1. DRCR Retina Network Overview

2. DRCR Retina Network Overview
The DRCR Retina Network's mission is to improve the lives of individuals with retinal pathology by performing high quality collaborative clinical research that leads to a better understanding of retinal diseases and advances their treatment. The DRCR Retina Network supports the identification, design, and implementation of multicenter clinical research initiatives focused on retinal disorders. Principal emphasis is placed on clinical trials, but epidemiologic outcomes and other research may be supported as well.

3. Collaborative Network
509 Current Investigators
Adam R. Glassman, MS
Jennifer K. Sun MD, MPH
Daniel F. Martin MD
Sangeeta Bhargava, PhD
NEI
Network Chairs
Clinical Sites
Coord-inating Center
The DRCR Retina Network has ~1800 members including Investigators, Coordinators, Technicians, and Coordinating Center staff.

4. Funding
National Eye Institute (NEI) and The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-sponsored cooperative agreement initiated September 2002.
Current award

5. 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 Network’s dedication to academic integrity and optimal clinical trial performance.

6. DRCR Retina Network Status (as of 4/16/19)
Active
Total
Sites (Community & Academic Centers)
163
369
Community Sites
113 (69%)
240 (65%)
Investigators
509
1,365
Other Personnel
1,254
4,841
States 37 49
Provinces in Canada 5 6
--Active Sites
select SiteID, SiteName
from tblSites
where DRCRStatus = 'Active'
order by SiteID
--active community sites
select *
where recdelete =0
and sitestatus = 'active'
and SiteType = 'Private'
active investigators
from vwPersonnel
and siterole = 'investigator'
and PersStatus = 'Active'
and siteid is not null
active other personnel
and isnull(siterole,'') <> 'investigator'
-- 36 active states
select distinct SiteState
and sitestate is not null
and SiteCountry = 'US'
-- 3 active provinces in canada
select distinct siteprovince
and siteprovince is not null
and SiteCountry = 'CA'

7. How to Join the Network
All retina specialists in the U.S. and Canada are welcome to apply
Your request will be reviewed and if approved the necessary paperwork will be sent to you

8. How to Submit a Protocol Idea
Go to the public* website: drcr.net
Click on Information for Investigators
Scroll down to Protocol Idea Form
form to
It will be reviewed by the Operations Group every six months
* Forms also available on the study website

9. Protocol Idea Review Process

10. Completed Protocols

11. Protocols Enrolling or in Follow-up
Over 10,500 DRCR.net Participants to Date Across 30 Protocols

12. What Has Been Learned? Diabetic Macular Edema Treatment
Protocol A: Although some ophthalmologists considered using a modified macular grid (MMG) photocoagulation technique over the focal photocoagulation technique modified from the ETDRS, this trial showed that at 12 months after treatment, the MMG technique was less effective at reducing OCT measured retinal thickening.
Protocol B: Over 2 years, focal/grid photocoagulation is more effective and has fewer side effects than 1 mg or 4 mg doses of preservative-free intravitreal triamcinolone.
Protocol E: In cases of DME with good visual acuity, peribulbar triamcinolone, with or without focal photocoagulation, is unlikely to be of substantial benefit.
Protocol H: Intravitreal bevacizumab can reduce DME in some eyes, but the study was not designed to determine whether the treatment was beneficial.

13. What Has Been Learned? Diabetic Macular Edema Treatment
Protocol I: Intravitreal ranibizumab with prompt or deferred (≥24 weeks) focal/grid laser is more effective through 2 years in increasing visual acuity compared with focal/grid laser treatment alone for the treatment of DME involving the central macula.
Focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better, and possibly worse, for vision outcomes than adding laser treatment only if needed after 24 weeks or more of anti-VEGF treatment in eyes with DME involving the fovea and with vision impairment.
Protocol K: Sixteen weeks after focal/grid laser for DME in eyes with a definite reduction, but not resolution, of central edema, 23% to 63% likely will continue to improve without additional treatment.

