalmol. 1987;105(10):1364–5. https://doi.org/10.1001/archopht.1987.01060100066027.CrossRefPubMed

Wheatcroft S, Sharma A, McAllister J. Reduction in mydriatic drop size in premature infants. Br J Ophthalmol. 1993;77(6):364–5. https://doi.org/10.1136/bjo.77.6.364.CrossRefPubMedPubMedCentral

10.

Elibol O, Alçelik T, Yüksel N, Çaǧlar Y. The influence of drop size of cyclopentolate, phenylephrine and tropicamide on pupil dilatation and systemic side effects in infants. Acta Ophthalmol Scand. 1997;75(2):178–80. https://doi.org/10.1111/j.1600-0420.1997.tb00119.x.CrossRefPubMed

11.

Kremer LJ, Broadbent R, Medlicott N, Sime MJ, McCaffrey F, Reith DM. Randomised controlled pilot trial comparing low dose and very low- dose microdrop administration of phenylephrine and cyclopentolate for retinopathy of prematurity eye examinations in neonates. Arch Dis Child. 2021;106(6):603–8. https://doi.org/10.1136/archdischild-2019-318733.CrossRefPubMed

12.

Seliniotaki AK, Lithoxopoulou M, Talimtzi P, Georgiou E, Diamanti E, Ziakas N, et al. Efficacy and safety of mydriatic microdrops for retinopathy of prematurity screening: an external pilot crossover randomized controlled trial. J Perinatol. 2022;42(3):371–7. https://doi.org/10.1038/s41372-021-01229-w.CrossRefPubMed

13.

Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Chin J Evid Based Med. 2013;13(3):1501–7. https://doi.org/10.7326/0003-4819-158-3-201302050-00583.CrossRef

14.

Pocock SJ. Clinical trials: a practical approach: Wiley; 2013. https://doi.org/10.1002/9781118793916.

15.

Walker J. Non-inferiority statistics and equivalence studies. BJA Educ. 2019;19(8):267–71. https://doi.org/10.1016/j.bjae.2019.03.004.CrossRefPubMedPubMedCentral

16.

Mataftsi A, Moutzouri S, Karagianni P, Ziakas N, Soubasi V, Brazitikos P, et al. Retinopathy of prematurity occurrence and evaluation of screening policy in a large tertiary Greek cohort. Int Ophthalmol. 2020;40(2):385–91. https://doi.org/10.1007/s10792-019-01195-5.CrossRefPubMed

17.

Mellander M. Diagnosis and management of life-threatening cardiac malformations in the newborn. Semin Fetal Neonatal Med. 2013;18(5):302–10. https://doi.org/10.1016/j.siny.2013.04.007.CrossRefPubMed

18.

Flynn JT. Neonatal hypertension: diagnosis and management. Pediatr Nephrol. 2000;14(4):332–41. https://doi.org/10.1007/s004670050771.CrossRefPubMed

19.

Eichenwald EC. Apnea of prematurity. Pediatrics. 2016;137(1). https://doi.org/10.1542/peds.2015-3757.

20.

Li YF, Lin HC, Torrazza RM, Parker L, Talaga E, Neu J. Gastric residual evaluation in preterm neonates: a useful monitoring technique or a hindrance? Pediatr Neonatol. 2014;55(5):335–40. https://doi.org/10.1016/j.pedneo.2014.02.008.CrossRefPubMed

21.

Abiramalatha T, Thanigainathan S, Ninan B. Routine monitoring of gastric residual for prevention of necrotising enterocolitis in preterm infants. Cochrane Database Syst Rev. 2019;2019:CD012937. https://doi.org/10.1002/14651858.CD012937.pub2.CrossRefPubMedCentral

22.

Bonthala S, Sparks JW, Musgrove KH, Berseth CL. Mydriatics slow gastric emptying in preterm infants. J Pediatr. 2000;137(3):327–30. https://doi.org/10.1067/mpd.2000.107842.CrossRefPubMed

23.

F Fanaro S. Feeding intolerance in the preterm infant. Early Hum Dev. 2013;89(Suppl 2):S13–20.CrossRef

24.

Lucchini R, Bizzarri B, Giampietro S, De Curtis M. Feeding intolerance in preterm infants. How to understand the warning signs. J Matern Neonatal Med. 2011;24(Suppl 1):72–4.CrossRef

25.

Sarıcı SÜ, Yurdakök M, Ünal Ş. Acute gastric dilatation complicating the use of mydriatics in a preterm newborn. Pediatr Radiol. 2001;31(8):581–3. https://doi.org/10.1007/s002470100498.CrossRefPubMed

26.

Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg. 1978;187(1):1–7. https://doi.org/10.1097/00000658-197801000-00001.CrossRefPubMedPubMedCentral

27.

FDA Approved drug products: phenylephrine intravenous injection (ready to use). https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212909s000lbl.pdf. Accessed 20 Feb 2022.

28.

Dionne JM, Abitbol CL, Flynn JT. Hypertension in infancy: diagnosis, management and outcome. Pediatr Nephrol. 2012;27(1):17–32. https://doi.org/10.1007/s00467-010-1755-z.CrossRefPubMed

29.

Piaggio G, Elbourne DR, Pocock SJ, Evans SJW, Altman DG. Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA. 2012;308(24):2594–604. https://doi.org/10.1001/jama.2012.87802.CrossRefPubMed

30.

D’Agostino RB, Massaro JM, Sullivan LM. Non-inferiority trials: design concepts and issues - the encounters of academic consultants in statistics. Stat Med. 2003;22(2):169–86. https://doi.org/10.1002/sim.1425.CrossRefPubMed

31.

Horton NJ, Kleinman KP. Much ado about nothing: a comparison of missing data methods and software to fit incomplete data regression models. Am Stat. 2007;61(1):79–90. https://doi.org/10.1198/000313007X172556.CrossRefPubMedPubMedCentral

Title: Efficacy and safety of Mydriatic Microdrops for Retinopathy Of Prematurity Screening (MyMiROPS): study protocol for a non-inferiority crossover randomized controlled trial
Authors: Aikaterini K. Seliniotaki
Anna-Bettina Haidich
Maria Lithoxopoulou
Helen Gika
Eleftheria Boutou
Christina Virgiliou
Martha Nikolaidou
Aristides Dokoumetzidis
Nikolaos Raikos
Elisavet Diamanti
Nikolaos Ziakas
Asimina Mataftsi
Publication date: 01-12-2022
Publisher: BioMed Central
Keyword: Tropicamide
Published in: Trials / Issue 1/2022
Electronic ISSN: 1745-6215
DOI: https://doi.org/10.1186/s13063-022-06243-7

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2024 ASCO Annual Meeting

Springer Medicine

Efficacy and safety of Mydriatic Microdrops for Retinopathy Of Prematurity Screening (MyMiROPS): study protocol for a non-inferiority crossover randomized controlled trial

Abstract

Background

Methods

Discussion

Trial registration

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Background

Methods

Discussion

Trial registration

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