`
`Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macul…
`
`Submit
`
`Log in
`
`Register
`
`Subscribe
`
`Access Subscription
`
`
`Reprints
`
`
`Request
`
`
`Share
`
` S
`
`ave
`
`
`Subscribe
`
`
`Purchase
`
`
`
`PlumX Metrics
`
`ORIGINAL ARTICLE
`
`Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred
`Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular
`Edema
`•
`The Diabetic Retinopathy Clinical Research Network •
`Michael J. Elman, MD Lloyd Paul Aiello, MD, PhD
`•
`•
`•
`Ingrid U. Scott, MD, MPH Cynthia R. Stockdale, MSPH Jennifer K. Sun, MD, MPH
`...
`
`•
`•
`
`
`
`Published: April 28, 2010 • DOI: https://doi.org/10.1016/j.ophtha.2010.02.031
`
`References
`
`Article info
`
`Related Articles
`
`Objective
`Evaluate intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with
`focal/grid laser alone for treatment of diabetic macular edema (DME).
`
`Design
`Multicenter, randomized clinical trial.
`
`Participants
`A total of 854 study eyes of 691 participants with visual acuity (approximate Snellen equivalent) of 20/32 to
`20/320 and DME involving the fovea.
`
`Methods
`Eyes were randomized to sham injection + prompt laser (n=293), 0.5 mg ranibizumab + prompt laser
`(n=187), 0.5 mg ranibizumab + deferred (≥24 weeks) laser (n=188), or 4 mg triamcinolone + prompt laser
`(n=186). Retreatment followed an algorithm facilitated by a web-based, real-time data-entry system.
`
`Main Outcome Measures
`Best-corrected visual acuity and safety at 1 year.
`
`Results
`The 1-year mean change (±standard deviation) in the visual acuity letter score from baseline was significantly
`greater in the ranibizumab + prompt laser group (+9±11, P<0.001) and ranibizumab + deferred laser group
`(+9±12, P<0.001) but not in the triamcinolone + prompt laser group (+4±13, P=0.31) compared with the sham
`+ prompt laser group (+3±13). Reduction in mean central subfield thickness in the triamcinolone + prompt
`laser group was similar to both ranibizumab groups and greater than in the sham + prompt laser group. In the
`subset of pseudophakic eyes at baseline (n=273), visual acuity improvement in the triamcinolone + prompt
`laser group appeared comparable to that in the ranibizumab groups. No systemic events attributable to study
`treatment were apparent. Three eyes (0.8%) had injection-related endophthalmitis in the ranibizumab groups,
`whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone +
`prompt laser group. Two-year visual acuity outcomes were similar to 1-year outcomes.
`
`Conclusions
`Intravitreal ranibizumab with prompt or deferred laser is more effective through at least 1 year compared with
`prompt laser alone for the treatment of DME involving the central macula. Ranibizumab as applied in this
`study, although uncommonly associated with endophthalmitis, should be considered for patients with DME
`and characteristics similar to those in this clinical trial. In pseudophakic eyes, intravitreal triamcinolone +
`prompt laser seems more effective than laser alone but frequently increases the risk of intraocular pressure
`elevation.
`
`Financial Disclosure(s)
`Proprietary or commercial disclosure may be found after the references.
`
`To read this article in full you will need to make a payment
`Purchase one-time access:
`
`Academic & Personal: 24 hour online access
`
`Corporate R&D Professionals: 24 hour online access
`
`https://www.aaojournal.org/article/S0161-6420(10)00243-5/fulltext
`
`One-time access price info
`
`1/6
`
`|
`
` VOLUME 117, ISSUE 6
`
`,
`
`P1064-1077.E35,
`
`JUNE 2010
`
`⁎
`
`Show all authors
`
`Show footnotes
`
`Celltrion Exhibit 1019
`Page 1
`
`
`
`3/13/23, 8:40 PM
`
`Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macul…
`
`Subscribe:
`
`Subscribe to Ophthalmology
`
`Already a print subscriber? Claim online access
`
`Already an online subscriber? Sign in
`
`Register: Create an account
`
`Institutional Access: Sign in to ScienceDirect
`
`References
`Klein R. • Klein B.E. • Moss S.E. • et al.