14. What Has Been Learned? Diabetic Macular Edema Treatment
Protocol R: At 1 year in eyes with non-central DME, this study could not identify a difference between topical nepafenac 0.1% and placebo on OCT parameters or visual acuity.
Protocol T*: The 2-year clinical trial compared 3 drugs for diabetic macular edema (DME) and found that gains in vision were greater for participants receiving the drug aflibercept than for those receiving bevacizumab, but only among participants starting treatment with 20/50 or worse vision. At one year aflibercept had superior gains to ranibizumab in this vision subgroup, however a difference could not be identified at 2 years. The 3 drugs yielded similar gains in vision for patients with 20/32 or 20/40 vision at the start of treatment.

15. What Has Been Learned? Diabetic Macular Edema Treatment
Protocol U: Although its use is more likely to reduce retinal thickness and increase intraocular pressure, the addition of intravitreous dexamethasone to continued ranibizumab therapy does not improve visual acuity at 24 weeks more than continued ranibizumab therapy alone among eyes with persistent DME following anti-VEGF therapy.

16. What Has Been Learned? Diabetic Retinopathy Treatment
Protocol F: Results suggest clinically meaningful differences are unlikely in OCT thickness or visual acuity following application of PRP in 1 sitting compared with 4 sittings.
Protocol J: The addition of 1 intravitreal triamcinolone injection or 2 intravitreal ranibizumab injections in eyes receiving focal/grid laser for DME and PRP is associated with better visual acuity and decreased macular edema by 14 weeks. Whether continued long-term intravitreal treatment is beneficial could not be determined from this study.

17. What Has Been Learned? Diabetic Retinopathy Treatment
Protocol N: The study suggested little likelihood of a clinically important difference between ranibizumab and saline on the rate of vitrectomy by 16 weeks in eyes with vitreous hemorrhage from PDR. Short-term secondary outcomes including visual acuity improvement, increased panretinal photocoagulation completion rates, and reduced recurrent vitreous hemorrhage rates suggest biologic activity of ranibizumab. Long-term benefits remain unknown.
Protocol S: This study showed that ranibizumab injections are effective in treating proliferative diabetic retinopathy. At two years, vision of the ranibizumab group on average improved by half a line on an eye chart. Vision of the laser group remained unchanged.

18. What Has Been Learned? OCT and Retinal Thickening
Protocol C: Although on average there are slight decreases in retinal thickening during the day, most eyes with diabetic macular edema have little meaningful change in OCT central subfield thickening or visual acuity between 8 AM and 4 PM.
Protocol C: Reproducibility of retinal thickness in DME was better for central subfield thickness measurements than for center point measurements. A change in central subfield thickness exceeding 11% is likely to be real.
Protocol G: While subclinical DME may be uncommon, this study suggests that between approximately one-quarter and one-half of eyes with subclinical DME will progress to more definite thickening or be judged to need treatment for DME within 2 years after its identification.

19. What Has Been Learned? Optical Coherence Tomography
Protocol G: CST (central subfield thickness) on Stratus OCT™ in people with diabetes and minimal or no retinopathy are similar to thicknesses reported from a normative database of people without diabetes. CST is greater in men than in women. Studies involving comparisons of retinal thickness to expected norms should consider different mean values for women and men.
Protocol O: Mean CST is ~70 µm thicker when measured with Heidelberg Spectralis OCT as compared with Stratus OCT among individuals with diabetes in the absence of retinopathy or with minimal non-proliferative retinopathy and a normal macular architecture.  CST values ≥320 µm for men and 305 µm for women are proposed as gender-specific thickness levels.

20. What Has Been Learned? Optical Coherence Tomography
Protocol O: Conversion equations may be used to transform CSF values obtained on a SD-OCT to a TD scale for group comparisons. However, the CST conversion equations do not appear to predict TD values for an individual accurately enough to warrant use of these conversion equations confidently in clinical decision-making at the patient level.

