The Diabetic Retinopathy Clinical Research Network Dedicated to

The Diabetic Retinopathy Clinical Research Network Dedicated to multicenter clinical research of diabetic retinopathy, macular edema and associated 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 Services EY 14231, EY 14229, EY 018817 1

DRCR. net Overview Ø Ø Objective: • The development of a collaborative network to facilitate multicenter clinical research on diabetic retinopathy, diabetic macular edema and associated conditions. Funding: • National Eye Institute-sponsored cooperative agreement initiated September 2002. o Current award 2009 -2013

Priority Initiatives Ø Involvement of community-based practices, as well as “academic” or university-based centers. Ø Collaborate with industry to facilitate investigations and pursue opportunities otherwise not possible and to do so in a manner consistent with the Network’s dedication to academic integrity and optimal clinical trial performance.

Organization: Clinical Sites of the Network Ø Overall Network Participation (as of 1/14/11) • • Ø 236 sites submitted application for Network 826 total Investigators; 2487 additional personnel Current Participation • • 98 active sites; 12 pending sites § 66 community based sites 293 Investigators 833 additional personnel 34 States & 4 countries

Network Organization: Central Resource Units Ø Coordinating Center • • Ø Network Chair • • Ø Adam Glassman, M. S. (Director) Roy Beck, M. D. , Ph. D. (President, Jaeb Center) Neil M. Bressler, M. D. (current) Lloyd Paul Aiello, M. D. , Ph. D. (inaugural & past chair) NEI • Eleanor B. Schron, Ph. D. , R. N.

Network Organization: DRCR. net Committees Ø Ø Executive Committee (18 members) Operations Group (8 members) Protocol Development Committees (as needed) Manuscript Writing Committees (as needed) NEI Appointed Committees Ø Data and Safety Monitoring Committee Ø External Protocol Review Committee

DRCR. net Policies (www. drcr. net) Ø Ø Ø Ø Publications, Presentations, Publicity Financial Disclosure Competing Studies Industry Collaboration Confidentiality Web site use Site visits/Data audit Research Integrity/Scientific Fraud

How Is a DRCR. net Protocol Created? • • Investigators solicited for protocol ideas Idea submitted to Operations Group (OG), which reviews ideas semiannually Ideas approved by OG are presented to Investigators at semiannual meetings for buy-in and interest Executive Committee (EC) prioritizes selected protocols OG creates Protocol Development Committee creates protocol Protocol independently reviewed by NIH-appointed External Protocol Review Committee – advisory to NEI Protocol approval: Executive Committee; NEI; DSMC; regulatory agencies as needed (e. g. , FDA); industry collaborators as needed

Protocol Idea Review Process Semiannual Solicitation of Protocol Ideas from Investigators submit ideas to CC Non-DRCR. net investigators submit ideas to CC (through Protocol Idea form posted on public website) Network Chair and CC PI conduct initial review for public health importance and potential expedited review Based on Investigator feedback, ideas are prioritized by EC Operations Group reviews ideas twice per year (and more promptly for expedited reviews) for merit and feasibility Selected ideas presented to Investigators at semiannual meeting 9

DRCR Network Protocols A through H with Enrollment Completed 2003 to 2007 # of Subjects Protocol A: Pilot Study of Laser Photocoagulation for DME 263 B: Randomized Trial Comparing Intravitreal Triamcinolone Acetonide and Laser Photocoagulation for DME 693 C: Temporal Variation in OCT Measurements of DME 114 D: Evaluation of Vitrectomy for DME 241 E: Pilot Study of Peribulbar Triamcinolone Acetonide for DME 113 F: Observational Study of the Development of DME Following Scatter Laser Photocoagulation 155 G: Subclinical Diabetic Macular Edema Study 68 H: Phase 2 Randomized Trial of Bevacizumab for DME 10 121

