Skip to main content
SpringerLink
Log in

Major Clinical Trials in ROP

  • Chapter
  • First Online:
Pediatric Vitreoretinal Surgery

  • 309 Accesses

Abstract

First described about 80 years ago, the management of retinopathy of prematurity (ROP) has changed tremendously since. This development was only possible due to the conduction of a number of clinical trials in the field of ROP. The following chapter will summarize the most important interventional clinical trials on ROP treatment. The chapter will describe the journey from cryocoagulation to laser coagulation and anti-VEGF treatment. In addition, it will describe trials aimed not on treatment but prevention of severe ROP by targeting exposure to oxygen, light or nutrition. And finally, the chapter will introduce some of the current non-interventional registry studies SWEDROP, Retina.net ROP registry and EU-ROP that aim to improve ROP care beyond clinical trials by collecting and analyzing real-world data.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AA:

Arachidonic Acid

BPD:

Bronchopulmonary Dysplasia

DHA:

Docosahexaenoic Acid

GA:

Gestational Age

IGF-1:

Insulin like Growth Factor 1

IGFBP:

IGF Binding Protein

IVH:

Intraventricular Hemorrhage

PAR:

Persistent Avascular Retina

PMA:

Postmenstrual Age

rhIGF-1:

Recombinant human Insulin-like Growth Factor 1

rhIGFBP-3:

Recombinant human Insulin-like Grow Factor 1 Binding Protein 3

ROP:

Retinopathy of Prematurity

VEGF:

Vascular Endothelial Growth Factor

References

  1. Hellström A, Hård A-L. Screening and novel therapies for retinopathy of prematurity–a review. Early Hum Dev. 2019;138: 104846.

    Article  PubMed  Google Scholar 

  2. Cryotherapy for Retinopathy of Prematurity Cooperative G. Multicenter trial of cryotherapy for retinopathy of prematurity. Snellen visual acuity and structural outcome at 5 1/2 years after randomization Arch Ophthalmol. 1996;114: 417–24.

    Google Scholar 

  3. Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Pediatrics. 1988; 81:697–706.

    Google Scholar 

  4. Multicenter trial of cryotherapy for retinopathy of prematurity. Three-month outcome. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Arch Ophthalmol. 1990; 108:195–204.

    Google Scholar 

  5. Palmer EA. Results of U.S. randomized clinical trial of cryotherapy for ROP (CRYO-ROP). Doc Ophthalmol Adv Ophthalmol. 1990;74:245–51.

    Article  CAS  Google Scholar 

  6. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity: ophthalmological outcomes at 10 years. Arch Ophthalmol Chic Ill. 2001;1960(119):1110–8.

    Google Scholar 

  7. Palmer EA, Hardy RJ, Dobson V, Phelps DL, Quinn GE, Summers CG, Krom CP, Tung B, Cryotherapy for Retinopathy of Prematurity Cooperative G. 15-year outcomes following threshold retinopathy of prematurity: final results from the multicenter trial of cryotherapy for retinopathy of prematurity Arch Ophthalmol. 2005; 123: 311–18.

    Google Scholar 

  8. Algawi K, Goggin M, O’Keefe M. Refractive outcome following diode laser versus cryotherapy for eyes with retinopathy of prematurity. Br J Ophthalmol. 1994;78:612–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Connolly BP, McNamara JA, Sharma S, Regillo CD, Tasman W. A comparison of laser photocoagulation with trans-scleral cryotherapy in the treatment of threshold retinopathy of prematurity. Ophthalmology. 1998;105:1628–31.

    Article  CAS  PubMed  Google Scholar 

  10. White JE, Repka MX. Randomized comparison of diode laser photocoagulation versus cryotherapy for threshold retinopathy of prematurity: 3-year outcome. J Pediatr Ophthalmol Strabismus. 1997;34:83–7; quiz 121–122.

    Google Scholar 

  11. Good WV, Early Treatment for Retinopathy of Prematurity Cooperative Group. Final results of the Early Treatment for Retinopathy of Prematurity (ETROP) randomized trial. Trans Am Ophthalmol Soc. 2004; 102:233–48; discussion 248–250.