21. Access to Publications and Presentations
Publications and Presentations can be found on the public website or on the study website (log in required)

22. Protocols Currently Enrolling

23. Protocol AE A Pilot Study Evaluating Photobiomodulation (PBM) Therapy for DME

24. Photobiomodulation (PBM)
Irradiation by light in the far-red (FR) to near-infrared (NIR) region of the spectrum ( nm) is collectively termed “photobiomodulation”
In the literature, beneficial effects on
Improved wound healing
Reduction in apoptosis
Reduction in oxidative stress
Reduced leukostasis & expression of ICAM-I (involved in capillary permeability) in diabetic animals
Saliba A, Du Y, Liu H, Patel S, Roberts R, Berkowitz BA, et al. (2015) Photobiomodulation Mitigates Diabetes-Induced Retinopathy by Direct and Indirect Mechanisms: Evidence from Intervention Studies in Pigmented Mice. PLoS ONE 10(10): e doi: /journal.pone

25. Potential Benefits Low treatment burden No known side effects
Possible high public health impact if this non-invasive treatment is effective in treating DME and can be implemented into clinical care
Potential intervention and/or prevention

26. DRCR Retina Network Pilot Study
This study will evaluate PBM compared with placebo for eyes with CI-DME and good vision to determine whether there is a short-term effect on central subfield thickness (CST).
The primary goal of this study is to determine whether there is sufficient evidence of effect to move forward with a larger more definitive trial.

27. Retilux® Device
Photobiomodulation Ophthalmic Treatment device by PhotoOpTx
Head strap for easier use
Active and placebo devices will be provided
Compliance data recording
Automatic shut off at 90 seconds

28. Study Design PBM Therapy Placebo
Multi-Center Randomized Clinical Trial
134 eyes that meet the following criteria:
Best corrected E-ETDRS VA letter score ≥ 79 (i.e., 20/25 or better)
CI-DME, confirmed by CST on spectral domain OCT:
Zeiss Cirrus: ≥290 µm in women, and ≥305 µm in men
Heidelberg Spectralis: ≥305 µm in women, and ≥320 µm in men
No or minimal prior treatment for DME
PBM Therapy
Placebo
Primary Outcome: Mean change in CST at 4 months

29. Informed Consent, Baseline Testing Observation (Placebo)
Study Design
Informed Consent, Baseline Testing
Dropped Ineligible
Randomization
Total study duration is 8 months
Primary outcome at end of Phase 1
(4 months)
Observation (Placebo)
PBM
1 week phone call
1 week phone call
1 Month
1 Month
2 Month
2 Month
3 Month
3 Month
Primary outcome visit
4 Month
4 Month

30. End of Primary Outcome Phase
Phase 2 – The Switch
At the 4-month visit, participants will switch to the alternative treatment, serving two purposes:
1) provide all participants opportunity to receive the active treatment and
2) explore the post-switch effects within treatment group (not a crossover design)
End of Primary Outcome Phase
Switch to Placebo
Switch to PBM
6 Month
6 Month
8 Month
8 Month
How long does treatment effect last?
Is there an effect after the switch?

31. Protocol AC Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab + Deferred Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (DME)

32. Background
Aflibercept treatment in Protocol T resulted in better VA, on average, for eyes with worse baseline VA than bevacizumab
However, bevacizumab was effective for many eyes with worse VA at baseline.
Approximately 2/3 of bevacizumab-treated eyes had >10 letter improvement at 2 years
Almost half had resolution of DME at 2 years
Cost is an issue

33. Background Real Life Application:
Compare starting with bevacizumab and switching to aflibercept if needed vs. starting with aflibercept?
What are the implications of insurance companies mandating this approach or patients choosing this approach?
Cost savings
Visual outcomes

34. Study Objective
To compare the efficacy of intravitreous aflibercept with intravitreous bevacizumab + deferred aflibercept if needed in eyes with CI DME and moderate vision loss.