DRCR Network Protocols with Enrollment From 2008 to 2010 (as of 2/23/11) # of Subjects Protocol I: Laser-Ranibizumab-Triamcinolone Study for DME* 691 J: Laser-Ranibizumab-Triamcinolone Study for DME + PRP*** 333 K: The Course of Response to Focal Photocoagulation for DME*** 128 L: Autorefraction and E-ETDRS Measurements in DME*** 490 N: Intravitreal Ranibizumab for Vitreous Hemorrhage from PDR Study** 138 O: Comparison of Time Domain OCT & Spectral Domain OCT in DME** 1004 P: Pilot Study of Individuals with DME Undergoing Cataract Surgery*** 68 Q: Individuals with Diabetes without DME Undergoing Cataract Surgery* 317 DRCR Network Participant Total Since 2003 11 * Enrollment done/in active follow-up; **Recruiting; ***Enrollment/follow-up done 4, 937

Completed Studies

Protocol A: A Pilot Study Comparing Modified. ETDRS and Mild Macular Grid Laser Photocoagulation for DME Ø Ø Ø Objectives • Hypothesis generation, gathering outcome data, and standardization of data collection methods, testing procedures, and treatment techniques Major Eligibility Criteria • DME involving or threatening the center of the macula • Best corrected visual acuity >19 letters (≈ 20/400) • No prior focal/grid laser photocoagulation for DME Enrollment (7/03 -11/04) • Total enrolled: 263 subjects/323 eyes at 79 sites 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 Apr; 125(4): 469 -80

Protocol B: A Randomized Trial Comparing Intravitreal Triamcinolone Acetonide and Laser Photocoagulation for DME Ø Ø Ø Objective • Determine whether IVT injections at doses of 1 mg or 4 mg produce greater benefit, with an acceptable safety profile, than macular laser photocoagulation. Major Eligibility Criteria • BCVA ≥ 24 letters (20/320 or better) and ≤ 73 letters (worse than 20/32) • Center-involved DME on clinical exam and OCT Enrollment (7/04 -5/06) • Total enrolled: 693 subjects/840 eyes at 88 sites Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008 Sep; 115(9): 1447 -9. e 1 -10

Protocol C: Temporal Variation in Optical Coherence Tomography Measurements of Retinal Thickening in DME Ø Objective • To determine the proportion of eyes that demonstrate a potentially meaningful change in central retinal thickening measured on OCT throughout the day. Ø Major Eligibility Criteria • Definite center involved retinal thickening due to DME • OCT central subfield thickness >=225 microns Ø Enrollment (10/04 -5/05) • Total enrolled: 114 subjects at 25 sites Diabetic Retinopathy Clinical Research Network. Diurnal variation in retinal thickening measurement by optical coherence tomography in center-involved diabetic macular edema. Arch Ophthalmol. 2006 Dec; 124(12): 1701 -7

Protocol D: Evaluation of Vitrectomy for DME Ø Ø Ø Objective • To provide information on outcomes in eyes with DME that undergo vitrectomy Major Eligibility Criteria • DME with vitrectomy being performed as treatment • Best corrected visual acuity >= 3 letters (≈ 20/800) Enrollment (5/05 – 1/08) • Total enrolled: 241 subjects at 50 sites • Sample size: 100 subjects Diabetic Retinopathy Clinical Research Network. Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular traction. Ophthalmology. 2010 Jun; 117: 1087 -1093. e 3

Protocol E: A Pilot Study of Peribulbar Triamcinolone Acetonide for DME Ø Ø Ø Objective • To determine whether posterior and anterior peribulbar injections of triamcinolone acetonide produce greater benefit, with an acceptable safety profile, than macular laser photocoagulation in the treatment of DME. Major Eligibility Criteria • Best corrected E-ETDRS acuity >= 69 letters (20/40) • OCT central subfield thickness >= 250 microns Enrollment (11/04 -9/05) • Total enrolled: 113 subjects/137 eyes at 32 sites Diabetic Retinopathy Clinical Research Network. Randomized trial of peribulbar triamcinolone acetonide with and without focal photocoagulation for mild diabetic macular edema: a pilot study. Ophthalmology. 2007 Jun; 114(6): 1190 -6