    Google Scholar 

  12. Quinn GE, Dobson V, Davitt BV, Wallace DK, Hardy RJ, Tung B, Lai D, Good WV, Early Treatment for Retinopathy of Prematurity Cooperative Group. Progression of myopia and high myopia in the Early Treatment for Retinopathy of Prematurity study: findings at 4 to 6 years of age J AAPOS Off Publ Am Assoc Pediatr Ophthalmol Strabismus. 2013; 17:124–8.

    Google Scholar 

  13. Fierson WM. American Academy of Pediatrics Section on Ophthalmology, American Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus, American Association of Certified Orthoptists. Screening examination of premature infants for retinopathy of prematurity. Pediatrics. 2018; 142:e20183061.

    Google Scholar 

  14. Gotz-Więckowska A, Bakunowicz-Łazarczyk A, Hautz W, Filipek E, Niwald AM. Polish Ophthalmological Society revised guidelines for the management of retinopathy of prematurity. Klin Oczna. 2020;2020:14–6.

    Article  Google Scholar 

  15. Maier RF, Hummler H, Kellner U, Krohne TU, Lawrenz B, Lorenz B, Mitschdörfer B, Roll C, Stahl A. Augenärztliche Screening-Untersuchung bei Frühgeborenen (S2k-Level, AWMF-Leitlinien-Register-Nr. 024/010, März 2020): Gemeinsame Empfehlung von Deutsche Ophthalmologische Gesellschaft (DOG), Retinologische Gesellschaft (RG), Berufsverband der Augenärzte Deutschlands (BVA), Deutsche Gesellschaft für Kinder-und Jugendmedizin (DGKJ), Berufsverband der Kinder-und Jugendärzte e. V. (BVKJ), Bundesverband „Das frühgeborene Kind“ e. V., Gesellschaft für Neonatologie und Pädiatrische Intensivmedizin (GNPI). Ophthalmol. 2021. https://doi.org/10.1007/s00347-021-01353-0.

  16. Sydney Local Health District. SLHD: Royal Prince Alfred Hospital Guideline: Women and Babies: Retinopathy of Prematurity 2018.

    Google Scholar 

  17. Mintz-Hittner HA, Kennedy KA, Chuang AZ, Group B-RC. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity N Engl J Med. 2011; 364:603–15.

    Google Scholar 

  18. Geloneck MM, Chuang AZ, Clark WL, Hunt MG, Norman AA, Packwood EA, Tawansy KA, Mintz-Hittner HA, Group B-RC 2014 Refractive outcomes following bevacizumab monotherapy compared with conventional laser treatment: a randomized clinical trial. JAMA Ophthalmol. 2014; 132:1327–33.

    Google Scholar 

  19. Kennedy KA, Mintz-Hittner HA, BEAT-ROP Cooperative Group. Medical and developmental outcomes of bevacizumab versus laser for retinopathy of prematurity J AAPOS Off Publ Am Assoc Pediatr Ophthalmol Strabismus. 2018; 22:61–65.e1.

    Google Scholar 

  20. Walz JM, Bemme S, Pielen A, et al. The German ROP registry: data from 90 infants treated for retinopathy of prematurity. Acta Ophthalmol. 2016. https://doi.org/10.1111/aos.13069.

    Article  PubMed  Google Scholar 

  21. Hu J, Blair MP, Shapiro MJ, Lichtenstein SJ, Galasso JM, Kapur R. Reactivation of retinopathy of prematurity after bevacizumab injection Arch Ophthalmol Chic Ill 1960. 2012; 130:1000–6.

    Google Scholar 

  22. Mintz-Hittner HA, Geloneck MM, Chuang AZ. Clinical management of recurrent retinopathy of prematurity after intravitreal bevacizumab monotherapy. Ophthalmology. 2016;123:1845–55.

    Article  PubMed  Google Scholar 

  23. Stahl A, Bründer M, Lagrèze WA, et al. Ranibizumab in retinopathy of prematurity–one‐year follow‐up of ophthalmic outcomes and two‐year follow‐up of neurodevelopmental outcomes from the CARE‐ROP study. Acta Ophthalmol (Copenh). 2021; aos.14852.

    Google Scholar 

  24. Kong L, Bhatt AR, Demny AB, Coats DK, Li A, Rahman EZ, Smith OE, Steinkuller PG. Pharmacokinetics of bevacizumab and its effects on serum VEGF and IGF-1 in infants with retinopathy of prematurity. Invest Ophthalmol Vis Sci. 2015;56:956–61.