35. Study Design At least 1 eye that meets all of the following criteria:
Multi-Center Randomized Clinical Trial
(312 Eyes, 260 Participants)
At least 1 eye that meets all of the following criteria:
VA letter score ≤ 68 and ≥ 24 (≈20/50 to 20/320)
Ophthalmoscopic evidence of CI-DME
Central-involved thickening on OCT
Cirrus: ≥ 290 µm for women; ≥ 305 µm for men
Spectralis: ≥ 305 µm for women; ≥ 320 µm for men
No history of anti-VEGF treatment for DME in past 12 months and no history of any other treatment for DME in past 4 months
No history of major ocular surgery within prior 4 months or anticipated within next 6 months
Bevacizumab (Aflibercept if needed)
Aflibercept
Primary Outcome: Mean change in VA over 2 years
(AUC)

36. Bevacizumab (Aflibercept if needed)
Treatment Groups
Aflibercept
Bevacizumab (Aflibercept if needed)
2.0-mg
intravitreous
aflibercept
Centrally repackaged 1.25-mg bevacizumab
Switched to intravitreous aflibercept if eye is not “successful”

37. Protocol AG Randomized Clinical Trial Assessing the Effects of Pneumatic Vitreolysis on Vitreomacular Traction

38. Study Objective Primary Secondary
To compare the proportion of eyes with foveal VMT (symptomatic VMA) release on OCT after PVL with gas injection vs. observation (sham injection) in eyes with VMT without an associated macular hole
Secondary
To evaluate visual function outcomes at 24 weeks after gas injection is performed compared with observation.

39. Multi-Center Randomized Clinical Trial Observation (Sham injection)
Study Design
Multi-Center Randomized Clinical Trial
(124 Eyes)
At least 1 eye that meets all of the following criteria:
Vitreomacular adhesion on OCT ≤3,000 µm
Reading center confirmation required for eligibility
Best corrected ETDRS visual acuity equivalent of 20/32 to 20/400
Decreased visual function attributed to VMT
No macular or lamellar hole
Prompt Vitrectomy not required
PVL
(Injection of C3F8 gas)
Observation (Sham injection)
Primary Outcome: Proportion of eyes with VMT release on OCT without rescue vitrectomy at 24 weeks

40. Protocol AH Single-Arm Study Assessing the Effects of Pneumatic Vitreolysis on Macular Hole

41. Rationale for Single-Arm Study
Eyes with MH need treatment, therefore randomization to a sham arm would be inappropriate
Vitrectomy results in nearly 100% hole closure making it an unnecessary (and expensive) control group choice
Even if this proposed study finds that PVL is only moderately successful, physicians and patients may decide to attempt PVL in the office first, before proceeding with more costly, invasive surgery
Thus, even without a control group, the results from this study will provide data of value for physicians and patients to make informed decisions about treatment course

42. Study Objective
To obtain estimates for the proportion of eyes with macular hole closure of the inner retinal layers for eyes with VMT and full-thickness macular holes treated with PVL

43. Multi-Center Single-Arm Study PVL (Injection of C3F8 gas)
Study Design
Multi-Center Single-Arm Study
(50 Eyes)
At least 1 eye that meets all of the following criteria:
Full-thickness macular hole ≤250 microns at the narrowest point, confirmed by central reading center
Vitreomacular adhesion on OCT ≤3,000 microns, confirmed by central reading center
Best corrected ETDRS visual acuity equivalent of 20/25 to 20/400
PVL (Injection of C3F8 gas)
Primary Outcome: Proportion of eyes with macular hole closure of the inner retinal layers at 8 weeks without rescue treatment

44. Genetics Genes in Diabetic Retinopathy Project

45. Genes in Diabetic Retinopathy Project
Objective
To create a repository of genetic material and clinical phenotype information as a resource for the research community
The database may provide the opportunity to assess genetic susceptibility and resistance to DR and also variants impacting visually-important biomarkers for ME and neovascularization.
Major Eligibility Criteria
Previous/current participant in a DRCR Retina Network study
Enrollment (Ongoing)
Total enrolled: 2,415 subjects (as of 4/16/19)