`The Wisconsin Epidemiologic Study of Diabetic Retinopathy.
`Ophthalmology. 1984; 91: 1464-1474
`
`1.
`
`View in Article
`Scopus (670) • PubMed • Abstract • Full Text PDF • Google Scholar
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`Moss S.E. • Klein R. • Klein B.E.
`The 14-year incidence of visual loss in a diabetic population.
`Ophthalmology. 1998; 105: 998-1003
`
`View in Article
`Scopus (397) • PubMed • Abstract • Full Text • Full Text PDF • Google Scholar
`
`Moss S.E. • Klein R. • Klein B.E.
`Ten-year incidence of visual loss in a diabetic population.
`Ophthalmology. 1994; 101: 1061-1070
`
`View in Article
`Scopus (201) • PubMed • Abstract • Full Text PDF • Google Scholar
`
`Early Treatment Diabetic Retinopathy Study Research Group
`Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report
`number 1.
`Arch Ophthalmol. 1985; 103: 1796-1806
`
`View in Article
`Scopus (2515) • PubMed • Crossref • Google Scholar
`
`Diabetic Retinopathy Clinical Research Network
`A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid
`photocoagulation for diabetic macular edema.
`Ophthalmology. 2008; 115: 1447-1459
`
`View in Article
`Scopus (529) • PubMed • Abstract • Full Text • Full Text PDF • Google Scholar
`
`Aiello L.P. • Avery R.L. • Arrigg P.G. • et al.
`Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other
`retinal disorders.
`N Engl J Med. 1994; 331: 1480-1487
`
`View in Article
`Scopus (3391) • PubMed • Crossref • Google Scholar
`
`Antonetti D.A. • Barber A.J. • Hollinger L.A. • et al.
`Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins
`occludin and zonula occluden 1: a potential mechanism for vascular permeability in diabetic
`retinopaty and tumors.
`J Bio Chem. 1999; 274: 23463-23467
`
`View in Article
`Scopus (557) • PubMed • Crossref • Google Scholar
`
`8.
`
`Macugen Diabetic Retinopathy Study Group
`Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals.
`Ophthalmology. 2006; 113: 23-28
`
`View in Article
`Scopus (225) • PubMed • Abstract • Full Text • Full Text PDF • Google Scholar
`
`9.
`
`Nguyen Q.D. • Shah S.M. • Heier J.S. • et al. • READ-2 Study Group
`Primary end point (six months) results of the Ranibizumab for Edema of the mAcula in Diabetes
`(READ-2) Study.
`Ophthalmology. 2009; 116: 2175-2181
`
`View in Article
`https://www.aaojournal.org/article/S0161-6420(10)00243-5/fulltext
`
`2/6
`
`Celltrion Exhibit 1019
`Page 2
`
`
`
`Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macul…
`3/13/23, 8:40 PM
`Scopus (291) • PubMed • Abstract • Full Text • Full Text PDF • Google Scholar
`
`10.
`
`Kang S.W. • Sa H.S. • Cho H.Y. • Kim J.I.
`Macular grid photocoagulation after intravitreal triamcinolone acetonide for diffuse diabetic
`macular edema.
`Arch Ophthalmol. 2006; 124: 653-658
`
`View in Article
`Scopus (86) • PubMed • Crossref • Google Scholar
`
`11.
`
`Beck R.W. • Moke P.S. • Turpin A.H. • et al.
`A computerized method of visual acuity testing: adaptation of the Early Treatment of Diabetic
`Retinopathy Study testing protocol.
`Am J Ophthalmol. 2003; 135: 194-205
`
`View in Article
`Scopus (406) • PubMed • Abstract • Full Text • Full Text PDF • Google Scholar
`
`12.
`
`Diabetic Retinopathy Clinical Research Network
`Relationship between optical coherence tomography-measured central retinal thickness and
`visual acuity in diabetic macular edema.
`Ophthalmology. 2007; 114: 525-536
`
`View in Article
`Scopus (438) • PubMed • Abstract • Full Text • Full Text PDF • Google Scholar
`
`13.
`
`Early Treatment Diabetic Retinopathy Study Research Group
`Fundus photographic risk factors for progression of diabetic retinopathy.