    Article  CAS  PubMed  Google Scholar 

  25. Sato T, Wada K, Arahori H, Kuno N, Imoto K, Iwahashi-Shima C, Kusaka S. Serum concentrations of bevacizumab (avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity. Am J Ophthalmol. 2012;153(327–333): e1.

    Google Scholar 

  26. Wu WC, Lien R, Liao PJ, Wang NK, Chen YP, Chao AN, Chen KJ, Chen TL, Hwang YS, Lai CC. Serum levels of vascular endothelial growth factor and related factors after intravitreous bevacizumab injection for retinopathy of prematurity. JAMA Ophthalmol. 2015;133:391–7.

    Article  PubMed  Google Scholar 

  27. Wallace DK, Kraker RT, Freedman SF, et al. Assessment of lower doses of intravitreous bevacizumab for retinopathy of prematurity: a phase 1 dosing study. JAMA Ophthalmol. 2017. https://doi.org/10.1001/jamaophthalmol.2017.1055.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Wallace DK, Dean TW, Hartnett ME, et al. A dosing study of bevacizumab for retinopathy of prematurity: late recurrences and additional treatments. Ophthalmology. 2018;125:1961–6.

    Article  PubMed  Google Scholar 

  29. Krohne TU, Holz FG, Meyer CH. Pharmacokinetics of intravitreally administered VEGF inhibitors. Ophthalmologe. 2014;111:113–20.

    Article  CAS  PubMed  Google Scholar 

  30. Stahl A, Krohne TU, Eter N, et al. Comparing alternative ranibizumab dosages for safety and efficacy in retinopathy of prematurity: A randomized clinical trial. JAMA Pediatr. 2018. https://doi.org/10.1001/jamapediatrics.2017.4838.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Stahl A, Lepore D, Fielder A, et al. Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial. The Lancet. 2019;394:1551–9.

    Article  CAS  Google Scholar 

  32. Fidler M, Fleck BW, Stahl A, et al. Ranibizumab population pharmacokinetics and free VEGF pharmacodynamics in preterm infants with retinopathy of prematurity in the RAINBOW trial. Transl Vis Sci Technol. 2020;9:43.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Marlow N, Stahl A, Lepore D, Fielder A, Reynolds JD, Zhu Q, Weisberger A, Stiehl DP, Fleck B. 2-year outcomes of ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW extension study): prospective follow-up of an open label, randomised controlled trial. Lancet Child Adolesc Health. 2021;5:698–707.

    Article  CAS  PubMed  Google Scholar 

  34. EMA.Europa.eu. 2020. Lucentis 10 mg/ml solution for injection SmPC.

    Google Scholar 

  35. Stahl A, Sukgen E, Wu W-C, Lepore D, Azuma N, Nakanishi H, Mazela J. Efficacy and safety of intravitreal aflibercept compared with laser photocoagulation for patients with retinopathy of prematurity: The FIREFLEYE study. 2021.

    Google Scholar 

  36. Avery RL, Castellarin AA, Steinle NC, et al. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD. Br J Ophthalmol. 2014;98:1636–41.

    Article  PubMed  Google Scholar 

  37. Kinsey VE. Retrolental fibroplasia; cooperative study of retrolental fibroplasia and the use of oxygen. AMA Arch Ophthalmol. 1956;56:481–543.

    Article  CAS  PubMed  Google Scholar 

  38. Avery ME, Oppenheimer EH. Recent increase in mortality from byaline membrane disease. J Pediatr. 1960;57:553–9.

    Article  CAS  PubMed  Google Scholar 

  39. The STOP-ROP Multicenter Study Group. Supplemental Therapeutic Oxygen for Prethreshold Retinopathy Of Prematurity (STOP-ROP), a randomized, controlled trial. I: primary outcomes. Pediatrics. 2000;105:295–310.

    Article  Google Scholar 

  40. Askie LM, Henderson-Smart DJ, Irwig L, Simpson JM. Oxygen-saturation targets and outcomes in extremely preterm infants. N Engl J Med. 2003;349:959–67.

    Article  CAS  PubMed  Google Scholar 

  41. Stenson B, Brocklehurst P, Tarnow-Mordi W. Increased 36-week survival with high oxygen saturation target in extremely preterm infants. N Engl J Med. 2011;364:1680–2.