46. Protocols Currently in Follow-up

47. Protocol AB Intravitreous Anti-VEGF vs. Vitrectomy
for Vitreous Hemorrhage from PDR

48. Study Objectives
Compare visual acuity outcomes over time for the following two treatment regimens:
Prompt Vitrectomy + PRP
Intravitreous Anti-VEGF injections
in eyes presenting with vitreous hemorrhage from PDR causing vision impairment for which intervention is deemed necessary.

49. Study Design At least one eye that meets the following criteria:
Multi-Center Randomized Clinical Trial
At least one eye that meets the following criteria:
Vitreous hemorrhage
causing vision impairment,
presumed to be from PDR, and
requiring intervention (vitrectomy or anti-VEGF)
Vitrectomy +
PRP
Anti-VEGF
Primary Outcome: Visual Acuity AUC over 6 months
Sample Size: 200 eyes

50. Protocol W
Intravitreous Anti-VEGF Treatment for Prevention of Vision Threatening Diabetic Retinopathy in Eyes at High Risk

51. Primary (Short-term) Objective
To determine safety and efficacy of
anti-VEGF versus observation in eyes presenting with severe NPDR and no CI-DME for prevention of vision threatening outcomes (DME or PDR)
Observation (sham injections)
Intravitreous anti-VEGF
Primary outcome: Proportion of eyes that develop PDR/PDR-related outcomes or center-involved DME causing visual acuity loss by 2 years

52. Rationale
The application of anti-VEGF therapy earlier in the course of disease could help to reduce future potential treatment burden in patients, at the same time resulting in similar or better long-term visual acuity outcomes.
If this study demonstrates that anti-VEGF treatment is effective and safe in the setting of severe NPDR, a new strategy to prevent vision-threatening complications will be available for patients.

53. Protocol AA
Peripheral Diabetic Retinopathy (DR) Lesions on Ultrawide-field Fundus Images and Risk of DR Worsening Over Time

54. Objectives Primary objective
To assess whether evaluation of the retinal far periphery on UWF images improves our ability to assess DR and predict rates of DR worsening over time as compared with evaluation only of the area within the 7 standard ETDRS fields.

55. Study Design Prospective, observational longitudinal study
At least one eye meeting all of the following criteria:
NPDR based on clinical exam (Confirmed ETDRS level on 7-field photos)
No CI-DME on clinical exam or OCT
No history of PRP or vitrectomy
No intravitreal Tx over prior 12 mos. and not anticipated for next 6 mos.
Annual Visits for 4 years
Primary outcome: Relative risk of 2 or more step worsening of DR severity over 4 years in groups with and without any predominantly peripheral lesions on UWF images at baseline.

56. Recently Completed Protocols

57. Protocol V
Treatment for Central-involved DME in Eyes with Very Good Visual Acuity

58. Study Design Randomized, multi-center clinical trial
At least one eye meeting all of the following criteria:
Central-involved DME on OCT (Cirrus/Spectralis only)*
VA letter score 20/25 (Snellen equivalent) or better*
Minimal prior treatment for DME **
Prompt
anti-VEGF
Prompt laser + deferred anti-VEGF
Observation + deferred anti-VEGF
Primary outcome: Proportion of eyes that have lost ≥5 letters of VA at 2 years
*Confirmed at 2 visits (screening and randomization 1-28 days apart)
**No more than 1 laser and/or 4 injections, at least 12 months ago

59. Protocols in Development

60. Topical Aqueous Humor Suppressants
Fenofibrate vs. Placebo for Prevention of DR Worsening
Antti-VEGF Plus PRP for PDR
DR Fast Progressors
Self-Testing Applications
Mifepristone for cCSC
Vitreous Samples Repository

61. DRCR Retina Network
Thank you