`Ophthalmology. 1991; 98: 823-833
`
`View in Article
`Scopus (930) • PubMed • Google Scholar
`
`14.
`
`Little R.J. • Rubin D.B. • Barnett V.
`Statistical analysis with missing data.
`in: Wiley Series in Probability and Mathematical Statistics. Wiley, New York1987: 255-259
`
`View in Article
`Google Scholar
`
`15.
`
`Moradian S. • Ahmadieh H. • Malihi M. • et al.
`Intravitreal bevacizumab in active progressive proliferative diabetic retinopathy.
`Graefes Arch Clin Exp Ophthalmol. 2008; 246: 1699-1705
`
`View in Article
`Scopus (122) • PubMed • Crossref • Google Scholar
`
`16.
`
`Arevalo J.F. • Maia M. • Flynn Jr, H.W. • et al.
`Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe
`proliferative diabetic retinopathy.
`Br J Ophthalmol. 2008; 92: 213-216
`
`View in Article
`Scopus (337) • PubMed • Crossref • Google Scholar
`
`17.
`
`ClinicalTrials.gov. Laser-Ranibizumab-Triamcinolone for Proliferative Diabetic Retinopathy
`(LRTforDME+PRP). NCT00445003. Available at: http://public.drcr.net/Studies.aspx?ReclD5147.
`Accessed January 5, 2010.
`
`View in Article
`Google Scholar
`
`18.
`
`Sabet-Peyman E.J. • Heussen F.M. • Thorne J.E. • et al.
`Progression of macular ischemia following intravitreal bevacizumab.
`Ophthalmic Surg Lasers Imaging. 2009; 40: 316-318
`
`View in Article
`Scopus (22) • PubMed • Crossref • Google Scholar
`
`19.
`
`Ockrim Z.K. • Sivaprasad S. • Falk S. • et al.
`Intravitreal triamcinolone versus laser photocoagulation for persistent diabetic macular oedema.
`Br J Ophthalmol. 2008; 92: 795-799
`
`View in Article
`Scopus (21) • PubMed • Crossref • Google Scholar
`
`20.
`
`Gillies M.C. • Sutter F.K. • Simpson J.M. • et al.
`Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a double-
`masked, placebo-controlled, randomized clinical trial.
`Ophthalmology. 2006; 113: 1533-1538
`
`https://www.aaojournal.org/article/S0161-6420(10)00243-5/fulltext
`
`3/6
`
`Celltrion Exhibit 1019
`Page 3
`
`
`
`3/13/23, 8:40 PM
`
`Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macul…
`
`View in Article
`Scopus (370) • PubMed • Abstract • Full Text • Full Text PDF • Google Scholar
`
`21.
`
`Martidis A. • Duker J.S. • Greenberg P.B. • et al.
`Intravitreal triamcinolone for refractory diabetic macular edema.
`Ophthalmology. 2002; 109: 920-927
`
`View in Article
`Scopus (902) • PubMed • Abstract • Full Text • Full Text PDF • Google Scholar
`
`22.
`
`Diabetic Retinopathy Clinical Research Network
`A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema.
`Ophthalmology. 2007; 114: 1860-1867
`
`View in Article
`Scopus (378) • PubMed • Abstract • Full Text • Full Text PDF • Google Scholar
`
`23.
`
`ClinicalTrials.gov. Efficacy and safety of ranibizumab (intravitreal injections) in patients with visual
`impairment due to diabetic macular edema (RESTORE). NCT00687804. Available at:
`http://www.clinicaltrials.gov/ct2/show/NCT00687804?term=nct00687804. Accessed January 5, 2010.
`
`View in Article
`Google Scholar
`
`24.
`
`ClinicalTrials.gov. A study of ranibizumab injection in subjects with clinically significant macular edema
`with center involvement secondary to diabetes mellitus (RIDE). NCT00473382. Available at:
`http://www.clinicaltrials.gov/ct2/show/NCT00473382?term=NCT00473382. Accessed January 5, 2010.
`
`View in Article
`Google Scholar
`
`25.
`
`ClinicalTrials.gov. A study of ranibizumab injection in subjects with clinically significant macular edema
`with center involvement secondary to diabetes mellitus (RISE). NCT00473330. Available at:
`http://www.clinicaltrials.gov/ct2/show/NCT00473330. Accessed January 5, 2010.