    Article  CAS  PubMed  Google Scholar 

  42. Askie LM, Darlow BA, Finer N, et al. Association between oxygen saturation targeting and death or disability in extremely preterm infants in the neonatal oxygenation prospective meta-analysis collaboration. JAMA. 2018;319:2190–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Reynolds JD, Hardy RJ, Kennedy KA, Spencer R, van Heuven WAJ, Fielder AR. Lack of efficacy of light reduction in preventing retinopathy of prematurity. N Engl J Med. 1998;338:1572–6.

    Article  CAS  PubMed  Google Scholar 

  44. Hellström A, Nilsson AK, Wackernagel D, et al. Effect of enteral lipid supplement on severe retinopathy of prematurity: a randomized clinical trial. JAMA Pediatr. 2021. https://doi.org/10.1001/jamapediatrics.2020.5653.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Hellström A, Engström E, Hård A-L, et al. Postnatal serum insulin-like growth factor I deficiency is associated with retinopathy of prematurity and other complications of premature birth. Pediatrics. 2003;112:1016–20.

    Article  PubMed  Google Scholar 

  46. Löfqvist C, Engström E, Sigurdsson J, Hård A-L, Niklasson A, Ewald U, Holmström G, Smith LEH, Hellström A. Postnatal head growth deficit among premature infants parallels retinopathy of prematurity and insulin-like growth factor-1 deficit. Pediatrics. 2006;117:1930–8.

    Article  PubMed  Google Scholar 

  47. Ley D, Hallberg B, Hansen-Pupp I, et al. rhIGF-1/rhIGFBP-3 in preterm infants: a phase 2 randomized controlled trial. J Pediatr. 2019;206:56-65.e8.

    Article  CAS  PubMed  Google Scholar 

  48. Holmström GE, Hellström A, Jakobsson PG, Lundgren P, Tornqvist K, Wallin A. Swedish National Register for Retinopathy of Prematurity (SWEDROP) and the evaluation of screening in Sweden. Arch Ophthalmol. 2012;130:1418.

    Article  PubMed  Google Scholar 

  49. Holmström G, Hellström A, Gränse L, Saric M, Sunnqvist B, Wallin A, Tornqvist K, Larsson E. New modifications of Swedish ROP guidelines based on 10-year data from the SWEDROP register. Br J Ophthalmol. 2020;104:943–9.

    Article  PubMed  Google Scholar 

  50. Stahl A, Krohne T, Limburg E. Register zur Erfassung behandlungsbedürftiger Frühgeborenenretinopathie. Z Prakt Augenheilkd. 2012;500–4.

    Google Scholar 

  51. Walz JM, Bemme S, Reichl S, et al. Behandelte Frühgeborenenretinopathie in Deutschland: 5-Jahres-Daten des Retina.net ROP-Registers. Ophthalmol Z Dtsch Ophthalmol Ges. 2018;115:476–88.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Ophthalmology, University Medicine Greifswald, Greifswald, Germany

    Johanna Madeleine Pfeil, Milena Grundel, Sonja Katharina Eilts, Marie-Christine Bruender & Andreas Stahl

Authors
  1. Johanna Madeleine Pfeil
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Milena Grundel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sonja Katharina Eilts
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marie-Christine Bruender
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andreas Stahl
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andreas Stahl .

Editor information

Editors and Affiliations

  1. Department of Ophthalmology, Gazi University School of Medicine, Ankara, Türkiye

    Şengül Özdek

  2. Bascom Palmer Eye Institute, Miami University, Florida, FL, USA

    Audina Berrocal

  3. Department of Ophthalmology, University of Uppsala, Uppsala, Sweden

    Ulrich Spandau

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Pfeil, J.M., Grundel, M., Eilts, S.K., Bruender, MC., Stahl, A. (2023). Major Clinical Trials in ROP. In: Özdek, Ş., Berrocal, A., Spandau, U. (eds) Pediatric Vitreoretinal Surgery. Springer, Cham. https://doi.org/10.1007/978-3-031-14506-3_15

Download citation

  • DOI: https://doi.org/10.1007/978-3-031-14506-3_15

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-031-14505-6

  • Online ISBN: 978-3-031-14506-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation