The Diabetic Retinopathy Clinical Research Network

1
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 EY14231,
  EY14229, EY018817 

2
DRCR.net Overview

• 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.
• Current award 2009-2013

3
Priority Initiatives

• Involvement of community-based practices, as well
  as academic or university-based centers.
• Collaborate with industry to facilitate
  investigations and pursue opportunities otherwise
  not possible and to do so in a manner consistent
  with the Networks dedication to academic
  integrity and optimal clinical trial performance.

4
Organization Clinical Sites of the Network

• Overall Network Participation (as of 1/14/11)
• 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

5
Network OrganizationCentral Resource Units

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

6
Network Organization DRCR.net Committees

• Executive Committee (18 members)
• Operations Group (8 members)
• Protocol Development Committees (as needed)
• Manuscript Writing Committees (as needed)
• NEI Appointed Committees
• Data and Safety Monitoring Committee
• External Protocol Review Committee

7
DRCR.net Policies (www.drcr.net)

• Publications, Presentations, Publicity
• Financial Disclosure
• Competing Studies
• Industry Collaboration
• Confidentiality
• Web site use
• Site visits/Data audit
• Research Integrity/Scientific Fraud

8
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
• 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

9
Protocol Idea Review Process
Non-DRCR.net investigators submit ideas to CC
(through Protocol Idea form posted on public
website)
10
DRCR Network Protocols A through H with
Enrollment Completed 2003 to 2007
Protocol of Subjects
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 121
11
DRCR Network Protocols with Enrollment From 2008
to 2010 (as of 2/23/11)
Protocol of Subjects
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 4,937
Enrollment done/in active follow-up
Recruiting Enrollment/follow-up done
12
Completed Studies
13
Protocol A A Pilot Study Comparing
Modified-ETDRS and Mild Macular Grid Laser
Photocoagulation for DME

• 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 gt19 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 Apr125(4)469-80

14
Protocol B A Randomized Trial Comparing
Intravitreal Triamcinolone Acetonide and Laser
Photocoagulation for DME

• Objective
• Determine whether IVT injections at doses of 1mg
  or 4mg 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 Sep115(9)1447-9.e1-10
15
Protocol C Temporal Variation in Optical
Coherence Tomography Measurements of Retinal
Thickening in DME

• Objective
• To determine the proportion of eyes that
  demonstrate a potentially meaningful change in
  central retinal thickening measured on OCT
  throughout the day.
• Major Eligibility Criteria
• Definite center involved retinal thickening due
  to DME
• OCT central subfield thickness gt225 microns
• 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 Dec124(12)1701-7
16
Protocol D Evaluation of Vitrectomy for DME

• 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 gt 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 Jun1171087-1093.e3
17
Protocol E A Pilot Study of Peribulbar
Triamcinolone Acetonide for DME

• 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 gt 69 letters
  (20/40)
• OCT central subfield thickness gt 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 Jun114(6)1190-6
18
Protocol F An Observational Study of the
Development of DME Following Scatter Laser
Photocoagulation

• 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 lt299 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 Feb127(2)132-40
19
Protocol G Subclinical Diabetic Macular Edema
Study

• 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 gt 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

20
Protocol H A Phase 2 Evaluation of Anti-VEGF
Therapy for Diabetic Macular Edema Bevacizumab
(Avastin)

• 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 gt 24 letters
  (20/320 or better)
• Center-involved DME present on clinical exam and
  OCT with central subfield thickness gt 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 Oct114(10)1860-7
21
Protocol J Intravitreal Ranibizumab or
Triamcinolone Acetonide as Adjunctive Treatment
to Panretinal Photocoagulation for Proliferative
Diabetic Retinopathy

• 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

22
Protocol K The Course of Response to Focal
Photocoagulation for Diabetic Macular Edema

• 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 gt250 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-Dec29(10)1436-43
23
Protocol L Evaluation of Visual Acuity
Measurements in Eyes with Diabetic Macular Edema

• 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)

24

• Active Studies

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Protocol I Intravitreal Ranibizumab or
Triamcinolone Acetonide in Combination with Laser
Photocoagulation for Diabetic Macular Edema

• 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
  

26
Protocol N An Evaluation of Intravitreal
Ranibizumab for Vitreous Hemorrhage Due to
Proliferative Diabetic Retinopathy

• 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
• 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)

27
Protocol O Comparison of Time Domain OCT and
Spectral Domain OCT Retinal Thickness Measurement
in Diabetic Macular Edema

• Objective
• To compare thickness measurements between Zeiss
  TD Stratus OCT and selected SD OCT machines
  (Zeiss Cirrus, Heidelberg Spectralis, Topcon
  3D-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)

28
Protocol P A Pilot Study in Individuals with
Center-Involved DME Undergoing Cataract Surgery

• 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)

29
Protocol Q An Observational Study in Individuals
with Diabetic Retinopathy without Center-Involved
DME Undergoing Cataract Surgery

• 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 lt250 microns)
• VA light perception or better
• Enrollment (Ongoing)
• Total enrolled 317 subjects/eyes at 45 sites (as
  of 2/23/11)

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Upcoming Protocols in 2011

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