Protocol F: An Observational Study of the Development of DME Following Scatter Laser Photocoagulation Ø Ø Ø Objective • To determine the incidence and extent of macular edema following PRP in eyes without macular edema and explore whether this varies according to the number of sittings included in the treatment regimen. Major Eligibility Criteria • OCT central subfield thickness <=299 microns • Early PDR or severe NPDR for which investigator intends to perform full scatter photocoagulation in either 1 sitting or 4 sittings Enrollment (9/05 – 4/07) • Total enrolled: 155 subjects at 27 sites Diabetic Retinopathy Clinical Research Network. Observational study of the development of diabetic macular edema following panretinal (scatter) photocoagulation given in 1 or 4 sittings. Arch Ophthalmol. 2009 Feb; 127(2): 132 -40

Protocol G: Subclinical Diabetic Macular Edema Study Ø Ø Ø Objective • To determine the incidence of progression of subclinical DME and to evaluate factors predictive of its presence and progression. Major Eligibility Criteria • Best corrected E-ETDRS acuity >= 74 letters (20/32 or better) • Macular thickness judged to be normal on exam • OCT center point thickness 200 -299 microns Enrollment (11/05 – 4/07) • Total enrolled: 68 subjects/106 eyes at 19 sites

Protocol H: A Phase 2 Evaluation of Anti-VEGF Therapy for Diabetic Macular Edema: Bevacizumab (Avastin) Ø Ø Ø Objective • To assess the dose and dose interval related effects of intravitreal administered bevacizumab on central retinal thickness and visual acuity in subjects with DME Major Eligibility Criteria • Best corrected E-ETDRS acuity >= 24 letters (20/320 or better) • Center-involved DME present on clinical exam and OCT with central subfield thickness >= 275 microns Enrollment (6/06 -8/06) • Total enrolled: 121 subjects at 36 sites Diabetic Retinopathy Clinical Research Network. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology. 2007 Oct; 114(10): 1860 -7

Protocol J: Intravitreal Ranibizumab or Triamcinolone Acetonide as Adjunctive Treatment to Panretinal Photocoagulation for Proliferative Diabetic Retinopathy Ø Ø Ø Objective • To determine whether intravitreal injection of an anti-VEGF drug or of a corticosteroid can reduce the risk of VA impairment that can occur following PRP and increase the chances of at least short-term VA improvement in eyes with center-involved macular edema that are undergoing PRP for severe NPDR or PDR Major Eligibility Criteria • Diabetic macular edema involving the center of the macula (OCT central subfield thickness ≥ 250 microns) responsible for visual acuity of 20/32 or worse • PRP required for severe NPDR or PDR Enrollment (Completed) • Total enrolled: 333 subjects/364 eyes at 48 sites

Protocol K: The Course of Response to Focal Photocoagulation for Diabetic Macular Edema Ø Ø Ø Objective • To determine the course of changes in OCT measured macular thickness and visual acuity following a single session of focal photocoagulation for center-involved DME Major Eligibility Criteria • DME involving the center of the macula (OCT central subfield thickness >250 microns • Investigator intends to treat the DME with focal photocoagulation Enrollment (1/07 – 6/07) • Total enrolled: 128 subjects at 26 sites Diabetic Retinopathy Clinical Research Network. The course of response to focal/grid photocoagulation for diabetic macular edema. Retina. 2009 Nov-Dec; 29(10): 1436 -43

Protocol L: Evaluation of Visual Acuity Measurements in Eyes with Diabetic Macular Edema Ø Ø Ø Objective • To compare visual acuity results obtained based on the results of an autorefraction with the results of acuity testing based on the DRCR. net manual refraction protocol • To determine the reproducibility of E-ETDRS visual acuity measurements in subjects with center-involved DME at multiple centers Major Eligibility Criteria • OCT central subfield thickness ≥ 250 microns • Visual acuity better than 20/400 (letter score ≥ 19) Enrollment (Complete) • Total enrolled: 408 subjects at 26 sites (as of 7/1/10)