`
`View in Article
`Google Scholar
`
`26.
`
`Fong D.S. • Strauber S.F. • Aiello L.P. • et al. •
`Writing Committee for the Diabetic Retinopathy Clinical Research Network
`Comparison of the modified Early Treatment Diabetic Retinopathy Study and mild macular grid
`laser photocoagulation strategies for diabetic macular edema.
`Arch Ophthalmol. 2007; 125: 469-480
`
`View in Article
`Scopus (204) • PubMed • Crossref • Google Scholar
`
`Article info
`Publication history
`Published online: April 28, 2010
`Accepted: February 26, 2010
`Received in revised form: February 26, 2010
`Received: January 22, 2010
`Available online: April 27, 2010.
`Footnotes
`Manuscript no. 2010-112.
`
`The most recently published list of the DRCR.net investigators and staff who participated in this study is
`available at www.drcr.net.
`
`Correspondence: Protocol I Correspondence, Jaeb Center for Health Research, 15310 Amberly Drive, Suite
`350, Tampa, FL 33647. E-mail: drcrstat4@jaeb.org
`
`This article contains online-only material. The following should appear online-only: Table 1, Table 2, Table 3,
`Table 4, Table 6, Table 7, Table 9, Table 10, Table 12, Table 13, Table 14, Table 16, Table 18, Table 19;
`Figure 1, Figure 2, Figure 5, Figure 7, Figure 8; Appendix 1, Appendix 2, Appendix 3, Appendix 4, Appendix
`5. (website).
`
`Financial Disclosure(s): Supported through a cooperative agreement from the National Eye Institute and the
`National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department
`of Health and Human ServicesEY14231, EY14229, and EY018817.
`
`The funding organization (National Institutes of Health) participated in oversight of the conduct of the study
`and review of the manuscript but not directly in the design or conduct of the study; the collection,
`management, analysis, or interpretation of the data; or the preparation of the manuscript. Genentech
`provided the ranibizumab for the study, and Allergan, Inc., provided the triamcinolone for the study. In
`addition, Genentech and Allergan, Inc., provided funds to the DRCR.net to defray the study's clinical site
`costs. As described in the DRCR.net Industry Collaboration Guidelines (available at www.drcr.net), the
`DRCR.net had complete control over the design of the protocol, the ownership of the data, and all editorial
`
`https://www.aaojournal.org/article/S0161-6420(10)00243-5/fulltext
`
`4/6
`
`Celltrion Exhibit 1019
`Page 4
`
`
`
`3/13/23, 8:40 PM
`
`Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macul…
`
`content of presentations and publications related to the protocol. A complete list of all DRCR.net investigator
`financial disclosures can be found at www.drcr.net.
`
`The lead author(s) have made the following disclosure(s): Scott M. Friedman: Sirion Therapeutics (S),
`MacuSight (S), Pfizer (S), Vitreoretinal Technologies (S), Allergan (S), EMMES Corporation (S). Ingrid U.
`Scott: Genentech (C). Lloyd P. Aiello: Genentech (C). Susan B. Bressler: GlaxoSmithKline (C). Frederick L.
`Ferris III; Bausch & Lomb (P).
`
`Neil M. Bressler:
`
`Grants to investigators at The Johns Hopkins University are negotiated and administered by the institution
`(e.g., the School of Medicine) that receives the grants, typically through the Office of Research
`Administration. Individual investigators who participate in the sponsored project(s) are not directly
`compensated by the sponsor but may receive salary or other support from the institution to support their
`effort on the projects(s).
`
`Dr. Neil M. Bressler is Principal Investigator of grants at The Johns Hopkins University sponsored by the
`following entities (not including the National Institutes of Health): Allergan, Bausch & Lomb, Carl Zeiss
`Meditec, EMMES Corporation, Genentech, Lumenis, Notal Vision Ltd.,* Novartis, QLT, Regeneron, Steba
`Biotech, Abbott Medical Optics, ForSight Labs, LLC, and Genzyme Corporation. Dr. Susan B. Bressler's
`consulting arrangement with Notal Vision in connection with Dr. Neil M. Bressler's role as principal
`investigator on a Notal Vision-sponsored research grant has been reviewed and managed by The Johns
`Hopkins University School of Medicine in accordance with its conflict of interest policy.