Active Studies

Protocol I: Intravitreal Ranibizumab or Triamcinolone Acetonide in Combination with Laser Photocoagulation for Diabetic Macular Edema Ø Ø Ø Objective • To evaluate the safety and efficacy of intravitreal anti. VEGF treatment in combination with focal laser photocoagulation, intravitreal anti-VEGF treatment alone, and intravitreal corticosteroids in combination with focal laser photocoagulation in eyes with center-involved DME Major Eligibility Criteria • Diabetic macular edema involving the center of the macula (OCT central subfield thickness ≥ 250 microns) responsible for visual acuity of 20/32 or worse Enrollment (Completed) • Total enrolled: 691 subjects/854 eyes at 52 sites

Protocol N: An Evaluation of Intravitreal Ranibizumab for Vitreous Hemorrhage Due to Proliferative Diabetic Retinopathy Ø Ø Objective • To determine if intravitreal injections of ranibizumab decrease the proportion of eyes in which vitrectomy is performed compared with saline injections in eyes presenting with vitreous hemorrhage from proliferative diabetic retinopathy Major Eligibility Criteria • Study eye with o o Ø Vitreous hemorrhage causing vision impairment, presumed to be from proliferative diabetic retinopathy, and precluding completion of panretinal photocoagulation Immediate vitrectomy not required Enrollment (Ongoing) • Total enrolled: 138 subjects at 49 sites (as of 2/23/11)

Protocol O: Comparison of Time Domain OCT and Spectral Domain OCT Retinal Thickness Measurement in Diabetic Macular Edema Ø Ø Ø Objective • To compare thickness measurements between Zeiss TD Stratus OCT and selected SD OCT machines (Zeiss Cirrus, Heidelberg Spectralis, Topcon 3 D-OCT, and Optovue RTVue), estimating a conversion factor between TD OCT and SD OCT • To assess and compare the reproducibility of the selected SD OCT machines utilizing their respective software analysis algorithms Major Eligibility Criteria • Media clarity adequate for obtaining OCT images • DME in at least one eye (OCT central subfield thickness ≥ 250 microns) Enrollment (Ongoing) • Total enrolled: 1004 subjects at 38 sites (as of 2/23/11)

Protocol P: A Pilot Study in Individuals with Center. Involved DME Undergoing Cataract Surgery Ø Ø Ø Objective • To determine the feasibility of a randomized trial in eyes with center-involved DME prior to cataract surgery • To describe all eyes with respect to how cataract surgeons and DRCR. net investigators manage these cases at the time of surgery • To evaluate exacerbation of DME and VA at 16 weeks Major Eligibility Criteria • Presence of cataract in study eye for which cataract surgery will be performed within 1 -14 days after enrollment • Presence of DME in study eye (OCT central subfield thickness ≥ 250 microns) • VA light perception or better Enrollment (8/09 -6/10) • Total enrolled: 68 subjects/eyes at 29 sites (as of 2/23/11)

Protocol Q: An Observational Study in Individuals with Diabetic Retinopathy without Center-Involved DME Undergoing Cataract Surgery Ø Ø Ø Objective • To determine the incidence of progression to center-involved macular edema 16 weeks after cataract surgery in eyes with diabetic retinopathy and without definite center-involved DME Major Eligibility Criteria • Presence of cataract in study eye for which cataract surgery is scheduled • Presence of microaneurysms or at least mild non-proliferative diabetic retinopathy (level 20 or higher) on clinical exam • No presence of center-involved DME in study eye (OCT central subfield thickness <250 microns) • VA light perception or better Enrollment (Ongoing) • Total enrolled: 317 subjects/eyes at 45 sites (as of 2/23/11)

Upcoming Protocols in 2011 Ø Protocol R – 1 st Quarter 2011 • Ø Protocol M – 1 st Quarter 2011 • Ø Effects of Diabetes Education during Retinal Ophthalmology Visits on Diabetes Control Protocol S – mid-2011 • Ø A Phase II Evaluation of Topical NSAIDs in Eyes with Non Central Involved DME Prompt Panretinal Photocoagulation Versus Intravitreal Ranibizumab with Deferred Panretinal Photocoagulation for Proliferative Diabetic Retinopathy Protocol T – 3 rd Quarter 2011 • Intravitreal Bevacizumab Compared with Intravitreal Ranibizumab for Diabetic Macular Edema 30