`Identification
`DOI: https://doi.org/10.1016/j.ophtha.2010.02.031
`
`Copyright
`© 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
`ScienceDirect
`Access this article on ScienceDirect
`
`Related Articles
`
`Diabetic Macular Edema and Diode Subthreshold Micropulse Laser: A Randomized Double-Masked
`Noninferiority Clinical Trial
`Lois et al.
`Ophthalmology, August 13, 2022
`Preview • Full-Text • PDF
`Open Access
`
`Baseline Diabetic Retinopathy Severity and Time to Diabetic Macular Edema Resolution with Ranibizumab
`Treatment: A Meta-analysis
`Talcott et al.
`Ophthalmology Retina , February 10, 2023
`Preview • Full-Text • PDF
`
`Intravitreal Ranibizumab for Diabetic Macular Edema with Prompt versus Deferred Laser Treatment: 5-Year
`Randomized Trial Results
`Elman et al.
`Ophthalmology, October 27, 2014
`Preview • Full-Text • PDF
`
`Cost-Effectiveness Analysis of Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt
`Laser for Diabetic Macular Edema
`Dewan et al.
`Ophthalmology, April 16, 2012
`Preview • Full-Text • PDF
`
`Time to Resolution of Diabetic Macular Edema after Treatment with Intravitreal Aflibercept Injection or Laser
`in VISTA and VIVID
`Valentim et al.
`Ophthalmology Retina , July 14, 2022
`Preview • Full-Text • PDF
`Open Access
`
`Home
`
`Commentaries
`
`ARTICLES & ISSUES
`
`COVID-19 Article Collection
`
`IOL Article Collection
`
`IRIS Registry Articles
`
`MULTIMEDIA
`
`Cover Art Gallery
`
`Articles In Press
`
`Current Issue
`
`List of Issues & Supplements
`
`COLLECTIONS
`
`The Collaborative Community on Ophthalmic
`Imaging
`
`Correspondence Archive
`
`Myopia
`
`Ophthalmology Journal Podcast
`
`Diversity, Equity and Inclusion (DEI)
`
`Ophthalmic Technology Assessments
`
`Pictures & Perspectives
`
`Editor's Choice
`
`Editorials
`
`Editorship Series
`
`Preferred Practice Pattern Guidelines
`
`Video Collection by Topic
`
`Top 10 Trending Articles
`
`Translational Science Reviews
`
`AUTHORS & REVIEWERS
`
`2020 Scientific Referees
`
`Guide for Authors
`
`Guide for Reviewers
`
`Miscellaneous Links
`
`Register to Review
`
`Researcher Academy
`
`Submit a Manuscript
`
`JOURNAL INFO
`
`https://www.aaojournal.org/article/S0161-6420(10)00243-5/fulltext
`
`5/6
`
`Celltrion Exhibit 1019
`Page 5
`
`
`
`3/13/23, 8:40 PM
`
`Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macul…
`
`About the Journal
`
`ABO Quarterly Questions
`
`About Open Access
`
`Contact Information
`
`Editorial Board
`
`Info for Advertisers
`
`New Content Alerts
`
`Reprints
`
`Subscribe
`
`Forget your membership login?
`
`Ophthalmology Glaucoma
`
`AMERICAN ACADEMY OF OPHTHALMOLOGY
`
`Membership Information
`
`Ophthalmology Science
`
`Academy Member Access
`
`News
`
`About the Academy
`
`Contact the Academy
`
`Ophthalmology Retina
`
`FOLLOW US
`
`
`We use cookies to help provide and enhance our service and tailor content. To update your cookie settings, please visit the Cookie settings | Your Privacy Choices for this site.
`Copyright © 2023 Elsevier Inc. except certain content provided by third parties. The content on this site is intended for healthcare professionals.
`
`Privacy Policy Terms and Conditions Accessibility Help & Contact
`
`https://www.aaojournal.org/article/S0161-6420(10)00243-5/fulltext
`
`6/6
`
`Celltrion Exhibit 1019
`Page 6
`
`